Here, we evaluated the role of BMSCs in liver regeneration and the underlying mechanisms. Methods: To assess the effects of cultured BMSCs on liver cirrhosis, BAY 57-1293 we systemically infused BMSCs into thioacetamide-induced NOD-SCID cirrhotic mice. Liver fibrosis and antioxidant effects were assessed with Sirius red staining and a kinetic study of inhibition of diammonium salt oxidation. We also screened the profile of microRNAs in BMSC-infused livers using a miRNA array. We used thioacetamide to induce oxidative stress in vitro and confirmed the protective effects of BMSCs or exosomes derived

from BMSCs on oxidant conditions. We then measured cellular reactive oxygen species (ROS) and factors related to oxidative stress resolution in hepatocytes co-cultured with BMSCs or their exosomes. Results: BMSC-infused NOD-SCID mice showed reduced liver fibrosis (p<0.05), higher serum antioxidant activity (p<0.001), lower levels of hepatic malondialdehyde (p<0.05) and significantly higher amounts of hepatic miR-200a-3p, Rucaparib solubility dmso which targets Keap1 mRNA (ratio 3.67 vs. controls). Hepatocytes co-cultured with not only BMSCs, but also their

exosomes, showed lower levels of ROS (p<0.001). Hepatocytes in which the miR-200a-3p target site was blocked showed significantly higher levels of ROS, despite supplementation with exosomes of BMSCs in vitro. Conclusions: These results suggest that the selleck chemicals llc infusion of cultured BMSCs secreting exosomes, including miR-200a-3p, helped to improve liver fibrosis by stabilizing redox homeostasis. This indicates that a less invasive liver regeneration therapy for liver cirrhotic

patients using cultured autologous BMSCs is highly possible. Disclosures: Shuji Terai – Speaking and Teaching: Otsuka Pharma. The following people have nothing to disclose: Taro Takami, Luiz Fernando Quintanilha, Bruno D. Paredes, Koichi Fujisawa, Naoki Yamamoto, Isao Sakaida [Background/Aims] Recently, we identified a novel liver fibrosis glycobiomarker Wisteria floribunda agglutinin (WFA)-reactive colony stimulating factor 1 receptor (WFA+-CSF1R) using a glycoproteomics-based strategy. Elevated expression of CSF1R has been reported in a variety of malignancies of epithelial origin, including breast, prostate, and ovarian carcinomas. The aim of the present study was to assess the utility of measuring WFA+-CSF1R levels for hepatocarcinogenesis and outcome in patients with liver cirrhosis (LC). [Methods] WFA+-CSF1R and total CSF1R levels were measured by an antibody-lectin sandwich ELISA in serum samples from 207 consecutive hepatitis C virus (HCV)-infected patients from 1998 to 2013 in order to evaluate impact on carcinogenesis and survival of LC patients. The median age was 64 (21-87) and male was 110 (53.1%).

Here, we evaluated the role of BMSCs in liver regeneration and the underlying mechanisms. Methods: To assess the effects of cultured BMSCs on liver cirrhosis, CHIR-99021 manufacturer we systemically infused BMSCs into thioacetamide-induced NOD-SCID cirrhotic mice. Liver fibrosis and antioxidant effects were assessed with Sirius red staining and a kinetic study of inhibition of diammonium salt oxidation. We also screened the profile of microRNAs in BMSC-infused livers using a miRNA array. We used thioacetamide to induce oxidative stress in vitro and confirmed the protective effects of BMSCs or exosomes derived

from BMSCs on oxidant conditions. We then measured cellular reactive oxygen species (ROS) and factors related to oxidative stress resolution in hepatocytes co-cultured with BMSCs or their exosomes. Results: BMSC-infused NOD-SCID mice showed reduced liver fibrosis (p<0.05), higher serum antioxidant activity (p<0.001), lower levels of hepatic malondialdehyde (p<0.05) and significantly higher amounts of hepatic miR-200a-3p, SCH727965 mw which targets Keap1 mRNA (ratio 3.67 vs. controls). Hepatocytes co-cultured with not only BMSCs, but also their

exosomes, showed lower levels of ROS (p<0.001). Hepatocytes in which the miR-200a-3p target site was blocked showed significantly higher levels of ROS, despite supplementation with exosomes of BMSCs in vitro. Conclusions: These results suggest that the click here infusion of cultured BMSCs secreting exosomes, including miR-200a-3p, helped to improve liver fibrosis by stabilizing redox homeostasis. This indicates that a less invasive liver regeneration therapy for liver cirrhotic

