[Combination therapy at an early stage of the novel coronavirus infection (COVID-19). Case series and design of the clinical trial "BromhexIne and Spironolactone for CoronаvirUs Infection requiring hospiTalization (BISCUIT)"].

The article focuses on effective treatment of the novel coronavirus infection (COVID-19) at early stages and substantiates the requirement for antiviral therapy and for decreasing the viral load to prevent the infection progression. The absence of a specific antiviral therapy for the SARS-CoV-2 virus is stated. The authors analyzed results of early randomized studies using lopinavir/ritonavir, remdesivir, and favipiravir in COVID-19 and their potential for the treatment of novel coronavirus infection. Among the drugs blocking the virus entry into cells, the greatest attention was paid to the antimalaria drugs, chloroquine and hydroxychloroquine. The article addresses in detail ineffectiveness and potential danger of hydroxychloroquine, which demonstrated neither a decrease in the time of clinical recovery nor any improvement of prognosis for patients with COVID-19. The major objective was substantiating a possible use of bromhexine, a mucolytic and anticough drug, which can inhibit transmembrane serin protease 2 required for entry of the SARS-CoV-2 virus into cells. Spironolactone may have a similar feature. Due to its antiandrogenic effects, spironolactone can inhibit X-chromosome-related synthesis of ACE-2 receptors and activation of transmembrane serin protease 2. In addition to slowing the virus entry into cells, spironolactone decreases severity of fibrosis in different organs, including the lungs. The major part of the article addresses clinical examples of managing patients with COVID-19 at the University Clinic of the Medical Research and Educational Centre of the M. V. Lomonosov Moscow State University, including successful treatment with schemes containing bromhexine and spironolactone. In conclusion, the authors described the design of a randomized, prospective BISCUIT study performed at the University Clinic of the M. V. Lomonosov Moscow State University with an objective of evaluating the efficacy of this scheme.

Mucolytics for bronchiectasis.

BACKGROUND: Bronchiectasis is predominantly an acquired disease process that represents the end stage of a variety of unrelated pulmonary insults. It is defined as persistent irreversible dilatation and distortion of medium-sized bronchi. It has been suggested that with widespread use of high-resolution computed tomography, more bronchiectasis diagnoses are being made. Patients diagnosed with bronchiectasis frequently have difficulty expectorating sputum. Sputum therefore is retained in the lungs and may become infected, leading to further lung damage. Mucolytic agents target hypersecretion or changed physiochemical properties of sputum to make it easier to clear. One drug, recombinant human DNase, breaks down the DNA that is released at the site of infection by neutrophils.Mucus clearance along with antimicrobial therapy remains an integral part of bronchiectasis management. Chest physiotherapy along with mucolytic agents is commonly used in practice without clear supportive evidence. OBJECTIVES: To determine whether ingested or inhaled mucolytics are effective in the treatment of patients with bronchiectasis. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register and reference lists of relevant articles. We contacted experts in the field and drug companies. Searches were current as of June 2013. SELECTION CRITERIA: Randomised trials of mucolytic treatment in people with bronchiectasis but not cystic fibrosis. DATA COLLECTION AND ANALYSIS: Data extraction was performed independently by two review authors. Study authors were contacted for confirmation. MAIN RESULTS: Four trials (with a combined total of 528 adult participants) were included, but almost none of the data from these studies could be aggregated in a meta-analysis.One trial (with 88 participants) compared bromhexine versus placebo. Compared with placebo, high doses of bromhexine with antibiotics eased difficulty in expectoration (mean difference (MD) -0.53, 95% confidence interval (CI) -0.81 to -0.25 at 16 days); the quality of the evidence was rated as low. A reduction in sputum production was noted with bromhexine (MD -21.5%, 95% CI -38.9 to -4.1 at day 16); again the quality of the evidence was rated as low. No significant differences between bromhexine and placebo were observed with respect to reported adverse events (odds ratio (OR) 2.93; 95% CI 0.12 to 73.97), and again the quality of the evidence was rated as low.In a single small, blinded but not placebo-controlled trial of older (> 55 years) participants with stable bronchiectasis and mucus hypersecretion, erdosteine combined with physiotherapy over a 15-day period improved spirometry and sputum purulence more effectively compared with physiotherapy alone. The spirometric improvement was small (MD 200 mL in forced expiratory volume in one second (FEV1) and 300 mL in forced vital capacity (FVC)) and was apparent only at day 15, not at earlier time points.The remaining two studies (with a combined total of 410 participants) compared recombinant human DNase (RhDNase) versus placebo. These two studies were very different (one was a two-week study of 61 participants, and the other ran for 24 weeks and included 349 participants), and the opportunity for combining data from the two studies was very limited. Compared with placebo, recombinant human DNase showed no difference in FEV1 or FVC in the smaller study but showed a significant negative effect on FEV1 in the larger and longer study. For reported adverse events, no significant differences between recombinant human DNase and placebo were noted. In all of the above comparisons of recombinant human DNase versus placebo, the quality of the evidence was judged to be low. AUTHORS' CONCLUSIONS: Given the harmful effects of recombinant human DNase in one trial and no evidence of benefit, this drug should be avoided in non-cystic fibrosis bronchiectasis, except in the context of clinical trials. Evidence is insufficient to permit evaluation of the routine use of other mucolytics for bronchiectasis. High doses of bromhexine coupled with antibiotics may help with sputum production and clearance, but long-term data and robust clinical outcomes are lacking. Similarly, erdosteine may be a useful adjunct to physiotherapy in stable patients with mucus hypersecretion, but robust longer-term trials are required.Generally, clinical trials in children on the use of various mucolytic agents are lacking. As the number of agents available on the market, such as RhDNase, acetylcysteine and bromhexine, is increasing, improvement of the evidence base is needed.

