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1.
Trials ; 23(1): 583, 2022 Jul 22.
Article in English | MEDLINE | ID: covidwho-1957067

ABSTRACT

BACKGROUND: The 2020 pandemic of SARS-CoV-2 causing COVID-19 disease is an unprecedented global emergency. COVID-19 appears to be a disease with an early phase where the virus replicates, coinciding with the first presentation of symptoms, followed by a later 'inflammatory' phase which results in severe disease in some individuals. It is known from other rapidly progressive infections such as sepsis and influenza that early treatment with antimicrobials is associated with a better outcome. The hypothesis is that this holds for COVID-19 and that early antiviral treatment may prevent progression to the later phase of the disease. METHODS: Trial design: Phase IIA randomised, double-blind, 2 × 2 design, placebo-controlled, interventional trial. RANDOMISATION: Participants will be randomised 1:1 by stratification, with the following factors: gender, obesity, symptomatic or asymptomatic, current smoking status presence or absence of comorbidity, and if the participant has or has not been vaccinated. BLINDING: Participants and investigators will both be blinded to treatment allocation (double-blind). DISCUSSION: We propose to conduct a proof-of-principle placebo-controlled clinical trial of favipiravir plus or minus nitazoxanide in health workers, their household members and patients treated at the Mexican Social Security Institute (IMSS) facilities. Participants with or without symptomatic COVID-19 or who tested positive will be assigned to receive favipiravir plus nitazoxanide or favipiravir plus nitazoxanide placebo. The primary outcome will be the difference in the amount of virus ('viral load') in the upper respiratory tract after 5 days of therapy. Secondary outcomes will include hospitalization, major morbidity and mortality, pharmacokinetics, and impact of antiviral therapy on viral genetic mutation rate. If favipiravir with nitazoxanide demonstrates important antiviral effects without significant toxicity, there will be a strong case for a larger trial in people at high risk of hospitalization or intensive care admission, for example older patients and/or those with comorbidities and with early disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT04918927 . Registered on June 9, 2021.


Subject(s)
COVID-19 , Amides , Antiviral Agents/adverse effects , COVID-19/drug therapy , Humans , Nitro Compounds , Pyrazines , SARS-CoV-2 , Secondary Prevention , Thiazoles , Treatment Outcome
2.
PLoS One ; 17(7): e0271385, 2022.
Article in English | MEDLINE | ID: covidwho-1951553

ABSTRACT

INTRODUCTION: Post-COVID symptoms are the new concern in the COVID-19 pandemic, where recovered patients experience residual symptoms affecting their quality of life. Therefore, it is imperative to evaluate the role of complete vaccination, prescribed medication, and micronutrients during COVID episodes in the occurrence of post-COVID symptoms. METHOD: A longitudinal evaluation of Indonesia's recovered COVID-19 patients was performed using the data collected from July 2021 and extracted in mid-February 2022. All participants were confirmed with a Real-Time Polymerase Chain Reaction test (PCR) and/or antigen test. This study collected demography and comorbidities information, symptoms and treatment of COVID-19, and collection of self-reported post-COVID symptoms every 30 days within 90 days after diagnosis/onset. Exposures of interest include vaccination status, Favipiravir administration, Vitamin C, Vitamin D, and Zinc. A Generalized Estimating Equation (GEE) was used to evaluate the longitudinal effect of exposures, presented with adjusted odds ratios and its 95% confidence interval. RESULTS: A total of 923 participants (18.2% fully-vaccinated) were involved in the study, with 79.7% being non-hospitalized. Only 25.7% did not develop any residual symptoms within 90 days. Fatigue was the most reported post-COVID symptom in each measurement time (39.5%, 16.3%, and 7.3%). Full-vaccination was effective against chronic cough (aOR 0.527, 95% CI 0.286-0.971), chronic headache (aOR 0.317, 95% CI 0.163-0.616), and chronic arthritis (aOR 0.285, 95% CI 0.116-0.703). The combination of micronutrient supplementations and Favipiravir gave no significant effect on all post-COVID symptoms. However, early initiation of Favipiravir and delaying vitamin D administration were associated with arthritis. CONCLUSION: Full vaccination of COVID-19 prevents the disease and the development of residual symptoms when infected with SARS-COV-2. Hence, it is crucial to reconsider the prescription of micronutrient supplementation or adjust the dose of Favipiravir in the current guideline.


