An ultrasensitive green synchronous factorized spectrofluorimetric approach for the simultaneous determination of Favipiravir and Molnupiravir: Application to pharmaceutical, environmental, and biological matrices.

During the pandemic, Favipiravir (FVP) and Molnupiravir (MPV) have been widely used for COVID-19 treatment, leading to their presence in the environment. A green synchronous spectrofluorimetric method was developed to simultaneously detect them in environmental water, human plasma, and binary mixtures. Maximum fluorescence intensity was achieved at pH 8, with MPV exhibiting two peaks at 300 and 430 nm, and FVP showing one peak at 430 nm. A fluorescence subtraction method effectively removed interference, enabling direct determination of MPV at 300 nm and FVP at 430 nm. The method showed linearity within 2-13 ng/mL for FVP and 50-600 ng/mL for MPV, with recoveries of 100.35% and 100.12%, respectively. Limits of detection and quantification were 0.19 and 0.57 ng/mL for FVP and 10.52 and 31.88 ng/mL for MPV. Validation according to ICH and FDA guidelines yielded acceptable results. The method demonstrated good recoveries of FVP and MPV in pharmaceuticals, tap water and Nile water (99.62% ± 0.96% and 99.69% ± 0.64%) as per ICH guidelines and spiked human plasma (94.87% ± 2.111% and 94.79% ± 1.605%) following FDA guidelines, respectively. Its environmental friendliness was assessed using Green Analytical Procedure Index (GAPI) and the Analytical Greenness Metric (AGREE) tools.

Convenient screening of the reproductive toxicity of favipiravir and antiviral drugs in Caenorhabditis elegans.

Reproductive toxicity is one of the major concerns in drug development. Thus, we have developed its screening system using Caenorhabditis elegans, which has a life cycle of three days and similar coding genes as humans. Antiviral nucleoside analogs used for acute infections are known to cause reproductive toxicity, contraindicated for pregnant women, and are used for comparing their reproductive toxicity in C. elegans and experimental animals. None of the drug treatments affected the number of offspring and the concentrations without toxicity to nematodes were consistent with no cytotoxicity or toxicity in experimental animals or humans. Favipiravir, ribavirin, molnupiravir (NHC), acyclovir, ganciclovir, zidovudine, and thalidomide significantly increased the incidence of arrested embryos but amenamevir, letermovir, and guanosine did not. RNA-dependent RNA polymerase (RdRp) inhibitors, in the order of favipiravir, ribavirin, and NHC increased the incidence of arrested embryos, possibly due to the specificity of favipiravir for RdRp and less cytotoxicity. RdRp inhibitors would impair RNA interference through RdRp expressed by telomerase reverse transcriptase during embryogenesis and cause embryo-fetal toxicity. The incidence of arrested embryos may be affected by differences in the substrate specificity of DNA polymerases and metabolism between C. elegans, animals, and humans. The concordance between the results of the screening system for reproductive toxicity of antivirals in C. elegans and those in experimental animals based on the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, reproductive toxicology confirms its appropriateness as a screening system for reproductive toxicity. Favipiravir and zidovudine were the least toxic to C. e legans among the antiviral drugs examined.

Enhanced favipiravir drug degradation using the synergy of PbO2-based anodic oxidation and Fe-MOF-based cathodic electro-Fenton.

