Effectiveness of antitussives, anticholinergics or honey versus usual care in adults with uncomplicated acute bronchitis: a study protocol of an open randomised clinical trial in primary care.

INTRODUCTION: Despite the frequent use of therapies in acute bronchitis, the evidence of their benefit is lacking, since only a few clinical trials have been published, with low sample sizes, poor methodological quality and mainly in children. The objective of this study is to compare the effectiveness of three symptomatic therapies (dextromethorphan, ipratropium or honey) associated with usual care and the usual care in adults with acute bronchitis. METHODS AND ANALYSIS: This will be a multicentre, pragmatic, parallel group, open randomised trial. Patients aged 18 or over with uncomplicated acute bronchitis, with cough for less than 3 weeks as the main symptom, scoring ≥4 in either daytime or nocturnal cough on a 7-point Likert scale, will be randomised to one of the following four groups: usual care, dextromethorphan 30 mg three times a day, ipratropium bromide inhaler 20 µg two puffs three times a day or honey 30 mg (a spoonful) three times a day, all taken for up to 14 days. The exclusion criteria will be pneumonia, criteria for hospital admission, pregnancy or lactation, concomitant pulmonary disease, associated significant comorbidity, allergy, intolerance or contraindication to any of the study drugs or admitted to a long-term residence. SAMPLE: 668 patients. The primary outcome will be the number of days with moderate-to-severe cough. All patients will be given a paper-based symptom diary to be self-administered. A second visit will be scheduled at day 2 or 3 for assessing evolution, with two more visits at days 15 and 29 for clinical assessment, evaluation of adverse effects, re-attendance and complications. Patients still with symptoms at day 29 will be called 6 weeks after the baseline visit. ETHICS AND DISSEMINATION: The study has been approved by the Ethical Board of IDIAP Jordi Gol (reference number: AC18/002). The findings of this trial will be disseminated through research conferences and peer-review journals. TRIAL REGISTRATION NUMBER: NCT03738917; Pre-results.

Intravenous magnesium sulphate as an adjuvant therapy in acute exacerbations of chronic obstructive pulmonary disease: a single centre, randomised, double-blinded, parallel group, placebo-controlled trial: a pilot study.

AIM: To investigate the effects on lung function of IV magnesium in acute exacerbations of COPD (AECOPD), when given in conjunction with standard bronchodilator therapy. METHODS: This was a pilot study to a randomised, double-blinded, placebo-controlled trial. 30 patients presenting to ED with AECOPD were included. In addition to standard bronchodilator therapy, 17 patients were given saline, and 13 received 2 g of magnesium sulphate intravenously. Spirometry was carried out at presentation (TA), after initial standard bronchodilator therapy (TB) and immediately (T0), at 60 minutes (T60) and 120 minutes (T120) after trial drug infusion. Primary outcomes were percentage change in FEV1 and FVC at T0, T60 and T120. Secondary outcomes were admission rates, length of stay and requirement for NIV or mechanical ventilation. Trial registration (ANZCTR), ACTRN12613000837729. RESULTS: Greater improvements were seen in FEV1 at T0, T60 and T120 compared to TB in magnesium group (at T120, mean percentage change in FEV1 was 27.07% with magnesium versus 11.39% in the placebo group, 95%CI 3.7 to 27.7, p=0.01). Similar significantly greater improvements were noted with FVC in the magnesium group, compared to TB. CONCLUSIONS: IV magnesium sulphate used as an adjunct therapy to standard bronchodilators in AECOPD presenting to ED may improve lung function in the short term.

Bronchodilation and safety of supratherapeutic doses of salbutamol or ipratropium bromide added to single dose GSK961081 in patients with moderate to severe COPD.

