Quality of life in patients with persistent allergic rhinitis treated with montelukast alone or in combination with levocetirizine or desloratadine.

BACKGROUND: Persistent allergic rhinitis often impairs quality of life. OBJECTIVE: We assessed the extent to which treating persistent allergic rhinitis with montelukast, desloratadine, and levocetirizine alone or in combination improved quality of life. METHODS: A 32-week randomized, double-blind, placebo-controlled, crossover study was performed in 2 arms: 20 patients received montelukast 10 mg/d and/or desloratadine 5 mg/d or placebo; 20 patients received montelukast 10 mg/d and/or levocetirizine 5 mg/d or placebo. The treatment periods were separated by 2-week washout periods. Quality of life was assessed on the day before starting treatment and on the last day of each treatment period using the Rhinoconjunctivitis Quality of Life Questionnaire. Sleep problems were also assessed. RESULTS: In the desloratadine plus montelukast arm, the mean (SEM) quality of life score before treatment was 3.1 (0.41). After placebo, this score was 2.16 (0.43), after desloratadine it was 1.79 (0.38), after montelukast it was 1.48 (0.37), and after montelukast plus desloratadine it was 1.59 (0.37). In the montelukast plus levocetirizine arm, the mean quality of life score before treatment was 2.58 (0.49). After placebo it was 1.78 (0.46), after levocetirizine it was 1.38 (0.42), after montelukast it was 1.36 (0.37), and after montelukast plus levocetirizine it was 1.26 (0.39). CONCLUSIONS: Placebo, montelukast, desloratadine and levocetirizine significantly improved quality of life. Combining montelukast with either levocetirizine or desloratadine gave additional benefits in comparison to each agent alone and could be considered for patients whose quality of life is impaired by persistent allergic rhinitis.

[Histamine releasing and immunomodulating activity of dental restorative materials].

Histamine releasing and immunomodulating activity of the following dental restorative materials (DRM) - Prizmafil, Filtek Z250, XRV Herculite Prodigy, Glasiosite, Te-Econol, Valux Plus, Polofil Supra were studied. It was shown that DRM under study as a rule did not possess the ability to release histamine (H) from human blood basophile (BB) excluding Filtek Z250 which release H from BB in patients with allergy and sound donors. The studied DRM implanted under mouse skin were able to modulate immune response to the allergen, at that some of them increased antibodies of IgE-class forming and other suppressed immune response caused by IgG-antibody forming. Received data have certain significance in the scheme of safety evaluation and individual assessment of DRM having acceptable biocompatibility for specific patient.

Differential expression of monocyte CD163 in single- and dual-asthmatic responders during allergen-induced bronchoconstriction.

BACKGROUND: Mononuclear phagocytes play an important role in modulating inflammatory reactions in response to antigen challenge. OBJECTIVE: To investigate the regulation of CD163, a marker of anti-inflammatory macrophages, during Dermatophagoides pteronyssinus (Dp)-induced bronchoconstriction. METHODS: Among 110 Dp-sensitive patients who underwent bronchial challenge with Dp, there were 51 dual responders (DR), 32 single responders (SR) and 27 non-responders (NR). Monocyte expression of CD14 and CD163 was evaluated by flow cytometry. Exhaled NO (eNO) concentration was determined on-line using a chemiluminescence analyser. In 21 DR, nine SR and 13 NR-soluble CD163 in plasma was measured by ELISA before, 1, 8 and 24 h after the challenge. RESULTS: In DR, the baseline expression of monocyte CD163 and eNO were significantly greater than in SR and NR. A pattern of (1) decreased monocyte CD163 expression, (2) unchanged sCD163 and (3) increased eNO in DR was contrasted by a pattern of (1) increased CD163 expression, (2) increased sCD163 and (3) unchanged eNO in SR. During allergen challenge, the changes in monocyte CD163 expression and sCD163 inversely correlated with the changes in eNO. CONCLUSION: Both pro-inflammatory and anti-inflammatory responses to allergen challenge are uniquely expressed among SR and DR.

IgE, allergic diseases, and omalizumab.

