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BACKGROUND: Camostat inhibits SARS-CoV-2 infection in vitro. We studied the safety and efficacy of camostat in ACTIV-2/A5401, a phase 2/3 platform trial of therapeutics for COVID-19 in non-hospitalized adults. METHODS: We conducted a phase 2 study in adults with mild-to-moderate COVID-19 randomized to oral camostat for 7 days or a pooled placebo arm. Primary outcomes were time to improvement in COVID-19 symptoms through day 28, proportion of participants with SARS-CoV-2 RNA below the lower limit of quantification (LLoQ) from nasopharyngeal (NP) swabs through day 14, and grade ≥3 treatment-emergent adverse events (TEAEs) through day 28. RESULTS: Of 216 participants (109 randomized to camostat, 107 to placebo) who initiated study intervention, 45% reported ≤5 days of symptoms at study entry and 26% met the protocol definition of higher risk of progression to severe COVID-19. Median age was 37 years. Median time to symptom improvement was 9 days in both arms (p=0.99). There were no significant differences in the proportion of participants with SARS-CoV-2 RNA
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Background: Severe viral pneumonia cases were observed in the people of Wuhan, China in December 2019. It has already affected almost every country around the globe and was declared a pandemic by the World Health Organization. We aim to evaluate the therapeutics and safety of various off label COVID-19 drugs. Method(s): PubMed, Research Gate, Science Direct, Google Scholar, Centre for Disease control and prevention (CDC) portal, Chinese Centre for Disease Control and prevention (CCDC) portal, World Health Organization (WHO) portal were searched for obtaining reliable data. Result(s): COVID-19 is creating a storm of deaths and active cases globally, which is forcing the pharmaceutical companies and scientists to work day and night to find an effective and safer anti-COVID-19 medication. Various in vitro and clinical trials had been performed as well as are currently ongoing to analyze the mechanisms and therapeutics of off label medications like Chloroquine, Hydroxychloro-quine, Amodiaquine, Azithromycin, Remdesivir, Favipiravir, Ritonavir/Lopinavir, Umifenovir, Osel-tamivir, Ribavirin, Nafamostat, Camostat, Tocilizumab, Ivermectin, Nitazoxanide, Famotidine, Vitamin D, Corticosteroids and Dexamethasone. In vitro studies were performed by utilizing Vero E6 cells and hSLAM cells while open/closed, randomized/non-randomized, single-centered/multi-centered and retrospective clinical trials and case studies were organized to determine their safety and efficacy. Conclusion(s): Although these drugs have shown promising results against COVID-19 patients, it cannot be concluded that these drugs are truly safe and effective because there are no conclusive evidence to support the facts since only limited researches and studies had been investigated.Copyright © 2021 Bentham Science Publishers.
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The 2019 novel coronavirus (SARS-CoV-2) causes severe pneumonia called COVID-19 and leads to severe acute respiratory syndrome with a high mortality rate. The SARS-CoV-2 virus in the human body leads to jumpstarting immune reactions and multi-organ inflammation, which has poorer outcomes in the presence of predisposing conditions, including hypertension, dyslipidemia, dysglycemia, abnormal adiposity, and even endothelial dysfunction via biomolecular mechanisms. In addition, leucopenia, hypoxemia, and high levels of both cytokines and chemokines in the acute phase of this disease, as well as some abnormalities in chest CT images, were reported in most patients. The spike protein in SARS-CoV-2, the primary cell surface protein, helps the virus anchor and enter the human host cells. Additionally, new mutations have mainly happened for spike protein, which has promoted the infection's transmissibility and severity, which may influence manufactured vaccines' efficacy. The exact mechanisms of the pathogenesis, besides molecular aspects of COVID-19 related to the disease stages, are not well known. The altered molecular functions in the case of immune responses, including T CD4+, CD8+, and NK cells, besides the overactivity in other components and outstanding factors in cytokines like interleukin-2, were involved in severe cases of SARS-CoV-2. Accordingly, it is highly needed to identify the SARS-CoV-2 bio-molecular characteristics to help identify the pathogenesis of COVID-19. This study aimed to investigate the bio-molecular aspects of SARS-CoV-2 infection, focusing on novel SARS-CoV-2 variants and their effects on vaccine efficacy.Copyright © 2022 NRITLD, National Research Institute of Tuberculosis and Lung Disease, Iran.
