favipiravir and umifenovir

The ongoing SARS-CoV-2 pandemic stresses the need for effective antiviral drugs that can quickly be applied in order to reduce morbidity, mortality, and ideally viral transmission. By repurposing of broadly active antiviral drugs and compounds that are known to inhibit viral replication of related viruses, several advances could be made in the development of treatment strategies against COVID-19. The nucleoside analog remdesivir, which is known for its potent in vitro activity against Ebolavirus and other RNA viruses, was recently shown to reduce the time to recovery in patients with severe COVID-19. It is to date the only approved antiviral for treating COVID-19. Here, we provide a mechanism and evidence-based comparative review of remdesivir and other repurposed drugs with proven in vitro activity against SARS-CoV-2.

Topics: Adenosine Monophosphate; Alanine; Amides; Antiviral Agents; Benzamidines; COVID-19 Drug Treatment; Drug Repositioning; Esters; Guanidines; Guanine; Humans; Indoles; Lopinavir; Protease Inhibitors; Pyrazines; Ribavirin; Ritonavir; SARS-CoV-2; Virus Internalization; Virus Replication

We are living through an unprecedented crisis with the rapid spread of the new coronavirus disease (COVID-19) worldwide within a short time. The timely availability of thousands of SARS-CoV-2 genomes has enabled the scientific community to study the origin, structures, and pathogenesis of the virus. The pandemic has spurred research publication and resulted in an unprecedented number of therapeutic proposals. Because the development of new drugs is time consuming, several strategies, including drug repurposing and repositioning, are being tested to treat patients with COVID-19. Researchers have developed several potential vaccine candidates that have shown promise in phase II and III trials. As of 12 November 2020, 164 candidate vaccines are in preclinical evaluation, and 48 vaccines are in clinical evaluation, of which four have cleared phase III trials (Pfizer/BioNTech's BNT162b2, Moderna's mRNA-1273, University of Oxford & AstraZeneca's AZD1222, and Gamaleya's Sputnik V vaccine). Despite the acquisition of a vast body of scientific information, treatment depends only on the clinical management of the disease through supportive care. At the pandemic's 1-year mark, we summarize current information on SARS-CoV-2 origin and biology, and advances in the development of therapeutics. The updated information presented here provides a comprehensive report on the scientific progress made in the past year in understanding of SARS-CoV-2 biology and therapeutics.

Topics: Adenosine Monophosphate; Alanine; Amides; Animals; Antiviral Agents; Chloroquine; Clinical Trials as Topic; Coronavirus; Coronavirus Infections; COVID-19; COVID-19 Vaccines; Drug Combinations; Drug Repositioning; Glucocorticoids; Humans; Hydroxychloroquine; Indoles; Ivermectin; Lopinavir; Mutation; Pandemics; Phytotherapy; Plant Extracts; Pyrazines; Ritonavir; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Tinospora; Viral Zoonoses

The whole world is battling through coronavirus disease 2019 (COVID-19) which is a fatal pandemic. In the early 2020, the World Health Organization (WHO) declared it as a global health emergency without definitive treatments and preventive approaches. In the absence of definitive therapeutic agents, this thorough review summarizes and outlines the potency and safety of all molecules and therapeutics which may have potential antiviral effects. A number of molecules and therapeutics licensed or being tested for some other conditions were found effective in different in vitro studies as well as in many small sample-sized clinical trials and independent case studies. However, in those clinical trials, there were some limitations which need to be overcome to find the most promising antiviral against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In conclusion, many of above-mentioned antivirals seems to have some therapeutic effects but none of them have been shown to have a strong evidence for their proper recommendation and approval in the treatment of COVID-19. Constantly evolving new evidences, exclusive adult data, language barrier, and type of study (observational, retrospective, small-sized clinical trials, or independent case series) resulted to the several limitations of this review. The need for multicentered, large sample-sized, randomized, placebo-controlled trials on COVID-19 patients to reach a proper conclusion on the most promising antiviral agent is warranted.

