-
Journal of Clinical Medicine Oct 2023(1) Background. Hepatitis C infection often leads to extrahepatic manifestations, including cryoglobulinemic vasculitis. This systematic review aimed to assess the... (Review)
Review
(1) Background. Hepatitis C infection often leads to extrahepatic manifestations, including cryoglobulinemic vasculitis. This systematic review aimed to assess the efficacy and safety of rituximab in treating hepatitis C-associated cryoglobulinemic vasculitis. (2) Methods. Following PRISMA guidelines, databases were searched for relevant studies. Eligibility criteria included studies on hepatitis C-associated cryoglobulinemic vasculitis treated with rituximab. (3) Results. Nine studies met the eligibility criteria and were included in this analysis. Rituximab was commonly administered at 375 mg/m weekly for one month. The results consistently demonstrated the efficacy of rituximab, whether as a standalone treatment or as part of a therapeutic regimen. The combination of rituximab with Peg-IFN-α and ribavirin significantly increased the complete response rate compared to Peg-IFN-α and ribavirin alone (54.5% vs. 33.3%, < 0.05). The 3-year sustained response rate was notably higher in the rituximab combination group (83.3% vs. 40%). In another trial, rituximab achieved remission in 83.3% of patients at 6 months, compared to only 8.3% in the control group. The efficacy of rituximab was supported by long-term experience, with clinical benefits in patients with severe cryoglobulinemic vasculitis, including those resistant to standard therapies. Mild adverse events were generally reported, with rare severe reactions in some studies. (4) Conclusions: In conclusion, rituximab appeared to be effective and safe in managing hepatitis C-associated cryoglobulinemic vasculitis, either alone or with antiviral therapy.
PubMed: 37959271
DOI: 10.3390/jcm12216806 -
International Journal of Molecular... Oct 2023The COVID-19 pandemic has spurred intense research efforts to identify effective treatments for SARS-CoV-2. In silico studies have emerged as a powerful tool in the drug... (Review)
Review
The COVID-19 pandemic has spurred intense research efforts to identify effective treatments for SARS-CoV-2. In silico studies have emerged as a powerful tool in the drug discovery process, particularly in the search for drug candidates that interact with various SARS-CoV-2 receptors. These studies involve the use of computer simulations and computational algorithms to predict the potential interaction of drug candidates with target receptors. The primary receptors targeted by drug candidates include the RNA polymerase, main protease, spike protein, ACE2 receptor, and transmembrane protease serine 2 (TMPRSS2). In silico studies have identified several promising drug candidates, including Remdesivir, Favipiravir, Ribavirin, Ivermectin, Lopinavir/Ritonavir, and Camostat Mesylate, among others. The use of in silico studies offers several advantages, including the ability to screen a large number of drug candidates in a relatively short amount of time, thereby reducing the time and cost involved in traditional drug discovery methods. Additionally, in silico studies allow for the prediction of the binding affinity of the drug candidates to target receptors, providing insight into their potential efficacy. This study is aimed at assessing the useful contributions of the application of computational instruments in the discovery of receptors targeted in SARS-CoV-2. It further highlights some identified advantages and limitations of these studies, thereby revealing some complementary experimental validation to ensure the efficacy and safety of identified drug candidates.
Topics: Humans; SARS-CoV-2; COVID-19; Antiviral Agents; Pandemics; Peptide Hydrolases
PubMed: 37958503
DOI: 10.3390/ijms242115518 -
Frontiers in Pharmacology 2023Hand, foot, and mouth disease (HFMD) caused by enterovirus A71 (EV-A71) infection, currently lacks specific preventive and therapeutic interventions. Here, we...