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Background: The newly emerged delta and omicron variants of severe acute respiratory syn-drome coronavirus (SARS-CoV-2) have affected millions of individuals globally with increased transmis-sible and infectivity rates. Although, numerous vaccines are available or under clinical trials to combat the SARS-CoV-2 and its variant, still, a therapeutic agent is awaited. Objective(s): The present work is focused on rigorous screening of chemical constituents of Azadirachta indica (A. indica) against delta and omicron variants of SARS-CoV-2 via inhibition of S-glycoprotein. Method(s): Total, 10 compounds of A. indica were subjected to molecular docking and pharmacophore modeling studies against the S-glycoprotein of delta and omicron variants of SARS-CoV-2. Furthermore, homology modeling was performed for omicron S-glycoprotein with the help of SWISS-MODEL and aligned by PyMOL software. Later on, the residues of protein were verified in the allowed region via Ramachandran plot. In addition, our docking results have also been validated by MMGBSA binding free energy calculations. Result(s): Our computed study demonstrated that nimbolinin B12-methyl ether and nimbidinin showed promising docking scores (>-6.0) as compared to docking scores (< 6.0) of reference drug 'camostat' against S-glycoproteins of both delta and omicron variants. Redocking by using MMGBSA calculation also reveals that both these compounds can effectively bind within the pockets of said protein receptors Conclusion(s): Nimbolinin B12-methyl ether and nimbidinin have potent anti-SARS-CoV activity against delta and omicron variants and thus, A. indica might be a useful source for developing novel anti-SARS-CoV-2 therapeutic agents.Copyright © 2022 Bentham Science Publishers.
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Although several antiviral agents have become available for coronavirus disease 2019 (COVID-19) treatment, oral drugs are still limited. Camostat mesylate, an orally bioavailable serine protease inhibitor, has been used to treat chronic pancreatitis in South Korea, and it has an in vitro inhibitory potential against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study was a double-blind, randomized, placebo-controlled, multicenter, phase 2 clinical trial in mild to moderate COVID-19 patients. We randomly assigned patients to receive either camostat mesylate (DWJ1248) or placebo orally for 14 days. The primary endpoint was time to clinical improvement of subject symptoms within 14 days, measured using a subjective 4-point Likert scale. Three hundred forty-two patients were randomized. The primary endpoint was nonsignificant, where the median times to clinical improvement were 7 and 8 days in the camostat mesylate group and the placebo group, respectively (hazard ratio [HR] = 1.09; 95% confidence interval [CI], 0.84 to 1.43; P = 0.50). A post hoc analysis showed that the difference was greatest at day 7, without reaching significance. In the high-risk group, the proportions of patients with clinical improvement up to 7 days were 45.8% (50/109) in the camostat group and 38.4% (40/104) in the placebo group (odds ratio [OR] = 1.33; 95% CI, 0.77 to 2.31; P = 0.31); the ordinal scale score at day 7 improved in 20.0% (18/90) of the camostat group and 13.3% (12/90) of the placebo group (OR = 1.68; 95% CI, 0.75 to 3.78; P = 0.21). Adverse events were similar in the two groups. Camostat mesylate was safe in the treatment of COVID-19. Although this study did not show clinical benefit in patients with mild to moderate COVID-19, further clinical studies for high-risk patients are needed. (This trial was registered with ClinicalTrials.gov under registration no. NCT04521296).
