- Three HIV drugs, atazanavir, ritonavir and tenofovir co-formulated in drug-combination nanoparticles exhibit long-acting and lymphocyte targeting properties in non-human primates. [Journal Article]
- JPJ Pharm Sci 2018 Aug 16
- Drug combination nanoparticles (DcNP) administered subcutaneously represent a potential long-acting lymphatic-targeting treatment for HIV-infection. The DcNP containing lopinavir-ritonavir-tenofovir,...
Drug combination nanoparticles (DcNP) administered subcutaneously represent a potential long-acting lymphatic-targeting treatment for HIV-infection. The DcNP containing lopinavir-ritonavir-tenofovir, Targeted-Long-Acting-Antiretroviral-Therapy product candidate 101 (TLC-ART 101), has shown to provide long-acting lymphocyte-targeting performance in non-human primates. To extend the TLC-ART platform, we replaced TLC-ART 101 lopinavir with second-generation protease inhibitor, atazanavir. Pharmacokinetics of atazanavir-ritonavir-tenofovir DcNP was assessed in macaques, in comparison to the equivalent free drug formulation and to the TLC-ART 101. After single subcutaneous administration of the DcNP formulation, atazanavir, ritonavir and tenofovir concentrations were sustained in plasma for up to 14 days, and in peripheral blood mononuclear cell for 8 to 14 days, compared to 1 to 2 days in those macaques treated with free drug combination. By one week, lymph node mononuclear cells showed significant levels for all 3 drugs from DcNP, whereas the free controls were undetectable. Compared to TLC-ART 101, the atazanavir-ritonavir-tenofovir DcNP exhibited similar lymphocyte targeted long-acting features for all 3 drugs, and similar pharmacokinetics for ritonavir and tenofovir, while some pharmacokinetics differences were observed for ATV vs. LPV. The present study demonstrated the flexibility of the TLC-ART' s DcNP platform to include different antiretroviral combinations that produce targeted long-acting effects on both plasma and cells.
- Combination ART-Induced Oxidative/Nitrosative Stress, Neurogenic Inflammation and Cardiac Dysfunction in HIV-1 Transgenic (Tg) Rats: Protection by Mg. [Journal Article]
- IJInt J Mol Sci 2018 Aug 15; 19(8)
- 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 prote...
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. Increased NT staining occurred within cART-treated HIV-Tg hearts, and significant decreases in cardiac systolic and diastolic contractile function occurred at 12 and 18 weeks. HIV-1 expression alone caused modest levels of oxidative stress and cardiac dysfunction. Significantly, cART caused up to 24% decreases in circulating Mg in HIV-1-Tg rats, associated with elevated renal NT staining, increased creatinine and urea levels, and elevated plasma substance P levels. Strikingly, Mg-supplementation (6-fold) suppressed all oxidative/nitrosative stress indices in the blood, heart and kidney and substantially attenuated contractile dysfunction (>75%) of cART-treated Tg rats. In conclusion, cART caused significant renal and cardiac oxidative/nitrosative stress/injury in Tg-rats, leading to renal Mg wasting and hypomagnesemia, triggering substance P-dependent neurogenic inflammation and cardiac dysfunction. These events were effectively attenuated by Mg-supplementation likely due to its substance P-suppressing and Mg's intrinsic anti-peroxidative/anti-calcium properties.
- Influence of organic modifier and separation modes for lipophilicity assessment of drugs using thin layer chromatography indices. [Journal Article]
- JCJ Chromatogr A 2018 Aug 04
- Lipophilicity constitutes one of the most important physicochemical properties in the design and development of drug molecules. In the present work thin layer chromatography (TLC) has been utilized t...
Lipophilicity constitutes one of the most important physicochemical properties in the design and development of drug molecules. In the present work thin layer chromatography (TLC) has been utilized to evaluate lipophilicity of 11 representative drugs, which included six proton pump inhibitors (omeprazole, pantoprazole, rabeprazole, lansoprazole, ilaprazole, and tenatoprazole), an anti-vertigo drug, betahistine, nonsteroidal anti-inflammatory drug, ibuprofen, anti-malarial drug, atovaquone, an anti-HIV agent, atazanavir and a hormonal drug, calcitriol. Normal as well as reversed-phase separation modes were evaluated to study the effect of different organic modifiers for the estimation of lipophilicity. The quantitative descriptor of lipophilicity, the partition coefficient (logP) was estimated by suitably optimizing the solvent systems for both the modes. The best mobile phase pairs for NPTLC and RPTLC were toluene-acetonitrile and water-methanol respectively. Principal component analysis, hierarchical cluster analysis, as well as non-parametric methods like sum of ranking differences and generalized pair wise correlation revealed the dominant pattern in the data. The results obtained from both the separation modes were comparable and were in good agreement with the computational data for all the drugs.
