The E-cigarette or Vaping Product Use-Associated Lung Injury Epidemic: Pathogenesis, Management, and Future Directions: An Official American Thoracic Society Workshop Report.

E-cigarette or vaping product use-associated lung injury (EVALI) is a severe pulmonary illness associated with the use of e-cigarettes or vaping products that was officially identified and named in 2019. This American Thoracic Society workshop was convened in 2021 to identify and prioritize research and regulatory needs to adequately respond to the EVALI outbreak and to prevent similar instances of disease associated with e-cigarette or vaping product use. An interdisciplinary group of 26 experts in adult and pediatric clinical care, public health, regulatory oversight, and toxicology were convened for the workshop. Four major topics were examined: 1) the public health and regulatory response to EVALI; 2) EVALI clinical care; 3) mechanisms contributing to EVALI; and 4) needed actions to address the health effects of EVALI. Oral presentations and group discussion were the primary modes used to identify top priorities for addressing EVALI. Initiatives including a national EVALI case registry and biorepository, integrated electronic medical record coding system, U.S. Food and Drug Administration regulation and enforcement of nicotine e-cigarette standards, regulatory authority over nontobacco-derived e-cigarettes, training in evaluating exogenous exposures, prospective clinical studies, standardized clinical follow-up assessments, ability to more readily study effects of cannabinoid e-cigarettes, and research to identify biomarkers of exposure and disease were identified as critical needs. These initiatives will require substantial federal investment as well as changes to regulatory policy. Overall, the workshop identified the need to address the root causes of EVALI to prevent future outbreaks. An integrated approach from multiple perspectives is required, including public health; clinical, basic, and translational research; regulators; and users of e-cigarettes. Improving the public health response to reduce the risk of another substantial disease-inducing event depends on coordinated actions to better understand the inhalational toxicity of these products, informing the public of the risks, and developing and enforcing regulatory standards for all e-cigarettes.

The Evolution of Vigilance and Its Atrophy Preceding the COVID-19 Global Pandemic.

Introduction: Recent infectious outbreaks preceding the COVID-19 crisis resulted in the evolution of vigilance for preparedness against the next pandemic. This vigilance was maintained to varying degrees in different jurisdictions. Objective: To evaluate the evolution of vigilance following previous epidemics and pandemics and the subsequent atrophy of vigilance prior to the COVID-19 global pandemic. Methods: We evaluated documentation discussing US, Canada, and South Korea from March 2002 to October 2021. Our policy search strategy was rooted in academic literature, government documents and media reports. Results: In the US, there were examples of atrophy of vigilance; however, there was clear understanding of pandemic readiness actions that were simply not executed amongst political chaos. In Canada, political mishaps were less evident at the time the pandemic unfolded. Nevertheless, atrophy was evident with erosion in preparedness programs following SARS. South Korea appeared least subjected to atrophy of vigilance. The more recent MERS outbreak prompted evolution of sustained vigilance and compliance with basic public health measures such as mask wearing. Recommendations: Policy options need to be explored and instituted that increase protection of preparedness programs through institutional safeguards and accountability measure.

Unsubstantiated health claims for COVID-19 infections are led by cannabidiol: return of snake oil medicine.

