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Biomedical subjects

Lanny J Rosenwasser

Publications and source records attributed to Lanny J Rosenwasser.

At least 19 recordsLinked to original sources
PubMed2006

Efficacy and safety of budesonide and formoterol in one pressurised metered-dose inhaler in adults and adolescents with moderate to severe asthma: a randomised clinical trial.

BACKGROUND: Inhaled corticosteroids (ICSs) are the preferred maintenance therapy for adults and children with mild, moderate and severe persistent asthma, with the addition of a long-acting beta(2)-adrenoceptor agonist to ICS therapy recommended for patients with moderate or severe persistent asthma. The efficacy and safety of the combination of budesonide and formoterol delivered via dry powder inhaler (DPI) is well documented. OBJECTIVE: To compare the efficacy and safety of budesonide/formoterol pressurised metered-dose inhaler (budesonide/formoterol pMDI; Symbicort pMDI, AstraZeneca LP, Wilmington, DE, USA) with budesonide pMDI (Pulmicort pMDI, Astra [corrected] Zeneca, Lund, Sweden), formoterol DPI (Oxis Turbuhaler, AstraZeneca, Lund, Sweden), budesonide plus formoterol in separate inhalers (budesonide pMDI + formoterol DPI) and placebo. STUDY DESIGN: This was a 12-week randomised, double-blind, double-dummy, placebo-controlled study. SETTING: This multicentre study was conducted in the respiratory specialty clinical practice setting. PATIENTS: The study included 596 patients > or =12 years of age with moderate to severe persistent asthma previously receiving ICSs. INTERVENTIONS: After 2 weeks on budesonide pMDI 80 microg x two inhalations (160 microg) twice daily, patients received budesonide/formoterol pMDI 160 microg/4.5 microg x two inhalations (320 microg/9 microg); budesonide pMDI 160 microg x two inhalations (320 microg) + formoterol DPI 4.5 microg x two inhalations (9 microg); budesonide pMDI 160 microg x two inhalations (320 microg); formoterol DPI 4.5 microg x two inhalations (9 microg); or placebo twice daily. MAIN OUTCOME MEASURES: There were two prespecified primary efficacy variables: mean change from baseline in morning predose forced expiratory volume in 1 second (FEV(1)), obtained approximately 12 hours after the most recent administration of study medication at home and immediately before the next administration of study medication at the clinic; and mean change from baseline in 12-hour FEV(1), assessed as the average change in FEV(1) from serial spirometry over the 12-hour period after administration of the morning dose of study medication at the clinic. RESULTS: Mean changes from baseline in morning predose FEV(1) at end of treatment were greater (p < or = 0.049) with budesonide/formoterol pMDI (0.19L) versus budesonide pMDI (0.10L), formoterol DPI (-0.12L) and placebo (-0.17L). Mean changes from baseline in 12-hour FEV(1) were greater (p < or = 0.001) with budesonide/formoterol pMDI after 1 day (0.37L), 2 weeks (0.34L) and at end of treatment (0.37L) versus budesonide pMDI (0.11, 0.15 and 0.15L) and placebo (0.09, -0.03 and -0.03L), and after 2 weeks and at end of treatment versus formoterol DPI (0.19 and 0.17L). Fewer (p < or = 0.025) patients receiving budesonide/formoterol pMDI versus monoproducts or placebo met worsening asthma criteria. Results were similar in the budesonide/formoterol pMDI group and the budesonide pMDI + formoterol DPI group on all measures. All treatments were well tolerated with similar safety profiles. CONCLUSIONS: In this population, twice-daily budesonide/formoterol pMDI provides asthma control significantly greater than the monocomponents or placebo and comparable with budesonide pMDI + formoterol DPI. Safety profiles were similar for all treatments.

Administration, Inhalation↗
PubMed2005

Allergy practice worldwide: a report by the World Allergy Organization Specialty and Training Council.

In 2004 the World Allergy Organization's Specialty and Training Council conducted a survey of World Allergy Organization (WAO) member societies to obtain information about the status of the specialty of allergy worldwide. Responses were received from 33 countries, representing a population of 1.39 billion people, of whom it was estimated that 22% may suffer from some form of allergic disease. Allergy was reported by 23 respondents to be a certified or accredited specialty in their country, and the number of certified allergists per head of population ranged from 1:25 million to 1:16,000. Allergists were ranked as the fifth most likely clinicians to see cases of allergic asthma, third most likely to see allergic rhinitis, and fourth most likely to see eczema or sinusitis. Nine countries only reported that children with allergic diseases would be seen by a pediatrician with appropriate training. The survey results highlight a pressing need for the development of allergy services worldwide.

