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1.
Sci Rep ; 11(1): 19998, 2021 10 07.
Article in English | MEDLINE | ID: covidwho-1462031

ABSTRACT

Understanding the effects of metabolism on the rational design of novel and more effective drugs is still a considerable challenge. To the best of our knowledge, there are no entirely computational strategies that make it possible to predict these effects. From this perspective, the development of such methodologies could contribute to significantly reduce the side effects of medicines, leading to the emergence of more effective and safer drugs. Thereby, in this study, our strategy is based on simulating the electron ionization mass spectrometry (EI-MS) fragmentation of the drug molecules and combined with molecular docking and ADMET models in two different situations. In the first model, the drug is docked without considering the possible metabolic effects. In the second model, each of the intermediates from the EI-MS results is docked, and metabolism occurs before the drug accesses the biological target. As a proof of concept, in this work, we investigate the main antiviral drugs used in clinical research to treat COVID-19. As a result, our strategy made it possible to assess the biological activity and toxicity of all potential by-products. We believed that our findings provide new chemical insights that can benefit the rational development of novel drugs in the future.


Subject(s)
Antiviral Agents/metabolism , COVID-19/drug therapy , Drug Discovery , SARS-CoV-2/drug effects , Adenine/adverse effects , Adenine/analogs & derivatives , Adenine/metabolism , Adenine/pharmacology , Adenosine/adverse effects , Adenosine/analogs & derivatives , Adenosine/metabolism , Adenosine/pharmacology , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/metabolism , Adenosine Monophosphate/pharmacology , Alanine/adverse effects , Alanine/analogs & derivatives , Alanine/metabolism , Alanine/pharmacology , Amides/adverse effects , Amides/metabolism , Amides/pharmacology , Antiviral Agents/adverse effects , Antiviral Agents/pharmacology , COVID-19/metabolism , Chloroquine/adverse effects , Chloroquine/analogs & derivatives , Chloroquine/metabolism , Chloroquine/pharmacology , Drug Design , Humans , Metabolic Networks and Pathways , Molecular Docking Simulation , Nitro Compounds/adverse effects , Nitro Compounds/metabolism , Nitro Compounds/pharmacology , Pyrazines/adverse effects , Pyrazines/metabolism , Pyrazines/pharmacology , Pyrrolidines/adverse effects , Pyrrolidines/metabolism , Pyrrolidines/pharmacology , Ribavirin/adverse effects , Ribavirin/metabolism , Ribavirin/pharmacology , SARS-CoV-2/metabolism , Thiazoles/adverse effects , Thiazoles/metabolism , Thiazoles/pharmacology
2.
Int Immunopharmacol ; 95: 107522, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1385749

ABSTRACT

BACKGROUND: We examined the safety and efficacy of a treatment protocol containing Favipiravir for the treatment of SARS-CoV-2. METHODS: We did a multicenter randomized open-labeled clinical trial on moderate to severe cases infections of SARS-CoV-2. Patients with typical ground glass appearance on chest computerized tomography scan (CT scan) and oxygen saturation (SpO2) of less than 93% were enrolled. They were randomly allocated into Favipiravir (1.6 gr loading, 1.8 gr daily) and Lopinavir/Ritonavir (800/200 mg daily) treatment regimens in addition to standard care. In-hospital mortality, ICU admission, intubation, time to clinical recovery, changes in daily SpO2 after 5 min discontinuation of supplemental oxygen, and length of hospital stay were quantified and compared in the two groups. RESULTS: 380 patients were randomly allocated into Favipiravir (193) and Lopinavir/Ritonavir (187) groups in 13 centers. The number of deaths, intubations, and ICU admissions were not significantly different (26, 27, 31 and 21, 17, 25 respectively). Mean hospital stay was also not different (7.9 days [SD = 6] in the Favipiravir and 8.1 [SD = 6.5] days in Lopinavir/Ritonavir groups) (p = 0.61). Time to clinical recovery in the Favipiravir group was similar to Lopinavir/Ritonavir group (HR = 0.94, 95% CI 0.75 - 1.17) and likewise the changes in the daily SpO2 after discontinuation of supplemental oxygen (p = 0.46) CONCLUSION: Adding Favipiravir to the treatment protocol did not reduce the number of ICU admissions or intubations or In-hospital mortality compared to Lopinavir/Ritonavir regimen. It also did not shorten time to clinical recovery and length of hospital stay.


Subject(s)
Amides/administration & dosage , Amides/adverse effects , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , COVID-19/drug therapy , Pyrazines/administration & dosage , Pyrazines/adverse effects , Adolescent , Adult , Aged , Aged, 80 and over , Drug Therapy, Combination , Female , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/adverse effects , Intubation , Kaplan-Meier Estimate , Length of Stay , Lopinavir/administration & dosage , Lopinavir/adverse effects , Male , Middle Aged , Oxygen/blood , Ritonavir/administration & dosage , Ritonavir/adverse effects , Severity of Illness Index , Treatment Outcome , Young Adult
3.
Eur J Clin Microbiol Infect Dis ; 40(12): 2575-2583, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1340465