BACKGROUND: The United States Food and Drug Administration (FDA) monitors, inspects, and enforces the promotion of products by companies that claim to mitigate, prevent, treat, diagnose, or cure COVID-19. The introduction of COVID-19-related diagnostics and therapeutics during the pandemic has highlighted the significance of rigorous clinical trials to ensure safety and efficacy of such interventions. The objective of this report is to provide a descriptive review of promotional violations of health products for COVID-19 infection. METHODS: Warning letters issued by the FDA's Center for Drug Evaluation and Research were retrieved over an 18 month period (March 6, 2020, to August 30, 2021) to identify promotional violations. FDA violation letters categorized as "Unapproved and Misbranded Products Related to Coronavirus Disease 2019 (COVID-19)" were reviewed. A content analysis was performed for each letter to identify categories for product type, promotional venue, violation type, and country of origin. For cannabidiol-related violations, a content analysis was repeated within its own product category. RESULTS: A total of 130 letters were reported. Across all letters, cannabidiol products were the most frequent subject of violation (15/130; 11.5%). Of the cannabidiol letters, all reported the promotion of unapproved products (15/15; 100%), misbranding (15/15; 100%), and/or had claims that lacked scientific substantiation (14/15; 93.3%). All promotional violations were linked to websites (15/15; 100%), along with other mainstream venues: Facebook, Instagram, YouTube, Twitter, LinkedIn, and email. Lastly, the cannabidiol products were described to provide therapeutic benefit to COVID-19, by acting as an anti-viral (5; 33.3%), pro-inflammatory (1; 6.7%), anti-inflammatory (7; 46.7%), immune-booster (5; 40%), immune-suppressor (2; 13.3%), and/or other (2; 13.3%). CONCLUSION: Despite the urgent need for COVID-19 treatments, promotional material by companies must comply with standard regulatory requirements, namely substantiation of claims. As the pandemic persists, the FDA must continue their efforts to monitor, inspect, and enforce violative companies. Cannabidiol-related substances led the spectrum of products with unsubstantiated claims to treat COVID-19 infection. Improving awareness among the public, healthcare providers, and stakeholders highlights the value of drug approval process, while protecting public safety.

How the Global COVID-19 Pandemic Brought Drug and Vaccine Development into the Public Mainstream.

Pharmaceutical development was at the forefront of efforts to prevent infection with the SARS-CoV-2 virus as well as to treat its often-devastating effects. Drug development, and its multifaceted and multi-disciplined activity toward effective vaccines and drugs, became part of everyday news. I review several key areas of vaccine and drug development that were brought into the public mainstream over the evolution of the pandemic. These include the unprecedented speed of vaccine discovery and development, issues uncovered from early clinical studies, and regulatory concepts that were highlighted throughout the development process. Among these was the importance of pharmacovigilance as each new agent was rapidly deployed to a mostly eager public. Critical challenges around production, packaging, and procurement of product for patient use were often centre stage. Finally, the ever-important need to transition not only from scientific concept to vaccine and drug, but from their authorized and approved use to their implementation in health systems to insure the intended effects both in individuals and populations.

The Emergency Use Authorization of Pharmaceuticals: History and Utility During the COVID-19 Pandemic.

The Emergency Use Authorization (EUA) originated in 2004 because of the need for emergency medical countermeasures (MCMs) against potential bioterrorist attacks. The EUA also proved useful in dealing with subsequent pandemics and has emerged as a critical regulatory pathway for therapeutics and vaccines throughout the Coronavirus Disease 2019 (COVID-19) pandemic. With the EUA process in the USA, we witnessed emergency authorizations, their expansions, as well as withdrawal of previously authorized products, which exemplifies the dynamic nature of scientific review of EUA products. EUAs proved vital for the first group of COVID-19 vaccines, including the temporary pause of one vaccine while emergency safety issues were evaluated. Although this review on the EUA is primarily focused on the USA, distinctions were made with other jurisdictions such as Europe and Canada with respect to the emergency authorizations of the vaccines. Finally, we discuss some important differences following EUA and formal new drug/vaccine application (NDA/BLA) approvals.

Compliance With Cannabis Act Regulations Regarding Online Promotion Among Canadian Commercial Cannabis-Licensed Firms.

