Why the lower reported prevalence of asthma in patients diagnosed with COVID-19 validates repurposing EDTA solutions to prevent and manage treat COVID-19 disease.

There currently is no specific antiviral drug or a vaccine for SARS-CoV-2/COVID-19 infections; now exceeding 10,300,000 infections worldwide. In the absence of animal models to test drugs, we need to find molecular explanations for any unforeseen peculiarities in clinical data, especially the recent reports describing an unexpected asthma paradox. Asthma is considered a high medical risk factor for susceptibility to SARS-CoV-2/COVID-19 infection, yet asthma is not on the list of top 10 chronic health problems suffered by people who died from SARS-CoV-2/COVID-19. Resolving this paradox requires looking beyond the binary model of a viral receptor-binding domain (RBD) attaching to the ACE-2 receptor. A NCBI pBlast analysis revealed that the SARS-CoV-2 surface spike protein contains key two calcium-dependent fusion domains that are almost identical to those that were recently discovered SARS-CoV-1. These viral calcium-dependent binding domains can facilitate membrane fusion only after cleavage by the host surface protease TMPRSS2. Importantly, TMPRSS2 also requires calcium for its SRCR (scavenger receptor cysteine-rich) domain and itsLDLRA(LDL receptor class A) domain. Thus, the presence of EDTA excipients in nebulized ß2-agonist medicines can disrupt SARS-CoV-2/COVID-19 infection and can explain the asthma paradox. This model validates repurposing EDTA in nebulizer solutions from a passive excipient to an active drug for treating COVID-19 infections. Repurposed EDTA delivery to respiratory tissues at an initial target dose of 2.4 mg per aerosol treatment is readily achievable with standard nebulizer and mechanical ventilator equipment. EDTA warrants further investigation as a potential treatment for SARS-CoV-2/COVID-19 in consideration of the new calcium requirements for virus infection and the regular presence of EDTA excipients in common asthma medications such as Metaproterenol. Finally, the natural history of Coronavirus diseases and further analysis of the fusion loop homologies between the Betacorona SARS-CoV-2 virus and the less pathogenic Alphacorona HC0V-229E virus suggest how to engineer a hybrid virus suitable for an attenuated alpha-beta SARS-CoV-2/COVID-19 vaccine. Thus, replacing SARS-CoV-2 fusion loops (amino acids 816-855) with the less pathogenic HCoV-229E fusion loop (amino acids 923-982) may provide antigenicity of COVID-19, but limit the pathogenicity to the level of HCoV-229E.

Combined inhaled beta-agonist and anticholinergic agents for emergency management in adults with asthma.