Topics: Adenosine Monophosphate; Alanine; Amides; Antibodies, Monoclonal, Humanized; Antiviral Agents; Azetidines; Chloroquine; COVID-19; COVID-19 Serotherapy; Drug Combinations; Humans; Hydroxychloroquine; Immunization, Passive; Indoles; Interferons; Ivermectin; Lopinavir; Nitro Compounds; Oseltamivir; Purines; Pyrazines; Pyrazoles; Ribavirin; Ritonavir; Sulfonamides; Thiazoles

Topics: Adenosine Monophosphate; Alanine; Amides; Anti-Inflammatory Agents; Antibodies, Monoclonal, Humanized; Antimalarials; Antiviral Agents; Chloroquine; Clinical Trials as Topic; COVID-19; COVID-19 Drug Treatment; COVID-19 Serotherapy; Humans; Hydroxychloroquine; Immunization, Passive; Indoles; Intensive Care Units; Length of Stay; Lopinavir; Methylprednisolone; Observational Studies as Topic; Patient Admission; Pyrazines; Ritonavir; SARS-CoV-2; Survival Rate

Despite aggressive efforts on containment measures for the coronavirus disease 2019 (COVID-19) pandemic around the world, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continuously spreading. Therefore, there is an urgent need for an effective antiviral agent. To date, considerable research has been conducted to develop different approaches to COVID-19 therapy. In addition to early observational studies, which could be limited by study design, small sample size, non-randomized design, or different timings of treatment, an increasing number of randomized controlled trials (RCTs) investigating the clinical efficacy and safety of antiviral agents are being carried out. This study reviews the updated findings of RCTs regarding the clinical efficacy of eight antiviral agents against COVID-19, including remdesivir, lopinavir/ritonavir, favipiravir, sofosbuvir/daclatasvir, sofosbuvir/ledipasvir, baloxavir, umifenovir, darunavir/cobicistat, and their combinations. Treatment with remdesivir could accelerate clinical improvement; however, it lacked additional survival benefits. Moreover, 5-day regimen of remdesivir might show adequate effectiveness in patients with mild to moderate COVID-19. Favipiravir was only marginally effective regarding clinical improvement and virological assessment based on the results of small RCTs. The present evidence suggests that sofosbuvir/daclatasvir may improve survival and clinical outcomes in patients with COVID-19. However, the sample sizes for analysis were relatively small, and all studies were exclusively conducted in Iran. Further larger RCTs in other countries are warranted to support these findings. In contrast, the present findings of limited RCTs did not indicate the use of lopinavir/ritonavir, sofosbuvir/ledipasvir, baloxavir, umifenovir, and darunavir/cobicistat in the treatment of patients hospitalized for COVID-19.

Topics: Adenosine Monophosphate; Alanine; Amides; Antiviral Agents; Carbamates; Cobicistat; COVID-19 Drug Treatment; Darunavir; Dibenzothiepins; Drug Combinations; Drug Therapy, Combination; Humans; Imidazoles; Indoles; Iran; Lopinavir; Morpholines; Pyrazines; Pyridones; Pyrrolidines; Randomized Controlled Trials as Topic; Ritonavir; SARS-CoV-2; Sofosbuvir; Treatment Outcome; Triazines; Valine

The pandemic of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an unprecedented challenge to identify effective drugs for prevention and treatment. Given the rapid pace of scientific discovery and clinical data generated by the large number of people rapidly infected by SARS-CoV-2, clinicians need accurate evidence regarding effective medical treatments for this infection.. No proven effective therapies for this virus currently exist. The rapidly expanding knowledge regarding SARS-CoV-2 virology provides a significant number of potential drug targets. The most promising therapy is remdesivir. Remdesivir has potent in vitro activity against SARS-CoV-2, but it is not US Food and Drug Administration approved and currently is being tested in ongoing randomized trials. Oseltamivir has not been shown to have efficacy, and corticosteroids are currently not recommended. Current clinical evidence does not support stopping angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients with COVID-19.. The COVID-19 pandemic represents the greatest global public health crisis of this generation and, potentially, since the pandemic influenza outbreak of 1918. The speed and volume of clinical trials launched to investigate potential therapies for COVID-19 highlight both the need and capability to produce high-quality evidence even in the middle of a pandemic. No therapies have been shown effective to date.