Favipiravir (FAV) is a widely utilized antiviral drug effective against various viruses, including SARS-CoV-2, influenza, and RNA viruses. This article aims to introduce a novel approach, known as Linear-Paired Electrocatalytic Degradation (LPED), as an efficient technique for the electrocatalytic degradation of emerging pollutants. LPED involves simultaneously utilizing a carbon-Felt/Co-PbO2 anode and a carbon-felt/Co/Fe-MOF-74 cathode, working together to degrade and mineralize FAV. The prepared anode and cathode characteristics were analyzed using XPS, SEM, EDX mapping, XRD, LSV, and CV analyses. A rotatable central composite design-based quadratic model was employed to optimize FAV degradation, yielding statistically desirable results. Under optimized conditions (pH = 5, current density = 4.2 mA/cm2, fFf concentration = 0.4 mM), individual processes of cathodic electro-Fenton and anodic oxidation with a CF/Co-PbO2 anode achieved degradation rates of 58.9% and 89.5% after 120 min, respectively. In contrast, using the LPED strategy resulted in a remarkable degradation efficiency of 98.4%. Furthermore, a cyclic voltammetric study of FAV on a glassy carbon electrode was conducted to gather additional electrochemical insights and rectify previously published data regarding redox behavior, pH-dependent properties, and adsorption activities. The research also offers a new understanding of the LPED mechanism of FAV at the surfaces of both CF/Co-PbO2 and CF/Co/Fe-MOF-74 electrodes, utilizing data from cyclic voltammetry and LC-MS techniques. The conceptual strategy of LPED is generalizable in order to the synergism of anodic oxidation and cathodic electro-Fenton for the degradation of other toxic and resistant pollutants.

Alleviation of favipiravir-induced hepatotoxicity using hepatoprotective herbal extracts in wistar rats.

Teratogenicity and hyperuricaemia are the main side effects of favipiravir, an antiviral drug recently found its use to treat mild to moderate coronavirus (COVID-19) infections. This study investigated the beneficial effect of herbal extracts like Picrorrhiza kurroa (PK) and Scutellaria baicalensis (SB) and their active chemical constituents (baicalin and baicalein) on favipiravir-induced hepatotoxicity in rats. The formulation combinations included favipiravir, favipiravir + PK extract, favipiravir + pure baicalin, favipiravir + pure baicalein, and favipiravir + SB extract designated as F1, F2, F3, F4 and F5 respectively that were administered to rats orally for 21 days. Favipiravir caused increased levels of SGOT, SGPT, ALP, total bilirubin, and uric acid and decreased liver weight which was alleviated when alloherbal formulation of favipiravir and baicalein combination and favipiravir and SB extract was used. This paper highlights an attractive proposition to ameliorate favipiravir-induced hepatotoxicity using hepatoprotective agents.

Favipiravir for COVID-19 in adults in the community in PRINCIPLE, an open-label, randomised, controlled, adaptive platform trial of short- and longer-term outcomes.

BACKGROUND: Evidence for the effect of favipiravir treatment of acute COVID-19 on recovery, hospital admissions and longer-term outcomes in community settings is limited. METHODS: In this multicentre. open-label, multi-arm, adaptive platform randomised controlled trial participants aged ≥18 years in the community with a positive test for SARS-CoV-2 and symptoms lasting ≤14 days were randomised to: usual care; usual care plus favipiravir tablets (loading dose of 3600mg in divided doses on day one, then 800mg twice a day for four days); or, usual care plus other interventions. Co-primary endpoints were time to first self-reported recovery and hospitalisation/death related to COVID-19, within 28 days, analysed using Bayesian models. Recovery at six months was the primary longer-term outcome. TRIAL REGISTRATION: ISRCTN86534580. FINDINGS: The primary analysis model included 8811 SARS-CoV-2 positive mostly COVID vaccinated participants, randomised to favipiravir (n=1829), usual care (n=3256), and other treatments (n=3726). Time to self-reported recovery was shorter in the favipiravir group than usual care (estimated hazard ratio 1·23 [95% credible interval 1·14 to 1·33]), a reduction of 2·98 days [1·99 to 3·94] from 16 days in median time to self-reported recovery for favipiravir versus usual care alone. COVID-19 related hospitalisations/deaths were similar (estimated odds ratio 0·99 [0·61 to 1·61]; estimated difference 0% [-0·9% to 0·6%]). 14 serious adverse events occurred in the favipiravir group and 4 in usual care. By six months, the proportion feeling fully recovered was 74·9% for favipiravir versus 71·3% for usual care (RR = 1·05, [1·02 to 1·08]). INTERPRETATION: In this open-label trial in a largely vaccinated population with COVID-19 in the community, favipiravir did not reduce hospital admissions, but shortened time to recovery and had a marginal positive impact on long term outcomes.

