The neutralization effect of montelukast on SARS-CoV-2 is shown by multiscale in silico simulations and combined in vitro studies

Small molecule inhibitors have previously been investigated in different studies as possible therapeutics in the treatment of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In the current drug repurposing study, we identified the leukotriene (D4) receptor antagonist montelukast as a novel agent that simultaneously targets two important drug targets of SARS-CoV-2. We initially demonstrated the dual inhibition profile of montelukast through multiscale molecular modeling studies. Next, we characterized its effect on both targets by different in vitro experiments including the enzyme (main protease) inhibition-based assay, surface plasmon resonance (SPR) spectroscopy, pseudovirus neutralization on HEK293T/hACE2+TMPRSS2, and virus neutralization assay using xCELLigence MP real-time cell analyzer. Our integrated in silico and in vitro results confirmed the dual potential effect of montelukast both on the main protease enzyme inhibition and virus entry into the host cell (spike/ACE2). The virus neutralization assay results showed that SARS-CoV-2 virus activity was delayed with montelukast for 20 h on the infected cells. The rapid use of new small molecules in the pandemic is very important today. Montelukast, whose pharmacokinetic and pharmacodynamic properties are very well characterized and has been widely used in the treatment of asthma since 1998, should urgently be completed in clinical phase studies and, if its effect is proved in clinical phase studies, it should be used against coronavirus disease 2019 (COVID-19).     

Complication and cost analysis of transbronchial lung cryobiopsy and awake video-assisted thoracic surgery in diagnosis of interstitial lung disease

Aim and introduction:Diagnosing of interstitial lung disease (ILD) is difficult and expensive. The standard diagnostical approaches to ILD are bronchoalveolar lavage, transbronchial lung biopsy, transbronchial lung cryobiopsy (TBLC) and surgical lung biopsy (SLB). SLB is gold standard for the confident diagnosis of ILD but because of the poor performance of the patients it’s use is limited. We conducted a retrospective study to point out that TBLC plays an important role in diagnosis of ILD and has fewer complications and lower cost than awake video-assisted thoracic surgery (AVATS).Material and methods:132 patients who underwent TBLC and AVATS with a pre-diagnosis of ILD in our hospital between 2015 and 2020 were evaluated retrospectively. Diagnosis rates, complications and costs were recorded.Results:There were no non-diagnostic materials in 44 patients in AVATS arm. Prolonged air leak was observed in 11(25.0%) of the patients, and six of them (13.6%) were discharged with Heimlich Valve (HV). Median length of stay in the hospital was 8 days, while average patient cost was $515.9 (415.2-2662.9) in the AVATS arm. Non-diagnostic material was obtained from 10 (11.3%) of 88 patients in TBLC arm. Six (6.8%) of them had pneumothorax, only one of them required a chest tube. No patient was discharged with HV (p=0.001). Median cost for each patient with a median hospital stay of 2.0 (1.0-21.0) (p<0.001) days was $171.9 (80.8-1493.3) (p<0.001).Discussion:Although TBLC is behind AVATS in terms of diagnostic accuracy, it may be an alternative diagnostic tool in the diagnosis of interstitial lung disease due to its acceptable safety profile and cost-effectiveness.     

High SARS-CoV-2 Prevalence among Healthcare Workers in Cochabamba,Bolivia

Healthcare workers (HCWs) are at increased risk of SARS-CoV-2 infection. The aim of the study was to estimate the SARS-CoV-2 seroprevalence among HCWs in Cochabamba, Bolivia and to determine the potential risk factors. In January 2021, a cross-sectional SARS-CoV-2 seroprevalence study was conducted in 783 volunteer clinical and non-clinical HCWs in tertiary care facilities. It was based on IgG detection using ELISA, chemiluminiscence, and seroneutralisation tests from dried blood spots. Analysis revealed a high seroprevalence (43.4%) of SARS-CoV-2 IgG antibodies. The combination of anosmia and ageusia (OR: 68.11; 95%-CI 24.83–186.80) was predictive of seropositivity. Belonging to the cleaning staff (OR: 1.94; 95%-CI 1.09–3.45), having more than two children in the same house (OR: 1.74; 95%-CI 1.12–2.71), and having been in contact with a close relative with COVID-19 (OR: 3.53; 95%-CI 2.24–5.58) were identified as risk factors for seropositivity in a multivariate analysis. A total of 47.5% of participants had received medication for COVID-19 treatment or prevention, and only ~50% of symptomatic subjects accessed PCR or antigenic testing. This study confirms a massive SARS-CoV-2 attack rate among HCWs in Cochabamba by the end of January 2021. The main risk factors identified are having a low-skilled job, living with children, and having been in contact with an infected relative in the household.     