ABSTRACT

We performed a systematic review and meta-analysis for the effectiveness of Favipiravir on the fatality and the requirement of mechanical ventilation for the treatment of moderate to severe COVID-19 patients. We searched available literature and reported it by using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Until June 1, 2021, we searched PubMed, bioRxiv, medRxiv, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar by using the keywords "Favipiravir" and terms synonymous with COVID-19. Studies for Favipiravir treatment compared to standard of care among moderate and severe COVID-19 patients were included. Risk of bias assessment was performed using Revised Cochrane risk of bias tool for randomized trials (RoB 2) and ROBINS-I assessment tool for non-randomized studies. We defined the outcome measures as fatality and requirement for mechanical ventilation. A total of 2702 studies were identified and 12 clinical trials with 1636 patients were analyzed. Nine out of 12 studies were randomized controlled trials. Among the randomized studies, one study has low risk of bias, six studies have moderate risk of bias, and 2 studies have high risk of bias. Observational studies were identified as having moderate risk of bias and non-randomized study was found to have serious risk of bias. Our meta-analysis did not reveal any significant difference between the intervention and the comparator on fatality rate (OR 1.11, 95% CI 0.64-1.94) and mechanical ventilation requirement (OR 0.50, 95% CI 0.13-1.95). There is no significant difference in fatality rate and mechanical ventilation requirement between Favipiravir treatment and the standard of care in moderate and severe COVID-19 patients.


Subject(s)
Amides/administration & dosage , Antiviral Agents/administration & dosage , COVID-19/drug therapy , Pyrazines/administration & dosage , Adolescent , Adult , Aged , Aged, 80 and over , Amides/adverse effects , Antiviral Agents/adverse effects , COVID-19/mortality , COVID-19/therapy , COVID-19/virology , Female , Humans , Male , Middle Aged , Observational Studies as Topic , Pyrazines/adverse effects , Randomized Controlled Trials as Topic , Respiration, Artificial , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Young Adult
4.
Virol J ; 18(1): 146, 2021 07 13.
Article in English | MEDLINE | ID: covidwho-1309916

ABSTRACT

BACKGROUND: Favipiravir is used in treatment of Covid-19 patients. We aimed to share of ocular surface fluorescence in a patient after Favipiravir treatment in this case report. CASE PRESENTATION: A 20-year-old male patient declared no known systemic disease prior to Covid-19. He applied to us with blurry vision and blue light reflection after Covid-19 treatment with Favipiravir. We observed bilateral fluorescence on his eyes and fluorescence of his nails. Biomicroscopic examination was insignificant. CONCLUSION: We investigated the fluorescence of favipiravir tablets under ultraviolet light. Drug demonstrated fluorescence. We recorded the favipiravir fluorescence in-vitro. This appears to be a strong evidence in terms of the linkage between the fluorescence of the ocular surface and favipiravir.


Subject(s)
Amides/adverse effects , Antiviral Agents/adverse effects , COVID-19/drug therapy , Eye/chemistry , Pyrazines/adverse effects , Adult , Amides/administration & dosage , Amides/chemistry , Antiviral Agents/administration & dosage , Antiviral Agents/chemistry , COVID-19/virology , Eye/virology , Fluorescence , Humans , Male , Pyrazines/administration & dosage , Pyrazines/chemistry , SARS-CoV-2/physiology
5.
BMC Infect Dis ; 21(1): 489, 2021 May 27.
Article in English | MEDLINE | ID: covidwho-1244908

ABSTRACT

BACKGROUND: Favipiravir possesses high utility for treating patients with COVID-19. However, research examining the efficacy and safety of favipiravir for patients with COVID-19 is limited. METHODS: We conducted a systematic review of published studies reporting the efficacy of favipiravir against COVID-19. Two investigators independently searched PubMed, the Cochrane Database of Systematic Reviews, MedRxiv, and ClinicalTrials.gov (inception to September 2020) to identify eligible studies. A meta-analysis was performed to measure viral clearance and clinical improvement as the primary outcomes. RESULTS: Among 11 eligible studies, 5 included a comparator group. Comparing to the comparator group, the favipiravir group exhibited significantly better viral clearance on day 7 after the initiation of treatment (odds ratio [OR] = 2.49, 95% confidence interval [CI] = 1.19-5.22), whereas no difference was noted on day 14 (OR = 2.19, 95% CI = 0.69-6.95). Although clinical improvement was significantly better in the favipiravir group on both days 7 and 14, the improvement was better on day 14 (OR = 3.03, 95% CI = 1.17-7.80) than on day 7 (OR = 1.60, 95% CI = 1.03-2.49). The estimated proportions of patients with viral clearance in the favipiravir arm on days 7 and 14 were 65.42 and 88.9%, respectively, versus 43.42 and 78.79%, respectively, in the comparator group. The estimated proportions of patients with clinical improvement on days 7 and 14 in the favipiravir group were 54.33 and 84.63%, respectively, compared with 34.40 and 65.77%, respectively, in the comparator group. CONCLUSIONS: Favipiravir induces viral clearance by 7 days and contributes to clinical improvement within 14 days. The results indicated that favipiravir has strong possibility for treating COVID-19, especially in patients with mild-to-moderate illness. Additional well-designed studies, including examinations of the dose and duration of treatment, are crucial for reaching definitive conclusions.


Subject(s)
Amides/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Pyrazines/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Amides/adverse effects , Antiviral Agents/adverse effects , Female , Humans , Male , Middle Aged , Pyrazines/adverse effects , SARS-CoV-2 , Treatment Outcome , Viral Load/drug effects , Young Adult
6.
Epilepsy Res ; 174: 106675, 2021 08.
Article in English | MEDLINE | ID: covidwho-1233420

ABSTRACT

In regard to the global pandemic of COVID-19, it seems that persons with epilepsy (PWE) are not more vulnerable to get infected by SARS-CoV-2, nor are they more susceptible to a critical course of the disease. However, management of acute seizures in patients with COVID-19 as well as management of PWE and COVID-19 needs to consider potential drug-drug interactions between antiseizure drugs and candidate drugs currently assessed as therapeutic options for COVID-19. Repurposing of several licensed and investigational drugs is discussed for therapeutic management of COVID-19. While for none of these approaches, efficacy and tolerability has been confirmed yet in sufficiently powered and controlled clinical studies, testing is ongoing with multiple clinical trials worldwide. Here, we have summarized the possible mechanisms of action of drugs currently considered as potential therapeutic options for COVID-19 management along with possible and confirmed drug-drug interactions that should be considered for a combination of antiseizure drugs and COVID-19 candidate drugs. Our review suggests that potential drug-drug interactions should be taken into account with drugs such as chloroquine/hydroxychloroquine and lopinavir/ritonavir while remdesivir and tocilizumab may be less prone to clinically relevant interactions with ASMs.