Investigation of substituent effects on the electronic structure and antiviral activity of favipiravir derivatives for Covid-19 treatment using DFT and molecular docking.

In this study, Density-functional theory/Time-dependent density-functional theory (DFT/TDDFT) and Molecular docking method was used to investigate the effect of methyl acetate, tetrahydrofuran and cyanobenzylidene substituents on the electronic structure and antiviral activity of favipiravir for treating COVID-19. The DFT and TDDFT computations were employed using the Gaussian 09 software package. The values were calculated using the 6-311++G(d, p) basis set and the hybrid B3LYP functional method. Autodock vina software was used for simulations to better predictions and to validate the modified compounds' binding affinities and poses. Results of the study indicate that compounds 1 to 6 all displayed a planar structure, where the pyrazine ring, carboxamide, hydroxyl groups, and other substituents are all situated within the same plane. In addition, the energy gaps (Egap) of these six compounds (Cpd 1, 2, 3, 4, 5, and 6) were compared. The significant dipole moment and binding affinity achieved implies a particular orientation for binding within the target protein, signaling the anticipated strength of the binding interaction. In all six compounds, the electrophilic domain is situated in the vicinity of the amine functional group within the carboxamide compound, whereas the nucleophilic domain encompasses both the carbonyl and hydroxyl groups. The most negatively charged sites are susceptible to electrophilic interactions. In conclusion, compounds 5 and 6 exhibit a high binding affinity of the target protein, while compound 6 has a high energy gap, which could enhance its antiviral activity against the COVID-19 virus.

Long term study on the fate and environmental risks of favipiravir in wastewater treatment plants and comparison with COVID-19 cases.

In recent years especially during COVID-19, the increased usage of antiviral drugs has led to increased interest in monitoring their presence in wastewater worldwide. In this study, it was examined the occurrence, fate and environmental risks of favipiravir which is used for COVID-19 treatment in two wastewater treatment plants (WWTPs) with different treatment processes in Istanbul, Turkey. Favipiravir was measured in WWTPs influent samples, effluent samples and sludge samples with maximum concentrations of 97 µg/L, 64.11 µg/L and 182.47 µg/g, respectively. Favipiravir had removal efficiency below 55 % for both WWTPs. Mass balance analysis showed that favipiravir removal in WWTPs mainly attributed to biodegradation/biotransformation. Statistical analysis revealed a significant correlation between favipiravir concentration and COVID-19 incidence in Istanbul. The microbial distribution analysis indicated that comparison of collected COVID-19 pandemic sludge and post-pandemic period sludge samples, a noteworthy reduction in the Chloroflexi and Actinobacteriota phyla at the phylum level was observed. Environmental risk assessment using risk quotients ranged from 168 to 704, indicating that the presence of this antiviral drug posed significant ecological risks to aquatic organisms. The study concluded that WWTPs were releasing antiviral drugs into the environment, thereby posing risks to both the aquatic ecosystem and public health. The results of this study demonstrate the persistence of favipiravir in WWTPs and offer crucial supporting data for further research into the advancement of wastewater treatment technology. Also, this study shows wastewater based monitoring is supplementary and early warning system for determining the occurrence of antiviral drugs.

Favipiravir-induced bradycardia: A case report.

