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This article discusses the different subfamilies and species of the Hepatitis E virus (HEV) and their impact on transplant patients. HEV belongs to the Orthohepevirinae subfamily and has four species: Paslahepevirus, Rocahepevirus, Chirohepevirus, and Avihepevirus. HEV-1 and HEV-2 infections are prevalent in developing countries and pose a high risk to pregnant women but do not lead to chronic hepatitis in immunosuppressed patients. In developed countries, HEV-3 and HEV-4 are more prevalent and can cause chronic infection in transplant patients, leading to cirrhosis if left untreated. Ribavirin is an effective treatment option for HEV infections, including Rocahepevirus. Rat HEV, a member of the Rocahepevirus species, has been identified as a cause of acute hepatitis and chronic infection in humans, particularly in immunosuppressed patients. Ribavirin has shown efficacy in treating Rocahepevirus infections. Overall, this article highlights the importance of understanding the different strains of HEV and their potential impact on transplant patients. [Extracted from the article]

Ribavirin and its analogues exhibit an in vitro antiproliferative effect in cancer cells. In this work, we studied the biological activities of a number of alkyl/aryloxymethyl derivatives of ribavirin’s aglycon—1,2,4-triazole-3-carboxamide. Alkyl/arylxymethyl derivatives of 1,2,4-triazole-3-carboxamide with substitutions at the fifth or first position of the triazole ring, were synthesized and their antiproliferative and antimicrobial effects were assessed. For both series, the presence of an antiproliferative effect was investigated, and 1-alkyl/aryloxymethyl derivatives were shown an antimicrobial potential against a Gram-positive bacteria Micrococcus luteus and Gram-negative bacterium Pseudomonas aeruginosa. The obtained results showed that the n-decyloxymethyl derivatives induced leukemia cell death at low micromolar concentrations. We confirmed that n-decyloxymethyl derivatives of ribavirin inhibited the cell cycle progression and induced an accumulation of leukemia cells in the subG1-phase. The molecular docking results suggest that alkyl/aryloxymethyl derivatives may act by inhibiting translation initiation, due to interference with eIF4E assembly. The outcome results revealed that active derivatives (1- or 5-n-decyloxymethyl-1,2,4-triazole-3-carboxamides) can be considered as a lead compound for anticancer treatments.

Abstract Ribavirin ampoule formulation remains a major challenge in managing Lassa fever disease. Lassa fever is an endemic viral hemorrhagic fever in the West Africa subregion, which has high-dose ribavirin as the standard of care. The high-dose therapy required makes the 200 mg/ml ampoule dosing of ribavirin a daunting task to administer, especially during disease outbreaks. This commentary highlights the challenges and makes a passionate call for vial dosage adjustment to fit the high-dose requirement of Lassa fever disease.