Subject(s)
Anti-Inflammatory Agents/adverse effects , Anticonvulsants/adverse effects , Antiviral Agents/adverse effects , COVID-19/drug therapy , Enzyme Inhibitors/adverse effects , Epilepsy/drug therapy , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/analogs & derivatives , Alanine/adverse effects , Alanine/analogs & derivatives , Amides/adverse effects , Antibodies, Monoclonal, Humanized/adverse effects , COVID-19/complications , Chloroquine/adverse effects , Cytochrome P-450 CYP3A Inducers/adverse effects , Dexamethasone/adverse effects , Drug Combinations , Drug Interactions , Epilepsy/complications , Glucocorticoids/adverse effects , Humans , Hydroxychloroquine/adverse effects , Interleukin 1 Receptor Antagonist Protein/adverse effects , Ivermectin/adverse effects , Lopinavir , Pyrazines/adverse effects , Ritonavir , SARS-CoV-2
7.
Int Immunopharmacol ; 97: 107702, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1198831

ABSTRACT

BACKGROUND: The clinical characteristics and treatment of patients who tested positive for COVID-19 after recovery remained elusive. Effective antiviral therapy is important for tackling these patients. We assessed the efficacy and safety of favipiravir for treating these patients. METHODS: This is a multicenter, open-label, randomized controlled trial in SARS-CoV-2 RNA re-positive patients. Patients were randomly assigned in a 2:1 ratio to receive either favipiravir, in addition to standard care, or standard care alone. The primary outcome was time to achieve a consecutive twice (at intervals of more than 24 h) negative RT-PCR result for SARS-CoV-2 RNA in nasopharyngeal swab and sputum sample. RESULTS: Between March 27 and May 9, 2020, 55 patients underwent randomization; 36 were assigned to the favipiravir group and 19 were assigned to the control group. Favipiravir group had a significantly shorter time from start of study treatment to negative nasopharyngeal swab and sputum than control group (median 17 vs. 26 days); hazard ratio 2.1 (95% CI [1.1-4.0], p = 0.038). The proportion of virus shedding in favipiravir group was higher than control group (80.6% [29/36] vs. 52.6% [10/19], p = 0.030, respectively). C-reactive protein decreased significantly after treatment in the favipiravir group (p = 0.016). The adverse events were generally mild and self-limiting. CONCLUSION: Favipiravir was safe and superior to control in shortening the duration of viral shedding in SARS-CoV-2 RNA recurrent positive after discharge. However, a larger scale and randomized, double-blind, placebo-controlled trial is required to confirm our conclusion.


Subject(s)
Amides/administration & dosage , Antiviral Agents/administration & dosage , COVID-19/drug therapy , Pyrazines/administration & dosage , Reinfection/drug therapy , Administration, Oral , Adult , Aged , Amides/adverse effects , Antiviral Agents/adverse effects , COVID-19/blood , Female , Humans , Lymphocyte Subsets/drug effects , Male , Middle Aged , Patient Discharge , Pyrazines/adverse effects , RNA, Viral/analysis , RNA, Viral/drug effects , Reinfection/blood , SARS-CoV-2/drug effects , Treatment Outcome
8.
Curr Med Res Opin ; 37(7): 1085-1097, 2021 07.
Article in English | MEDLINE | ID: covidwho-1199382

ABSTRACT

INTRODUCTION: Favipiravir is a repurposed drug to treat coronavirus 2019 (COVID-19). Due to a lack of available real-world data, we assessed its effectiveness and safety in moderately to critically ill COVID-19 patients. METHODS: This retrospective study was conducted in two public/specialty hospitals in Saudi Arabia. We included patients ≥18 years) admitted April-August 2020 with confirmed SARS-CoV-2 diagnosed by real-time polymerase chain reaction (RT-PCR) from nasopharyngeal swab. Patients received either favipiravir (1800 mg or 1600 mg twice daily loading dose, followed by 800 mg or 600 mg twice daily) or supportive-care treatment. Patients were excluded if they were outside the study period, classified as having a mild form of the disease per WHO criteria, or had an incomplete patient file. Kaplan-Meier (KM) models were used to estimate median time to discharge. Discharge ratios, progression to mechanical ventilation, and mortality outcomes were estimated across the severity spectrum using Cox proportional-hazards models. As a sensitivity analysis, we performed propensity score-matching (PSM) analysis. RESULTS: Overall, median time to discharge was 10 days (95%CI = 9-10) in the favipiravir arm versus 15 days (95%CI = 14-16) in the supportive-care arm. The accelerated discharge benefit was seen across the COVID-19 spectrum of severity. The adjusted discharge ratio was 1.96 (95%CI = 1.56-2.46). Progression to mechanical ventilation was slower with favipiravir (HRadj = 0.10, 95%CI = 0.04-0.29). There was no significant effect on mortality (HRadj = 1.56, 95%CI = 0.73-3.36). There was a statistically non-significant trend toward worse outcomes in the critical category (HRadj = 2.80, 95%CI = 0.99-7.89). Age was an independent risk factor for mortality in mechanically ventilated patients. PSM analyses confirmed these findings. CONCLUSION: Favipiravir was associated with clinical benefits, including accelerated discharge rate and less progression to mechanical ventilation; however, no overall mortality benefits were seen across the severity spectrum.