Effect of bromhexine in hospitalized patients with COVID-19.

BACKGROUND: Bromhexine is a potent inhibitor of transmembrane serine protease 2 and appears to have an antiviral effect in controlling influenza and parainfluenza infection; however, its efficacy in COVID-19 is controversial. METHODS: A group of hospitalized patients with confirmed COVID-19 pneumonia were randomized using 1:1 allocation to either standard treatment lopinavir/ritonavir and interferon beta-1a or bromhexine 8 mg four times a day in addition to standard therapy. The primary outcome was clinical improvement within 28 days, and the secondary outcome measures were time to hospital discharge, all-cause mortality, duration of mechanical ventilation, the temporal trend in 2019-nCoV reverse transcription-polymerase chain reaction positivity and the frequency of adverse drug events within 28 days from the start of medication. RESULTS: A total of 111 patients were enrolled in this randomized clinical trial and data from 100 patients (48 patients in the treatment arm and 52 patients in the control arm) were analyzed. There was no significant difference in the primary outcome of this study, which was clinical improvement. There was no significant difference in the average time to hospital discharge between the two arms. There were also no differences observed in the mean intensive care unit stay, frequency of intermittent mandatory ventilation, duration of supplemental oxygenation or risk of death by day 28 noted between the two arms. CONCLUSION: Bromhexine is not an effective treatment for hospitalized patients with COVID-19. The potential prevention benefits of bromhexine in asymptomatic postexposure or with mild infection managed in the community remain to be determined.

[Use of the mucoregulator ascoril for respiratory diseases].

The paper deals with the use of the combined mucoregulatory drug ascoril in pulmonological care. Due to its multicomponent composition, the drug has mucoregulatory properties that combine a bronchodilator effect and an ability to dilute sputum and to synthesize the surfactant. The mechanism of action of each ascoril component is analyzed; the results of basic experimental and clinical studies on the use of the drug are given. A wide range of indications, such as respiratory system diseases, for ascoril use is demonstrated.

[Treatment of mild exacerbations of chronic obstructive pulmonary disease].