Jatropha variegata and Jatropha spinosa (family: Euphorbiaceae) are utilized in Yemeni traditional medicine to treat respiratory tract infection and in different skin conditions such as wound healing, as antibacterial and hemostatic. In this study, we evaluated the cytotoxicity and the antiviral activities of the methanolic J. variegata (leaves: Ext-1, stems: Ext-2, and roots: Ext-3), and J. spinosa extracts (aerial parts: Ext-4 and roots: Ext-5), in addition to their methylene chloride fractions of roots extracts (F-6 and F-7, respectively). All samples were tested against three human cancer cell lines in vitro (MCF-7, HepG2, and A549) and two viruses (HSV-2 and H1N1). Both plants showed significant cytotoxicity, among them, the methylene chloride fractions of roots of J. variegata (F-6) and J. spinosa roots (F-7) showed the highest activity on MCF-7 (IC50 = 1.4 and 1 μg/mL), HepG2 (IC50 = 0.64 and 0.24 μg/mL), and A549 (IC50 = 0.7 and 0.5 μg/mL), respectively, whereas the IC50 values of the standard doxorubicin were (3.83, 4.73, and 4.57 μg/mL) against MCF-7, HepG2, and A549, respectively. These results revealed that the roots of both plants are potential targets for cytotoxic activities. The in vitro results revealed potential antiviral activity for each of Ext-3, Ext-5, F-6, and F-7 against HVS-2 with IC50 of 101.23, 68.83, 4.88, 3.24 μg/mL and against H1N1 with IC50 of 51.29, 27.92, 4.24, and 3.06 μg/mL respectively, whereas the IC50 value of the standard acyclovir against HVS-2 was 83.19 μg/mL and IC50 value of the standard ribavirin against H1N1 was 52.40 μg/mL.The methanol extracts of the roots (Ext-3 and Ext-5) of both plants were characterized using UPLC/MS. A total of 73 metabolites were annotated, including fourteen diterpenoids, eleven flavonoids, ten phenolic acid conjugates, twelve fatty acids and their conjugates, five triterpenes and steroids, two sesquiterpenes, and six coumarins. The cytotoxicity and antiviral activities determined in the present work are explained by the existence of flavonoids, coumarins and diterpenes with commonly known cytotoxicity and antiviral activities. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, leading to liver steatosis, fibrosis, and hepatocellular carcinoma (HCC). Despite the accumulation of clinical data showing the impact of amino acid substitutions at positions 70 (R70Q/H) and/or 91 (L91M) in the HCV core protein in progressive liver diseases, including HCC, the underlying mechanisms have not been elucidated. We analyzed 72 liver biopsy specimens from patients with chronic HCV genotype 1b (HCV-1b) infection prior to antiviral treatment. Levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG) and nuclear factor erythroid 2-related factor 2 (NRF2) in the nucleus were quantified using liver tissue immunohistochemistry. The effects of amino acid substitutions in the HCV core region on hepatocellular oxidative stress were investigated using wild-type or double-mutant (R70Q/H+L91M) HCV-1b core transfection and stable expression in human hepatoma HuH-7 cells. Overall, 24, 19, 11, and 18 patients had the wild-type, R70Q/H, L91M, and R70Q/H+L91M genotypes, respectively, in the HCV core. A significantly higher accumulation of hepatocellular 8-OHdG and a lower NRF2/8-OHdG ratio were observed in patients with R70Q/H+L91M than in those with the wild-type disease. Increased levels of intracellular superoxide and hydrogen peroxide in the cytoplasm and mitochondria, mRNA expression of enzymes generating oxidative stress, and nuclear expression of nicotinamide adenine dinucleotide phosphate oxidase 4 were augmented in cells treated with R70Q+L91M. HCV core proteins harboring either or both substitutions of R70Q/H or L91M enhanced hepatocellular oxidative stress in vivo and in vitro. These amino acid substitutions may affect HCC development by enhancing hepatic oxidative stress in patients with chronic HCV-1b infection. [Display omitted] • Amino acid substitutions in HCV core mutants result in an elevated risk of HCC. • Higher 8-OHdG and lower 8-OHdG/NRF2 levels were observed in livers with HCV core mutants. • HCV core mutants are associated with higher oxidative stress and ROS-generating enzymes, including NOX4. • HCV core mutants may affect the development of HCC via severe oxidative stress. [ABSTRACT FROM AUTHOR]

Conventional single-signal or emerging sandwich-type double-signal electrochemiluminescence (ECL) immunosensors/aptasensors have offered accurate detection of small molecules, yet suffer from complicated setup, long processing time, and non-reusability. Here, we demonstrate a simplified molecularly imprinted ECL sensor based on Mn2SnO4 nanocubes. As an n-type semiconductor, Mn2SnO4 has numerous active sites that can capture electrons to accelerate chemical reactions, resulting in enhanced ECL activity and stability. For the first time, we verify a robust cathodic ECL emission of Mn2SnO4 luminophores in the presence of K2S2O8 coreactants. The proposed ECL sensor applies to the sensitive detection of ribavirin (RBV), endowing a wide linear range (1–2000 ng mL−1), low detection limit (0.85 ng mL−1, S/N = 3), high stability, specificity, and reproducibility, and the detection capability in real milk and chicken samples. This work highlights single semiconductor luminophore-driven molecularly imprinted ECL sensors, meeting the original aspiration of uncomplicated but high-performance sensing in food safety inspection. [ABSTRACT FROM AUTHOR]

This article provides a detailed account of the synthesis of ledipasvir, a direct-acting antiviral used to treat hepatitis C virus (HCV) infection. The synthesis process involves the use of various reagents and techniques, including late-stage fluorination and cyclopropanation. The new synthetic process is more efficient, reducing the number of steps and expensive reagents required. The article also describes the synthesis and characterization of several chemical compounds, providing valuable information for researchers studying organic chemistry and chemical synthesis. The process described in the article has been patented by CSIR. [Extracted from the article]

Recent clinical data have identified infant patients with lethal ITPA deficiencies. ITPA is known to modulate ITP concentrations in cells and has a critical function in neural development which is not understood. Polymorphism of the ITPA gene affects outcomes for both ribavirin and thiopurine based therapies and nearly one third of the human population is thought to harbor ITPA polymorphism. In a previous site-directed mutagenesis alanine screen of the ITPA substrate selectivity pocket, we identified the ITPA mutant, E22A, as a gain-of function mutant with enhanced ITP hydrolysis activity. Here we report a rational enzyme engineering experiment to investigate the biochemical properties of position 22 ITPA mutants and find that the E22D ITPA has two- and four-fold improved substrate selectivity for ITP over the canonical purine triphosphates ATP and GTP, respectively, while maintaining biological activity. The novel E22D ITPA should be considered as a platform for further development of ITPA therapies. [ABSTRACT FROM AUTHOR]