Subject(s)
Amides , Antiviral Agents , COVID-19 , Pyrazines , Amides/adverse effects , Amides/therapeutic use , Antiviral Agents/adverse effects , Antiviral Agents/therapeutic use , COVID-19/epidemiology , COVID-19/therapy , Critical Illness/epidemiology , Critical Illness/therapy , Humans , Propensity Score , Pyrazines/adverse effects , Pyrazines/therapeutic use , Respiration, Artificial/statistics & numerical data , Retrospective Studies , SARS-CoV-2 , Saudi Arabia , Sensitivity and Specificity
9.
Sci Rep ; 11(1): 7282, 2021 03 31.
Article in English | MEDLINE | ID: covidwho-1164906

ABSTRACT

Favipiravir is considered a potential treatment for COVID-19 due its efficacy against different viral infections. We aimed to explore the safety and efficacy of favipiravir in treatment of COVID-19 mild and moderate cases. It was randomized-controlled open-label interventional phase 3 clinical trial [NCT04349241]. 100 patients were recruited from 18th April till 18th May. 50 patients received favipiravir 3200 mg at day 1 followed by 600 mg twice (day 2-day 10). 50 patients received hydroxychloroquine 800 mg at day 1 followed by 200 mg twice (day 2-10) and oral oseltamivir 75 mg/12 h/day for 10 days. Patients were enrolled from Ain Shams University Hospital and Assiut University Hospital. Both arms were comparable as regards demographic characteristics and comorbidities. The average onset of SARS-CoV-2 PCR negativity was 8.1 and 8.3 days in HCQ-arm and favipiravir-arm respectively. 55.1% of those on HCQ-arm turned PCR negative at/or before 7th day from diagnosis compared to 48% in favipiravir-arm (p = 0.7). 4 patients in FVP arm developed transient transaminitis on the other hand heartburn and nausea were reported in about 20 patients in HCQ-arm. Only one patient in HCQ-arm died after developing acute myocarditis resulted in acute heart failure. Favipiravir is a safe effective alternative for hydroxychloroquine in mild or moderate COVID-19 infected patients.


Subject(s)
Amides/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Hydroxychloroquine/therapeutic use , Pyrazines/therapeutic use , Adult , Amides/adverse effects , Antiviral Agents/adverse effects , COVID-19/etiology , Female , Ferritins/blood , Fibrin Fibrinogen Degradation Products/analysis , Humans , Hydroxychloroquine/adverse effects , Male , Middle Aged , Oseltamivir/therapeutic use , Pyrazines/adverse effects , Treatment Outcome
10.
Int J Infect Dis ; 106: 33-35, 2021 May.
Article in English | MEDLINE | ID: covidwho-1144720

ABSTRACT

As of October 2020, there is still no specific drug to treat COVID-19 as it rages worldwide. Favipiravir, indicated for the treatment of new and re-emerging influenza infections, has been suggested to be effective against SARS-CoV-2, although this is not yet fully validated. We administered favipiravir to a 64-year-old female patient with COVID-19. Her symptoms resolved quickly after the start of treatment, with reduction of SARS-CoV-2 viral load, but she developed a fever again on day 12. Since the fever was relieved by discontinuation of favipiravir, and based on positive results with a drug-induced lymphocyte stimulation test, we diagnosed her with favipiravir-induced drug fever. A decrease in the serum concentration of favipiravir was observed along with resolution of the fever. The present case suggests that drug fever should be considered in the differential diagnosis of relapsing fever episodes in COVID-19 patients receiving favipiravir.


Subject(s)
Amides/adverse effects , COVID-19/drug therapy , COVID-19/immunology , Fever/chemically induced , Lymphocyte Activation/drug effects , Pyrazines/adverse effects , Amides/pharmacology , Amides/therapeutic use , COVID-19/diagnosis , Female , Humans , Middle Aged , Pyrazines/pharmacology , Pyrazines/therapeutic use , Viral Load/drug effects
11.
Recenti Prog Med ; 112(3): 195-206, 2021 03.
Article in Italian | MEDLINE | ID: covidwho-1123708

