Phytomedicine ELOM-080 in Acute Viral Rhinosinusitis: A Randomized, Placebo-Controlled, Blinded Clinical Trial.

BACKGROUND: ELOM-080 is a phytomedicine approved for the treatment of acute and chronic inflammatory diseases of the respiratory tract, sinusitis, and bronchitis in particular. This prospective, randomized, placebo-controlled, double-blind clinical trial was conducted to assess efficacy and safety of ELOM-080 in the treatment of acute viral rhinosinusitis (AVRS). METHODS: Patients with AVRS received oral treatment (4 × 1 capsule per day) with either ELOM-080 or matching placebo. Primary endpoints were the change in major symptom score (MSS) after 7 and 14 days of treatment assessed by the investigator (MSSINV ). Secondary endpoints were changes in MSS assessed by the patients (MSSPAT ), olfactory function (12-item Sniffin' Sticks), 20-Item Sino-Nasal Outcome Test (SNOT-20 GAV; German adapted version), influence of treatment on viral load, and safety. RESULTS: Four hundred and sixty-three patients were randomized. At day 4, subjective burden of disease (MSS) was significantly ameliorated compared to placebo (p = 0.012). During the first treatment week MSS scores improved about 1 day earlier, and 3 days earlier in the second week. Effect with ELOM-080 on mean MSSINV was statistically significantly superior to placebo at visit 3 (p = 0.016) and visit 4 (p = 0.014). In chemosensory testing identification scores improved comparably in both treatments. The improvement of the SNOT-20 GAV was more pronounced in ELOM-080 patients. Treatment with ELOM-080 indicated a potential for decreasing viral load. Both treatments were well tolerated. CONCLUSION: ELOM-080 improves the burden of AVRS significantly in comparison to placebo, remission of symptoms occurred 3 days earlier. The results confirm the efficacy and safety of ELOM-080 for treatment of AVRS. LEVEL OF EVIDENCE: 1 Laryngoscope, 133:1576-1583, 2023.

Dual-Energy Computed Tomography Collagen Density Mapping of the Cranio-Cervical Ligaments-A Retrospective Feasibility Study.

The objectives of this study were to investigate the mean collagen content of the atlanto-axial joint (AAJ) ligaments in a cohort without inflammatory disease and to analyze clinical confounders such as age, sex, and presence of ligamentous calcifications. A total of 153 patients who underwent dual-energy computed tomography (DECT) due to various reasons (e.g., suspected cancer or infection) were included in this retrospective study. Reconstruction of collagen density maps from the DECT dataset was performed. Region of interest (ROI) analysis was performed to assess densities in the following regions: ligamentum transversum atlantis (LTA), ligamenta alaria, fasciculi longitudinales, ligamentum nuchae, and retro-odontoid soft tissue (RDS). Osteoarthritis (OA) and the presence of calcifications were assessed by two experienced readers blinded to clinical data. Subgroup comparisons were performed using unpaired t-tests. The correlation of collagen density and clinical factors was investigated using Pearson's correlation coefficient. Mean LTA collagen density was 141.7 (SD 35.7). Ligamentous calcifications were rare (14.4 %). OA of the AAJ was common (91.5 %). LTA collagen density was not associated with age (Pearson's r of 0.109; p = 0.180) and was not significantly higher in patients with OA (p = 0.070). No correlations between RDS thickness, collagen density or calcifications were found. Our results show collagen density mapping of the cranio-cervical joint ligaments to be feasible; collagen densities are not significantly associated with age, sex, AAJ degeneration, or asymptomatic ligamentous calcification.

Efficacy and Safety of ELOM-080 as Add-On Therapy in COVID-19 Patients with Acute Respiratory Insufficiency: Exploratory Data from the Prospective Placebo-Controlled COVARI Trial.