Subject(s)
Arthritis , COVID-19 , Amides , COVID-19/drug therapy , Dietary Supplements , Humans , Longitudinal Studies , Pandemics/prevention & control , Pyrazines , Quality of Life , SARS-CoV-2 , Vaccination , Vitamin D , Vitamins
3.
Med Sci (Basel) ; 10(3)2022 07 14.
Article in English | MEDLINE | ID: covidwho-1938903

ABSTRACT

COVID-19 can cause symptoms that last weeks or months after the infection has gone, with a significant impairment of quality of life. Palmitoylethanolamide (PEA) is a naturally occurring lipid mediator that has an entourage effect on the endocannabinoid system mitigating the cytokine storm. The aim of this retrospective study is to evaluate the potential efficacy of PEA in the treatment of long COVID. Patients attending the Neurological Out Clinic of the IRCCS Centro Neurolesi Bonino-Pulejo (Messina, Italy) from August 2020 to September 2021 were screened for potential inclusion in the study. We included only long COVID patients who were treated with PEA 600 mg two times daily for about 3 months. All patients performed the post-COVID-19 Functional Status (PCFS) scale. Thirty-three patients (10 males, 43.5%, mean age 47.8 ± 12.4) were enrolled in the study. Patients were divided into two groups based on hospitalization or home care observation. A substantial difference in the PCFS score between the two groups at baseline and after treatment with PEA were found. We found that smoking was a risk factor with an odds ratio of 8.13 CI 95% [0.233, 1.167]. Our findings encourage the use of PEA as a potentially effective therapy in patients with long COVID.


Subject(s)
COVID-19 , Adult , Amides , COVID-19/complications , COVID-19/drug therapy , Ethanolamines , Female , Humans , Male , Middle Aged , Palmitic Acids , Quality of Life , Retrospective Studies
4.
Bioorg Med Chem ; 67: 116788, 2022 08 01.
Article in English | MEDLINE | ID: covidwho-1926241

ABSTRACT

A series of amino acid based 7H-pyrrolo[2,3-d]pyrimidines were designed and synthesized to discern the structure activity relationships against the SARS-CoV-2 nsp3 macrodomain (Mac1), an ADP-ribosylhydrolase that is critical for coronavirus replication and pathogenesis. Structure activity studies identified compound 15c as a low-micromolar inhibitor of Mac1 in two ADP-ribose binding assays. This compound also demonstrated inhibition in an enzymatic assay of Mac1 and displayed a thermal shift comparable to ADPr in the melting temperature of Mac1 supporting binding to the target protein. A structural model reproducibly predicted a binding mode where the pyrrolo pyrimidine forms a hydrogen bonding network with Asp22 and the amide backbone NH of Ile23 in the adenosine binding pocket and the carboxylate forms hydrogen bonds to the amide backbone of Phe157 and Asp156, part of the oxyanion subsite of Mac1. Compound 15c also demonstrated notable selectivity for coronavirus macrodomains when tested against a panel of ADP-ribose binding proteins. Together, this study identified several low MW, low µM Mac1 inhibitors to use as small molecule chemical probes for this potential anti-viral target and offers starting points for further optimization.


Subject(s)
COVID-19 , SARS-CoV-2 , Adenosine Diphosphate Ribose/metabolism , Amides , COVID-19/drug therapy , Humans , Protein Domains
5.
Biochemistry ; 61(13): 1392-1403, 2022 07 05.
Article in English | MEDLINE | ID: covidwho-1900399

ABSTRACT

The two RNA-dependent RNA polymerase inhibitors remdesivir and favipiravir were originally developed and approved as broad-spectrum antiviral drugs for the treatment of harmful viral infections such as Ebola and influenza. With the outbreak of the global SARS-CoV-2 pandemic, the two drugs were repurposed for the treatment of COVID-19 patients. Clinical studies suggested that the efficacy of the drugs is enhanced in the case of an early or even prophylactic application. Because the contact between drug molecules and the plasma membrane is essential for a successful permeation process of the substances and therefore for their intracellular efficiency, drug-induced effects on the membrane structure are likely and have already been shown for other substances. We investigated the impact of remdesivir and favipiravir on lipid bilayers in model and cell membranes via several biophysical approaches. The measurements revealed that the embedding of remdesivir molecules in the lipid bilayer results in a disturbance of the membrane structure of the tested phospholipid vesicles. Nevertheless, in a cell-based assay, the presence of remdesivir induced only weak hemolysis of the treated erythrocytes. In contrast, no experimental indication for an effect on the structure and integrity of the membrane was detected in the case of favipiravir. Regarding potential prophylactic or accompanying use of the drugs in the therapy of COVID-19, the physiologically relevant impacts associated with the drug-induced structural modifications of the membrane might be important to understand side effects and/or low effectivities.


