Extended-Release Guaifenesin/Pseudoephedrine Hydrochloride for Symptom Relief in Support of a Wait-and-See Approach for the Treatment of Acute Upper Respiratory Tract Infections: A Randomized, Double-Blind, Placebo-Controlled Study.

BACKGROUND: Despite the well-known fact that antibiotics (AB) are not effective against viruses, many patients ask for - and all too often doctors provide - AB for treating URTIs. Over-prescribing of AB is one of the key causes for the development of bacterial resistance, which the U.S. Centers for Disease Control and Prevention (CDC) calls "one of the world's most pressing public health problems". In addition to the CDC initiated "Get Smart About Antibiotics" campaign, focused on educating doctors the public about the importance of appropriate AB use, other programs tackling this problem include the development of new treatment paradigms. Data published at the Oregon Health & Science University demonstrated that a 'wait-and-see' approach, without an AB prescription for the treatment of acute childhood ear infections, was as quick, safe, and effective in resolving the infections as an AB prescription (Spiro DM, Tay KY, Arnold DH, Dziura JD, Baker MD, Shapiro ED. Wait-and-See Prescription for the Treatment of Acute Otitis Media. JAMA 2006; 296:1235-1241). OBJECTIVE: To try and reduce inappropriate prescribing practices, a wait and see or delayed approach requires patients to return for a prescription if their symptoms persist or worsen. The aim of this study was to determine whether treatment with Mucinex D (Reckitt Benckiser LLC, Parsippany, New Jersey) lowers the use of antibiotics in the treatment of URTIs when compared with placebo. METHODS: Patients aged 18 to 75 years with symptoms of acute URTIs were randomized to 1200 mg guaifenesin/120 mg pseudoephedrine hydrochloride extended-release, bilayer tablets or matching placebo for 7 consecutive days. Eligible patients met physician's criteria for antibiotic therapy but were considered suitable for a wait and see approach (withholding antibiotics for ≥48 hours). Patients recorded symptom ratings via an interactive voice response system. RESULTS: One thousand one hundred eighty-nine patients enrolled; data are presented for the modified intent-to-treat population (n = 1179). At Day 8, significantly fewer patients receiving guaifenesin/pseudoephedrine versus placebo desired antibiotics (4.2% vs 8.0%). No adverse effects were reported due to patients not taking antibiotics. Significant reductions in URTI symptoms were observed for extended-release guaifenesin/pseudoephedrine versus placebo, from Day 1 throughout the study; however, the proportion of patients experiencing overall relief at the Day 4 evening assessment (primary end point) did not reach statistical significance. Treatment-related adverse events were reported in 9.8% and 4.7% of patients receiving guaifenesin/pseudoephedrine and placebo, respectively. CONCLUSIONS: The study found that a wait and see approach was associated with decreased antibiotic use. In addition, the use of a guaifenesin pseudoephedrine combination product provided an effective symptom control compared to a placebo and a well-tolerated first-line strategy for the management of URTIs. This study was not designed to assess the effects of guaifenesin or pseudoephedrine individually. Other limitations include the need for better clinical methods to assess the effectiveness of treatments for acute symptoms of patients with URTIs. ClinicalTrials.gov identifier: NCT01202279.

Can Big Data Analyses Help Speed Up the Clinical Development of Mucoactive Drugs for Symptomatic RTIs?

This paper highlights the need for validated models to demonstrate mucoactive drug efficacy in relieving respiratory tract infection (RTI) symptoms and suggests new concepts to further ongoing research. The review is based on the analyses of studies published on mucoactive drug in respiratory diseases, data supporting FDA's expectorant monograph, and related US consumer use and attitude surveys. The changes in the volume and consistency of respiratory mucus during RTIs may result in ciliary dysfunction, mucus accumulation, and symptoms like cough and chest congestion. Mucoactive drugs can provide relief, but limited choices exist in the US, due to the unavailability of validated clinical models and unequivocal efficacy results. Ongoing developments have not provided definitive solutions, and Big Data analysis techniques may help overcome current clinical research limitations by identifying differentiating disease and patient factors to speed up the development process to substantiate the effectiveness of expectorant/mucoactive drugs in relieving RTI symptoms.