Subject(s)
COVID-19 , Humans , Adult , SARS-CoV-2 , Guanidines , Esters , Double-Blind Method , Treatment OutcomeABSTRACT
The current viral pandemic, coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), creates health, mental, economic, and other serious challenges that are better to say global crisis. Despite the existence of successful vaccines, the possible mutations which can lead to the born of novel and possibly more dangerous variants of the virus as well as the absence of definitive treatment for this potentially fatal multiple-organ infection in critically ill patients make us keep searching. Theoretically targeting human and viral receptors and enzymes via molecular docking and dynamics simulations can be considered a wise, rational, and efficient way to develop therapeutic agents against COVID-19. In this way, The RNA-dependent RNA polymerase (RdRP), main protease, and spike glycoprotein of SARS-CoV-2 as well as the human angiotensin-converting enzyme 2 receptor and transmembrane serine protease 2 are the most discussed and studied targets that play essential roles in the viral life and infection cycle. In the current in silico investigation, the guanidine functionality containing drugs and medicinal substances such as metformin, famotidine, neuraminidase inhibitors, antimalarial medications, anticancer drug imatinib, CGP compounds, and human serine protease inhibitor camostat were studied against the above-mentioned therapeutic targets and most of them (especially imatinib) have revealed an incredible spectrum of free docking scores and MD results. The current in silico investigation that its novel perspective of view is corroborated by the different experimental and clinical evaluations, confirms that the guanidine moiety can be considered as a missing promising pharmacophore in drug design and development approaches against SARS-CoV-2. Considering the chemical potency of this polyamine group in chemical interaction creation, the observed outcomes in this virtual screening were not surprising. On the other hand, the guanidine functional group has unique physico-chemical properties such as basicity that can make the target cells intracellular pH undesirable for the virus entry, uncoating, and cytosolic lifecycle. According to the obtained results in the current study that are interestingly confirmed by the previously reported efficacy of some the guanidine carrying drugs in COVID-19, guanidine as a potential multi-target anti-SARS-CoV-2 functional scaffold deserves further comprehensive investigations. Supplementary Information: The online version contains supplementary material available at 10.1007/s11696-022-02528-y.
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BACKGROUND: In vitro drug screening studies have indicated that camostat mesilate (FOY-305) may prevent SARS-CoV-2 infection into human airway epithelial cells. This study was conducted to investigate whether camostat mesilate is an effective treatment for SARS-CoV-2 infection (COVID-19). METHODS: This was a multicenter, double-blind, randomized, parallel-group, placebo-controlled study. Patients were enrolled if they were admitted to a hospital within 5 days of onset of COVID-19 symptoms or within 5 days of a positive test for asymptomatic patients. Severe cases (e.g., those requiring oxygenation/ventilation) were excluded. Patients were enrolled, randomized, and allocated to each group using an interactive web response system. Randomization was performed using a minimization method with the factors medical institution, age, and underlying diseases (chronic respiratory disease, chronic kidney disease, diabetes mellitus, hypertension, cardiovascular diseases, and obesity). The patients, investigators/subinvestigators, study coordinators, and other study personnel were blinded throughout the study. Patients were administered camostat mesilate (600 mg qid; four to eight times higher than the clinical doses in Japan) or placebo for up to 14 days. The primary efficacy endpoint was the time to the first two consecutive negative tests for SARS-CoV-2. RESULTS: One-hundred fifty-five patients were randomized to receive camostat mesilate (n = 78) or placebo (n = 77). The median time to the first test was 11.0 days (95% confidence interval [CI]: 9.0-12.0) in the camostat mesilate group and 11.0 days (95% CI: 10.0-13.0) in the placebo group. Conversion to negative viral status by day 14 was observed in 45 of 74 patients (60.8%) in the camostat mesilate group and 47 of 74 patients (63.5%) in the placebo group. The primary (Bayesian) and secondary (frequentist) analyses found no significant differences in the primary endpoint between the two groups. No additional safety concerns beyond those already known for camostat mesilate were identified. CONCLUSIONS: Camostat mesilate did not substantially reduce the time to viral clearance, based on upper airway viral loads, compared with placebo for treating patients with mild to moderate SARS-CoV-2 infection with or without symptoms. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04657497. Japan Registry for Clinical Trials, jRCT2031200198.
