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Hiv and pharmacokinetics

Ka-Yee Au, Wei-Wei Shi, Shuai Qian, Zhong Zuo, Pang-Chui Shaw
To improve the pharmacological properties of maize ribosome-inactivating protein (maize RIP) for targeting HIV-infected cells, the previously engineered TAT-fused active form of maize RIP (MOD) was further engineered for cysteine-directed PEGylation. In this work, two potential antigenic sites, namely Lys-78 and Lys-264, were identified. They were mutated to cysteine residue and conjugated with PEG5k or PEG20k. The resultant PEG derivatives of MOD variants were examined for ribosome-inactivating activity, circulating half-life and immunogenicity...
October 17, 2016: Toxins
Monica R P Rao, Chaitanya Shirsath
Efavirenz is a non-nucleoside reverse transcriptase inhibitor which is chronically prescribed for HIV patients. However, it exhibits solubility-limited bioavailability. Aim of this work was to enhance the solubility and dissolution of the Biopharmaceutical Classification System (BCS) class II drug efavirenz, using beta-cyclodextrin-based nanosponges. Nanosponges have high drug loading capacity and are effective for solubility enhancement. Beta-cyclodextrin was crosslinked with carbonates in different ratios to prepare nanosponges...
October 18, 2016: AAPS PharmSciTech
N A Giraldo, P Amariles, M Monsalve, M J Faus
BACKGROUND: Highly active antiretroviral therapy has extended the expected lifespan of patients with HIV/AIDS. However, the therapeutic benefits of some drugs used simultaneously with highly active antiretroviral therapy may be adversely affected by drug interactions. OBJECTIVE: The goal was to design and develop a free software to facilitate analysis, assessment, and clinical decision making according to the clinical relevance of drug interactions in patients with HIV/AIDS...
September 23, 2016: Research in Social & Administrative Pharmacy: RSAP
Diana F Clarke, Inci Yildirim, Ellen R Cooper
We report our experience with two infants with in utero HIV-1 infection who began very early combination antiretroviral therapy within 4 hours of birth. Further neonatal studies of antiretroviral pharmacokinetics, safety, efficacy, and treatment strategies are critically needed for the development of more potent regimens for use in HIV-infected infants.
October 3, 2016: Pediatric Infectious Disease Journal
Carmela E Corallo, Louise Grannell, Huyen Tran
A 62-year-old man was admitted to hospital for elective revision of a left total hip arthroplasty. His history was significant for human immunodeficiency virus (HIV) infection for which he was taking the following antiretroviral agents (ARVs): etravirine, ritonavir, darunavir, raltegravir and tenofovir/emtricitabine. Rivaroxaban 10 mg daily was commenced on the second postoperative day for venous thromboembolism (VTE) prophylaxis. Approximately 24 h later, the patient developed hypotension and anaemia, accompanied by thigh swelling due to bleeding at the surgical site...
December 2015: Drug Saf Case Rep
Saghi Sepehri, Lotfollah Saghaie, Afshin Fassihi
The fusion of viral and host cell membranes is mediated using gp41 subunit of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein. As the HIV-1 enters the host cells, the two helical regions (HR1 and HR2) in the ectodomain of gp41 form a six-helix bundle, which carries the target and viral cell membranes to close proximity. Steps of this process serve as attractive targets for developing HIV-1 fusion inhibitors. Identification of some novel HIV fusion inhibitors with the goal of blocking the formation of the six-helix bundle was accomplished by computer-aided drug design techniques...
October 12, 2016: Molecular Informatics
Julie Fox, Juan M Tiraboschi, Carolina Herrera, Laura Else, Deirdre Egan, Laura Dickinson, Akil Jackson, Natalia Olejniczak, David Back, Saye Khoo, Robin Shattock, Marta Boffito
To investigate the pharmacokinetics/pharmacodynamics of single-dose maraviroc 300 mg in HIV-1 exposure compartments. Maraviroc concentrations in blood, secretions (vaginal, urethral, oral, and rectal), and tissue (vaginal and rectal) were measured, and ex vivo challenge was performed in 54 healthy volunteers to study protection from HIV infection. Maraviroc Cmax occurred within 4 hours in most compartments. Concentrations from 4 to 72 hours were above intracellular (IC) IC90 in all compartments, range 15-8095 ng/mL...
November 1, 2016: Journal of Acquired Immune Deficiency Syndromes: JAIDS
Bella Devaleenal D, Geetha Ramachandran, Soumya Swaminathan
Inter-individual variations in the pharmacokinetics (PK) of anti-TB drugs are known to occur, which could have important therapeutic implications in patient management. Areas covered: We compiled factors responsible for PK variability of anti-TB drugs reported from different settings that would give a better understanding about the challenges of PK variability of anti-TB medications. We searched PubMed data base and Google scholar from 1976 to the present using the key words "Pharmacokinetics", "pharmacokinetic variability", "first-line anti-TB therapy", "Rifampicin", "Isoniazid", "Ethambutol", "Pyrazinamide", "food", "nutritional status", "HIV", "diabetes", "genetic polymorphisms" and "pharmacokinetic interactions"...