patients using cultured autologous BMSCs is highly possible. Disclosures: Shuji Terai – Speaking and Teaching: Otsuka Pharma. The following people have nothing to disclose: Taro Takami, Luiz Fernando Quintanilha, Bruno D. Paredes, Koichi Fujisawa, Naoki Yamamoto, Isao Sakaida [Background/Aims] Recently, we identified a novel liver fibrosis glycobiomarker Wisteria floribunda agglutinin (WFA)-reactive colony stimulating factor 1 receptor (WFA+-CSF1R) using a glycoproteomics-based strategy. Elevated expression of CSF1R has been reported in a variety of malignancies of epithelial origin, including breast, prostate, and ovarian carcinomas. The aim of the present study was to assess the utility of measuring WFA+-CSF1R levels for hepatocarcinogenesis and outcome in patients with liver cirrhosis (LC). [Methods] WFA+-CSF1R and total CSF1R levels were measured by an antibody-lectin sandwich ELISA in serum samples from 207 consecutive hepatitis C virus (HCV)-infected patients from 1998 to 2013 in order to evaluate impact on carcinogenesis and survival of LC patients. The median age was 64 (21-87) and male was 110 (53.1%).

It was this glaring difference in clinical presentation that prompted me to prescribe indomethacin preventively to my patient with hemicrania continua, as opposed to considering him as having medication-overuse headache and discontinuing his use Everolimus concentration of aspirin, which he took

abortively on a daily basis, several times per day. Medication overuse represents the intake of analgesic and/or vasoconstrictor medications at a frequency that is detrimental rather than beneficial to the headache condition. Their intake may provide some temporary headache relief short term, but in the long run promotes the occurrence of headaches. The mechanisms involved include neglect of underlying headache pathophysiology and creation of a vascular rebound cycle, respectively. The latter occurs with the use of vasoconstrictor medications at intervals selleck compound that allow them to accumulate in the system, causing rebound vasodilation and headache whenever their effects wear off. Medication overuse is a common accompaniment of chronic daily headache, simply because of the frequency of headache occurrence. The vasoconstrictor agent most commonly involved in medication-overuse

headache is caffeine, either in caffeinated beverages or in combination products, such as the butalbital combinations. It is often not realized that caffeine’s plasma elimination is quite variable, and its half-life can be as long as 10 hours.[14] It takes up to 5 times the half-life for a medication to be eliminated from the system, which for caffeine means potentially up to 50 hours or a little over 2 days. In order to avoid accumulation in the system and, hence, rebound or medication-overuse headache, caffeine should not be taken for headache more often than 2 or 3 times per week. This precludes the

use of caffeine-containing medications, such as the butalbital combinations, for the treatment of chronic migraine with its occurrence of headache on a daily or almost daily click here basis. Interestingly, a study of 116 episodic migraineurs with regular caffeine intake found that complete cessation of caffeine intake produced a greater than 50% reduction in headache frequency, compared with 9.9% who reduced intake by 50% or more and 0% in those who made no change in their caffeine intake (P < .001).[15] In the studies reviewed above conducted by Robbins,[7] Robbins and Maides,[6] and Piekos and Spierings,[1] and as mentioned, the patients were not deliberately placed on daily triptan but rather discovered, on their own, that the triptan is highly effective for the treatment of their daily headaches.

It was this glaring difference in clinical presentation that prompted me to prescribe indomethacin preventively to my patient with hemicrania continua, as opposed to considering him as having medication-overuse headache and discontinuing his use PD0325901 ic50 of aspirin, which he took

abortively on a daily basis, several times per day. Medication overuse represents the intake of analgesic and/or vasoconstrictor medications at a frequency that is detrimental rather than beneficial to the headache condition. Their intake may provide some temporary headache relief short term, but in the long run promotes the occurrence of headaches. The mechanisms involved include neglect of underlying headache pathophysiology and creation of a vascular rebound cycle, respectively. The latter occurs with the use of vasoconstrictor medications at intervals EGFR activity that allow them to accumulate in the system, causing rebound vasodilation and headache whenever their effects wear off. Medication overuse is a common accompaniment of chronic daily headache, simply because of the frequency of headache occurrence. The vasoconstrictor agent most commonly involved in medication-overuse