Importance: As global jurisdictions shift toward cannabis legalization, 2 areas of public health importance relate to exposure to youth and to truthful promotion. Although Canada's Cannabis Act specifies many prohibitions related to cannabis promotion, no systematic monitoring or enforcement among licensed firms exists. Compliance with marketing regulations has effects beyond Canadian citizens because of the global outreach of websites and social media. Objectives: To evaluate compliance among licensed firms with the Cannabis Act and analyze trends among violations regarding promotional material. Design, Setting, and Participants: This cross-sectional study evaluated cannabis-licensed firms after cannabis legalization. Data were extracted from online public platforms, including company websites, Facebook, Instagram, and Twitter, from October 1, 2019, to March 31, 2020. Descriptive statistics, Poisson regression, and logistic regression were used to analyze the associations of covariates with promotion violations. Main Outcomes and Measures: The primary outcome was characterization of type and prevalence of promotion violations. Secondary outcomes were the role of various covariates (namely, licensed firm characteristics and online platforms) in the frequency and probability of violations. Hypotheses were formulated before data collection. Results: Among 261 licensed firms, 211 (80.8%) had an online platform, including 204 (96.7%) with websites, 128 (60.7%) with Facebook, 123 (58.3%) with Instagram, and 123 (58.3%) with Twitter. Of all licensed firms with an online platform, 182 (86.3%) had at least 1 violation. Compared with websites, the risk of violations was significantly higher on Facebook (rate ratio [RR], 1.24; 95% CI, 1.11-1.39) and Instagram (RR, 1.19; 95% CI, 1.05-1.34). The most common violations included lack of age restrictions, brand glamorization, and omission of risk information. With websites as the reference group, lack of age restrictions was approximately 15 times more likely to occur on Facebook (odds ratio [OR], 14.76; 95% CI, 8.06-27.05); the odds of an age restriction violation were also higher on Instagram (OR, 2.48; 95% CI, 1.43-4.32) and Twitter (OR, 4.03; 95% CI, 2.29-7.09). For unsubstantiated claims, the odds of violations were significantly decreased on Facebook (OR, 0.23; 95% CI, 0.11-0.48) and Instagram (OR, 0.28; 95% CI, 0.14-0.57). The odds of glamorization were associated with an increase on Instagram (OR, 2.90; 95% CI, 1.72-4.88). Conclusions and Relevance: In this cross-sectional study, widespread violations were observed in online Canadian cannabis promotion. To protect public health and safety amid legalization, decision-makers should make explicit federal regulation and enforcement regarding promotional activities of cannabis retailers. These results suggest that policy and enforcement of cannabis promotion in Canada would have an international impact, from ease of access to online media and downstream consequences of unregulated promotion.

Drug Advertising Violations: A Longitudinal Trend Analysis of FDA Enforcement Letters from 2005 to 2019.

INTRODUCTION: In the United States, all pharmaceutical promotional activities must comply with regulatory standards set by the Food and Drug Administration (FDA); failure to comply may lead to receiving an FDA enforcement letter. Letters include details of the specific advertisement in violation, as well as the action that is required by the company to rectify the non-compliant promotion. OBJECTIVES: The aim of this study was to determine trends in enforcement letters from the FDA to parties responsible for pharmaceutical promotion violations from 2005 to 2019. METHODS: A longitudinal trend analysis was conducted of FDA enforcement letters sent to pharmaceutical companies from 2005 to 2019 (n = 318). Publicly available enforcement letters released by the Office of Prescription Drug Promotion were accessed and analysed online through the Center for Drug Evaluation and Research, a part of the FDA. Variables analysed included number of letters by year, violation categories, venues, intended audience, drug age and company revenues. Publicly available revenue was the major source for company revenue information. RESULTS: The total number of enforcement letters significantly decreased over time. Violations concerning risk information were significantly more prevalent than all other violation categories. Online promotional materials were most frequently cited. Proportionally, larger companies received the majority of letters in earlier years of observation, and smaller companies in later years (2013-2019). CONCLUSIONS: These trends are of value for industry and regulators alike in refining policy to ensure fair, balanced and meaningful information in pharmaceutical promotion. The frequency of violation letters has decreased in recent years; however, smaller companies have increasingly received the majority of letters. Small firms must increase their compliance around informing drug risk potential with balanced safety information across all promotional venues. Specifically, these findings are useful for pharmaceutical companies to direct educational efforts to promotional staff and their advertising agencies, especially regarding online advertising.

Please don't call it medical marijuana unless it is; but it probably isn't.

