scholarly journals Favipiravir Inhibits Mayaro Virus Infection in Mice

Viruses ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2213
Author(s):  
Michèle Bengue ◽  
Ai-rada Pintong ◽  
Florian Liegeois ◽  
Antoine Nougairède ◽  
Rodolphe Hamel ◽  
...  
Keyword(s):  
Antiviral Treatment ◽  
Antiviral Drug ◽  
Viral Rna ◽  
In Vivo Model ◽  
Blood Levels ◽  
Viral Particles ◽  
Mayaro Virus ◽  
Immunocompetent Mice

Mayaro virus (MAYV) is an emergent alphavirus that causes MAYV fever. It is often associated with debilitating symptoms, particularly arthralgia and myalgia. MAYV infection is becoming a considerable health issue that, unfortunately, lacks a specific antiviral treatment. Favipiravir, a broad-spectrum antiviral drug, has recently been shown to exert anti-MAYV activity in vitro. In the present study, the potential of Favipiravir to inhibit MAYV replication in an in vivo model was evaluated. Immunocompetent mice were orally administrated 300 mg/kg/dose of Favipiravir at pre-, concurrent-, or post-MAYV infection. The results showed a significant reduction in infectious viral particles and viral RNA transcripts in the tissues and blood of the pre- and concurrently treated infected mice. A significant reduction in the presence of both viral RNA transcript and infectious viral particles in the tissue and blood of pre- and concurrently treated infected mice was observed. By contrast, Favipiravir treatment post-MAYV infection did not result in a reduction in viral replication. Interestingly, Favipiravir strongly decreased the blood levels of the liver disease markers aspartate- and alanine aminotransferase in the pre- and concurrently treated MAYV-infected mice. Taken together, these results suggest that Favipiravir is a potent antiviral drug when administered in a timely manner.

CMV Specific Immunotherapy: How Many Patients Will Benefit?.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2244-2244
Author(s):  
Russell J. Garland ◽  
Paraskevi Diamanti ◽  
Samantha E. West ◽  
Ann Green ◽  
David Carrington ◽  
...  
Keyword(s):  
Stem Cell ◽  
Ex Vivo ◽  
Antiviral Treatment ◽  
Antiviral Drug ◽  
Disease Free Survival ◽  
Group B ◽  
Selection Factors ◽  
Cmv Reactivation

Abstract Cytomegalovirus (CMV) infection is associated with increased transplant related mortality and decreased overall survival after stem cell transplantation (SCT) despite major advances in early detection, prophylaxis and treatment. This effect is most marked in CMV seropositive patients who have a statistically significant decrement in overall or disease free survival of 20–46% when compared to low risk (−/−) transplants (Boeckh Blood 2004 103: 2003–8). Transfer of cellular immunity from a seropositive donor results in reconstitution of T cells to CMV and protection from CMV disease post-SCT, and this underlies the recent development of cellular immunotherapeutic manoeuvres. As a centre looking to develop such therapy, we have carried out a retrospective analysis of a patient cohort in order to estimate how many patients would require this intervention. We used twice weekly quantitative PCR surveillance to analyse the CMV reactivation profiles of 104 recipients of 106 allogeneic SCT, transplanted between April 2002 and April 2004. Hence follow up was 5–27 months. The cohort comprised 41 adults and 65 children. Transplants were from related (42), unrelated (52) and haploidentical donors (12). T cell depletion was performed either (i) in vivo using either CAMPATH-1H (44 transplants) or ATG (5), (ii) ex vivo by either CD34 (8) or CAMPATH-1H in vitro (1), or (iii) by combinations of (i) and (ii) (26). SCTs were for malignancies in 92 cases and non-neoplastic disorders in 14. Many patients were considered high risk, necessitating short search to transplant times. A hierarchy of donor selection factors was considered: HLA matching was the primary determinant, with other factors including stem cell dose, age, gender and CMV status. Seventy-one patients were at risk of CMV reactivation. There were 28 episodes of CMV reactivation in 27 of these patients, with the following Recipient/Donor serostatus combinations: 0 (of 16) −/+, 22 (of 38) +/− and 6 (of 17) +/+. Seven patients (Group A) resolved their infections without intervention. Nine patients (Group B) resolved infections after antiviral drug treatment, whilst the remaining 12 reactivators (Group C) did not clear their CMV DNA load despite antiviral treatment (of whom 3 died, 1 relapsed and the remainder have ongoing CMV PCR positivity). As a minimum a CMV immunotherapy programme should allow prophylaxis or early treatment of all patients in groups B and C. However, using our current selection criteria only 5/21 cases had a CMV seropositive donor. Logistical problems e.g. CTL precursor frequency or availability of an immunodominant tetramer might have rendered some donors inappropriate providers of anti-CMV CTL. Thus a maximum of 5 out of 106 transplanted patients in our unit could have benefited, although this figure could be slightly improved by deliberate selection of CMV positive donors for CMV positive patients. Such numbers should be borne in mind by any centre contemplating the development of antiviral immunotherapy programmes.