ABSTRACT

BACKGROUND: SARS-CoV-2 is a coronavirus that causes a disease which can leads to a severe form of fatal pneumonia. At december 2020 in Italy, more than 2 million people have contracted the virus and 78,755 people have died. The scientific community is studying and testing numerous compounds that can be effective and safe for treating people with covid-19. AIM: To synthesize and evaluate the quality of evidence of efficacy and safety for the treatment. The available evidence is summarized in a living systematic review, a review that is constantly updated on the basis of the results of the new clinical studies. METHODS: A bibliographic search is launched weekly on the electronic databases and on the main clinical trial registers. Two researchers independently select the articles and assess the quality of the studies using the criteria developed by the Cochrane Collaboration, the certainty of the overall quality of the evidence is assessed using the GRADE criteria. RESULTS: At 31/12/2020, 101 randomized controlled studies were included that consider 72 different comparisons and include a total of 55,281 patients. 37 drugs are tested with respect to the standard treatment, 6 are evaluated against placebo and finally 29 compare different drugs with each other. By selecting studies that evaluate the efficacy and safety of a drug compared to standard treatment, which include at least 2 studies and which have low to high certainty of evidence, results show that corticosteroids, remdesivir, favipiravir, immunoglobulins, colchicine, and umbilical cord mesenchymal stem cell infusion could reduce overall mortality. No differences for the risk of any adverse events are observed between convalescent plasma and remdesivir compared to standard treatment. Remdesivir probably reduces the risk of serious adverse events; a similar effect, although less strong, is also noted for tocilizumab and the lopinavir-ritonavir combination. In contrast, hydroxychloroquine, corticosteroids and convalescent plasma transfusion are associated with safety concerns with respect to the risk of serious adverse events. CONCLUSIONS: The 101 studies included consider 72 comparisons and numerous outcomes, the results often coming from single studies and of small dimensions, and for 61% with a very low certainty of evidence, are difficult to summarize and the final result is to increase the uncertainty rather than providing useful information to the clinic and research. From all the work carried out it seems to us that the pandemic has highlighted the many shadows of scientific literature as tool to improve knowledge.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , SARS-CoV-2 , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Adrenal Cortex Hormones/adverse effects , Adrenal Cortex Hormones/therapeutic use , Alanine/adverse effects , Alanine/analogs & derivatives , Alanine/therapeutic use , Amides/adverse effects , Amides/therapeutic use , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Antiviral Agents/adverse effects , Antiviral Agents/pharmacology , COVID-19/epidemiology , COVID-19/therapy , Combined Modality Therapy , Drug Combinations , Drug Repositioning , Humans , Hydroxychloroquine/adverse effects , Hydroxychloroquine/therapeutic use , Immunization, Passive , Immunoglobulins, Intravenous/therapeutic use , Lopinavir/adverse effects , Lopinavir/therapeutic use , Mesenchymal Stem Cell Transplantation , Pandemics , Pyrazines/adverse effects , Pyrazines/therapeutic use , Randomized Controlled Trials as Topic , Ritonavir/adverse effects , Ritonavir/therapeutic use , SARS-CoV-2/drug effects , Treatment Outcome , Uncertainty
12.
Riv Psichiatr ; 56(1): 53-55, 2021.
Article in English | MEDLINE | ID: covidwho-1073191

ABSTRACT

Infection outbreak has been prevalent since previous decades. The impact of infection outbreak not merely limited to physical suffering but grounded for massive mental health issues. The fear of getting contagion and persistent exposure to diverse medication and vaccination contribute enormously to develop mental health issues among people. During previous infection treatment with diverse vaccination and antiviral agent, the common mental health issues found to be a mood disorder, delirium, schizophrenia, and psychotic symptoms. Cumbersomely, it is almost impossible to treat mental health issues during the pandemic with the help of only pharmacological availability. Hence psychological intervention is also important to ameliorate better consequences. The current study highlights the impact of CoViD-19 related diverse medication and vaccination on the mental health of the people.


Subject(s)
Antiviral Agents/adverse effects , COVID-19/drug therapy , Mental Disorders/chemically induced , Mental Health , Pandemics , SARS-CoV-2 , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/analogs & derivatives , Alanine/adverse effects , Alanine/analogs & derivatives , Amides/adverse effects , COVID-19/psychology , COVID-19 Vaccines/adverse effects , Drug Combinations , Fear , Humans , Lopinavir/adverse effects , Mental Disorders/psychology , Oseltamivir/adverse effects , Pyrazines/adverse effects , Ribavirin/adverse effects , Ritonavir/adverse effects
13.
Biomed Pharmacother ; 133: 110825, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1002354

ABSTRACT

BACKGROUND: Since December 2019, COVID-19 has spread to almost every corner of the world. In theory, tocilizumab and favipiravir are considered to be reliable drugs for the treatment of COVID-19 with elevated IL-6. We aimed to assess the efficacy and safety of tocilizumab combined with favipiravir in patients with COVID-19. METHODS: This was a multicenter trial in adults with COVID-19. Patients were randomly assigned (3:1:1) to a 14-day combination of favipiravir combined with tocilizumab (combination group), favipiravir, and tocilizumab. The primary outcome was the cumulative lung lesion remission rate (lung CT examination indicated absorption of lung inflammation). RESULTS: Between Feb 2 and March 15, 2020, 26 patients were recruited; 14 were randomly assigned to the combination group, 7 were assigned to the favipiravir group and 5 were assigned to the tocilizumab group. The cumulative lung lesion remission rate at day 14 was significantly higher in combination group as compared with favipiravir group (P = 0.019, HR 2.66 95 % CI [1.08-6.53]). And there was also a significant difference between tocilizumab and favipivavir (P = 0.034, HR 3.16, 95 % CI 0.62-16.10). In addition, there was no significant difference between the combination group and the tocilizumab group (P = 0.575, HR 1.28 95 %CI 0.39-4.23). Furthermore, combined therapy can also significantly relieve clinical symptoms and help blood routine to return to normal. No serious adverse events were reported. CONCLUSION: Tocilizumab combined with or without favipiravir can effectively improve the pulmonary inflammation of COVID-19 patients and inhibit the deterioration of the disease.