Subject(s)
COVID-19 , Lipid Bilayers , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/pharmacology , Amides , Antiviral Agents/chemistry , COVID-19/drug therapy , Humans , Pyrazines , RNA-Dependent RNA Polymerase , SARS-CoV-2
6.
Pharmacol Res Perspect ; 9(3): e00800, 2021 05.
Article in English | MEDLINE | ID: covidwho-1898944

ABSTRACT

Antiprotozoal drug nitazoxanide (NTZ) has shown diverse pharmacological properties and has appeared in several clinical trials. Herein we present the synthesis, characterization, in vitro biological investigation, and in silico study of four hetero aryl amide analogs of NTZ. Among the synthesized molecules, compound 2 and compound 4 exhibited promising antibacterial activity against Escherichia coli (E. coli), superior to that displayed by the parent drug nitazoxanide as revealed from the in vitro antibacterial assay. Compound 2 displayed zone of inhibition of 20 mm, twice as large as the parent drug NTZ (10 mm) in their least concentration (12.5 µg/ml). Compound 1 also showed antibacterial effect similar to that of nitazoxanide. The analogs were also tested for in vitro cytotoxic activity by employing cell counting kit-8 (CCK-8) assay technique in HeLa cell line, and compound 2 was identified as a potential anticancer agent having IC50 value of 172 µg which proves it to be more potent than nitazoxanide (IC50  = 428 µg). Furthermore, the compounds were subjected to molecular docking study against various bacterial and cancer signaling proteins. The in vitro test results corroborated with the in silico docking study as compound 2 and compound 4 had comparatively stronger binding affinity against the proteins and showed a higher docking score than nitazoxanide toward human mitogen-activated protein kinase (MAPK9) and fatty acid biosynthesis enzyme (FabH) of E. coli. Moreover, the docking study demonstrated dihydrofolate reductase (DHFR) and thymidylate synthase (TS) as probable new targets for nitazoxanide and its synthetic analogs. Overall, the study suggests that nitazoxanide and its analogs can be a potential lead compound in the drug development.


Subject(s)
Amides , Anti-Bacterial Agents , Antineoplastic Agents , Antiparasitic Agents , Nitro Compounds , Thiazoles , Amides/chemistry , Amides/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antiparasitic Agents/chemistry , Antiparasitic Agents/pharmacology , Bacterial Proteins/metabolism , Biological Assay , Cell Survival/drug effects , Escherichia coli/drug effects , Escherichia coli/growth & development , HeLa Cells , Humans , Mitogen-Activated Protein Kinase 9/metabolism , Molecular Docking Simulation , Nitro Compounds/chemistry , Nitro Compounds/pharmacology , Tetrahydrofolate Dehydrogenase/metabolism , Thiazoles/chemistry , Thiazoles/pharmacology , Thymidylate Synthase/metabolism
7.
Int J Infect Dis ; 120: 217-227, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1889488

ABSTRACT

OBJECTIVES: This study aimed to evaluate the efficacy and adverse events of favipiravir in patients with COVID-19. METHODS: Our protocol was registered on PROSPERO (CRD42020206305). Fourteen databases were searched until February 8th, 2021. An update search for new RCTs was done on March 2nd, 2022. Meta-analysis was done for randomized controlled trials (RCTs) and non-RCTs. RESULTS: Overall, 157 studies (24 RCTs, 1 non-RCT, 21 observational studies, 2 case series, and 106 case reports) were included. On hospitalized patients, in comparison to standard of care, favipiravir showed a higher rate of viral clearance at day 5 (RR = 1.60, p = 0.02), defervescence at day 3-4 (RR = 1.99, p <0.01), chest radiological improvement (RR = 1.33, p <0.01), hospital discharge at day 10-11 (RR = 1.19, p <0.01), and shorter clinical improvement time (MD = -1.18, p = 0.05). Regarding adverse events, favipiravir groups had higher rates of hyperuricemia (RR = 9.42, p <0.01), increased alanine aminotransferase (RR = 1.35, p <0.01) but lower rates of nausea (RR = 0.42, p <0.01) and vomiting (R R= 0.19, p=0.02). There were no differences regarding mortality (RR=1.19, p=0.32), and increased aspartate aminotransferase (RR = 1.11, p = 0.25). On nonhospitalized patients, no significant differences were reported. CONCLUSIONS: Adding favipiravir to the standard of care provides better outcomes for hospitalized patients with COVID-19. Pregnant, lactating women, and patients with a history of hyperuricemia should avoid using favipiravir.