scholarly journals Ganciclovir and Cidofovir Treatment of Cytomegalovirus-Induced Myocarditis in Mice

2001 ◽  
Vol 45 (5) ◽  
pp. 1444-1449 ◽  
Author(s):  
Jason C. Lenzo ◽  
Geoffrey R. Shellam ◽  
Cassandra M. Lawson
Keyword(s):  
Acute Phase ◽  
Antiviral Treatment ◽  
Antiviral Drug ◽  
Viral Myocarditis ◽  
Chronic Phase ◽  
Myocardial Inflammation ◽  
Mcmv Infection ◽  
Chronic Myocarditis

ABSTRACT The cardiovascular disease myocarditis is characterized by inflammation and necrosis of cardiac muscle. This disease has been associated with various viral etiologies, including cytomegalovirus (CMV). Murine CMV (MCMV) infection of adult BALB/c mice produces a disease with acute and chronic phases similar to that found in humans. In our murine model, we have investigated the therapeutic efficacy of antiviral drug administration on myocarditis. Two drugs commonly used for CMV treatment, ganciclovir and cidofovir, were subjected to trials, with both drugs showing potent antiviral activity against MCMV both in vitro and in vivo. The acute phase of myocarditis was significantly reduced when antiviral therapy commenced 24 h postinfection. Such treatment also reduced the severity of the chronic phase of myocarditis. In contrast, antiviral treatment commencing after the acute phase had no effect on chronic myocarditis. Reinfection of mice with MCMV caused exacerbation of myocardial inflammation. Such an increase in severity of myocarditis could be prevented with either ganciclovir or cidofovir treatment, but the preexisting inflammation and necrosis of the myocardium persisted. These data highlight possible therapeutic uses of antiviral drugs in viral myocarditis as well as further elucidating the pathogenic nature of the disease.

scholarly journals The Cytomegalovirus Protein Kinase pUL97: Host Interactions, Regulatory Mechanisms and Antiviral Drug Targeting

2020 ◽  
Vol 8 (4) ◽  
pp. 515 ◽  
Author(s):  
Mirjam Steingruber ◽  
Manfred Marschall
Keyword(s):  
Protein Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Antiviral Treatment ◽  
Antiviral Drug ◽  
Host Interaction ◽  
Nuclear Egress ◽  
Viral Regulatory Proteins

Human cytomegalovirus (HCMV) expresses a variety of viral regulatory proteins that undergo close interaction with host factors including viral-cellular multiprotein complexes. The HCMV protein kinase pUL97 represents a viral cyclin-dependent kinase ortholog (vCDK) that determines the efficiency of HCMV replication via phosphorylation of viral and cellular substrates. A hierarchy of functional importance of individual pUL97-mediated phosphorylation events has been discussed; however, the most pronounced pUL97-dependent phenotype could be assigned to viral nuclear egress, as illustrated by deletion of the UL97 gene or pharmacological pUL97 inhibition. Despite earlier data pointing to a cyclin-independent functionality, experimental evidence increasingly emphasized the role of pUL97-cyclin complexes. Consequently, the knowledge about pUL97 involvement in host interaction, viral nuclear egress and additional replicative steps led to the postulation of pUL97 as an antiviral target. Indeed, validation experiments in vitro and in vivo confirmed the sustainability of this approach. Consequently, current investigations of pUL97 in antiviral treatment go beyond the known pUL97-mediated ganciclovir prodrug activation and henceforward include pUL97-specific kinase inhibitors. Among a number of interesting small molecules analyzed in experimental and preclinical stages, maribavir is presently investigated in clinical studies and, in the near future, might represent a first kinase inhibitor applied in the field of antiviral therapy.