headache is caffeine, either in caffeinated beverages or in combination products, such as the butalbital combinations. It is often not realized that caffeine’s plasma elimination is quite variable, and its half-life can be as long as 10 hours.[14] It takes up to 5 times the half-life for a medication to be eliminated from the system, which for caffeine means potentially up to 50 hours or a little over 2 days. In order to avoid accumulation in the system and, hence, rebound or medication-overuse headache, caffeine should not be taken for headache more often than 2 or 3 times per week. This precludes the

use of caffeine-containing medications, such as the butalbital combinations, for the treatment of chronic migraine with its occurrence of headache on a daily or almost daily selleck chemicals llc basis. Interestingly, a study of 116 episodic migraineurs with regular caffeine intake found that complete cessation of caffeine intake produced a greater than 50% reduction in headache frequency, compared with 9.9% who reduced intake by 50% or more and 0% in those who made no change in their caffeine intake (P < .001).[15] In the studies reviewed above conducted by Robbins,[7] Robbins and Maides,[6] and Piekos and Spierings,[1] and as mentioned, the patients were not deliberately placed on daily triptan but rather discovered, on their own, that the triptan is highly effective for the treatment of their daily headaches.

41,42 It therefore seems likely that modest increases in CXCR2 ligands may promote liver regeneration, while massive increments can be hepatotoxic. This concept has been further supported by in vitro studies which describe VDA chemical low dose MIP-2 pre-treatment was hepatoprotective

against hypoxia-reoxygenation injury, whilst hepatocytoxicity was observed with higher concentrations.39 An exactly analogous situation is observed with TNF, which is a hepatoprotective, pro-proliferative pathway of ischemic preconditioning, yet a key mediator of liver injury after IR in naïve livers.43 Toll-like receptors (TLRs) are trans-membrane proteins which form the major pattern recognition receptors that transduce signals in response to diverse pathogen-associated

molecular patterns (PAMPs).44 TLRs are ubiquitous. Their expression rapidly changes after exposure to triggers such as pathogens, cytokines and environmental stressors.44,45 PAMPs consist of lipids, lipoproteins, proteins and/or nucleic acids. Each TLR recognizes distinct PAMPs and their activation initiates innate and adaptive responses via cytokines, interferons, chemokines and their associated receptors.44–46 TLR activation also increases effector functions, such as phagocytosis, and enhances the capacity of T cell antigen presentation. selleck inhibitor Moreover, TLRs can recognize degradation products of host-derived molecules, called damage-associated molecular patterns (DAMPs); the latter includes extracellular matrix components such as heparan sulphate, hyaluronan fragments and fibronectin.47–49 There is growing evidence that TLRs in the liver, expressed on hepatocytes, Kupffer cells (KCs) as well as neutrophils, play an important role in the activation of immune cells in IR injury, and in mediating hepatocyte damage (Table 1).44,50 TLR signals emanate from either click here the cell surface (TLR1, TLR2, TLR4, TLR5, TLR6), or from the endolysosomal compartment (TLR3, TLR7, TLR9).44,46 Upon ligation, they undergo

conformational change and recruit cytoplasmic adaptor proteins via a Toll/Il-1 receptor (TIR) domain. The proximal adaptor proteins that mediate TLR signalling are myeloid-differentiation primary response gene 88 (MyD88), MyD88 adaptor-like protein (also known as Toll/Il-1 receptor adaptor-like protein, TIRAP), TIR domain-containing adaptor protein inducing interferon-β (TRIF) and TRIF-related adaptor molecule (TRAM). TIRAP and MyD88 mediate signals from TLR3, and together with TRAM, also from TLR4. Downstream of MyD88, regulatory kinases are recruited, leading to activation of NF-κB and mitogen activated protein kinase (MAPK) pathways. Type 1 interferons are activated downstream of TRIF. TLR4 is the only TLR that can activate both TIRAP-MyD88 and the TRAM-TRIF pathways. MyD88 is associated with all TLR types except TLR3 (Fig. 2).45,46 Its signalling via TLR2 and TLR4 requires TIRAP.