Immunoglobulin E (IgE) plays a central role in the development of allergic diseases. In sensitized individuals, IgE antibodies bind to receptors on mast cell and basophil surfaces, releasing preformed and newly generated mediators that initiate an immunologic cascade and inflammatory symptoms. Omalizumab (Xolair) is a humanized monoclonal antibody designed to bind specifically to IgE. It was approved by the United States Food and Drug Administration in 2003 for the treatment of patients with moderate-to-severe persistent asthma that is inadequately controlled with inhaled corticosteroids (ICS) and who have a positive skin test or in vitro reactivity to a perennial aeroallergen. In clinical trials in such patients, omalizumab reduced the incidence of asthma exacerbations, severe exacerbations, the use of rescue medication, and improved both symptoms and quality of life (QOL).

Platelet activation in allergic asthma patients during allergen challenge with Dermatophagoides pteronyssinus.

BACKGROUND: Animal models of allergic asthma indicate that intravascular platelet activation is necessary for the development of allergen-induced chronic airway inflammation. OBJECTIVE: To evaluate whether the development of a late asthmatic response (LAR) in allergic asthma patients challenged with a relevant allergen is consequent to platelet activation. METHODS: Thirty-three house dust mite sensitive asthmatic patients were challenged intrabronchially with Dermatophagoides pteronyssinus (Dp) extract. Twelve non-atopic healthy subjects (HC) were used as controls. Platelet count and plasma levels of beta-thromboglobulin (beta-TG), platelet factor-4 (PF-4) and soluble P-selectin (sP-selectin) were assessed before the challenge (T(0)) and 30 min (T(EAR)), 6 h (T(LAR)) and 24 h (T(24)) after the challenge. RESULTS: Eleven patients responded to allergen challenge with an isolated early asthmatic response (single responders, SR). In 22 patients dual asthmatic response was demonstrated (dual responders, DR). At T(0) neither the platelet count nor the mean plasma level of beta-TG in DR or SR were different from HC, the mean plasma level of PF-4 in SR was significantly greater than in HC (P=0.01) or DR (P=0.001), the mean plasma level of sP-selectin was significantly greater in DR than in HC (0.0002) but not statistically different from SR (P=0.055). A significant decrease in the platelet count and increase in the plasma level of all the studied markers was seen at T(EAR), which was followed by a gradual return to the baseline values in the SR. Elevated plasma levels of platelet activation markers and decreased platelet count were seen in the DR even at T(24). Strong correlation was found between the increase in plasma concentration of beta-TG at T(EAR) and the maximum fall in forced expiratory volume in 1 s at T(LAR) (r=-0.57; P=0.0006). CONCLUSION: In allergic asthma patients development of prolonged airway inflammation after allergen challenge is associated with intravascular platelet activation.

Prevalence of skin test reactions to natural rubber latex in hospital personnel in Russia and eastern Europe.

BACKGROUND: Allergic reactions to natural rubber latex have increased during the past 10 years, especially in many health care workers (HCWs) who have high exposure to latex allergens. The prevalence of skin test reactions to natural rubber latex in Russia, the Commonwealth of Independent States (CIS), and eastern Europe is unknown. OBJECTIVE: The purpose of this study was to determine the prevalence of skin test reactivity to natural rubber latex in a population of HCWs exposed to latex. METHODS: Nine hundred one HCWs regularly exposed to latex were evaluated using an allergy history questionnaire. Subjects were tested for latex allergy by titrated skin prick test with a biologically standardized latex extract. The diagnosis of latex allergy was defined by the presence of clinical symptoms when exposed to latex along with a positive skin prick test to latex. RESULTS: Forty-nine (5.4%) HCWs were skin test-positive to latex. Seventeen (1.9%) HCWs were classified as latex-allergic based upon positive skin tests to latex associated with allergy symptoms with exposure. Seven of 901 HCWs had experienced anaphylactic reactions to latex. The most frequently reported symptom related to latex exposure was contact urticaria. CONCLUSIONS: The prevalence of latex allergy among HCWs in Russia, the CIS, and adjacent eastern European countries is considerably less than reported in HCWs exposed to latex in western Europe and the United States. The low prevalence of latex allergy in Russia and the CIS suggests that lessened exposure to natural latex powdered gloves may diminish the prevalence of latex sensitization in HCWs in Russia and the CIS.

Mediator antagonists in the treatment of allergic disease.