Hand, foot, and mouth disease (HFMD) caused by enterovirus A71 (EV-A71) infection, currently lacks specific preventive and therapeutic interventions. Here, we demonstrated that Pien Tze Huang (PZH) could dose-dependently inhibit EV-A71 replication at the cellular level, resulting in significant reductions in EV-A71 virus protein 1 (VP1) expression and viral yields in Vero and human rhabdomyosarcoma cells. More importantly, we confirmed that PZH could protect mice from EV-A71 infection for the first time, with Ribavirin serving as a positive control. PZH treatment reduced EV-A71 VP1 protein expression, viral yields in infected muscles, and improved muscle pathology. Additionally, we conducted a preliminary mechanism study using quantitative proteomics. The results suggested that the suppression of the PI3K/AKT/mTOR and NF-κB signaling pathways may contribute to the anti-EV-A71 activity of PZH. These findings provide strong evidence supporting the potential therapeutic application of PZH for EV-A71 infection management.
PubMed: 37954857
DOI: 10.3389/fphar.2023.1251731 -
Open Life Sciences 2023() infections of the central nervous system are deadly and have vague symptoms. Traditional cerebro spinal fluid culture has a low positive rate, and because antibiotic...
() infections of the central nervous system are deadly and have vague symptoms. Traditional cerebro spinal fluid culture has a low positive rate, and because antibiotic use is common following therapy, it is more challenging to assess the response from pathogen content. In this case, a 66-year-old man who had a fever, a headache, and vomit was admitted to the hospital. He had diabetes, decline in thyroid function, and a history of pituitary tumor removal surgery. His initial treatment with ribavirin, ceftriaxone antibiotic, and moxifloxacin did not go well. Using two etiological tests (culture and metagenomic next-generation sequencing [mNGS]), his cerebrospinal fluid tested positively for . Ampicillin-sulbactam and meropenem were used as treatments once meningitis was identified. After treatment, his cerebrospinal fluid was assessed once more. Culture: negative; targeted next-generation sequencing (tNGS): positive and shows changes in the copy number of the . After 44 days of treatment, the patient finally stopped taking antibiotics, and the prognosis was good. Our study showed that mNGS and tNGS, as novel approaches for pathogen detection, are capable of identifying pathogens quickly, sensitively, and accurately, especially when there are few infections present (such as after antibiotic treatment). The two methods can be a powerful assistance for helping clinicians to choose the best course of action.
PubMed: 37954099
DOI: 10.1515/biol-2022-0738 -
Virus Research Jan 2024Hand, foot, and mouth disease (HFMD) caused by a group of enteroviruses is a global public health problem. In recent years, coxsackievirus A6 (CVA6) has emerged as an...
Hand, foot, and mouth disease (HFMD) caused by a group of enteroviruses is a global public health problem. In recent years, coxsackievirus A6 (CVA6) has emerged as an important HFMD agent. Previous studies have shown that mutations of glycine 64 in RNA-dependent RNA polymerase (3D polymerase), which is central to viral replication, cause phenotypic changes such as ribavirin resistance, increased replication fidelity, and virulence attenuation in poliovirus and enterovirus A71. In this study, we constructed CVA6 mutants with G64R, G64S, and G64T substitutions by site-directed mutagenesis in full-length cDNA of an infectious CVA6 strain cloned in pcDNA3.1. Viral RNA was obtained by in vitro transcription, and the rescued virus strains were propagated in RD cells. Sequencing after six passages revealed that G64S and G64T mutations were stably inherited, whereas G64R was genetically unstable and reversed to the wild type. Comparison of the biological characteristics of the wild-type and mutant CVA6 strains in an in vivo model (one-day-old ICR mice) revealed that the pathogenicity of CVA6-G64S and CVA6-G64T was significantly reduced compared to wild-type CVA6. In vitro experiments indicated the mutant CVA6-G64S and CVA6-G64T strains had increased resistance to 0.8 mM ribavirin and a decreased replication rate in the presence of 0.8 mM guanidine hydrochloride. Our results show that mutation of residue 64 reduces CVA6 susceptibility to ribavirin and increases CVA6 susceptibility to guanidine hydrochloride, together with increased replication fidelity and attenuated viral pathogenicity, thus laying a foundation for the development of safe and effective live attenuated CVA6 vaccine.