BACKGROUND: There are few data on the bronchodilatory effects of adding short-acting bronchodilators (SABA) to maintenance, long-acting bronchodilator therapy. This study assessed the additional bronchodilation and safety of adding supratherapeutic doses of salbutamol (SALB) or ipratropium bromide (IPR) to the novel bi-functional molecule (or dual pharmacophore) GSK961081 400 µg (MABA 400) or 1200 µg (MABA 1200). METHODS: This randomised, double-blind, complete, crossover study in 44 patients with moderate to severe COPD, evaluated 6 treatments with a washout of at least 7 days between treatments: single doses of MABA 400 or MABA 1200 followed by cumulative doses of either SALB (3× 200 µg at 20 min intervals), IPR (20 µg, 20 µg and 40 µg at 20 min intervals) or placebo (PLA) (three doses at 20 min intervals) at 1 h, 12 h and 24 h post-MABA dose. The primary endpoint was maximal increase in FEV1, from pre-dose bronchodilator (SABA/PLA), measured 15 min after each cumulative dose of SALB, IPR or PLA. Systemic pharmacodynamics (potassium, heart rate, glucose and QTc), adverse events and systemic pharmacokinetics were also assessed. RESULTS: The additional bronchodilatory effects at 12 h and 24 h for both SALB and IPR were of a similar magnitude and statistically significant relative to PLA; mean differences (SE) (L) following MABA 400 dosing: 0.139 (0.023) after SALB at 12 h; 0.123 (0.022) after SALB at 24 h; 0.124 (0.023) after IPR at 12 h; 0.141 (0.021) after IPR at 24 h; and after MABA 1200 dosing: 0.091 (0.023) after SALB at 12 h; 0.126 (0.022) after SALB at 24 h; 0.055 (0.023) after IPR at 12 h; 0.122 (0.022) after IPR at 24 h. Any additional bronchodilator effects at 1 h were small and not clinically significantly different from PLA. There were small, non-clinically significant increases in mean heart rate after both MABA doses plus SALB, and decreased potassium levels in four patients after MABA 1200 plus SALB (×3) or PLA (×1) were observed but overall all treatments were well tolerated and raised no significant safety signals. CONCLUSION: The additional bronchodilation achieved following supratherapeutic doses of SALB and IPR on top of single doses of MABA 400 or 1200 was comparable for the two agents and neither were associated with any clinically relevant systemic pharmacodynamic effects other than the small transient hypokalemic effect in a 3 out of 41 patients receiving additional high dose salbutamol and MABA 1200. Either short-acting bronchodilator could potentially be used as rescue medication on top of MABA therapy.

Onions, myths, beliefs, fashion and reality in asthma.

Some myths and unsupported beliefs about asthma are very popular and enjoy general public acceptance and fairly strong support on the Internet. Onions for cough; dairy products avoidance for asthma; and some other popular myths are reviewed, along with some other medical and mixed (popular and medical) myths comparing their popular and scientific support. Classifying medical statements as realities or unsupported beliefs is a hard and serious work nowadays addressed by Evidence Based Medicine methods, which are not devoid of the influence of medical fashion: the medical community is more prone to accept fashionable statements compared to non-fashionable or old-fashioned statements.

The effects of racemic albuterol versus levalbuterol in very low birth weight infants.

Bronchodilators have been used in premature infants. Levalbuterol (LEV) an R-isomer of Albuterol has fewer hemodynamic side effects than Racemic Albuterol (RAC) in adults and children. In a retrospective study we sought to investigate the effects of LEV (0.31 mg) versus RAC (1.25 mg) in very low-birth weight infants (VLBW) who were treated with a beta-2 agonist for > or =2 weeks. Medical records (between January 2001 and December 2006) were reviewed for patients' demographics, medications use, hemodynamic and respiratory parameters, hypokalemia and hyperglycemia. Among 811 VLBW infants who were admitted to our NICU, 16 infants received RAC and 31 infants received LEV for > or =2 weeks. Infants who received RAC were younger, smaller, and received less Ipratropium Bromide (IB) than infants who received LEV [26.1 +/- 1.2 weeks vs. 28.1 +/- 3.7 weeks (P = 0.01), 817 +/- 211 g vs. 1,127 +/- 589 g (P = 0.01) and 2/16 (12%) vs. 15/31 (48%; P = 0.01); respectively]. In infants treated exclusively with RAC or LEV without IB, mean arterial blood pressures were lower in the RAC (n = 14) than the LEV group (n = 16, P = 0.05 by general linear model with repeated measures); however there were no differences in daily heart rates, oxygen supplementations, oxygen saturations, or respiratory rates. Also there were no differences between the two groups in hypokalemia or hyperglycemia. We conclude that LEV at a dose of 0.31 mg might have an indication in VLBW infants who are at risk for hemodynamic instability.