Psychometric validation and testing of the 10-item pediatric daily chest-related electronic patient reported outcome (ePRO) diary.

BACKGROUND AND OBJECTIVE: The chest-related electronic patient reported outcome (ePRO) diary was recently developed to assess chest-related symptoms experienced by pediatric and adolescent populations during upper respiratory tract infections (URTI). The objective of this research was the psychometric evaluation of the chest-related ePRO diary in pediatric, adolescent and adult participants. METHODS: This non-interventional, psychometric validation study involved participants (N = 195; n = 42 6-8 years; n = 47 9-11 years; n = 55 12-17 years, n = 51 18+ years) completing the chest-related ePRO diary twice daily for 10 days while experiencing an acute URTI. Preliminary item-level performance and dimensionality results, along with consideration of previous qualitative findings, were used to inform item reduction decisions, the structure of the measure and scoring algorithm development. Subsequent analyses on the finalized measure included assessments of reliability (internal consistency and test-retest reliability), construct validity (convergent validity and known groups validity) and ability to detect change. Comparisons of findings were made between the different age groups as part of the analyses to assess the psychometric properties of the chest-related ePRO diary and to characterize potential differences in the symptom experience of children, adolescents, and adults. RESULTS: The measure demonstrated strong quality of completion and showed relatively similar trajectories of symptom scores over time within different age subgroups and good item response distribution properties. Exploratory factor analysis supported a one-factor solution in the total population and within age subgroups, and test-retest reliability of the measure was strong (Intra-class correlation: 0.843-0.894 between Visit 1 and Day 1). The measure also demonstrated strong construct validity through high correlations with relevant items on the Child Cold Symptom Questionnaire (CCSQ), strong known groups validity (with statistically significant differences between severity groups) and was responsive to change over time with change groups defined based on change on global items. CONCLUSION: The findings demonstrate that the chest-related ePRO diary provides a valid, reliable, responsive measure of chest congestion symptoms experienced with the common cold in pediatric and adolescent populations, and that only minor differences are present in the disease trajectory when comparing adults to younger participants, supporting the use of the measure in interventional studies.

Effects of guaifenesin, N-acetylcysteine, and ambroxol on MUC5AC and mucociliary transport in primary differentiated human tracheal-bronchial cells.

BACKGROUND: Therapeutic intervention in the pathophysiology of airway mucus hypersecretion is clinically important. Several types of drugs are available with different possible modes of action. We examined the effects of guaifenesin (GGE), N-acetylcysteine (NAC) and ambroxol (Amb) on differentiated human airway epithelial cells stimulated with IL-13 to produce additional MUC5AC. METHODS: After IL-13 pre-treatment (3 days), the cultures were treated with GGE, NAC or Amb (10-300 µM) in the continued presence of IL-13. Cellular and secreted MUC5AC, mucociliary transport rates (MTR), mucus rheology at several time points, and the antioxidant capacity of the drugs were assessed. RESULTS: IL-13 increased MUC5AC content (~25%) and secretion (~2-fold) and decreased MTR, but only slightly affected the G' (elastic) or G" (viscous) moduli of the secretions. GGE significantly inhibited MUC5AC secretion and content in the IL-13-treated cells in a concentration-dependent manner (IC50s at 24 hr ~100 and 150 µM, respectively). NAC or Amb were less effective. All drugs increased MTR and decreased G' and G" relative to IL-13 alone. Cell viability was not affected and only NAC exhibited antioxidant capacity. CONCLUSIONS: Thus, GGE effectively reduces cellular content and secretion of MUC5AC, increases MTR, and alters mucus rheology, and may therefore be useful in treating airway mucus hypersecretion and mucostasis in airway diseases.

Development and content validity testing of patient-reported outcome (PRO) items to assess chest congestion associated with the common cold for use in children and adolescents.