Objective To investigate the efficacy and safety of sofosbuvir/velpatasvir alone or in combination with ribavirin in Chinese patients with genotype 3B HCV/HIV infection. Methods A total of 299 patients with genotype 3B HCV/HIV infection who attended The Third People’s Hospital of Kunming from January 2017 to December 2020 were enrolled and treated with sofosbuvir/velpatasvir alone or in combination with ribavirin for 12 weeks, and they were followed up for 12 weeks after drug withdrawal. The patients were evaluated in terms of sustained virologic response at 12 weeks after treatment (SVR12) and adverse reactions. The independent-samples t test or the Mann-Whitney U test was used for comparison of continuous data between two groups, and the chi-square test was used for comparison of categorical data between two groups； the Agresti-Coull method was used to evaluate the 95% confidence interval (CI) of SVR12； univariate and multivariate non-conditional logistic regression analyses were used to investigate the influencing factors for SVR. Results The 299 patients with genotype 3B HCV/HIV infection had a mean age of 43.92±6.84 years, among whom the male patients accounted for 77.3% (231/299), the patients with liver cirrhosis accounted for 36.5% (109/299), the patients with a history of antiviral therapy accounted for 13.4% (40/299), and the patients receiving sofosbuvir/velpatasvir combined with ribavirin accounted for 27.8% (83/299) . The overall SVR was 87.0% (260/299) for all patients, and there was no significant difference in SVR12 between the patients receiving sofosbuvir/velpatasvir alone and those receiving sofosbuvir/velpatasvir combined with ribavirin (87.5% vs 85.5%，χ2 =0.203，P=0.653) . There was a significant difference in SVR12 between the patients without liver cirrhosis and those with liver cirrhosis (90.0% vs 81.7%，χ2 =4.256，P=0.039), and the patients receiving antiviral therapy for the first time had a significantly higher SVR12 than the treatment-experienced patients (93.4% vs 45.0%，χ2 =71.670，P<0.001) . The univariate and multivariate logistic regression analyses showed that platelet count (odds ratio ［OR］=0.957，95%CI：0.931— 0.984，P=0.002), liver stiffness measurement (OR=1.446，95%CI：1.147— 1.822，P= 0.002), and experience in treatment (OR=13.807，95%CI：2.970—64.174，P=0.001) were independent influencing factors for SVR in patients with genotype 3B HCV/HIV infection. There were 41 cases of serious adverse events, all of which occurred within 2 weeks after antiviral therapy, and 28 cases were resolved without drug withdrawal or active treatment, while 13 cases were not resolved after active treatment and were resolved after the antiviral drugs were stopped for 2—5 days, with no similar reactions observed when the drugs were used again after remission. Conclusion Sofosbuvir/velpatasvir alone or in combination with ribavirin has relatively good efficacy and safety in patients with genotype 3B HCV/HIV infection. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) is an RNA virus with a high mutation rate, making it prone to developing resistance. There is currently no vaccine for this disease, and the existing treatments are often costly. Therefore, this study aimed to provide alternative and complementary antiviral options from plant by evaluating the activity of Piper betle (P. betle) against HCV and its combination with existing antiviral drugs, Ribavirin and Simeprevir. The antiviral inhibition was identified by in vitro culture using Huh7it-1 cells and JFH1a HCV. The phytochemistry profile was also determined by Thin Layer Chromatography (TLC) and High-Performance Liquid Chromatography (HPLC). The result showed that the ethanol extract of P. betle had strong activity with an IC50 value of 0.08 ± 0.028 µg/mL. The mechanism of action showed that the extract dominantly inhibited the post-entry steps. Furthermore, the combination of P. betle extract with simeprevir showed higher anti-HCV activity compared to the single use of the drug, but no effect was observed in the combination with ribavirin. The Western blotting analysis showed that the inhibition of NS3 protein levels was in a dosedependent manner. Based on the phytochemistry evaluation, the extract was found to contain flavonoids, polyphenols, and alkaloids. These results suggested that the ethanolic extract of P. betle could be a good candidate for the development of alternative anti-HCV drugs. [ABSTRACT FROM AUTHOR]