Allergy and Immunology↗
PubMed2005

Association of transforming growth factor-beta1 single nucleotide polymorphism C-509T with allergy and immunological activities.

BACKGROUND: A single nucleotide polymorphism (SNP) C-509T within the tumor growth factor beta1 (TGFbeta1) gene has been associated with atopic asthma and asthma severity. To further understand the mechanisms involved, the association of C-509T with allergy, T-lymphocyte proliferation and plasma TGFbeta1 concentration has been explored in a case-control study with allergic and non-allergic subjects. METHODS: The recruited subjects including allergic (n = 38) and nonallergic (n = 25) participants have been genotyped for C-509T using allele discrimination assay. Association of C-509T with allergy status was examined using logistic regression analysis in both dominant and recessive models. Association of C-509T with T-cell proliferation in control and antigen-stimulated peripheral blood mononuclear cells (PBMCs), plasma TGFbeta1 and total IgE level were tested by multiple regression analysis. RESULTS: Individuals with homozygous mutant TT genotype showed a higher risk of allergy (TT: odds ratio = 5.099, 95% confidence limit: 1.355-19.190, p = 0.016) after covariates were adjusted. A trend to increased plasma TGFbeta1 in subjects with T allele has been discovered. In the meantime, the T allele is associated with lower T cell proliferation in controls and maximum response to above antigens. A low T-cell proliferation is correlated with higher plasma TGFbeta1 concentration (p < 0.01). The in vitro studies confirmed the suppressing effect of TGFbeta1 on T-cell proliferation at physiological range. A significant inhibitory effect on IL-4 production was also observed. CONCLUSIONS: A C to T base change in TGFbeta1 SNP C-509T has been associated with a higher risk of allergy. The mechanisms are not clear. Elevated TGFbeta1 levels associated with the C-509T polymorphism might suppress immune activation as well as Th2 cytokine production.

Alleles↗
PubMed2005

The role of immunoglobulin E and immune inflammation: implications in allergic rhinitis.

Immunoglobulin E (IgE) plays a critical role in the allergic inflammatory process in diseases such as allergic rhinitis. Cross-linking IgE bound to its receptor on cells by multivalent allergens initiates a chain of events resulting in allergic immune responses. Mast cells and basophils are involved in the early, immediate response, which is marked by cellular degranulation and the release of proinflammatory mediators, including histamine. Antigen-presenting cells are also activated by allergen-loaded IgE, resulting in immunomodulation of T-cell responses. The IgE molecule binds to two types of receptors, the high-affinity (Fc epsilonRI) and low-affinity (Fc epsilonRII or CD23) receptors, that have differing properties important in mediating allergen-induced responses. New therapies targeting the IgE molecule reduce allergen-stimulated immune responses and improve the clinical symptoms in subjects with allergic rhinitis. Understanding the role of the IgE molecule is necessary to appreciate the development and use of novel therapies targeting its actions.

Antibodies, Anti-Idiotypic↗
PubMed2005

Anti-CD23 monoclonal antibody, lumiliximab, inhibited allergen-induced responses in antigen-presenting cells and T cells from atopic subjects.

BACKGROUND: CD23 plays a role in the regulation of IgE production and allergy-induced immune and inflammatory responses. A novel anti-CD23 monoclonal antibody, lumiliximab, is a potential therapeutic antibody recently demonstrated to be safe in human beings. OBJECTIVE: This study investigated the effects of lumiliximab on allergen-induced immune responses from atopic subjects compared with blocking HLA-DR and costimulatory molecules, CD80 and CD86. METHODS: Allergen-stimulated PBMCs from atopic subjects were pretreated with lumiliximab or antibodies to CD80, CD86, and HLA-DR. Cultures were analyzed for cell proliferation and IL-1beta, TNF-alpha, and IL-5 cytokine secretion. An allergen-specific T-cell line was developed and analyzed for lymphocyte proliferation in response to allergen with or without lumiliximab. Lumiliximab's effect on CD86 expression was evaluated by flow cytometry in the U937 monocytic cell line. RESULTS: Lumiliximab reduced allergen-induced PBMC proliferation by 50% (n = 6; P = .006). In addition, cultures pretreated with lumiliximab had a reduction in the proinflammatory cytokines IL-1beta (P < .003) and TNF-alpha (P = .05) and the T(H)2 cytokine IL-5 (P = .002). Blocking CD86 resulted in greater reduction in proliferation than lumiliximab (P = .003) but similar effects in cytokine secretion. The anti-CD80 blocking antibody had no effect on cytokine production but did reduce proliferation. Furthermore, the addition of lumiliximab to cytokine stimulated U937 cells reduced surface expression of CD86 (P = .012). CONCLUSION: These results indicate that the anti-CD23 mAb, lumiliximab, may be involved in modulating antigen presenting cells and reducing TH2-type immune responses. The use of this antibody may provide clinical benefit for treating allergic diseases.