Topics: Adenosine Monophosphate; Adrenal Cortex Hormones; Alanine; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antiviral Agents; Azithromycin; Betacoronavirus; Chloroquine; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Humans; Hydroxychloroquine; Immunoglobulins; Immunologic Factors; Indoles; Lopinavir; Oseltamivir; Pandemics; Pneumonia, Viral; Pyrazines; Ribavirin; Ritonavir; SARS-CoV-2; Withholding Treatment

The virus severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is currently affecting more than 200 countries and territories worldwide. It has been declared as pandemic by World Health Organization (WHO) and the whole world is suffering from corona virus disease 2019 (COVID-19). Currently, no treatment for SARS-CoV-2 are approved because of lack of evidence, but a number of clinical trials are in process and we are expecting fruitful results very soon. This review focuses on various approaches of treatment and few of the most recent clinical trials carried out in this field.

Topics: Adenosine Monophosphate; Alanine; Amides; Antibodies, Monoclonal, Humanized; Antiviral Agents; Betacoronavirus; Chloroquine; Clinical Trials as Topic; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; COVID-19 Serotherapy; Darunavir; Drug Combinations; Humans; Hydroxychloroquine; Immunization, Passive; Indoles; Interferon-alpha; Interferon-beta; Lopinavir; Pandemics; Pneumonia, Viral; Pyrazines; Ritonavir; SARS-CoV-2

Antiviral medications are being given empirically to some patients with coronavirus disease 2019 (COVID-19). To support the development of a COVID-19 management guideline, we conducted a systematic review that addressed the benefits and harms of 7 antiviral treatments for COVID-19.. We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), PubMed and 3 Chinese databases (CNKI, WANFANG and SinoMed) through Apr. 19, medRxiv and Chinaxiv through Apr. 27, and Chongqing VIP through Apr. 30, 2020. We included studies of ribavirin, chloroquine, hydroxychloroquine, umifenovir (arbidol), favipravir, interferon and lopinavir/ritonavir. If direct evidence from COVID-19 studies was not available, we included indirect evidence from studies of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) for efficacy outcomes and other acute respiratory viral infections for safety outcomes.. In patients with nonsevere COVID-19 illness, the death rate was extremely low, precluding an important effect on mortality. We found only very low-quality evidence with little or no suggestion of benefit for most treatments and outcomes in both nonsevere and severe COVID-19. An exception was treatment with lopinavir/ritonavir, for which we found low-quality evidence for a decrease in length of stay in the intensive care unit (risk difference 5 d shorter, 95% confidence interval [CI] 0 to 9 d) and hospital stay (risk difference 1 d shorter, 95% CI 0 to 2 d). For safety outcomes, evidence was of low or very low quality, with the exception of treatment with lopinavir/ritonavir for which moderate-quality evidence suggested likely increases in diarrhea, nausea and vomiting.. To date, persuasive evidence of important benefit in COVID-19 does not exist for any antiviral treatments, although for each treatment evidence has not excluded important benefit. Additional randomized controlled trials involving patients with COVID-19 will be needed before such treatments can be administered with confidence.

Topics: Amides; Antiviral Agents; Betacoronavirus; Chloroquine; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Evidence-Based Medicine; Humans; Hydroxychloroquine; Indoles; Influenza, Human; Lopinavir; Observational Studies as Topic; Pandemics; Pneumonia, Viral; Pyrazines; Ribavirin; Ritonavir; SARS-CoV-2

The fight against the novel coronavirus pneumonia (namely COVID-19) that seriously harms human health is a common task for all mankind. Currently, development of drugs against the novel coronavirus (namely SARS-CoV-2) is quite urgent. Chinese medical workers and scientific researchers have found some drugs to play potential therapeutic effects on COVID-19 at the cellular level or in preliminary clinical trials. However, more fundamental studies and large sample clinical trials need to be done to ensure the efficacy and safety of these drugs. The adoption of these drugs without further testing must be careful. The relevant articles, news, and government reports published on the official and Preprint websites, PubMed and China National Knowledge Infrastructure (CNKI) databases from December 2019 to April 2020 were searched and manually filtered. The general pharmacological characteristics, indications, adverse reactions, general usage, and especially current status of the treatment of COVID-19 of those potentially effective drugs, including chemical drugs, traditional Chinese medicines (TCMs), and biological products in China were summarized in this review to guide reasonable medication and the development of specific drugs for the treatment of COVID-19.