The COVID-19 is recognized as one of the deadly disease in the history of human life. It is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since its first case appeared in December 2019 in Wuhan, China, number of COVID-19 cases are still growing worldwide, till now number of confirmed COVID-19 cases reported globally are 594 million and number of fatalities are 6.29 million. It creates panic situation on every individual as well as put an extraordinary challenge on every country, especially on the health care system. The ruthlessness of the disease and its noxious complexities need development of suitable and effective drug on urgent basis to prevent as well as treat COVID-19. Though specific drug with proper efficacy is not yet found, a number of research and clinical trials are still going on to check the suitability and effectiveness of existing drug, i.e. repurposed drug to treat patients of COVID-19. In this article, repurposed drug—arbidol, baricitinib, favipiravir, galidesivir and ribavirin are reported by using Conceptual Density Functional Theory (CDFT) approach. Optimization energy, spin multiplicity, zero point energy correction, CDFT-based descriptors, optical and thermochemical properties of these repurposed drugs are computed and analysed. Result signify that favipiravir is the most reactive compound whereas ribavirin is found as the most stable among these molecular species. Favipiravir has the lowest thermal energy, heat capacity and entropy, whereas arbidol has the maximum thermal energy, heat capacity and entropy. There is an interesting correlation found between optimization energy, zero point energy correction, polarizability and thermochemical properties of these repurposed drugs. [ABSTRACT FROM AUTHOR]

This work focuses on applying a combined process combining electro-Fenton (EF) pretreatment with biological degradation to mineralize the antiviral Ribavirin in an efficient, economical and ecological manner. First, the main experimental parameters affecting the efficiency of the electro-Fenton process, namely applied current intensity, Fe(II) catalyst concentration and initial Ribavirin concentration were evaluated and optimized. Indeed, the mineralization rate reaches maximum residual values of 99% after 4 hours of electrolysis applying a current of 200 mA. This mineralization is accompanied by an increase in biodegradability, evaluated from the BOD5/COD ratio, which goes from 0.04 at the beginning of treatment (1 h) to 0.45 after 2 hours of electrolysis, demonstrating the feasibility of a biological treatment. In addition, the energy efficiency decreased when the treatment time was extended due to the limitation of mass transport. Thus, the feasibility of coupling electro-Fenton and biological treatment has been successfully demonstrated on a laboratory-scale was, achieving a 96.66% removal rate by the Bio-EF process. A Box-Behnken design based on response surface methodology was applied to develop a model for predicting Rib removal rate. The interaction of factors such as Rib concentration (X1), catalyst concentration (X2) and electrolysis time (X3) was analyzed to identify optimal operating conditions. The model results obtained are statistically significant with an R2 of 0.99, indicating that the proposed model is significant and relevant. In addition, the iso-response curves obtained enabled us to determine the optimal experimental conditions required for effective mineralization of the targeted antiviral. [ABSTRACT FROM AUTHOR]

During in vitro potato multiplication process, of three Romanian potato varieties (Sarmis, Foresta and Castrum) infected with Potato Virus S (PVS), detected by ELISA test, an experiment was performed with reference of influence of salicylic acid and antiviral ribavirin over two plantlets parameters: height (cm) and leaves number. The trifactorial experience (2 x 3 x 3), on 3 repetitions had the following factors: experimental factor A- the culture medium used before antiviral treatment, with two graduations: a1 - classical medium (as control) Murashige -Skoog (1962); a2 - MS+ salicylic acid (100 mg/l); experimental factor B - the variety, with three graduations: b1 - Sarmis (as control), b2 - Foresta, b3 - Castrum; experimental factor C - ribavirin concentration: c1 - 0 mg/l (as control); c2 - 50 mg/l; c3 - 100 mg/l. The objective of the study is to eradicate PVS. Using of ribavirin drastically decreased the height of the plantlets and the number of leaves, causing very significant negative differences for the two parameters (for both concentrations). [ABSTRACT FROM AUTHOR]

The human respiratory syncytial virus (RSV) creates a pandemic every year in several countries in the world. Lack of target therapeutics and absence of vaccines have prompted scientists to create novel vaccines or small chemical treatments against RSV's numerous targets. The matrix (M) protein and fusion (F) glycoprotein of RSV are well characterized and attractive drug targets. Five bioactive compounds from Alnus japonica (Thunb.) Steud. were taken into consideration as lead compounds. Drug-likeness characters of them showed the drugs are non-toxic and non-mutagenic and mostly lipophobic. Molecular docking reveals that all bioactive compounds have better binding and better inhibitory effect than ribavirin which is currently used against RSV. Praecoxin A appeared as the best lead compound between them. It creates 7 different types of bonds with amino acids of M protein and 5 different types of bonds with amino acids of F protein. Van der Waals interactions highly influenced the binding energies. Molecular dynamic simulations represent the non-deviated and less fluctuating nature of praecoxin A. Principal Component Analysis showed praecoxin A complex with RSV matrix protein is more stable than ribavirin complex. This study will help to develop a new drug to inhibit RSV. All ligands were minimized through semi-empirical PM3 process with MOPAC. Toxicity was tested by ProTox-II server. Molecular docking studies were carried out using AutoDock 4.2. Molecular dynamics simulations for 100 ns were carried out through GROMACS 5.12 MD and GROMOS96 43a1 force field. The graphs were produced by GROMACS's XMGrace program. [ABSTRACT FROM AUTHOR]

