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Viruses May 2019Hepatitis E virus (HEV) is an underestimated disease, leading to estimated 20 million infections and up to 70,000 deaths annually. Infections are mostly asymptomatic but... (Review)
Review
Hepatitis E virus (HEV) is an underestimated disease, leading to estimated 20 million infections and up to 70,000 deaths annually. Infections are mostly asymptomatic but can reach mortality rates up to 25% in pregnant women or become chronic in immunocompromised patients. The current therapy options are limited to the unspecific antivirals Ribavirin (RBV) and pegylated Interferon-α (pegIFN-α). RBV leads to viral clearance in only 80% of patients treated, and is, similar to pegIFN-α, contraindicated in the major risk group of pregnant women, emphasizing the importance of new therapy options. In this review, we focus on the urgent need and current efforts in HEV drug development. We provide an overview of the current status of HEV antiviral research. Furthermore, we discuss strategies for drug development and the limitations of the approaches with respect to HEV.
Topics: Antiviral Agents; Drug Development; Drug Therapy, Combination; Female; Hepatitis E; Humans; Immunocompromised Host; Interferon-alpha; Pregnancy; Ribavirin
PubMed: 31141919
DOI: 10.3390/v11060485 -
Cancer Research Dec 2014Cancer cells rapidly evolve a multitude of defense mechanisms to evade the effects of the oncologist's drug arsenal. Unfortunately, clinical strategies to overcome these... (Review)
Review
Cancer cells rapidly evolve a multitude of defense mechanisms to evade the effects of the oncologist's drug arsenal. Unfortunately, clinical strategies to overcome these lag far behind. This mismatch likely underlies our inability to implement new durable treatment strategies. Here, a new form of multidrug resistance, inducible drug glucuronidation, is discussed. This form was discovered while developing means to target a specific oncogene, the eukaryotic translation initiation factor 4E (eIF4E), with its inhibitor ribavirin. In two clinical studies, ribavirin treatment led to substantial clinical responses, but all responding patients eventually relapsed. In most cases, this was due to the overexpression of the sonic hedgehog transcription factor Gli1, which elevated the UDP glucuronsyltransferase UGT1A enzymes. UGT1As add glucuronic acid to many drugs. Indeed, these cells are resistant to not only ribavirin, but also Ara-C, and likely other drugs. Inhibition of Gli1 reduced UGT1As, eliminated drug glucuronides, and renewed sensitivity to ribavirin and Ara-C. These studies highlight that cancer cells and their resistant counterparts metabolize drugs differently from each other as well as from normal cells. Likely, these inducible modifications go beyond glucuronidation. Understanding the extent of inducible drug modifications and the pathways that drive expression of the corresponding enzymatic machinery will better position us to finally make resistance futile.
Topics: Drug Resistance, Neoplasm; Eukaryotic Initiation Factor-4E; Glucuronic Acid; Glucuronosyltransferase; Humans; Neoplasms; Ribavirin; Transcription Factors; Zinc Finger Protein GLI1
PubMed: 25477336
DOI: 10.1158/0008-5472.CAN-14-2607 -
Nature Medicine Nov 2023Previous studies showed a low-grade enterovirus infection in the pancreatic islets of patients with newly diagnosed type 1 diabetes (T1D). In the Diabetes Virus... (Randomized Controlled Trial)
Randomized Controlled Trial
Previous studies showed a low-grade enterovirus infection in the pancreatic islets of patients with newly diagnosed type 1 diabetes (T1D). In the Diabetes Virus Detection (DiViD) Intervention, a phase 2, placebo-controlled, randomized, parallel group, double-blind trial, 96 children and adolescents (aged 6-15 years) with new-onset T1D received antiviral treatment with pleconaril and ribavirin (n = 47) or placebo (n = 49) for 6 months, with the aim of preserving β cell function. The primary endpoint was the mean stimulated C-peptide area under the curve (AUC) 12 months after the initiation of treatment (less than 3 weeks after diagnosis) using a mixed linear model. The model used longitudinal log-transformed serum C-peptide AUCs at baseline, at 3 months, 6 months and 1 year. The primary endpoint was met with the serum C-peptide AUC being higher in the pleconaril and ribavirin treatment group compared to the placebo group at 12 months (average marginal effect = 0.057 in the linear mixed model; 95% confidence interval = 0.004-0.11, P = 0.037). The treatment was well tolerated. The results show that antiviral treatment may preserve residual insulin production in children and adolescent with new-onset T1D. This provides a rationale for further evaluating antiviral strategies in the prevention and treatment of T1D. European Union Drug Regulating Authorities Clinical Trials identifier: 2015-003350-41 .
Topics: Child; Adolescent; Humans; Diabetes Mellitus, Type 1; Ribavirin; C-Peptide; Double-Blind Method; Antiviral Agents
PubMed: 37789144
DOI: 10.1038/s41591-023-02576-1 -
Journal of Clinical Virology : the... Feb 2020Recent recognition of invasive astrovirus infections, including encephalitis and viremia in humans, have highlighted the need for effective anti-astrovirus therapeutics....