Subject(s)
COVID-19 Drug Treatment , Bayes Theorem , Double-Blind Method , Esters/adverse effects , Esters/therapeutic use , Guanidines/adverse effects , Guanidines/therapeutic use , Humans , SARS-CoV-2 , Treatment OutcomeABSTRACT
Three directly acting antivirals (DAAs) demonstrated substantial reduction in COVID-19 hospitalizations and deaths in clinical trials. However, these agents did not completely prevent severe illness and are associated with cases of rebound illness and viral shedding. Combination regimens can enhance antiviral potency, reduce the emergence of drug-resistant variants, and lower the dose of each component in the combination. Concurrently targeting virus entry and virus replication offers opportunities to discover synergistic drug combinations. While combination antiviral drug treatments are standard for chronic RNA virus infections, no antiviral combination therapy has been approved for SARS-CoV-2. Here, we demonstrate that combining host-targeting antivirals (HTAs) that target TMPRSS2 and hence SARS-CoV-2 entry, with the DAA molnupiravir, which targets SARS-CoV-2 replication, synergistically suppresses SARS-CoV-2 infection in Calu-3 lung epithelial cells. Strong synergy was observed when molnupiravir, an oral drug, was combined with three TMPRSS2 (HTA) oral or inhaled inhibitors: camostat, avoralstat, or nafamostat. The combination of camostat plus molnupiravir was also effective against the beta and delta variants of concern. The pyrimidine biosynthesis inhibitor brequinar combined with molnupiravir also conferred robust synergistic inhibition. These HTA+DAA combinations had similar potency to the synergistic all-DAA combination of molnupiravir plus nirmatrelvir, the protease inhibitor found in paxlovid. Pharmacodynamic modeling allowed estimates of antiviral potency at all possible concentrations of each agent within plausible therapeutic ranges, suggesting possible in vivo efficacy. The triple combination of camostat, brequinar, and molnupiravir further increased antiviral potency. These findings support the development of HTA+DAA combinations for pandemic response and preparedness. IMPORTANCE Imagine a future viral pandemic where if you test positive for the new virus, you can quickly take some medicines at home for a few days so that you do not get too sick. To date, only single drugs have been approved for outpatient use against SARS-CoV-2, and we are learning that these have some limitations and may succumb to drug resistance. Here, we show that combinations of two oral drugs are better than the single ones in blocking SARS-CoV-2, and we use mathematical modeling to show that these drug combinations are likely to work in people. We also show that a combination of three oral drugs works even better at eradicating the virus. Our findings therefore bode well for the development of oral drug cocktails for at home use at the first sign of an infection by a coronavirus or other emerging viral pathogens.
Subject(s)
COVID-19 Drug Treatment , SARS-CoV-2 , Humans , Antiviral Agents/pharmacology , Protease Inhibitors/pharmacology , Drug Combinations , PyrimidinesABSTRACT
Diabetes is a chronic metabolic disorder emerging as a global burden. Diabetes serves as a risk factor for many complications inclusive of COVID-19. The SARS – 2 pathogens have led to Coronavirus disease. Coronaviruses are enveloped viruses with a single-stranded, positive-sense RNA genome recognized to cause respiratory infections in human beings. Diabetes patients being affected by coronavirus become more critical due to worsening hyperglycemia induces aggravation, endothelial dysfunction, and occlusion of blood vessels through the era of oxidative stress riding the down-regulation of glucose metabolism and hyperglycemia. Increased glucose level causes inflammation and tissue damage serves as a supportive factor for higher tissue damage in COVID patients. Sufferers with extreme COVID-19 have an exceptionally impaired interferon type 1 response with low IFN alpha activity in the blood, indicating excessive blood viral load, and an impaired inflammatory response. This can be alleviated by regular screening and appropriate therapy as like as metformin, camostat mesylate, chloroquine, and adjunctive therapy. Metformin is the desired preliminary drug to deal with T2DM. Camostat mesylate drug accelerated glycemia and insulin resistance and reduced fat buildup in mammalian models. Adjunctive treatment can be used to obviate the evolution of COVID-19.
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The pandemic, COVID-19, has caused social and economic disruption at a larger pace all over the world. Identification of an effective drug for the deadliest disease is still an exigency. One of the most promising approaches to combat the lethal disease is use of repurposed drugs. This study provides insights into some of the potential repurposed drugs viz. camostat mesylate, hydroxychloroquine, nitazoxanide, and oseltamivir in terms of the computational quantum chemical method. Properties of these compounds have been elucidated in terms of Conceptual Density Functional Theory (CDFT)-based descriptors, IR spectra, and thermochemical properties. Computed results specify that hydroxychloroquine is the most reactive drug among them. Thermochemical data reveals that camostat mesylate has the utmost heat capacity, entropy, and thermal energy. Our findings indicate that camostat mesylate and hydroxychloroquine may be investigated further as potential COVID-19 therapeutics. We anticipate that the current study will aid the scientific community to design and develop viable therapeutics against COVID-19.