6 The onset and severity of denture stomatitis is of multifactorial origin, being influenced by factors such as salivary flow, denture cleanliness, age of prosthesis, denture base material, denture trauma, continuous denture wearing, smoking, and nutritional intake.7–10 Nevertheless, fungal biofilms play the most important role clinically.11,12 Denture-induced stomatitis is primarily caused by the opportunistic fungal pathogen Candida albicans; however, an increasing proportion of other Candidal species are

being implicated in pathogenesis, including C. glabrata.13 Although not life threatening per se, the collective presence of Candida species within the saliva, adhesion to the oral mucosa, and the colonization and development of biofilms on the denture surface are associated MAPK Inhibitor Library datasheet with mild-to-severe pathophysiological effects, according to Newton’s criteria.14–17 Once formed, cells within the biofilm undergo profound phenotypic changes. Most notably, they exhibit increased resistance

to antifungal agents.18,19 It has also been demonstrated that formation of biofilms in the cracks and imperfections of denture bases makes the biofilm resilient to physical forces, most notably removal by brushing.13,17,20 These studies highlight the inherent difficulties experienced by denture wearers in minimizing the fungal Protein Tyrosine Kinase inhibitor burden of their dentures, thereby preventing the onset of denture-induced stomatitis. Recent studies have established that sonication significantly

reduces the fungal burden upon removable dentures, and that microwave technology may this website offer a potential method of denture disinfection;21,22 however, these technologies have limited applicability due to either excessive costs or the capacity to damage the denture base material.23 Denture wearers therefore have to rely on the use of over-the-counter oral hygiene products, which has increased based on the large consumer base in this specialized healthcare market.6 This study aims to examine the efficacy of four over-the-counter denture cleansers to establish their respective capacities to remove and/or kill C. albicans biofilms. C. albicans-type strain ATCC 90028 and 16 clinical strains of C. albicans isolated from a recent denture stomatitis study were used in these investigations.13 All the isolates were stored on Sabouraud dextrose (SAB) agar plates (Oxoid, Cambridge, UK) at 4°C. C. albicans were propagated on SAB agar plates at 37°C overnight. A colony of each isolate was inoculated into 10 ml of yeast peptone dextrose (YPD, Oxoid) and placed in a shaker at 30°C overnight. The cells were washed by centrifugation in sterile phosphate-buffered saline (PBS; pH 7.4, Oxoid). The yeast cells were then counted using a Neubauer hemocytometer and adjusted to the required concentration in RPMI 1640 medium (Sigma, Dorset, UK).

The purpose of splenectomy was to improve hypersplenic thrombocytopenia and introduce IFN for clearance of the HCV virus. Forty-eight patients who underwent hepatectomy due to liver tumors were recruited as controls (control group 1). PB samples from 10 healthy adult volunteers (control group 2) and spleen tissues obtained by splenectomy from seven patients because of trauma (control group 3) were also used as controls. In addition, all patients were HIV negative. Patients received no medical treatment except splenectomy during the study period. All samples were studied after

obtaining EPZ-6438 supplier the appropriate institutional informed consent. We also obtained permission from the ethical review board. A total of 26 pieces from the resected liver specimens of patients with HCV-related liver cirrhosis and hypersplenism who underwent splenectomy were also examined for the immunohistochemical expression of CD4+ lymphocytes, CD8+ lymphocytes, FOXP3, granzyme B and TGF-β1 positive cells (Fig. 1). We classified liver specimens into five stages according to the degree of fibrosis as follows: F0, no fibrosis in the portal tract; F1, portal fibrosis without septa; F2, portal fibrosis with a few septa; F3, numerous septa without cirrhosis; and F4, cirrhosis. We

collected resected liver specimens from 10 cases PI3K activation each of F1, F2, F3 and F4 with HCV-related liver disease. We also collected specimens from eight cases of liver hemangioma of F0 with both negative hepatitis B surface antigen and HCV antibody. Follow-up liver biopsy sections find more were obtained from the same part of the liver if possible from seven of the 26 patients at various intervals after splenectomy

(Table 2). These sections were used for CD4 and CD8 immunostaining and Masson-trichrome staining for the morphometric evaluation of fibrotic areas. A total of 26 spleens with HCV-related liver cirrhosis and hypersplenism were examined for the immunohistochemical expression of CD4 positive lymphocytes, CD8 positive lymphocytes, FOXP3, granzyme B and TGF-β1 positive cells. We measured the same parameters in spleens from the seven control cases in control group 3 as a non-cirrhotic control (Fig. 1). Spleen and liver tissues were pathologically assessed by two pathologists (Y. N. and M. K.). Peripheral blood samples were serially collected from 26 patients with HCV-related liver cirrhosis and hypersplenism just before and 14 days, 1 month, 3 months, 6 months and 1 year after splenectomy. We examined the ratio of CD4+ T cells to all lymphocytes, CD8+ T cells to all lymphocytes, and the CD4+/CD8+ ratio in PB samples using flow cytometry. TGF-β1 levels in PB were also measured using enzyme-linked immunoassays in the sera just before and 14 days, 1 month, 3 months, 6 months and 1 year after splenectomy. Patients were excluded from the protocol if IFN or other therapeutics were introduced for the liver disease.