October 11, 2016: Expert Review of Clinical Pharmacology
Rajesh Krishna, Lilly East, Patrick Larson, Tara Siringhaus, Lisa Herpok, Crystal Bethel-Brown, Helen Manthos, John Brejda, Michael Gartner
Raltegravir is a human immunodeficiency virus (HIV)-1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice daily (BID). Raltegravir for once daily regimen (QD) at a dose of 1200 mg (2 x 600 mg) is under development and offers a new treatment option for HIV-1 infected treatment-naive subjects. Since raltegravir is eliminated mainly by metabolism via an UDP-glucuronosyltransferase (UGT) 1A1-mediated glucuronidation pathway, co-administration of UGT1A1 inducers may alter plasma levels of raltegravir...
October 5, 2016: Biopharmaceutics & Drug Disposition
Emilie R Elliot, Aikaterini Theodoraki, Lakshmi R Jain, Neal J Marshall, Marta Boffito, Stephanie E Baldeweg, Laura J Waters
Ritonavir and cobicistat, used as pharmacokinetic enhancers in combination with some antiretrovirals (ARVs) for the treatment of HIV, are potent inhibitors of the CYP3A4 isoenzyme. Most glucocorticoids are metabolised via the CYP3A4 pathway and iatrogenic Cushing's syndrome (ICS), with possible secondary adrenal insufficiency (SAI), is a recognised complication following co-administration with ritonavir or cobicistat. A structured approach for identifying and managing potentially affected individuals has not been established...
October 2016: Clinical Medicine: Journal of the Royal College of Physicians of London
Rajesh Krishna, Lilly East, Patrick Larson, Chandni Valiathan, Kristin Butterfield, Yang Teng, Martha Hernandez-Illas
OBJECTIVES: Raltegravir is a human immunodeficiency virus (HIV)-1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice daily (BID). Raltegravir for once-daily regimen (QD) at a dose of 1200 mg is under development. The effect of calcium carbonate and magnesium/aluminium hydroxide antacids on the pharmacokinetics of a 1200 mg dose of raltegravir was assessed in this study. METHODS: An open-label, four-period, four-treatment, fixed-sequence study in 20 HIV-infected patients was performed...
September 27, 2016: Journal of Pharmacy and Pharmacology
Almudena Sánchez-Martín, Salvador Cabrera Figueroa, Raquel Cruz, Liliana Porras-Hurtado, Fernando Calvo-Boyero, Mahmood Rasool, Alfonso Domínguez-Gil Hurlé, Angel Carracedo
Genetic factors have a significant impact on the PK variability of EFV, much higher than other non-genetic factors, such as demography. In this work we have performed a comprehensive PG analysis of genes encoding the major metabolizing enzymes and transporters of EFV, establishing a clear relationship between the PK parameters and genetic factors, which explain 50% of the variability in EFV PK parameters. The most relevant associations for metabolizing enzymes were found in CYP2B6 (rs3745274), in agreement with previous studies...
October 2016: Drug Metabolism and Pharmacokinetics
Bruce Green, Herta Crauwels, Thomas N Kakuda, Simon Vanveggel, Anne Brochot
BACKGROUND: Etravirine is a non-nucleoside reverse transcriptase inhibitor indicated in combination with other antiretrovirals for treatment-experienced HIV patients ≥6 years of age. Etravirine is primarily metabolized by cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A. This analysis determined the impact of concomitant antiretrovirals and CYP2C9/CYP2C19 phenotype on the pharmacokinetics of etravirine. METHODS: We used 4728 plasma concentrations from 817 adult subjects collected from four clinical studies to develop the population pharmacokinetic model...
September 24, 2016: Clinical Pharmacokinetics
Cassilda Cunha-Reis, Alexandra Machado, Luísa Barreiros, Francisca Araújo, Rute Nunes, Vítor Seabra, Domingos Ferreira, Marcela A Segundo, Bruno Sarmento, José das Neves
Combining two or more antiretroviral drugs in one medical product is an interesting but challenging strategy for developing topical anti-HIV microbicides. We developed a new vaginal delivery system comprising the incorporation of nanoparticles (NPs) into a polymeric film base - NPs-in-film - and tested its ability to deliver tenofovir (TFV) and efavirenz (EFV). EFV-loaded poly(lactic-co-glycolic acid) NPs were incorporated alongside free TFV into fast dissolving films during film manufacturing. The delivery system was characterized for physicochemical properties, as well as genital distribution, local and systemic 24h pharmacokinetics (PK), and safety upon intravaginal administration to mice...