BACKGROUND
Recent recognition of invasive astrovirus infections, including encephalitis and viremia in humans, have highlighted the need for effective anti-astrovirus therapeutics. However, there is a paucity of data regarding the in vitro activity of broad-spectrum RNA antivirals against astroviruses, including ribavirin and favipiravir.
OBJECTIVES
We quantified the EC50 values for ribavirin and favipiravir against two human astrovirus strains, astrovirus VA1 (VA1) and human astrovirus 4 (HAstV4).
STUDY DESIGN
Caco-2 cells were infected with VA1 or HAstV4 in the presence of ribavirin or favipiravir (dose range 0.1-1000 μM), and the cells were maintained in media containing the drugs for 72 h. Viral RNA was extracted and quantified by qRT-PCR. As a surrogate for cytotoxicity, cellular adenosine triphosphate (ATP) from each drug treatment was also measured.
RESULTS
VA1 replication was inhibited 10-100-fold by both ribavirin (EC50 = 154 μM) and favipiravir (EC50 = 246 μM). In contrast, ribavirin inhibited HAstV4 replication (EC50 = 268 μM) but favipiravir only reduced replication by 44% at the highest dose. Mild reductions in ATP (17-31%) was only observed at the highest concentration of ribavirin (1000 μM) and no significant decrease in ATP was detected for any concentration of favipiravir.
CONCLUSIONS
Ribavirin inhibited both human astrovirus species and favipiravir was only active against VA1. In the future, the in vivo efficacy of these drugs could be tested with development of an animal model of human astrovirus infection.
Topics: Amides; Antiviral Agents; Caco-2 Cells; Humans; Mamastrovirus; Pyrazines; Ribavirin; Virus Replication
PubMed: 31864069
DOI: 10.1016/j.jcv.2019.104247 -
Viruses Nov 2012Lymphocytic choriomeningitis virus (LCMV) has contributed to unveil some of the molecular mechanisms of lethal mutagenesis, or loss of virus infectivity due to increased... (Review)
Review
Lymphocytic choriomeningitis virus (LCMV) has contributed to unveil some of the molecular mechanisms of lethal mutagenesis, or loss of virus infectivity due to increased mutation rates. Here we review these developments, and provide additional evidence that ribavirin displays a dual mutagenic and inhibitory activity on LCMV that can be relevant to treatment designs. Using 5-fluorouracil as mutagenic agent and ribavirin either as inhibitor or mutagen, we document an advantage of a sequential inhibitor-mutagen administration over the corresponding combination treatment to achieve a low LCMV load in cell culture. This advantage is accentuated in the concentration range in which ribavirin acts mainly as an inhibitor, rather than as mutagen. This observation reinforces previous theoretical and experimental studies in supporting a sequential inhibitor-mutagen administration as a possible antiviral design. Given recent progress in the development of new inhibitors of arenavirus replication, our results suggest new options of ribavirin-based anti-arenavirus treatments.
Topics: Animals; Antiviral Agents; Arenaviridae Infections; Arenavirus; Drug Therapy, Combination; Genes, Lethal; Genes, Viral; Humans; Lymphocytic choriomeningitis virus; Mutagenesis; Mutation; Ribavirin
PubMed: 23202505
DOI: 10.3390/v4112786 -
Basic & Clinical Pharmacology &... Jul 2022Protein arginine methyltransferases 1 and 5 (PRMT1 and PRMT5) are frequently overexpressed in diverse types of cancers and correlate with poor prognosis, thus making...
Protein arginine methyltransferases 1 and 5 (PRMT1 and PRMT5) are frequently overexpressed in diverse types of cancers and correlate with poor prognosis, thus making these enzymes potential therapeutic targets. The aim of this study was to assess and elucidate the anti-tumour effect and epigenetic regulatory mechanism of ribavirin in soft tissue sarcomas (STS). We showed that ribavirin inhibited growth and metastasis and prolonged survival in animals bearing STS cells by downregulating the mRNA and protein levels of PRMT1/PRMT5 and attenuating the accumulation of asymmetric and symmetric di-methylation of arginine (ADMA and SDMA). Furthermore, ribavirin lowered the permeability of the peritoneum in KM mice bearing S180 ascites via decreasing the level of vascular endothelial growth factor (VEGF). Ribavirin was a potent inhibitor of cell proliferation and metastasis in STS cells through downregulation of both type I PRMT1 and type II PRMT5. Ribavirin could be used to enhance the efficacy of doxorubicin in STS allograft tumour models.
Topics: Animals; Arginine; Cell Proliferation; Mice; Protein-Arginine N-Methyltransferases; Ribavirin; Sarcoma; Vascular Endothelial Growth Factor A
PubMed: 35470570
DOI: 10.1111/bcpt.13736 -
Journal of Hepatology Jan 2010
Topics: Antineoplastic Agents; Antiviral Agents; Carcinoma, Hepatocellular; Drug Delivery Systems; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Humans; Liver Neoplasms; Ribavirin; Treatment Outcome
PubMed: 19923033
DOI: 10.1016/j.jhep.2009.10.017 -
American Journal of Health-system... Apr 2021To report a case of ribavirin-associated severe hyperuricemia in an immunocompromised patient treated for respiratory syncytial virus (RSV) infection.
