Efficacy and safety outcomes of sofosbuvir-based treatment regimens for hepatitis C virus-infected patients with or without cirrhosis from phase III clinical trials

Yang, Young-Mo,Choi, Eun Joo Dove Medical Press 2017 THERAPEUTICS AND CLINICAL RISK MANAGEMENT Vol.13 No.-

<P><B>Background</B></P><P>With the appearance of oral direct-acting antivirals (DAAs), the field of hepatitis C virus (HCV) treatment has been dramatically changed. This evolution makes possible for all oral treatments to be available for the treatment of HCV-infected patients. The aims of this review were to report the efficacy and safety of sofosbuvir (SOF)-based regimens for the treatment of patients with chronic HCV infection and to provide our clinical perspectives on these regimens.</P><P><B>Methods</B></P><P>A literature search of clinical studies published in PubMed and posted on ClinicalTrials.gov website was performed to identify studies evaluating the efficacy or safety of SOF-containing treatment regimens.</P><P><B>Results</B></P><P>A total of 23 clinical trials were examined in the review. The evaluated SOF-based regimens are as follows: SOF/daclatasvir (DCV) ± ribavirin (RBV), SOF/ledipasvir (LDV) ± RBV, SOF/simeprevir (SMV), SOF/velpatasvir (VEL) ± RBV, and SOF/RBV ± peginterferon (peg-IFN). These SOF-based regimens were at least effective and safe for HCV-infected patients with or without cirrhosis. The SOF/VEL ± RBV regimen, a pan-genotypic DAA regimen, was effective for the treatment of patients with HCV genotype 1, 2, 3, 4, 5, or 6 infection. The 24-week SOF/RBV regimen was as effective as the 12-week SOF/RBV/peg-IFN regimen. Patients with HCV genotype 3 infection could have benefits from the use of the 24-week SOF/RBV regimen. For cirrhotic patients with HCV genotype 3 infection, the 12-week SOF/RBV/peg-IFN regimen could be considered as an alternative treatment option when access to SOF-based regimens with other DAAs is limited. In the included studies, significant adverse events due to SOF-based regimens were not reported.</P><P><B>Conclusion</B></P><P>The clinical trials suggest that SOF-based treatment regimens for HCV-infected patients with or without cirrhosis can be at least effective and safe patient-convenient medications. However, it is necessary to monitor HCV-infected patients, since rare adverse events, drug–drug interactions, and drug–disease interactions can occur in real clinical settings.</P>

Comparative study of antiretroviral drug regimens and drug–drug interactions between younger and older HIV-infected patients at a tertiary care teaching hospital in South Korea

Park, Mi Seon,Yang, Young-Mo,Kim, Ju-Sin,Choi, Eun Joo Dove Medical Press 2018 THERAPEUTICS AND CLINICAL RISK MANAGEMENT Vol.14 No.-

<P><B>Background</B></P><P>With the advent of combination antiretroviral therapy (ART), people living with HIV have lived to older age. So they have experienced age-related illnesses and have taken non-antiretroviral (ARV) medications to manage these illnesses. The aims of this study were to investigate the use patterns of ARV agents in HIV-positive patients by age and to evaluate potential or contraindicated drug–drug interactions (DDIs) between ARV and non-ARV.</P><P><B>Methods</B></P><P>This study was retrospectively conducted with HIV-infected patients receiving ART medications between October 2011 and September 2017 at Chonbuk National University Hospital in South Korea. Data were collected by reviewing patients’ electronic medical charts.</P><P><B>Results</B></P><P>Among 207 patients diagnosed with HIV infection, 183 (86.9% males; 104 aged <50 years and 79 aged ≥50 years) were selected based on inclusion criteria. In 2017, the most frequently prescribed ART regimen was nucleoside reverse transcriptase inhibitors (NRTIs)/integrase strand transfer inhibitors (INSTIs; total, 66.3%; <50 years, 36.3%; ≥50 years, 30.0%) followed by NRTIs/protease inhibitors (PIs; total, 23.8%; <50 years, 15.0%; ≥50 years, 8.8%). In 2017, the most frequently prescribed NRTI combination was abacavir/lamivudine (total, 34.4%; <50 years, 20.6%; ≥50 years, 13.8%) followed by tenofovir alafenamide/emtricitabine (FTC; total, 31.3%; <50 years, 16.3%; ≥50 years, 15.0%) and tenofovir disoproxil fumarate/FTC (total, 28.1%; <50 years, 16.9%; ≥50 years, 11.3%). In 2017, elvitegravir (EVG)/cobicistat (COBI; total, 57.1%; <50 years, 30.4%; ≥50 years, 26.8%) was most frequently prescribed followed by dolutegravir (total, 32.1%; <50 years, 19.6%; ≥50 years, 12.5%). Potential or contraindicated DDIs between boosted PIs with ritonavir or EVG/COBI and coprescribed drugs occurred most frequently.</P><P><B>Conclusion</B></P><P>Currently, NRTIs/INSTIs is the most frequently prescribed ARV combination. Abacavir/lamivudine, tenofovir alafenamide/FTC, and tenofovir disoproxil fumarate/FTC are the most used NRTIs, and EVG/COBI followed by dolutegravir is the most prescribed INSTIs. Potential or contraindicated DDIs occur mainly between boosted PIs or EVG/COBI and non-ARV medications.</P>