New approaches to allergic inflammation include specific cytokine antagonists and monoclonal antibodies against IgE, against chemokines, and against adhesion molecules. Currently available therapies, such as leukotriene antagonists, may soon be approved for allergic rhinitis. New generation antihistamines such as desloratadine have wide-ranging anti-allergic, anti-inflammatory profiles, including suppression of cytokine, chemokine, and adhesion molecule expression. Recent desloratadine studies have demonstrated that this highly potent H1 receptor antagonist consistently provides relief of nasal congestion and may provide benefits similar to montelukast in mild asthma patients. New generation intra-nasal corticosteroids such as fluticasone and mometasone provide high corticosteroid potency while being minimally bioavailable when administered as intranasal preparations. Future advances in allergy therapy also include improved T-cell selective formats of immunotherapy. The range of therapies for allergic rhinitis is likely to substantially increase in the coming years.

Appropriate and inappropriate use of immunotherapy.

OBJECTIVE: The primary objective of this review is to discuss indications for appropriate and inappropriate use of allergen immunotherapy (IT), including discussion of contraindications, adverse events, and alternative protocols and methods. DATA SOURCES: A review of the literature on indications, contraindications, adverse events, and alternative methods and protocols associated with allergen IT was conducted. STUDY SELECTION: The opinion of the author was used to select and review relevant data. RESULTS: Clinical trials have proven the benefit of allergen IT, for allergic rhinitis, asthma, and anaphylaxis because of stinging insects, such as Hymenoptera and fire ants. Allergen IT may improve quality of life and decrease medication requirement for allergic rhinitis and asthma, especially for younger patients, and probably will assist in the prevention of the progression of allergic disease from rhinitis to asthma. Subcutaneous allergen IT is well established as clinically effective through multiple, blinded, placebo-controlled studies. The data for alternate therapies and routes of therapy are extensively reviewed and critiqued. CONCLUSIONS: Allergen IT is a highly valuable form of treatment of IgE-mediated diseases. Documentation of sensitivity to allergen sensitization associated with symptoms is critical before use of allergen IT. Symptoms should also be of sufficient duration and severity to warrant IT. Before allergen IT is used, there must be an available allergen extract that is suitable for treatment of the relative sensitivity. It is essential for patients receiving allergen IT to understand the treatment principle, the frequency of injections, the duration of treatment, the risk and signs of adverse events, the magnitude of the efficacy, and the essential nature of patient compliance. Subcutaneous allergen IT is the only current mode of therapy in the United States that has been shown to be effective.

Assessment of IgE allergen specificity among latex-allergic health care workers: review of IgE-binding components of various latex extracts.

BACKGROUND: Allergic reactions to natural rubber latex have increased during the past 10 years, especially in many health care workers who have high exposure to latex allergens both by direct skin contact and by inhalation of latex particles from powdered gloves. Development of satisfactory diagnostic methods to verify the presence of latex allergy in health care workers requires characterization of the immunoreactive proteins in latex products and identification of specific IgE antibodies in sensitized patients. A number of different latex preparations are now available for in vitro evaluations. OBJECTIVES: Utilizing different in vitro methods, this study examines IgE sensitization to components of latex in a selected population of hospital employees, employing a raw natural latex glove extract and various commercial latex extracts. METHODS: Two hundred hospital employees exposed to latex were evaluated using an allergy history questionnaire. To further identify sensitized patients, two different specific IgE tests and leukocyte histamine release tests were performed using a panel of latex extracts obtained from different manufacturers. Sodium dodecylsulfate polyacrylamide electrophoresis (SDS-PAGE) profiles were obtained. Sera from 34 subjects suspected to be latex-sensitized were IgE immunoblotted to assess the presence of IgE antibodies directed toward specific latex proteins. RESULTS: Thirty-four participants (17%) were considered sensitized to latex by a positive clinical history in conjunction with positive specific IgE tests (18 individuals) and/or positive histamine release tests (26 individuals). Significant extract differences in both the histamine release response profile and the frequency of positive test results were noted in the histamine release test. Significant individual differences in patients' latex epitope-specificity were found by IgE immunoblotting, substantiated by sodium dodecylsulfate polyacrylamide profiles revealing differences in protein band patterns among the various extracts. The IgE immunoblots indicated that the majority of patients reacted to proteins with molecular weights of 14, 21, 30 to 35, and 42 kD; the 30 to 35 kD protein being predominant. Seven subjects (22%) of the 34 considered to be latex-sensitized did not reveal binding of specific IgE in immunoblots. One latex extract (Stallergene) with the widest IgE-reacting protein repertoire identified the majority of subjects (63%) as latex sensitive by leukocyte histamine release and also provided the best quantitative histamine release test results. CONCLUSION: Only by testing with a combination of latex extracts were all sensitized individuals identified. This study demonstrates that currently several in vitro methods may be necessary to detect IgE sensitization to latex. Latex extracts to be employed in future skin tests must contain a wide epitope repertoire of IgE-binding proteins to identify all latex-sensitized individuals.