The drug development process of demonstrating an agent is safe, effective and pure has, with rare exception, proven an exemplary path in translational research. The basic science, the clinical trials and the chemistry, manufacturing and control have served public health well. This carefully regulated approach forms the basis of a drug label with data from these studies also used to convey risk and benefit to prescribing physicians through the channels of medical literature and drug promotion by the industry. The latter is also important to public health in that such promotion must be based in the approved indication, be truthful, not be misleading and be substantiated by sufficient evidence. Why then is the emergence of "medical marijuana" any different? While substantial evidence exists for some conditions and some related products have undergone careful investigation through to NDA approval, most claims are not substantiated by research but driven by misguided enthusiasm. While recreational use of marijuana is not at debate here, nor is the right of an individual patient to explore cannabis therapeutically; however, allowing broad unsubstantiated claims around medicinal cannabis to infiltrate the general public is a disservice. To distill the potential medical benefits through the pharmacologic understanding of the endocannabinoid system, cannabis should follow the traditional drug development process or one that improves upon it. Until then, claims should remain as stated hypothesis to accept or reject.

RéSUMé: Le processus de développement de médicament qui consiste à démontrer l'innocuité, l'efficacité et la pureté d'un agent s'est avéré, à de rares exceptions près, un parcours exemplaire en recherche translationnelle. La science fondamentale, les essais cliniques, la chimie, la fabrication et le contrôle ont bien servi la santé publique. Cette approche étroitement réglementée constitue la base d'une étiquette de médicament, et les données des études servent aussi à communiquer les risques et les avantages aux médecins prescripteurs par la voie des publications médicales et de la promotion des médicaments par l'industrie. Ce dernier aspect a aussi son importance pour la santé publique, car la promotion doit être fondée sur l'indication approuvée, être véridique, ne pas induire en erreur et être justifiée par des preuves suffisantes. Pourquoi donc n'en va-t-il pas de même pour l'émergence de la « marijuana médicale ¼? Il existe des preuves substantielles pour certaines affections, et des produits apparentés ont fait l'objet d'enquêtes approfondies jusqu'à l'approbation de la PNM (présentation de nouveau médicament), mais la plupart des allégations concernant la marijuana médicale sont animées par un enthousiasme malavisé et non pas étayées par la recherche. Il n'est pas question ici de l'usage récréatif de la marijuana, ni du droit d'un patient particulier d'explorer les effets thérapeutiques du cannabis; il est toutefois dommage de permettre l'infiltration dans le grand public d'allégations générales non fondées concernant le cannabis médicinal. Pour distiller les éventuels avantages médicaux par la compréhension pharmacologique du système endocannabinoïde, il faudrait suivre le processus classique de développement de médicament ou une version améliorée. D'ici là, les allégations devraient rester des énoncés d'hypothèses à accepter ou à rejeter.

The natural history of community-acquired common colds symptoms assessed over 4-years.

BACKGROUND: The common cold is the most frequently experienced infection among humans, but limited data exist to characterize the onset, duration, severity and intersection of symptoms in community-acquired colds. A more complete understanding of the symptom frequency and burden in naturally occurring colds is needed. METHODOLOGY: We characterized common cold symptoms from 226 cold episodes experienced by 104 male or female subjects. Subjects were enrolled in the work environment in an attempt to start symptom evaluation (frequency and severity) at the earliest sign of their cold. We also assessed the symptom that had the greatest impact on the subject by asking them to identify their single most bothersome symptom. RESULTS: Symptom reporting started within 24 hours of cold onset for most subjects. Sore throat was a harbinger of the illness but was accompanied by multiple symptoms, including nasal congestion, runny nose and headache. Cough was not usually the most frequent symptom, but was present throughout the cold, becoming most bothersome later in the cold. Nasal congestion, pain (eg, sore throat, headache, muscle pains) or feverishness and secretory symptoms (eg, runny nose, sneezing), and even cough, were simultaneously experienced with high incidence over the first 4 days of illness. The single most bothersome symptom was sore throat on day 1, followed by nasal congestion on days 2-5 and cough on days 6 and 7. CONCLUSION: There is substantial overlap in the appearance of common cold symptoms over the first several days of the common cold. Nasal congestion, secretory and pain symptoms frequently occur together, with cough being somewhat less prominent, but quite bothersome when present. These data establish the typical symptomatology of a common cold and provide a foundation for the rational treatment of cold symptoms typically experienced by cold sufferers.