Poly(L-histidine)-tagged 5-aminolevulinic acid prodrugs: new photosensitizing precursors of protoporphyrin IX for photodynamic colon cancer therapy

Johnson, Renjith P,Chung, Chung-Wook,Jeong, Young-Il,Kang, Dae Hwan,Suh, Hongsuk,Kim, Il Dove Medical Press 2012 INTERNATIONAL JOURNAL OF NANOMEDICINE Vol.7 No.-

<P><B>Background</B></P><P>5-Aminolevulinic acid (ALA) and its derivatives have been widely used in photodynamic therapy. The main drawback associated with ALA-based photodynamic therapy (ALA-PDT) and ALA fluorescence diagnosis results from the hydrophilic nature of ALA and lack of selectivity for tumor versus nontumor cells. The application of certain triggers, such as pH, into conventional sensitizers for controllable <SUP>1</SUP>O<SUB>2</SUB> release is a promising strategy for tumor-targeted treatment.</P><P><B>Methods</B></P><P>A series of pH-sensitive ALA-poly(L-histidine) [p(L-His)<SUB>n</SUB>] prodrugs were synthesized via ring opening polymerization of 1-benzyl-<I>N</I>-carboxy-L-histidine anhydride initiated by the amine hydrochloride group of ALA itself. As an alternative to ALA for PDT, the synthesized prodrugs were used to treat a cultured human colon cancer HCT116 cell line under different pH conditions. The effect of ALA-p(L-His)<SUB>n</SUB> derivatives was evaluated by monitoring the fluorescence intensity of protoporphyrin IX, and measuring the cell survival rate after suitable light irradiation.</P><P><B>Results</B></P><P>The cytotoxicity and dark toxicity of ALA and synthesized ALA-p(L-His) derivatives in HEK293T and HCT116 cells in the absence of light at pH 7.4 and 6.8 shows that the cell viability was relatively higher than 100%. ALA-p(L-His)<SUB>n</SUB> showed high phototoxicity and selectivity in different pH conditions compared with ALA alone. Because the length of the histidine chain increases in the ALA-p(L-His)<SUB>n</SUB> prodrugs, the PDT effect was found to be more powerful. In particular, high phototoxicity was observed when the cells were treated with ALA-p(L-His)<SUP>15</SUP>, compared with treatment using ALA alone.</P><P><B>Conclusion</B></P><P>The newly synthesized ALA-p(L-His)<SUB>n</SUB> derivatives are an effective alternative to ALA for enhancing protoporphyrin IX production and the selectivity of the phototoxic effect in tumor cells.</P>

Pharmacokinetics, pharmacodynamics and safety of CKD-519, a CETP inhibitor, in healthy subjects

Kim, Choon Ok,Oh, Eun Sil,Choi, Chungam,Kim, Yeonjoo,Lee, Sera,Kim, Semi,Park, Min Soo Dove Medical Press 2016 Drug design, development and therapy Vol.10 No.-