Effect of misoprostol on the secretion of histamine from basophils of whole blood.

BACKGROUND: Misoprostol (MSP), the synthetic prostaglandin E1 (PGE1) analog, possesses multifunctional features, including modulating some inflammatory aspects of immune and allergic disorders. OBJECTIVES: To investigate the effect of MSP on histamine release (HR) from basophils of whole blood using anti-IgE, specific allergens, and calcium ionophore. METHODS: The study was performed using the automated glass fiber-based whole blood leukocyte histamine release test (LHRT). RESULTS: Very low concentrations of MSP produced a marked inhibition of HR induced with anti-IgE. Maximum inhibition was observed at 10-9 M. It was also shown that the levels of HR inhibition with MSP varied at different incubation times. The greatest inhibition of HR was noted at 1 to 2 hours of incubation at MSP concentrations of 10-8 and 10-9 M, respectively. Incubation of blood from allergic patients at the optimal MSP concentration and optimal elapsed time (2 hours) resulted in significant reductions of allergen-specific HR induced by both Timothy pollen grass allergen and D.pteronissinus. Incubation of blood with varying concentrations of MSP and subsequent stimulation with calcium ionophore A23187 also inhibited HR from basophils. In the latter case, the most effective concentrations of MSP ranged from 10-8 to 10-6 M. CONCLUSIONS: This study demonstrated that MSP can inhibit basophil HR indicating a potentially beneficial role of PGE1 analogs as pharmacotherapy for allergic diseases.

Second-generation antihistamines: the risk of ventricular arrhythmias.

Some second-generation antihistamines, notably terfenadine and astemizole, have been associated with prolongation of the QT interval and the development of torsades de pointes, a potentially fatal ventricular arrhythmia. This rare adverse event has been associated with greatly elevated blood levels of these agents, resulting from drug overdose, hepatic insufficiency (dysfunction), or interactions with other drugs that inhibit their metabolism. This paper reviews the data concerning the effects of selected second-generation antihistamines on cardiac conduction, particularly the QT interval, to evaluate whether ventricular arrhythmias are a class effect of these agents. Electrocardiographic studies indicate that terfenadine and astemizole, but not loratadine or cetirizine, prolong the QT interval in laboratory animals. In vitro studies demonstrate that terfenadine and astemizole block the cardiac K+ channels, leading to delayed ventricular repolarization and QT-interval prolongation; in contrast, neither loratadine nor its metabolite, desloratadine, significantly inhibits cardiac K+ channels at clinically achievable blood levels. Studies in human volunteers confirm the absence of electrocardiographic effects of azelastine, cetirizine, fexofenadine, and loratadine administered at several times the recommended dose or concomitantly with agents that inhibit their metabolism and elimination. In conclusion, the data indicate that the potential to cause ventricular arrhythmias is not a class effect of second-generation antihistamines and that loratadine, cetirizine, azelastine, and fexofenadine are not associated with torsades de pointes or other ventricular arrhythmias.

[Chemical modification of allergen leading to changes in its epitopic activity]. / Khimicheskaia modifikatsiia allergena, vedushchaia k izmeneniiu ego épitopnoi aktivnosti.

Modification of a model allergen ovalbumin (OA) with succinylation led to a decrease of its allergenicity measured by passive cutaneous anaphylaxis reaction, RAST inhibition assay and basophil histamine release. Modified OA stimulated OA-specific T-cell hybrid 3DO-548 to produce IL-2 at the same level as in case of non-modified OA. Modified OA did not induce anti-OA IgE, but did induce anti-OA IgG antibodies. This approach to chemical modification of allergen-selective blockade of B-cell epitopes while not affecting T-cell epitopes suggests new opportunities in creation of safe and effective allergovaccines.