BACKGROUND: Inhaled short-acting anticholinergics (SAAC) and short-acting beta2-agonists (SABA) are effective therapies for adult patients with acute asthma who present to the emergency department (ED). It is unclear, however, whether the combination of SAAC and SABA treatment is more effective in reducing hospitalisations compared to treatment with SABA alone. OBJECTIVES: To conduct an up-to-date systematic search and meta-analysis on the effectiveness of combined inhaled therapy (SAAC + SABA agents) vs. SABA alone to reduce hospitalisations in adult patients presenting to the ED with an exacerbation of asthma. SEARCH METHODS: We searched MEDLINE, Embase, CINAHL, SCOPUS, LILACS, ProQuest Dissertations & Theses Global and evidence-based medicine (EBM) databases using controlled vocabulary, natural language terms, and a variety of specific and general terms for inhaled SAAC and SABA drugs. The search spanned from 1946 to July 2015. The Cochrane Airways Group provided search results from the Cochrane Airways Group Register of Trials which was most recently conducted in July 2016. An extensive search of the grey literature was completed to identify any other potentially relevant studies. SELECTION CRITERIA: Included studies were randomised or controlled clinical trials comparing the effectiveness of combined inhaled therapy (SAAC and SABA) to SABA treatment alone to prevent hospitalisations in adults with acute asthma in the emergency department. Two independent review authors assessed studies for inclusion using pre-determined criteria. DATA COLLECTION AND ANALYSIS: For dichotomous outcomes, we calculated individual and pooled statistics as risk ratios (RR) or odds ratios (OR) with 95% confidence intervals (CI) using a random-effects model and reporting heterogeneity (I²). For continuous outcomes, we reported individual trial results using mean differences (MD) and pooled results as weighted mean differences (WMD) or standardised mean differences (SMD) with 95% CIs using a random-effects model. MAIN RESULTS: We included 23 studies that involved a total of 2724 enrolled participants. Most studies were rated at unclear or high risk of bias.Overall, participants receiving combination inhaled therapy were less likely to be hospitalised (RR 0.72, 95% CI 0.59 to 0.87; participants = 2120; studies = 16; I² = 12%; moderate quality of evidence). An estimated 65 fewer patients per 1000 would require hospitalisation after receiving combination therapy (95% 30 to 95), compared to 231 per 1000 patients receiving SABA alone. Although combination inhaled therapy was more effective than SABA treatment alone in reducing hospitalisation in participants with severe asthma exacerbations, this was not found for participants with mild or moderate exacerbations (test for difference between subgroups P = 0.02).Participants receiving combination therapy were more likely to experience improved forced expiratory volume in one second (FEV1) (MD 0.25 L, 95% CI 0.02 to 0.48; participants = 687; studies = 6; I² = 70%; low quality of evidence), peak expiratory flow (PEF) (MD 36.58 L/min, 95% CI 23.07 to 50.09; participants = 1056; studies = 12; I² = 25%; very low quality of evidence), increased percent change in PEF from baseline (MD 24.88, 95% CI 14.83 to 34.93; participants = 551; studies = 7; I² = 23%; moderate quality of evidence), and were less likely to return to the ED for additional care (RR 0.80, 95% CI 0.66 to 0.98; participants = 1180; studies = 5; I² = 0%; moderate quality of evidence) than participants receiving SABA alone.Participants receiving combination inhaled therapy were more likely to experience adverse events than those treated with SABA agents alone (OR 2.03, 95% CI 1.28 to 3.20; participants = 1392; studies = 11; I² = 14%; moderate quality of evidence). Among patients receiving combination therapy, 103 per 1000 were likely to report adverse events (95% 31 to 195 more) compared to 131 per 1000 patients receiving SABA alone. AUTHORS' CONCLUSIONS: Overall, combination inhaled therapy with SAAC and SABA reduced hospitalisation and improved pulmonary function in adults presenting to the ED with acute asthma. In particular, combination inhaled therapy was more effective in preventing hospitalisation in adults with severe asthma exacerbations who are at increased risk of hospitalisation, compared to those with mild-moderate exacerbations, who were at a lower risk to be hospitalised. A single dose of combination therapy and multiple doses both showed reductions in the risk of hospitalisation among adults with acute asthma. However, adults receiving combination therapy were more likely to experience adverse events, such as tremor, agitation, and palpitations, compared to patients receiving SABA alone.

Beta2-adrenoceptor agonists for dysmenorrhoea.