Key Clinical Message: The purpose of this case report is to reveal one of the cardiovascular side effects of favipiravir, sinus bradycardia. Abstract: Favipiravir has emerged as a potential treatment for COVID-19, with its antiviral properties showing promise in inhibiting viral replication. However, concerns regarding its safety profile, particularly its cardiac adverse effects, remain a subject of debate. We present the case of a 58-year-old man with a history of diabetes mellitus and chronic obstructive pulmonary disease who developed bradycardia following treatment with favipiravir for COVID-19 pneumonia. Despite being asymptomatic, the patient exhibited sinus bradycardia, which resolved upon discontinuation of favipiravir. Favipiravir has been associated with QT prolongation and sinus bradycardia, though the exact mechanisms remain unclear. Our case adds to the growing body of evidence highlighting the potential cardiac complications of favipiravir therapy in COVID-19 patients. Further research is warranted to clarify the underlying mechanisms and optimize patient management strategies. Clinicians should be cautious for cardiac adverse events when prescribing favipiravir for COVID-19 treatment, especially in patients with preexisting cardiac conditions. Continued research is essential to ensure the safe and effective use of favipiravir in the management of COVID-19.

Comparison of Routes of Administration, Frequency, and Duration of Favipiravir Treatment in Mouse and Guinea Pig Models of Ebola Virus Disease.

Favipiravir is a ribonucleoside analogue that has been explored as a therapeutic for the treatment of Ebola Virus Disease (EVD). Promising data from rodent models has informed nonhuman primate trials, as well as evaluation in patients during the 2013-2016 West African EVD outbreak of favipiravir treatment. However, mixed results from these studies hindered regulatory approval of favipiravir for the indication of EVD. This study examined the influence of route of administration, duration of treatment, and treatment schedule of favipiravir in immune competent mouse and guinea pig models using rodent-adapted Zaire ebolavirus (EBOV). A dose of 300 mg/kg/day of favipiravir with an 8-day treatment was found to be fully effective at preventing lethal EVD-like disease in BALB/c mice regardless of route of administration (oral, intraperitoneal, or subcutaneous) or whether it was provided as a once-daily dose or a twice-daily split dose. Preclinical data generated in guinea pigs demonstrates that an 8-day treatment of 300 mg/kg/day of favipiravir reduces mortality following EBOV challenge regardless of route of treatment or duration of treatments for 8, 11, or 15 days. This work supports the future translational development of favipiravir as an EVD therapeutic.

Clinical Characteristics and Outcomes of Pediatric COVID-19 Pneumonia Treated with Favipiravir in a Tertiary Care Center.

The COVID-19 pandemic, caused by SARS-CoV-2, has posed significant health challenges worldwide. While children generally experience less severe illness compared to adults, pneumonia remains a substantial risk, particularly for those under five years old. This study examines the clinical characteristics and treatment outcomes of pediatric COVID-19 pneumonia patients treated with favipiravir in Thailand, aiming to identify associated factors for pneumonia. A retrospective review was performed on pediatric patients aged 1 month to 18 years hospitalized with COVID-19 at Srinagarind Hospital, Khon Kaen University, from 13 January 2020 to 15 November 2021. Data on demographics, clinical symptoms, treatment, and outcomes were collected, and logistic regression analysis was used to identify factors associated with pneumonia. Among 349 hospitalized children, the median age was 8 years, with 51.9% being male. Symptoms included a fever (100%), a cough (74.2%), and a rash (24.9%). COVID-19 pneumonia was diagnosed in 54.7% of the children. Favipiravir was administered as the standard treatment, showing mild adverse effects, including a rash (4.3%) and nausea (2.8%). Monocytosis was significantly associated with COVID-19 pneumonia (aOR 30.85, 95% CI: 9.03-105.41, p < 0.001), with an ROC curve area of 0.77 (95% CI: 0.71-0.83). Pediatric COVID-19 patients typically exhibit mild-to-moderate symptoms, with pneumonia being common in the early pandemic phase. Monocytosis is a significant factor associated with COVID-19 pneumonia. Favipiravir demonstrated mild adverse effects. Further studies are needed to validate these findings across different settings and phases of the pandemic.

Coadministration of LHF-535 and favipiravir protects against experimental Junín virus infection and disease.