scholarly journals Understanding the phase separation characteristics of nucleocapsid protein provides a new therapeutic opportunity against SARS-CoV-2

2020 ◽  
Author(s):  
Dan Zhao ◽  
Weifan Xu ◽  
Xiaofan Zhang ◽  
Xiaoting Wang ◽  
Enming Yuan ◽  
...  
Keyword(s):  
Phase Separation ◽  
Drug Target ◽  
Antiviral Drug ◽  
Viral Rna ◽  
N Protein ◽  
Therapeutic Opportunity ◽  
Further Development ◽  
Liquid Liquid Phase Separation

AbstractThe ongoing coronavirus disease 2019 (COVID-19) pandemic has raised an urgent need to develop effective therapeutics against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As a potential antiviral drug target, the nucleocapsid (N) protein of SARS-CoV-2 functions as a viral RNA chaperone and plays vital and multifunctional roles during the life cycle of coronavirus1-3. In this study, we discovered that the N protein of SARS-CoV-2 undergoes liquid-liquid phase separation (LLPS) both in vitro and in vivo, which is further modulated by viral RNA. In addition, we found that, the core component of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2, nsp12, preferentially partitions into the N protein condensates. Moreover, we revealed that, two small molecules, i.e., CVL218 and PJ34, can be used to intervene the N protein driven phase separation and loosen the compact structures of the condensates of the N-RNA-nsp12 complex of SARS-CoV-2. The discovery of the LLPS-mediated interplay between N protein and nsp12 and the corresponding modulating compounds illuminates a feasible way to improve the accessibility of antiviral drugs (e.g., remdesivir) to their targets (e.g., nsp12/RdRp), and thus may provide useful hints for further development of effective therapeutic strategies against SARS-CoV-2.

scholarly journals Rethinking antiviral effects for COVID-19 in clinical studies: early initiation is key to successful treatment

2020 ◽  
Author(s):  
Shoya Iwanami ◽  
Keisuke Ejima ◽  
Kwang Su Kim ◽  
Koji Noshita ◽  
Yasuhisa Fujita ◽  
...  
Keyword(s):  
Symptom Onset ◽  
Clinical Studies ◽  
Randomized Clinical Trials ◽  
Antiviral Treatment ◽  
Antiviral Drug ◽  
Antiviral Effect ◽  
Short Period ◽  
Effective Drugs

AbstractDevelopment of an effective antiviral drug for COVID-19 is a global health priority. Although several candidate drugs have been identified through in vitro and in vivo models, consistent and compelling evidence for effective drugs from clinical studies is limited. The lack of evidence could be in part due to heterogeneity of virus dynamics among patients and late initiation of treatment. We first quantified the heterogeneity of viral dynamics which could be a confounder in compassionate use programs. Second, we demonstrated that an antiviral drug is unlikely to be effective if initiated after a short period following symptom onset. For accurate evaluation of the efficacy of an antiviral drug for COVID-19, antiviral treatment should be initiated before or soon after symptom onset in randomized clinical trials.One Sentence SummaryStudy design to evaluate antiviral effect.

scholarly journals Combination Treatment With Remdesivir and Ivermectin Exerts Highly Synergistic and Potent Antiviral Activity Against Murine Coronavirus Infection