Nipah Virus (NiV) is a highly virulent pathogen that poses a significant threat to human and animal populations. This review provides a comprehensive overview of the latest control and prevention strategies against NiV, focusing on vaccine development, antiviral drug discovery, early diagnosis, surveillance, and high-level biosecurity measures. Advancements in vaccine research, including live-attenuated vaccines, virus-like particles, and mRNA-based vaccines, hold promise for preventing NiV infections. In addition, antiviral drugs, such as remdesivir, ribavirin, and favipiravir, have the potential to inhibit NiV replication. Early diagnosis through molecular and serological assays, immunohistochemistry, and real-time reverse transcription polymerase chain reaction plays a crucial role in timely detection. Surveillance efforts encompassing cluster-based and case-based systems enhance outbreak identification and provide valuable insights into transmission dynamics. Furthermore, the implementation of high-level biosecurity measures in agriculture, livestock practices, and healthcare settings is essential to minimize transmission risks. Collaboration among researchers, public health agencies, and policymakers is pivotal in refining and implementing these strategies to effectively control and prevent NiV outbreaks and safeguard public health on a global scale. [ABSTRACT FROM AUTHOR]

Here, we report the in-host hepatitis E virus (HEV) quasispecies evolution in a chronically infected patient who was treated with three different regimens of ribavirin (RBV) for nearly 6 years. Sequential plasma samples were collected at different time points and subjected to RNA extraction and deep sequencing using the MiSeq Illumina platforms. Specifically, we RT-PCR amplified a single amplicon from the core region located in the open-reading frame 2 (ORF2). At the nucleotide level (genotype), our analysis showed an increase in the number of rare haplotypes and a drastic reduction in the frequency of the master (most represented) sequence during the period when the virus was found to be insensitive to RBV treatment. Contrarily, at the amino acid level (phenotype), our study revealed conservation of the amino acids, which is represented by a high prevalence of the master sequence. Our findings suggest that using mutagenic antivirals concomitant with high viral loads can lead to the selection and proliferation of a rich set of synonymous haplotypes that express the same phenotype. This can also lead to the selection and proliferation of conservative substitutions that express fitness-enhanced phenotypes. These results have important clinical implications, as they suggest that using mutagenic agents as a monotherapy treatment regimen in the absence of sufficiently effective viral inhibitors can result in diversification and proliferation of a highly diverse quasispecies resistant to further treatment. Therefore, such approaches should be avoided whenever possible. [ABSTRACT FROM AUTHOR]

Hepatitis E Virus (HEV) is a positively oriented RNA virus having a 7.2 kb genome. HEV consists of three open reading frames (ORF1-3). Of these, ORF1 codes for the enzymes Methyltransferase (Mtase), Papain-like cysteine protease (PCP), RNA helicase, and RNA-dependent RNA polymerase (RdRp). Unavailability of a vaccine or effective drug against HEV and considering the side effects associated with the off-label use of ribavirin (RBV) and pegylated interferons, an alternative approach is required by the modulation of specific enzymes to prevent the infection. HEV helicase is involved in unwinding the double-stranded RNA, RNA processing, transcriptional regulation, and pre-mRNA processing. Therefore, we screened FDA-approved compounds from the ZINC15 database against the modelled 3D structure of HEV helicase and found that methotrexate and compound A (Pubchem ID BTB07890) inhibit the NTPase and dsRNA unwinding activity leading to inhibition of HEV RNA replication. This may be further authenticated by in vivo study. [ABSTRACT FROM AUTHOR]