Airway responses to the inhalation of cotton dust and cotton bract extracts.

BACKGROUND: Exposure to dust in the cotton industry is associated with respiratory dysfunction. Healthy subjects challenged with cotton bract extract (CBE) develop transient airway hyperresponsiveness. CBE, a major component of cotton dust, is potentially an important agent for studying byssinosis. OBJECTIVES: To compare airway responses to cotton dust extract (CDE) and CBE in healthy subjects. METHODS: In 21 healthy, non-smoking subjects we compared the effects of CBE and CDE in a double-blind random order, following a 10-min aerosol inhalation. The response to methacholine (MCh) 2 h following CBE or CDE was measured. Lung function was recorded using maximal (MEFV) and partial expiratory flow volume (PEFV) curves, measuring MEF at 60% of baseline vital capacity below total lung capacity [MEF40%(P)] on the PEFV curve. Responders were subjects who developed a 20% or greater fall in MEF40%(P) following extract challenge. Endotoxin levels were low for CBE (5.71 EU/mg) and CDE (31.88 EU/mg). RESULTS: There were 18 responders to CBE and 17 responders to CDE. The average maximal falls in MEF40%(P) were 70 +/- 4.9 and 70 +/- 4.4% of baseline (nonsignificant) following CBE and CDE, respectively. All subjects enhanced their MCh response following CBE or CDE. The MCh dose which reduced MEF40%(P) by 40% was identical for CBE and CDE (1.3 microg/ml). CONCLUSIONS: We conclude that CBE and CDE exert similar physiologic effects.

Improvement in exercise tolerance with the combination of tiotropium and pulmonary rehabilitation in patients with COPD.

STUDY OBJECTIVES: Pulmonary rehabilitation (PR) improves exercise tolerance in COPD patients. Tiotropium is a once-daily, inhaled anticholinergic bronchodilator that provides sustained 24-h improvements in airflow and lung hyperinflation reduction. We hypothesized that ventilatory mechanics improvements from tiotropium would permit enhanced ability to train muscles of ambulation and therefore augment exercise tolerance benefits of PR. DESIGN: In a randomized, double-blind, placebo-controlled trial (tiotropium, n = 47; placebo, n = 44), tiotropium (18 microg qd) was administered to COPD patients participating in 8 weeks of PR (treadmill training three times a week; >/= 30 min per session) at 17 sites. Study drug was administered 5 weeks prior to, 8 weeks during, and 12 weeks following PR. The primary end point was treadmill walking (0% incline) endurance time at 80% of maximum speed attained in an initial incremental test. The transition dyspnea index (TDI), St. George's respiratory questionnaire (SGRQ), and rescue albuterol use were secondary end points. PARTICIPANTS: Mean age of the 93 participants was 67 years, 57% were men, and mean FEV(1) was 0.88 L (34% predicted). RESULTS: Mean endurance time differences (tiotropium minus placebo) prior to PR, at the end of PR, and 12 weeks after PR were 1.65 min (p = 0.183), 5.35 min (p = 0.025), and 6.60 min (p = 0.018), respectively. Mean TDI focal scores at the end of PR were 1.75 for tiotropium and 0.91 for placebo (p > 0.05). At 12 weeks after PR, TDI focal scores were 1.75 for tiotropium and 0.08 for placebo (p < 0.05). Relative to placebo, tiotropium improved SGRQ total scores by 3.86 at the end of PR and 4.44 at 12 weeks after PR (p > 0.05). Mean albuterol use declined following PR plus tiotropium, compared to PR alone (p

The MCID of the transition dyspnea index is a total score of one unit.