- Evolution of protease inhibitor resistance in HIV-1-infected patients failing protease inhibitor monotherapy as second-line therapy in low-income countries: an observational analysis within the EARNEST randomised trial. [Journal Article]
- CIClin Infect Dis 2018 Jul 28
- CONCLUSIONS: Most develop intermediate/high-level lopinavir resistance within one year when lopinavir/ritonavir is exposed to sustained VL replication without protection from other drugs. Even in this extreme situation, annual VL testing (current WHO recommendation) would identify failure when most would still benefit from switching to darunavir.
- Adverse Drug Reactions Among Patients Initiating Second-Line Antiretroviral Therapy in South Africa. [Journal Article]
- DSDrug Saf 2018 Jul 24
- CONCLUSIONS: The rates of AEs were lowest among patients receiving a TDF-based second-line regimen. Patients with poorer health at the time of switch were at higher risk of AEs when receiving second-line ART and may require closer monitoring to improve the durability of second-line therapy.
- Drugs and Lactation Database (LactMed) [BOOK]
- BOOKNational Library of Medicine (US): Bethesda (MD)
- In the United States and other developed countries, HIV-infected mothers should generally not breastfeed their infants. Published experience with atazanavir during breastfeeding is limited. In countr...
In the United States and other developed countries, HIV-infected mothers should generally not breastfeed their infants. Published experience with atazanavir during breastfeeding is limited. In countries in which no acceptable, feasible, sustainable and safe replacement feeding is available, World Health Organization guidelines recommend that all women with an HIV infection who are pregnant or breastfeeding should be maintained on antiretroviral therapy for at least the duration of risk for mother-to-child transmission. Mothers should exclusively breastfeed their infants for the first 6 months of life; breastfeeding with complementary feeding should continue through at least 12 months of life up to 24 months of life. The first choice regimen for nursing mothers is tenofovir, efavirenz and either lamivudine or emtricitabine. If these drugs are unavailable, alternative regimens include: 1) zidovudine, lamivudine and efavirenz; 2) zidovudine, lamivudine and nevirapine; or 3) tenofovir, nevirapine and either lamivudine or emtricitabine. Exclusively breastfed infants should also receive 6 weeks of prophylaxis with nevirapine. The combination product Evotaz, which also contains the CYP3A inhibitor cobicistat, has not been studied during breastfeeding, but would be expected to have similar concerns.
- Inhibition of the precursor and mature forms of HIV-1 protease as a tool for drug evaluation. [Journal Article]
- SRSci Rep 2018 Jul 11; 8(1):10438
- HIV-1 protease (PR) is a homodimeric enzyme that is autocatalytically cleaved from the Gag-Pol precursor. Known PR inhibitors bind the mature enzyme several orders of magnitude more strongly than the...
HIV-1 protease (PR) is a homodimeric enzyme that is autocatalytically cleaved from the Gag-Pol precursor. Known PR inhibitors bind the mature enzyme several orders of magnitude more strongly than the PR precursor. Inhibition of PR at the precursor level, however, may stop the process at its rate-limiting step before the proteolytic cascade is initiated. Due to its structural heterogeneity, limited solubility and autoprocessing, the PR precursor is difficult to access by classical methods, and limited knowledge regarding precursor inhibition is available. Here, we describe a cell-based assay addressing precursor inhibition. We used a reporter molecule containing the transframe (TFP) and p6* peptides, PR, and N-terminal fragment of reverse transcriptase flanked by the fluorescent proteins mCherry and EGFP on its N- and C- termini, respectively. The level of FRET between EGFP and mCherry indicates the amount of unprocessed reporter, allowing specific monitoring of precursor inhibition. The inhibition can be quantified by flow cytometry. Additionally, two microscopy techniques confirmed that the reporter remains unprocessed within individual cells upon inhibition. We tested darunavir, atazanavir and nelfinavir and their combinations against wild-type PR. Shedding light on an inhibitor's ability to act on non-mature forms of PR may aid novel strategies for next-generation drug design.
- Evaluation of Cardiovascular Disease Risk in HIV-1-Infected Patients Treated with Darunavir. [Journal Article]
- DRDrugs R D 2018 Jul 10
- CONCLUSIONS: This comprehensive review of Janssen-sponsored clinical trial, post-marketing, and epidemiological data does not suggest that CVD should be considered an important risk for users of darunavir.
- Chronic granulomatous interstitial nephritis and urothelial metaplasia associated with ritonavir-boosted atazanavir: a case study and literature review. [Letter]
- PPathology 2018; 50(5):565-568
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- Efficacy and safety of switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from boosted protease inhibitor-based regimens in virologically suppressed adults with HIV-1: 48 week results of a randomised, open-label, multicentre, phase 3, non-inferiority trial. [Journal Article]
- LHLancet HIV 2018; 5(7):e347-e356
- CONCLUSIONS: Fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide might be a safe and efficacious alternative to continued boosted protease inhibitor therapy in adults with HIV-1 infection.