Allergens↗
PubMed2005

Mast cell stabilization and anti-histamine effects of olopatadine ophthalmic solution: a review of pre-clinical and clinical research.

BACKGROUND: Histamine receptor activation and degranulation of mast cells are the mechanisms by which the ocular itching, hyperemia, chemosis, eyelid swelling, and tearing of seasonal allergic conjunctivitis are induced. Some of the topical solutions available as anti-allergy therapies are intended to interfere with these mechanisms, and the body of research regarding the capabilities of these therapeutic molecules continues to expand. OBJECTIVE: To review the currently available literature regarding one topical ophthalmic anti-allergy agent, olopatadine (Patanol), and its anti-histaminic and mast cell stabilizing actions, both in pre-clinical and clinical settings. DESIGN AND METHODS: Relevant research of laboratory, animal model, and clinical trial studies performed using olopatadine was reviewed. MEDLINE literature searches were conducted and supplemented by additional reports which furthered relevant discussion or were necessary to verify the information resulting from original searches. RESULTS: Olopatadine demonstrates unique properties both pre-clinically and clinically which differentiate it from other therapeutic molecules in its class of dual action mast cell stabilizer/anti-histamine. Its non-perturbation of cell membranes, human conjunctival mast cell stabilization in vivo and in vitro, and superior efficacy as compared to other topical anti-allergic medications including mast cell stabilizers, anti-histamines, and dual action agents, all contribute to olopatadine's profile. CONCLUSIONS: Peer-reviewed literature suggests that olopatadine is clinically superior to the other anti-allergic molecules because of its strong anti-histaminic qualities and its unique ocular mast cell stabilizing properties.

Anti-Allergic Agents↗
PubMed2005

Anti-CD23.

CD23, the low-affinity immunoglobulin (Ig)E receptor (FcepsilonRII), is widely distributed on the surface of various human cells. CD23 mediates numerous IgE-related immune responses (including allergen focusing) by enhancing IgE antigen complex presentation, regulating IgE synthesis, influencing cell differentiation and growth of both B- and T-cells, and stimulating production of pro-inflammatory mediators from monocytes/macrophages, eosinophils, and even airway smooth muscle cells. Both membrane and soluble CD23 play an important role in allergic reactions. Cellular contacts and cytokines modulate its expression in a concerted manner as needed for allergic reactions. Expression of CD23 and soluble CD23 has been associated with allergic diseases. Targeting CD23 with monoclonal antibody (MAb) is a promising candidate therapy in allergic diseases. A newly developed agent known as Lumiliximab, which is an anti-CD23 MAb (Lumiliximab), was demonstrated to be a well-tolerated agent in a phase I clinical trial (a placebo-controlled study with allergic asthma). Adverse events were mild, and no relationship was apparent between the dose of Lumilixilab and the frequency, severity, or type of event. Sustained and dose-dependent decreases in mean serum total IgE concentrations were noted. The serum half-life of Lumilixilab increased from 2 to 10 d with increasing doses. Blocking antigen presentation, preventing costimulation signals, and reducing production of pro-inflammatory mediators are some of the potential mechanisms involved for anti-CD23 activity. Although the safety and clinical efficacy of Lumilixilab in allergic asthma and rhinitis require confirmation, the observed data imply that anti-CD23 is a promising candidate therapy option for future treatment of allergic diseases.

Animals↗
PubMed2004

Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids.

Corticosteroids mediate a variety of immunological actions and are commonly utilized in the treatment of a wide range of diseases. Unfortunately, therapy with this class of medications is associated with a large proportion of non-responders and significant side effects. Inhaled corticosteroids are the most commonly used asthma controller therapy. However, asthmatic response to corticosteroids also varies widely between individuals. We investigated the genetic contribution to the variation in response to inhaled corticosteroid therapy in asthma. The association of longitudinal change in lung function and single nucleotide polymorphisms from candidate genes crucial to the biologic actions of corticosteroids were evaluated in three independent asthmatic clinical trial populations utilizing inhaled corticosteroids as the primary therapy in at least one treatment arm. Variation in one gene, corticotropin-releasing hormone receptor 1 (CRHR1) was consistently associated with enhanced response to therapy in each of our three populations. Individuals homozygous for the variants of interest manifested a doubling to quadrupling of the lung function response to corticosteroids compared with lack of the variants (P-values ranging from 0.006 to 0.025 for our three asthmatic populations). As the primary receptor mediating the release of adrenocorticotropic hormone, which regulates endogenous cortisol levels, CRHR1 plays a pivotal, pleiotropic role in steroid biology. These data indicate that genetic variants in CRHR1 have pharmacogenetic effects influencing asthmatic response to corticosteroids, provide a rationale for predicting therapeutic response in asthma and other corticosteroid-treated diseases, and suggests this gene pathway as a potential novel therapeutic target.