Nocturnal asthma: effect of salmeterol on quality of life and clinical outcomes.

OBJECTIVE: To evaluate the effect of salmeterol on asthma-specific quality of life in patients experiencing significant nocturnal symptoms. DESIGN: Randomized, double-blind, placebo-controlled, multicenter clinical trial. SETTING: Allergy/respiratory care clinics. PATIENTS: Nonsmokers > or = 12 years of age with nocturnal asthma symptoms on at least 6 of 14 days during screening and > or = 15% decrease in peak expiratory flow (PEF) from baseline on nocturnal awakening at least once during screening. INTERVENTIONS: Salmeterol, 42 microg, or placebo twice daily. Patients were allowed to continue theophylline, inhaled corticosteroids, and "as-needed" albuterol. MEASUREMENTS AND RESULTS: Outcome measures included Asthma Quality of Life Questionnaire (AQLQ) global and individual domain scores, FEV1, PEF, nighttime awakenings, asthma symptoms, and supplemental albuterol use. Mean change from baseline for the global and domain AQLQ scores was significantly greater (p < or = 0.005) with salmeterol compared with placebo. At week 12, salmeterol significantly (p < 0.001 compared with placebo) increased mean change from baseline in FEV1, morning and evening PEF, percentage of symptom-free days, percentage of nights with no awakenings due to asthma, and the percentage of days and nights with no supplemental albuterol use. Significant improvements in PEF were observed after treatment with salmeterol regardless of concomitant treatment with theophylline (p < 0.05). CONCLUSIONS: These results provide evidence that validates the role of salmeterol in improving quality of life in patients with moderate persistent asthma who exhibited nocturnal asthma symptoms and supports the efficacy of salmeterol compared with that of placebo (ie, "as-needed" albuterol).

The link between allergy and asthma.

Patients with asthma and concomitant allergic rhinitis are among the most costly patients. A survey of over 34,000 patients with asthma indicated that the cost of those patients who have asthma alone without allergic rhinitis was roughly half the overall cost of patients who had concomitant allergic rhinitis and asthma. Asthma and allergic rhinitis are linked in several ways. The shared immunologic pathogenesis are nasal bronchial reflex, allergen sensitization, and epidemiologic studies that link asthma and allergy. There is an interrelatedness of the upper and lower airway function, the link operating directionally from the sinuses to the lungs. In addition, there is a co-occurrence of asthma and allergic rhinitis in the population. Furthermore, both conditions respond to similar treatments, including antihistamine-containing therapies that may ameliorate allergic rhinitis and also potentially help alleviate asthma symptoms.

In vivo and in vitro immunomodulation induced by the extract of the mycelium fungus Polyporus squamosus.

The mycelial mass of the fungus Polyporus Squamosus strain 64 (PS-64) was disintegrated by mechanical and ultrasound treatments. After centrifugation, the supernatant containing the disintegrate was dialyzed and lyophilized. The resultant PS-64 extract was subsequently investigated as an immunomodulator of IgE and IgG responses to ovalbumin (OA) in (CBAxC57BL/6)F1 mice using passive cutaneous anaphylaxis (PCA) and enzyme-linked immunosorbent assay (ELISA), respectively. Multiple injections of PS-64 extract in doses of 1.5, 15, and 150 mg/kg administered before the primary or secondary immunization of mice with OA resulted in a dose-dependent inhibition of both IgE and IgG antibody responses to OA. In contrast to the inhibition of the anti-OA IgE response noted during the entire 3-week observation period, the anti-OA IgG response was restored to control level by the third week of secondary immunization. The glass microfiber-based whole blood histamine release assay demonstrated that various concentrations of the PS-64 extract did not influence histamine release induced either by anti-IgE or by specific allergens from basophils derived from whole blood of allergen-sensitized patients. Using the hemolytic plaque assay, significant suppression of IgM-secreting cell formation was noted in (CBAxC57BL/6)F1 mice administered various doses of the PS-64 extract before immunization. The PS-64 extract inhibited the in vitro proliferation of human mononuclear cells upon stimulation with phytohemagglutinin (PHA). In a dose-dependent manner, the PS-64 extract also inhibited delayed-type hypersensitivity reaction and skin graft rejection, similar to the effect noted with usage of Cyclosporin A (CsA) in (CBAxC57BL/6)F1 mice. Our investigation suggests that the immunomodulatory effects of PS-64 should be studied further for potential clinical therapeutic utility.