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Lipid rafts in cell plasma membranes play a critical role in the life cycle of many viruses. However, the involvement of membrane cholesterol-rich lipid rafts in the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into target cells is not well known. In this study, we investigated whether the presence of cholesterol-rich microdomains is required for the entry of SARS-CoV-2 into host cells. Our results show that depletion of cholesterol in the rafts by methyl-beta-cyclodextrin (MßCD) treatment impaired the expression of the cell surface receptor angiotensin-converting enzyme 2 (ACE2), resulting in a significant increase in SARS-CoV-2 entry into cells. The effects exerted by MßCD could be substantially reversed by exogenous cholesterol replenishment. In contrast, disturbance of intracellular cholesterol homeostasis by statins or siRNA knockdown of key genes involved in the cholesterol biosynthesis and transport pathways reduced SARS-CoV-2 entry into cells. Our study also reveals that SREBP2-mediated cholesterol biosynthesis is involved in the process of SARS-CoV-2 entry in target cells. These results suggest that the host membrane cholesterol-enriched lipid rafts and cellular cholesterol homeostasis are essential for SARS-CoV-2 entry into cells. Pharmacological manipulation of intracellular cholesterol might provide new therapeutic strategies to alleviate SARS-CoV-2 entry into cells.
Subject(s)
COVID-19 , SARS-CoV-2 , Cholesterol/metabolism , Homeostasis , Humans , Membrane Microdomains , Virus InternalizationABSTRACT
Background: To date, no oral antiviral drug has proven to be beneficial in hospitalized patients with COVID-19. Methods: In this randomized, controlled, open-label, platform trial, we randomly assigned patients ≥18 years hospitalized with COVID-19 pneumonia to receive either camostat mesylate (CM) (considered standard-of-care) or lopinavir/ritonavir (LPV/RTV). The primary endpoint was time to sustained clinical improvement (≥48 h) of at least one point on the 7-category WHO scale. Secondary endpoints included length of stay (LOS), need for mechanical ventilation (MV) or death, and 29-day mortality. Results: 201 patients were included in the study (101 CM and 100 LPV/RTV) between 20 April 2020 and 14 May 2021. Mean age was 58.7 years, and 67% were male. The median time from symptom onset to randomization was 7 days (IQR 5-9). Patients in the CM group had a significantly shorter time to sustained clinical improvement (HR = 0.67, 95%-CI 0.49-0.90; 9 vs. 11 days, p = 0.008) and demonstrated less progression to MV or death [6/101 (5.9%) vs. 15/100 (15%), p = 0.036] and a shorter LOS (12 vs. 14 days, p = 0.023). A statistically nonsignificant trend toward a lower 29-day mortality in the CM group than the LPV/RTV group [2/101 (2%) vs. 7/100 (7%), p = 0.089] was observed. Conclusion: In patients hospitalized for COVID-19, the use of CM was associated with shorter time to clinical improvement, reduced need for MV or death, and shorter LOS than the use of LPV/RTV. Furthermore, research is needed to confirm the efficacy of CM in larger placebo-controlled trials. Systematic Review Registration: [https://clinicaltrials.gov/ct2/show/NCT04351724, https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001302-30/AT], identifier [NCT04351724, EUDRACT-NR: 2020-001302-30].