Topics: Adenosine Monophosphate; Alanine; Amides; Antiviral Agents; Betacoronavirus; China; Chloroquine; Coronavirus Infections; COVID-19; Drug Combinations; Drugs, Chinese Herbal; Humans; Indoles; Interferons; Lopinavir; Lung; Pandemics; Pneumonia, Viral; Pyrazines; Ribavirin; Ritonavir; SARS-CoV-2; Survival Analysis

The Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become a global pandemic. Up to now, numerous medicines have been applied or approved for the prevention and control of the virus infection. However, the efficiency of each medicine or combination is completely different or still unknown. In this review, we discuss the types, characteristics, antiviral mechanisms, and shortcomings of recommended candidate medicines for SARS-CoV-2 infection, as well as perspectives of the drugs for the disease treatment, which may provide a theoretical basis for drug screening and application.

Topics: Adenosine Monophosphate; Alanine; Amides; Antiviral Agents; Betacoronavirus; China; Coronavirus Infections; COVID-19; Drug Combinations; Drugs, Chinese Herbal; Humans; Hydroxychloroquine; Indoles; Interferons; Lopinavir; Pandemics; Pneumonia, Viral; Pyrazines; Ribavirin; Ritonavir; SARS-CoV-2; Survival Analysis; Teicoplanin

Since a novel coronavirus pneumonia outbreak in late December 2019, coronavirus disease -19 (COVID-19) epidemic has gradually spread worldwide, becoming a major public health event. No specific antivirals are currently available for COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The treatments for COVID-19 are mainly based on the experiences of similar virus such SARS-CoV, MERS-CoV, HIV and influenza viruses. Scientists have taken great efforts to investigate the effective methods for the treatment of COVID-19. Up to now, there are over 1000 clinical studies for COVID-19 all over the world. In this article, we reviewed the current options for COVID-19 therapy including small molecules such as Remdesivir, Favipiravir, Lopinavir/Ritonavir etc, peptide inhibitors of ACE2, Traditional Chinese Medicines and Biologics such as SARS-CoV-2-specific neutralizing antibodies, mesenchymal stem cells and vaccines etc. Meanwhile, we systematically reviewed their clinical safety, clinical applications and progress of antiviral researches. The therapeutic effect of these antiviral drugs is summarized and compared, hoping to provide some ideas for clinical options of COVID-19 treatment and also provide experiences for the life-threatening virus diseases in the future.

Topics: Adenosine Monophosphate; Alanine; Amides; Angiotensin-Converting Enzyme Inhibitors; Antimalarials; Antiviral Agents; Betacoronavirus; Biomedical Research; Coronavirus Infections; COVID-19; COVID-19 Serotherapy; Drug Combinations; Drug Development; Drugs, Chinese Herbal; Humans; Hydroxychloroquine; Immunization, Passive; Indoles; Interferons; Lopinavir; Pandemics; Pneumonia, Viral; Pyrazines; Ribavirin; Ritonavir; SARS-CoV-2

Topics: Adenosine Monophosphate; Adrenal Cortex Hormones; Alanine; Amides; Antibodies, Monoclonal, Humanized; Antiviral Agents; Betacoronavirus; Coronavirus Infections; COVID-19; Cytokine Release Syndrome; Drug Hypersensitivity; Humans; Immunity, Innate; Immunologic Factors; Indoles; Infliximab; Interleukin 1 Receptor Antagonist Protein; Nitriles; Pandemics; Pneumonia, Viral; Pyrazines; Pyrazoles; Pyrimidines; SARS-CoV-2; Severity of Illness Index

The unprecedented challenge faced by mankind due to emergence of coronavirus 2019 (COVID-19) pandemic has obligated researchers across the globe to develop effective medicine for prevention and treatment of this deadly infection. The aim of this review is to compile recently published research articles on anti-COVID 19 management with their benefits and risk to facilitate decision making of the practitioners and policy makers. Unfortunately, clinical outcomes reported for antivirals are not consistent. Initial favorable reports on lopinavir/ritonavir contradicted by recent studies. Ostalmovir has conflicting reports. Short term therapy of remdesivir claimed to be beneficial. Favipiravir demonstrated good recovery in some of the cases of COVID-19. Umifenovir (Arbidol) was associated with reduction in mortality in few studies. Overall, until now, U.S. Food and Drug administration issued only emergency use authorization to remdesivir for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease.