High-dose continuous nebulized levalbuterol for pediatric status asthmaticus: a randomized trial.

OBJECTIVE: To assess the use of high-dose continuous levalbuterol (LEV), the single active (R)-enantiomer of racemic albuterol (RAC), in the treatment of status asthmaticus. STUDY DESIGN: Children age 6 to 18 years with severe asthma exacerbation were enrolled in this randomized, double-blind trial if they failed initial emergency department (ED) therapy with RAC and systemic steroids. Subjects received equipotent doses of RAC (20 mg/hour) or LEV (10 mg/hour) within a standardized inpatient protocol. Blood samples for measurements of albuterol enantiomer, potassium, and glucose levels were obtained from the first 40 subjects. The median time until discontinuation of continuous therapy was compared using the rank-sum test, and other outcomes were compared using general linear mixed models. RESULTS: A total of 81 subjects (40 in the RAC group and 41 in the LEV group) were enrolled; the 2 groups were similar at baseline. Both groups tolerated continuous therapy with similar changes in heart rate and serum potassium and glucose levels but higher serum (S)-albuterol concentrations in the subjects treated with RAC. The median time for continuous therapy was similar in the RAC and LEV groups (18.3 hours vs 16.0 hours), as were the other clinical measures. CONCLUSIONS: Substituting high-dose continuous LEV for RAC did not reduce the time on continuous therapy and had similar adverse effects in children who had failed initial treatment with RAC.

Seasonal allergic rhinitis: limited effectiveness of treatments.

(1) Seasonal allergic rhinitis, otherwise known as hayfever, is a harmless condition, although it can cause major discomfort and interfere with activities of daily living. We conducted a review of the literature, based on our in-house methodology, to determine the risk-benefits of treatments used in this setting. (2) Placebo-controlled trials show that sodium cromoglicate relieves symptoms, especially if it is used before symptoms appear. Adverse effects are rare with sodium cromoglicate nasal solutions and eye drops. (3) Nasal steroids have well-documented efficacy. Beclometasone is the best choice. Adverse effects include epistaxis, nasal irritation and, occasionally, systemic disorders. (4) Oral antihistamines are less effective than nasal steroids. They also provoke adverse effects, especially drowsiness. Nasal azelastine seems to have a similar efficacy as oral antihistamines. (5) The adverse effects of systemic steroids must not be overlooked, especially with long-term use. Oral administration is an alternative for severe symptoms that do not respond to other treatments, although this is rarely the case. Long-acting intramuscular steroids carry an increased risk of adverse effects. (6) Despite evaluation in several randomised controlled trials, there is no firm evidence that homeopathic preparations have any specific efficacy in allergic rhinitis. (7) Vasoconstrictors, ipratropium and montelukast, have negative risk-benefit balances in hay fever. (8) When a single allergen is responsible (grasses, ragweed, birch), clinical trials suggest that specific desensitisation can provide a modest improvement. However, this treatment carries a risk of local adverse effects, as well as a risk of rare but severe anaphylactic reactions, especially in patients who also have unstable severe asthma. (9) Sublingual desensitisation seems to be even less effective than subcutaneous desensitisation in adults. Follow-up is too short to know whether there is a risk of severe anaphylactic reactions. The results of paediatric studies are even less convincing. (10) In practice, when drug therapy is needed to relieve symptoms of seasonal allergic rhinitis, sodium cromoglicate is the first-line treatment. If a nasal steroid solution is chosen, it should be used for the shortest possible period.

