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Journal of Pharmaceutical Sciences Apr 2024Ribavirin, an antiretroviral agent targeting the hepatitis C virus, causes male reproductive toxicity. This study investigated the mechanism of ribavirin transport at...
Ribavirin, an antiretroviral agent targeting the hepatitis C virus, causes male reproductive toxicity. This study investigated the mechanism of ribavirin transport at the blood-testis barrier (BTB). In vivo mouse integration plot analysis after intravenous administration revealed that the net influx clearance of [H]ribavirin in the testis was 3.6-fold greater than that of [C]D-mannitol, a paracellular transport marker, implying transcellular transport of ribavirin across the BTB. Moreover, [H]ribavirin uptake by TM4 cells, mouse-derived Sertoli cells, was time- and concentration-dependent, with a K value of 2.49 mM. S-[(4-nitrophenyl)methyl]-6-thioinosine, an inhibitor of Na-independent equilibrative nucleoside transporters (ENTs), strongly inhibited the [H]ribavirin uptake by TM4 cells at 100 µM. Compared to the uptake of [H]adenosine, a typical endogenous nucleoside, [H]ribavirin uptake was relatively similar to ENT2 transport. [H]Ribavirin uptake was also observed in mouse ENT2-expressing Xenopus laevis oocytes, and gene silencing via the transfection of ENT2 small interfering RNA significantly reduced the [H]ribavirin transport into TM4 cells by 13%. Taken together, these results suggest that ENT2 partially contributes to ribavirin transport at the BTB.
PubMed: 38679231
DOI: 10.1016/j.xphs.2024.04.020 -
Viruses Apr 2024is the largest and most diverse genus in the family Peribunyaviridae. Orthobunyaviruses are widely distributed globally and pose threats to human and animal health....
is the largest and most diverse genus in the family Peribunyaviridae. Orthobunyaviruses are widely distributed globally and pose threats to human and animal health. Ebinur Lake virus (EBIV) is a newly classified Orthobunyavirus detected in China, Russia, and Kenya. This study explored the antiviral effects of two broad-spectrum antiviral drugs, favipiravir and ribavirin, in a BALB/c mouse model. Favipiravir significantly improved the clinical symptoms of infected mice, reduced viral titer and RNA copies in serum, and extended overall survival. The median survival times of mice in the vehicle- and favipiravir-treated groups were 5 and 7 days, respectively. Favipiravir significantly reduced virus titers 10- to 100-fold in sera at all three time points compared to vehicle-treated mice. And favipiravir treatment effectively reduced the virus copies by approximately 10-fold across the three time points, relative to vehicle-treated mice. The findings expand the antiviral spectrum of favipiravir for orthobunyaviruses in vivo.
Topics: Animals; Pyrazines; Amides; Antiviral Agents; Mice, Inbred BALB C; Mice; Disease Models, Animal; Viral Load; Female; Ribavirin; RNA Virus Infections
PubMed: 38675972
DOI: 10.3390/v16040631 -
Viruses Apr 2024This review article describes the current knowledge about the use of antiviral chemotherapeutics in avian species, such as farm poultry and companion birds. Specific... (Review)
Review
This review article describes the current knowledge about the use of antiviral chemotherapeutics in avian species, such as farm poultry and companion birds. Specific therapeutics are described in alphabetical order including classic antiviral drugs, such as acyclovir, abacavir, adefovir, amantadine, didanosine, entecavir, ganciclovir, interferon, lamivudine, penciclovir, famciclovir, oseltamivir, ribavirin, and zidovudine, repurposed drugs, such as ivermectin and nitazoxanide, which were originally used as antiparasitic drugs, and some others substances showing antiviral activity, such as ampligen, azo derivates, docosanol, fluoroarabinosylpyrimidine nucleosides, and novel peptides. Most of them have only been used for research purposes and are not widely used in clinical practice because of a lack of essential pharmacokinetic and safety data. Suggested future research directions are also highlighted.
Topics: Antiviral Agents; Animals; Birds; Virus Diseases; Bird Diseases; Poultry
PubMed: 38675934
DOI: 10.3390/v16040593 -
Hematology Reports Mar 2024We report a patient with hemophilia A who underwent partial splenic embolization (PSE) for severe thrombocytopenia secondary to portal hypertension-induced splenomegaly,...