Topics: Adenosine Monophosphate; Alanine; Amides; Antiviral Agents; Betacoronavirus; Coronavirus Infections; COVID-19; Drug Combinations; Humans; Indoles; Lopinavir; Pandemics; Pneumonia, Viral; Pyrazines; Ritonavir; SARS-CoV-2

Coronavirus disease 2019, also known as COVID-19, is caused by a novel coronavirus named severe acute respiratory syndrome coronavirus 2, or SARS-CoV-2. The infection has now catapulted into a full-blown pandemic across the world, which has affected more than 2 million people and has led to approximately 150,000 fatalities all over the world (WHO). In this review, we elaborate all currently available data that shed light on possible methods for treatment of COVID-19, such as antiviral drugs, corticosteroids, convalescent plasma, and potentially effective vaccines. Additionally, ongoing and discontinued clinical trials that have been carried out for validating probable treatments for COVID-19 are discussed. The review also elaborates the prospective approach and the possible advantages of using convalescent plasma and stem cells for the improvement of clinical symptoms and meeting the demand for an instantaneous cure.

Topics: Adenosine Monophosphate; Adrenal Cortex Hormones; Alanine; Amides; Antibodies, Monoclonal, Humanized; Antiviral Agents; Betacoronavirus; Coronavirus Infections; COVID-19; COVID-19 Serotherapy; COVID-19 Vaccines; Cytokine Release Syndrome; Drug Combinations; Humans; Hydroxychloroquine; Immunization, Passive; Immunologic Factors; Indoles; Interleukin 1 Receptor Antagonist Protein; Lopinavir; Pandemics; Pneumonia, Viral; Pyrazines; Ritonavir; SARS-CoV-2; Severity of Illness Index; Viral Vaccines

The coronavirus disease 2019 (COVID-19) is declared as an international emergency in 2020. Its prevalence and fatality rate are rapidly increasing but the medication options are still limited for this perilous disease. The emergent outbreak of COVID-19 triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) keeps propagating globally. The present scenario has emphasized the requirement for therapeutic opportunities to relive and overcome this latest pandemic. Despite the fact, the deteriorating developments of COVID-19, there is no drug certified to have considerable effects in the medical treatment for COVID-19 patients. The COVID-19 pandemic requests for the rapid testing of new treatment approaches. Based on the evidence, hydroxychloroquine is the first medicine opted for the treatment of disease. Umifenovir, remdesivir, and fevipiravir are deemed the most hopeful antiviral agent by improving the health of infected patients. The dexamethasone is a first known steroid medicine that can save the lives of seriously ill patients, and it is shown in a randomized clinical trial by the United Kingdom that it reduced the death rate in COVID-19 patients. The current review recapitulates the existing evidence of possible therapeutic drugs, peptides, humanized antibodies, convulsant plasma, and vaccination that has revealed potential in fighting COVID-19 infections. Many randomized and controlled clinical trials are taking place to further validate these agent's safety and effectiveness in curing COVID-19.

Topics: Adenosine Monophosphate; Alanine; Amides; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antibodies, Monoclonal, Humanized; Antibodies, Neutralizing; Antiparasitic Agents; Antiviral Agents; Cannabinoids; Chloroquine; Complement Inactivating Agents; COVID-19; COVID-19 Drug Treatment; COVID-19 Serotherapy; COVID-19 Vaccines; Dexamethasone; Drug Combinations; Enzyme Inhibitors; Humans; Hydroxychloroquine; Immunization, Passive; Indoles; Interferons; Ivermectin; Lopinavir; Nitro Compounds; Pyrazines; Ritonavir; SARS-CoV-2; Teicoplanin; Tetracyclines; Thiazoles

The SARS-CoV-2 virus emerged in December 2019 and then spread rapidly worldwide, particularly to China, Japan, and South Korea. Scientists are endeavoring to find antivirals specific to the virus. Several drugs such as chloroquine, arbidol, remdesivir, and favipiravir are currently undergoing clinical studies to test their efficacy and safety in the treatment of coronavirus disease 2019 (COVID-19) in China; some promising results have been achieved thus far. This article summarizes agents with potential efficacy against SARS-CoV-2.