Subject(s)
COVID-19 , Drug-Related Side Effects and Adverse Reactions , Hyperuricemia , Amides , COVID-19/drug therapy , Female , Humans , Pyrazines , SARS-CoV-2 , Treatment Outcome
8.
Molecules ; 27(12)2022 Jun 07.
Article in English | MEDLINE | ID: covidwho-1884288

ABSTRACT

In 2018, the discovery of carcinogenic nitrosamine process related impurities (PRIs) in a group of widely used drugs led to the recall and complete withdrawal of several medications that were consumed for a long time, unaware of the presence of these genotoxic PRIs. Since then, PRIs that arise during the manufacturing process of the active pharmaceutical ingredients (APIs), together with their degradation impurities, have gained the attention of analytical chemistry researchers. In 2020, favipiravir (FVR) was found to have an effective antiviral activity against the SARS-COVID-19 virus. Therefore, it was included in the COVID-19 treatment protocols and was consequently globally manufactured at large-scales during the pandemic. There is information indigence about FVR impurity profiling, and until now, no method has been reported for the simultaneous determination of FVR together with its PRIs. In this study, five advanced multi-level design models were developed and validated for the simultaneous determination of FVR and two PRIs, namely; (6-chloro-3-hydroxypyrazine-2-carboxamide) and (3,6-dichloro-pyrazine-2-carbonitrile). The five developed models were classical least square (CLS), principal component regression (PCR), partial least squares (PLS), genetic algorithm-partial least squares (GA-PLS), and artificial neural networks (ANN). Five concentration levels of each compound, chosen according to the linearity range of the target analytes, were used to construct a five-level, three-factor chemometric design, giving rise to twenty-five mixtures. The models resolved the strong spectral overlap in the UV-spectra of the FVR and its PRIs. The PCR and PLS models exhibited the best performances, while PLS proved the highest sensitivity relative to the other models.


Subject(s)
COVID-19 , Algorithms , Amides , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Calibration , Humans , Least-Squares Analysis , Pyrazines/therapeutic use
9.
Viruses ; 14(5)2022 05 17.
Article in English | MEDLINE | ID: covidwho-1869812

ABSTRACT

Lipids play a crucial role in the entry and egress of viruses, regardless of whether they are naked or enveloped. Recent evidence shows that lipid involvement in viral infection goes much further. During replication, many viruses rearrange internal lipid membranes to create niches where they replicate and assemble. Because of the close connection between lipids and inflammation, the derangement of lipid metabolism also results in the production of inflammatory stimuli. Due to its pivotal function in the viral life cycle, lipid metabolism has become an area of intense research to understand how viruses seize lipids and to design antiviral drugs targeting lipid pathways. Palmitoylethanolamide (PEA) is a lipid-derived peroxisome proliferator-activated receptor-α (PPAR-α) agonist that also counteracts SARS-CoV-2 entry and its replication. Our work highlights for the first time the antiviral potency of PEA against SARS-CoV-2, exerting its activity by two different mechanisms. First, its binding to the SARS-CoV-2 S protein causes a drop in viral infection of ~70%. We show that this activity is specific for SARS-CoV-2, as it does not prevent infection by VSV or HSV-2, other enveloped viruses that use different glycoproteins and entry receptors to mediate their entry. Second, we show that in infected Huh-7 cells, treatment with PEA dismantles lipid droplets, preventing the usage of these vesicular bodies by SARS-CoV-2 as a source of energy and protection against innate cellular defenses. This is not surprising since PEA activates PPAR-α, a transcription factor that, once activated, generates a cascade of events that leads to the disruption of fatty acid droplets, thereby bringing about lipid droplet degradation through ß-oxidation. In conclusion, the present work demonstrates a novel mechanism of action for PEA as a direct and indirect antiviral agent against SARS-CoV-2. This evidence reinforces the notion that treatment with this compound might significantly impact the course of COVID-19. Indeed, considering that the protective effects of PEA in COVID-19 are the current objectives of two clinical trials (NCT04619706 and NCT04568876) and given the relative lack of toxicity of PEA in humans, further preclinical and clinical tests will be needed to fully consider PEA as a promising adjuvant therapy in the current COVID-19 pandemic or against emerging RNA viruses that share the same route of replication as coronaviruses.


Subject(s)
COVID-19 , SARS-CoV-2 , Amides , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Ethanolamines , Humans , Palmitic Acids/pharmacology , Pandemics , Peas , Peroxisome Proliferator-Activated Receptors , Spike Glycoprotein, Coronavirus
10.
Biotechnol Lett ; 44(7): 831-843, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1859022

ABSTRACT

PURPOSE: In the wake of SARS-CoV-2's global spread, human activities from health to social life to education have been affected. Favipiravir and Molnupiravir exhibited novel hexokinase inhibition and we discuss advantages of this property in their COVID-19 inhibition potential. METHODS: This paper describes molecular docking data of human hexokinase II with Favipiravir, Cyan 20, Remdesivir, 2DG, and Molnupiravir along with hexokinase inhibition assays. RESULTS: Favipiravir, an antiviral drug previously cleared for treating the flu and ebola, has shown some promise in early trials to treat COVID-19. We observed potent human hexokinase inhibiting potential of Favipiravir (50%) as against 4% and merely 0.3% hexokinase inhibition with Molnupiravir and 2 Deoxy D glucose at 0.1 mM concentration supported by molecular docking studies. CONCLUSION: Favipiravir could continue to be part of the COVID-19 treatment regimen due to its resistance to host esterases, hexokinase inhibition potential and proven safety through human trials.