BACKGROUND: This article describes qualitative interviews conducted with children (aged 6-11), adolescents (aged 12-17), and adults with the common cold as well as parents/caregivers of the 6-8-year-old children. The aim was to support the refinement and content validity testing of patient-reported outcome (PRO) items assessing chest congestion that could be used as pediatric clinical trial endpoints. Feasibility and acceptability of administering the PRO items electronically on a hand-held touch-screen device were also evaluated. The sample included children aged 6-8 years (n = 14), 9-11 years (n = 13), adolescents aged 12-17 years (n = 12), and adults (n = 10), all of who had current (n = 38) or recent (n = 11) cold. Both concept elicitation (CE) and cognitive debriefing (CD) interviews were conducted with all of these participants, conducted over in two rounds. Ten parents/caregivers of participants aged 6-8 years were also interviewed (separately from their child) regarding how they thought their children would understand the items. The CE interviews explored the qualitative experience of having chest congestion and related symptoms of the common cold. Following their CE interview, participants completed draft items on an electronic patient-reported outcome (ePRO) device twice daily for 2-5 days prior to their CD interview. During the CD interview participants were asked about relevance, understanding and interpretation of the draft PRO items. Qualitative analysis of the interview data and descriptive analyses of the ePRO data were conducted following both rounds of interviews, with modifications to the items implemented following Round 1 and tested in Round 2. RESULTS: Eight symptoms were reported by children during concept elicitation. Findings from the child, adolescent, and adult/parent interviews supported revisions to the items and enabled the selection of the best performing items. The results provided evidence that the final items were well understood by participants and relevant to their experiences of chest congestion as part of a common cold. Findings also provide support for using the same items across age groups. CONCLUSIONS: The results of the CE and CD interviews provide evidence supporting the content validity of new PRO items assessing the experience of chest congestion symptoms associated with common cold experienced by children, adolescents, and adults.

A Multicenter, Randomized, Placebo-Controlled Study of Pseudoephedrine for the Temporary Relief of Nasal Congestion in Children With the Common Cold.

This multicenter, double-blind, placebo-controlled, randomized study was designed to evaluate the efficacy and safety of pseudoephedrine hydrochloride 30-mg tablets in children aged 6 to 11 years for the temporary relief of nasal congestion due to the common cold. The primary efficacy end point was the weighted sum of the change from baseline in instantaneous nasal congestion severity score over the period from 1 to 8 hours following the first dose of study drug on day 1. Safety assessments included adverse events, sleepiness ratings, and vital signs. Pseudoephedrine was superior to placebo in reducing instantaneous nasal congestion severity in pediatric children over the first 8 hours after dosing on day 1 (least squares mean difference between treatment groups was 1.2; P = .029). Overall, secondary end points associated with nasal congestion were supportive on day 1, whereas secondary end points on day 2 were only numerically favorable. Somnolence was reported in a greater percentage of children on pseudoephedrine compared to placebo (71.9% vs 63.9%), while similar percentages of children in the same respective groups reported insomnia (34.4% and 38.9%) and nervousness (20.0% and 23.6%).Pseudoephedrine provides temporary relief of nasal congestion associated with the common cold in children 6 to <12 years of age at the current over-the-counter monograph dose. Multiple dosing of pseudoephedrine for up to 7 days, when given as needed for symptom relief, was generally safe in this population of children with the common cold.

Role of guaifenesin in the management of chronic bronchitis and upper respiratory tract infections.