Modelling the 5-year cost effectiveness of tiotropium, salmeterol and ipratropium for the treatment of chronic obstructive pulmonary disease in Spain.

Our objective was to assess the 5-year cost effectiveness of bronchodilator therapy with tiotropium, salmeterol or ipratropium for chronic obstructive pulmonary disease (COPD) from the perspective of the Spanish National Health System (NHS). A probabilistic Markov model was designed wherein patients moved between moderate, severe or very severe COPD and had the risk of exacerbation and death. Probabilities were derived from clinical trials. Spanish healthcare utilisation, costs and utilities were estimated for each COPD and exacerbation state. Outcomes were exacerbations, exacerbation-free months, quality-adjusted life years (QALYs), and cost(-effectiveness). The mean (SE) 5-year number of exacerbations was 3.50 (0.14) for tiotropium, 4.16 (0.40) for salmeterol and 4.71 (0.54) for ipratropium. The mean (SE) number of QALYs was 3.15 (0.08), 3.02 (0.15) and 3.00 (0.20), respectively. Mean (SE) 5-year costs were 6,424 euro (305 euro) for tiotropium, 5,869 euro (505 euro) for salmeterol, and 5,181 euro (682 euro) for ipratropium (2005 values). Ipratropium and tiotropium formed the cost-effectiveness frontier, with tiotropium being preferred when willingness to pay (WTP) exceeded 639 euro per exacerbation-free month and 8,157 euro per QALY. In Spain, tiotropium demonstrated the highest expected net benefit for ratios of the willingness to pay per QALY, well within accepted limits.

[Cost-effectiveness analysis of tiotropium compared to ipratropium and salmeterol]. / Análisis del coste-eficacia del tiotropio frente al ipratropio y salmeterol.

OBJECTIVE: The constant increase in health care costs, in a context of limited resources and the appearance of more costly though more effective drugs, justifies an assessment of the pharmacoeconomics of these drugs. The objective of this study was to evaluate the cost-effectiveness of one of the newest drugs for the treatment of chronic obstructive pulmonary disease (COPD)-tiotropium. MATERIAL AND METHOD: A cost-effectiveness analysis (costs and outcomes) within the framework of the Spanish National Health System was done. The alternatives to tiotropium analyzed were ipratropium and salmeterol. Direct health care costs associated with hospital treatment were calculated. Forced expiratory volume in 1 second, quality of life (with the Saint George's Respiratory Questionnaire), dyspnea transitional index, mean stay in hospital, and exacerbations were the variables used to measure effectiveness. Values for these variables were taken from the main reviews and randomized clinical trials published for tiotropium. RESULTS: For COPD patients, treatment with tiotropium leads to a greater reduction in exacerbations (37% compared to ipratropium and 25% compared to salmeterol 25%), and a reduction in the number of days in hospital (33% compared to ipratropium and 14% compared to salmeterol). Therefore, use of tiotropium could save ;100 000 for the current rates of admission and lengths of hospital stay in Spain. CONCLUSIONS: Tiotropium was more effective than ipratropium and salmeterol as measured by objective clinical variables (forced expiratory volume in 1 second) and subjective ones (the Saint George's Respiratory Questionnaire and dyspnea transitional index). Hospital stays were shorter and exacerbations fewer with tiotropium. In all cases, tiotropium was more cost-effective than the alternatives, thus use of tiotropium could help hospitals to save money.

[Efficacy of a complementary antiinflammatory treatment with erespal in chronic obstructive and nonobstructive bronchitis]. / Effektivnost' dopolnitel'noi protivovospalitel'noi terapii érespalom pri khronicheskom obstruktivnom i neobstruktivnom bronkhite.

