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Biomedical subjects

Nicola A Hanania

Publications and source records attributed to Nicola A Hanania.

16 recordsLinked to original sources

Predicting episodes of poor asthma control in treated patients with asthma.

BACKGROUND: Asthma exacerbations are dangerous, expensive, and difficult to anticipate. OBJECTIVE: To characterize patients with asthma who had asthma episodes and exacerbations during 4 weeks of observation. METHODS: A total of 2032 volunteers with asthma (age, 3-64 years; 62% female subjects) were studied over two 2-week intervals after flu vaccine and placebo. Baseline data, including several asthma questionnaires, were analyzed for prediction of subsequent asthma events as recorded on diaries detailing peak flow, medication use, and health care use. RESULTS: During 28 days of diary collection, 43.2% of participants had at least 1 episode of poor asthma control. Most episodes were characterized by increased use of rescue medications or reductions in peak flow, but nearly 15% of participants had exacerbations characterized by use of systemic corticosteroids, unscheduled health care visits, or both. Episode frequency was highest in children <10 years of age. Additional risk factors were smoking, African American ethnicity, low lung function, and past history of severe asthma. The best predictors were symptom questionnaires, and a simple questionnaire concerning the preceding 2 weeks worked as well as more complex questionnaires or those reflecting longer periods. In regression analyses, questionnaire results, smoking, lung function, ethnicity, and asthma history all were associated with asthma episodes in people older than 10 years, whereas only asthma history was predictive in those <10 years. CONCLUSION: Symptom questionnaires are predictive of subsequent asthma episodes in people older than age 10 years, but not in younger people. CLINICAL IMPLICATIONS: Simple assessments may be helpful in identifying patients most at risk for future asthma episodes.

Adolescent↗

The role of intrinsic efficacy in determining response to a beta2-agonist in acute severe asthma.

BACKGROUND: Current guidelines recommend repeated doses of albuterol for the emergency treatment of acute asthma. However, approximately one-third of patients show little or no initial response to this partial beta(2)-agonist. METHODS: We conducted a randomized, double-blind, proof-of-concept study to investigate whether a full beta(2)-agonist, isoproterenol, offers a therapeutic advantage in adults presenting with acute severe asthma (FEV(1)<50%) who fail to respond to an initial treatment of the partial beta(2)-agonist, albuterol. Study subjects were randomized to receive a 2-h continuous nebulization of either albuterol (7.5mg/h) (n=10, mean FEV(1)=37% predicted) or isoproterenol (7.5mg/h) (n=9, mean FEV(1)=33% predicted). Respiratory symptoms, vital signs and pulmonary function measures were collected. RESULTS: Subjects from both treatment groups had similar baseline characteristics. The percent improvements from baseline FEV(1) at 60 and 120min were significantly higher in subjects receiving isoproterenol than those receiving albuterol (44 vs. 17% and 63 vs. 24%, respectively, P<0.05). The change in symptoms measured by the modified Borg score was also significantly greater in subjects receiving isoproterenol (P<0.01). Both treatments were well tolerated, though the mean increase in pulse rate at 60 and 120min (21 vs. 1 and 23 vs. 6beats/min, respectively, P<0.05) and the mean change in serum potassium at 120min (-0.52 vs. -0.07meq/L, P<0.05) from baseline were significantly greater in the isoproterenol group. CONCLUSIONS: Our data suggest that in subjects presenting with acute severe asthma who fail to show an initial response to albuterol, the use of a beta(2)-agonist of higher intrinsic efficacy can be more effective in improving lung function and symptoms.

Acute Disease↗

Salmeterol stimulation dissociates beta2-adrenergic receptor phosphorylation and internalization.