Argentine hemorrhagic fever, caused by Junín virus (JUNV), is the most common of the South American arenaviral hemorrhagic fevers. The disease has a case fatality rate of 15-30% in untreated patients. Although early intervention with immune plasma is effective, diminishing stocks and limited availability outside of Argentina underscores the need for new therapeutics. Ideally, these would be broadly active agents effective against all the pathogenic arenaviruses. The fusion inhibitor LHF-535 and the nucleoside analog favipiravir have shown promise in animal models of Lassa fever, a disease endemic in parts of Africa and the most prominent of the arenaviral hemorrhagic fevers. Against JUNV, a high dose of favipiravir is required to achieve protection in the gold-standard guinea pig infection model. Here, we demonstrate a synergistic effect by the coadministration of LHF-535 with a sub-optimal dose of favipiravir in guinea pigs challenged with JUNV. Administered individually, LHF-535 and sub-optimal favipiravir only delayed the onset of severe disease. However, combined dosing of the drugs afforded complete protection against lethal JUNV infection in guinea pigs. The benefits of the drug combination were also evident by the absence of viremia and infectious virus in tissues compared to guinea pigs treated with only the placebos. Thus, combined targeting of JUNV-endosomal membrane fusion and the viral polymerase with pan-arenaviral LHF-535 and favipiravir may expand their indication beyond Lassa fever, providing a significant barrier to drug resistance.

Insights on multi-spectroscopic approaches for estimating the in vitro binding of favipiravir with adenine nucleotide.

Favipiravir (FVP) is an oral antiviral drug approved in 2021 for the treatment of COVID-19. It is a pyrazine derivative that can be integrated into anti-viral RNA products to inhibit viral replication. While, adenine is a purine nucleobase that is found in deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) to generate genetic information. For the first time, the binding mechanism between FVP and adenine was determined using different techniques, including UV-visible spectrophotometry, spectrofluorimetry, synchronous fluorescence (SF) spectroscopy, Fourier transform infrared (FTIR), fluorescence resonance energy transfer (FRET), and metal ion complexation. The fluorescence spectra indicated that FVP is bound to adenine via Van der Waals forces and hydrogen bonding through a spontaneous binding process (ΔGο < 0). The quenching mechanism was found to be static. Various temperature settings were used to investigate thermodynamic characteristics, such as binding forces, binding constants, and the number of binding sites. The reaction parameters, including the enthalpy change (ΔHο) and entropy change (ΔSο), were calculated using Van't Hoff's equation. The findings demonstrated that the adenine-FVP binding was endothermic. Furthermore, the results of the experiments revealed that some metal ions (K+, Ca+2, Co+2, Cu+2, and Al+3) might facilitate the binding interaction between FVP and adenine. Slight changes are observed in the FTIR spectra of adenine, indicating the binding interaction between adenine and FVP. This study may be useful in understanding the pharmacokinetic characteristics of FVP and how the drug binds to adenine to prevent any side effects.

Assessment of the potential interactions between favipiravir and radiocontrast agents.

BACKGROUND: In cases of coronavirus disease 2019 (COVID-19), favipiravir is commonly included to the therapy regimen. Drug interactions between favipiravir and other COVID-19 therapy drugs are frequently researched. However, no research on possible drug interactions between Favipiravir and radiocontrast agents, which have become almost crucial in diagnostic processes while not being part of the treatment, has been found. AIM: To determine potential medication interactions between Favipiravir and radiocontrast agents. METHODS: The study comprised patients who were taking Favipiravir for COVID-19 therapy and underwent a contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) test while taking the medicine. The computerized patient files of the cases included in the study, as well as the pharmacovigilance forms in the designated hospital, were evaluated for this purpose. RESULTS: The study included the evaluation of data from 1046 patients. The study sample's mean age was 47.23 ± 9.48 years. The mean age of cases with drug interactions was statistically significant greater than that of cases with no drug interactions (P = 0.003). When evaluated with logistic regression analysis, a 1-year raises in age increases the risk of developing drug interactions by 1.63 times (P = 0.023). There was no statistically significant difference in the occurrence of medication interactions between the sexes (P = 0.090). Possible medication interactions were discovered in 42 cases (4%). CONCLUSION: The findings of this study revealed that the most notable findings as a result of the combined use of contrast agents and favipiravir were increased creatinine and transaminase values, as well as an increase in the frequency of nausea and vomiting. The majority of drug interactions discovered were modest enough that they were not reflected in the clinic. Drug interactions become more common as people get older.