Performance characteristics of a new automated enzyme immunoassay for the measurement of allergen-specific IgE. Summary of the probability outcomes comparing results of allergen skin testing to results obtained with the HYTEC system and CAP system.

BACKGROUND: Measurement of allergen-specific IgE may assist in the diagnosis of allergy in selected patients. The development of new assays for determination of allergen-specific IgE should be optimized with respect to analytical sensitivity, precision, automation, and reporting of test results in mass units. OBJECTIVE: The objectives of this study were to evaluate the analytical performance of the new automated HYTEC method for the measurement of allergen-specific IgE and to compare the performance of this new assay to that of the Pharmacia CAP system. METHODS: To demonstrate parallelism, allergen-specific IgE dilution curves were generated by diluting four patient sera containing cat (19.8 kU/L), D. pteronyssinus (5.4 kU/L), birch pollen (2.6 kU/L), and timothy grass (1.0 kU/L) with equine serum. The precision study utilized sera from three different atopic donors with low levels (0.62 +/- 0.05 kU/L), moderate levels (1.45 +/- 0.18 kU/L), and high levels (13.59 +/- 0.89 kU/L) of allergen-specific IgE to three common inhalant allergens: D. pteronyssinus, timothy grass, and birch. Sera for outcome probability determinations were obtained from 54 patients who were evaluated for the presence of inhalant allergy by skin prick test and physical examination. Only sera from patients with at least one positive skin prick test that clinically correlate with the physician's evaluation of case history and physical examination were selected for study material. In this study, sensitivity and specificity are conditional probabilities describing performances of the CAP system and the HYTEC system to skin prick testing. The lowest threshold, 0.35 kU/L, recommended for detection of allergen-specific IgE was used for both systems. RESULTS: The HYTEC system accurately detected a reduction in allergen-specific IgE antibody with different serum concentrations of allergen-specific IgE ranging from 0.10 kU/L to 20 kU/L. The median interdilutional coefficient of variation of 12.5% was obtained with assay samples containing 19.8 to 0.1 kU/L allergen-specific IgE antibody. During a 20-day trial period, three standard allergen-specific IgE controls, 0.62, 1.45 and 13.39 kU/L, respectively, demonstrated a mean coefficient of variation less than 18%. In 20% of the patients, duplicate assay determinations of allergen-specific IgE measurements resulted in a one-class discrepancy in the lowest assay range, 0.35 to 0.70 kU/L, only. The correlation coefficient between the HYTEC and CAP allergen-specific IgE assays was 0.77, rank correlation coefficients, being allergen-dependent and ranging from 0.62 to 0.91. Allergen-specific IgE assay sensitivity of the HYTEC system ranged from 0.78 to 1.00, whereas the assay sensitivity for the CAP system ranged from 0.50 to 1.00. Assay specificity ranged from 0.66 to 0.93 for the HYTEC system and from 0.70 to 0.87 for the CAP system. Eighty-nine percent of HYTEC-positive patients had a positive skin prick test (3% standard error) and 87% of CAP-positive patients had a positive skin prick test (4% standard error). Ninety-two percent of HYTEC-negative patients had a negative skin prick test (4% standard error), whereas 76% of CAP-negative patients had a negative skin prick test (5% standard error). CONCLUSION: The HYTEC system fulfills the current analytical requirements necessary to measure allergen-specific IgE antibody quantitatively and qualitatively, and compares favorably in performance with the CAP system.

Modulation of Basophil Histamine Release and T Cell Reactivity by Chemically Modified Allergen.

Modification of a model allergen ovalbumin (OA) with succinylation (Suc-OA) led to inhibition of allergen histamine releasing activity as it was tested on basophils of OA-sensitive patients. A whole blood leukocyte histamine release was performed by glass fibre based histamine assay. IgE-binding activity of Suc-OA was significantly reduced as it was shown by RAST inhibition technique. Suc-OA stimulated OA-specific T cell hybrid 3DO-548 and ACP:LK35 to produce cytokine release at the same level as in the case of non-modified OA. Succinylation of OA was concluded to result in selective blockade of B cell and preservation of T cell epitopes of the allergen suggesting a new approach for allergen specific immunotherapy.