Topics: Animals; Mice; Antibodies, Viral; Enterovirus; Enterovirus Infections; Guanidine; Mice, Inbred ICR; Ribavirin; RNA-Dependent RNA Polymerase; Virulence; Viral Replicase Complex Proteins
PubMed: 37949376
DOI: 10.1016/j.virusres.2023.199268 -
Biochemistry Dec 2023Bacterial riboswitches are structured RNAs that bind small metabolites to control downstream gene expression. Two riboswitch classes have been reported to sense...
Bacterial riboswitches are structured RNAs that bind small metabolites to control downstream gene expression. Two riboswitch classes have been reported to sense nicotinamide adenine dinucleotide (NAD), which plays a key redox role in cellular metabolism. The NAD-I (class I) riboswitch stands out because it comprises two homologous, tandemly arranged domains. However, previous studies examined the isolated domains rather than the full-length riboswitch. Crystallography and ligand binding analyses led to the hypothesis that each domain senses NAD but with disparate equilibrium binding constants () of 127 μM (domain I) and 3.4 mM (domain II). Here, we analyzed individual domains and the full-length riboswitch by isothermal titration calorimetry to quantify the cofactor affinity and specificity. Domain I senses NAD with a of 24.6 ± 8.4 μM but with a reduced ligand-to-receptor stoichiometry, consistent with nonproductive domain self-association observed by gel-filtration chromatography; domain II revealed no detectable binding. By contrast, the full-length riboswitch binds a single NAD with a of 31.5 ± 1.5 μM; dinucleotides NADH and AP-ribavirin also bind with one-to-one stoichiometry. Unexpectedly, the full-length riboswitch also binds a single ATP equivalent ( = 11.0 ± 3.5 μM). The affinity trend of the full-length riboswitch is ADP = ATP > NAD = AP-ribavirin > NADH. Although our results support riboswitch sensing of a single NAD at concentrations significantly below the intracellular levels of this cofactor, our findings do not support the level of specificity expected for a riboswitch that exclusively senses NAD. Gene regulatory implications and future challenges are discussed.
Topics: Riboswitch; NAD; Adenosine Triphosphate; Nucleic Acid Conformation; Ligands; Ribavirin
PubMed: 37947391
DOI: 10.1021/acs.biochem.3c00391 -
Antiviral Research Dec 2023The study aimed to assess the phenomenon of achieving sustained virologic response (SVR) in patients with detectable ribonucleic acid (RNA) of hepatitis C virus (HCV) at...
BACKGROUND & AIMS
The study aimed to assess the phenomenon of achieving sustained virologic response (SVR) in patients with detectable ribonucleic acid (RNA) of hepatitis C virus (HCV) at the end of treatment (ET) with direct-acting antivirals (DAA), find how this is affected by the type of regimen, and how patients experiencing this differed from non-responders with detectable HCV RNA at the ET.
METHODS
The study included all consecutive patients with detectable HCV RNA at the ET selected from the EpiTer-2 database, a retrospective national multicentre project evaluating antiviral treatment in HCV-infected patients in 2015-2023.
RESULTS
Of the 16106 patients treated with IFN-free regimens with available HCV RNA assessment at the ET and at follow-up 12 weeks after treatment completion (FU), 1253 (7.8%) had detectable HCV RNA at the ET, and 1120 of them (89%) finally achieved SVR. This phenomenon was significantly more frequent in pangenotypic regimens, 10.3% vs. 4.7% in genotype-specific options (p < 0.001), and the highest proportion was documented for glecaprevir/pibrentasvir (13.7%), and velpatasvir/sofosbuvir ± ribavirin (6.9%). Patients ET + FU- treated with these two pangenotypic regimens (n = 668) had less advanced liver disease, were less frequently infected with genotype (GT) 3, and were significantly more likely to be treatment-naïve than 61 non-responders.