INTRODUCTION: Enhancement of mucociliary clearance (MCC) might be a potential target in treating COVID-19. The phytomedicine ELOM-080 is an MCC enhancer that is used to treat inflammatory respiratory diseases. PATIENTS/METHODS: This randomised, double-blind exploratory study (EudraCT number 2020-003779-17) evaluated 14 days' add-on therapy with ELOM-080 versus placebo in patients with COVID-19 hospitalised with acute respiratory insufficiency. RESULTS: The trial was terminated early after enrolment of 47 patients as a result of poor recruitment. Twelve patients discontinued prematurely, leaving 35 in the per-protocol set (PPS). Treatment with ELOM-080 had no significant effect on overall clinical status versus placebo (p = 0.49). However, compared with the placebo group, patients treated with ELOM-080 had less dyspnoea in the second week of hospitalisation (p = 0.0035), required less supplemental oxygen (p = 0.0229), and were more often without dyspnoea when climbing stairs at home (p < 0.0001). CONCLUSION: These exploratory data suggest the potential for ELOM-080 to improve respiratory status during and after hospitalisation in patients with COVID-19.

[Mucociliary clearance in COVID-19 - an underestimated danger area in early phase of disease?] / Mukoziliäre Clearance bei COVID-19-Erkrankungen : Ein unterschätztes Gefahrengebiet in der Frühphase?

BACKGROUND: As with other inflammatory diseases, the (dry) cough in COVID-19 patients indicates that mucociliary clearance (MCC) is at least at risk, if not overloaded, damaged or largely inoperable. Coughing is an important secondary mechanism that only takes over bronchial cleansing as a replacement if the MCC has failed. METHOD: The review article describes the physiology and pathophysiology of MCC and its possible role in the pathogenesis of COVID-19. RESULTS AND CONCLUSIONS: Human and animal studies as well as autopsy reports indicate that MCC could also be important for the COVID-19 pathogenesis. In primary care, MCC plays a major role in inflammatory respiratory diseases. In Germany, drugs for self-medication are approved for treatment and, due to the high quality of studies, are also recommended in the respective guidelines. A symptomatic approach to stabilize the airway barrier would also be conceivable in the early outpatient phase of COVID-19.

Intermittent Administration of Nitroglycerin Sublingual Powder Compared with Placebo in Outpatients with Peripheral Artery Disease: Results of a Randomised Proof of Concept Study.

OBJECTIVE: Treatment of peripheral artery disease (PAD), Fontaine Stage IIb with vasoactive substances is of limited efficacy and does not last beyond the active treatment. Glyceryl trinitrate (GTN) is a vasodilating agent that relaxes vascular smooth muscle cells. The aim was to prove the concept that GTN sublingual powder has sustained clinical efficacy and adequate safety in these patients. METHODS: This was a multicentre, randomised, double blind, placebo controlled, forced titration, proof of concept study (phase IIa). Patients had a treadmill test at baseline, after 12 weeks of GTN/placebo administration, and at 19 and 26 weeks (without treatment). Primary objectives were an increase in initial claudication distance (ICD) and absolute claudication distance (ACD) at 12 weeks. RESULTS: Ninety-five patients were screened and 73 randomised, of which 53 patients completed the 12 week treatment phase (GTN 26, placebo 27). At a baseline ICD of 59.2 ± 32.8 m (GTN) and 57.5 ± 39.7 m (placebo), GTN led to a placebo corrected ICD increase of 23.2% vs. baseline (p = .35). Baseline ACD was 105.3 ± 52.9 m (GTN) and 106.1 ± 95.0 m (placebo), and GTN led to a placebo corrected increase of 3.6% (p = .44), with substantial interindividual variation. The change in claudication distance was greater in patients with an ICD of ≥50 m at baseline (ΔICD 29.3%; p = .19), and an ACD ≥ 100 m (ΔACD 8.5%; p = .40). The effect lasted beyond the active treatment period as shown by a 49.3% increase in ICD (p = .31) and a 20.6% increase in ACD (p = .21) by week 26. GTN sublingual powder was well tolerated. CONCLUSION: Intermittent treatment with nitroglycerin sublingual powder may represent a potential treatment option for patients with PAD stage Fontaine IIb, with an immediate and a sustained effect. The observed increases in ACD and ICD were however not statistically significant in this phase IIa proof of concept study. Further studies are required.

An evaluation of bird and bat mortality at wind turbines in the Northeastern United States.