AIM: To compare efficacy of atrovent alone and in combination with erespal in patients with chronic bronchitis (CB) and chronic obstructive pulmonary disease (COPD). MATERIAL AND METHODS: Of 80 participants of the trial (51 male and 29 female--63.75 and 36.25%, respectively) who had CB or COPD, 39 patients (28 with CB and 11 with COPD) received 6-month combined treatment with erespal (160 mg/day) and atrovent (160 mcg/day) and 41 patients (32 with CB and 9 with COPD) received atrovent monotherapy in the same dosage. RESULTS: Combined therapy produced positive changes in dyspnea, sputum characteristics and its discharge, cough, monotherapy improved sputum discharge and relieved cough; pulmonary ventilation improved in both groups especially in those on monotherapy. CB patients showed low cytosis, percentage and absolute count of neutrophils, absolute count of lymphocytes and eosinophils in induced sputum. In CB patients percentage of lymphocytes reduced while count of macrophages went up. Combined treatment including erespal also promoted a significant fall of serum and sputum TNFalpha and IL-8 reduction in the sputum. CONCLUSION: Erespal+atrovent treatment proved more effective than atrovent alone. It is recommended for both CB and COPD patients without marked disorders of external respiration function.

An economic assessment of inhaled formoterol dry powder versus ipratropium bromide pressurized metered dose inhaler in the treatment of chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is debilitating and costly to manage. A recent clinical trial concluded that formoterol, a long-acting beta(2)-adrenoceptor agonist, was more clinically effective than inpratropium bromide in the management of COPD. OBJECTIVE: The aim of this study was to perform an economic assessment of the management of COPD with formeterol versus ipratropium bromide. METHODS: Assessment were based on the results of a previously published 12-week, multicenter, double-masked, randomized, parallel-group, placebo-controlled clinical trial comparing inhaled formoterol dry powder 12 and 24 microg BID with ipratropium bromide 40 microg QID pressurized metered dose inhaler and with placebo in 780 COPD patients. Treatment costs for study drugs and rescue medications were estimated from resource utilization and average wholesale prices. Costs were assessed with respect to forced expiratory lung volume in 1 second (FEV(1)) and patient-reported quality of life (QOL) as assessed via the St. George's Respiratory Questionnaire. Cost-effectiveness ratios were calculated for each treatment arm and incremental cost-effectiveness ratios (ICERs) were calculated for each treatment relative to the next best alternative. Economic efficiency frontiers were identified. Sensitivity analysis was conducted. RESULTS: Cost analysis with respect to FEV(1) revealed an economic efficiency frontier formed by placebo, ipratropium bromide 40 microg, and formoterol 12 microg at their respective FEV(1) levels, with cost-effectiveness ratios of $30.18, $53.50, and $142.04, respectively, per FEV(1). The ICER for ipratropium over placebo was $273.03; for formoterol 12 microg over ipratropium, $1611.32. Cost analysis with respect to QOL showed an economic efficiency frontier formed by placebo and formoterol 12 microg at their respective QOL outcomes, with cost-effectiveness ratios of $25.96 and $32.56, respectively, per QOL score change. The cost-effectiveness ratio for ipratropium was $69.40,which was not on the QOL economic efficiency frontier. The ICER for formoterol 12 microg over placebo was $34.51 per QOL score point. CONCLUSIONS: Formoterol 12 microg provided greater QOL outcome than ipratropium bromide at an additional cost of $554.28 per year. Further research would be necessary to assess whether the differences in outcomes, particularly QOL, observed in the short term with formoterol would lead to favorable long-term health and economic outcomes.

Ipratropium bromide plus nebulized albuterol for the treatment of hospitalized children with acute asthma.