Salmeterol is a long-acting beta(2)-adrenergic receptor (beta(2)AR) agonist commonly used in the treatment of asthma and chronic obstructive pulmonary disease. It differs from other beta-agonists in that it has a very low intrinisic efficacy, especially when compared with the other available long-acting beta-agonist, formoterol. Receptor desensitization and down-regulation has been described with the chronic use of beta-agonists. This effect may not be the same with all beta-agonists and may be related to their stabilization of altered receptor states. The extreme hydrophobicity and high-affinity quasi-irreversible binding of salmeterol have rendered studies examining the mechanisms by which it mediates receptor desensitization, down-regulation, and internalization difficult. We determined the capacity of salmeterol to induce beta(2)AR endocytosis, G protein-coupled receptor kinase (GRK)-site phosphorylation, degradation, and beta-arrestin2 translocation in HEK293 cells as compared with other agonists of varying intrinsic efficacies. Despite stimulating GRK-mediated phosphorylation of Ser355,356 after 30 min and 18 h to an extent similar to that observed with agonists of high intrinsic efficacy, such as epinephrine and formoterol, salmeterol did not induce significant beta(2)AR internalization or degradation and was incapable of stimulating the translocation of enhanced green fluorescent protein-beta-arrestin2 chimera (EGFP-beta-arrestin2) to the cell surface. Salmeterol-induced receptor endocytosis was rescued, at least in part, by the overexpression of EGFP-beta-arrestin2. Our data indicate that salmeterol binding induces an active receptor state that is unable to recruit beta-arrestin or undergo significant endocytosis or degradation despite stimulating considerable GRK-site phosphorylation. Defects in these components of salmeterol-induced receptor desensitization may be important determinants of its sustained bronchodilation with chronic use.

Adrenergic beta-2 Receptor Agonists↗

Revisiting asthma control: how should it best be defined?

Management guidelines for asthma emphasize a stepwise approach in treating this disease based on daytime symptoms, nighttime symptoms, and lung function assessed by peak expiratory flow or forced expiratory volume at 1s (FEV(1)). Although improvement of lung function is a key goal in managing asthma, clinicians often see patients who may have achieved a normal FEV(1) with guideline-recommended treatment but continue to experience limitations in their daily activities. In such situations, focusing the assessment solely on pulmonary function (e.g. FEV(1)) is often inadequate and may lead to undertreatment. Alternate assessment measures are therefore often needed to assess asthma control and achieve a successful treatment outcome. This review will provide practical guidance relevant to the clinical assessment of asthma control.

Anti-Asthmatic Agents↗

A comparison of levalbuterol with racemic albuterol in the treatment of acute severe asthma exacerbations in adults.

UNLABELLED: This multicenter, randomized, double-blind trial compared nebulized levalbuterol (Lev) and racemic albuterol (Rac) in the treatment of acute asthma. METHODS: Adults with acute asthma exacerbations (FEV(1) 20%-55% predicted) received prednisone and either Lev (1.25 mg, n = 315) or Rac (2.5 mg, n = 312). Nebulized treatments were administered every 20 minutes in the first hour, then every 40 minutes for 3 additional doses, then as necessary for up to 24 hours. The primary end point was time to meet discharge criteria. Secondary end points included changes in lung function and hospitalization rates. A subset of 160 patients had plasma (S)-albuterol concentrations determined at study entry. RESULTS: Time to meet discharge criteria did not differ between the 2 treatments. FEV(1) improvement was greater following Lev compared with Rac, both after dose 1 and cumulatively over the entire treatment period (dose 1 in intent to treat [ITT] group: Lev 0.50 +/- 0.43 L, Rac 0.43 +/- 0.37 L; P = .02), particularly among the 60% of patients not on recent steroid therapy (dose 1: Lev 0.58 +/- 0.47 L, Rac 0.44 +/- 0.37 L; P < .01), and patients whose entry (S)-albuterol concentrations were in the highest quartile of those measured. A small and similar proportion of Lev-treated (7.0%) and Rac-treated (9.3%) patients required hospitalization (P = .28). Among patients not on steroids, fewer Lev- than Rac-treated patients required admission (3.8% vs 9.3%, P = .03), as was also the case for patients with high plasma (S)-albuterol concentrations. Asthma relapses (5% in 30 days) were lower than in previous reports and did not differ between groups. CONCLUSIONS: This study suggests that early, regular nebulized beta(2)-agonist and systemic corticosteroid therapy may reduce hospitalization and relapse rates in patients with acute severe asthma. Lev was well tolerated and compared favorably with Rac in improving airway function, particularly in those who were not on inhaled or oral corticosteroids and in those who had high plasma (S)-albuterol concentrations at presentation.

