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Anthony Markham, Susan J Keam
Ascletis has developed danoprevir (Ganovo® ), an orally-administered hepatitis C virus NS3 protease inhibitor, as a treatment for hepatitis C. Based on positive results in phase II and phase III trials in patients with hepatitis C, danoprevir, in combination with ritonavir, peginterferon alfa and ribavirin was recently approved for marketing in China for the treatment of treatment-naive patients with non-cirrhotic genotype 1b chronic hepatitis C. This article summarizes the milestones in the development of danoprevir leading to this first approval...
August 16, 2018: Drugs
Vijay Gayam, Amrendra Kumar Mandal, Mazin Khalid, Osama Mukhtar, Arshpal Gill, Pavani Garlapati, Benjamin Tiongson, Jagannath Sherigar, Mohammed Mansour, Smruti Mohanty
Background: Low serum vitamin D levels in chronic hepatitis C (CHC) is associated with advanced liver fibrosis; and there remains an imprecise relationship with the treatment response based on the vitamin D levels. Previous studies have shown conflicting results on the vitamin D levels, and association with treatment response in CHC treated with interferon-based regimens. Methods: Patients with CHC treated with direct-acting antivirals (DAAs) between January 2016 and December 2017 in the community clinic setting were retrospectively analyzed...
August 2018: Gastroenterology Research
I Tong Mak, Joanna J Chmielinska, Christopher F Spurney, William B Weglicki, Jay H Kramer
Chronic effects of a combination antiretroviral therapy (cART = tenofovir/emtricitatine + atazanavir/ritonavir) on systemic and cardiac oxidative stress/injury in HIV-1 transgenic (Tg) rats and protection by Mg-supplementation were assessed. cART (low doses) elicited no significant effects in normal rats, but induced time-dependent oxidative/nitrosative stresses: 2.64-fold increased plasma 8-isoprostane, 2.0-fold higher RBC oxidized glutathione (GSSG), 3.2-fold increased plasma 3-nitrotyrosine (NT), and 3-fold elevated basal neutrophil superoxide activity in Tg rats...
August 15, 2018: International Journal of Molecular Sciences
Kunjal Patel, Jane Lindsey, Konstantia Angelidou, Grace Aldrovandi, Paul Palumbo
OBJECTIVE: To estimate the long-term metabolic effects of initiating a lopinavir/ritonavir (LPV/r)-based regimen as first-line therapy for HIV-infected children less than three years of age in resource-limited settings. DESIGN: Prospective cohort study after conclusion of the P1060 randomized clinical trials ( Identifier: NCT00307151), with an overall follow-up of seven years. METHODS: Longitudinal total cholesterol and triglyceride measures were compared between 222 and 227 children randomized to initiate LPV/r- and NVP-based regimens respectively...
August 9, 2018: AIDS
Anyan Xie, René J Robles, Samiran Mukherjee, Haohai Zhang, Linda Feldbrügge, Eva Csizmadia, Yan Wu, Keiichi Enjyoji, Alan C Moss, Leo E Otterbein, Francisco J Quintana, Simon C Robson, Maria Serena Longhi
In Crohn's disease, pathogenic Th17-cells express low levels of CD39 ectonucleotidase and are refractory to the immunosuppressive effects of unconjugated bilirubin (UCB), an endogenous ligand for aryl-hydrocarbon-receptor (AhR). This resistance to AhR ligation might be associated with alterations in responses to hypoxia. Limited exposure to hypoxia appears beneficial in acute tissue injury. However, in protracted inflammation, hypoxemia may paradoxically result in Th17-cell activation. We report here that in vitro exposure of Th17-cells from Crohn's disease patients to hypoxia limits responsiveness to AhR stimulation by UCB, as reflected by lower CD39 levels...
August 8, 2018: Journal of Autoimmunity
Muhammad Sajawal Ali, Shravan Kooragayalu, Benjamin I Mba, Farah Ciftci Olsen
No abstract text is available yet for this article.
August 8, 2018: Archivos de Bronconeumología
J A Perez-Molina, F Pulido, S Di Giambenedetto, E Ribera, S Moreno, J Zamora, C Coscia, B Alejos, J Pitch, J M Gatell, A De Luca, J R Arribas
Background: Dual therapy (DT) with a ritonavir-boosted PI (PI/r) plus lamivudine has proven non-inferior (12% margin) to triple therapy (TT) with PI/r plus two nucleos(t)ide reverse transcriptase inhibitors [N(t)RTIs] in four clinical trials. It remains unclear whether DT is non-inferior based on the US FDA endpoint (virological failure with a margin of 4%) or in specific subgroups. Methods: We performed a systematic search (January 1990 to March 2017) of randomized controlled trials that compared switching of maintenance ART from TT to DT...