Unveiling therapeutic dynamics: An in-depth comparative analysis of neutralizing monoclonal antibodies and favipiravir in alleviating COVID-19 outpatients impacts among middle-aged and special populations (MA-FAST).

BACKGROUND: Neutralizing monoclonal antibodies (NMabs) are recognized for their efficacy against non-severe COVID-19. However, spike protein mutations may confer resistance. This study evaluates the effectiveness of favipiravir (FPV) versus NMabs in preventing severe COVID-19 in special populations. METHODS: A retrospective cohort was conducted on middle-aged, elderly, diabetic, or obese patients with COVID-19 treated with either FPV or NMabs. Propensity score matching (PSM) was used for analysis. RESULTS: The study included 1410 patients, resulting in four cohorts: middle-aged (36), elderly (48), diabetic (46), and obese (28) post-PSM. No significant differences were noted in 28-day emergency department (ED) visits across all groups between NMabs and FPV treatments, despite lower immunity in the FPV group. However, the diabetic group treated with FPV had higher 28-day hospitalization and oxygen supplemental, with no differences in the other groups. Intensive care unit (ICU) admissions, invasive mechanical ventilation, and mortality rates were similar between the two treatments. CONCLUSIONS: Early dose-adjusted FPV showed no difference from NMabs in preventing ED visits, ICU admissions, ventilator needs, or mortality among patients with major comorbidities. Diabetic patients on FPV experienced higher hospitalizations and oxygen needs, with no observed differences in other groups. FPV may be a viable alternative, especially in settings with limited resources.

Remdesivir versus Favipiravir in Hospitalized Patients with Moderate to Severe COVID-19 Pneumonia: A Propensity Score-Matched Retrospective Cohort Study.

Background: Remdesivir treatment was associated with a reduced 28-day mortality and recovery time among patients hospitalized with severe COVID-19. Favipiravir is broadly used to treat COVID-19. However, various studies have had conflicting results on the efficacy of favipiravir for COVID-19. We hypothesized that remdesivir is more effective in clinical outcomes regarding the 29-day mortality rates, length of stay, and recovery rate than favipiravir in patients with moderate to severe COVID-19 pneumonia. Methods: We performed a retrospective cohort study that included adult hospitalized COVID-19 pneumonia patients with hypoxemia. Patients were classified into two groups according to the antiviral drugs. Age, oxygen saturation, fraction of inspired oxygen, and Charlson comorbidity index were used for propensity score matching. The primary objective was to determine whether the type of antiviral agent is associated with 29-day mortality. Other outcomes were the 15-day recovery rate and the length of intensive care unit or hospital stay. Results: A total of 249 patients with moderate to severe COVID-19 pneumonia were included. With an adjustment for propensity score-matched, there were 204 patients for further analysis (102 patients in each antiviral drug group). Remdesivir patients had higher Radiographic Assessment of Lung Edema (RALE) scores on Chest X-ray (14.32±9.08 vs 11.34±8.46; standardized mean difference =33.9%). The Charlson Comorbidity Index Scores were comparable. The prevalences of diabetes, obesity, hypertension, and non-HIV immunocompromised state were higher in the remdesivir group. Regarding the primary outcomes, after adjusting by diabetes, obesity, and RALE score, there was no difference in the 29-day mortality rate between both groups [26 patients (25.5%) in the remdesivir group vs 28 patients (27.5%) in the favipiravir group]. The Kaplan-Meier curve analysis at 29 days indicated no significant difference in cumulative survival rate. The two groups' adjusted hazard ratio was 0.72; 95% CI, 0.41 to 1.25, p=0.24. A Kaplan-Meier analysis on the 15-day cumulative survival rate observed a trend towards a higher survival rate in the remdesivir group (adjusted hazard ratio 0.41; 95% CI, 0.20 to 0.84; p= 0.02) The proportion of patients who recovered on day 15, the length of intensive care unit(ICU) stays, and the hospital stay were not different between remdesivir and favipiravir groups (62 patients (60.8%) vs 56 patients (54.9%), p=0.39; 11.48 ± 11.88 days vs 10.87 ± 9.31 days, p=0.69; and 16.64±14.28 days vs 16.59 ±11.31 days, p=0.98, respectively). Conclusion: In patients with moderate to severe COVID-19 pneumonia, Remdesivir did not demonstrate superior benefits over Favipiravir regarding 29-day mortality, 15-day recovery rates, or hospital and ICU stay lengths. However, further investigation into the 15-day cumulative survival rate revealed a trend towards improved survival in the Remdesivir group.

