Long-and short-acting beta 2-adrenergic agonists. Effects on airway function in patients with asthma.

Inhaled beta-adrenergic agonist bronchodilators are integral components of effective asthma treatment. However, the risk of asthma morbidity and mortality associated with the regular use of certain inhaled beta-agonists was first noted in the United Kingdom during the 1960s and in New Zealand during the 1970s. There are also concerns that long-term use of both long-acting and short-acting inhaled beta-agonists may cause a loss of asthma control in some patients.

Fluticasone Propionate Reduces Oral Prednisone Use While it Improves Asthma Control.

This study examined the effect of fluticasone propionate aerosol on oral prednisone requirements in patients with severe asthma. Ninety-six patients dependent on oral prednisone were treated with placebo or fluticasone propionate aerosol (750 or 1000 &mgr;g twice daily) for 16 weeks. The dosage of oral prednisone was adjusted weekly according to predetermined criteria.

Respiratory syncytial virus infection enhances neutrophil and eosinophil adhesion to cultured respiratory epithelial cells. Roles of CD18 and intercellular adhesion molecule-1.

Respiratory syncytial virus (RSV) infections in children precipitate acute episodes of respiratory obstruction that are associated with influx of inflammatory cells into the airway. Since RSV can induce the expression of adhesion molecules, particularly intercellular adhesion molecule-1 (ICAM-1), by the respiratory epithelium, the hypothesis has been proposed that ICAM-1 expression contributes to airway inflammation by supporting adhesion and retention of infiltrating inflammatory leukocytes. To test this hypothesis, A549 cells (an immortalized human alveolar epithelial type II cell-like fine) were infected with RSV, and the ability of these infected monolayers to support adhesion by human neutrophils (NEUT) and eosinophils (EOS) was measured.

Comparison of triamcinolone acetonide nasal inhaler with astemizole in the treatment of ragweed-induced allergic rhinitis.

Background: Few clinical trials have directly compared the efficacy of antihistamines with topical nasal corticosteroids.

Objective: The study was performed to compare the efficacy and safety of triamcinolone acetonide nasal spray at a dose of 110 micro g in each nostril once daily with 10 mg of oral astemizole once daily for the treatment of seasonal allergic rhinitis.

Methods: A multicenter, double-blind, parallel-group study was conducted in 239 patients who were randomized to receive either triamcinolone acetonide or astemizole.

Ragweed immunotherapy in adult asthma.

Background: Although allergen immunotherapy is effective for allergic rhinitis, its role in treating asthma is unclear.

Methods: We examined the efficacy of immunotherapy for asthma exacerbated by seasonal ragweed exposure. During an observation phase, adults with asthma who were sensitive to ragweed kept daily diaries and recorded peak expiratory flow rates between July and October.

IL-5 activates a 45-kilodalton mitogen-activated protein (MAP) kinase and Jak-2 tyrosine kinase in human eosinophils.

IL-5 is a member of the hemopoietic cytokine family and has profound effects on the differentiation, survival, migration, and effector function of human eosinophils. Increased tyrosine phosphorylation has been observed as an early event in IL-5 signal transduction in eosinophils; most notably, proteins of 45 and 135 kDa became tyrosine phosphorylated following IL-5 treatment. Some of these phosphotyrosine-containing proteins may represent intermediates in IL-5 signal transduction pathways.

Rhinovirus enters but does not replicate inside monocytes and airway macrophages.

Potential interactions between rhinovirus (RV) and both the airway macrophage and its precursor cell, the blood monocyte, were investigated in terms of direct binding, intracellular replication, cell survival, and cytokine production. When HeLa cell suspensions are inoculated with RV as a positive control, virus titer increases by 100-fold in the first 24 h, confirming intracellular replication. In contrast, RV titer in monocyte and macrophage suspensions steadily decreased.

Vocational training for medicinal chemists: views from industry.

The Medicinal Chemistry Section of IUPAC sent a questionnaire regarding academic training for medicinal chemists to major research pharmaceutical companies in various countries in July 1992 and again in July 1993. A total of 102 replies were received from 65 companies, mainly from Germany, Italy, Japan, the UK and the USA, and these have been analysed and the results are presented. Most companies (> 90%) indicated that they seek to hire organic chemists who may have received some additional education in medicinal chemistry, rather than hire specialists in medicinal chemistry.

Clinical aspects of anti-inflammatory therapy in asthma.

Anti-inflammatory therapy is now considered first-line treatment for mild to moderate asthma. Corticosteroids remain the most potent anti-inflammatory therapy available (although their mode of action is not clearly understood), and recent investigations suggest that earlier institution of anti-inflammatory therapy may be more beneficial than delayed therapy in newly diagnosed asthmatic patients. Inhaled corticosteroids have far fewer adverse effects than their oral counterparts; however, their risks must be carefully considered before use in mild asthma.

Corticosteroid-sparing effect of azelastine in the management of bronchial asthma.

The objective of this double-blind trial was to evaluate the corticosteroid-sparing effect of azelastine in patients with chronic bronchial asthma. A total of 193 subjects received either 6 mg of azelastine twice per day or placebo (in a 2:1 ratio) in combination with beclomethasone dipropionate (6 to 16 inhalations per day). The number of daily inhalations of the corticosteroid was reduced until maximum reduction or elimination was achieved.

Inflammation and asthma.