The aim of the study was to compare clinical efficacy of two variants of broncho- and mucolytic therapy for patients with mild or moderately severe chronic obstructive pulmonary disease (COPD). It included 49 patients in the phase of exacerbation divided into 2 groups. Group 1 (n = 25) received ascoril (10 ml tid), group 2 salbutamol (200 mcg two inhalations tid) plus bromhexin (8 mg tid) for 10 days. The efficacy of therapy was estimated from dynamics of clinical symptoms (cough, spiting patterns, PEFmorn/REV1, number of inhalations). Therapy decreased the intensity and frequency of daytime and especially night-time coughing. The effect of ascoril on these symptoms was more pronounced than that of two other drugs that practically did not reduce expectoration. PEFmorn/REV1 in group 1 significantly increased 80% of the patients in this group ceased using salbutamol "on demand" whereas all patients of group 2 continued to inhale it once or twice daily. It is concluded that ascoril is most efficacious and safe for the treatment of mild or moderately severe COPD and elimination of its exacerbation. The early prescription of this therapy permits to avoid hospitalization and expensive therapy.

Interventions for treatment of COVID-19: Second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project).

BACKGROUND: COVID-19 is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19 are urgently needed. This is the second edition of a living systematic review of randomized clinical trials assessing the effects of all treatment interventions for participants in all age groups with COVID-19. METHODS AND FINDINGS: We planned to conduct aggregate data meta-analyses, trial sequential analyses, network meta-analysis, and individual patient data meta-analyses. Our systematic review was based on PRISMA and Cochrane guidelines, and our eight-step procedure for better validation of clinical significance of meta-analysis results. We performed both fixed-effect and random-effects meta-analyses. Primary outcomes were all-cause mortality and serious adverse events. Secondary outcomes were admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and non-serious adverse events. According to the number of outcome comparisons, we adjusted our threshold for significance to p = 0.033. We used GRADE to assess the certainty of evidence. We searched relevant databases and websites for published and unpublished trials until November 2, 2020. Two reviewers independently extracted data and assessed trial methodology. We included 82 randomized clinical trials enrolling a total of 40,249 participants. 81 out of 82 trials were at overall high risk of bias. Meta-analyses showed no evidence of a difference between corticosteroids versus control on all-cause mortality (risk ratio [RR] 0.89; 95% confidence interval [CI] 0.79 to 1.00; p = 0.05; I2 = 23.1%; eight trials; very low certainty), on serious adverse events (RR 0.89; 95% CI 0.80 to 0.99; p = 0.04; I2 = 39.1%; eight trials; very low certainty), and on mechanical ventilation (RR 0.86; 95% CI 0.55 to 1.33; p = 0.49; I2 = 55.3%; two trials; very low certainty). The fixed-effect meta-analyses showed indications of beneficial effects. Trial sequential analyses showed that the required information size for all three analyses was not reached. Meta-analysis (RR 0.93; 95% CI 0.82 to 1.07; p = 0.31; I2 = 0%; four trials; moderate certainty) and trial sequential analysis (boundary for futility crossed) showed that we could reject that remdesivir versus control reduced the risk of death by 20%. Meta-analysis (RR 0.82; 95% CI 0.68 to 1.00; p = 0.05; I2 = 38.9%; four trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of difference between remdesivir versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of remdesivir on serious adverse events. Meta-analysis (RR 0.40; 95% CI 0.19 to 0.87; p = 0.02; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of intravenous immunoglobulin versus control on all-cause mortality, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analysis (RR 0.63; 95% CI 0.35 to 1.14; p = 0.12; I2 = 77.4%; five trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of a difference between tocilizumab versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of tocilizumab on serious adverse events. Meta-analysis (RR 0.70; 95% CI 0.51 to 0.96; p = 0.02; I2 = 0%; three trials; very low certainty) showed evidence of a beneficial effect of tocilizumab versus control on mechanical ventilation, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm of reject realistic intervention effects. Meta-analysis (RR 0.32; 95% CI 0.15 to 0.69; p < 0.00; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of bromhexine versus standard care on non-serious adverse events, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that hydroxychloroquine versus control reduced the risk of death and serious adverse events by 20%. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that lopinavir-ritonavir versus control reduced the risk of death, serious adverse events, and mechanical ventilation by 20%. All remaining outcome comparisons showed that we did not have enough information to confirm or reject realistic intervention effects. Nine single trials showed statistically significant results on our outcomes, but were underpowered to confirm or reject realistic intervention effects. Due to lack of data, it was not relevant to perform network meta-analysis or possible to perform individual patient data meta-analyses. CONCLUSIONS: No evidence-based treatment for COVID-19 currently exists. Very low certainty evidence indicates that corticosteroids might reduce the risk of death, serious adverse events, and mechanical ventilation; that remdesivir might reduce the risk of serious adverse events; that intravenous immunoglobin might reduce the risk of death and serious adverse events; that tocilizumab might reduce the risk of serious adverse events and mechanical ventilation; and that bromhexine might reduce the risk of non-serious adverse events. More trials with low risks of bias and random errors are urgently needed. This review will continuously inform best practice in treatment and clinical research of COVID-19. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020178787.