The Baseline (BDI) and Transition (TDI) Dyspnea Indexes provide interview-based measurements of breathlessness related to activities of daily living. The BDI is a discriminative instrument that includes specific criteria for each of three components at a single point in time. The TDI is an evaluative instrument that includes specific criteria for each of three components to measure changes from a baseline state. Observational studies have shown that patients with COPD generally experience a gradual progression of breathing difficulty as measured by the TDI over time. Randomized controlled trials have demonstrated excellent measurement characteristics of the TDI; these include responsiveness (ability to detect change) and construct validity (a change in the TDI correlates with changes in other variables). Supporting evidence for one unit as the minimal clinically important difference (MCID) of the TDI is based on: expert preference; use of the physician's global evaluation score as an anchor; and distribution estimates (standard error of measurement and 0.5 of the standard deviation). As an alternative to the interview process, self-administered computerized (SAC) versions of the BDI/TDI have been developed to provide direct patient-reported ratings of dyspnea. To further establish the MCID of the interview-administered and/or the SAC TDI, we recommend that a patient's report of global ratings of change by used as an independent standard or anchor.

Meaningful effect size and patterns of response of the transition dyspnea index.

Ths object of this study was to examine validity, meaningful effect sizes, and patterns of response of the Transition Dyspnea Index (TDI) in a clinical trial cohort of chronic obstructive pulmonary disease (COPD) patients. The design was a retrospective analysis of data from a randomized, double-blind placebo-controlled clinical trial. We analyzed fifty clinical investigation sites in United States. There were 921 patients with stable COPD. Tiotropium 18 microg dry powder or matching placebo was used. Patients were allowed to remain on usual care less ipratropium bromide. Construct validity was demonstrated by significant correlations (P <.05) between Baseline Dyspnea Index (BDI) and other baseline measures, as well as between TDI and changes in other measures at the end of 1 year. Concurrent validity was observed by the significant correlation between TDI and dyspnea diary responses. Changes in TDI focal score were in the range of one unit when the group was stratified by a minimal change in the physician's global evaluation. Significantly less (P <.05) supplemental albuterol was observed in the group of responders defined by a one-unit improvement in TDI. Responders also had few exacerbations and better health status. The validity of the TDI is supported in a large clinical trial setting. A one-unit change in the TDI focal score represented the minimal important difference.

One-Year Evaluation of the Safety and Efficacy of Ipratropium Bromide HFA and CFC Inhalation Aerosols in Patients with Chronic Obstructive Pulmonary Disease.

INTRODUCTION: Ipratropium bromide (IB) is an established and effective first-line maintenance treatment for patients with chronic obstructive pulmonary disease (COPD). A new IB metered-dose inhaler (MDI) using hydrofluoroalkane 134a propellant (IB HFA) has been developed as an alternative to the MDI containing chlorofluorocarbon (IB CFC). OBJECTIVE: To compare the long-term safety and efficacy of IB HFA and IB CFC in patients with COPD. STUDY DESIGN: This was a randomised, open-label, parallel-group, 1-year, multi-centre trial. Primary endpoints included adverse events (AEs) and vital signs. Secondary endpoints included therapeutic response (>15% increase in forced expiratory volume in 1 second [FEV(1)] peak change from baseline), FEV(1) area under the response-time curve (AUC). PATIENTS AND INTERVENTIONS: Patients (n = 456) with moderate-to-severe COPD, who received either IB HFA (n = 305) or IB CFC (n = 151 ), both 42µg four times daily. RESULTS: There were no significant differences in the incidences of individual AEs between groups over the short and long term; respiratory disorders were the most common. The incidence of anticholinergic AEs possibly related to treatment was low (1.3% IB HFA, 0.7% IB CFC). Serious AEs occurred in 19.0% and 20.5%, and discontinuations due to AEs in 7.2% and 7.3%, of patients receiving IB HFA and IB CFC, respectively. Therapeutic bronchodilatory responses were achieved in 76-81% and 72-84% of patients, and AUC ranged from 0.117-0.148L and 0.117-0.174L, in patients receiving IB HFA and IB CFC, respectively. CONCLUSIONS: IB HFA had similar efficacy and tolerability to IB CFC over 1 year, supporting a seamless transition from the CFC MDI to the HFA MDI in both short- and long-term treatment.

