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Hong-Jie Li, Dong-Sheng Gao, Yong-Tao Li, Yong-Sheng Wang, Hong-Ying Liu, Jun Zhao
Porcine epidemic diarrhea virus (PEDV), a member of the Coronaviridae family, causes acute diarrhea, vomiting, dehydration, and high mortality rates in neonatal piglets. Severe outbreaks of PEDV variants have re-emerged in Asia and North America since 2010, causing tremendous economic losses to the swine industry. The lack of effective therapeutic treatment promotes the research for new antivirals. Lithium chloride (LiCl) has been reported as a potential antiviral drug for certain viruses. In this study, the antiviral effect of LiCl on PEDV in Vero cells was evaluated...
March 5, 2018: Research in Veterinary Science
D Czock, V Schwenger, D Kindgen-Milles, M Joannidis, S John, M Schmitz, A Jörres, A Zarbock, M Oppert, J T Kielstein, C Willam
BACKGROUND: Many anti-infective drugs require dose adjustments in critically ill patients with acute kidney injury (AKI) and renal replacement therapy, in order to achieve adequate therapeutic drug concentrations. OBJECTIVES: The fundamental pharmacokinetic and pharmacodynamic principles of drug dose adjustment are presented. Recommendations on anti-infective drug dosage in intensive care are provided. MATERIALS AND METHODS: We established dose recommendations of selected anti-infective drugs based on information in the summary of product characteristics, published studies and recommendations, pharmacokinetic and pharmacodynamic considerations, and the experience and expert opinion of the authors...
March 15, 2018: Medizinische Klinik, Intensivmedizin und Notfallmedizin
Andrea Galli, Helene Mens, Judith M Gottwein, Jan Gerstoft, Jens Bukh
Ribavirin (RBV) is a broad-spectrum antiviral active against a wide range of RNA viruses. Despite having been used for decades in the treatment of chronic hepatitis C virus (HCV) infection, the precise mechanism of action of RBV is unknown. In other viruses, it inhibits propagation by increasing the rate of G-to-A and C-to-U transitions. Here, we utilized the J6/JFH1 HCV cell-culture system to investigate whether RBV inhibits HCV through the same mechanism. Infected Huh7.5 cells were treated with increasing concentrations of RBV or its phosphorylated forms...
March 15, 2018: Scientific Reports
Jiantao Zhang, Yanmei Hu, Christopher Foley, Yuanxiang Wang, Rami Musharrafieh, Shuting Xu, Yongtao Zhang, Chunlong Ma, Christopher Hulme, Jun Wang
Influenza viruses are respiratory pathogens that are responsible for seasonal influenza and sporadic influenza pandemic. The therapeutic efficacy of current influenza vaccines and small molecule antiviral drugs is limited due to the emergence of multidrug-resistant influenza viruses. In response to the urgent need for the next generation of influenza antivirals, we utilized a fast-track drug discovery platform by exploring multi-component reaction products for antiviral drug candidates. Specifically, molecular docking was applied to screen a small molecule library derived from the Ugi-azide four-component reaction methodology for inhibitors that target the influenza polymerase PAC -PB1N interactions...
March 15, 2018: Scientific Reports
Aida Siyahian, Saad Ullah Malik, Adeela Mushtaq, Carol L Howe, Aneela Majeed, Tirdad Zangeneh, Samar Iftikhar, Shahid Habib, Umar Zahid, Irbaz Bin Riaz, Zabih Warraich, Warda Faridi, Faiz Anwer
Patients undergoing allogenic hematopoietic stem cell transplantation (allo-HSCT) are at a very high risk of hepatitis B virus reactivation (HBVr). Lamivudine is commonly used as prophylaxis against HBVr in high risk patients undergoing allo-HSCT. Unfortunately, its efficacy is diminishing due to the development of HBV mutant drug resistant strains. With the availability of newer antiviral agents like Entecavir, Telbivudine, Adefovir and Tenofovir, it is important to assess their role in HBVr prophylaxis. A comprehensive search of seven databases was performed to evaluate efficacy of antiviral prophylaxis against HBVr in allo-HSCT patients (PubMed/Medline, Embase, Scopus, Cochrane Library, Web of Science, CINAHL, and ClinicalTrials...
March 12, 2018: Biology of Blood and Marrow Transplantation
Alexandre Karras
Cryoglobulins are immunoglobulins that undergo reversible precipitation at low temperatures. They can induce systemic vasculitis, characterized by purpuric cutaneous lesions, arthritis, peripheral neuropathy, hypocomplementemia and glomerular disease. Renal pathology reveals membranoproliferative glomerulonephritis, with particularly intense mesangial cell proliferation and infiltration by macrophages, associated with intracapillary thrombi. This renal disease presents as a nephritic syndrome, with heavy proteinuria, haematuria severe hypertension and rapidly progressive kidney failure that can lead to end-stage renal disease...