Wind energy offers substantial environmental benefits, but wind facilities can negatively impact wildlife, including birds and bats. Researchers and managers have made major efforts to chronicle bird and bat mortality associated with wind facilities, but few studies have examined the patterns and underlying mechanisms of spatial patterns of fatalities at wind facilities. Understanding the horizontal fall distance between a carcass and the nearest turbine pole is important in designing effective search protocols and estimating total mortality. We explored patterns in taxonomic composition and fall distance of bird and bat carcasses at wind facilities in the Northeastern United States using publicly available data and data submitted to the US Fish and Wildlife Service under scientific collecting and special purpose utility permits for collection and study of migratory birds. Forty-four wind facilities reported 2,039 bird fatalities spanning 128 species and 22 facilities reported 418 bat fatalities spanning five species. Relative to long-distance migratory birds, short-distance migrants were found farther from turbines. Body mass of birds and bats positively influenced fall distance. Turbine size positively influenced fall distance of birds and bats when analyzed collectively and of birds when analyzed separately from bats. This suggests that as turbines increase in size, a greater search radius will be necessary to detect carcasses. Bird and bat fall distance distributions were notably multimodal, but only birds exhibited a high peak near turbine bases, a novel finding we attribute to collisions with turbine poles in addition to blades. This phenomenon varied across bird species, with potential implications for the accuracy of mortality estimates. Although pole collisions for birds is intuitive, this phenomenon has not been formally recognized. This finding may warrant an updated view of turbines as a collision threat to birds because they are a tall structure, and not strictly as a function of their motion.

ELOM-080 as Add-On Treatment for Respiratory Tract Diseases - A Review of Clinical Studies Conducted in China.

ELOM-080, also known as Myrtol, represents a distillate of a mixture of 4 rectified essential oils: eucalyptus oil, sweet orange oil, myrtle oil, and lemon oil. ELOM-080 is an approved herbal medicinal product for the secretolytic therapy and facilitation of expectoration in acute and chronic bronchitis and for the secretolytic therapy of sinusitis. Its clinical efficacy has been reported by several randomized control trials. Interestingly, in the recent past, a considerable number of clinical studies on the use of ELOM-080 as add-on treatment of different respiratory tract diseases has been conducted and published in China. As these publications were only available in Chinese, the international attention in the literature was limited. Based on the translation of these studies into English, this review aims to provide a brief overview of the studies' major results, which contribute to the knowledge on the efficacy of ELOM-080 in the treatment of respiratory tract diseases: ELOM-080 was shown to be of great value as add-on treatment not only for the well-established indications bronchitis and sinusitis, but also for pharyngitis, asthma, chronic obstructive pulmonary disease, and, most importantly, otitis media. Besides this clinical evidence, this review also summarizes the great progress in deciphering the mode of action of ELOM-080 that has been made by Chinese publications.