Bromhexine Hydrochloride Tablets for the Treatment of Moderate COVID-19: An Open-Label Randomized Controlled Pilot Study.

This open-label randomized controlled pilot study aimed to test the study feasibility of bromhexine hydrochloride (BRH) tablets for the treatment of mild or moderate coronavirus disease 2019 (COVID-19) and to explore its clinical efficacy and safety. Patients with mild or moderate COVID-19 were randomly divided into the BRH group or the control group at a 2:1 ratio. Routine treatment according to China's Novel Coronavirus Pneumonia Diagnosis and Treatment Plan was performed in both groups, whereas patients in the BRH group were additionally given oral BRH (32 mg t.i.d.) for 14 consecutive days. The efficacy and safety of BRH were evaluated. A total of 18 patients with moderate COVID-19 were randomized into the BRH group (n = 12) or the control group (n = 6). There were suggestions of BRH advantage over placebo in improved chest computed tomography, need for oxygen therapy, and discharge rate within 20 days. However, none of these findings were statistically significant. BRH tablets may potentially have a beneficial effect in patients with COVID-19, especially for those with lung or hepatic injury. A further definitive large-scale clinical trial is feasible and necessary.

Pulmonary surfactant itself must be a strong defender against SARS-CoV-2.

Pulmonary surfactant is considered to be one of the soaps. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the other enveloped viruses become very weak against surfactant. The SARS virus binds to angiotensin-converting enzyme (ACE2) receptor and causes pneumonia. In the lung, the ACE2 receptor sits on the top of lung cells known as alveolar epithelial type II (AE2) cells. These cells play an important role in producing surfactant. Pulmonary surfactant is believed to regulate the alveolar surface tension in mammalian lungs. To our knowledge, AE2 cells are believed to act as immunoregulatory cells; however, pulmonary surfactant itself has not been believed to act as a defender against the enveloped viruses. This study hypothesises that pulmonary surfactant may be a strong defender of enveloped viruses. Therefore, old coronaviruses merely cause pneumonia. On the contrary, new SARS-CoV-2 can suppress the production of surfactant that binds to the ACE2 of AE2 cells. The coronavirus can survive in the lung tissue because of the exhaustion of pulmonary surfactant.

Potential new treatment strategies for COVID-19: is there a role for bromhexine as add-on therapy?

Of huge importance now is to provide a fast, cost-effective, safe, and immediately available pharmaceutical solution to curb the rapid global spread of SARS-CoV-2. Recent publications on SARS-CoV-2 have brought attention to the possible benefit of chloroquine in the treatment of patients infected by SARS-CoV-2. Whether chloroquine can treat SARS-CoV-2 alone and also work as a prophylactic is doubtful. An effective prophylactic medication to prevent viral entry has to contain, at least, either a protease inhibitor or a competitive virus ACE2-binding inhibitor. Using bromhexine at a dosage that selectively inhibits TMPRSS2 and, in so doing, inhibits TMPRSS2-specific viral entry is likely to be effective against SARS-CoV-2. We propose the use of bromhexine as a prophylactic and treatment. We encourage the scientific community to assess bromhexine clinically as a prophylactic and curative treatment. If proven to be effective, this would allow a rapid, accessible, and cost-effective application worldwide.

Comparison of Bromhexine and its Active Metabolite - Ambroxol as Potential Analgesics Reducing Oxaliplatin-induced Neuropathic Pain - Pharmacodynamic and Molecular Docking Studies.

