Desloratadine, Clarinex for COVID-19

AbstractThe 2019 global coronavirus (COVID-19) pandemic has brought the world to a grinding halt, highlighting the urgent need for therapeutic and preventive solutions to slow the spread of emerging viruses. The objective of this study was to assess the anti-SARS-CoV-2 effectiveness of 8 FDA-approved cationic amphiphilic drugs (CADs). SARS-CoV-2-infected Vero cells, Calu-3 cells and primary Human Nasal Epithelial Cells (HNEC) were used to investigate the effects of CADs and revealed their antiviral mode of action. Among the CADs tested, desloratadine, a commonly used antiallergic, well-tolerated with no major side effects, potently reduced the production of SARS-CoV-2 RNA in Vero-E6 cells. Interestingly, desloratadine was also effective against HCoV-229E and HCoV-OC43 showing that it possessed broad-spectrum anti-coronavirus activity. Investigation of its mode of action revealed that it targeted an early step of virus lifecycle and blocked SARS-CoV-2 entry through the endosomal pathway. Finally, the ex vivo kinetic of the antiviral effect of desloratadine was evaluated on primary Human Nasal Epithelial Cells (HNEC), showing a significant delay of viral RNA production with a maximal reduction reached after 72 h of treatment. Thus, this treatment could provide a substantial contribution to prophylaxis and systemic therapy of COVID-19 or other coronaviruses infections and requires further studies.

<title>Abstract</title> <p>Background Coronavirus disease 2019 (COVID-19) pandemic has led to numerous cases of acute respiratory distress syndrome (ARDS), with a significant number of survivors developing pulmonary fibrosis as a chronic sequela. This condition poses severe long-term health challenges, significantly burdening public health systems. Despite significant research on the acute phase of COVID-19, the mechanisms underlying pulmonary fibrosis following COVID-19 associated ARDS remain poorly understood, and effective therapies are yet to be established. This study aims to elucidate the molecular mechanisms, identify potential biomarkers, and explore therapeutic options for pulmonary fibrosis post-COVID-19-related ARDS through comprehensive transcriptomic and bioinformatic analyses. Methods We collected datasets from Gene Expression Omnibus (GEO) database, including transcriptional profiles of COVID-19, ARDS, and pulmonary fibrosis. Differentially expressed genes (DEGs) common to these conditions were identified, reflecting the transcriptional landscape of pulmonary fibrosis post-COVID-19 ARDS. Functional and pathway enrichment analyses was conducted. Protein-protein interaction (PPI) network was constructed to determine the hub genes and their regulatory networks. Drugs that interact with hub genes were explored and gene-disease associations were analyzed to identify potential therapeutic strategies. Results We identified 116 common DEGs among COVID-19, ARDS, and pulmonary fibrosis datasets. Functional enrichment highlighted critical processes including inflammatory response, apoptosis, transcription regulation, and MAPK cascade. PPI network revealed hub genes which may play crucial roles in the pathogenesis of pulmonary fibrosis post-COVID-19-related ARDS. Notably, FCER1A, associated with immune response and inflammation, GATA2, involved in macrophage function and erythropoiesis, and CLC, indicative of eosinophil activity, emerged as central players. Regulatory network analysis highlighted significant transcription factors (TFs) and microRNAs (miRNAs) associated with hub genes. We found FDA-approved drugs that could interact with these hub genes, including omalizumab, mizolastine, desloratadine, epoetin alfa, and moxidectin. Gene-disease interaction analysis revealed that diseases caused by GATA2 deficiency and immunodeficiency were associated with hub genes. Conclusion Our findings provide valuable insights into the molecular underpinnings of pulmonary fibrosis post-COVID-19 ARDS and highlight potential biomarkers and therapeutic targets. The repurpose of drugs offers a promising avenue for rapid clinical application, potentially improving outcomes. This study provides ideas for improved treatment for pulmonary fibrosis post-COVID-19 ARDS.</p>

ABSTRACT Numerous host factors, in addition to human angiotensin-converting enzyme 2 (hACE2), have been identified as coreceptors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), demonstrating broad viral tropism and diversified druggable potential. We and others have found that antihistamine drugs, particularly histamine receptor H1 (HRH1) antagonists, potently inhibit SARS-CoV-2 infection. In this study, we provided compelling evidence that HRH1 acts as an alternative receptor for SARS-CoV-2 by directly binding to the viral spike protein. HRH1 also synergistically enhanced hACE2-dependent viral entry by interacting with hACE2. Antihistamine drugs effectively prevent viral infection by competitively binding to HRH1, thereby disrupting the interaction between the spike protein and its receptor. Multiple inhibition assays revealed that antihistamine drugs broadly inhibited the infection of various SARS-CoV-2 mutants with an average IC50 of 2.4 µM. The prophylactic function of these drugs was further confirmed by authentic SARS-CoV-2 infection assays and humanized mouse challenge experiments, demonstrating the therapeutic potential of antihistamine drugs for combating coronavirus disease 19. IMPORTANCE In addition to human angiotensin-converting enzyme 2, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can utilize alternative cofactors to facilitate viral entry. In this study, we discovered that histamine receptor H1 (HRH1) not only functions as an independent receptor for SARS-CoV-2 but also synergistically enhances ACE2-dependent viral entry by directly interacting with ACE2. Further studies have demonstrated that HRH1 facilitates the entry of SARS-CoV-2 by directly binding to the N-terminal domain of the spike protein. Conversely, antihistamine drugs, primarily HRH1 antagonists, can competitively bind to HRH1 and thereby prevent viral entry. These findings revealed that the administration of repurposable antihistamine drugs could be a therapeutic intervention to combat coronavirus disease 19.