Acute Disease↗

Influenza vaccine in patients with asthma.

Influenza virus continues to be a major cause of respiratory infection and is an important contributor to morbidity and mortality in at-risk populations, including those with underlying pulmonary conditions such as asthma. Vaccination with inactivated influenza vaccine remains the most popular method in controlling influenza through prevention. Current guidelines recommend the administration of the influenza vaccine to all patients with asthma. However, a third or fewer of those patients with asthma are currently receiving this vaccine. In this review, the risk-versus-benefit of influenza vaccination in children and adults with asthma is evaluated, based on the current evidence.

Asthma↗

Treatments for COPD.

The multicomponent nature of chronic obstructive pulmonary disease (COPD) has provided a challenging environment in which to develop successful treatments. A combination of pharmacological and non-pharmacological approaches is used to combat this problem, and an overview of these approaches and their possible future direction is given. Bronchodilators are the mainstay of COPD treatment and can be combined with inhaled corticosteroids for greater efficacy and fewer side effects. A new generation of pharmacotherapeutic agents, most notably phosphodiesterase-4 inhibitors, which are already in the advanced stages of clinical development, and leukotriene B4 inhibitors (in early clinical development), may shape future treatment as further insight is gained into the pathological mechanisms underlying COPD. Non-pharmacologic treatments for COPD include long-term oxygen therapy (LTOT), nasal positive pressure ventilation (nPPV), pulmonary rehabilitation and lung-volume-reduction surgery (LVRS). Apart from smoking cessation, LTOT is the only treatment to date which has been shown to modify survival rates in severe cases; thus its role in COPD is well defined. The roles of nPPV and LVRS are less clear, though recent progress is reported here. In the future, it will be important to establish the precise value of the different treatments available for COPD--evaluating both clinical and physiological endpoints and using the data to more accurately define candidate patients accordingly. The challenge will be to develop this base of knowledge in order to shape future research and allow clinicians to deliver tailored COPD management programmes for the growing number of patients afflicted with this disease.

Bronchodilator Agents↗

The efficacy and safety of inhaled fluticasone propionate/salmeterol and ipratropium/albuterol for the treatment of chronic obstructive pulmonary disease: an eight-week, multicenter, randomized, double-blind, double-dummy, parallel-group study.

BACKGROUND: The pathology of chronic obstructive pulmonary disease (COPD) includes both obstructive and inflammatory components. OBJECTIVE: The aim of this study was to confirm the findings of a previous study that compared the efficacy of a combination of 2 short-acting bronchodilators with the use of an inhaled corticosteroid and a long-acting beta-agonist in the treatment of COPD. METHODS: We conducted an 8-week, multicenter, randomized, double-blind, double-dummy, parallel-group study of subjects with moderate to severe COPD to compare fluticasone propionate/salmeterol 250/50 microg BID (FSC) with ipratropium/albuterol 36/206 microg QID (IB/ALB). The primary efficacy measure was morning preadministration forced expiratory volume in 1 second (FEV(1)). Secondary measures were morning peak expiratory flow (PEF), 6-hour FEV(1) AUC, percentage of symptom-free nights, Transition Dyspnea Index (TDI) score, and overall daytime symptom score. Additional measures included sleep symptoms, supplemental albuterol use, and nighttime awakenings due to respiratory symptoms. Safety evaluations were based on clinical adverse events and COPD exacerbations. RESULTS: Baseline characteristics were similar between the FSC (n = 180) and IB/ALB (n = 181) groups, including mean age (63.7 and 65.4 years, respectively), mean body weight (81 and 79 kg, respectively), screening pulmonary function (mean [SD], 43.7% [14.2%] and 41.6% [13.4%] of predicted FEV(1)), race (82% and 91% white), and sex (64% and 62% male). FSC resulted in greater improvements in morning preadministration FEV(1), morning PEF, and 6-hour FEV(1) AUC (all, P < 0.001), TDI score (P = 0.026), overall daytime symptom score (P = 0.024), percentage of symptom-free nights (P = 0.010), nighttime awakenings due to respiratory symptoms (P = 0.002), sleep symptom score (P = 0.003), and percentage of days and nights without rescue albuterol use compared with IB/ALB (P = 0.021 and P < 0.001, respectively). Compared with day 1, the FEV(1) AUC at week 8 increased by 0.38 L-h with FSC and decreased by 0.18 L-h with IB/ALB (P < 0.001 between groups). The type and incidence of adverse events were similar between the 2 groups. One or more adverse event was reported for 81 (45%) and 85 (47%) subjects in the FSC and IB/ALB groups, respectively. CONCLUSION: In this 8-week study, subjects with moderate to severe COPD experienced greater improvements in lung function and symptom measures with FSC than with IB/ALB.