BACKGROUND: Painful peripheral neuropathy is a dose-limiting adverse effect of the antitumor drug oxaliplatin. The main symptoms of neuropathy: tactile allodynia and cold hyperalgesia, appear in more than 80% of patients on oxaliplatin therapy and are due to the overexpression of neuronal sodium channels (Navs) and neuroinflammation. OBJECTIVE: This study assessed antiallodynic and antihyperalgesic properties of two repurposed drugs with antiinflammatory and Nav-blocking properties (bromhexine and its pharmacologically active metabolite - ambroxol) in a mouse model of neuropathic pain induced by oxaliplatin. Using molecular docking techniques, we predicted targets implicated in the observed in vivo activity of bromhexine. METHODS: Oxaliplatin (a single intraperitoneal dose of 10 mg/kg) induced tactile allodynia and cold hyperalgesia in CD-1 mice and the effectiveness of single-dose or repeated-dose bromhexine and ambroxol to attenuate pain hypersensitivity was assessed in von Frey and cold plate tests. Additionally, Veber analysis and molecular docking experiments of bromhexine on mouse (m) and human (h) Nav1.6-1.9 were carried out. RESULTS: At the corresponding doses, ambroxol was more effective than bromhexine as an antiallodynic agent. However, at the dose of 150 mg/kg, ambroxol induced motor impairments in mice. Repeated-dose bromhexine and ambroxol partially attenuated the development of late-phase tactile allodynia in oxaliplatin-treated mice. Only 7-day administration of bromhexine attenuated the development of late-phase cold hyperalgesia. Bromhexine was predicted to be a strong inhibitor of mNav1.6, mNav1.7, mNav1.9, and hNav1.7-hNav1.9. CONCLUSION: The conversion of bromhexine to other than ambroxol active metabolites should be considered when interpreting some of its in vivo effects. Nav-blocking properties of bromhexine (and previously also predicted for ambroxol) might underlie its ability to attenuate pain caused by oxaliplatin.

Comprehensive analysis of drugs to treat SARS­CoV­2 infection: Mechanistic insights into current COVID­19 therapies (Review).

The major impact produced by the severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) focused many researchers attention to find treatments that can suppress transmission or ameliorate the disease. Despite the very fast and large flow of scientific data on possible treatment solutions, none have yet demonstrated unequivocal clinical utility against coronavirus disease 2019 (COVID­19). This work represents an exhaustive and critical review of all available data on potential treatments for COVID­19, highlighting their mechanistic characteristics and the strategy development rationale. Drug repurposing, also known as drug repositioning, and target based methods are the most used strategies to advance therapeutic solutions into clinical practice. Current in silico, in vitro and in vivo evidence regarding proposed treatments are summarized providing strong support for future research efforts.

Plant-based formulation in the management of chronic obstructive pulmonary disease: a randomized double-blind study.

BACKGROUND: A randomized double-blind placebo controlled clinical study was undertaken to investigate the safety and efficacy of a plant-based formulation (DCBT1234-Lung KR), which earlier through 2 trials was found to improve FEV1 and the quality of life of COPD patients. OBJECTIVE: The efficacy of DCBT1234-Lung KR was assessed using pulmonary function tests, arterial blood gas (ABG) analyses and the clinical symptoms of COPD in a 6-month study period against a matching placebo and a biomedical drug combination (salbutamol+theophylline+bromhexine). METHODS: One hundred and five subjects aged between 35 and 85 years with a smoking history of more than 20 pack years, showing little or no improvement in FEV1 upon a bronchial challenge of 200 microg of inhaled salbutamol and exhibiting ABG percentage of less than 85% of oxygen saturation were taken up for the study. The study had 3 arms viz., the plant-based formulation (DCBT1234-Lung KR), placebo and salbutamol (12 mg/day) plus theophylline (300 mg/day) plus bromhexine (24 mg/day). The end point of the study was determined as an improvement of FEV1 by 200 mL and/or increased ABG values (>90% PaO2) and clinical symptoms like dyspnoea, wheezing, cough, expectoration, disability, and sleep disturbances. RESULTS: DCBT1234-Lung KR patients showed statistically significant (95% level) improvement in FEV1 and PaO2 in comparison with salbutamol+theophylline+bromhexine and placebo patients. Twenty-three per cent of DCBT1234-Lung KR patients, 19% of salbutamol+theophylline+bromhexine group and 12% of placebo group patients showed the desired 200 mL improvement in FEV1 values in comparison with the other 2 arms. Improved PaO2 was observed in 15.4% of the DCBT1234-Lung KR patients while no improvement was seen with patients in any other arms. Symptoms like dyspnoea, wheezing, cough, expectoration, disability and sleep disturbances also significantly reduced in DCBT1234-Lung KR and the biomedical group patients, but not in the placebo arm. CONCLUSIONS: DCBT1234-Lung KR was equivalent, if not better than the present day treatment with salbutamol, theophylline and bromhexine combination in COPD patients and this was ascertained using FEV1 and ABG values.