We report a patient with hemophilia A who underwent partial splenic embolization (PSE) for severe thrombocytopenia secondary to portal hypertension-induced splenomegaly, resulting in a stable long-term quality of life. The patient was diagnosed with hemophilia A and unfortunately contracted human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) from blood products. He subsequently developed progressive splenomegaly due to portal hypertension from chronic HCV, resulting in severe thrombocytopenia. PSE was performed because he had occasional subcutaneous bleeding and needed to start interferon (IFN) and ribavirin (RBV) treatment for curing his HCV infection at that time. His platelet counts increased, and no serious adverse events were observed. Currently, he continues to receive outpatient treatment, regular factor VIII (FVIII) replacement therapy for hemophilia A, and antiretroviral therapy for HIV infection. Vascular embolization has been reported to be an effective and minimally invasive treatment for bleeding in hemophilia patients. PSE also provided him with a stable quality of life without the side effects of serious infections and thrombocytopenia relapses. We conclude that PSE is a promising therapeutic option for patients with hemophilia A.
PubMed: 38651448
DOI: 10.3390/hematolrep16020019 -
Frontiers in Microbiology 2024Arenaviruses belonging to the Arenaviridae family, genus mammarenavirus, are enveloped, single-stranded RNA viruses primarily found in rodent species, that cause severe... (Review)
Review
Arenaviruses belonging to the Arenaviridae family, genus mammarenavirus, are enveloped, single-stranded RNA viruses primarily found in rodent species, that cause severe hemorrhagic fever in humans. With high mortality rates and limited treatment options, the search for effective antivirals is imperative. Current treatments, notably ribavirin and other nucleoside inhibitors, are only partially effective and have significant side effects. The high lethality and lack of treatment, coupled with the absence of vaccines for all but Junín virus, has led to the classification of these viruses as Category A pathogens by the Centers for Disease Control (CDC). This review focuses on entry inhibitors as potential therapeutics against mammarenaviruses, which include both New World and Old World arenaviruses. Various entry inhibition strategies, including small molecule inhibitors and neutralizing antibodies, have been explored through high throughput screening, genome-wide studies, and drug repurposing. Notable progress has been made in identifying molecules that target receptor binding, internalization, or fusion steps. Despite promising preclinical results, the translation of entry inhibitors to approved human therapeutics has faced challenges. Many have only been tested in or animal models, and a number of candidates showed efficacy only against specific arenaviruses, limiting their broader applicability. The widespread existence of arenaviruses in various rodent species and their potential for their zoonotic transmission also underscores the need for rapid development and deployment of successful pan-arenavirus therapeutics. The diverse pool of candidate molecules in the pipeline provides hope for the eventual discovery of a broadly effective arenavirus antiviral.
PubMed: 38650890
DOI: 10.3389/fmicb.2024.1382953 -
Frontiers in Chemistry 2024Theophylline, a nitrogen-containing heterocycle, serves as a promising focal point for medicinal researchers aiming to create derivatives with diverse pharmacological...
Exploring theophylline-1,2,4-triazole tethered -phenylacetamide derivatives as antimicrobial agents: unraveling mechanisms via structure-activity relationship, validation, and insights.
Theophylline, a nitrogen-containing heterocycle, serves as a promising focal point for medicinal researchers aiming to create derivatives with diverse pharmacological applications. In this work, we present an improved synthetic method for a range of theophylline-1,2,4-triazole-S-linked N-phenyl acetamides (4a‒g) utilizing ultrasound-assisted synthetic approach. The objective was to assess the effectiveness of synthesized theophylline-1,2,4-triazoles (4a‒g) as inhibitors of HCV serine protease and as antibacterial agents against QB-928 and AB-274. Theophylline-1,2,4-triazoles were obtained in good to excellent yields (69%-95%) in a shorter time than conventional approach. 4-Chlorophenyl moiety containing theophylline-1,2,4-triazole 4c displayed significantly higher inhibitory activity against HCV serine protease enzyme (IC = 0.015 ± 0.25 mg) in comparison to ribavirin (IC = 0.165 ± 0.053 mg), but showed excellent binding affinity (-7.55 kcal/mol) with the active site of serine protease, better than compound 4c (-6.90 kcal/mol) as well as indole-based control compound 5 (-7.42 kcal/mol). In terms of percentage inhibition of serine protease, 2-chlorophenyl compound 4b showed the maximum percentage inhibition (86%), more than that of the 3,4-dichlorophenyl compound 4c (76%) and ribavirin (81%). 3,4-Dimethylphenyl-based theophylline-1,2,4-triazole 4g showed the lowest minimum inhibitory concentration (MIC = 0.28 ± 0.50 μg/mL) against the bacterial strain as compared to the standard drug penicillin (MIC = 1 ± 1.50 μg/mL). The other 4-methylphenyl theophylline-1,2,4-triazole 4e (MIC = 0.20 ± 0.08 μg/mL) displayed the most potent antibacterial potential against in comparison to the standard drug penicillin (MIC = 2.4 ± 1.00 μg/mL). Molecular docking studies further helped in an extensive understanding of all of the interactions between compounds and the enzyme active site, and DFT studies were also employed to gain insights into the molecular structure of the synthesized compounds. The results indicated that theophylline-linked triazole derivatives 4b and 4c showed promise as leading contenders in the fight against the HCV virus. Moreover, compounds 4e and 4g demonstrated potential as effective chemotherapeutic agents against and , respectively. To substantiate these findings, additional studies and clinical trials are imperative, laying the groundwork for their integration into future drug design and development.
