Chloroquine and Hydroxychloroquine: Efficacy in the Treatment of the COVID-19

Ho, Tzu-Chuan; Wang, Yung-Hsuan; Tsai, Wan–Chi; Lee, Che‐Hsin; Chuang, Kui-Hao; Chen, Yi-Ming Arthur; Yuan, Cheng-Hui; Ho, Sheng-Yow; Yang, Minghui; Tyan, Yu‐Chang

doi:10.3390/pathogens10020217

Cited by 27 publications

(22 citation statements)

References 29 publications

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“…Inhibition of MASP-2 using HG4 significantly impairs complement C3b deposition on the surface of HEK 293T cells expressing S protein. Many other complement inhibitors and anti-inflammatory drugs have been re-purposed and evaluated in COVID-19 clinical trials but, to date, none of those other agents have yielded a breakthrough in the treatment of severe COVID-19 (22)(23)(24)(25)(26)(27). While vaccination is reducing hospitalisation, there is a fear of possible reduction in the efficacy against the new variants, which are responsible for severe cases of COVID-19 in younger age groups.…”

Section: Discussionmentioning

confidence: 99%

Lectin Pathway Mediates Complement Activation by SARS-CoV-2 Proteins

et al. 2021

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Early and persistent activation of complement is considered to play a key role in the pathogenesis of COVID-19. Complement activation products orchestrate a proinflammatory environment that might be critical for the induction and maintenance of a severe inflammatory response to SARS-CoV-2 by recruiting cells of the cellular immune system to the sites of infection and shifting their state of activation towards an inflammatory phenotype. It precedes pathophysiological milestone events like the cytokine storm, progressive endothelial injury triggering microangiopathy, and further complement activation, and causes an acute respiratory distress syndrome (ARDS). To date, the application of antiviral drugs and corticosteroids have shown efficacy in the early stages of SARS-CoV-2 infection, but failed to ameliorate disease severity in patients who progressed to severe COVID-19 pathology. This report demonstrates that lectin pathway (LP) recognition molecules of the complement system, such as MBL, FCN-2 and CL-11, bind to SARS-CoV-2 S- and N-proteins, with subsequent activation of LP-mediated C3b and C4b deposition. In addition, our results confirm and underline that the N-protein of SARS-CoV-2 binds directly to the LP- effector enzyme MASP-2 and activates complement. Inhibition of the LP using an inhibitory monoclonal antibody against MASP-2 effectively blocks LP-mediated complement activation. FACS analyses using transfected HEK-293 cells expressing SARS-CoV-2 S protein confirm a robust LP-dependent C3b deposition on the cell surface which is inhibited by the MASP-2 inhibitory antibody. In light of our present results, and the encouraging performance of our clinical candidate MASP-2 inhibitor Narsoplimab in recently published clinical trials, we suggest that the targeting of MASP-2 provides an unsurpassed window of therapeutic efficacy for the treatment of severe COVID-19.

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Section: Discussionmentioning

confidence: 99%

Lectin Pathway Mediates Complement Activation by SARS-CoV-2 Proteins

et al. 2021

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“…Recent studies show that CQ is not effective in treating patients with severe COVID-19. Moreover, it causes serious side effects, which may cause potential cardiac toxicity in patients with severe COVID-19 [ 138 ].…”

Section: Viral Infection and Autophagymentioning

confidence: 99%

Autophagy, Unfolded Protein Response, and Neuropilin-1 Cross-Talk in SARS-CoV-2 Infection: What Can Be Learned from Other Coronaviruses