August 3, 2018: Journal of Antimicrobial Chemotherapy
Cecile Cames, Lea Pascal, Aissatou Ba, Hélène Mbodj, Baly Ouattara, Ndeye-Fatou Diallo, Philippe Msellati, Ngagne Mbaye, Haby Sy Signate, Stephane Blanche, Aminata Diack
BACKGROUND: The long-term benefits of antiretroviral treatment (ART) are associated with metabolic complications, especially lipodystrophy, which has been well described among HIV-infected adults and children on ART in developed settings. Specifically, stavudine, and to a lesser extent zidovudine and protease inhibitors (PI), have been consistently implicated in the development of lipodystrophy. In 2006, following advice from the WHO, Senegal began phasing out stavudine from first-line ART...
August 6, 2018: BMC Infectious Diseases
Daniela Machová, Eva Koziolová, Petr Chytil, Kristýna Venclíková, Tomáš Etrych, Olga Janoušková
Ritonavir (RIT) is a widely used antiviral drug that acts as an HIV protease inhibitor with emerging potential in anticancer therapies. RIT causes inhibition of P-glycoprotein, which plays an important role in multidrug resistance (MDR) in cancer cells when overexpressed. Moreover, RIT causes mitochondrial dysfunction, leading to decreased ATP production and reduction of caveolin I expression, which can affect cell migration and tumor progression. To increase its direct antitumor activity, decrease severe side effects induced by the use of free RIT and improve its pharmacokinetics, ritonavir 5-methyl-4-oxohexanoate (RTV) was synthesized and conjugated to a tumor-targeted polymer carrier based on a N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer...
July 31, 2018: European Journal of Pharmaceutics and Biopharmaceutics
Noah Machuki Onchieku, Reagan Mogire, Loise Ndung'u, Peter Mwitari, Francis Kimani, Damaris Matoke-Muhia, Daniel Kiboi, Gabriel Magoma
Retroviral protease inhibitors (RPIs) such as lopinavir (LP) and saquinavir (SQ) are active against Plasmodium parasites. However, the exact molecular target(s) for these RPIs in the Plasmodium parasites remains poorly understood. We hypothesised that LP and SQ suppress parasite growth through inhibition of aspartyl proteases. Using reverse genetics approach, we embarked on separately generating knockout (KO) parasite lines lacking Plasmepsin 4 (PM4), PM7, PM8, or DNA damage-inducible protein 1 (Ddi1) in the rodent malaria parasite Plasmodium berghei ANKA...
2018: PloS One
Lucia Taramasso, Paola Tatarelli, Elena Ricci, Giordano Madeddu, Barbara Menzaghi, Nicola Squillace, Giuseppe Vittorio De Socio, Canio Martinelli, Roberto Gulminetti, Paolo Maggi, Giancarlo Orofino, Francesca Vichi, Antonio Di Biagio, Paolo Bonfanti
BACKGROUND: Dyslipidemia represents a significant non-infectious comorbidity among people living with HIV. The aim of this study is to evaluate the impact on lipid profile of switches from an efavirenz (EFV) or protease inhibitor/ritonavir (PI/r)-based regimen to a rilpivirine (RPV) or a once-daily integrase inhibitor-based regimen. METHODS: We analyzed data from SCOLTA prospective database. All patients with HIV-RNA < 50 copies/ml in therapy with two NRTI + EFV or PI/r were included if they switched from EFV to dolutegravir (group EFV-DTG), elvitegravir (EFV-EVG), or RPV (EFV-RPV) and from PI/r to DTG (PI/r-DTG), PI/r to EVG (PI/r-EVG), or PI/r to RPV (PI/r-RPV)...
July 31, 2018: BMC Infectious Diseases
Jennifer A Thompson, Cissy Kityo, David Dunn, Anne Hoppe, Emmanuel Ndashimye, James Hakim, Andrew Kambugu, Joep J van Oosterhout, Jose Arribas, Peter Mugyenyi, A Sarah Walker, Nicholas I Paton
Background: Limited viral load (VL) testing in HIV-infected individuals on treatment in low-income countries often results in late detection of treatment failure. The impact of remaining on failing second-line, protease inhibitor (PI) containing regimens is unclear. Methods: We retrospectively tested VL from 2,164 stored plasma samples from 386 patients randomised to receive PI-monotherapy (ritonavir-boosted lopinavir, after initial PI+raltegravir induction) in the EARNEST trial...
July 28, 2018: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Raza M Alvi, Anne M Neilan, Noor Tariq, Magid Awadalla, Maryam Afshar, Dahlia Banerji, Adam Rokicki, Connor Mulligan, Virginia A Triant, Markella V Zanni, Tomas G Neilan
BACKGROUND: Incident heart failure (HF) is increased in persons with human immunodeficiency virus (PHIV). Protease inhibitors (PIs) are associated with adverse cardiac remodeling and vascular events; however, there are no data on the use of PIs in PHIV with HF. OBJECTIVES: This study sought to compare characteristics, cardiac structure, and outcomes in PHIV with HF who were receiving PI-based versus non-PI (NPI) therapy. METHODS: This was a retrospective single-center study of all 394 antiretroviral therapy-treated PHIV who were hospitalized with HF in 2011, stratified by PI and NPI...