Subject(s)
Amides/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Pyrazines/therapeutic use , SARS-CoV-2/drug effects , Adult , Aged , Aged, 80 and over , Amides/administration & dosage , Amides/adverse effects , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , COVID-19/diagnostic imaging , COVID-19/pathology , COVID-19/therapy , Drug Therapy, Combination , Female , Humans , Interleukin-6/blood , Kaplan-Meier Estimate , Lung/diagnostic imaging , Lung/pathology , Male , Middle Aged , Models, Immunological , Pyrazines/administration & dosage , Pyrazines/adverse effects , Receptors, Interleukin-6/antagonists & inhibitors , Respiration, Artificial/statistics & numerical data , Sample Size , Treatment Outcome
14.
Expert Rev Anti Infect Ther ; 19(8): 1029-1037, 2021 08.
Article in English | MEDLINE | ID: covidwho-998153

ABSTRACT

INTRODUCTION: At this time, there is no specific therapeutic or vaccine for treatment of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Hence, available drugs for treatment of other viral infections may be useful to treat COVID-19. AREAS COVERED: The focus of the current review was studying the main characteristics of favipiravir and its usefulness to treat COVID-19. An electronic search was done by using Pubmed and Google scholar. EXPERT OPINION: Based on the mechanism of action and safety of favipiravir, the drug may be a promising candidate for compassionate use against the SARS-CoV-2 infection. Favipiravir has a wide range of activity against many single-stranded RNA viruses, is well tolerated in humans and has a high barrier to resistance. However, high doses of the agent are necessary to obtain an efficient antiviral activity. Favipiravir is teratogen in pregnant women and associated with the hyperuricemia. Therefore, the administration of the drug should be well controlled. Investigating the antiviral prophylactic potency of favipiravir and search for its pro-drugs and/or analogs showing improved activity and/or safety are critical.


Subject(s)
Amides/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Pyrazines/therapeutic use , Adult , Amides/adverse effects , Amides/pharmacology , Antiviral Agents/adverse effects , Antiviral Agents/pharmacology , Female , Humans , Pregnancy , Pyrazines/adverse effects , Pyrazines/pharmacology
15.
J Infect Chemother ; 27(2): 390-392, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-988379

ABSTRACT

Favipiravir is an antiviral drug that is expected to have a therapeutic effect on SARS-CoV2 infection. Teratogenicity and hyperuricemia are known as the main side effects of favipiravir, but little is known about other side effects. This report describes a case of cholestatic liver injury induced by favipiravir. A 73-year-old Japanese with a history of alcoholic hepatitis was infected with SARS-CoV2. Drug therapy was instituted with lopinavir/ritonavir combined with interferon ß-1b. However, his condition worsened despite additional support with continuous hemodiafiltration and veno-venous extracorporeal membrane oxygenation. We suspected complications of bacterial pneumonia and started favipiravir in addition to antimicrobial therapy. Favipiravir was administered at 6000 mg/day on the first day and 2400 mg/day for the second and subsequent days for 14 days. After the initiation of antibiotics, transaminase and total bilirubin were elevated, suggesting a transient cholestasic liver dysfunction. The liver dysfunction in this case may have been triggered by antibacterial treatment, and high dose of favipiravir may have promoted the deterioration of liver function. Monitoring of liver function is vital and close attention should be paid when using favipiravir at high doses or in patients with impaired liver function.


Subject(s)
Amides/adverse effects , Antiviral Agents/adverse effects , COVID-19/drug therapy , Chemical and Drug Induced Liver Injury/etiology , Cholestasis/etiology , Pyrazines/adverse effects , Aged , Amides/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/complications , Drug Therapy, Combination , Extracorporeal Membrane Oxygenation , Humans , Lopinavir/therapeutic use , Male , Pyrazines/therapeutic use , Ritonavir/therapeutic use , SARS-CoV-2
16.
Int J Infect Dis ; 103: 62-71, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-988025

ABSTRACT

OBJECTIVE: To assess the efficacy and safety of favipiravir in adults with mild-to-moderate coronavirus disease 2019 (COVID-19). METHODS: In this randomized, open-label, parallel-arm, multicenter, phase 3 trial, adults (18-75 years) with RT-PCR confirmed COVID-19 and mild-to-moderate symptoms (including asymptomatic) were randomized 1:1 to oral favipiravir (day 1: 1800 mg BID and days 2-14: 800 mg BID) plus standard supportive care versus supportive care alone. The primary endpoint was time to the cessation of viral shedding; time to clinical cure was also measured. RESULTS: From May 14 to July 3, 2020, 150 patients were randomized to favipiravir (n = 75) or control (n = 75). Median time to the cessation of viral shedding was 5 days (95% CI: 4 days, 7 days) versus 7 days (95% CI: 5 days, 8 days), P = 0.129, and median time to clinical cure was 3 days (95% CI: 3 days, 4 days) versus 5 days (95% CI: 4 days, 6 days), P = 0.030, for favipiravir and control, respectively. Adverse events were observed in 36% of favipiravir and 8% of control patients. One control patient died due to worsening disease. CONCLUSION: The lack of statistical significance on the primary endpoint was confounded by limitations of the RT-PCR assay. Significant improvement in time to clinical cure suggests favipiravir may be beneficial in mild-to-moderate COVID-19.