Effect of ELOM-080 on exacerbations and symptoms in COPD patients with a chronic bronchitis phenotype - a post-hoc analysis of a randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Treating symptoms and preventing exacerbations are key components of chronic obstructive pulmonary disease (COPD) long-term management. Recently, a more tailored treatment approach has been proposed, in particular for two well-established clinical phenotypes, frequent exacerbators and chronic bronchitis-dominant COPD. ELOM-080 has demonstrated clinical efficacy in treating symptoms and preventing exacerbations in subjects with chronic bronchitis. However, little is known about the potential effects of ELOM-080 in COPD patients. AIM: To evaluate the effect on exacerbation, cough sputum, and general state of health of long-term treatment with ELOM-080 in COPD patients with an exacerbation history and chronic bronchitis. METHODS: We performed a post-hoc analysis of a randomized, double-blinded, placebo-controlled parallel-group clinical trial of a 6-month treatment with ELOM-080 (3×300 mg) in patients with chronic bronchitis and concomitant COPD. The primary outcome was the proportion of subjects with at least one exacerbation over the 6-month study period. Secondary outcomes included the total number of exacerbations (ie, cumulative occurrence of exacerbations during the study period) and the proportion of acute exacerbations necessitating an antibiotic treatment, monthly evaluations of sputum and cough symptoms, and the general state of health and a safety analysis. RESULTS: Of 260 randomized subjects, 64 patients fulfilled the inclusion criteria for COPD (ELOM-080: 35, placebo: 29). Compared to placebo, ELOM-080 reduced the percentage of subjects with at least one exacerbation (29% versus 55%, P=0.031) and a reduction in the overall occurrence of exacerbations (ELOM-080: 10, placebo: 21, P=0.012) during the winter season. The percentage of asymptomatic or mildly symptomatic patients (sputum/expectoration and cough) was consistently higher in the ELOM-080 group compared to placebo, with statistical significant differences after 2 and 3 months of treatment (2 months: ELOM-080 25%, placebo 11%, P<0.005; 3 months: ELOM-080 26%, placebo 14%, P<0.05). Likewise the subjective rating of general health status was better in the ELOM-080 group with statistically significant superiority after 2 and 3 months of treatment (2-month treatment: P=0.015; 3-month treatment: P=0.024). Tolerability results were comparable between ELOM-080 and placebo. CONCLUSION: ELOM-080 is efficacious in patients with COPD and a chronic bronchitis phenotype. Prophylactic use reduces the rate of exacerbations and improves the key symptoms of sputum and cough with a favorable long-term tolerability profile.

Patterns of bird-window collisions inform mitigation on a university campus.

Bird-window collisions cause an estimated one billion bird deaths annually in the United States. Building characteristics and surrounding habitat affect collision frequency. Given the importance of collisions as an anthropogenic threat to birds, mitigation is essential. Patterned glass and UV-reflective films have been proven to prevent collisions. At Duke University's West campus in Durham, North Carolina, we set out to identify the buildings and building characteristics associated with the highest frequencies of collisions in order to propose a mitigation strategy. We surveyed six buildings, stratified by size, and measured architectural characteristics and surrounding area variables. During 21 consecutive days in spring and fall 2014, and spring 2015, we conducted carcass surveys to document collisions. In addition, we also collected ad hoc collision data year-round and recorded the data using the app iNaturalist. Consistent with previous studies, we found a positive relationship between glass area and collisions. Fitzpatrick, the building with the most window area, caused the most collisions. Schwartz and the Perk, the two small buildings with small window areas, had the lowest collision frequencies. Penn, the only building with bird deterrent pattern, caused just two collisions, despite being almost completely made out of glass. Unlike many research projects, our data collection led to mitigation action. A resolution supported by the student government, including news stories in the local media, resulted in the application of a bird deterrent film to the building with the most collisions: Fitzpatrick. We present our collision data and mitigation result to inspire other researchers and organizations to prevent bird-window collisions.

A randomized, double-blind, placebo-controlled, crossover, dose-ranging multicenter study to determine the effect of sublingual nitroglycerin spray on exercise capacity in patients with chronic stable angina.

BACKGROUND: Sublingual nitroglycerin increases exercise duration in patients with stable angina. Brief results from this study were published previously in German. Here, we more fully describe the study methodology, patient characteristics, and detailed results. METHODS: This double-blind, crossover study enrolled 51 patients with stable angina. Patients were randomized to 1 of 5 treatment sequences and were administered placebo or nitroglycerin spray (0.2 mg, 0.4 mg, 0.8 mg, or 1.6 mg). Patients carried out 1 control exercise tolerance test (ETT) and 1 investigational ETT at each visit. RESULTS: Dose-dependent increases in time to onset of angina, time to onset of moderate angina, and the occurrence of a minimum 1.0-mm ST-segment depression were seen following administration of nitroglycerin spray. CONCLUSIONS: These results support the use of sublingual nitroglycerin spray in patients with stable angina who are being managed with medical therapy and in patients who have persistent angina post-revascularization.

Effect of myrtol standardized and other substances on the respiratory tract: ciliary beat frequency and mucociliary clearance as parameters.