Administration, Inhalation↗
PubMed2004

Should beta-blockers be given to patients with heart disease and peanut-induced anaphylaxis? A decision analysis.

BACKGROUND: Beta-blocker therapy postmyocardial infarction is generally recommended because it reduces mortality. However, beta-blockers may increase anaphylaxis mortality in the growing population of patients with peanut-induced anaphylaxis. OBJECTIVE: We sought to assess the risks and benefits of beta-blocker therapy among patients with peanut allergy and heart disease. METHODS: We created a Markov model for patients with heart disease at risk for peanut-induced anaphylaxis to compare life expectancy with the following strategies: (1) beta-blocker and (2) no beta-blocker. Meta-analysis and a literature review were used to estimate model parameters. We performed sensitivity analysis to explore parameter uncertainty. RESULTS: For peanut-allergic patients who are postmyocardial infarction or who have congestive heart failure, the heart disease benefit of beta-blockers outweighs the increased likelihood of dying from anaphylaxis, increasing life expectancy by 9.4 and 17.4 months, respectively. Beta-blocker was preferred unless (1) the annual rate of moderate to severe anaphylaxis exceeded 6.0% for postmyocardial infarction and 15% for congestive heart failure patients; (2) beta-blocker therapy increased the incidence of moderate to severe anaphylaxis >2.5-fold for postmyocardial infarction and >5.8-fold for congestive heart failure patients; (3) anaphylaxis case fatality exceeded 6.5% postmyocardial infarction; or (4) beta-blocker therapy increased anaphylaxis case fatality >25-fold postmyocardial infarction. CONCLUSION: Our results suggest that for patients postmyocardial infarction or with congestive heart failure who are at risk for peanut-induced anaphylaxis, beta-blocker use should still improve survival. However, the epidemiology of anaphylaxis and effects of beta-blocker therapy on anaphylaxis incidence and mortality require further study.

Adrenergic beta-Antagonists↗
PubMed2004

Dose dependence and time course of the immunologic response to administration of standardized cat allergen extract.

BACKGROUND: The immunologic response to allergen immunotherapy with 3 serial 5-fold doses of cat extract has been studied after approximately 5 weeks of immunotherapy. The highest dose containing 15 mug of Fel d 1 produced the most consistent and favorable response. It is unknown whether the comparative response on reaching a maintenance dose is maintained with long-term maintenance therapy. OBJECTIVE: The purpose of this investigation was to evaluate the immunologic responses with these 3 serial doses of cat hair and dander extract at baseline, after reaching the maintenance dose (approximately 5 weeks), and after 1 year of maintenance immunotherapy. METHODS: Twenty-eight patients with cat allergy randomized in a double-blind study were assigned to one of 4 treatment groups: placebo or cat hair and dander extract containing 0.6 mug of Fel d 1, 3 mug of Fel d 1, and 15 mug of Fel d 1 at maintenance. Studies included skin prick tests and late cutaneous reactions with cat hair and dander extract, titrated nasal challenges with the extract, serum cat allergen-specific IgG4 and IgE measurement, and flow cytometric and ELISA analysis of whole blood and intranasal cytokines (TGF-beta, IL-10, IFN-gamma, IL-4, and IL-5). RESULTS: Twenty-six subjects completed the study. After both 5 weeks and 1 year, significant and dose-dependent differences were seen with total symptom scores on nasal challenge ( P < .0001), with titrated skin prick testing with cat dander extract at 5 weeks ( P = .014) and 1 year ( P < .0001), and with cat-specific IgG4 measurement at 5 weeks ( P = .004) and 1 year ( P = .003). At 1 year, neither flow cytometry of whole blood nor ELISA evaluation of nasal cytokines demonstrated any significant differences among the treatment groups. CONCLUSION: The response to titrated nasal allergen challenge, titrated skin prick testing, and allergen-specific IgG4 measurement to cat immunotherapy at 5 weeks is predictive of the response at 1 year.

Allergens↗
PubMed2003

Allergic asthma and an anti-CD23 mAb (IDEC-152): results of a phase I, single-dose, dose-escalating clinical trial.