<P>CKD-519 is a selective and potent cholesteryl ester transfer protein (CETP) inhibitor being developed for the treatment of dyslipidemia to raise high-density lipoprotein cholesterol. We investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of CKD-519 in healthy adult subjects. A randomized, double-blinded, placebo-controlled, single ascending dose study was performed. Eight healthy subjects were enrolled in each CKD-519 dose group (25, 50, 100, 200, or 400 mg) and randomized to CKD-519 (n=6) or matching placebo (n=2). CKD-519 reached the maximum plasma concentration (C<SUB>max</SUB>) at 5–6 h post-dose, and had a long terminal half-life ranging between 40–70 h. The area under the plasma concentration–time curve (AUC) and C<SUB>max</SUB> increased with the dose, however, C<SUB>max</SUB> and AUC normalized by dose decreased with each incremental dose. CETP activity decreased with dose, and the maximum decrease (63%–83%) was observed at 6–8 h post-dose. A sigmoid E<SUB>max</SUB> model best described the relationship between CKD-519 plasma concentrations and CETP activity with an EC<SUB>50</SUB> of 17.3 ng/mL. Overall, 11 adverse events (AEs) were observed. All AEs were mild or moderate in intensity, and resolved without any complications. There were no clinically significant effects on blood pressure. In conclusion, single doses of CKD-519 up to 400 mg were well tolerated and showed potent inhibition of CETP activity.</P>

Intracellular delivery of cell-penetrating peptide-transcriptional factor fusion protein and its role in selective osteogenesis

Suh, Jin Sook,Lee, Jue Yeon,Choi, Yoon Jung,You, Hyung Keun,Hong, Seong-Doo,Chung, Chong Pyoung,Park, Yoon Jeong Dove Medical Press 2014 INTERNATIONAL JOURNAL OF NANOMEDICINE Vol.9 No.-

<P>Protein-transduction technology has been attempted to deliver macromolecular materials, including protein, nucleic acids, and polymeric drugs, for either diagnosis or therapeutic purposes. Herein, fusion protein composed of an arginine-rich cell-penetrating peptide, termed low-molecular-weight protamine (LMWP), and a transcriptional coactivator with a PDZ-binding motif (TAZ) protein was prepared and applied in combination with biomaterials to increase bone-forming capacity. TAZ has been recently identified as a specific osteogenic stimulating transcriptional coactivator in human mesenchymal stem cell (hMSC) differentiation, while simultaneously blocking adipogenic differentiation. However, TAZ by itself cannot penetrate the cells, and thus needs a transfection tool for translocalization. The LMWP-TAZ fusion proteins were efficiently translocalized into the cytosol of hMSCs. The hMSCs treated with cell-penetrating LMWP-TAZ exhibited increased expression of osteoblastic genes and protein, producing significantly higher quantities of mineralized matrix compared to free TAZ. In contrast, adipogenic differentiation of the hMSCs was blocked by treatment of LMWP-TAZ fusion protein, as reflected by reduced marker-protein expression, adipocyte fatty acid-binding protein 2, and peroxisome proliferator-activated receptor-γ messenger ribonucleic acid levels. LMWP-TAZ was applied in alginate gel for the purpose of localization and controlled release. The LMWP-TAZ fusion protein-loaded alginate gel matrix significantly increased bone formation in rabbit calvarial defects compared with alginate gel matrix mixed with free TAZ protein. The protein transduction of TAZ fused with cell-penetrating LMWP peptide was able selectively to stimulate osteogenesis in vitro and in vivo. Taken together, this fusion protein-transduction technology for osteogenic protein can thus be applied in combination with biomaterials for tissue regeneration and controlled release for tissue-engineering purposes.</P>

Delivery of bone morphogenetic protein-2 and substance P using graphene oxide for bone regeneration

La, Wan-Geun,Jin, Min,Park, Saibom,Yoon, Hee-Hun,Jeong, Gun-Jae,Bhang, Suk Ho,Park, Hoyoung,Char, Kookheon,Kim, Byung-Soo Dove Medical Press 2014 INTERNATIONAL JOURNAL OF NANOMEDICINE Vol.9 No.1

<P>In this study, we demonstrate that graphene oxide (GO) can be used for the delivery of bone morphogenetic protein-2 (BMP-2) and substance P (SP), and that this delivery promotes bone formation on titanium (Ti) implants that are coated with GO. GO coating on Ti substrate enabled a sustained release of BMP-2. BMP-2 delivery using GO-coated Ti exhibited a higher alkaline phosphatase activity in bone-forming cells in vitro compared with bare Ti. SP, which is known to recruit mesenchymal stem cells (MSCs), was co-delivered using Ti or GO-coated Ti to further promote bone formation. SP induced the migration of MSCs in vitro. The dual delivery of BMP-2 and SP using GO-coated Ti showed the greatest new bone formation on Ti implanted in the mouse calvaria compared with other groups. This approach may be useful to improve osteointegration of Ti in dental or orthopedic implants.</P>