2021 ◽  
Vol 11 ◽  
Author(s):  
Yu Ling Tan ◽  
Kevin S. W. Tan ◽  
Justin Jang Hann Chu ◽  
Vincent T. Chow
Keyword(s):  
Clinical Trials ◽  
Hepatitis Virus ◽  
Antiviral Drug ◽  
Viral Rna ◽  
Murine Hepatitis Virus ◽  
Combination Drug ◽  
Live Virus ◽  
Raw264.7 Macrophages

The recent COVID-19 pandemic has highlighted the urgency to develop effective antiviral therapies against the disease. Murine hepatitis virus (MHV) is a coronavirus that infects mice and shares some sequence identity to SARS-CoV-2. Both viruses belong to the Betacoronavirus genus, and MHV thus serves as a useful and safe surrogate model for SARS-CoV-2 infections. Clinical trials have indicated that remdesivir is a potentially promising antiviral drug against COVID-19. Using an in vitro model of MHV infection of RAW264.7 macrophages, the safety and efficacy of monotherapy of remdesivir, chloroquine, ivermectin, and doxycycline were investigated. Of the four drugs tested, remdesivir monotherapy exerted the strongest inhibition of live virus and viral RNA replication of about 2-log10 and 1-log10, respectively (at 6 µM). Ivermectin treatment showed the highest selectivity index. Combination drug therapy was also evaluated using remdesivir (6 µM) together with chloroquine (15 µM), ivermectin (2 µM) or doxycycline (15 µM) – above their IC50 values and at high macrophage cell viability of over 95%. The combination of remdesivir and ivermectin exhibited highly potent synergism by achieving significant reductions of about 7-log10 of live virus and 2.5-log10 of viral RNA in infected macrophages. This combination also resulted in the lowest cytokine levels of IL-6, TNF-α, and leukemia inhibitory factor. The next best synergistic combination was remdesivir with doxycycline, which decreased levels of live virus by ~3-log10 and viral RNA by ~1.5-log10. These results warrant further studies to explore the mechanisms of action of the combination therapy, as well as future in vivo experiments and clinical trials for the treatment of SARS-CoV-2 infection.

scholarly journals Efficacy of Colistin versus β-Lactams, Aminoglycosides, and Rifampin as Monotherapy in a Mouse Model of Pneumonia Caused by Multiresistant Acinetobacter baumannii

2002 ◽  
Vol 46 (6) ◽  
pp. 1946-1952 ◽  
Author(s):  
A. Montero ◽  
J. Ariza ◽  
X. Corbella ◽  
A. Doménech ◽  
C. Cabellos ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
In Vivo Model ◽  
Carbapenem Resistant ◽  
Bactericidal Efficacy ◽  
Life Threatening ◽  
Resistant Strains ◽  
Immunocompetent Mice ◽  
Moderately Resistant

ABSTRACT The treatment of life-threatening infections due to carbapenem-resistant Acinetobacter baumannii has become a serious challenge for physicians worldwide. Often, only colistin shows in general good in vitro activity against these carbapenem-resistant strains, but its antibacterial efficacy in comparison with the antibiotics most used in clinical practice is not well known. We studied the efficacy of colistin versus those of imipenem, sulbactam, tobramycin, and rifampin in an experimental pneumonia model with immunocompetent mice. We used three strains of A. baumannii corresponding to the main clones (A, D, and E) involved in the outbreaks of our hospital, with different grades of resistance to imipenem (imipenem MICs of 1, 8, and 512 μg/ml, respectively) and to the other antibiotics. The MIC of colistin was 0.5 μg/ml for the three strains. Reduction of log10 CFU/g in lung bacterial counts, clearance of bacteremia, and survival versus results with controls were used as parameters of efficacy. Imipenem and sulbactam (Δlung counts: −5.38 and −4.64 log10 CFU/ml) showed the highest level of bactericidal efficacy in infections by susceptible and even intermediate strains. Tobramycin and rifampin (−4.16 and −5.15 log10 CFU/ml) provided good results against intermediate or moderately resistant strains, in agreement with killing curves and pharmacodynamics. On the contrary, colistin showed the weakest antibacterial effect among the antibiotics tested, both in killing curves and in the in vivo model (−2.39 log10 CFU/ml; P < 0.05). We conclude that colistin did not appear as a good option for treatment of patients with pneumonia due to carbapenem-resistant A. baumannii strains. Other alternatives, including combinations with rifampin, may offer better therapeutic profiles and thus should be studied.