Siri

Dastghaib

Zamani

et al. 2021

IJMS

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The COVID-19 pandemic is caused by the 2019–nCoV/SARS-CoV-2 virus. This severe acute respiratory syndrome is currently a global health emergency and needs much effort to generate an urgent practical treatment to reduce COVID-19 complications and mortality in humans. Viral infection activates various cellular responses in infected cells, including cellular stress responses such as unfolded protein response (UPR) and autophagy, following the inhibition of mTOR. Both UPR and autophagy mechanisms are involved in cellular and tissue homeostasis, apoptosis, innate immunity modulation, and clearance of pathogens such as viral particles. However, during an evolutionary arms race, viruses gain the ability to subvert autophagy and UPR for their benefit. SARS-CoV-2 can enter host cells through binding to cell surface receptors, including angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP1). ACE2 blockage increases autophagy through mTOR inhibition, leading to gastrointestinal complications during SARS-CoV-2 virus infection. NRP1 is also regulated by the mTOR pathway. An increased NRP1 can enhance the susceptibility of immune system dendritic cells (DCs) to SARS-CoV-2 and induce cytokine storm, which is related to high COVID-19 mortality. Therefore, signaling pathways such as mTOR, UPR, and autophagy may be potential therapeutic targets for COVID-19. Hence, extensive investigations are required to confirm these potentials. Since there is currently no specific treatment for COVID-19 infection, we sought to review and discuss the important roles of autophagy, UPR, and mTOR mechanisms in the regulation of cellular responses to coronavirus infection to help identify new antiviral modalities against SARS-CoV-2 virus.

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“…At the onset of the pandemic, chloroquine and hydroxychloroquine with or without antibiotics, including azithromycin were recommended. Subsequent investigations demonstrated that these agents do not affect mortality (7)(8)(9)(10). Meanwhile, the effect of remdesivir was indicated to be different in variable studies (11,12).…”

Section: Introductionmentioning

confidence: 99%

Cost-Effectiveness of Remdesivir Plus Supportive Care for Patients with COVID-19 in Iran

Gholamhoseini

Goudarzi

Yazdi‐Feyzabadi

et al. 2021

Preprint

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Background: Remdesivir is a medication used for moderate to severe Coronavirus disease 2019 (COVID-19) patients with favorable effects. However, it is an expensive medication. Therefore, the present study aimed to assess the cost-effectiveness of remdesivir plus supportive care (SC) for COVID-19 patients in Iran.Methods: Markov model was used to compare costs and quality-adjusted life-days (QALDs) of remdesivir+SC and SC for patients with COVID-19. The model simulated a cycle length of one day and a 30-day time horizonin TreeAge 2020 software. The costs from the healthcare system perspective were obtained from Afzalipour hospital as a referral hospital for the hospitalization of COVID-19 patients in Kerman, Iran. All the costs were converted to 2018 purchasing power parity (PPP) US dollars. Utility values were derived from published sources. The results were presented as an incremental cost-effectiveness ratio (ICER) at a willingness-to-pay (WTP) threshold of three times the Gross Domestic Product per capita of Iran. Both deterministic and probabilistic sensitivity analyses were performed.Results: The base-case results showed that the treatment of COVID-19 patients with remdesivir+SC had a cost of 8795 PPP US dollars for 21.13 QALD gained. The SC alone cost 8637 PPP US dollars with a gain of 20.20 QALD. Our findings demonstrated that at a WTP threshold of 159 PPP US dollars per QALD, remdesivir+SC was not cost-effective with an ICER of 168 PPP US dollars per QALD. Deterministic sensitivity analysis indicated ICER to be sensitive to the transition probabilities and costs. Probabilistic sensitivity analysis revealed that remdesivir+SC was cost-effective at a WTP of 159 PPP US dollars per QALD in 47% of iterations.Conclusions: Our findings demonstrated thatremdesivir+SC is not cost-effective, compared to SC alone. Considering the lack of studies on the effectiveness of remdesivir, the findings should be interpreted with caution. Further evaluations are recommended to determine the efficacy and effectiveness of remdesivir in COVID-19 patients.

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Chloroquine and Hydroxychloroquine: Efficacy in the Treatment of the COVID-19

Cited by 27 publications

References 29 publications

Lectin Pathway Mediates Complement Activation by SARS-CoV-2 Proteins

Lectin Pathway Mediates Complement Activation by SARS-CoV-2 Proteins

Autophagy, Unfolded Protein Response, and Neuropilin-1 Cross-Talk in SARS-CoV-2 Infection: What Can Be Learned from Other Coronaviruses

Cost-Effectiveness of Remdesivir Plus Supportive Care for Patients with COVID-19 in Iran

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