The effectiveness of gabapentin and gabapentin/montelukast combination compared with dextromethorphan in the improvement of COVID-19- related cough: A randomized, controlled clinical trial.

INTRODUCTION: Cough is one of the most common presenting symptoms of COVID-19, which can persist for weeks or months. OBJECTIVE: The goal of this study was to evaluate the effectiveness of gabapentin (GBT) alone and in combination with montelukast (MTL) for improving cough. METHODS: In this open-label randomized controlled clinical trial, eligible cases were patients hospitalized with moderate to severe COVID-19 who had cough with a Breathlessness, Cough, and Sputum Scale (BCSS) score of at least 2 based on its cough subscale. The participants were randomly assigned to three groups including two experimental groups and one control group. The first and second experimental groups received GBT and GBT/MTL, respectively, whereas the control group received dextromethorphan (DXM). Treatment duration was 5 days in all groups. Before and after the interventions, the severity of cough was evaluated using BCSS scale and Visual Analog Scale (VAS). RESULTS: A total of 180 patients were included; GPT, GPT/MTL, and DXM consisted of 76, 51, and 53 patients, respectively. There was no significant difference between the three groups in terms of age, gender, and comorbidities (P > 0.05). Regarding BCSS and VAS scores, there was significant reduction from the baseline values in all groups (P < 0.0001), with the change rate being significantly higher in DXM group. The amount of reduction of BCSS in the GPT/MTL group was significantly more than the GPT group, whereas there was no significant difference between the two groups regarding VAS score. Although the duration of hospitalization differed between the groups with the GPT/MTL group having the shortest duration, the difference was statistically significant only between the GPT and GPT/MTL groups (P < 0.0001). CONCLUSION: GPT, both alone and in combination with MTL, improves cough frequency and severity in hospitalized patients with COVID-19, with the combination being more efficacious. This regimen may be useful in patients who cannot tolerate opioids.

Insights into the biased activity of dextromethorphan and haloperidol towards SARS-CoV-2 NSP6: in silico binding mechanistic analysis.

The outbreak of novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus continually led to infect a large population worldwide. SARS-CoV-2 utilizes its NSP6 and Orf9c proteins to interact with sigma receptors that are implicated in lipid remodeling and ER stress response, to infect cells. The drugs targeting the sigma receptors, sigma-1 and sigma-2, have emerged as effective candidates to reduce viral infectivity, and some of them are in clinical trials against COVID-19. The antipsychotic drug, haloperidol, exerts remarkable antiviral activity, but, at the same time, the sigma-1 benzomorphan agonist, dextromethorphan, showed pro-viral activity. To explore the potential mechanisms of biased binding and activity of the two drugs, haloperidol and dextromethorphan towards NSP6, we herein utilized molecular docking-based molecular dynamics simulation studies. Our extensive analysis of the protein-drug interactions, structural and conformational dynamics, residual frustrations, and molecular switches of NSP6-drug complexes indicates that dextromethorphan binding leads to structural destabilization and increase in conformational dynamics and energetic frustrations. On the other hand, the strong binding of haloperidol leads to minimal structural and dynamical perturbations to NSP6. Thus, the structural insights of stronger binding affinity and favorable molecular interactions of haloperidol towards viral NSP6 suggests that haloperidol can be potentially explored as a candidate drug against COVID-19. KEY MESSAGES: •Inhibitors of sigma receptors are considered as potent drugs against COVID-19. •Antipsychotic drug, haloperidol, binds strongly to NSP6 and induces the minimal changes in structure and dynamics of NSP6. •Dextromethorphan, agonist of sigma receptors, binding leads to overall destabilization of NSP6. •These two drugs bind with NSP6 differently and also induce differences in the structural and conformational changes that explain their different mechanisms of action. •Haloperidol can be explored as a candidate drug against COVID-19.