Effects of Heparin Oligosaccharides with High Affinity for Antithrombin III in Experimental Venous Thrombosis

1982 ◽  
Vol 47 (03) ◽  
pp. 244-248 ◽  
Author(s):  
D P Thomas ◽  
Rosemary E Merton ◽  
T W Barrowcliffe ◽  
L Thunberg ◽  
U Lindahl
Keyword(s):  
Antithrombin Iii ◽  
Specific Activity ◽  
High Specific Activity ◽  
Factor Xa ◽  
Blood Levels ◽  
Thrombin Time ◽  
High Affinity ◽  
Very High

SummaryThe in vitro and in vivo characteristics of two oligosaccharide heparin fragments have been compared to those of unfractionated mucosal heparin. A decasaccharide fragment had essentially no activity by APTT or calcium thrombin time assays in vitro, but possessed very high specific activity by anti-Factor Xa assays. When injected into rabbits at doses of up to 80 ¼g/kg, this fragment was relatively ineffective in impairing stasis thrombosis despite producing high blood levels by anti-Xa assays. A 16-18 monosaccharide fragment had even higher specific activity (almost 2000 iu/mg) by chromogenic substrate anti-Xa assay, with minimal activity by APTT. When injected in vivo, this fragment gave low blood levels by APTT, very high anti-Xa levels, and was more effective in preventing thrombosis than the decasaccharide fragment. However, in comparison with unfractionated heparin, the 16-18 monosaccharide fragment was only partially effective in preventing thrombosis, despite producing much higher blood levels by anti-Xa assays.It is concluded that the high-affinity binding of a heparin fragment to antithrombin III does not by itself impair venous thrombogenesis, and that the anti-Factor Xa activity of heparin is only a partial expression of its therapeutic potential.

Tamarix articulata (T. articulata) - An Important Halophytic Medicinal Plant with Potential Pharmacological Properties

2019 ◽  
Vol 20 (4) ◽  
pp. 285-292 ◽  
Author(s):  
Abdullah M. Alnuqaydan ◽  
Bilal Rah
Keyword(s):  
Medicinal Plant ◽  
Biological Activities ◽  
Wide Spectrum ◽  
Biological Properties ◽  
In Vivo Model ◽  
Drug Candidate ◽  
Phytochemical Analysis ◽  
Pharmacological Properties

Background:Tamarix Articulata (T. articulata), commonly known as Tamarisk or Athal in Arabic region, belongs to the Tamaricaece species. It is an important halophytic medicinal plant and a good source of polyphenolic phytochemical(s). In traditional medicines, T. articulata extract is commonly used, either singly or in combination with other plant extracts against different ailments since ancient times.Methods:Electronic database survey via Pubmed, Google Scholar, Researchgate, Scopus and Science Direct were used to review the scientific inputs until October 2018, by searching appropriate keywords. Literature related to pharmacological activities of T. articulata, Tamarix species, phytochemical analysis of T. articulata, biological activities of T. articulata extracts. All of these terms were used to search the scientific literature associated with T. articulata; the dosage of extract, route of administration, extract type, and in-vitro and in-vivo model.Results:Numerous reports revealed that T. articulata contains a wide spectrum of phytochemical(s), which enables it to have a wide window of biological properties. Owing to the presence of high content of phytochemical compounds like polyphenolics and flavonoids, T. articulata is a potential source of antioxidant, anti-inflammatory and antiproliferative properties. In view of these pharmacological properties, T. articulata could be a potential drug candidate to treat various clinical conditions including cancer in the near future.Conclusion:In this review, the spectrum of phytochemical(s) has been summarized for their pharmacological properties and the mechanisms of action, and the possible potential therapeutic applications of this plant against various diseases discussed.

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