Favipiravir does not improve viral clearance in mild to moderate COVID-19 - A systematic review and meta-analysis of randomized controlled trials.

Purpose: Favipiravir has been used in the therapy of COVID-19, including patients with mild to moderate symptoms in certain countries. The aim of our systematic review and meta-analysis was to investigate its efficacy and safety in mild-to-moderate COVID-19 infections. Methods: The PubMed, Embase, Web of Science, and Cochrane databases were systematically reviewed for articles reporting the results of randomized controlled trials published until January 6, 2023, resulting in the identification of 20 eligible studies. Results: There were no significant differences in viral clearance time (HR = 1.20, p = 0.09) compared to those without favipiravir therapy. However, in the subgroup analyses, favipiravir treatment significantly increased viral clearance by 59 % (HR = 1.59, p < 0.01) and 42 % (HR = 1.42, p < 0.01], I2 = 20 %) compared to the comparator group in patients with moderate severity of COVID-19 and in the inpatient care setting, respectively. Favipiravir had no beneficial effects in the case of patients with mild symptoms and treated in ambulatory care. Conclusions: The use of favipiravir is questionable in the treatment of outpatients with COVID-19 with mild symptoms. Moderate beneficial effects in the case of patients with moderate symptoms and inpatients should be treated with care due to the limitations of the analysed trials.

Tenofovir disoproxil fumarate in the treatment of COVID-19: Evaluation of 78 patients.

One of the drugs that has been suggested for the treatment of SARS-CoV-2 infection is tenofovir disoproxil (TDF). Herein, it was aimed to evaluate the outcomes of TDF receiving COVID-19 cases in terms of day 7-10 PCR negativity and day 30 survival. Patients who received TDF due to PCR-confirmed COVID-19 between 27.04.2021 and 31.12.2021 were included in our study. The primary outcome was considered to be 7-10 days of PCR negativity, while the secondary outcome was considered 30-day survival after diagnosis of COVID-19. Patients who died before completing the treatment period (7-10 days) were also considered as PCR failures. Data were analyzed both in terms of intention to treat basis and in the subgroup that survived to the end of treatment. A total of 78 patients (30 women, mean age: 61.15±18.5 years) met the inclusion criteria. In the intention to treat analysis group, one-month-mortality was 44.87% (35/78) in the overall cohort. In the end of treatment analysis group, one-month-mortality was 29.5% (18/61) in the overall cohort. Day 7-10 PCR negativity was detected in 55.7% of the overall EOT cohort. Our data suggest that TDF may be an alternative salvage treatment option in antiviral unresponsive patients. We suggest evaluating TDF in well-designed controlled trials involving treatment-naïve cases.