Topics: Adenosine Monophosphate; Alanine; Amides; Antiviral Agents; Betacoronavirus; Chloroquine; Clinical Studies as Topic; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Drug Discovery; Humans; Indoles; Pandemics; Pneumonia, Viral; Pyrazines; Ribonucleotides; SARS-CoV-2; Virus Replication

Topics: Adenine; Adenosine Monophosphate; Alanine; Amides; Antimalarials; Antiviral Agents; Betacoronavirus; China; Chloroquine; Clinical Trials as Topic; Cobicistat; Coronavirus 3C Proteases; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Cysteine Endopeptidases; Dibenzothiepins; Drug Combinations; Drug Discovery; Drug Therapy, Combination; Emtricitabine; Humans; Hydroxychloroquine; Indoles; Lopinavir; Medicine, Chinese Traditional; Morpholines; Oseltamivir; Oxazines; Pandemics; Pneumonia, Viral; Pyrazines; Pyridines; Pyridones; Ritonavir; RNA-Dependent RNA Polymerase; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Tenofovir; Thiepins; Triazines; Viral Nonstructural Proteins

Here we report on the most recent updates on experimental drugs successfully employed in the treatment of the disease caused by SARS-CoV-2 coronavirus, also referred to as COVID-19 (COronaVIrus Disease-19). In particular, several cases of recovered patients have been reported after being treated with lopinavir/ritonavir [which is widely used to treat Human Immunodeficiency Virus (HIV) infection] in combination with the anti-flu drug oseltamivir. In addition, remdesivir, which has been previously administered to Ebola virus patients, has also proven effective in the U.S. against coronavirus, while antimalarial chloroquine and hydroxychloroquine, favipiravir and co-administered darunavir and umifenovir (in patient therapies) were also recently recorded as having anti-SARS-CoV-2 effects. Since the recoveries/deaths ratio in the last weeks significantly increased, especially in China, it is clear that the experimental antiviral therapy, together with the availability of intensive care unit beds in hospitals and rigorous government control measures, all play an important role in dealing with this virus. This also stresses the urgent need for the scientific community to devote its efforts to the development of other more specific antiviral strategies.

Topics: Adenosine Monophosphate; Alanine; Amides; Antiviral Agents; Betacoronavirus; China; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Darunavir; Drug Combinations; Humans; Hydroxychloroquine; Indoles; Lopinavir; Pandemics; Pneumonia, Viral; Pyrazines; Ritonavir; SARS-CoV-2

Mice lacking the type I interferon receptor (IFNAR-/- mice) reproduce relevant aspects of Crimean-Congo hemorrhagic fever (CCHF) in humans, including liver damage. We aimed at characterizing the liver pathology in CCHF virus-infected IFNAR-/- mice by immunohistochemistry and employed the model to evaluate the antiviral efficacy of ribavirin, arbidol, and T-705 against CCHF virus.. CCHF virus-infected IFNAR-/- mice died 2-6 days post infection with elevated aminotransferase levels and high virus titers in blood and organs. Main pathological alteration was acute hepatitis with extensive bridging necrosis, reactive hepatocyte proliferation, and mild to moderate inflammatory response with monocyte/macrophage activation. Virus-infected and apoptotic hepatocytes clustered in the necrotic areas. Ribavirin, arbidol, and T-705 suppressed virus replication in vitro by ≥3 log units (IC50 0.6-2.8 µg/ml; IC90 1.2-4.7 µg/ml). Ribavirin [100 mg/(kg×d)] did not increase the survival rate of IFNAR-/- mice, but prolonged the time to death (p<0.001) and reduced the aminotransferase levels and the virus titers. Arbidol [150 mg/(kg×d)] had no efficacy in vivo. Animals treated with T-705 at 1 h [15, 30, and 300 mg/(kg×d)] or up to 2 days [300 mg/(kg×d)] post infection survived, showed no signs of disease, and had no virus in blood and organs. Co-administration of ribavirin and T-705 yielded beneficial rather than adverse effects.. Activated hepatic macrophages and monocyte-derived cells may play a role in the proinflammatory cytokine response in CCHF. Clustering of infected hepatocytes in necrotic areas without marked inflammation suggests viral cytopathic effects. T-705 is highly potent against CCHF virus in vitro and in vivo. Its in vivo efficacy exceeds that of the current standard drug for treatment of CCHF, ribavirin.

Topics: Amides; Animals; Antiviral Agents; Chlorocebus aethiops; Disease Models, Animal; Female; Hemorrhagic Fever Virus, Crimean-Congo; Hemorrhagic Fever, Crimean; Indoles; Liver; Male; Mice; Mice, Transgenic; Pyrazines; Receptor, Interferon alpha-beta; Ribavirin; Vero Cells