Objective: To compare the Sustained viral response (SVR) in patients who had taken Sofosbuvir plus Ribavirin for 24 weeks and Sofosbuvir plus Daclatasvir for 12 weeks to treat hepatitis C. Study Design: Randomized Control Trial. Setting: Medical Division of Mayo Hospital, Lahore. Period: One Year duration, 2021. Material & Methods: 130 patients of chronic Hepatitis C were divided into two categories based on whether they met the inclusion requirements. In Group A patients used sofosbuvir plus ribavirin for six months, whereas patients of Group B took sofosbuvir plus daclatasvir for 3 months. In order to determine SVR, PCR for HCV RNA Quantitative was done at week twelve after completion of the course. SPSS 23.0 was applied to enter and analyze the data. Results: All cases had an average age of 48.80 + 16.63 years, whereas it was 48.09 +16.43 years for group A and 49.51+ 16.92 years for groups B. In group A, there were 39 cases (60%) of men and 26 cases (40%) of women, while in group B, there were 34 instances (52.3% men and 31 cases (47.7% women). SVR was attained in 34 (52.34%) of group A participants and 54 (83.12%) of group B participants (p-value of 0.001). Conclusion: Sof+Dacla group had significantly high SVR than Sof+Riba group especially in non-cirrhotic and treatment-naïve individuals. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To estimate the comprehensive value of direct-acting antivirals (DAAs) for the treatment of hepatitis C virus (HCV) compared with peginterferon alfa and ribavirin (PEG/riba) employing a generalized cost-effectiveness analysis (GCEA). STUDY DESIGN: To assess the societal-level costeffectiveness of DAA treatment for HCV, we extended a previously published discrete-time Markov simulation model of HCV transmission and progression to include market dynamics and broader elements of value. METHODS: We followed a stepwise process to add novel value elements to a traditional CEA model for HCV treatments. For each additional element of value, we estimated incremental cost-effectiveness ratios (ICERs) of DAAs compared with PEG/riba. RESULTS: The health technology assessment (HTA)--style model yielded an ICER value of $64,512 per quality-adjusted life-year (QALY). Adding transmission dynamics resulted in an ICER value of $52,971 per QALY, whereas accounting for transmission dynamics and dynamic price and efficacy further decreased ICER values by 90% to $6406 per QALY. Incorporating genericization, productivity loss, caregiver spillover, and differential valuations of LYs vs quality of life, disease severity, and insurance value further decreased the ICER value to $4487 per QALY, a 93% reduction from the baseline HTA-style CEA to the fully realized GCEA. CONCLUSIONS: Our GCEA study results confirm that DAAs are a cost-effective treatment for HCV compared with PEG/riba even when using conventional cost-effectiveness approaches. Incorporating broader elements of value resulted in more than a 10-fold improvement in costeffectiveness, emphasizing the substantive impact of a generalized approach and the importance of incorporating GCEAs into decision-making. [ABSTRACT FROM AUTHOR]

The degradation of ribavirin(RBV) by ferrate(Fe(Ⅵ)) was systematically investigated for the first time by experiment and degradation process fitting. The results indicated that the reaction between Fe(Ⅵ) and RBV is pH dependent and followed second order kinetics. The species-specific rate constants of the Fe(Ⅵ) species(HFeO 4 -) were higher than FeO 4 2- species when react with RBV. Fe(VI) made significant contribution to the removal of RBV. Liquid chromatography-triple quadrupole mass spectrometry(LC-TQ-MS) was used to determine the intermediate of RBV which degradated by Fe(Ⅵ), in order to infer its main degradation pathway. This study used Dual Descriptor and Fukui function to calculate the active sites of RBV and its intermediates during the degradation of RBV by Fe(Ⅵ), then verified their accuracy with actual reaction sites deduced based on LC-TQ-MS data. The results showed that Dual Descriptor prediction was more accurate than Fukui function in the process of RBV degradation by Fe(Ⅵ). Some common anions in natural waters, such as SO 4 2-, NO 3 -, Cl- and CO 3 2- had no effect on the removal of RBV by Fe(Ⅵ). 50 mg/L HA reduced the 120 min removal efficiency of RBV by 15.07%. Both toxicity analysis by ECOSAR software and E. coli toxicity experiments showed that Fe(VI) achieves toxicity reduction of RBV. This study indicated that Fe(Ⅵ) can effectively remove RBV from water and using Dual Descriptor to analyze the active sites of intermediates in the RBV degradation pathway can enhance the rationality of predicting the reaction pathway. [Display omitted] [ABSTRACT FROM AUTHOR]

Peste des petits ruminants virus (PPRV), a member of the family Paramyxoviridae, belongs to the genus Morbillivirus. It causes devastating viral diseases in small ruminants and has been rapidly spreading over various regions in Africa, the Middle East, and Asia. Although vaccination is thought to be an effective management strategy against PPR infections, the heat sensitivity of PPRV vaccines severely restricts their use in regions with hot climates. In this research, we studied the antiviral activities of ribavirin and aimed to understand the potential mechanisms of action of ribavirin in the African green monkey kidney cells (Vero cells). In brief, the adsorption, intrusion, replication, and release of PPRV, as well as the mRNA expression level of RNA-dependent RNA polymerase (RdRp), were significantly inhibited in the ribavirin-treated Vero cells compared to those in the PPRVinfected cells that were not treated with ribavirin. Additionally, ribavirin has potential as an antiviral drug against PPRV, and its antiviral activity is mediated by the Janus kinase signal transducer and activator of transcription (JAK/STAT) and PI3K/AKT pathways. [ABSTRACT FROM AUTHOR]