CONCLUSIONS
We documented 7.8% rate of patients with detectable HCV RNA at the ET, of whom 89% subsequently achieved SVR, significantly more frequently in the population treated with pangenotypic regimens. Less severe liver disease, more often GT3 infection, and a higher percentage of treatment-naive patients distinguished this group from non-responders.
Topics: Humans; Antiviral Agents; Hepatitis C, Chronic; Retrospective Studies; Drug Therapy, Combination; Sofosbuvir; Treatment Failure; Hepatitis C; Hepacivirus; RNA; Genotype; Treatment Outcome
PubMed: 37944825
DOI: 10.1016/j.antiviral.2023.105742 -
Parasites & Vectors Oct 2023In its 'Road map for neglected tropical diseases 2021-2030', the World Health Organization outlined its targets for control and elimination of neglected tropical... (Review)
Review
In its 'Road map for neglected tropical diseases 2021-2030', the World Health Organization outlined its targets for control and elimination of neglected tropical diseases (NTDs) and research needed to achieve them. For many NTDs, this includes research for new treatment options for case management and/or preventive chemotherapy. Our review of small-molecule anti-infective drugs recently approved by a stringent regulatory authority (SRA) or in at least Phase 2 clinical development for regulatory approval showed that this pipeline cannot deliver all new treatments needed. WHO guidelines and country policies show that drugs may be recommended for control and elimination for NTDs for which they are not SRA approved (i.e. for 'off-label' use) if efficacy and safety data for the relevant NTD are considered sufficient by WHO and country authorities. Here, we are providing an overview of clinical research in the past 10 years evaluating the anti-infective efficacy of oral small-molecule drugs for NTD(s) for which they are neither SRA approved, nor included in current WHO strategies nor, considering the research sponsors, likely to be registered with a SRA for that NTD, if found to be effective and safe. No such research has been done for yaws, guinea worm, Trypanosoma brucei gambiense human African trypanosomiasis (HAT), rabies, trachoma, visceral leishmaniasis, mycetoma, T. b. rhodesiense HAT, echinococcosis, taeniasis/cysticercosis or scabies. Oral drugs evaluated include sparfloxacin and acedapsone for leprosy; rifampicin, rifapentin and moxifloxacin for onchocerciasis; imatinib and levamisole for loiasis; itraconazole, fluconazole, ketoconazole, posaconazole, ravuconazole and disulfiram for Chagas disease, doxycycline and rifampicin for lymphatic filariasis; arterolane, piperaquine, artesunate, artemether, lumefantrine and mefloquine for schistosomiasis; ivermectin, tribendimidine, pyrantel, oxantel and nitazoxanide for soil-transmitted helminths including strongyloidiasis; chloroquine, ivermectin, balapiravir, ribavirin, celgosivir, UV-4B, ivermectin and doxycycline for dengue; streptomycin, amoxicillin, clavulanate for Buruli ulcer; fluconazole and isavuconazonium for mycoses; clarithromycin and dapsone for cutaneous leishmaniasis; and tribendimidine, albendazole, mebendazole and nitazoxanide for foodborne trematodiasis. Additional paths to identification of new treatment options are needed. One promising path is exploitation of the worldwide experience with 'off-label' treatment of diseases with insufficient treatment options as pursued by the 'CURE ID' initiative.
Topics: Humans; Ivermectin; Rifampin; Doxycycline; Fluconazole; Off-Label Use; Anti-Infective Agents; Drug Combinations; Neglected Diseases
PubMed: 37907954
DOI: 10.1186/s13071-023-05909-8 -
Medicine Oct 2023To investigate associations between inosine triphosphatase (ITPA) gene polymorphisms and long-term outcomes among chronic hepatitis C (CHC) patients in Northeast China...