Administration, Inhalation↗

Acute asthma in pregnancy.

OBJECTIVES: To provide an overview on the interrelationship between asthma and pregnancy, focusing on management of pregnant women presenting with an acute severe exacerbation. DESIGN: A review of the current English-language published clinical trials was performed based on MEDLINE search using the Medical Subject Headings pregnancy and asthma. Current reviews on the topic and practice guidelines were also reviewed. RESULTS: Asthma is the most common medical condition to complicate pregnancy, and episodes of acute asthma requiring emergency department visits or hospitalization have been reported in 9-11% of pregnant women managed by asthma specialists. Pregnancy can affect the course of asthma, and the risk of asthma exacerbations requiring intervention in pregnant women is higher than in nonpregnant women. Similarly, asthma can affect pregnancy outcomes. Maternal inflammatory pathways may contribute to the poor pregnancy outcomes, especially in women with uncontrolled asthma. Although data on the effects of maternal asthma on pregnancy have been conflicting, mainly because many published studies have not corrected for asthma severity, it has generally been observed that poorly managed asthma during pregnancy is associated with a higher risk of preterm delivery, low birth weight, and complications such as preeclampsia. Optimal therapy of asthma has been shown to contribute to improved maternal and fetal outcomes. CONCLUSIONS: Asthma can complicate the course of pregnancy, and pregnancy can worsen asthma control in some women. Optimal management of asthma during pregnancy is key in ensuring the safety of the mother and the fetus.

Acute Disease↗

Selective phosphodiesterase-4 inhibitors in chronic obstructive lung disease.

PURPOSE OF REVIEW: Chronic obstructive pulmonary disease (COPD) is a disease state characterized by airflow limitation that is usually progressive. In addition, an abnormal inflammatory response of the lungs to noxious particles or gases can be seen throughout the airways, parenchyma, and pulmonary vasculature. So far, anti-inflammatory medications (eg, inhaled corticosteroids) have failed to show a major effect on the decline of lung function in COPD patients. Novel anti-inflammatory therapies such as selective phosphodiesterase 4 (PDE4) inhibitors are in clinical development. Their potential role in the management of COPD is described in this review. RECENT FINDINGS: Some of the selective PDE4 inhibitors have demonstrated in vitro and in vivo anti-inflammatory activity on cells commonly linked to airway inflammation in COPD, such as neutrophils. While these agents seem to offer only a modest improvement in lung function compared with other bronchodilators, their anti-inflammatory effects appear to provide some substantial benefits in reducing exacerbations and improving health-related quality of life. SUMMARY: Based on the available data, the second generation of selective PDE4 inhibitors will likely provide additional therapeutic options for the management of COPD. These agents may become an important tool in the treatment of this disease, since they target three important components of COPD: airway obstruction, inflammation, and structural changes.

3',5'-Cyclic-AMP Phosphodiesterases↗

Acute asthma in pregnancy.