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Background: The effectiveness of combination therapy for COVID-19 pneumonia remains unclear. We evaluated favipiravir, camostat, and ciclesonide combination therapy in patients with moderate COVID-19 pneumonia. Methods: In this open-label phase 3 study, hospitalized adults who were positive for SARS-CoV-2 and had COVID-19 pneumonia were enrolled prior to official vaccination drive in Japan. Participants were randomly assigned to favipiravir monotherapy or favipiravir + camostat + ciclesonide combination therapy. The primary outcome was the length of hospitalization due to COVID-19 infection after study treatment. The hospitalization period was calculated from the time of admission to the time of patient discharge using the clinical management guide of COVID-19 for front-line healthcare workers developed by the Japanese Ministry of Health, Labour, and Welfare (Version 3). Cases were registered between November 11, 2020, and May 31, 2021. Japan Registry of Clinical Trials registration: jRCTs031200196. Findings: Of 121 enrolled patients, 56 received monotherapy and 61 received combination therapy. Baseline characteristics were balanced between the groups. The median time of hospitalization was 10 days for the combination and 11 days for the monotherapy group. The median time to discharge was statistically significantly lower in the combination therapy vs monotherapy group (HR, 1·67 (95% CI 1·03-2·7; P = 0·035). The hospital discharge rate was statistically significantly higher in the combination therapy vs monotherapy group in patients with less severe COVID-19 infections and those who were ≤60 years. There were no significant differences in clinical findings between the groups at 4, 8, 11, 15, and 29 days. Adverse events were comparable between the groups. There were two deaths, with one in each group. Interpretation: Combination oral favipiravir, camostat and, ciclesonide therapy could decrease the length of hospitalization stays without safety concerns in patients with moderate COVID-19 pneumonia. However, lack of hard clinical primary outcome is one of the major limitations of the study. Funding: This research was supported by Japan Agency for Medical Research and Development (AMED) under Grant Number 20fk0108261h0001.
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OBJECTIVES: This study aimed to assess the efficacy and safety of 300 mg camostat mesylate three times daily in a fasted state to treat early phase COVID-19 in an ambulatory setting. METHODS: We conducted a phase II randomized controlled trial in symptomatic (maximum 5 days) and asymptomatic patients with confirmed COVID-19 infection. Patients were randomly assigned in a 2:1 ratio to receive either camostat mesylate or a placebo. Outcomes included change in nasopharyngeal viral load, time to clinical improvement, the presence of neutralizing antibodies, and safety. RESULTS: Of 96 participants randomized between November 2020 and June 2021, analyses were performed on the data of 90 participants who completed treatment (N = 61 camostat mesylate, N = 29 placebo). The estimated mean change in cycle threshold between day 1 and day 5 between the camostat and placebo group was 1.183 (P = 0.511). The unadjusted hazard ratio for clinical improvement in the camostat group was 0.965 (95% confidence interval, 0.480-1.942, P = 0.921 by Cox regression). The percentage distribution of the 50% neutralizing antibody titer at day 28 visit and frequency of adverse events were similar between the two groups. CONCLUSION: Under this protocol, camostat mesylate was not found to be effective as an antiviral drug against SARS-CoV-2. TRIAL REGISTRATION: ClinicalTrials.gov NCT04625114; November 12, 2020.
Subject(s)
COVID-19 Drug Treatment , Double-Blind Method , Esters , Guanidines , Humans , SARS-CoV-2 , Treatment OutcomeABSTRACT
Background: Camostat, an oral protease inhibitor, blocks entry and replication of SARS-CoV-1 and SARS-CoV-2 in vitro. It is approved for therapy of recurrent pancreatitis in several countries. Camostat has an excellent safety profile and repurposing for COVID-19 treatment was proposed. Methods: We conducted a Phase II randomized, placebo-controlled trial of camostat in adult outpatients with confirmed COVID-19 and one or more risk factors for severe disease (including age ≥65 years, severe obesity, hypertension, diabetes, chronic lung, heart or liver disease). Participants were randomized 2:1 to oral camostat 200 mg or matching placebo four times a day for 14 days. Exclusion criteria were end-stage liver disease, severe renal impairment, oxygen saturation ≤94% on room air, and experimental treatment for COVID-19. The primary efficacy endpoint was hospitalization or death within 28 days. Secondary efficacy included positivity for SARS-CoV-2 by PCR on mid-nasal turbinate swabs on days 7 and 15 compared to baseline. Results: We enrolled 295 participants, 57.3% were female, 15.6% Black and 60% Latinx. Mean age was 51 years (18-93 years). Most (75.3%) were randomized ≤5 days after symptom onset. Common risk factors were hypertension (63.4%), chronic lung disease (33.2%) and diabetes (25.4%), with 46.8% having >1 risk factor. With a lower than anticipated event rate, the primary endpoint of hospitalization or death was not significantly different in the camostat (5.3%, 10/194) and placebo groups (6.1%, 6/99;p=0.78). In the intention-to-treat population, there was a trend towards a lower proportion of PCR positivity in the camostat compared to the placebo group at day 7 (65.2% vs. 75.7%, p=0.12) and day 15 (22.0% vs. 34.3%, p=0.06). Similarly, in a post hoc as treated population, fewer participants in the camostat than in the placebo group remained PCR positive at day 7 (64.7%, 88/136 vs. 76.8%, 53/96;p=0.077) and day 15 (21.8%, 29/133, vs. 34.8%, 23/66;p=0.05). Adverse events occurred in 13% of participants in the placebo and 9% in the camostat group. All severe adverse events (5% in both groups) were related to COVID-19. Conclusion: With a low overall event rate, we did not observe a decrease in risk of hospitalization or death in camostat treated outpatients with COVID-19 at risk for severe disease. SARS-CoV-2 PCR turned negative faster on camostat treatment. Camostat was well tolerated.