September 21, 2016: Journal of Controlled Release: Official Journal of the Controlled Release Society
Ian McGowan, Charlene S Dezzutti, Aaron Siegel, Jarret Engstrom, Alexiy Nikiforov, Kathryn Duffill, Cory Shetler, Nicola Richardson-Harman, Kaleab Abebe, David Back, Laura Else, Deidre Egan, Saye Khoo, James E Egan, Ronald Stall, Peter E Williams, Khaleel K Rehman, Amy Adler, Rhonda M Brand, Beatrice Chen, Sharon Achilles, Ross D Cranston
BACKGROUND: Long-acting injectable antiretroviral agents are being developed for HIV-1 prevention. The MWRI-01 study was done to characterise the safety, acceptability, and pharmacokinetic and pharmacodynamic profile of long-acting rilpivirine. METHODS: We did a phase 1 open-label study at the University of Pittsburgh. We enrolled healthy individuals (aged 18-45 years) who were seronegative for HIV-1. Participants were assigned alternately one intramuscular dose of either 1200 mg or 600 mg long-acting rilpivirine, beginning with the 1200 mg dose...
September 16, 2016: Lancet HIV
Richard H Beigi, Lisa M Noguchi, Elizabeth Montgomery, Joseph Biggio, Craig W Hendrix, Mark A Marzinke, James Y Dai, Jason Pan, Ratiya Kunjara Na Ayudhya, Jill L Schwartz, Karen Isaacs, Jeanna M Piper, D Heather Watts
INTRODUCTION: Vaginal tenofovir (TFV) 1% gel may reduce incident HIV-1 and herpes simplex virus 2 infection. Pregnancy may increase risk of HIV acquisition, and incident HIV in pregnancy potentiates perinatal HIV transmission. Our objective was to investigate the safety and pharmacokinetics of seven days of TFV 1% vaginal gel in term and near-term pregnancy. METHODS: Ninety-eight healthy pregnant women, stratified to a term cohort followed by a near-term cohort, were enrolled into a 2:1 randomized, double-blinded, placebo-controlled trial...
2016: Journal of the International AIDS Society
Andrew J Yee, William I Bensinger, Jeffrey G Supko, Peter M Voorhees, Jesus G Berdeja, Paul G Richardson, Edward N Libby, Ellen E Wallace, Nicole E Birrer, Jill N Burke, David L Tamang, Min Yang, Simon S Jones, Catherine A Wheeler, Robert J Markelewicz, Noopur S Raje
BACKGROUND: Histone deacetylase (HDAC) inhibitors are an important new class of therapeutics for treating multiple myeloma. Ricolinostat (ACY-1215) is the first oral selective HDAC6 inhibitor with reduced class I HDAC activity to be studied clinically. Motivated by findings from preclinical studies showing potent synergistic activity with ricolinostat and lenalidomide, our goal was to assess the safety and preliminary activity of the combination of ricolinostat with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma...
September 16, 2016: Lancet Oncology
Pierre Frange, Naïm Bouazza, Patricia Fassinou, Josiane Warszawski, Stéphane Blanche
INTRODUCTION: Antiretroviral therapy is extremely effective in both children and adults infected with HIV. Treatment indications have rapidly expanded; ideally, with rare exceptions, all infected children should now be treated. AREAS COVERED: The use of antiretroviral drugs in children is based largely on extrapolations from experience with adult patients. Pharmacokinetic studies are required in addition to formal studies, which are difficult to conduct in pediatric situations, extending from birth to adolescence...
September 22, 2016: Expert Review of Anti-infective Therapy
Andrea Calcagno, Jessica Cusato, Antonio D'Avolio, Stefano Bonora
BACKGROUND: Antiretroviral treatment is highly effective in enhancing HIV-positive patients' survival and quality of life. Despite an increased tolerability in recent years, a substantial amount of patients experience side effects. Antiretrovirals' efficacy and tolerability have been associated with plasma concentrations and single nucleotide polymorphisms in selected genes involved in drug disposition. OBJECTIVE: Our aim was to review the current knowledge in genetic polymorphisms affecting plasma, intracellular or compartmental concentrations of antiretrovirals...
September 19, 2016: Clinical Pharmacokinetics
Mohamed El Kassas, Tamer Elbaz, Yasmeen Abd El Latif, Gamal Esmat
INTRODUCTION: During the last few years, treatment of hepatitis C virus (HCV) revolutionized with the appearance of direct antiviral agents especially for patients with HCV genotypes 1 and 4 infections. Elbasvir (NS5A inhibitor) and grazoprevir (NS3/4A protease inhibitor) are newly developed drugs that are presented in fixed dose combination tablets. AREAS COVERED: This review covers the mechanism of action, pharmacokinetic and pharmacodynamics properties, clinical uses, safety and efficacy of elbasvir/grazoprevir in managing a wide variety of easy and difficult to treat populations (such as presence of cirrhosis, treatment experienced, co-infection with HIV and patients with inherited blood disorders)...
September 7, 2016: Expert Review of Clinical Pharmacology
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