PubMed: 38645776
DOI: 10.3389/fchem.2024.1372378 -
Revista Espanola de Quimioterapia :... Jun 2024
Topics: Humans; Male; Middle Aged; Aminoisobutyric Acids; Antiviral Agents; Benzimidazoles; Cyclopropanes; Drug Therapy, Combination; Hepacivirus; Hepatitis C, Chronic; Lactams, Macrocyclic; Leucine; Proline; Pyrrolidines; Quinoxalines; Ribavirin; Salvage Therapy; Sulfonamides
PubMed: 38638059
DOI: 10.37201/req/020.2024 -
Saudi Pharmaceutical Journal : SPJ :... May 2024Skin 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...
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 and , 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 studies are required to confirm its safety and effectiveness.
PubMed: 38601973
DOI: 10.1016/j.jsps.2024.102058 -
European Journal of Case Reports in... 2024This report presents the influence of immunosuppression by new rheumatological therapies on hepatitis E virus infection in a 54-year-old male patient with an...
BACKGROUND
This report presents the influence of immunosuppression by new rheumatological therapies on hepatitis E virus infection in a 54-year-old male patient with an anti-synthetase syndrome and treatment with methotrexate and rituximab.
CASE DESCRIPTION
The patient arrived at the Emergency Department with epigastric pain, vomiting and dark urine. Initial examination revealed signs of inflammation and hepatic dysfunction. Subsequent laboratory tests and imaging confirmed acute hepatitis E infection in the context of recent initiation of rituximab therapy. Despite initial suspicion of pancreatitis, subsequent investigations ruled out pancreatic involvement. Treatment with ribavirin, along with supportive measures, led to significant clinical improvement with resolution of jaundice, ascites, and oedema.
CONCLUSIONS
This case underscores the importance of considering hepatitis E in patients with autoimmune conditions, especially when initiating immunosuppressive therapies, a situation that is not well described in scientific literature and is increasingly common, necessitating proper recognition.
LEARNING POINTS
Suspect hepatitis E virus infection in the presence of persistent liver failure of unknown cause.Recognise immunosuppression as a cause of increased risk of hepatitis E infection.Take into account the repercussions of immunosuppressive therapy such as rituximab regarding hepatitis E infections in immunocompromised patients.
PubMed: 38584892
DOI: 10.12890/2024_004378 -
Frontiers in Microbiology 2024SARS-CoV-2 isolates of a given clade may contain low frequency genomes that encode amino acids or deletions which are typical of a different clade.
INTRODUCTION
SARS-CoV-2 isolates of a given clade may contain low frequency genomes that encode amino acids or deletions which are typical of a different clade.
METHODS
Here we use high resolution ultra-deep sequencing to analyze SARS-CoV-2 mutant spectra.
RESULTS
In 6 out of 11 SARS-CoV-2 isolates from COVID-19 patients, the mutant spectrum of the spike (S)-coding region included two or more amino acids or deletions, that correspond to discordant viral clades. A similar observation is reported for laboratory populations of SARS-CoV-2 USA-WA1/2020, following a cell culture infection in the presence of remdesivir, ribavirin or their combinations. Moreover, some of the clade-discordant genome residues are found in the same haplotype within an amplicon.
DISCUSSION
We evaluate possible interpretations of these findings, and reviewed precedents for rapid selection of genomes with multiple mutations in RNA viruses. These considerations suggest that intra-host evolution may be sufficient to generate minority sequences which are closely related to sequences typical of other clades. The results provide a model for the origin of variants of concern during epidemic spread─in particular Omicron lineages─that does not require prolonged infection, involvement of immunocompromised individuals, or participation of intermediate, non-human hosts.
PubMed: 38559344
DOI: 10.3389/fmicb.2024.1358258