Subject(s)
COVID-19 , Amides , Antiviral Agents/pharmacology , COVID-19/drug therapy , Cytidine/analogs & derivatives , Deoxyglucose/pharmacology , Hexokinase , Humans , Hydroxylamines , Molecular Docking Simulation , Pyrazines , SARS-CoV-2
11.
J Sep Sci ; 45(14): 2582-2590, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1850137

ABSTRACT

Favipiravir, molnupiravir, and ritonavir have been recently approved as the first oral antivirals for treatment of SARS-CoV-2 viral infections. Their combination was reported in several clinical studies, alternatively, to enhance the viral eradication and improve patient's recovery times and rates. Being all orally administered, therefore, the development of new sensitive and validated methodologies for their simultaneous determination is a necessitate. In the proposed research, a sensitive, selective, and simple high-performance thin layer chromatography method was developed and validated for determination of favipiravir, molnupiravir, and ritonavir. Silica gel 60F254 thin layer chromatography plates were used as stationary phase for this separation using mobile phase composed of methylene chloride:ethyl acetate:methanol:25% ammonia (6:3:4:1, v/v/v/v). Densitometric detection was performed at wavelength 289 nm. Peaks of favipiravir, molnupiravir, and ritonavir were resolved at retention factors 0.22, 0.42, and 0.63, respectively. The proposed method was found linear within the specified ranges of 3.75-100.00 µg/mL for molnupiravir and favipiravir, and 2.75-100.00 µg/mL for ritonavir. Limits of detection were found to be 1.12, 1.21, and 0.89 µg/mL for favipiravir, molnupiravir, and ritonavir, respectively. This is the first method to be reported for the simultaneous determination of the cited three antiviral drugs. The method was assessed on novel greenness metrics.


Subject(s)
COVID-19 , Ritonavir , Amides , Antiviral Agents , COVID-19/drug therapy , Chromatography, High Pressure Liquid/methods , Chromatography, Thin Layer/methods , Cytidine/analogs & derivatives , Drug Compounding , Humans , Hydroxylamines , Pyrazines , Reproducibility of Results , SARS-CoV-2
12.
Geroscience ; 44(3): 1263-1268, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1838400

ABSTRACT

Since the appearance of coronavirus disease 2019 (COVID-19), numerous studies have been conducted to find effective therapeutics. Favipiravir (FVP) is one of the repurposed drugs which has been authorized in a few countries on an emergency basis to treat COVID-19. Elderly individuals especially 65 years or older are more prone to develop severe illness. We aim to provide a short summary of the current knowledge of the antiviral efficacy of favipiravir with respect to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected elderly patients. We found that it is rather controversial whether favipiravir is effective against SARS-CoV-2 infection. Data regarding patients 65 years or older is not sufficient to support or reject the usage of favipiravir for COVD-19 treatment. Further studies would be advisable to elicit the efficiency of favipiravir in elderly COVID-19 patients.


Subject(s)
COVID-19 , Aged , Amides , COVID-19/drug therapy , Humans , Pyrazines/therapeutic use , SARS-CoV-2 , Treatment Outcome
13.
Viruses ; 14(4)2022 03 24.
Article in English | MEDLINE | ID: covidwho-1834918

ABSTRACT

The effect of treatment with favipiravir, an antiviral purine nucleoside analog, for coronavirus disease 2019 (COVID-19) on the production and duration of neutralizing antibodies for SARS-CoV-2 was explored. There were 17 age-, gender-, and body mass index-matched pairs of favipiravir treated versus control selected from a total of 99 patients recovered from moderate COVID-19. These subjects participated in the longitudinal (>6 months) analysis of (i) SARS-CoV-2 spike protein's receptor-binding domain IgG, (ii) virus neutralization assay using authentic virus, and (iii) neutralization potency against original (WT) SARS-CoV-2 and cross-neutralization against B.1.351 (beta) variant carrying triple mutations of K417N, E484K, and N501Y. The results demonstrate that the use of favipiravir: (1) significantly accelerated the elimination of SARS-CoV-2 in the case vs. control groups (p = 0.027), (2) preserved the generation and persistence of neutralizing antibodies in the host, and (3) did not interfere the maturation of neutralizing potency of anti-SARS-CoV-2 and neutralizing breadth against SARS-CoV-2 variants. In conclusion, treatment of COVID-19 with favipiravir accelerates viral clearance and does not interfere the generation or maturation of neutralizing potency against both WT SARS-CoV-2 and its variants.