March 12, 2018: Néphrologie & Thérapeutique
Lin Cao, Jizheng Chen, Yaxin Wang, Yuting Yang, Jie Qing, Zihe Rao, Xinwen Chen, Zhiyong Lou
Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. Although several HCV protease/polymerase inhibitors were recently approved by U.S. FDA, the combination of antivirals targeting multiple processes of HCV lifecycle would optimize anti-HCV therapy and against potential drug-resistance. Viral entry is an essential target step for antiviral development, but FDA-approved HCV entry inhibitor remains exclusive. Here we identify serotonin 2A receptor (5-HT2A R) is a HCV entry factor amendable to therapeutic intervention by a chemical biology strategy...
March 14, 2018: Protein & Cell
Antonios Drakopoulos, Christina Tzitzoglaki, Kelly McGuire, Anja Hoffmann, Athina Konstantinidi, Dimitrios Kolokouris, Chunlong Ma, Kathrin Freudenberger, Johanna Hutterer, Günter Gauglitz, Jun Wang, Michaela Schmidtke, David D Busath, Antonios Kolocouris
Recently, the binding kinetics of a ligand-target interaction, such as the residence time of a small molecule on its protein target, are seen as increasingly important for drug efficacy. Here, we investigate these concepts to explain binding and proton blockage of rimantadine variants bearing progressively larger alkyl groups to influenza A virus M2 wild type (WT) and M2 S31N protein proton channel. We showed that resistance of M2 S31N to rimantadine analogues compared to M2 WT resulted from their higher k off rates compared to the k on rates according to electrophysiology (EP) measurements...
March 8, 2018: ACS Medicinal Chemistry Letters
Ivan Schietroma, Giuseppe Corano Scheri, Claudia Pinacchio, Maura Statzu, Arnolfo Petruzziello, Vincenzo Vullo
Introduction: Globally, between 64 and 103 million people are chronically infected with Hepatitis C virus (HCV), with more than 4.6 million people in the United States and is associated with more than 15.000 deaths annually. Chronic infection can result in cirrhosis and hepatocellular carcinoma. Explanation: Epidemiological studies have indicated that persistent infection with hepatitis C virus (HCV) is a major risk for the development of hepatocellular carcinoma (HCC), mainly through chronic inflammation, cell deaths, and proliferation...
2018: Open Virology Journal
Carin K Ingemarsdotter, Jingwei Zeng, Ziqi Long, Andrew M L Lever, Julia C Kenyon
BACKGROUND: NSC260594, a quinolinium derivative from the NCI diversity set II compound library, was previously identified in a target-based assay as an inhibitor of the interaction between the HIV-1 (ψ) stem-loop 3 (SL3) RNA and Gag. This compound was shown to exhibit potent antiviral activity. Here, the effects of this compound on individual stages of the viral lifecycle were examined by qRT-PCR, ELISA and Western blot, to see if its actions were specific to the viral packaging stage...
March 14, 2018: Retrovirology
Xiujuan Zhang, Yuanmei Zhu, Hao Hu, Senyan Zhang, Pengfei Wang, Huihui Chong, Jinsheng He, Xinquan Wang, Yuxian He
The deep hydrophobic pocket of HIV-1 gp41 has been considered a drug target, but short-peptides targeting this site usually lack potent antiviral activity. By applying the M-T hook structure, we previously generated highly potent short-peptide fusion inhibitors that specifically targeted the pocket site, such as MT-SC22EK, HP23L, and LP-11. Here, the crystal structures of HP23L and LP-11 bound to the target mimic peptide N36 demonstrated the critical intrahelical and interhelical interactions, especially verifying that the hook-like conformation was finely adopted while the methionine residue was replaced by the oxidation-less prone residue leucine, and that addition of an extra glutamic acid significantly enhanced the binding and inhibitory activities...
2018: Frontiers in Cellular and Infection Microbiology
Boshi Huang, Xinhao Liu, Ye Tian, Dongwei Kang, Zhongxia Zhou, Dirk Daelemans, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu
In the present work, we described the synthesis, antiviral profiles and metabolic stability in human plasma of compound 6, a potential carbonate prodrug of HIV-1 NNRTI drug candidate RDEA427. Compound 6 was found to inhibit the wild-type (WT) and K103N/Y181C double mutant HIV-1 strains at nano- and submicromolar concentrations, respectively. Moreover, it displayed potent HIV-1 reverse transcriptase inhibitory activity (IC50  = 0.264 μM). Further stability test in human plasma showed that 6 could release its active form RDEA427 in a linearly time-independent manner, possibly acting as a potential prodrug...
March 5, 2018: Bioorganic & Medicinal Chemistry Letters
Joy Y Feng
Nucleoside and nucleotide analogs have played significant roles in antiviral therapies and are valued for their impressive potency and high barrier to resistance. They have been approved for treatment of herpes simplex virus-1, HIV, HBV, HCV, and influenza, and new drugs are being developed for the treatment of RSV, Ebola, coronavirus MERS, and other emerging viruses. However, this class of compounds has also experienced a high attrition rate in clinical trials due to toxicity. In this review, we discuss the utility of different biochemical and cell-based assays and provide recommendations for assessing toxicity liability before entering animal toxicity studies...
