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SARS-CoV-2 and COVID-19
Published in Patricia G. Melloy, Viruses and Society, 2023
In addition to monoclonal antibody therapy, antiviral drugs specific to SARS-CoV-2 are starting to be developed. In late 2021, successful clinical trials were completed on two antiviral drugs given in the form of a pill to fight SARS-CoV-2: Molnupiravir and Paxlovid. Molnupiravir works by causing errors in the viral genome during replication, and Paxlovid works by interfering with the maturing of certain viral proteins to stop SARS-CoV-2 (Jayk Bernal et al. 2021; Gordon et al. 2021; Mahase 2021; Ledford 2021).
Drug Repurposing and Novel Antiviral Drugs for COVID-19 Management
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Shailendra Dwivedi, Aakanksha Rawat, Amit Ranjan, Ruchika Agrawal, Radhieka Misra, Sunil Kumar Gupta, Surekha Kishore, Sanjeev Misra
Molnupiravir (MK-4482 [previously EIDD-2801]; Merck) is an oral antiviral agent that is a prodrug of the nucleoside derivative N4-hydroxycytidine. It elicits antiviral effects by introducing copying errors during viral RNA replication of the SARS-CoV-2. Preliminary results from the phase II dose-ranging MOVe-OUT study (n = 2,020) showed at an average of 10 days after symptoms onset, 24% of patients in the placebo group remained positive for infectious SARS-CoV-2, whereas no infectious virus could be detected in any molnupiravir-treated outpatient. The in-patient molnupiravir study (MOVe-IN) has been discontinued, but the phase III trial in outpatients who have at least one risk factor for poor outcomes (for example, advanced age, obesity, diabetes) is proceeding with patients receiving 800 mg molnupiravir orally twice daily [16].
Chest
Published in Henry J. Woodford, Essential Geriatrics, 2022
Steroids have a clear mortality benefit in severe COVID-19 but no beneficial effect in mild disease. Dexamethasone reduced 28-day mortality in people receiving mechanical ventilation (29.3% v 41.4%) and people receiving oxygen without ventilation (23.3% v 26.2%).68 There was no benefit for people not requiring oxygen. IL-6 receptor blockers (e.g. tocilizumab and sarilumab) are monoclonal antibodies originally used for rheumatoid arthritis. Their action reduces cytokine release. Trial results have been mixed.60 The RECOVERY trial recruited people (mean age 63) with hypoxia (oxygen saturation < 92% on air or requiring oxygen therapy) and evidence of systemic inflammation (serum CRP 75 mg/L or over).69 Mortality with tocilizumab was significantly lower than with usual care (31% v 35%). IL-6 receptor blockers are recommended, in addition to steroids, for people with severe or critical COVID-19.64 The monoclonal antibodies casirivimab and imdevimab can be used in combination for people hospitalised with COVID-19 who have no detectable serum SARS-CoV-2 antibodies.70 Remdesivir is an anti-viral drug that inhibits viral RNA transcription. It may improve time to recovery but has no mortality benefit for COVID-19. At the time of writing, its use is not currently recommended outside of clinical trials.70 Oral antiviral medications, including molnupiravir, are also being developed and appear to reduce the risk of hospital admission or death in people with mild to moderate symptoms.71
Molnupiravir as the COVID-19 panacea: false beliefs in low- and middle-income countries
Published in Pathogens and Global Health, 2023
Ngoc-Ha Tran, Nguyen Khoi Quan, Van Phu Tran, Dang Nguyen, Ngoc Phuong Hong Tao, Nguyen Ngoc Hoang Linh, Nguyen Tien Huy
COVID-19 has led to a skyrocketing demand for advanced pharmaceutical interventions, primarily antiviral drugs and vaccines. In terms of vaccinations, literature has shown that receiving a full two-dose immunization with some vaccines offer only sporadic defense against symptomatic illness. Even though a booster could significantly enhance protection, it rapidly deteriorates over time [1]. There are still questions about the safety and efficacy of some medications, such as molnupiravir, which are used in conjunction with other treatments. In the early stages of the COVID-19 pandemic, molnupiravir was one of the first drugs officially acknowledged to significantly reduce the risk of hospitalization and death in adults with mild to moderate COVID-19 symptoms [2]. There is a lack of long-term safety data for this treatment, which is expected given that this is a rapid medical breakthrough. However, a trial has recently found that molnupiravir is not more effective than a placebo at reducing the risk of death and hospitalization [3].