Randomized trial of zileuton in patients with moderate asthma: effect of reduced dosing frequency and amounts on pulmonary function and asthma symptoms. Zileuton Study Group.

This 6-month, randomized, multicenter study was designed to determine whether patients who had been treated with the leukotriene pathway inhibitor zileuton 600 mg four times daily (QID) for 2 months could be maintained at the same level of pulmonary function, symptom control, and beta-agonist use with less frequent dosing--first 600 or 800 mg three times daily (TID) and then twice daily (BID). A total of 278 patients with chronic asthma, ages 16 to 70, participated at 25 US centers. All had a 1-second forced expiratory volume (FEV1) of 35%-75%, reversible airway disease, and a nonsmoking history of 1 year. An 8-week open-label period (zileuton 600 mg QID) was followed by a 16-week double-blind period, in which patients who responded to the QID treatment were randomized to receive zileuton 600 or 800 mg TID for 8 weeks and then rerandomized to receive zileuton 600 or 800 mg BID for another 8 weeks. Primary outcomes were FEV1 and asthma symptom scores; secondary outcomes were peak expiratory flow rate, beta-agonist use, and asthma exacerbations requiring steroid rescue. Patients who showed improvements in lung function when treated with zileuton 600 mg QID demonstrated minimal decreases in FEV1 and comparable peak expiratory flow rates, symptom control, beta-agonist use, and systemic corticosteroid rescue when being treated with lower doses and/or less frequent doses of zileuton. Patients who demonstrate improved asthma control with zileuton 600 mg QID may be able to reduce their daily dosage and/or frequency while still maintaining the same level of symptom control.

Basophils, cytokines, and the allergic inflammatory response.

Immediate allergic response has long been recognized to be related to the activation of mast cells by antigen. The role of the mast cells as producers of cytokines, however, has only more recently been extensively studied. The effect of TH2 lymphocytes in the inflammatory process is now well recognized in animal models. The central role of cytokines in the allergic inflammatory response is currently an area of intense clinical investigation. Cytokines influence production, migration, and activation of basophils. A wide array of cytokines is produced by mast cells upon initiation of the immediate allergic response. These cytokines influence a number of other different cells including basophils and eosinophils, and also activate lymphocytes, thus perpetuating allergic inflammation.

Immunological properties of allergen chemically modified with synthetic copolymer of N-vinylpyrrolidone and maleic anhydride.

Several conjugates of model allergen ovalbumin (OA) and the copolymer of N-vinyl pyrrolidone and maleic anhydride (VMA) modified with epsilon-aminocaproic acid (Acp) were prepared in different OA/Acp-VMA ratios. All conjugates were separated by ultrafiltration and analyzed by HPLC. Their compositions were determined by amino acid analysis and UV spectrometry. To detect immunogenicity, all conjugates were injected intraperitoneally into (CBAxC57BL/6)F1 mice three times in 3-week intervals in OA doses equivalent to 0.5, 10, and 100 micrograms/mouse. Only the conjugate containing 20%OA (OA(20%)-Acp-VMA) did not induce significant quantities of anti-OA IgE, but did induce anti-OA IgG antibodies in dose-dependent manner comparable to that of unmodified OA. Mixtures of OA and Acp-VMA or OA modified only with VMA without Acp activation with Acp induced dose-dependent anti-OA IgE and IgG antibody formation comparable to that of OA. Using passive cutaneous anaphylaxis, RAST inhibition and leukocyte histamine release, a significant reduction of allergenicity was noted using OA(20%)-Acp-VMA. This conjugate stimulated activation of the OA-specific T-cell hybrid 3DO-548 comparable to that of unconjugated OA. During experimental allergen-specific hyposensitization with OA(20%)-Acp-VMA, suppression of anti-OA IgE response and elevation of anti-OA IgG responses were noted when compared with unmodified OA. Selective blockade of B-cell epitopes of allergen may occur using the carrier Acp-VMA to reduce allergenicity while not affecting T-cell epitopes, thereby preserving immunogenicity. This approach of chemical modification of allergen suggests new opportunities in the creation of preparations for allergen-specific immunotherapy.