Electromagnetic drop-on-demand (DoD) technology as an innovative platform for amorphous solid dispersion production.

Production of amorphous solid dispersions (ASDs) is an effective strategy to promote the solubility and bioavailability of poorly water soluble medicinal substances. In general, ASD is manufactured using a variety of classic and modern techniques, most of which rely on either melting or solvent evaporation. This proof-of-concept study is the first ever to introduce electromagnetic drop-on-demand (DoD) technique as an alternative solvent evaporation-based method for producing ASDs. Herein 3D printing of ASDs for three drug-polymer combinations (efavirenz-Eudragit L100-55, lumefantrine-hydroxypropyl methylcellulose acetate succinate, and favipiravir-polyacrylic acid) was investigated to ascertain the reliability of this technique. Polarized light microscopy, differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and Fourier Transform  Infrared (FTIR) spectroscopy results supported the formation of ASDs for the three drugs by means of DoD 3D printing, which significantly increases the equilibrium solubility of efavirenz from 0.03 ± 0.04 µg/ml to 21.18 ± 4.20 µg/ml, and the equilibrium solubility of lumefantrine from 1.26 ± 1.60 µg/ml to 20.21 ± 6.91 µg/ml. Overall, the reported findings show how this new electromagnetic DoD technology can have a potential to become a cutting-edge 3D printing solvent-evaporation technique for on-demand and continuous manufacturing of ASDs for a variety of drugs.

Radiologic and histopathologic effects of favipiravir and hydroxychloroquine on fracture healing in rats.

Fracture healing is a process in which many factors interact. In addition to many treatments, physical and biological therapy methods that affect different steps of this process, there are many biological and chemical agents that cause fracture union delay. Although the number of studies on fracture healing is increasing day by day, the mechanism of fracture healing, which is not fully understood, still attracts the attention of all researchers. In this study, we aimed to investigate the effects of favipiravir and hydroxychloroquine used in the treatment of COVID-19. In this study, 48 male Wistar rats weighing 300 ± 50 g were used. Each group was divided into eight subgroups of six rats each to be sacrificed at the 2nd and 4th weeks and evaluated radiologically and histologically. Favipiravir (group 1), hydroxychloroquine (group 2), favipiravir + hydroxychloroquine (group 3), and random control (group 4) were used. A statistically significant difference was observed between the 15th day histological scoring averages of the groups (p < 0.05). Although there was no statistically significant difference between the 15th day radiological score distributions of the groups (p > 0.05), we obtained different results in terms of complete bone union distributions and radiological images of the fracture line. Although favipiravir has a negative effect on fracture union in the early period, favipiravir may have a positive effect on fracture union in the late period. We did not find any effect of hydroxychloroquine on fracture union.

Drug Interaction Between Favipiravir and Warfarin: A Case Series.

Introduction: Initiating favipiravir in COVID-19 patients with long-term warfarin use can lead to increased INR. However, data on the onset and duration of the increasing INR are limited. Method: We reviewed patient charts to include COVID-19 adult patients who received favipiravir for at least 5 days and used warfarin at the same dose for at least 12 weeks. Data on demographics, comorbidities, other medical characteristics, international normalized ratio (INR), and signs of bleeding were collected. Result: Eight patients, with a mean age of 70.88 ± 8.49 years old, received the standard dose of favipiravir. The mean maximum INR (4.30 ± 1.26) was statistically different from the baseline INR (P = .00029) and the change was observed within 4.38 ± 1.99 days after initiating favipiravir. Warfarin was then discontinued without favipiravir discontinuation in most patients, allowing the INR to gradually decrease within 2 to 3 days. Conclusion: Concurrent use of favipiravir and warfarin led to INR prolongation within approximately 4 days. The effect of such interaction can be acute as the prolongation occurred within 1 day in 1 of the patients.