Guaifenesin, a mucoactive drug, acts by loosening mucus in the airways and making coughs more productive. It is used for relief of wet cough and chest congestion due to the common cold, and remains the only legally marketed expectorant in the US (per OTC Monograph). An ingredient in numerous over-the-counter (OTC) cough/cold medications, guaifenesin has a secondary indication for use in stable chronic bronchitis (professional indication). Clinical pharmacology and patient studies support the clinical utility of guaifenesin in respiratory conditions where mucus hypersecretion is prevalent: acute upper respiratory tract infections (URTIs), stable chronic bronchitis, and possibly rhinosinusitis. Guaifenesin has a well-established and favorable safety and tolerability profile in adult and pediatric populations. Its dosing range (200-400 mg 4-hourly, up to 6× daily) allows flexible dose titration to allow an increase of plasma concentrations. Multiple daily doses are needed to maintain 24-h therapeutic effect with immediate-release formulations. Extended-release guaifenesin tablet formulations are available, providing convenience with 12-hourly dosing and portability compared to liquids. Guaifenesin is considered as a safe and effective expectorant for the treatment of mucus-related symptoms in acute URTIs and stable chronic bronchitis. Its clinical efficacy has been demonstrated most widely in chronic respiratory conditions, where excess mucus production and cough are more stable symptoms. Progress is being made to establish clinical models and measures that are more appropriate for studying symptomatic relief with guaifenesin in acute respiratory infections. This will help generate the up-to-date and high-quality data needed to optimize guaifenesin's effectiveness in established uses, and in new respiratory indications associated with mucus hypersecretion.

Guaifenesin Pharmacokinetics Following Single-Dose Oral Administration in Children Aged 2 to 17 Years.

This study characterized guaifenesin pharmacokinetics in children aged 2 to 17 years (n = 40) who received a single oral dose of guaifenesin (age-based doses of 100-400 mg) 2 hours after breakfast. Plasma samples were obtained before and for 8 hours after dosing and analyzed for guaifenesin using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods, relationships with age were assessed using linear regression, and dose proportionality was assessed on 95% confidence intervals. Based on the upper dose recommended in the monograph (for both children and adolescents), area under the curve from time zero to infinity and maximum plasma concentration both increased with age. However, when comparing the upper dose for children aged 2 to 11 years with the lower dose for adolescents aged 12 to 17 years, similar systemic exposure was observed. As expected due to increasing body size, oral clearance (CLo ) and terminal volume of distribution (Vz /F) increased with age. Due to a larger increase in Vz /F than CLo , an increase in terminal exponential half-life was also observed. Allometric scaling indicated no maturation-related changes in CLo and Vz /F.

Efficacy of topical diclofenac diethylamine gel in osteoarthritis of the knee.

OBJECTIVE: To assess the efficacy and safety of topical diclofenac diethylamine gel, 1.16%, 4 g applied qid for 3 weeks to relieve the symptoms of osteoarthritis (OA) of the knee. METHODS: Patients with OA of the knee washed out their OA medications for at least 5 drug half-lives. Patients with adequately high baseline pain scores were randomized to apply either double-blind active or placebo gel for 3 weeks. Acetaminophen (up to 2 g/day) was supplied as rescue medication. In a diary, patients recorded compliance to dosing and use of rescue medication and assessed daily pain on movement, spontaneous pain, and pain relief. At weekly site visits, patients completed the Western Ontario and McMaster (WOMAC) Osteoarthritis Index Questionnaire, which includes assessment of pain, stiffness, and physical function, and assessed pain intensity "right now." At the final visit, a global assessment of treatment efficacy was completed. RESULTS: Of 238 randomized patients, 237 were included in the intent to treat efficacy analysis. Treatments differed significantly for daily pain on movement at Day 5, and continued on most days through end of study. Peak differences were achieved in the second week. On the primary outcome, average pain on movement over Days 1-14, diclofenac gel was significantly superior to placebo gel. Scores for all 3 WOMAC indices for diclofenac gel treatment were significantly superior to placebo at Weeks 2 and 3. A significant difference was achieved on pain intensity "right now" at all 3 weeks. At the end of the study, patients rated diclofenac gel as significantly more effective in treating the pain of OA of the knee (p = 0.03) compared to placebo. There were no safety issues concerning adverse events or laboratory values. CONCLUSION: Diclofenac gel was effective and safe for relief of symptoms of OA of the knee over 3 weeks of dosing.