Background: Chronic hepatitis E virus (HEV) infection may progress to end-stage liver disease in immunosuppressed individuals. Ribavirin therapy is efficient in most chronic HEV patients, but 10% remain without a sustained virological response (SVR). Objectives: We aimed to study whether zinc supplementation could represent a therapeutic approach in these patients. Methods: Antiviral properties of zinc salts were studied in vitro (subgenomic-replicon system), in vivo (rabbit model), and retrospectively in patients with chronic hepatitis E who did not achieve SVR under ribavirin monotherapy. Results: Zinc inhibited HEV genotype 3 replication in vitro. In a model of acute HEV infection in immunocompetent rabbits, zinc + ribavirin did not improve viral clearance compared to ribavirin monotherapy. In chronically HEV-infected patients not responding to ribavirin (n = 12), viral clearance was observed in 4/12 (33%) patients receiving additional zinc supplementation. Conclusions: Oral zinc, an inexpensive, harmless dietary supplement, could potentially represent a rescue treatment option for a few patients with chronic hepatitis E without SVR under ribavirin monotherapy. Further studies are needed to elucidate the role of zinc in HEV. [ABSTRACT FROM AUTHOR]

Worldwide, genotype 3 is the second most prevalent major variant among patients with chronic hepatitis C virus (HCV) infection and the most difficult to treat with direct-acting antivirals (DAAs). Further, subtype 3b, which is highly prevalent in Southeast Asia with increasing transmission in high-risk populations, carries paired NS5A resistance-associated substitutions (RAS), NS5A-A30K+L31M, conferring resistance to DAA therapy and lowering cure rates with pan-genotypic regimens. However, no complete genomic sequence or infectious clone exists for HCV genotype 3b. We determined the entire genome sequences, including 5' and 3' termini, of HCV genotype 3b isolates from three treatment naïve chronic hepatitis C patients, and by clonal analysis of the entire coding sequence demonstrated heterogeneous genome population compositions all carrying RAS A30K+L31M in NS5A. We generated a full-length HCV genotype 3b cDNA clone (pODN) and transfected Huh7.5 and Huh-Lunet/SEC14L2 cells with derived RNA transcripts without detecting HCV antigens by immunofluorescence staining. In contrast, intrahepatic transfection with RNA transcripts from pODN, and subsequent virus passages, in human-liver chimeric mice resulted in robust infection with serum HCV RNA titers of up to 7.9 log10 genome equivalents/mL. Consensus HCV sequences of virus recovered from the transfected mouse contained no coding mutations exceeding 5% frequency, and sequences from the passage-infected mice likewise had no consensus changes. Thus, we developed the first HCV genotype 3b full-length cDNA clone which by its infectivity and genetic stability in human-liver chimeric mice proved functionality, and potential utility in future development of infectious cell culture systems needed for this DAA treatment-resistant subtype. [ABSTRACT FROM AUTHOR]

Background: Skin is regarded as an essential first line of defense against harmful pathogens and it hosts an ecosystem of microorganisms that create a widely diverse skin microbiome. In chronic wounds, alterations in the host-microbe interactions occur forming polymicrobial biofilms that hinder the process of wound healing. Ribavirin, an antiviral drug, possesses antimicrobial activity, especially against Pseudomonas aeruginosa and Candida albicans, which are known as the main opportunistic pathogens in chronic wounds. Rationale: In this study, electrospun nanofiber systems loaded with ribavirin were developed as a potential wound dressing for topical application in chronic wounds. Ribavirin was chosen in this study owing to the emerging cases of antimicrobial (antibiotics and antifungal) resistance and the low attempts to discover new antimicrobial agents, which encouraged the repurposing use of current medication as an alternative solution in case of resistance to the available agents. Additionally, the unique mechanism of action of ribavirin, i.e., perturbing the bacterial virulence system without killing or stopping their growth and rendering the pathogens disarmed, might be a promising choice to prevent drug resistance. Cyclodextrin (CD) was utilized to formulate ribavirin as an electrospun nanofibers delivery system to enhance the absorption and accelerate the release of ribavirin for topical use. Results: The results demonstrated a successful ribavirin nanofibers fabrication that lacked beads and pores on the nanofibrous surfaces. Ribavirin underwent a physical transformation from crystalline to amorphous form, as confirmed by X-ray diffraction analysis. This change occurred due to the molecular dispersion after the electrospinning process. Additionally, the CD enhanced the encapsulation efficiency of ribavirin in the nanofibers as observed from the drug-loading results. Polyvinylpyrrolidone (PVP) and CD increased ribavirin released into the solution and the disintegration of fibrous mats which shrank and eventually dissolved into a gel-like substance as the ribavirin-loaded fibers began to break down from their border toward the midpoint. Cytotoxicity of ribavirin and CD was evaluated against human dermal fibroblasts (HFF-1) and the results showed a relatively safe profile of ribavirin upon 24-hour cell exposure, while CD was safe within 24- and 48-hour. Conclusion: This study provides valuable insights into the potential application of our nanofibrous system for treating chronic wounds; however, further antimicrobial and in-vivo studies are required to confirm its safety and effectiveness.