Cells were maintained at 37°C and 5% CO2 for 0-24 hours. Notably, all cell-culture experiments using LC3 western blotting (a protein central to autophagosome formation) as an endpoint were performed with the addition of the protease inhibitors, E-64d (10 mg/mL; Enzo Life Sciences) and pepstatinA (10 mg/mL; Sigma). Cells were then either harvested for protein extraction or fixed to coverslips with paraformaldehyde for immunohistochemistry. Animal protocols were approved by the University of Pittsburgh

Institutional Animal Care and Use Committee. Experiments CH5424802 price were performed in adherence to the National Institutes of Health Guidelines on the Use of Laboratory Animals. Cecal ligation and perforation (CLP) was performed on C57BL/6 male mice (Jackson Laboratories, Bar Harbor, ME) 6-8 weeks in age and weighing 20-25 g. These animals were anesthetized with pentobarbital (70 mg/kg, intraperitoneal [IP]). A 1- to 2-cm midline laparotomy was performed, and the cecum was identified. The stool was then manipulated to the tip of the C59 wnt clinical trial cecum and was subsequently ligated 1 cm from the tip with a 2-0 silk tie. The cecum was then perforated with a 22-gauge needle and returned into the abdomen. The muscle and skin were closed with a running 2-0 silk suture. Sham-operated animals underwent laparotomy

and bowel manipulation without ligation or perforation. Tissue and blood collection occurred at either 8 or 20 hours post-CLP. No antibiotics were used,

and animals had free access to food and water pre- and postoperatively. HO was inhibited in vivo through an IP injection of SnPP (50 mg/kg) 1 hour before CLP or with the use of in vivo HO-1–specific siRNA (50 μM/kg) (Invitrogen). This was administered via hydrodynamic tail vein injection, where the siRNA was made to the correct concentration in 2 mL of lactated ringers and given 3 days before CLP. The rapid injection of this large volume creates significant pressure to help promote siRNA uptake. Scrambled siRNA (50 μM/kg) was used as a control again via hydrodynamic tail vein injection. Autophagy was inhibited selleck kinase inhibitor through the use of in vivo siRNA against VPS34 (50 μM/kg; Invitrogen). p38 MAPK was inhibited in vivo through IP injections of SB203580 (10 mg/kg; Calbiochem) 1 hour before CLP. Cells were fixed on coverslips with paraformaldehyde for 15 minutes and then rinsed with cold phosphate-buffered saline (PBS). Slides were then stained for LC3 (Novus) to monitor autophagy. Liver tissue from mice was removed after perfusion with cold PBS and paraformaldehyde. Tissue was then placed in paraformaldehyde for 1 hour, then switched to 30% sucrose solution for 12 hours. The tissue was then slowly frozen in 2-methylbutane. Sections were stained using antibodies against LC3, HO-1 (Enzo Life Sciences), VPS34 (Invitrogen), and phosphorylated p38 MAPK (Cell Signaling). Images were taken with a Zeiss 510 inverted confocal microscope.

Cells were maintained at 37°C and 5% CO2 for 0-24 hours. Notably, all cell-culture experiments using LC3 western blotting (a protein central to autophagosome formation) as an endpoint were performed with the addition of the protease inhibitors, E-64d (10 mg/mL; Enzo Life Sciences) and pepstatinA (10 mg/mL; Sigma). Cells were then either harvested for protein extraction or fixed to coverslips with paraformaldehyde for immunohistochemistry. Animal protocols were approved by the University of Pittsburgh

Institutional Animal Care and Use Committee. Experiments Vincristine order were performed in adherence to the National Institutes of Health Guidelines on the Use of Laboratory Animals. Cecal ligation and perforation (CLP) was performed on C57BL/6 male mice (Jackson Laboratories, Bar Harbor, ME) 6-8 weeks in age and weighing 20-25 g. These animals were anesthetized with pentobarbital (70 mg/kg, intraperitoneal [IP]). A 1- to 2-cm midline laparotomy was performed, and the cecum was identified. The stool was then manipulated to the tip of the selleck kinase inhibitor cecum and was subsequently ligated 1 cm from the tip with a 2-0 silk tie. The cecum was then perforated with a 22-gauge needle and returned into the abdomen. The muscle and skin were closed with a running 2-0 silk suture. Sham-operated animals underwent laparotomy