Antitussive effect of a fixed combination of Justicia adhatoda, Echinacea purpurea and Eleutherococcus senticosus extracts in patients with acute upper respiratory tract infection: A comparative, randomized, double-blind, placebo-controlled study.

BACKGROUND: Kan Jang® oral solution (KJ) is a fixed combination of aqueous ethanolic extracts of Justicia adhatoda L. leaf, Echinacea purpurea (L.) Moench root, and Eleutherococcus senticosus (Rupr. & Maxim.) Harms root. It is approved in Scandinavia as an herbal medicinal product for respiratory tract infection treatment. PURPOSE: The present clinical trial aimed to compare the antitussive effect of KJ with placebo (PL) and bromhexine (BH) among patients of 18-65 years old with non-complicated upper respiratory infections (URI; i.e., common cold). STUDY DESIGN: We performed a parallel-group, randomized, double-blinded, placebo-controlled trial in in 177 patients with acute URI over a 5 day period. METHODS: We investigated the antitussive effects of a KJ (30 ml/day; 762 mg genuine extracts with standardized contents of 0.2 mg/ml vasicine, 0.8 mg/ml chicoric acid, and 0.03 mg/ml eleutherosides B and E), bromhexine hydrochloride (24 mg/30 ml/day) and PL on cough and blood markers. The primary outcome was cough relief, which was assessed as the change of cough frequency from baseline (cough index). Secondary outcomes were safety with regards to reported adverse events (AEs) and hematological data. RESULTS: Both KJ and BH relieved cough more effectively than placebo. On the third and fourth days of treatment, we observed faster improvement in the group receiving KJ compared to in the groups receiving BH (100%) or PL (100%), indicating a slightly shorter recovery time in the KJ group. KJ showed a good tolerability and safety profile. CONCLUSION: KJ exerted significant antitussive effects in URI. The present data further support the therapeutic use of KJ in upper respiratory tract infections.

A controlled trial of bromhexine ('Bisolvon') in out-patients with chronic bronchitis.

Bromhexine, 16 mg. 3-times daily, was compared with placebo in a double-blind crossover trial in 41 out-patients with chronic bronchitis and irreversible airways obstruction, and who were considered to be in a steady state. Each treatment was given for 3 weeks with a week of placebo in between; in addition, all patients took oxytetracycline, 500 mg. twice daily, starting 1 week before the trial and continuing throughout the duration of it. All patients completed the trial but the results from 5 were excluded because during the first 3 weeks they developed an influenza-like illness accompanied by a decrease in FEV1,and peak expiratory flow rate. Results from the remaining 36 patients showed a statistically significant reduction in phlegm stickiness (p smaller than 0.05) as judged by the patient, and a significant improvement in overall clinical state (p smaller than 0.05) as judged by the physician during bromhexine treatment, but no significant change in symptoms like cough, chest tightness, ease of breathing or sputum volume, peak expiratory flow rate and FEV1 etc. Five patients reported 6 side-effects, 3 with bromhexine, 1 with placebo and 1 with both treatments.

Systemic therapy of salivary gland hypofunction.