BACKGROUND: Dysmenorrhoea is a common gynaecological complaint that can affect as many as 50% of premenopausal women, 10% of whom suffer severely enough to be rendered incapacitated for one to three days during each menstrual cycle. Primary dysmenorrhoea is where women suffer from menstrual pain but lack any pathology in their pelvic anatomy. Beta2-adrenoceptor agonists have been used in the treatment of women with primary dysmenorrhoea but their effects are unclear. OBJECTIVES: To determine the effectiveness and safety of beta2-adrenoceptor agonists in the treatment of primary dysmenorrhoea. SEARCH METHODS: We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register; CENTRAL (The Cochrane Library 2011, Issue 8); MEDLINE; EMBASE; PsycINFO and the EBM Reviews databases. The last search was on 22 August 2011. SELECTION CRITERIA: Randomised controlled trials comparing beta2-adrenoceptor agonists with placebo or no treatment, each other or any other conventional treatment in women of reproductive age with primary dysmenorrhoea. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted the data. MAIN RESULTS: Five trials involving 187 women with an age range of 15 to 40 years were included. Oral isoxsuprine was compared with placebo in two trials; terbutaline oral spray, ritodrine chloride and oral hydroxyphenyl-orciprenalin were compared with placebo in a further three trials. Clinical diversity in the studies in terms of the interventions being evaluated, assessments at different time points and the use of different assessment tools mitigated against pooling of outcome data across studies in order to provide a summary estimate of effect for any of the comparisons. Only one study, with unclear risk of bias, reported pain relief with a combination of isoxsuprine, acetaminophen and caffeine. None of the other studies reported any significant clinical difference in effectiveness between the intervention and placebo. Adverse effects were reported with all of these medications in up to a quarter of the total number of participants. They included nausea, vomiting, dizziness, quivering, tremor and palpitations. AUTHORS' CONCLUSIONS: The evidence presented in this review was based on a few relatively small-sized studies that were categorised to have unclear to high risk of bias, which does not allow confident decision-making at present about the use of beta2-adrenoceptor agonists for dysmenorrhoea. The benefits as reported in one study should be balanced against the wide array of unacceptable side effects documented with this class of medication. We have emphasised the lack of precision and limitations in the reported data where appropriate.

Cromoglycate, reproterol, or both--what's best for exercise-induced asthma?

OBJECTIVE: International guidelines recommend short- (SABA) or long-acting b-agonists for the prevention of bronchoconstriction after exercise (EIB) in patients with exercise-induced asthma (EIA). However, other drugs are still in discussion for the prevention of EIB. We investigated the efficacy of a combination of inhaled sodium cromoglycate and the ß-mimetic drug reproterol versus inhaled reproterol alone and both versus inhaled placebo in subjects with exercise-induced asthma (EIA). METHODS: The study aimed to prove the preventive effect of a combination of 1-mg reproterol and 2-mg disodium cromoglycate (DSCG) and its single components vs. placebo, measuring the decrease of FEV1 after a standardized treadmill test in 11 patients with recorded EIA. The study medication was twice as high as those of drugs which are commercially available (e.g., Allergospasmin®, Aarane®). RESULTS: The results revealed that the combination of reproterol and DSCG was significantly effective against a decrease of FEV1 after a standardized exercise challenge test (ECT) compared to placebo. The short-acting b-agonist reproterol alone had almost the same effectiveness as the combination of reproterol and DNCG. The difference between the combination with DNCG and reproterol alone was less than 10% and insignificant (p 0.48). DNCG alone did not show a difference in the effectiveness compared to placebo. CONCLUSION: Prevention of EIA with the combination of reproterol and DSCG or with reproterol only is effective. An exclusive recommendation in favor of the combination cannot be given due to the low difference in the effectiveness versus reproterol alone. Due to the limited number of subjects and some probands showing protection under DSCG, it cannot be completely excluded that there is some preventive power of DSCG in individual cases.

Use of ozone-depleting substances; removal of essential-use designation (flunisolide, etc.). Final rule.

The Food and Drug Administration (FDA), after consultation with the Environmental Protection Agency (EPA), is amending FDA's regulation on the use of ozone-depleting substances (ODSs) in self-pressurized containers to remove the essential-use designations for flunisolide, triamcinolone, metaproterenol, pirbuterol, albuterol and ipratropium in combination, cromolyn, and nedocromil used in oral pressurized metered-dose inhalers (MDIs). The Clean Air Act requires FDA, in consultation with the EPA, to determine whether an FDA-regulated product that releases an ODS is an essential use of the ODS. FDA has concluded that there are no substantial technical barriers to formulating flunisolide, triamcinolone, metaproterenol, pirbuterol, albuterol and ipratropium in combination, cromolyn, and nedocromil as products that do not release ODSs, and therefore they will no longer be essential uses of ODSs as of the effective dates of this rule. MDIs for these active moieties containing an ODS may not be marketed after the relevant effective date.

Electrical storm in Brugada syndrome successfully treated with orciprenaline; effect of low-dose quinidine on the electrocardiogram.