BACKGROUND: CD23, a cell-surface molecule, is involved in a variety of pathways likely to influence IgE production and inflammation in allergic disorders, such as allergic rhinitis and allergic asthma. OBJECTIVE: This study investigated the safety, clinical activity, and pharmacokinetic profile of IDEC-152, an IgG1 anti-CD23 antibody, in patients with mild-to-moderate persistent allergic asthma. METHODS: This single-dose, dose-escalating, placebo-controlled study involved 30 patients. Cohorts of 3 to 6 patients received single intravenous infusions of either placebo or IDEC-152 (0.05, 0.25, 1.0, 4.0, 10.0, or 15.0 mg/kg) on study day 1. Safety, clinical activity, and pharmacokinetics were assessed for 12 weeks after treatment. RESULTS: IDEC-152 was well tolerated. Adverse events (AEs) were mild, no grade 4 or serious AEs were reported, and no relationships were apparent between the dose of IDEC-152 and the frequency, severity, or type of event. The most common AEs in the IDEC-152 group included ecchymosis at the injection site, sinusitis, headache, arthralgia, cold syndrome, infection, throat irritation, and dysmenorrhea. Commonly reported AEs in the placebo group included headache, abdominal pain, and infection. Sustained and dose-dependent decreases in mean IgE concentrations were noted. The mean maximum concentration and area under the curve of IDEC-152 were proportional to the dose administered for the dose range 4.0 to 15.0 mg/kg. The serum half-life of the IDEC-152 antibody increased from 2 to 10 days with increasing doses. After single-dose administration of IDEC-152, no dose-dependent change in FEV(1) was observed, and most changes in peak expiratory flow rate were within 10% of baseline values. CONCLUSION: These data suggest that IDEC-152 is safe and has the potential for clinical activity in allergic asthma.

Adult↗
PubMed2003

5. Genetics of hypersensitivity.

Genetics provides the basis for the host response to a variety of environmental factors that can play a role in the generation of complex genetic diseases, such as asthma and atopy. An understanding of the genetic bases for these conditions is therefore essential to understand their pathophysiology. Studies of the genetics of asthma and atopy have suffered from several daunting challenges. These include the recognition that these are conditions caused by numerous genes, with each gene assuming variable roles in different individuals. In addition, each gene presumably contributes only a small percentage to a given individual's genetic risk of asthma. This has led to the current situation, in which studies often demonstrate a lack of replication that can be explained by their being insufficiently powered. Furthermore, the pathophysiologies of asthma and atopy are incompletely understood, and the lack of clearly defined phenotypes also contributes to the inadequacies of the current literature. Nonetheless, regions of the human genome have been reproducibly associated with asthma and atopy. These regions have undergone intense study, and many genetic variants within them have been implicated as asthma and allergy genes. In addition, through candidate gene approaches, several genetic polymorphisms have been convincingly linked to increased risks for the development of asthma and atopy. Many of these genes are associated with alterations in responsiveness to therapeutic agents used in the treatment of these conditions. These genetic studies have an exciting potential for individually tailoring the therapeutic regimen to a given subject's genotype. It is to be hoped that they will also define new targets for the next generation of asthma and allergy therapeutic agents.

Animals↗
PubMed2003

Mechanisms of asthma.

Airway inflammation is a key factor in the mechanisms of asthma. Articles published in the Journal of Allergy and Clinical Immunology this past year have highlighted the utility of investigative bronchoscopy with segmental antigen challenge and induced sputum analyses to evaluate features of airway inflammation in relationship to asthma severity. Peripheral blood cell generation of cytokines IFN-gamma (T(H)1) and IL-5 (T(H)2) was used to evaluate the relationship of the balance of T(H)1/T(H)2 cytokines to asthma persistence and severity in a 42-year, longitudinal study. Chemokines, including thymus and activation-regulated chemokine, are important to the regulation of inflammation and IgE synthesis. Their potential role in asthma has also been evaluated. Finally, albuterol (R)- and (S)-enantiomers may have distinct effects on airway relaxation and regulation of inflammation, suggesting the possibility that monoisomeric therapy has therapeutic advantages. The potential contribution of genetic factors and mechanisms to airway inflammation and remodeling also continues to be an area of intense investigation. During the past year a number of articles published in the Journal of Allergy and Clinical Immunology have identified and clarified potential genetic mechanisms in asthma. The contribution of genetics to asthma has been examined in a wide variety of studies, ranging from epidemiologic association and twin studies all the way to molecular analysis through microarray gene expression experiments.

Adenine↗