There is little doubt that chronic asthma represents a unique inflammatory process in which the airway has become the target. Observations that were originally made nearly 100 years ago have been borne out through the use of animal models and technologically sophisticated techniques that allow experimentation on isolated regions of the human bronchial tree. It is also apparent that the pathophysiologic processes responsible for the airway changes observed in asthma are more complex than those presented in this discussion.

Differential effects of granulocyte-macrophage colony-stimulating factor on eosinophil and neutrophil superoxide anion generation.

Eosinophils (EOS) are specifically recruited to sites of allergic inflammation and parasitic infection, while neutrophil (NEUT) influx predominates in bacterial infections. This biologic selectivity suggests that granulocytes may respond differently to inflammatory mediators such as granulocyte-macrophage-CSF (GM-CSF). To establish the mechanisms of the response of granulocytes to GM-CSF, isolated human peripheral blood EOS and NEUT were obtained from allergic rhinitis patients and incubated in vitro with this cytokine.

Cytokines in bronchoalveolar lavage fluid of patients with nocturnal asthma.

Airflow obstruction can have a circadian pattern with nocturnal worsening. Airway inflammation is a cardinal feature of asthma, and it has been shown to increase at night in association with the decline in pulmonary function. Although the mechanisms regulating enhanced airway inflammation in asthma at night have yet to be ascertained, we hypothesized that circadian variation in cytokine expression or production is an important factor in the development of nocturnal airflow limitation.

Fluticasone propionate reduces oral prednisone use while it improves asthma control and quality of life.

This study examined the ability of fluticasone propionate aerosol to reduce oral prednisone requirements in patients with severe asthma. Ninety-six patients dependent on oral prednisone were treated for 16 wk with placebo or fluticasone propionate aerosol (750 or 1,000 micrograms twice daily). Their dosage of oral prednisone was adjusted weekly according to predetermined criteria.

Adhesion of activated eosinophils to respiratory epithelial cells is enhanced by tumor necrosis factor-alpha and interleukin-1 beta.

Eosinophilic infiltration and damage to airway epithelium are characteristic features of asthma. To assess possible interactions between eosinophils and airway epithelium, Percoll-purified human peripheral blood eosinophils were evaluated for their ability to adhere to respiratory epithelial cell (REC) cultures. REC (an immortalized cell line, A549, and primary bronchial epithelial cells) were grown in 96-well tissue culture plates, treated with proinflammatory cytokines (TNF-alpha or IL-1 beta), and eosinophil adhesion to these tissues was determined.

The effects of rhinovirus infections on allergic airway responses.

Although it has long been recognized that the common cold is a potent trigger for symptoms of asthma, the mechanisms underlying the association between upper respiratory infection and increased lower airway obstruction remain obscure. The use of experimental infection of volunteers with or without respiratory allergies has enabled direct comparisons of common cold symptoms in these two groups. Furthermore, techniques such as bronchoalveolar lavage and segmental antigen challenge have been used to directly sample lower airway fluids and tissues during acute viral infection.

Effect of interleukin-5 and granulocyte-macrophage colony stimulating factor on in vitro eosinophil function: comparison with airway eosinophils.

Eosinophils are hypothesized to be crucial in the development of allergic airway inflammation; however, the actual mechanisms that determine their inflammatory activity are still largely undefined. To investigate the factors that regulate eosinophil function in allergic airway disease, we have previously used segmental bronchoprovocation with allergen to study ex vivo eosinophil function. To determine whether the functional changes associated with airway eosinophils obtained by bronchoalveolar lavage 48 hours after antigen challenge are caused by exposure to airway-generated cytokines, normodense blood eosinophils were cultured in vitro with recombinant human interleukin-5 (IL-5) or granulocyte-macrophage colony stimulating factor (GM-CSF).

Eosinophil adhesion to vascular cell adhesion molecule-1 activates superoxide anion generation.

Adhesion to the adhesion protein, VCAM-1, on vascular endothelium is proposed to be an important factor in the selective accumulation of eosinophils at sites of allergic inflammation. To determine whether eosinophil adhesion to VCAM-1 is also associated with an alteration of eosinophil function, human peripheral blood eosinophils were isolated from allergic donors and incubated in VCAM-1-coated wells. Spontaneous adherence of isolated eosinophils to VCAM-1-coated wells was greater than cells incubated in FCS-treated control wells (38.

Mechanisms of persistent airway inflammation in asthma. A role for T cells and T-cell products.

The role of T cells in human allergic inflammation is just beginning to be understood. However, the data presented indicate how the T cell may be a pivotal cell to direct features of allergic inflammation in asthma, how the T cell may be able to transfer hyperresponsiveness, which is a feature of bronchial asthma, what some of the genetic factors are that may determine this process, and how an important precipitant of asthma, viral respiratory infections, may participate in this process. Its cells are isolated from patients with asthma and studied for their ability to generate proinflammatory failure.

Viral infections in humans.

Viral respiratory infections can increase asthma symptoms in many patients. Although the mechanisms of these effects are not fully established, there is evidence that respiratory viruses can promote some components of allergic inflammation. In this regard, there is evidence that rhinovirus respiratory infections can lead to the development of late allergic reactions to inhaled allergen.

A common cold virus, rhinovirus 16, potentiates airway inflammation after segmental antigen bronchoprovocation in allergic subjects.

Many patients with asthma have increased wheezing with colds. We hypothesized that rhinovirus colds might increase asthma by augmenting airway allergic responses (histamine release and eosinophil influx) after antigen challenge. Seven allergic rhinitis patients and five normal volunteers were infected with rhinovirus type 16 (RV16) and evaluated by segmental bronchoprovocation and bronchoalveolar lavage.