To investigate associations between inosine triphosphatase (ITPA) gene polymorphisms and long-term outcomes among chronic hepatitis C (CHC) patients in Northeast China treated with Peg-interferon (IFN)/ribavirin (RBV). CHC patients who received Peg-IFN-2a/RBV treatment during between 2011 and 2013 at 5 hepatitis centers in Northeast China were enrolled. ITPA single nucleotide polymorphisms rs1127354 and rs7270101 from all patients were detected and their associations with 5-year outcomes were analyzed. A total of 635 patients, including 421 infected with hepatitis C virus (HCV) genotype 1 and 214 infected with non-genotype 1 were included. No significant differences were observed in the distribution frequencies of ITPA rs1127354 variants and ITPase activity between patients with HCV genotype 1 and non-genotype 1. In patients who received more than 80% of the planned RBV dose, the 5-year virological response rate and the improvement in liver fibrosis were higher in those with ITPA rs1127354 non-CC with ITPase activity <25% compared with these outcomes in patients with ITPA rs1127354 CC with 100% ITPase activity. Multiple regression analysis revealed that HCV genotype non-1, low baseline HCV ribose nucleic acid (RNA) levels (≤4 × 105 IU/mL), interleukin-28B rs12979860 CC genotype, low baseline liver fibrosis (Fibroscan 0-2), and ITPA rs1127354 non-CC genotype were independent predictors for a high long-term virological response rate, whereas interleukin-28B rs12979860 CC genotype, ITPA rs1127354 non-CC genotype, and low baseline liver fibrosis were independent predictors for improvement of liver fibrosis. ITPA rs1127354 polymorphisms is predictors of long-term outcomes in CHC patients treated with Peg-IFN/RBV.
Topics: Humans; Ribavirin; Hepatitis C, Chronic; Antiviral Agents; Follow-Up Studies; Treatment Outcome; Pyrophosphatases; Interferons; Polymorphism, Single Nucleotide; Genotype; Hepacivirus; Liver Cirrhosis; Interleukins; Inosine Triphosphatase
PubMed: 37904484
DOI: 10.1097/MD.0000000000035508 -
Frontiers in Microbiology 2023Hantaviruses are a significant and emerging global public health threat, impacting more than 200,000 individuals worldwide each year. The single-stranded RNA viruses... (Review)
Review
Hantaviruses are a significant and emerging global public health threat, impacting more than 200,000 individuals worldwide each year. The single-stranded RNA viruses belong to the family and are responsible for causing two acute febrile diseases in humans: Hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS). Currently, there are no licensed treatments or vaccines available globally for HTNV infection. Various candidate drugs have shown efficacy in increasing survival rates during the early stages of HTNV infection. Some of these drugs include lactoferrin, ribavirin, ETAR, favipiravir and vandetanib. Immunotherapy utilizing neutralizing antibodies (NAbs) generated from Hantavirus convalescent patients show efficacy against HTNV. Monoclonal antibodies such as MIB22 and JL16 have demonstrated effectiveness in protecting against HTNV infection. The development of vaccines and antivirals, used independently and/or in combination, is critical for elucidating hantaviral infections and the impact on public health. RNA interference (RNAi) arised as an emerging antiviral therapy, is a highly specific degrades RNA, with post-transcriptional mechanism using eukaryotic cells platform. That has demonstrated efficacy against a wide range of viruses, both and . Recent antiviral methods involve using small interfering RNA (siRNA) and other, immune-based therapies to target specific gene segments (S, M, or L) of the Hantavirus. This therapeutic approach enhances viral RNA clearance through the RNA interference process in Vero E6 cells or human lung microvascular endothelial cells. However, the use of siRNAs faces challenges due to their low biological stability and limited targeting ability. Despite their successful inhibition of Hantavirus replication in host cells, their antiviral efficacy may be hindered. In the current review, we focus on advances in therapeutic strategies, as antiviral medications, immune-based therapies and vaccine candidates aimed at enhancing the body's ability to control the progression of Hantavirus infections, with the potential to reduce the risk of severe disease.
PubMed: 37901807
DOI: 10.3389/fmicb.2023.1233433