July 31, 2018: Journal of the American College of Cardiology
V Sai Krishna Anand, Sujata D Sakhare, K S Navya Sree, Athira R Nair, K Raghava Varma, Karthik Gourishetti, Swapnil J Dengale
Ritonavir and Lopinavir have previously been demonstrated to decrease the maximum solubility advantage and flux in the presence of each other. The present study investigated the ability of Ritonavir and Lopinavir co-amorphous materials to generate a supersaturated state. Further, it explored the precipitation and flux behavior of co-amorphous materials. The co-amorphous materials of Ritonavir and Lopinavir were prepared by quench cool method and characterized in the solid state using XRPD, DSC, FTIR. The solubility studies were conducted in USP phosphate buffer (pH 6...
July 23, 2018: European Journal of Pharmaceutical Sciences
Joshua S Davis, Melissa Young, Sandra Lennox, Tracey Jones, Kim Piera, Robert Pickles, Stephen Oakley
BACKGROUND: Epidemiological data suggest that chronic hepatitis C virus infection (CHC) is associated with increased cardiovascular risk, but it is unknown if it is associated with endothelial dysfunction. We aimed to assess the effect of antiviral treatment on endothelial function in non-cirrhotic adults with CHC. METHODS: Self-controlled before and after study. All patients had genotype 1 CHC and were treated with 12 weeks of paritaprevir/ritonavir, ombitasvir and dasabuvir (PrOD), with ribavirin added for those with genotype 1a infection...
July 26, 2018: Antiviral Therapy
Marcus A Neumann, Jacco van de Streek
Based on a thorough and critical analysis of the commercial crystal structure prediction studies of 41 pharmaceutical compounds, we conclude that for between 15 and 45% of all small-molecule drugs currently on the market the most stable experimentally observed polymorph is not the thermodynamically most stable crystal structure and that the appearance of the latter is kinetically hindered.
July 26, 2018: Faraday Discussions
Eric G Sahloff, Joan M Duggan
BACKGROUND: Limited data exist on the use of a boosted protease inhibitor plus <2 active nucleoside/nucleotide reverse transcriptase inhibitors without use of additional classes of antiretroviral (ARV) therapy in treatment-experienced patients with background resistance. OBJECTIVE: To evaluate clinical outcomes in HIV-infected patients harboring single- or multiclass resistant virus and receiving once-daily tenofovir/emtricitabine (TDF/FTC) plus darunavir/ritonavir (DRV/r) administered for >24 weeks...
July 26, 2018: Annals of Pharmacotherapy
Kyle John Wilby, Nesma Ahmed Eissa
Doravirine is a new HIV-1 non-nucleoside reverse transcriptase inhibitor that has demonstrated a good efficacy and safety profile in clinical trials. It has a therapeutic profile that makes it an attractive option for treatment of HIV-1 infection. As such, there has been an increase in the published literature regarding the pharmacokinetics of doravirine and potential for drug-drug interactions. This review aimed to identify pharmacokinetic literature pertaining to doravirine, used findings from the literature to summarize its pharmacokinetic profile, and finally evaluated literature describing actual and potential drug interactions...
July 25, 2018: European Journal of Drug Metabolism and Pharmacokinetics
Temitope Adeloye, Omair Sahgal, Adeep Puri, Steve Warrington, Takamasa Endo, Jeremy Dennison, Atholl Johnston
Amenamevir (formerly ASP2151) is a helicase-primase inhibitor being developed for the treatment of herpesvirus infection. Amenamevir is both a substrate and inducer of cytochrome P450 (CYP) 3A4. Three studies were done in healthy volunteers to investigate potential CYP3A pharmacokinetic interactions with the following drugs: (1) Midazolam (probe substrate for CYP3A): After 10 days' pretreatment with amenamevir 400 mg daily, geometric mean maximum concentration of drug in blood plasma (Cmax ) and area under the plasma drug concentration-time curve from time zero to infinity (AUC0-∞ ) of midazolam 7...
July 25, 2018: Clinical Pharmacology in Drug Development
Sanne Jespersen, Bo Langhoff Hønge, Henrik Krarup, Patrik Medstrand, Allan Sørensen, Candida Medina, David da Silva Té, Faustino Gomes Correira, Christian Erikstrup, Lars Østergaard, Christian Wejse, Alex Lund Laursen
BACKGROUND: NNRTIs are recommended as part of first-line treatment for HIV-1 in Africa. However, NNRTI-based regimens are more prone to resistance development than protease inhibitors (PIs) in a context in which drug interruptions are frequent. The aim of this study was to compare the efficacy and tolerability of NNRTIs with PIs in HIV-1-infected patients in Guinea-Bissau. METHODS: This open-label randomised, two-arm superiority trial compared the use of two NRTIs plus either one NNRTI (efavirenz or nevirapine) or one PI (lopinavir/ritonavir) in treatment-naïve HIV-1-infected adults in the Bissau HIV Cohort (ClinicalTrials...
July 20, 2018: Journal of Acquired Immune Deficiency Syndromes: JAIDS
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