Neutralizing anti-spike monoclonal antibodies for COVID-19 in vulnerable populations: lessons learned and future directions
Published in Expert Opinion on Biological Therapy, 2023
Intravenous remdesivir and oral ritonavir-boosted nirmatrelvir have emerged as two highly effective first-line treatment options for mild-to-moderate COVID-19 in high-risk individuals. Their use is supported by RCT, which demonstrated that they were safe and efficacious [42–44]. Molnupiravir is a less effective oral antiviral drug that is available as alternative for patients unable to receive remdesivir or ritonavir-boosted nirmatrelvir. These small molecule antiviral drugs have supplemented the COVID-19 therapeutic landscape with the loss of anti-spike monoclonal antibodies. Reassuringly, SARS-CoV-2 resistance to these antiviral drugs remain uncommon. Ritonavir-boosted nirmatrelvir is particularly an attractive first-line option because it is given orally, and provides the convenience of treatment at home, without the need for intravenous access. However, ritonavir-boosted nirmatrelvir is loaded with many potential drug interactions that limits its use in many high-risk patients, especially those receiving certain cardiac, neurologic, and immunosuppressive drugs. For these patients, intravenous remdesivir is another option, but this is logistically challenging to administer as it will require once daily infusions at COVID-19 dedicated infusion facilities. Many COVID-19 infusion facilities have closed after the demise of the outpatient monoclonal antibody therapies. An oral formulation of remdesivir is currently undergoing clinical trials.
Ligand-based design, synthesis, computational insights, and in vitro studies of novel N-(5-Nitrothiazol-2-yl)-carboxamido derivatives as potent inhibitors of SARS-CoV-2 main protease
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Mohamed Elagawany, Ayman Abo Elmaaty, Ahmed Mostafa, Noura M. Abo Shama, Eman Y. Santali, Bahaa Elgendy, Ahmed A. Al-Karmalawy
Lately, a new synthetic nucleoside derivative prodrug, named molnupiravir, was approved in the U.K for COVID-19 treatment. Molnupiravir acts by copying errors during RNA virus replication26. It is an active orally RdRp inhibitor with reasonable pharmacokinetic features. It has gained significant attention for its capability to inhibit the spreading of SARS-CoV-2, with a remarkable reduction in the viral load and quick recovery time27. A single-dose administration of molnupiravir produces a mean Cmax of 13.2 ng/mL and tmax between 0.25 and 0.75 h with a biological t1/2 of 7 h. It was suggested that molnupiravir has no accumulative toxicity and that was assured by its area under the plasma concentration versus time following multiple doses, increases with no accumulation in a dose-proportional manner27. Moreover, molnupiravir could exhibit rapid onset, a wide therapeutic window, and fewer side effects with good tolerability and safety profile. Hence, it can be considered a very promising therapeutic intervention against SARS-CoV-227. Additionally, the oral antiviral drug, named PF-07321332, was developed by Pfizer For COVID-19 treatment as well. PF-07321332 acts as an active Mpro inhibitor of the virus26. Protease inhibitors act by interrupting the protease enzyme cutting, thus, the polypeptide processing to smaller protein is blocked. PF-07321332 is co-administered with ritonavir in low doses as a booster to enhance the PF-07321332 bloodstream levels28. The combination of ritonavir/PF-07321332 was marketed as paxlovid26.