Virgin olive oil blended polyurethane micro/nanofibers ornamented with copper oxide nanocrystals for biomedical applications

Amna, Touseef,Hassan, M Shamshi,Yang, Jieun,Khil, Myung-Seob,Song, Ki-Duk,Oh, Jae-Don,Hwang, Inho Dove Medical Press 2014 INTERNATIONAL JOURNAL OF NANOMEDICINE Vol.9 No.-

<P>Recently, substantial interest has been generated in using electrospun biomimetic nanofibers of hybrids, particularly organic/inorganic, to engineer different tissues. The present work, for the first time, introduced a unique natural and synthetic hybrid micronanofiber wound dressing, composed of virgin olive oil/copper oxide nanocrystals and polyurethane (PU), developed via facile electrospinning. The as-spun organic/inorganic hybrid micronanofibers were characterized by scanning electron microscopy (SEM), energy dispersive X-ray analysis, X-ray diffraction, electron probe microanalysis, and transmission electron microscopy. The interaction of cells with scaffold was studied by culturing NIH 3T3 fibroblasts on an as-spun hybrid micronanofibrous mat, and viability, proliferation, and growth were assessed. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay results and SEM observation showed that the hybrid micronanofibrous scaffold was noncytotoxic to fibroblast cell culture and was found to benefit cell attachment and proliferation. Hence our results suggest the potential utilization of as-spun micronanoscaffolds for tissue engineering. Copper oxide–olive oil/PU wound dressing may exert its positive beneficial effects at every stage during wound-healing progression, and these micronanofibers may serve diverse biomedical applications, such as tissue regeneration, damaged skin treatment, wound healing applications, etc. Conclusively, the fabricated olive oil–copper oxide/PU micronanofibers combine the benefits of virgin olive oil and copper oxide, and therefore hold great promise for biomedical applications in the near future.</P>

Differential microRNA expression signatures and cell type-specific association with Taxol resistance in ovarian cancer cells

Kim, Yong-Wan,Kim, Eun Young,Jeon, Doin,Liu, Juinn-Lin,Kim, Helena Suhyun,Choi, Jin Woo,Ahn, Woong Shick Dove Medical Press 2014 Drug design, development and therapy Vol.8 No.-

<P>Paclitaxel (Taxol) resistance remains a major obstacle for the successful treatment of ovarian cancer. MicroRNAs (miRNAs) have oncogenic and tumor suppressor activity and are associated with poor prognosis phenotypes. miRNA screenings for this drug resistance are needed to estimate the prognosis of the disease and find better drug targets. miRNAs that were differentially expressed in Taxol-resistant ovarian cancer cells, compared with Taxol-sensitive cells, were screened by Illumina Human MicroRNA Expression BeadChips. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to identify target genes of selected miRNAs. Kaplan–Meier survival analysis was applied to identify dysregulated miRNAs in ovarian cancer patients using data from The Cancer Genome Atlas. A total of 82 miRNAs were identified in ovarian carcinoma cells compared to normal ovarian cells. miR-141, miR-106a, miR-200c, miR-96, and miR-378 were overexpressed, and miR-411, miR-432, miR-494, miR-409-3p, and miR-655 were underexpressed in ovarian cancer cells. Seventeen miRNAs were overexpressed in Taxol-resistant cells, including miR-663, miR-622, and HS_188. Underexpressed miRNAs in Taxol-sensitive cells included miR-497, miR-187, miR-195, and miR-107. We further showed miR-663 and miR-622 as significant prognosis markers of the chemo-resistant patient group. In particular, the downregulation of the two miRNAs was associated with better survival, perhaps increasing the sensitivity of cancer cells to Taxol. In the chemo-sensitive patient group, only miR-647 could be a prognosis marker. These miRNAs inhibit several interacting genes of p53 networks, especially in TUOS-3 and TUOS-4, and showed cell line-specific inhibition effects. Taken together, the data indicate that the three miRNAs are closely associated with Taxol resistance and potentially better prognosis factors. Our results suggest that these miRNAs were successfully and reliably identified and would be used in the development of miRNA therapies in treating ovarian cancer.</P>

<i>Ginkgo biloba</i> : a natural reducing agent for the synthesis of cytocompatible graphene

Gurunathan, Sangiliyandi,Han, Jae Woong,Park, Jung Hyun,Eppakayala, Vasuki,Kim, Jin-Hoi Dove Medical Press 2014 INTERNATIONAL JOURNAL OF NANOMEDICINE Vol.9 No.-