A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol.

BACKGROUND: Tiotropium, a once-daily anticholinergic, and salmeterol represent two inhaled, long-acting bronchodilators from different pharmacologic classes. A trial was designed to examine the efficacy and safety of both compounds with multiple outcome measures, including lung function, dyspnea, and health-related quality of life (HRQoL) in patients with COPD. METHODS: A 6-month, randomized, placebo-controlled, double-blind, double-dummy, parallel-group study of tiotropium, 18 microg once daily via dry-powder inhaler, compared with salmeterol, 50 microg bid via metered-dose inhaler, was conducted in patients with COPD. Efficacy was assessed by 12-h monitoring of spirometry, transition dyspnea index (TDI), and the St. George's Respiratory Questionnaire (SGRQ). RESULTS: A total of 623 patients participated (tiotropium, n= 209; salmeterol, n = 213; and placebo, n = 201). The groups were similar in age (mean, 65 years), gender (75% men), and baseline FEV(1) (mean, 1.08 +/- 0.37 L; percent predicted, 40 +/- 12% [+/- SD]). Compared with placebo treatment, the mean predose morning FEV(1) following 6 months of therapy increased significantly more for the tiotropium group (0.14 L) than the salmeterol group (0.09 L; p < 0.01). The average FEV(1) (0 to 12 h) for tiotropium was statistically superior to salmeterol (difference, 0.08 L; p < 0.001). Tiotropium improved TDI focal score by 1.02 U compared with placebo (p = 0.01), whereas there was no significant change in TDI focal score with salmeterol (0.24 U). Tiotropium was superior to salmeterol in improving TDI focal score (p < 0.05). At 6 months, the mean improvement in SGRQ total score vs baseline was tiotropium, - 5.14 U (p < 0.05 vs placebo); salmeterol, - 3.54 U (p = 0.4 vs placebo); and placebo, - 2.43 U. A statistically higher proportion of patients receiving tiotropium achieved at least a 4-U change in SGRQ score compared to patients receiving placebo. Both active drugs reduced the need for rescue albuterol (p < 0.0001). CONCLUSIONS: Tiotropium once daily produces superior bronchodilation, improvements in dyspnea, and proportion of patients achieving meaningful changes in HRQoL compared to twice-daily salmeterol in patients with COPD.

Expression of ICAM-1 in nasal epithelium and levels of soluble ICAM-1 in nasal lavage fluid during human experimental rhinovirus infection.

Most rhinovirus serotypes use intercellular adhesion molecule-1 (ICAM-1) as the receptor to enter cells, but ICAM-1 expression has not been detected on normal nasal epithelial cells. During experimental rhinovirus infection, expression of ICAM-1 on nasal epithelial cells was examined with immunohistochemical staining of nasal scrape biopsy specimens, and levels of soluble ICAM-1 in nasal lavage fluid were measured by sandwich enzyme-linked immunosorbent assay technique. Expression of ICAM-1 on nasal epithelial cells increased following inoculation in 20 of 23 infected subjects. The median number of ICAM-1-positive cells per 6.25-mm(2) area of stained biopsy specimen was 0 in control samples (day 20 or 33 after inoculation), and in those without infection, 6 on day 1 (P< or =.05), 14.5 on day 3 (P< or =.01), 1.5 on day 5, and 0 on day 9. In a different group of volunteers, soluble ICAM-1 in nasal lavage fluid was higher on days 1 and 3 compared with preinoculation levels (P< or =.001), but only 11 of 23 infected subjects had a 2-fold or greater increase. Up-regulation of ICAM-1 receptor expression on nasal epithelial cells occurred within 24 hours after inoculation in experimental rhinovirus infections (prior to onset of symptoms) and declined promptly by day 5.