Background and Objectives This study was aimed to determine the effect of antihistamines on Covid-19 disease. Subjects and Methods Two researchers searched online electronic databases PubMed, MEDLINE and Google Scholar from the beginning of the pandemic until December 30, 2022 using Mesh and keywords such as: "SARS-CoV-2" or "COVID-19" and "Antihistamine". Results The results depicted that levocetirizine, diphenhydramine, hydroxyzine, azelastine, dexchlorpheniramine, cetirizine, loratadine, desloratadine, fexofenadine, triprolidine, dimetindene, and famotidine are effective in treating and reducing the symptoms of Covid-19. Among them, famotidine had contradictory results, and although it may be a useful supplement in the treatment of covid-19, laboratory studies have failed to show the direct role of famotidine in controlling this disease. Conclusion From the above-discussed findings regarding antihistamines and Covid-19, specific antihistamines should be identified and included as an essential therapeutic approach for the management of Covid-19 alongside other approaches. In fact, antihistamines appear to be promising in the management of Covid-19 with a short time to relieve symptoms while giving the body enough time to reset its defense mechanism, thus reaching a rapid recovery. They work by both modulating histamine pathways and suppressing virus growth. Despite the fact that more trials and clinical studies still need to be done on the identification and deployment of potential antihistamines in the management of Covid-19, there is not enough time for this given the enormous threat of this global health crisis. Selective antihistamines, particularly histamine H1 receptor antagonists, should now be approved for emergency use for the management of Covid-19.

AbstractRecently, COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants, caused &gt; 6 million deaths. Symptoms included respiratory strain and complications, leading to severe pneumonia. SARS-CoV-2 attaches to the ACE-2 receptor of the host cell membrane to enter. Targeting the SARS-CoV-2 entry may effectively inhibit infection. Acid sphingomyelinase (ASMase) is a lysosomal protein that catalyzes the conversion of sphingolipid (sphingomyelin) to ceramide. Ceramide molecules aggregate/assemble on the plasma membrane to form “platforms” that facilitate the viral intake into the cell. Impairing the ASMase activity will eventually disrupt viral entry into the cell. In this review, we identified the metabolism of sphingolipids, sphingolipids' role in cell signal transduction cascades, and viral infection mechanisms. Also, we outlined ASMase structure and underlying mechanisms inhibiting viral entry 40 with the aid of inhibitors of acid sphingomyelinase (FIASMAs). In silico molecular docking analyses of FIASMAs with inhibitors revealed that dilazep (S = − 12.58 kcal/mol), emetine (S = − 11.65 kcal/mol), pimozide (S = − 11.29 kcal/mol), carvedilol (S = − 11.28 kcal/mol), mebeverine (S = − 11.14 kcal/mol), cepharanthine (S = − 11.06 kcal/mol), hydroxyzin (S = − 10.96 kcal/mol), astemizole (S = − 10.81 kcal/mol), sertindole (S = − 10.55 kcal/mol), and bepridil (S = − 10.47 kcal/mol) have higher inhibition activity than the candidate drug amiodarone (S = − 10.43 kcal/mol), making them better options for inhibition.

Given the current scarcity of curative treatment of COVID-19, the search for an effective treatment modality among all available medications has become a priority. This study aimed at investigating the role of functional inhibitors of acid sphingomyelinase (FIASMAs) on in-hospital COVID-19 mortality. In this retrospective cohort study, we included adult in-patients with laboratory-confirmed COVID-19 between 1 March 2020 and 31 August 2020 with definite outcomes (discharged hospital or deceased) from Erasme Hospital (Brussels, Belgium). We used univariate and multivariate logistic regression models to explore the risk factors associated with in-hospital mortality. We included 350 patients (205 males, 145 females) with a mean age of 63.24 years (SD = 17.4, range: 21–96 years). Seventy-two patients died in the hospital and 278 were discharged. The four most common comorbidities were hypertension (184, 52.6%), chronic cardiac disease (110, 31.4%), obesity (96, 27.8%) and diabetes (95, 27.1%). Ninety-three participants (26.6%) received a long-term prescription for FIASMAs. Among these, 60 (64.5%) received amlodipine. For FIASMAs status, multivariable regression showed increasing odds ratio (OR) for in-hospital deaths associated with older age (OR 1.05, 95% CI: 1.02–1.07; p = 0.00015), and higher prevalence of malignant neoplasm (OR 2.09, 95% CI: 1.03–4.22; p = 0.039). Nonsignificant decreasing OR (0.53, 95% CI: 0.27–1.04; p = 0.064) was reported for FIASMA status. For amlodipine status, multivariable regression revealed increasing OR of in-hospital deaths associated with older age (OR 1.04, 95% CI: 1.02–1.07; p = 0.0009), higher prevalence of hypertension (OR 2.78, 95% CI: 1.33–5.79; p = 0.0062) and higher prevalence of malignant neoplasm (OR 2.71, 95% CI: 1.23–5.97; p = 0.013), then secondarily decreasing OR of in-hospital death associated with long-term treatment with amlodipine (OR 0.24, 95% CI: 0.09–0.62; p = 0.0031). Chronic treatment with amlodipine could be significantly associated with low mortality of COVID-19 in-patients.