We report a case of an electrical storm occurring in a patient implanted with a cardioverter defibrillator for symptomatic Brugada syndrome. Recurrent ventricular fibrillation was initiated by short-coupled premature ventricular beats of right ventricular origin, associated with a fixed Brugada type 2 electrocardiographic pattern. Low-dose orciprenaline application as an intravenous bolus followed by an infusion inhibited the recurrence of ventricular fibrillation and normalized the electrocardiographic pattern. Low-dose oral quinidine had only a moderate effect on the ST-elevation.

Prevention of exercise-induced asthma by a fixed combination of disodium cromoglycate plus reproterol compared with montelukast in young patients.

BACKGROUND: The leukotriene inhibitor montelukast has been recommended against exercise-induced asthma (EIA), however, single-dose agents might be favourable in several aspects. OBJECTIVE: To compare the protective effects against EIA of a single inhalation of the combination disodium cromoglycate (DSCG, CAS 16110-51-3) and reproterol (REP, CAS 54063-54-6) with 3 days oral treatment of montelukast (MON, CAS 158966-92-8). METHODS: Open-label, cross-over, single-centre trial. Twenty-four 6 to 18-year-old children and adolescents, with reversible and stable airway obstruction, baseline FEV1 > or = 70%, predicted and proven EIA (i.e. a maximum decrease of FEV1 by > or = 20% compared with baseline) were treated with MON, orally for 3 days in the evening, or one single inhalation of DSCG/REP 20 min before the exercise challenge. The treatment sequence was randomised. The exercise test on a treadmill was performed under standardised conditions. RESULTS: 24 patients completed both periods. Both treatments clearly provided protection against EIA; however, protection of DSCG/REP was more pronounced than that of MON. This difference was statistically significant even if the data were adjusted for the increase in FEV1 between inhalation of DSCG/REP and challenge (DSCG/REP(adjusted). The nadir FEV1 level after exercise following prophylaxis with DSCG/REP was even higher than the pre-inhalation FEV1 value. From these data, protection indices of 66%, 81%, and 113% for MON, DSCG/REP(adjusted), and DSCG/REP(unadjusted), respectively, were estimated. CONCLUSIONS: Inhalation of DSCG/REP before exercise provides significantly better protection against EIA than three days treatment with MON.

Effect of reproterol either alone or combined with disodium cromoglycate on airway responsiveness to methacholine.

Regular use of inhaled beta2-agonists might lead to tolerance as reflected in a loss of bronchoprotection. In vitro-data suggest that this might be prevented by disodium cromoglycate (DSCG). Therefore, we studied the effect of the beta2-agonist reproterol in combination with DSCG. In a cross-over design, 19 subjects with airway hyperresponsiveness inhaled either placebo, 1mg reproterol, 2 mg DSCG, or 1mg reproterol plus 2 mg DSCG 4x daily over 2 weeks. Treatment periods were separated by > or = 7 days. Before and at the end of periods, lung function and methacholine responsiveness were determined in the morning, and 6h later the bronchodilator effect and the protection against methacholine-induced bronchoconstriction. Reproterol or DSCG or their combination did not exert detrimental effects on lung function, airway responsiveness, or bronchodilator capacity. However, bronchoprotection was significantly reduced (p < 0.05) after treatment with placebo, reproterol or reproterol plus DSCG, the respective changes being 0.59, 0.96 and 1.37 doubling concentrations. All changes were small as compared to intraindividual variability. In this model all treatments except with DSCG caused a significant but small loss of protection against methacholine-induced bronchoconstriction. Thus, tolerance was not prevented by 2 weeks of additional treatment with DSCG, in contrast to in vitro findings.

Effects of a beta2-agonist on airway hyperreactivity in subjects with cervical spinal cord injury.