Subject(s)
Amides/therapeutic use , COVID-19/drug therapy , Pyrazines/therapeutic use , RNA-Dependent RNA Polymerase/antagonists & inhibitors , SARS-CoV-2 , Adolescent , Adult , Aged , Amides/adverse effects , Female , Humans , Male , Middle Aged , Pyrazines/adverse effects , Young Adult
17.
Indian J Pharmacol ; 52(5): 414-421, 2020.
Article in English | MEDLINE | ID: covidwho-962440

ABSTRACT

Multiple options are being tried for the management of 2019-nCoV infection since its pandemic started. Favipiravir (FPV) is one of drugs, which is also being tried for the management of 2019-nCoV infection. The present study aimed to evaluate the efficacy and safety of FPV in published literature. Comparative randomized or nonrandomized controlled clinical trials comparing FPV to the standard of care (SOC)/control or other antiviral agent/combinations were included. A total of 12 databases were searched and identify four studies which were further used for final analysis. The data analysis was done as pooled prevalence using a random effect model by "RevMan manager version 5.4.1 and "R" software. The point estimate, odds ratio (OR) with 95% confidence interval (CI) was calculated for dichotomous data. In the present study, the marginal beneficial effect was seen in the FPV group in overall clinical improvement comparison to SOC/control, i.e., (4 studies, log OR [95% CI] (-0.19 [-0.51, 0.13]). However, in all other outcomes, it was found to be comparable to the SOC/control arm namely "clinical improvement on day 7-10" (3 studies, OR [95% CI] 1.63 [1.07, 2.48]) while "clinical improvement on day 10-14" (3 studies, OR [95% CI] 1.37 [0.24, 7.82]) and viral negativity was seen (4 studies, OR [95% CI] 1.91 [0.91, 4.01]). No difference in efficacy was found between FPV versus lopinavir/ritonavir or arbidol groups. Regarding adverse effects, except for the occurrence of rash (higher in the FPV group), safety was comparable to SOC. In our study, there was a marginal difference between the FPV and the SOC arm in terms of "clinical improvement" on day 7-10 or 10-14, and "virological negativity" on day 10-14." However, some benefit was observed in a few studies, but it was also comparable to the control drugs or SOC.


Subject(s)
Amides/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Pyrazines/therapeutic use , Amides/adverse effects , Antiviral Agents/adverse effects , Humans , Pyrazines/adverse effects , Randomized Controlled Trials as Topic
18.
Intern Med ; 59(22): 2951-2953, 2020.
Article in English | MEDLINE | ID: covidwho-941724

ABSTRACT

We herein report the first case of a fever induced by favipiravir, a potential coronavirus disease 2019 therapeutic drug. An 82-year-old man diagnosed with bilateral pneumonia was transferred to our hospital following a positive severe acute respiratory syndrome coronavirus 2 polymerase chain reaction test. He was treated with compassionate use of favipiravir. Both his oxygen demand and fever gradually improved after admission; however, his fever relapsed, and the C-reactive protein (CRP) levels increased on day 7. We diagnosed his fever as being favipiravir-induced. The fever resolved a few days after favipiravir discontinuation, demonstrating the accuracy of the diagnosis. This case revealed that favipiravir can induce a fever.


Subject(s)
Amides/adverse effects , Betacoronavirus , Coronavirus Infections/drug therapy , Fever/chemically induced , Pneumonia, Viral/drug therapy , Pyrazines/adverse effects , Aged, 80 and over , Amides/therapeutic use , Antiviral Agents/adverse effects , Antiviral Agents/therapeutic use , COVID-19 , Coronavirus Infections/epidemiology , Humans , Male , Pandemics , Pneumonia, Viral/epidemiology , Pyrazines/therapeutic use , SARS-CoV-2
19.
Antimicrob Agents Chemother ; 64(12)2020 11 17.
Article in English | MEDLINE | ID: covidwho-939841

ABSTRACT

Favipiravir is an oral broad-spectrum inhibitor of viral RNA-dependent RNA polymerase that is approved for treatment of influenza in Japan. We conducted a prospective, randomized, open-label, multicenter trial of favipiravir for the treatment of COVID-19 at 25 hospitals across Japan. Eligible patients were adolescents and adults admitted with COVID-19 who were asymptomatic or mildly ill and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned at a 1:1 ratio to early or late favipiravir therapy (in the latter case, the same regimen starting on day 6 instead of day 1). The primary endpoint was viral clearance by day 6. The secondary endpoint was change in viral load by day 6. Exploratory endpoints included time to defervescence and resolution of symptoms. Eighty-nine patients were enrolled, of whom 69 were virologically evaluable. Viral clearance occurred within 6 days in 66.7% and 56.1% of the early and late treatment groups (adjusted hazard ratio [aHR], 1.42; 95% confidence interval [95% CI], 0.76 to 2.62). Of 30 patients who had a fever (≥37.5°C) on day 1, times to defervescence were 2.1 days and 3.2 days in the early and late treatment groups (aHR, 1.88; 95% CI, 0.81 to 4.35). During therapy, 84.1% developed transient hyperuricemia. Favipiravir did not significantly improve viral clearance as measured by reverse transcription-PCR (RT-PCR) by day 6 but was associated with numerical reduction in time to defervescence. Neither disease progression nor death occurred in any of the patients in either treatment group during the 28-day participation. (This study has been registered with the Japan Registry of Clinical Trials under number jRCTs041190120.).


Subject(s)
Amides/administration & dosage , Antiviral Agents/administration & dosage , COVID-19/drug therapy , Pyrazines/administration & dosage , SARS-CoV-2/drug effects , Viral Load/drug effects , Adolescent , Adult , Amides/adverse effects , Antiviral Agents/adverse effects , Asymptomatic Diseases , COVID-19/physiopathology , COVID-19/virology , Female , Hospitalization , Humans , Hyperuricemia/chemically induced , Hyperuricemia/diagnosis , Hyperuricemia/physiopathology , Japan , Male , Middle Aged , Prospective Studies , Pyrazines/adverse effects , Random Allocation , SARS-CoV-2/pathogenicity , Secondary Prevention/organization & administration , Severity of Illness Index , Time-to-Treatment/organization & administration , Treatment Outcome
20.
Trials ; 21(1): 904, 2020 Oct 31.
Article in English | MEDLINE | ID: covidwho-901915