January 2018: Antiviral Chemistry & Chemotherapy
Han Gao, Gang Li, Hong-Xiang Lou
Exploration of structurally novel natural products greatly facilitates the discovery of biologically active pharmacophores that are biologically validated starting points for the development of new drugs. Endophytes that colonize the internal tissues of plant species, have been proven to produce a large number of structurally diverse secondary metabolites. These molecules exhibit remarkable biological activities, including antimicrobial, anticancer, anti-inflammatory and antiviral properties, to name but a few...
March 13, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Ornella Franzese, Maria Luisa Barbaccia, Enzo Bonmassar, Grazia Graziani
Since the introduction of highly active antiretroviral therapy more than 2 decades ago, HIV-related deaths have dramatically decreased and HIV infection has become a chronic disease. Due to the inability of antiretroviral drugs to eradicate the virus, treatment of HIV infection requires a systemic lifelong therapy. However, even when successfully treated, HIV patients still show increased incidence of age-associated co-morbidities compared with uninfected individuals. Virus- induced immunosenescence, a process characterized by a progressive decline of immune system function, contributes to the premature ageing observed in HIV patients...
March 13, 2018: Chemotherapy
Marta Runowska, Dominik Majewski, Karolina Niklas, Mariusz Puszczewicz
Chikungunya virus (CHIKV) is an arthropod-borne alphavirus, transmitted by Aedes aegypti and Aedes albopictus mosquitoes. It is responsible for a febrile illness, typically accompanied by maculopapular rash and severe, incapacitating arthralgia. The disease, although generally self-limiting, frequently evolves into a long-lasting, debilitating rheumatic disorder, which shares many clinical features with rheumatoid arthritis (RA). The underlying mechanism by which CHIKV induces persistent arthritis remains under investigation, however, currently, attention is drawn to the fact, that chronic chikungunya (CHIK) and RA have many common cellular and cytokine pathways involved in their pathogenesis...
March 2, 2018: Clinical and Experimental Rheumatology
Omid Aghajanzadeh, Mojtaba Sharifi, Shabnam Tashakori, Hassan Zohoor
A new robust adaptive controller is developed for the control of the hepatitis B virus (HBV) infection inside the body. The non-linear HBV model has three state variables: uninfected cells, infected cells and free viruses. A control law is designed for the antiviral therapy such that the volume of infected cells and the volume of free viruses are decreased to their desired values which are zero. One control input represents the efficiency of drug therapy in inhibiting viral production and the other control input represents the efficiency of drug therapy in blocking new infection...
April 2018: IET Systems Biology
Simin Dashti-Khavidaki, Hossein Khalili, Mohsen Nasiri-Toosi
There was no report of nephrotoxicity during clinical trials assessed sofosbuvir for treatment of hepatitis C (HCV) infection. This may be due to excluding patients with severe kidney dysfunction, as a main population at risk for drug-induced nephrotoxicity from these studies. There are some reports of acute kidney injury (AKI) possibly related to sofosbuvir-containing treatments from real-life experiences. Areas covered: Available data on epidemiology, type, and possible risk factors for nephrotoxicity of sofosbuvir-containing treatment are reviewed...
March 14, 2018: Expert Review of Clinical Pharmacology
Takashi Azuma, Kana Otomo, Mari Kunitou, Mai Shimizu, Kaori Hosomaru, Shiori Mikata, Yoshiki Mino, Tetsuya Hayashi
The fate of pharmaceuticals after discharged from hospital into wastewater was clarified experimentally by using a new lab-scale conventional activated sludge (CAS) treatment reactor. The 43 target compounds belong to nine therapeutic classes (antivirals, antibacterials, anticancer drugs, psychotropics, antihypertensives, analgesic-antipyretics, contrast media, herbal medicines, and phytoestrogens) were selected with inclusion of 16 newly estimated compounds. The efficiency of the present reactor was estimated by comparing the reaction rate constant of the solid-water partition coefficients (log Kd ) between liquid and solid samples and half-life during 48-h experiment obtained by using hospital effluents with those obtained by using STP wastewater...
March 12, 2018: Environmental Science and Pollution Research International
Mitsutaka Kitano, Myra Hosmillo, Edward Emmott, Jia Lu, Ian Goodfellow
Human norovirus (HuNoV) is a major cause of nonbacterial gastroenteritis worldwide yet, despite their impact on society, vaccines and antivirals are currently lacking. A HuNoV replicon system has been widely applied to the evaluation of antiviral compounds and has thus accelerated the process of drug discovery against HuNoV infection. Rupintrivir, an irreversible inhibitor of the human rhinovirus 3C protease, has been reported to inhibit the replication of the Norwalk virus replicon via the inhibition of the norovirus protease...
March 12, 2018: Antimicrobial Agents and Chemotherapy
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