INTRODUCTION: Myrtol standardized is a phytomedicine obtained by distillation, consisting of many constituents. In vitro and in vivo, the major monterpenes, d-limonene, 1,8-cineole, and alpha-pinene, are used as biological marker substances. Myrtol standardized has secretolytic, secretomotor, and mucolytic effects in addition to anti-inflammatory and antioxidative actions. The aim of the study was to investigate the effects of different concentrations of Myrtol standardized on in vivo mucociliary clearance in mice and the ciliary beat frequency (CBF) in rat tracheal rings. METHODS: Data regarding the effects of 1,8-cineole and N-acetylcysteine (NAC) were compared. Salbutamol was used as a positive control. CBF was measured using rat tracheal explants and a high-speed video camera linked to a microscope with specific software equipment. Mucociliary clearance was determined using the microdialysis technique, which measured the acceleration of a fluorescent sample in the trachea in vivo. RESULTS: Myrtol standardized accelerated both CBF and mucociliary transport in a concentration-dependent manner. Significant effects were seen at a concentration of 0.01% Myrtol regarding CBF (P<0.01) and 17.1 mg/kg body weight regarding mucociliary clearance experiments (P<0.05) according to doses relevant to humans. The 1,8-cineole dosage relative to humans only accelerated the mucociliary clearance in vivo without having an effect on the CBF. Extremely high doses of Myrtol were not able to additionally increase the CBF effect in comparison to salbutamol. Compared to NAC, also used in a dosage relative to humans, Myrtol standardized showed a tendency to be more effective. CONCLUSION: In summary, the present data suggest that Myrtol standardized is a pharmacologically important drug which, when used at a dose relative to humans, shows positive effects on both measured parameters, CBF and mucociliary clearance, in vivo.

Dopamine/serotonin receptor ligands. 9. Oxygen-containing midsized heterocyclic ring systems and nonrigidized analogues. A step toward dopamine D5 receptor selectivity.

Eleven-membered heterocycles (dibenz[g,j]-1-oxa-4-azacycloundecenes) and open-chain analogues were synthesized and investigated for affinities to human dopamine receptor subtypes. The moderately rigidized rings displayed nanomolar and subnanomolar Ki values at D1-like receptors with a significant D1 to D2 and a slight D5 to D1 selectivity. The open-chain analogues showed lower affinities but significant D1 to D2 selectivities. Compound 3 (Ki(D5) = 0.57 nmol) showed antagonistic or inverse agonistic binding characteristics in a functional Ca assay.

Dopamine/serotonin receptor ligands. Part IV [1]: synthesis and pharmacology of novel 3-benzazecines and 3-benzazonines as potential 5-HT2A and dopamine receptor ligands.

LE 300 represents a structurally novel type of antagonist acting preferentially at the dopamine D1/D5 receptors and the serotonin 5-HT2A receptor. The compound consists of a 10-membered central azecine ring fused to indole on one and to benzene on the other side. To estimate the importance of the indole moiety in this highly active benz-indolo-azepine, the indole has to be removed and the "de-indolised" analog reinvestigated pharmacologically. Accordingly, we synthesized 3-benzazecines and in addition some homologuous 3-benzazonines. Methoxylated beta-phenylethylamines were treated with ethyl omega-bromo-butanoates and -pentanoates, respectively, to give the corresponding lactams which were cyclized (POCl3) and reduced (NaBH4), yielding the cis-annelated (X-ray) benzindolizines and -quinolizines. The 10- and 9-membered rings were obtained by cleavage of the central C-N bond, which was performed in the following two ways: Quarternisaion with methyl iodide and cleavage with sodium in liquid ammonia gave the NCH3 derivatives, reaction with benzyloxycarbonyl chloride/NaBH4 followed by catalytic debenzylation yielded a corresponding NH compound. Functional experiments on rat artery segments precontracted with ketanserin and radioligand binding experiments using human cloned dopamine receptor subtypes were conducted with all of the benzazecine and benzazonine derivatives. In contrast to the benz-indolo-compound LE 300 they did not show any significant affinity towards the D1, D2, D4, and D5 receptors and only moderate antagonistic activity at the 5-HT2A receptor. It can be concluded from our study that an indole moiety or at least another second aromatic system at the central azecine ring is part of the pharmacophore and thus essential for high biological activity.