Asthma is one of the most common medical conditions that can complicate pregnancy. Although most pregnant women with asthma have controlled disease, some women may experience exacerbation of their disease, necessitating immediate intervention. This article discusses the interrelations between asthma and pregnancy and presents an overview on the management of pregnant women presenting to the hospital with acute severe asthma. Treating physicians must overcome the common belief that pregnant women should not take any medications during pregnancy, and they should keep asthma in pregnant women under control to minimize the risk for maternal and fetal hypoxia.

Acute Disease↗

Immune response to influenza vaccination in children and adults with asthma: effect of corticosteroid therapy.

BACKGROUND: Annual influenza vaccination is currently recommended as a preventative measure for all patients with asthma. However, the effect of maintenance corticosteroid therapy on the immune response to influenza vaccine has received limited evaluation. OBJECTIVE: In this study, we evaluated the effect of corticosteroid therapy on the immune response to influenza vaccine in children and adults with asthma. METHODS: This was a substudy of a larger multicenter, randomized, double-masked, placebo-controlled, crossover study investigating the safety of trivalent influenza vaccine in patients with asthma. At baseline, 294 subjects were randomized to receive either placebo first (n=139) or inactivated trivalent split-virus influenza vaccine first (n=155). Study subjects were categorized into 2 groups: subjects in group 1 (n=148) were receiving medium-dose or high-dose inhaled corticosteroids (ICSs) or oral corticosteroids, whereas subjects in group 2 (n=146) were not receiving corticosteroids or were receiving low-dose ICSs. Serum hemagglutination inhibition antibody titers for the vaccine antigens were measured before and 4 weeks after the administration of placebo or vaccine. RESULTS: Serologic responses to each influenza vaccine antigen were significantly higher in vaccine than in placebo recipients and were similar among influenza vaccine recipients in groups 1 and 2 for the following endpoints: rise in antibody titer, percent of participants who developed a serological response, and percent of subjects who developed a serum hemagglutination inhibition antibody titer > or =1:32. Post hoc subgroup analyses demonstrated an attenuated response to influenza B antigen in subjects receiving high-dose ICS compared with subjects who were steroid-naïve (P<.05). CONCLUSION: The immune response to the A antigens of the inactivated influenza vaccine in subjects with asthma is not adversely affected by ICS therapy. High-dose ICS therapy may diminish the response to the B antigen of the vaccine, an observation that needs further investigation.

Adolescent↗

Anti-inflammatory activities of beta2-agonists.

Beta2-adrenergic agonists (beta2-agonists) play a pivotal role in the acute and chronic management of asthma. Their major action on the airways is the relaxation of smooth muscle cells. In addition to their bronchodilator properties, beta2-agonists may have other effects through their activation of beta2-receptors expressed on resident airway cells such as epithelial cells and mast cells and circulating inflammatory cells such as eosinophils and neutrophils. These non-bronchodilator activities of beta2-agonists may enhance their efficacy in the management of asthma. In pre-clinical studies, the anti-inflammatory effects of beta2-agonists are demonstrated through their stabilizing effect on mast cells and their inhibition of mediator release from eosinophils, macrophages T-lymphocytes, and neutrophils. In addition, beta2-agonists may inhibit plasma exudation in the airway, the release of neuropeptides from sensory nerves, and mediator release from epithelial cells. These in vitro observations are not as clearly demonstrated in clinical trials, which may be explained by the rapid desensitization of beta2-adrenergic receptors on airway inflammatory cells. The regular use of short-acting beta2-agonists alone has been shown to have deleterious effects on asthma control. Therefore, short-acting agents should only be used when needed for rescue of acute symptoms. Monotherapy with long-acting beta2-agonists has also been associated with poor asthma control. However, when given concomitantly with inhaled corticosteroids, beta2-agonists may potentiate the anti-inflammatory effect of corticosteroids, improve asthma control and prevent exacerbations.

Adrenal Cortex Hormones↗

The efficacy and safety of fluticasone propionate (250 microg)/salmeterol (50 microg) combined in the Diskus inhaler for the treatment of COPD.