Subject(s)
Antibodies, Neutralizing , COVID-19 , SARS-CoV-2 , Amides/therapeutic use , Antibodies, Neutralizing/metabolism , Antibodies, Viral , COVID-19/drug therapy , Humans , Immunoglobulin G , Neutralization Tests , Pyrazines/therapeutic use , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
14.
Sao Paulo Med J ; 140(3): 372-377, 2022.
Article in English | MEDLINE | ID: covidwho-1833818

ABSTRACT

BACKGROUND: Favipiravir is generally used in treating coronavirus disease 2019 (COVID-19) pneumonia in Turkey. OBJECTIVE: To determine the side effects of favipiravir and whether it is a good treatment option. DESIGN AND SETTING: Retrospective study conducted in Atatürk Chest Diseases and Chest Surgery Training and Research Hospital, Ankara, Turkey. METHODS: 357 patients who completed favipiravir treatment at the recommended dose were included. 37 patients with drug side effects and 320 patients without drug side effects were examined in two groups. RESULTS: Side effects were observed in 37 (10.36%) out of 357 patients using favipiravir. The most common side effect was liver dysfunction, in 26 (7.28%) of the patients. The following other side effects were also observed: diarrhea (1.4%), nausea (0.84%), abdominal pain (0.28%) and thrombocytopenia (0.28%). One patient (0.28%) presented both increased transaminases and nausea. CONCLUSION: In this study, it was determined that favipiravir may constitute an alternative for treating COVID-19 pneumonia given that its side effects are generally well tolerated and not serious.


Subject(s)
COVID-19 , Drug-Related Side Effects and Adverse Reactions , Amides , Antiviral Agents/adverse effects , COVID-19/drug therapy , Drug-Related Side Effects and Adverse Reactions/drug therapy , Humans , Nausea/chemically induced , Nausea/drug therapy , Pyrazines , Retrospective Studies , SARS-CoV-2 , Treatment Outcome
15.
Am J Health Syst Pharm ; 79(16): 1330-1336, 2022 08 05.
Article in English | MEDLINE | ID: covidwho-1830999

ABSTRACT

PURPOSE: To describe a case of increased viral load in a patient with HIV-1 infection receiving treatment with crushed bictegravir/emtricitabine/tenofovir alafenamide (B/FTC/TAF). SUMMARY: A 43-year-old man, newly diagnosed with HIV, was hospitalized due to failure to thrive, neurological changes, and hypotension. Before treatment, the HIV viral load (VL) was 769,704 copies/mL and the CD4+ T-cell count was 36 cells/µL. On hospital day (HD) 8, B/FTC/TAF by mouth daily was initiated. During the hospitalization, the patient's course was complicated by opportunistic infections, bilateral pneumothorax, seizure activity, and acute respiratory distress, requiring multiple intubations and extended time in the intensive care unit. A repeat VL measurement on HD 28 was 5,887 copies/mL after the patient had received 14 of 20 scheduled B/FTC/TAF doses. Because of a failed swallow study and continued nutritional deficits, a percutaneous endoscopic gastrostomy (PEG) tube was placed on HD 38 and continuous tube feeds via the PEG tube were initiated. Subsequently, the B/FTC/TAF order was modified to be crushed, mixed in 30 mL water, and administered daily via the PEG tube. A repeat VL measurement on HD 65 showed an increase to 8,047 copies/mL, despite receipt of 37 consecutive doses of B/FTC/TAF. B/FTC/TAF was discontinued and dolutegravir 50 mg twice daily, darunavir 800 mg plus ritonavir 100 mg (DRV/r), and tenofovir disoproxil fumarate/FTC 300 mg/200 mg were started due to virological increase, need for a viable option compatible with PEG tube delivery, and potential for integrase inhibitor resistance. At the time of regimen change (HD 67), a resistance panel showed minor mutations, E157Q and V118I. The regimen was streamlined with discontinuation of DRV/r on HD 92. The patient was discharged on HD 161. The PEG tube was removed 2 months after discharge, oral B/FTC/TAF was reinitiated, and the patient was virologically suppressed at 1 year after discharge. CONCLUSION: Controlled studies are needed to verify acceptable pharmacokinetic and pharmacodynamic metrics for crushed B/FTC/TAF given via tube, with and without tube feeds, before use in this manner.


