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6 protocols using ritonavir

1

Hepatitis C Therapeutic Regimens Evaluation

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Therapeutic regimens included Daclatasvir (Bristol-Myers Squibb S.r.l., Contrada Fontana del Ceraso, Italy), Ledipasvir (Gilead Sciences Ireland UC, Carrigtohill, Ireland), Simeprevir (Janssen-Cilag, Borgo San Michele, Italy), Sofosbuvir (Gilead Sciences Ireland UC, Carrigtohill, Ireland), the combination of Paritaprevir, Ritonavir and Ombitasvir (AbbVie Deutschland, Ludwigshafen, Germany) with or without Dasabuvir (AbbVie Deutschland, Ludwigshafen, Germany) and Velpatasvir (Gilead Sciences Ireland UC, Carrigtohill, Ireland) and Ribavirin (Roche Pharma, Grenzach-Wyhlen, Germany). All medications were administered as recommended by the manufacturer. The
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2

Norvir and Nexium Tablet Protocol

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Norvir (100 mg ritonavir; Abbvie, North Chicago, IL, USA) and Nexium (40 mg esomeprazole; AstraZeneca, London, UK) tablets were ordered via the hospital pharmacy of the University Hospitals Leuven (UZ Leuven, Leuven, Belgium).
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3

SIV Infection and ART Therapy in Rhesus Macaques

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Chinese rhesus macaques (n = 18) that were confirmed to be seronegative for SIV, STLV-1 (simian T leukemia virus type 1), SRV-1 (simian type D retrovirus 1) and herpes B viruses were infected with SIVmac251 at 10 AID50 intravenously. Four days post-infection, 11 out of 18 animals were treated daily with tenofovir (TFV, 20 mg/kg; Gilead, Foster City, CA, USA) and emtricitabine (FTC, 40 mg/kg; Gilead) subcutaneously and raltegravir (RAL, 20 mg/kg; Merck, Kenilworth, NJ, USA) or dolutegravir (DTG, 5 mg/kg; ViiV, London, UK) and ritonavir (RTV, 20 mg/kg; Abbvie, North Chicago, IL, USA) orally, as previously described [48 (link)]. From the 11 ART-treated animals, n  =  3 received ART for the duration of the study until they had an undetectable plasma viral load and were euthanized at that time (SIV[+]/ART). n  =  8 had analytic therapy interruption (SIV[+]/ATI) at different time points after SIV suppression, and the animals were euthanized when they had a detectable plasma viral load. This duration varied from 10 to 28 days, with two animals requiring 159 and 161 days to rebound. Several animals (n = 7) did not receive ART (SIV[+]) and were euthanized 38 to 104 days post-infection. The animals were sacrificed at different time points post-infection, and the harvesting of the plasma, CSF and brain was performed immediately after the sacrifice [48 (link)].
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4

Investigating SIV Pathogenesis and Treatment

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Twenty-five RMs seronegative for SIV, simian T leukemia virus type 1, SRV-1 (type D retrovirus) and herpes B virus were infected intravenously with SIVmac251 (20 AID50). At day 4 postinfection, 10 RMs were treated with tenofovir (20 mg/kg, Gilead) and emtricitabine (40 mg/kg, Gilead) subcutaneously and raltegravir (20 mg/kg, Merck) or dolutegravir (5 mg/kg, ViiV) and ritonavir (20 mg/kg; AbbVie) by oral route. Five individuals of the early ART-treated RMs interrupted the treatment 8 weeks after ART administration. RMs were sacrificed at different time points postinfection during natural infection (no ART, n = 15), under ART (ART, n = 5), and after ATI (n = 5), as shown in Supplemental Table 1. Liver, lungs, and spleen were recovered immediately after euthanasia for flow cytometry analysis and cell sorting. Cells were isolated after a mechanical process (3 (link)). To limit the negative effects on the expression of cell surface markers, tissues were not digested with collagenase or other proteases.
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5

Formulation Development of Ritonavir Tablets

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Ritonavir (purity >99.8%) was obtained from AbbVie Inc. (North Chicago, US). Copovidone (polyvinylpyrrolidone–vinyl acetate copolymer, Kollidon® VA 64) was purchased from BASF SE (Ludwigshafen, Germany), fumed silicon dioxide (Aerosil® 200) from Evonik Industries (Essen, Germany), sorbitan monolaurate (Span® 20) from CRODA (Nettetal, Germany), dicalcium phosphate anhydrous (DI-CAFOS® A60) from Chemische Fabrik Budenheim (Budenheim, Germany), and sodium stearyl fumarate (PRUV®) from JRS Pharma (Rosenberg, Germany). Acetone (Emprove® Essential, purity 96%) and methanol (Emprove® Essential, purity 99.5%) were obtained from Merck KGaA (Darmstadt, Germany).
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6

Ritonavir Amorphous Solid Dispersion Characterization

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Neat ritonavir and ritonavir-ASD were provided by AbbVie Germany, Ludwigshafen, Germany. The ritonavir-ASD was prepared as extrudate beads by hot melt extrusion on a co-rotating twin-screw extruder, and composed of ritonavir (15%), copovidone (74%), sorbitan monolaurate (10%), and colloidal silicon dioxide (1%). The purity of the ingredients was according to the compendial specifications (Ph.Eur./USP). The absence of API-related crystallinity in the ASD was confirmed by polarized light microscopy (Model DMLM, Leica Microsystems, Wetzlar, Germany). Tri-potassium phosphate (Alfa Aesar, Kandel, Germany), tri-potassium citrate (Carl Roth, Karlsruhe, Germany), and sodium hydroxide (VWR Chemicals, Darmstadt, Germany) were used for the buffer concentrate. Lecithin, 1-decanol, and sodium taurocholate were obtained from Alfa Aesar (Kandel, Germany). Glitter powder was purchased from Jofrika Cosmetics, Bergisch-Gladbach, Germany. The high performance liquid chromatography HPLC chemicals consisted of methanol (VWR Chemicals, Darmstadt, Germany), acetonitrile (VWR Chemicals, Darmstadt, Germany), and demineralized water (Merck Milli-Q, Darmstadt, Germany). Samples for HPLC were filtered through a 0.45 µm cellulose acetate syringe filter (VWR Chemicals, Darmstadt, Germany).
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