STUDY OBJECTIVE: Aerosolized ipratropium bromide or orally administered baclofen or oxybutynin chloride (Ditropan) block methacholine-associated airway hyperreactivity in subjects with chronic cervical spinal cord injury (SCI), whereas these agents do not inhibit airway hyperreactivity associated with the inhalation of histamine. The present study was performed to determine whether pretreatment with a beta2-agonist attenuates airway hyperresponsiveness in these subjects. PARTICIPANTS: Subjects with chronic cervical SCI previously demonstrating airway hyperreactivity were challenged with methacholine (n = 9) or histamine (n = 16) alone and, on a separate day, 25 min following inhalation of nebulized metaproterenol sulfate. RESULTS: Inhalation of the beta2-agonist was associated with an increase in provocative concentration causing a 20% decrease in FEV1 (PC20) values (geometric mean) from 1.01+/-2.76 to 20.54+/-6.24 mg/mL for methacholine and from 2.29+/-2.26 to 19.82+/-5.93 mg/mL for histamine. No correlation was found between specific PC20 values for individual subjects and percentage improvement in FEV1 (liter) following inhalation of metaproterenol sulfate and between PC20 values and baseline FEV1 percent. CONCLUSION: These data, combined with findings that patients with chronic high cervical SCI experience increased breathlessness following exposure to exogenous agents, suggest that long-term prophylactic beta2-agonist therapy may reduce respiratory symptoms associated with airway hyperreactivity in these patients.

Comparative effects of a fixed combination of reproterol hydrochloride and disodium cromoglycate with each agent alone on antigen-induced airway responses in sheep.

The purpose of this study was to compare the effectiveness of an eight day treatment with clinically relevant doses of a fixed combination of the beta 2 mimetic reproterol hydrochloride and disodium cromoglycate with each agent given alone against antigen-induced early (EAR) and late airway responses (LAR) as well as post-antigen-induced airway hyperresponsiveness (AHR) in allergic sheep. Animals were treated in a randomized fashion with either the inhaled combination (n = 6), reproterol hydrochloride alone (n = 6), disodium cromoglycate alone (n = 6), or placebo (n = 8). Treatments (two puffs from a metered dose inhaler) were given three times a day for 7 days and once on the 8th day 1 h before airway challenge with Ascaris suum antigen. In the placebo trial, antigen challenge resulted in EAR and LAR as measured by increases in specific lung resistance; these changes were followed 24h later by AHR to inhaled carbachol. With respect to the placebo trial, treatment with reproterol hydrochloride reduced the EAR (P < 0.05) and blocked the LAR (P < 0.05), but had no effect on the post-challenge AHR. Treatment with disodium cromoglycate also reduced the EAR (P < 0.05), blocked the LAR (P < 0.05), and blocked the post-antigen-induced AHR (P < 0.05). Treatment with the fixed combination reduced the EAR (P < 0.05), blocked the LAR (P < 0.05), and blocked the post-antigen-induced AHR (P < 0.05). Comparison of the different agents indicated that the fixed combination gave significantly increased protection against the EAR than either agent alone, gave slightly better (P < 0.05) protection against the late response than cromolyn sodium and gave better protection against post-antigen-induced AHR than reproterol hydrochloride alone. These results suggest that a fixed combination of a beta 2-mimetic and disodium cromoglycate provides some increased protection against antigen-induced airway responses when compared to either agent alone in a controlled laboratory setting.

Formic acid inhalation injury: a case report.

We report a case in which a patient sustained an inhalation injury as a result of aerosolized formic acid. The patient sustained a partial-thickness burn to the face from a chemical spray; however, as a result of aerosolization, he also inhaled formic acid. This resulted in a reversible pulmonary chemical injury. Inhalation of formic acid results in a reactive airway dysfunction syndrome--a common response to inhalation of an occupational irritant.

Comparison of nebulized glycopyrrolate and metaproterenol in chronic obstructive pulmonary disease.