Subject(s)
Anti-HIV Agents , HIV Infections , HIV-1 , Adenine , Adult , Alanine , Amides , Drug Combinations , Emtricitabine/therapeutic use , HIV Infections/drug therapy , Heterocyclic Compounds, 3-Ring , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Humans , Male , Piperazines , Pyridones/therapeutic use , Tenofovir/analogs & derivatives , Viral Load
16.
J Infect Dev Ctries ; 16(3): 422-426, 2022 03 31.
Article in English | MEDLINE | ID: covidwho-1786129

ABSTRACT

INTRODUCTION: Early experience with favipiravir in the treatment of COVID-19 is promising, but no clinical data have been published in medical journals. This study aimed to review the experience with favipiravir treatment for COVID-19 pneumonia and to examine whether there are any predictors of treatment response. METHODOLOGY: Fifty-six patients with severe or progressive pneumonia associated with COVID-19 who were treated with favipiravir monotherapy for at least five days were included in this retrospective study. Treatment response was defined as clinical recovery without any need for admission into the intensive care unit and/or anti-cytokine therapy. The demographic, clinical, laboratory and radiographic features of the patients were compared between favipiravir-responders and non-responders. RESULTS: Of the 56 patients, 34 patients (60.7%) responded to treatment and recovered. There was no difference in the demographic, clinical, and radiographic findings between the responders and non-responders. The inflammatory biomarkers were also similar except for the CRP levels on the day favipiravir was started [74 (36-111) vs. 118.5 (46.5-203) mg/L, respectively, p = 0.043]. There was also a significant difference in the median time to defervescence [1 (1-2) vs. 3.5 (1.75-9.25) days, respectively]. Of clinical interest, 27 (79.4%) and 31 (91.2%) of the responders became afebrile within two and four days, respectively. The response rate was lower in patients who presented severe pneumonia associated with respiratory failure. CONCLUSIONS: Patients with non-severe pneumonia at admission and whose fever resolved within two days of treatment are more likely to improve with favipiravir.


Subject(s)
COVID-19 , Amides , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Humans , Pyrazines , Retrospective Studies , SARS-CoV-2 , Treatment Outcome
17.
Molecules ; 27(7)2022 Mar 31.
Article in English | MEDLINE | ID: covidwho-1785841

ABSTRACT

Nanomaterial technology has attracted much attention because of its antibacterial and drug delivery properties, among other applications. Metal-organic frameworks (MOFs) have advantages, such as their pore structure, large specific surface area, open metal sites, and chemical stability, over other nanomaterials, enabling better drug encapsulation and adsorption. In two examples, we used the common pathogenic bacterium Staphylococcus aureus and highly infectious influenza A virus. A novel complex MIL-101(Fe)-T705 was formed by synthesizing MOF material MIL-101(Fe) with the drug favipiravir (T-705), and a hot solvent synthesis method was applied to investigate the in vitro antibacterial and antiviral activities. The results showed that MIL-101(Fe)-T705 combined the advantages of nanomaterials and drugs and could inhibit the growth of Staphylococcus aureus at a concentration of 0.0032 g/mL. Regarding the inhibition of influenza A virus, MIL-101(Fe)-T705 showed good biosafety at 12, 24, 48, and 72 h in addition to a good antiviral effect at concentrations of 0.1, 0.2, 0.4, 0.8, 1.6, and 3 µg/mL, which were higher than MIL-101(Fe) and T-705.


Subject(s)
Metal-Organic Frameworks , Amides , Anti-Bacterial Agents , Antiviral Agents/pharmacology , Metal-Organic Frameworks/chemistry , Metal-Organic Frameworks/pharmacology , Pyrazines
18.
Jpn J Radiol ; 40(8): 800-813, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1782926

ABSTRACT

PURPOSE: Using CT findings from a prospective, randomized, open-label multicenter trial of favipiravir treatment of COVID-19 patients, the purpose of this study was to compare the utility of machine learning (ML)-based algorithm with that of CT-determined disease severity score and time from disease onset to CT (i.e., time until CT) in this setting. MATERIALS AND METHODS: From March to May 2020, 32 COVID-19 patients underwent initial chest CT before enrollment were evaluated in this study. Eighteen patients were randomized to start favipiravir on day 1 (early treatment group), and 14 patients on day 6 of study participation (late treatment group). In this study, percentages of ground-glass opacity (GGO), reticulation, consolidation, emphysema, honeycomb, and nodular lesion volumes were calculated as quantitative indexes by means of the software, while CT-determined disease severity was also visually scored. Next, univariate and stepwise regression analyses were performed to determine relationships between quantitative indexes and time until CT. Moreover, patient outcomes determined as viral clearance in the first 6 days and duration of fever were compared for those who started therapy within 4, 5, or 6 days as time until CT and those who started later by means of the Kaplan-Meier method followed by Wilcoxon's signed-rank test. RESULTS: % GGO and % consolidation showed significant correlations with time until CT (p < 0.05), and stepwise regression analyses identified both indexes as significant descriptors for time until CT (p < 0.05). When divided all patients between time until CT of 4 days and that of more than 4 days, accuracy of the combined quantitative method (87.5%) was significantly higher than that of the CT disease severity score (62.5%, p = 0.008). CONCLUSION: ML-based CT texture analysis is equally or more useful for predicting time until CT for favipiravir treatment on COVID-19 patients than CT disease severity score.