OBJECTIVE: To determine whether the addition of repeated doses of nebulized ipratropium bromide (IB) to a standardized inpatient asthma care algorithm (ACA) for children with status asthmaticus improves clinical outcome. STUDY DESIGN: Children with acute asthma (N = 210) age 1 to 18 years admitted to the ACA were assigned to the intervention or placebo group in randomized double-blind fashion. Both groups received nebulized albuterol, systemic corticosteroids, and oxygen according to the ACA. The intervention group received 250 microg IB combined with 2.5 mg albuterol by jet nebulization in a dosing schedule determined by the ACA phase. The placebo group received isotonic saline solution substituted for IB. Progression through each ACA phase occurred based on assessments of oxygenation, air exchange, wheezing, accessory muscle use, and respiratory rate performed at prescribed intervals. RESULTS: No significant differences were observed between treatment groups in hospital length of stay (P =.46), asthma carepath progression (P =.37), requirement for additional therapy, or adverse effects. Children >6 years (N = 70) treated with IB had shorter mean hospital length of stay (P =.03) and more rapid mean asthma carepath progression (P =.02) than children in the placebo group. However, after adjustment was done for baseline group differences, the observed benefit of IB therapy in older children no longer reached statistical significance. CONCLUSION: The routine addition of repeated doses of nebulized IB to a standardized regimen of systemic corticosteroids and frequently administered beta-2 agonists confers no significant enhancement of clinical outcome for the treatment of hospitalized children with status asthmaticus.

Pharmacological studies of allergic cough in the guinea pig.

The pharmacological mechanisms of allergic cough in the guinea pig were studied. Actively sensitized guinea pigs were exposed to aerosols of antigen to elicit coughing. In separate experiments, naive guinea pigs were exposed to aerosols of capsaicin to elicit coughing. Both allergic and capsaicin-induced cough were inhibited by loratadine (0.3-10 mg kg-1 p.o.) and chlorpheniramine (0.1-3.0 mg kg-1 p.o.). Neither cimetidine (10 mg kg-1 s.c.), nor thioperamide (3-10 mg kg-1 s.c.), inhibited allergic or capsaicin-induced cough. Codeine (3-30 mg kg-1 p.o.), salbutamol (0.003-3.0 mg kg-1 s.c.) and ipratropium (0.03-1.0 mg kg-1 s.c.) inhibited both allergic and capsaicin-induced cough. Hexamethonium (10 and 30 mg kg-1 s.c.) inhibited allergic, but not capsaicin-induced cough. Allergic and capsaicin-induced cough were unaffected by phenidone (5.0 and 10.0 mg kg-1 s.c.). Indomethacin (5.0 and 10.0 mg kg-1 s.c.) had no effect on allergic cough but slightly inhibited capsaicin-induced cough. We conclude that allergic and capsaicin-induced cough are modulated by histamine H1 receptor and cholinergic mechanisms. Histamine H2 or histamine H3 receptor mechanisms, and lipoxygenase and cyclooxygenase products of arachidonic acid metabolism do not influence allergic and capsaicin-induced cough. Ganglionic mechanisms play a minor role in the production of allergic cough and no role in capsaicin-induced cough.

The protective effects of ipratropium bromide and terbutaline on distilled water-induced bronchoconstriction.

In a randomized, double-blind, placebo-controlled study, we investigated the protective effects of ipratropium bromide 160 micrograms and 320 micrograms and terbutaline 500 micrograms on ultrasonically nebulized distilled water (UNDW)-induced bronchoconstriction in nine stable asthmatic patients. Both drugs caused a significant increase (P < 0.001) in baseline FEV1 with no significant differences between the drugs or both doses of ipratropium bromide. Pre-inhalation of ipratropium bromide 320 micrograms and terbutaline 500 micrograms inhibited UNDW-induced bronchoconstriction (P < 0.01), whereas ipratropium bromide 160 micrograms had no protective effect. The protective effects of ipratropium bromide showed a large interindividual variation. There was no correlation between the increase in baseline FEV1 and PD20 UNDW, indicating that the protective effect on UNDW-induced bronchoconstriction is not dependent on the bronchodilation induced by terbutaline and ipratropium bromide. It also appears that the UNDW-induced bronchoconstriction is at least partly vagally mediated.

Comparison of preservative-free and preservative-containing ipratropium bromide.

A double-blind crossover study was performed on 33 children with asthma to compare the effectiveness of nebulized solutions of preservative-containing and preservative-free ipratropium bromide. Both solutions produced bronchodilation. No significant differences were found between the two solutions at any time after nebulization in minimum and maximum changes from baseline value or in the areas under the lung function time curves. The presently formulated preservative-containing ipratropium bromide solution was not shown to be inferior to a preservative-free compound.