We assessed the bronchodilating effect of glycopyrrolate (GP) and compared it with that of metaproterenol (MP), alone and in combination (GP+MP), in patients with chronic obstructive pulmonary disease (COPD). In a double-blind study, 11 patients (aged (mean +/- SD) 69 +/- 6 yrs; forced expiratory volume in one second (FEV1) 1.2 +/- 0.4 L) with stable COPD inhaled nebulized GP 1.0 mg, MP 15 mg, or GP 1.0 mg+MP 15 mg. Spirometry was performed before inhalation and at hourly intervals for 8 h after inhalation. It was found that GP produced a bronchodilating effect that was about equal to that of MP but lasted longer (8 vs 5 h). The combination of GP and MP produced a bronchodilating effect that was greater than that of either drug alone and was evident mostly during the effect of MP. The mean peak percentage improvement in FEV1 over baseline was 35% for GP+MP and 25% for either drug alone. These data suggest that nebulized glycopyrrolate is an effective bronchodilator in some patients with chronic obstructive pulmonary disease. Concurrent administration of glycopyrrolate and metaproterenol produces additional bronchodilation that is primarily apparent during the bronchodilator effect of metaproterenol.

A multicenter study of nebulized bronchodilator solutions in chronic obstructive pulmonary disease.

A multicenter, 85-day, double-blind, randomized study was conducted to compare the effects of a single-dose and chronic inhalation of ipratropium bromide solution (500 micrograms) to the beta-adrenergic agonist metaproterenol (5% solution, 15 mg) in patients with chronic obstructive pulmonary disease (COPD). Patients were required to have a relatively stable, moderately severe COPD, forced expiratory volume in 1 second (FEV1) < 65% of predicted normal, FEV1 <70% of forced vital capacity (FVC), and a smoking history of > 10 pack-years. Following a 2-week baseline period, patients were randomized into either the ipratropium bromide (106 patients) or metaproterenol (107 patients) study groups. Pulmonary function testing was performed on days 1, 43, and 85. Secondary efficacy variables examined included peak expiratory flow rates, physician's global evaluation, quality of life, COPD symptom score, and use of concomitant medications. FEV1 was comparable between the two groups on day 1 (1.00 and 1.02 liters, ipratropium bromide vs metaproterenol, respectively; p = nonsignificant). The baseline FEV1 increased significantly in the ipratropium bromide group between day 1 and 43 by 10% (from 1.00 to 1.10 liters, p < 0.002) and remained 7% elevated on day 85 (1.07 liters) compared to day 1 (p < 0.02); it did not change in the metaproterenol group across all three test days. A clinically significant (> 15%) mean FEV1 response was observed on each of the 3 test days following drug inhalation in both treatment groups. The median duration of action was similar between groups (5 hours) on test day 1, but on day 85 the median duration for ipratropium bromide was r.5 hours compared to 3.0 hours for metaproterenol (p < 0.04). The secondary efficacy variables were uniformly better in the ipratropium bromide than the metaproterenol group. Side effects were infrequent and generally mild in both groups. These data suggest that the availability of a high-dose ipratropium bromide solution offers a safe and effective means of producing prolonged bronchodilation in patients with COPD.

Results of a multicenter study of nebulized inhalant bronchodilator solutions.

The efficacy, persistence of bronchodilator action, and safety of the quaternary ammonium anticholinergic agent, ipratropium bromide (500 microgram), and placebo were compared when each was added in solution form to the beta-adrenergic agonist solution, metaproterenol sulfate (15 mg), and administered three times daily for 12 weeks to a total of 213 patients with chronic obstructive pulmonary disease (COPD). Subjects had a mean forced expiratory volume in 1 second (FEV1) of approximately 1 liter (37% of predicted) and were permitted to use nonanticholinergic therapy for COPD throughout the trial. The study was a randomized, double-blind, 85-day, parallel-group, eight-center study. On a 3 test days, 1, 43, and 85, mean peak responses for FEV1 and forced vital capacity and mean area under the curve were significantly higher for the iprathropium bromide-metaproterenol combination than for metaproterenol only. Duration of action was also significantly longer for the combination therapy than for the beta-agonist alone on test days 1 and 43. Neither treatment regimen produced an demonstrable effect on daily morning peak expiratory flow rates, reported respiratory symptoms, or quality of life. Both treatment regimens were similarly well tolerated with a comparable frequency of adverse events. These results suggest that the combination of iprathropium bromide and metaproterenol inhalation solutions offers a potential therapeutic advantage to patients with symptomatic COPD over nebulized metaproterenol alone without the risk of increased side effects.