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Background: Camostat, a serine protease inhibitor, prevents activation of the SARS-CoV-2 spike protein and blocks SARS-CoV-2 infection in vitro. We studied the safety and antiviral and clinical efficacy of orally administered camostat in non-hospitalized adults with mild-moderate COVID-19. Methods: ACTIV-2/A5401 is a platform trial to evaluate therapies for non-hospitalized adults with mild-moderate COVID-19. In a Phase II portion of the study, participants were enrolled within 10 days of COVID-19 related symptom onset and randomized to camostat 200 mg orally every 6 hours for 7 days or the pooled placebo group. Objectives were to evaluate the safety and efficacy of camostat to reduce the duration of COVID-19 symptoms and increase the proportion of participants with SARS-CoV-2 RNA below the lower limit of quantification (LLoQ) from nasopharyngeal (NP) swabs on days 3, 7, and 14. Participants completed a study diary from day 0 to day 28 scoring COVID-19 symptoms as absent, mild, moderate, or severe. Results: Of the 224 participants enrolled from 54 US sites, 215 participants (108 camostat, 107 placebo) initiated study intervention and formed the modified intent-to-treat population. Fifty-four percent were female, >99% cis-gender, 85% White, 9% Black, and 51% Latinx. Median age was 37 years;47% reported ≤5 days of symptoms at study entry and 26% met the protocol definition of higher risk of progression to severe COVID-19. Most frequent symptoms on day 0 were cough (86%), fatigue (85%), nasal obstruction/congestion (71%) and body/muscle aches (71%). There was no significant difference between camostat and placebo arms in grade 3 or higher adverse events (7.4% vs. 6.5%, respectively). Median (Q1, Q3) time to symptom improvement was 9 days for both camostat (5, 20) and placebo (6, 19). There were no significant differences in the proportion of participants with NP SARS-CoV-2 RNA<="" div=""> Conclusion: Camostat was well-tolerated. Despite compelling in vitro data, camostat did not show evidence of antiviral or clinical efficacy in ACTIV-2/A5401. This highlights the critical importance of randomized controlled trials in the evaluation of therapies for COVID-19.
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The coronavirus family is as old as the 1930s when it first showed symptoms in chicken. The virus thereafter kept evolving and it has significantly taken over a large percentage of people worldwide in the form of this new pandemic. As of the present day, there is no treatment available for coronavirus disease 2019 (COVID-19) (caused by the severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]), although supportive therapy and preventive measures have shown a tremendous control rate among certain patients. Drugs like remdesivir, camostat, nafamostat, ritonavir/lopinavir, several monoclonal antibodies, and CPs are in their early phases of trials. There are approved by the WHO under an emergency use authorization program. Favipiravir has entered its phase 3 clinical trial and is supported by evidence to show no or less adverse effects in patients infected with SARS-CoV-2. Vaccine development is accelerating its pace, and vaccines will probably become available by the end of the year 2020. © 2022 Elsevier Inc.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was responsible for over 4 million confirmed cases of severe acute respiratory syndrome, of which more than 300, 000 cases were confirmed to be dead as of May 2020. The virulent endocytotic activities of SARS-CoV-2 have been associated with angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). Previous studies on the viral activation of TMPRSS2 focused most often than not on the isoform 2 of TMPRSS2, but the isoform 1 (529 residues) has also been shown to be expressed in target cells and contribute to viral activation in host. The inhibition of TMPRSS2 has been reported to grossly reduce the pathogenic effects of SARS-CoV-2 endocytotic activities. In this study therefore, we developed two machine learning models using random forest classifier (RFC) and neural networks (NNs) based on 2251 serine protease inhibitors to screen a database of 21, 000, 000 virtual compounds. We screened the hit compounds using absorption, distribution, metabolism, and excretion (ADME) properties and finally docked the filtered compounds into the predicted binding site of TMPRSS2 isoform 1 homology model to determine their corresponding binding affinity and plausible molecular interactions. One (ASONN) and four (ASOIRFC1-4) lead compounds were obtained from the ADME-NN and RFC filtered hits, respectively, having better binding affinity and lead-likeness properties than those of camostat;this could be due to extensive hydrogen and hydrophobic interactions. © 2022 Elsevier Inc.