ABSTRACT

OBJECTIVES: The selected combination was based on limited evidence clinically and in vitro on the efficacy of the Favipiravir and Hydroxychloroquine in SARS-CoV-2. The two medications were listed in many guidelines as treatment options and ongoing trials assessing their efficacy and safety. Thus, we want to prove the clinical effectiveness of the combination as therapy. TRIAL DESIGN: This is an Open label, multicenter, randomized controlled clinical trial to evaluate the safety and efficacy of novel therapeutic agents in hospitalized adults diagnosed with COVID-19. It is a multicenter trial that will compare Favipiravir plus Hydroxychloroquine combination (experimental arm) to a control arm. PARTICIPANTS: All study procedures will be conducted in eight centres in Saudia Arabia: King Abdulaziz Medical City National Guard Health Affairs in Riyadh. King Abdulaziz Hospital - Al Ahsa, Saudi Arabia AlMadina General Hospital, Madnia, Saudi Arabia Al-Qatif Central Hospital, Saudi Arabia Imam Abdulrahman Al Faisal Hospital, Dammam, Saudi Arabia King Abdulaziz Medical City, Jeddah, Saudi Arabia King Abdulaziz Hospital, Makkah, Saudi Arabia Imam Abdulrahman Alfaisal Hospital, Riyadh, Saudi Arabia Inclusion Criteria • Should be at least 18 years of age, • Male or nonpregnant female, • Diagnosed with COVID-19 by PCR confirmed SARS-coV-2 viral infection. • Able to sign the consent form and agree to clinical samples collection (or their legal surrogates if subjects are or become unable to make informed decisions).. • Moderate or Severe COVID-19, defined as oxygen saturation (Sao2) of 94% or less while they were breathing ambient air or significant clinical symptoms that require hospital admission. • patients had to be enrolled within 10 days of disease onset. Exclusion Criteria • Patients who are pregnant or breastfeeding. • Will be transferred to a non-study site hospital or discharged from hospital within 72 hours. • Known sensitivity/allergy to hydroxychloroquine or Favipiravir • Current use of hydroxychloroquine for another indication • Prior diagnosis of retinopathy • Prior diagnosis of glucose-6-phosphate dehydrogenase (G6PD) deficiency • Major comorbidities increasing the risk of study drug including: i. Hematologic malignancy, ii. Advanced (stage 4-5) chronic kidney disease or dialysis therapy, iii. Known history of ventricular arrhythmias, iv. Current use of drugs that prolong the QT interval, Severe liver damage (Child-Pugh score ≥ C, AST> 5 times the upper limit), HIV. • The investigator believes that participating in the trial is not in the best interests of the patient, or the investigator considers unsuitable for enrollment (such as unpredictable risks or subject compliance issues). • Clinical prognostic non-survival, palliative care, or in deep coma and no have response to supportive treatment within three hours of admission • Patient with irregular rhythm • Patient with a history of heart attack (myocardial infarction) • Patient with a family history of sudden death from heart attack before the age of 50 • Take other drugs that can cause prolonged QT interval • Patient who is receiving immunosuppressive therapy (cyclosporin) which cannot be switched to another agent or adjusted while using the investigational drug • Gout/history of Gout or hyperuricemia (above the ULN), hereditary xanthinuria or xanthine calculi of the urinary tract. INTERVENTION AND COMPARATOR: The treatment intervention would be for a maximum of 10 days from randomization and it would be as follows: Favipiravir for 10 days: Administer 1800 mg (9 tablets) by mouth twice daily for one day, followed by 800mg (4 tablets) twice daily (total days of therapy is 10 days) Hydroxychloroquine for 5 days: (400mg) twice daily on day 1; for days 2-5 (200mg) twice daily. Reference Comparator Therapy: Standard of care is defined as: Treatment that is accepted by medical experts as a proper treatment for Covid-19 disease. Standard care comprised of, as necessary, supplemental oxygen, noninvasive and invasive ventilation, antibiotic agents, vasopressor support, renal-replacement therapy, extracorporeal membrane oxygenation (ECMO), and antiviral therapy except Favipiravir. Also, it may include intravenous fluids and medications for symptoms relief . MAIN OUTCOMES: The primary endpoint is the time to clinical improvement, defined as the time from randomization to an improvement of two points (from the status at randomization) on a seven-category ordinal scale or live discharge from the hospital, whichever came first (14 days from Randomization). RANDOMISATION: Eligible participants will be randomized in a 1:1 ratio to either the combination group (Favipiravir and Hydroxychloroquine) or a control group. The patients will be randomized utilizing Web based data entry System with a stratification based on the centre and the ICU admission. BLINDING (MASKING): This is an Open label study and only the analyst will be blinded during the study conduct. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Under the classical two arm parallel design the total effective sample sizes needed is 472 subjects (236 subjects per group). TRIAL STATUS: Protocol version 3.1 (dated 11 Aug 2020), and currently recruitment is ongoing. The date recruitment started was May 21, 2020 and the investigators anticipate the trial will finish recruiting by the end of December 2020. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04392973 , 19 May 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
Amides/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus/pathogenicity , Coronavirus Infections/drug therapy , Hydroxychloroquine/therapeutic use , Pneumonia, Viral/drug therapy , Pyrazines/therapeutic use , Amides/adverse effects , Antiviral Agents/adverse effects , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Drug Therapy, Combination , Female , Host-Pathogen Interactions , Humans , Hydroxychloroquine/adverse effects , Inpatients , Male , Multicenter Studies as Topic , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , Pyrazines/adverse effects , Randomized Controlled Trials as Topic , SARS-CoV-2 , Saudi Arabia , Time Factors , Treatment Outcome
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