STUDY OBJECTIVES: To compare the efficacy and safety of the inhaled corticosteroid fluticasone propionate (FP) and the inhaled long-acting beta(2)-agonist salmeterol (SM), when administered together in a single device (Diskus; GlaxoSmithKline, Inc; Research Triangle Park, NC), with that of placebo and the individual agents alone in patients with COPD. DESIGN: Randomized, double-blind, multicenter, placebo-controlled study. SETTING: Seventy-six investigative sites in the United States. PATIENTS: Seven hundred twenty-three patients > or =40 years of age with COPD and a mean baseline FEV(1) of 42% predicted. INTERVENTIONS: FP (250 microg), SM (50 microg), FP plus SM combined in a single inhaler (FSC), or placebo administered twice daily through the Diskus device for 24 weeks. MEASUREMENTS: Primary efficacy measures were morning predose (ie, trough FEV(1)) for FSC compared with SM and 2-h postdose FEV(1) for FSC compared with FP. Other efficacy measures were as follows: morning peak expiratory flow rate (PEF); transition dyspnea index; chronic respiratory disease questionnaire; chronic bronchitis symptom questionnaire; exacerbations; and other symptomatic measures. RESULTS: At Endpoint (ie, the last on-treatment, post-baseline assessment), treatment with FSC significantly (p < or = 0.012) increased the morning predose FEV(1) (165 mL) compared with SM (91 mL) and placebo (1 mL), and significantly (p < or = 0.001) increased the 2-h postdose FEV(1) (281 mL) compared with FP (147 mL) and placebo (58 mL). Improvements in lung function with FSC compared with FP and SM, and with FP and SM compared with placebo, as measured by the average daily morning PEF, was observed within approximately 24 h after the initiation of treatment, indicating an early onset of effect (p < or = 0.034). Compared with placebo, FSC significantly improved dyspnea, quality of life, and symptoms of chronic bronchitis. The incidence of adverse effects (except for an increase in oral candidiasis with FSC and FP) were similar among the treatment groups. CONCLUSIONS: Treatment with FSC (FP, 250 microg, and SM, 50 microg) twice daily substantially improved morning lung function and sustained these improvements for over a period of 24 weeks compared with FP or SM treatment alone in patients with COPD, with no additional safety concerns for the combination treatment vs that with the individual components.

Adrenergic beta-Agonists↗

Regression of a plasmablastic lymphoma in a patient with HIV on highly active antiretroviral therapy.

We describe an HIV-infected 44-year-old man who presented 1 month after discontinuation of HAART therapy with a large mass extending from the mediastinum, enclosing the heart and extending through the diaphragm to the epigastric region. Biopsies subsequently revealed a highly aggressive non-Hodgkin's lymphoma (NHL) producing sheets of cells with an organoid distribution. The cells had abundant basophilic cytoplasm and a plasmacytic appearance. Although immunohistochemistry failed to show either B- or T-cell markers, antigens consistent with plasma cells were found. An immunoglobulin heavy chain clonal rearrangement was identified by PCR analysis. These studies were supportive of a diagnosis of a plasmablastic lymphoma. While awaiting the results of these tests, the patient was reinitiated on his HAART regimen. He was found on follow-up a month later to have complete resolution of his bulky mediastinal mass. He remained free of disease for 3 months with subsequent rectal and abdominal recurrence. Treatment with CHOP chemotherapy with filgrastim support was begun which resulted in another remission. Plasmablastic lymphoma is now reported in some studies to account for 2.6% of all HIV-related NHL. Originally described in 1997 in a series of 16 patients, this entity is highly associated with HIV infection in its later stages. Often, patients present with oral or jaw lesions with a rapidly progressive course. The tumors have the morphologic appearance of a plasmacytoid tumor with high proliferative index. Markers are positive mainly for LCA, CD79a, VS38C, and CD138. Co-infection with HHV-8 and EBV has not been consistently reported. Therapy with standard regimens has variable response. One case has been reported with a 3.5 year disease free survival. The regression of disease after resumption of HAART therapy alone in this patient suggests that HAART has an important role in the treatment of lymphoma in the HIV infected patient.

Adult↗