and bowel manipulation without ligation or perforation. Tissue and blood collection occurred at either 8 or 20 hours post-CLP. No antibiotics were used,

and animals had free access to food and water pre- and postoperatively. HO was inhibited in vivo through an IP injection of SnPP (50 mg/kg) 1 hour before CLP or with the use of in vivo HO-1–specific siRNA (50 μM/kg) (Invitrogen). This was administered via hydrodynamic tail vein injection, where the siRNA was made to the correct concentration in 2 mL of lactated ringers and given 3 days before CLP. The rapid injection of this large volume creates significant pressure to help promote siRNA uptake. Scrambled siRNA (50 μM/kg) was used as a control again via hydrodynamic tail vein injection. Autophagy was inhibited selleck screening library through the use of in vivo siRNA against VPS34 (50 μM/kg; Invitrogen). p38 MAPK was inhibited in vivo through IP injections of SB203580 (10 mg/kg; Calbiochem) 1 hour before CLP. Cells were fixed on coverslips with paraformaldehyde for 15 minutes and then rinsed with cold phosphate-buffered saline (PBS). Slides were then stained for LC3 (Novus) to monitor autophagy. Liver tissue from mice was removed after perfusion with cold PBS and paraformaldehyde. Tissue was then placed in paraformaldehyde for 1 hour, then switched to 30% sucrose solution for 12 hours. The tissue was then slowly frozen in 2-methylbutane. Sections were stained using antibodies against LC3, HO-1 (Enzo Life Sciences), VPS34 (Invitrogen), and phosphorylated p38 MAPK (Cell Signaling). Images were taken with a Zeiss 510 inverted confocal microscope.

Reverse-transcription of RNA was performed using a SuperScript III First Strand Synthesis Supermix kit (Invitrogen, Carlsbad, CA) with random hexamers according

to the manufacturer’s instructions. Polymerase chain reaction was conducted with a Platinum PCR SuperMix kit (Invitrogen). Reaction products were purified on a Biomek FX system (Beckman Coulter, Fullerton, CA) using a magnetic bead kit (Agencourt Bioscience Corporation, Beverly, MA). DNA sequencing of purified material was conducted on a 3730xl DNA Analyzer (Applied Biosystems). To investigate a potential correlation between exposure to narlaprevir and antiviral activity, plasma samples were collected over the course of the study for pharmacokinetic profiling of narlaprevir with or without ritonavir. In period 1, serial blood narlaprevir pharmacokinetic samples were LY2157299 cell line taken on days 1 and 7. Additional narlaprevir pharmacokinetic learn more sampling was performed on days 2, 5, 6, and 7 for trough level (Cmin) determination. In period 2, serial blood narlaprevir pharmacokinetic samples were collected on days 1, 7, and 14, and additional pharmacokinetic samples for Cmin determination were obtained on days 2, 8, 10, 12, and 14. Plasma

concentrations of narlaprevir were determined using a validated liquid chromatographic–tandem mass spectrometric method with a limit of quantification of 6.08 ng/mL. Patients were monitored for safety and tolerability at regular intervals from the start of dosing through a follow-up visit 24 weeks after completion of SOC. Safety assessments included physical examination, vital signs, clinical laboratory tests, electrocardiograms, and the recording of all adverse events. Forty-one patients (10 patients each in cohorts 1-3 and 11 patients in cohort 4) were enrolled in the study. One patient in cohort 4 discontinued

immediately after the first dose on day 1 because of intolerance to the drug suspension; study medication was stopped at the discretion of the investigator, and this find more patient was replaced. A total of 40 patients completed the narlaprevir treatment phase of the study and initiated SOC immediately after period 2. Treatment-experienced patients consisted of 12 relapse patients and eight nonresponders. Demographic and other baseline characteristics of the randomized patients are shown in Table 1. The pharmacokinetic profile of narlaprevir 800 mg three times daily or 400 mg with ritonavir two times daily was characterized (Table 2). Exposure to narlaprevir with and without coadministration of PEG-IFN-α-2b for both treatment-naïve and treatment-experienced patients was comparable. Narlaprevir was eliminated more slowly when coadministered with ritonavir than when administered alone. Dose-normalized daily exposures (area under the curve) on day 14 in the presence of PEG-IFN-α-2b and ritonavir increased 7.