Subject(s)
COVID-19 , Algorithms , Amides , Artificial Intelligence , COVID-19/diagnostic imaging , Humans , Lung/pathology , Prospective Studies , Pyrazines , SARS-CoV-2 , Tomography, X-Ray Computed/methods
19.
Molecules ; 27(7)2022 Apr 04.
Article in English | MEDLINE | ID: covidwho-1776291

ABSTRACT

Following the spread of the COVID-19 pandemic crisis, a race was initiated to find a successful regimen for postinfections. Among those trials, a recent study declared the efficacy of an antiviral combination of favipiravir (FAV) and molnupiravir (MLP). The combined regimen helped in a successful 60% eradication of the SARS-CoV-2 virus from the lungs of studied hamster models. Moreover, it prevented viral transmission to cohosted sentinels. Because both medications are orally bioavailable, the coformulation of FAV and MLP can be predicted. The developed study is aimed at developing new green and simple methods for the simultaneous determination of FAV and MLP and then at their application in the study of their dissolution behavior if coformulated together. A green micellar HPLC method was validated using an RP-C18 core-shell column (5 µm, 150 × 4.6 mm) and an isocratic mixed micellar mobile phase composed of 0.1 M SDS, 0.01 M Brij-35, and 0.02 M monobasic potassium phosphate mixture and adjusted to pH 3.1 at 1.0 mL min-1 flow rate. The analytes were detected at 230 nm. The run time was less than five minutes under the optimized chromatographic conditions. Four other multivariate chemometric model methods were developed and validated, namely, classical least square (CLS), principal component regression (PCR), partial least squares (PLS-1), and genetic algorithm-partial least squares (GA-PLS-1). The developed models succeeded in resolving the great similarity and overlapping in the FAV and MLP UV spectra unlike the traditional univariate methods. All methods were organic solvent-free, did not require extraction or derivatization steps, and were applied for the construction of the simultaneous dissolution profile for FAV tablets and MLP capsules. The methods revealed that the amount of the simultaneously released cited drugs increases up until reaching a plateau after 15 and 20 min for FAV and MLP, respectively. The greenness was assessed on GAPI and found to be in harmony with green analytical chemistry concepts.


Subject(s)
COVID-19 , Amides , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Chromatography, High Pressure Liquid/methods , Cytidine/analogs & derivatives , Humans , Hydroxylamines , Micelles , Pandemics , Pyrazines , Reproducibility of Results , SARS-CoV-2 , Spectrophotometry, Ultraviolet/methods
20.
Int J Clin Pract ; 2022: 3098527, 2022.
Article in English | MEDLINE | ID: covidwho-1770029

ABSTRACT

Objective: In a setting with a limited capacity for hospitalization, "hospitels" have been developed by using hotels as extension healthcare facilities for patients with mild illness. This study examined the clinical evidence of patients with coronavirus disease 2019 (COVID-19) who were treated with favipiravir, the main medication for treating COVID-19, in the hospitel setting in Thailand. Methods: We retrospectively collected demographic and clinical information, medication treatment, and outcome data for all patients who received favipiravir for COVID-19 during admission to a hospitel from April 27, 2021, to July 2, 2021. Risk factors for adults who could not complete treatment in a hospitel and who required hospitel transfer were analyzed. Results: In total, 421 patients were included in the study. Most patients (94.5%) received favipiravir to treat COVID-19 pneumonia. Adjunctive corticosteroids were prescribed to 42.3% of patients. Concerning the treatment outcome, 83.6% of patients completed treatment at a hospitel, and only two deaths occurred. No serious adverse drug reactions were observed. On multivariate analysis, age (odds ratio (OR) = 1.06; 95% confidence interval (CI) = 1.02-1.10, P=0.002), dyspnea (OR = 2.84; 95% CI = 1.25-6.44, P=0.013), loss of taste (OR = 107.63; 95% CI = 1.24-9337.39, P=0.040), corticosteroid use (OR = 12.56; 95% CI = 3.65-43.18, P < 0.001), and an extended duration of favipiravir use (OR = 16.91; 95% CI = 7.29-39.24, P < 0.001) were associated with a higher risk of hospitel transfer. Conclusions: Low rates of hospitel transfer and mortality were observed in mild-to-moderate COVID-19 patients treated with favipiravir at hospitel. Caution might be required in elderly patients, patients with dyspnea or a loss of taste, and patients receiving a 10-day course of favipiravir or adjunctive corticosteroids because these patients might require further management in the hospitel.


Subject(s)
Ageusia , COVID-19 , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Ageusia/chemically induced , Ageusia/drug therapy , Amides , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Dyspnea , Humans , Pyrazines , Retrospective Studies , SARS-CoV-2
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