Salivary gland hypofunction occurs most often as a consequence of numerous drug therapies, anti-neoplastic treatments, or systemic disease. There are no universally accepted means of treating gland dysfunction and the resultant subjective xerostomia. A few studies have suggested that treatment of underlying inflammatory connective tissue disease will improve salivary performance in Sjögren's syndrome. Most of these reports, however, have either been limited to a small number of patients or have failed to include objective measures of salivary gland output. A larger body of literature deals with attempts using many different sialogogues to stimulate salivary function in a variety of conditions. Again, many studies have failed to document salivary improvement objectively. Recently, interest has focused on three drugs: bromhexine, anethole-trithione, and pilocarpine hydrochloride. Studies with these agents are reviewed, and current clinical investigations with pilocarpine are presented in detail.

Primary Sjögren's syndrome: a subjective description of the disease.

Forty patients with primary Sjögren's syndrome were interviewed to clarify the onset and course of the disease. In 50% of the cases, the first subjective signs of disease were recorded at age 30 to 50 years. A large variation was, however, observed, and some patients even recalled symptoms as early as in childhood. About one third described the onset as sudden, whereas the rest described an insidious deterioration. Keratoconjunctivitis sicca was the most frequent debut symptom, followed by xerostomia and weariness. Regardless of age, extreme weariness was a major problem. Pain in joints and muscles tended to be more severe in younger patients; ocular and oral problems tended to be more severe the higher the age of debut. Finally, most patients eventually came to have more or less the same complex of symptoms, which could lead to a devastating condition affecting the patients not only physically but also psychically and socially. The large variety of symptoms could easily be overlooked or misinterpreted, and because the patients did not appear to be ill, diagnosis was first established after an average period of nine years. Most patients used artificial tears, and obtained significantly greater benefit from this remedy than from all other drugs. A certain familial disposition towards the disease was found.

Effect of bromhexeine on sputum amoxycillin levels in lower respiratory infections.

Bromhexeine has been widely used as an adjunct in the management of lower respiratory infections and is useful in altering the physical characteristics of sputum. Its effect on the sputum penetration of an antibiotic has been sparsely studied. The present study highlights the improvement in sputum amoxycillin (amoxy) levels when a combination tablet, amoxy 500 mg plus bromhexeine 8 mg, is administered as compared to plain amoxy 500 mg. Sputum amoxy levels were significantly higher in the combination group (0.674 +/- 0.588 micrograms ml-1) as compared to 0.272 +/- 0.19 micrograms ml-1 in the amoxy group (P = 0.028). The clinical responses assessed by the physician as well as the patient were significantly better in the amoxy plus bromhexeine group as compared to the amoxy group. The radiological and bacteriological responses were similar in both groups. There was no increase in the side-effects due to bromhexeine and, overall, its use can be recommended in the treatment of acute lower respiratory infections.

Mucolytics for bronchiectasis.

BACKGROUND: Bronchiectasis is usually characterised by the production of large quantities of sputum that patients frequently have difficulty in expectorating. Mucolytic agents target hyper-secretion or changed physiochemical properties of sputum to make it easier to clear. One drug, recombinant human DNase, breaks down the DNA that is released at the site of infection by neutrophils. OBJECTIVES: The objective of this review was to assess the effects of ingested or inhaled mucolytics in patients with bronchiectasis. SEARCH STRATEGY: We searched the Cochrane Airways Group trials register, reference lists of relevant articles. We also contacted experts in the field and drug companies. SELECTION CRITERIA: Randomised trials of mucolytic treatment in people with bronchiectasis but not cystic fibrosis. DATA COLLECTION AND ANALYSIS: Data extraction was performed independently by two reviewers. Study authors were contacted for confirmation. MAIN RESULTS: Two trials were included. In one study, compared to placebo, high doses of bromhexine combined with antibiotics eased difficulty in expectoration (weighted mean difference -0.53, 95% confidence interval -0.81 to -0.25 at 16 days). There was also a reduction in sputum production with bromhexine (weighted mean difference -21.5%, 95% confidence interval -38.9 to -4.1 at day 16). There was no difference in forced expiratory volume. In a second study, compared to placebo, recombinant human DNase showed no difference in forced expiratory volume or forced vital capacity. Adverse effects, including influenza-like symptoms, were more common in the group receiving recombinant human DNase. REVIEWER'S CONCLUSIONS: There is not enough evidence to evaluate the routine use of mucolytics for bronchiectasis. High doses of bromhexine coupled with antibiotics may help with sputum production and clearance.