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Background/Aim: There is no proven specific or effective treatment for COVID-19 infection;therefore, many drugs are used empirically to establish control of the infection. Viral infection creates an immunologic environment and facilitate drug sensitization. With the advent of new vaccines, the future holds promise for optimism in establishing control of the pandemic. However, even vaccines are not devoid of side effects. In part II of these review series, we aimed to review the published data on mucocutaneous reactions induced by medications used for COVID-19 infection and vaccines used for COVID-19 prophylaxis. Materials and methods: Literature search was performed in the databases PubMed, Scopus, and Web of Science for the relevant studies, starting from the beginning of COVID-19 pandemic until October 2021. Research on animals, studies utilizing in vitro techniques and publications irrelevant to the study’s framework were excluded. Results: The mucocutaneous side effects liable to medications (antimalarials, azithromycin, lopinavir/ritonavir, remdesivir, ribavirin/interferon, oseltamivir/favipiravir, darunavir, imatinib, tocilizumab, anakinra baricitinib, and other Janus kinase inhibitors, immunoglobulin therapy, colchicine, anti-TNF-α biologics, low molecular weight heparins, camostat mesylate) and vaccines used for COVID-19 infection are reviewed herein. Conclusion: There is a great amount of accumulated data regarding the mucocutaneous side effects of drugs and vaccines used for COVID-19 infection. In the pandemic era, it is a major goal to diagnose drug or vaccine-related mucocutaneous eruptions and distinguish them from pathognomonic, specific, or SARS-CoV-2 virus-related cutaneous eruptions. Timely diagnosis of a mucocutaneous drug/ vaccine reaction will allow for identification of the culprit and appropriate management and protect the patient from forthcoming severe drug/ vaccine reactions. Therefore, it is essential for physicians to update their knowledge regularly on mucocutaneous side effects of COVID-19 therapeutics and vaccines.
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Coronavirus disease 2019 (COVID-19) can lead to multi-organ failure influenced by comorbidities and age. Binding of the severe acute respiratory syndrome coronavirus 2 spike protein (SARS-CoV-2 S protein) to angiotensin-converting enzyme 2 (ACE2), along with proteolytic digestion of the S protein by furin and transmembrane protease serine subtype 2 (TMPRSS2), provokes internalization of SARS-CoV-2 into the host cell. Productive infection occurs through viral replication in the cytosol and cell-to-cell transmission. The catalytic activity of TMPRSS2 can be blocked by the trypsin-like serine protease inhibitor camostat, which impairs infection by SARS-CoV-2. At the site of infection, immune cells, such as neutrophils, infiltrate and become activated, releasing neutrophil serine proteases (NSPs), including cathepsin G (CatG), neutrophil elastase (NE), and proteinase 3 (PR3), which promote the mounting of a robust immune response. However, NSPs might be involved in infection and the severe outcome of COVID-19 since the uncontrolled proteolytic activity is responsible for many complications, including autoimmunity, chronic inflammatory disorders, cardiovascular diseases, and thrombosis. Here, we demonstrate that camostat does not inhibit the catalytic activity of CatG, NE, and PR3, indicating the need for additional selective serine protease inhibitors to reduce the risk of developing severe COVID-19.