PURPOSE
To report a case of ribavirin-associated severe hyperuricemia in an immunocompromised patient treated for respiratory syncytial virus (RSV) infection.
SUMMARY
A 21-year-old male with a past medical history of B-cell acute lymphoblastic leukemia was in full remission after allogenic bone marrow transplantation complicated with chronic graft-versus-host disease. He was hospitalized due to fever, malaise, and respiratory symptoms. A diagnosis of RSV upper respiratory tract infection complicated by secondary pneumonia was made, and oral ribavirin (600 mg in 3 divided doses daily) and intravenous levofloxacin (750 mg once daily) were initiated. On day 2 of the hospital admission, the patient's uric acid levels had increased from a baseline of 4 to 6 mg/dL to 19.3 and 22.2 mg/dL after the fourth and fifth doses of ribavirin, respectively, and his serum creatinine steadily had increased from a baseline of 0.7 to 0.8 mg/dL to 1.6 mg/dL. Ribavirin was discontinued after the sixth dose, and a single dose of intravenous rasburicase (7.5 mg) was administered. On day 3, the patient's serum uric and creatinine concentrations had decreased to 4.7 mg/dL and 1.1 mg/dL, respectively. He continued to recover on antibiotics and was discharged with normal uric acid and serum creatinine levels.
CONCLUSION
We report a case of severe hyperuricemia and acute kidney injury that developed early after initiation of ribavirin for RSV infection and suspected bacterial pneumonia in an immunocompromised patient without hepatitis C, requiring ribavirin discontinuation and rasburicase administration. To our knowledge, this is the first reported case of severe hyperuricemia in a patient treated with ribavirin for RSV infection rather than chronic hepatitis C. Clinicians should be aware of the possibility of acute and severe hyperuricemia following ribavirin administration.
Topics: Acute Kidney Injury; Adult; Creatinine; Humans; Hyperuricemia; Male; Ribavirin; Uric Acid; Young Adult
PubMed: 33617629
DOI: 10.1093/ajhp/zxab043 -
Liver International : Official Journal... Jan 2017Over the past two decades, ribavirin has been an integral component of treatment for hepatitis C virus (HCV) infection, where it has been shown to improve the efficacy... (Review)
Review
Over the past two decades, ribavirin has been an integral component of treatment for hepatitis C virus (HCV) infection, where it has been shown to improve the efficacy of (pegylated) interferon. However, because of treatment-limiting side effects and its additive toxicity with interferon, the search for interferon- and ribavirin-free regimens has been underway. The recent approvals of all-oral direct acting antivirals (DAAs) have revolutionized the HCV therapeutic landscape, and initially it was expected that the role of ribavirin with DAA regimens would be eliminated. On the contrary, what we have witnessed is that ribavirin retains an important role in the optimal treatment of some subgroups of patients, particularly those that historically have been considered the most difficult to cure. Fortunately, it has also been recognized that the safety profile of ribavirin is improved when co-administered with all-oral DAA combinations in the absence of interferon. Despite the antiviral mechanism of action of ribavirin being poorly understood, we now have a range of novel insights into the potential role of ribavirin in all-oral DAA HCV treatment and greater insight into the antiviral mechanism by which it continues to provide clinical benefit for defined patient groups.
Topics: Antiviral Agents; Delayed-Action Preparations; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Humans; Interferon-alpha; Randomized Controlled Trials as Topic; Ribavirin
PubMed: 27473533
DOI: 10.1111/liv.13212 -
Annual Review of Pharmacology and... 2013Two selective inhibitors of the hepatitis C virus (HCV) protease nearly double the cure rates for this infection when combined with peginterferon alfa and ribavirin.... (Review)
Review
Two selective inhibitors of the hepatitis C virus (HCV) protease nearly double the cure rates for this infection when combined with peginterferon alfa and ribavirin. These drugs, boceprevir and telaprevir, received regulatory approval in 2011 and are the first direct-acting antiviral agents (DAAs) that selectively target HCV. During 2012, at least 30 additional DAAs were in various stages of clinical development. HCV protease inhibitors, polymerase inhibitors, and NS5A inhibitors (among others) can achieve high cure rates when combined with peginterferon alfa and ribavirin and demonstrate promise when used in combination with one another. Current research is attempting to improve the pharmacokinetics and tolerability of these agents, define the best regimens, and determine treatment strategies that produce the best outcomes. Several DAAs will reach the market simultaneously, and resources will be needed to guide the use of these drugs. We review the clinical pharmacology, trial results, and remaining challenges of DAAs for the treatment of HCV.
Topics: Animals; Antiviral Agents; Drug Therapy, Combination; Hepacivirus; Hepatitis C; Humans; Interferon-alpha; Ribavirin
PubMed: 23140245
DOI: 10.1146/annurev-pharmtox-011112-140254