Migraine susceptibility is modulated by food triggers and analgesic overuse via sulfotransferase inhibition

Background/aimCertain constituents in migraine food triggers and non-steroidal anti-inflammatory drugs (NSAIDs) inhibit sulfotransferases (SULTs) that detoxify drugs/chemicals and play role in the metabolism of neurotransmitters. We aimed to dissect SULT1A1 modulation of CSD susceptibility and behavior in an in vivo experimental model using hesperidin, a SULT1A1 inhibitor found in citrus fruits (known migraine triggers) and mefenamic acid (SULT1A1 inhibitor), an NSAID to simulate medication overuse.MethodsHesperidin was used as SULT1A1 inhibitor found in citrus fruits, known migraine triggers and mefenamic acid (NSAID), another SULT1A1 inhibitor, was used to induce MO in rats. The groups were; 1) Hesperidin (ip) or its vehicle-DMSO (ip) 2) Chronic (4 weeks) mefenamic acid (ip) or its vehicle (ip) 3) Chronic mefenamic acid+hesperidin (ip) or DMSO (ip). CSD susceptibility was evaluated and behavioral testing was performed. SULT1A1 enzyme activity was measured in brain samples.ResultsSingle-dose of hesperidin neither changed CSD susceptibility nor resulted in any behavioral change. Chronic mefenamic acid exposure resulted in increased CSD susceptibility, mechanical-thermal hypersensitivity, increased head shake, grooming and freezing and decreased locomotion. Single dose hesperidin administration after chronic mefenamic acid exposure resulted in increased CSD susceptibility and mechanical-thermal hypersensitivity, increased freezing and decreased locomotion. SULT1A1 enzyme activity was lower in mefenamic acid and mefenamic acid+hesperidin groups compared to their vehicles.ConclusionMefenamic acid and hesperidin have synergistic effect in modulating CSD susceptibility and pain behavior. Sulfotransferase inhibition may be the common mechanism by which food triggers and NSAIDs modulate migraine susceptibility. Further investigations regarding human provocation studies using hesperidin in migraine patients with medication overuse are needed.     

Coronavirus disease 2019 (COVID‐19) as a potential trigger for benign recurrent intrahepatic cholestasis

Benign recurrent intrahepatic cholestasis (BRIC) is a rare disease characterized by recurrent severe itching and jaundice. Coronavirus disease 2019 (COVID‐19) is a multisystemic acute viral disease and the liver is frequently affected. Here, we wanted to present a BRIC case triggered by COVID‐19 infection, discussing it together with current information.     

The effect of chloroform,orange oil and eucalyptol on root canal transportation in endodontic retreatment

The purpose of the present study was to assess the effect of solvents on root canal transportation in endodontic retreatment. Sixty extracted human permanent mandibular first molars with curved root canals were selected. All of the root canals were prepared using Twisted File Adaptive instruments (SybronEndo, Orange, CA, USA) and filled with gutta‐percha and AH Plus sealer (Dentsply DeTrey, Konstanz, Germany) using the cold lateral compaction technique. The teeth were assigned to four retreatment groups as follows (n = 15): eucalyptol, chloroform, orange oil and control. The canals were scanned using cone‐beam computed tomography scanning before and after instrumentation. The chloroform group showed a significantly higher mean transportation value than the orange oil and control groups at the 3 and 5 mm levels (P = 0.011 and P = 0.003, respectively). There was no significant difference among the orange oil, eucalyptol and control groups in terms of canal transportation (P > 0.61). The chloroform led to more canal transportation than the eucalyptol and orange oil during endodontic retreatment.     

Effect of polylactide/glycolide (PLGA) membranes loaded with metronidazole on periodontal regeneration following guided tissue regeneration in dogs

BACKGROUND: Bioabsorbable membranes have been successfully used for guided tissue regeneration (GTR) and local delivery systems because they are biocompatible and do not require second surgery for removal. Several studies have demonstrated that metronidazole, when applied topically, produced immediate effects on microbiological and clinical parameters, most notably a reduction in probing depth and loss of attachment. The purpose of this study was to evaluate the regenerative potential of a metronidazole-loaded biodegradable (polylactide/glycolide) (PLGA) GTR membrane in dogs. METHODS: Six male adult dogs with 36 created osseous defects were enrolled. Bilateral dehiscence type defects in 5 mm diameter were created at buccal aspect of the alveolar bone in maxillary premolar teeth. After full thickness flap elevation, exposed root surfaces were thoroughly planed. In the experimental sites, PLGA membranes with or without metronidazole were fitted and placed over the defects. On the control defects only root planing was performed. Gingival flaps were replaced slightly coronal to the cemento-enamel junction. Animals were sacrificed at 60 days. The histometric analysis was evaluated with the following parameters: defect height (DH), apical extension of junctional epithelium (AEJE), new cementum height (NCH), new bone height (NBH), and new gingival connective tissue height (NCTH). RESULTS: Postoperative clinical healing was similar in the 3 groups. There were no statistically significant differences between the 2 experimental groups in any parameters. Statistically significant differences were observed for AEJE, NCH, NBH, and NCTH in experimental groups when compared with the controls. Statistically significantly greater NCH, NBH, and NCTH were seen in the experimental groups than the controls and control defects showed longer AEJE than the experimental defects. CONCLUSIONS: These results suggest that PLGA membranes with and without metronidazole may have a beneficial effect on periodontal regeneration.