<P><B>Background</B></P><P>Graphene is a novel two-dimensional planar nanocomposite material consisting of rings of carbon atoms with a hexagonal lattice structure. Graphene exhibits unique physical, chemical, mechanical, electrical, elasticity, and cytocompatible properties that lead to many potential biomedical applications. Nevertheless, the water-insoluble property of graphene restricts its application in various aspects of biomedical fields. Therefore, the objective of this work was to find a novel biological approach for an efficient method to synthesize water-soluble and cytocompatible graphene using <I>Ginkgo biloba</I> extract (GbE) as a reducing and stabilizing agent. In addition, we investigated the biocompatibility effects of graphene in MDA-MB-231 human breast cancer cells.</P><P><B>Materials and methods</B></P><P>Synthesized graphene oxide (GO) and GbE-reduced GO (Gb-rGO) were characterized using various sequences of techniques: ultraviolet-visible (UV-vis) spectroscopy, Fourier-transform infrared spectroscopy (FTIR), dynamic light scattering (DLS), scanning electron microscopy (SEM), atomic force microscopy (AFM), and Raman spectroscopy. Biocompatibility of GO and Gb-rGO was assessed in human breast cancer cells using a series of assays, including cell viability, apoptosis, and alkaline phosphatase (ALP) activity.</P><P><B>Results</B></P><P>The successful synthesis of graphene was confirmed by UV-vis spectroscopy and FTIR. DLS analysis was performed to determine the average size of GO and Gb-rGO. X-ray diffraction studies confirmed the crystalline nature of graphene. SEM was used to investigate the surface morphologies of GO and Gb-rGO. AFM was employed to investigate the morphologies of prepared graphene and the height profile of GO and Gb-rGO. The formation of defects in Gb-rGO was confirmed by Raman spectroscopy. The biocompatibility of the prepared GO and Gb-rGO was investigated using a water-soluble tetrazolium 8 assay on human breast cancer cells. GO exhibited a dose-dependent toxicity, whereas Gb-rGO-treated cells showed significant biocompatibility and increased ALP activity compared to GO.</P><P><B>Conclusion</B></P><P>In this work, a nontoxic natural reducing agent of GbE was used to prepare soluble graphene. The as-prepared Gb-rGO showed significant biocompatibility with human cancer cells. This simple, cost-effective, and green procedure offers an alternative route for large-scale production of rGO, and could be used for various biomedical applications, such as tissue engineering, drug delivery, biosensing, and molecular imaging.</P>

All- <i>trans</i> retinoic acid-incorporated nanoparticles of deoxycholic acid-conjugated dextran for treatment of CT26 colorectal carcinoma cells

Jeong, Young Il,Chung, Kyu Don,Kim, Da Hye,Kim, Yoon Hyuk,Lee, Yeon Soo,Choi, Ki Choon Dove Medical Press 2013 INTERNATIONAL JOURNAL OF NANOMEDICINE Vol.8 No.-

<P><B>Purpose</B></P><P>All-<I>trans</I> retinoic acid (RA)-incorporated nanoparticles were prepared using deoxycholic acid-conjugated dextran (DexDA). Anticancer activity of RA-incorporated DexDA nanoparticles were tested in vitro and in vivo.</P><P><B>Methods</B></P><P>RA-incorporated nanoparticles were prepared by dialysis. Antiproliferative and anti-invasive potential of RA-incorporated nanoparticles were studied using CT26 colorectal carcinoma cells.</P><P><B>Results</B></P><P>RA-incorporated nanoparticles have small particle sizes of around 70–300 nm and spherical shapes. The higher drug-feeding ratio and higher substitution degree of deoxycholic acid in the conjugates resulted in higher drug contents, lower loading efficiency, and larger particle size. RA release rate became slower at higher drug contents and higher substitution degree of deoxycholic acid in the DexDA conjugates. The antiproliferation activity, anti-invasive activity, and matrix metalloproteinase 2 expression of RA-incorporated nanoparticles against CT26 cells in vitro was similar to RA. However, RA-incorporated nanoparticles had superior antimetastatic activity in an animal pulmonary metastatic model of CT26 cells compared to RA itself.</P><P><B>Conclusion</B></P><P>RA-incorporated nanoparticles showed similar anticancer activity in vitro and superior antimetastatic activity in vivo in a pulmonary metastatic model of CT26 cells. We suggest that RA-incorporated nanoparticles are promising vehicles for efficient delivery of RA.</P>