During the COVID-19 pandemic, the extensive use of ribavirin (RBV) raised concerns about its environmental residues and associated risks, necessitating remedial actions. This study investigates the degradation efficiency, mechanism, and biotoxicity of RBV using ferrous (Fe2+) activated persulfate (PS) advanced oxidation technology (Fe2+/PS oxidation). Experiments conducted under various conditions revealed that at pH = 3, PS concentration of 4 mM, PS/Fe2+ molar ratio of 2:1, and citric acid of 0.5 mM with Fe2+ added twice, the degradation rate of RBV reached 98.70 %. The degradation process of RBV by Fe2+/PS from 0 to 5 mins followed a first-order reaction kinetics model. The presence of halide ions (Cl-, Br-, I-) was found to inhibit the degradation efficiency. The active species involved were identified as SO4-·, ·OH, 1O2, and FeO2+, with SO4-· and ·OH being the most significant. Moreover, the products of ribavirin were determined and their degradation pathways were proposed. Dehydration, deamidation, C-N bond breaking and hydroxylation were the major pathways. Additionally, toxicity assessment showed that Fe2+/PS oxidation reduced the inhibition rate of bioluminescence in Vibrio fischeri from 31.58 % to 3.88 %, effectively controlling RBV toxicity during the reaction. This study provides insights into managing water environmental risks associated with pharmaceutical residues in the post-pandemic era.

Introduction: Crimean-Congo hemorrhagic fever (CCHF) is an acute tick-borne infection which is associated with significant mortality (up to 50%) and serious risk in pregnancy. Ribavirin is an antiviral and of course a teratogenic drug that has significant effects in the treatment of CCHF. The present study was performed with aim to examine the level of awareness of people with CCHF about the teratogenicity of the drug in the embryonic period and the outcome of pregnancy during six months after taking ribavirin. Methods: In this retrospective study, the files of all the hospitalized patients with a definite diagnosis of Crimean Congo fever in two hospitals of Mashhad were assessed over 10 years. Telephone calls were made to the patients and their families and the required information was collected. Data were analyzed using SPSS software (version 22) and Chi-square and Exact Fisher tests. P< 0.05 was considered statistically significant. Results: In this study, 177 CCHF patients were assessed, and their information regarding education or lack of education about pregnancy at discharge was available for 84 patients, only 9 people (5.1% of all patients) were trained about contraception after treatment with Ribavirin. In the follow-up of the patients, 3 pregnancies resulted in abortion and 7 unhealthy children were reported due to lack of attention to the principles of pregnancy prevention at the time of taking ribavirin and 6 months later. Conclusion: Considering the effects of teratogenicity of ribavirin, it seems necessary to provide adequate training to patients about the risks of pregnancy during the 9-month after receiving ribavirin.

Recently, ribavirin has demonstrated effectiveness in treating glioblastoma through intranasal administration utilizing the nose-to-brain delivery route. Enhancing ribavirin’s bioavailability can be achieved by utilizing intranasal stimuli-responsive systems that create a gel on the nasal mucosa. The research examined thermosensitive, pH-sensitive, and ion-selective polymers in various combinations and concentrations, chosen in line with the current Quality by Design (QbD) approach in pharmaceutical development. Following a thorough assessment of key parameters, the optimal composition of gellan gum at 0.5%, Poloxamer 124 at 2%, and purified water with ribavirin concentration at 100 mg/mL was formulated and subjected to in vivo testing. Through experiments on male rats, the nose-to-brain penetration mechanism of the active pharmaceutical ingredient (API) was elucidated, showcasing drug accumulation in the olfactory bulbs and brain.