The benefits of prophylaxis in haemophilia have been demonstrated repeatedly. Prevention of bleeding and arthropathy [10, 11], better quality of life [16, 17], fewer school absences and higher academic achievement in young school-age children have been documented [18]. Importantly, children with VWD in a Swedish

cohort who started prophylaxis early never developed joint disease [12]. A few additional investigations have been reported using different VWF-containing concentrates [19, 20], [21, 22]. Common among these was the finding that prophylaxis appears to be effective at decreasing or eliminating bleeding, and that side effects are mild. No cases of thromboembolism have been reported. Neratinib purchase In the Swedish cohort, one patient developed an inhibitor. In a recent publication from Germany, a retrospective study of 32 patients was reported. Following a 12-month period, the monthly bleeding frequency was significantly reduced compared with the preprophylaxis values (3 vs. 0.07), and an selleck chemical inhibitor developed in one patient. Allo-antibodies against VWF are a rare complication of treatment with plasma-derived concentrates containing VWF [23]. They usually occur in type 3 VWD characterized by large deletions

of the VWF gene; however, there are currently no data regarding the clinical and molecular markers of these complications. In particular, there is no evidence that prophylaxis with VWF concentrates triggers their appearance as in almost all cases reported, the antibodies developed during on-demand treatment. In this study, the effect of prophylaxis appeared to be most pronounced in the case of joint bleeding, as has been observed in other investigations [12]. Joint haemorrhage occurs when FVIII levels are low. Haemarthroses are prevented primarily by the increase in FVIII levels during prophylaxis and not impacted by the VWF levels, per se. Mucosal bleeding, i.e. epistaxis, GI bleeding

and menorrhagia, was reduced but not to the same degree, perhaps because these haemorrhages are not only dependent on normal circulating levels of active VWF, but also on the presence of discrete concentrations Liothyronine Sodium of normal VWF inside the platelets and within endothelial matrices. These considerations of the biology and physiopathology of VWF should be kept in mind when therapeutic approaches are chosen to stop or prevent mucosal bleeding, especially in patients with VWD types 3 or 2A, which are characterized by absent or abnormal VWF in platelet and endothelial sites. In ex vivo experiments, the lack of normal platelet VWF was reported to be the major factor for impaired platelet adhesion to subendothelium in patients with VWD types 3 and 2A [24]. More importantly, when patients with VWD type 3 were given large doses of cryoprecipitate containing all the VWF multimers, all could correct VWF:RCo whereas 60% still showed prolonged bleeding time (BT), the surrogate marker of the cellular defect of VWF at the vascular sites.

Accordingly, low-dose prednisolone and azathioprine doses (50 mg/day) were administrated to recover her liver function, after which her liver function regained normalcy. This case illustrates that a pregnant woman with non-comatose autoimmune acute liver failure in the first or second trimester of pregnancy and her fetus can be rescued

by PE/CHDF therapy and safe moderate doses of prednisolone. “
“Background:  The significance of H63D homozygosity remains uncertain, although it is associated with a tendency for patients to develop iron overload. Aims:  To study the prevalence of homozygotic H63D mutation in patients with phenotypic hemochromatosis (PH) and to compare the results with those of the general population and with patients with porphyria cutanea tarda (PCT) in the Basque Country, Spain. A secondary aim was to evaluate the differences in phenotypic expression and liver injury according to different genotypes in the PH cohort. Methods:  Selleckchem Nutlin3 Mutations of the HFE gene were obtained by polymerase chain reaction (PCR). Forty consecutive patients diagnosed with PH, 116 PCI-32765 price controls and 54 patients with PCT were included in the study. We performed liver biopsies, measured liver iron concentration (LIC), by

atomic spectrophotometry, serum ferritin and transferrin saturation, and compared the histology according to the genotype. Results:  The H63D homozygote mutation was identified in 7.76% of the control group, in 7.50% of the PH group, and in 11.11% of patients with PCT (P > 0.05). The C282Y/C282Y mutation was present in 50% of patients with PH, and LIC was identified in 15/20. The LIC in C282Y/C282Y patients was higher than in H63D/H63D patients (P = 0.26), while H63D homozygosis caused greater iron overload in PH patients than other genotypes. All the C282Y/C282Y genotype patients had elevated serum ferritin and transferrin saturation. The H63D homozygotes had high ferritin, but two out of three had normal transferrin Alanine-glyoxylate transaminase saturation. Six of the eight patients with high-grade fibrosis

and genetic study results were found to be C282Y/C282Y. Conclusions:  The prevalence of H63D mutation in patients with PH in our region does not differ from that of the general Basque population. “
“The effects of various medications on lower gastrointestinal tract remains unknown. Here, we investigated the effects of nonsteroidal anti-inflammatory drugs (NSAIDs), low-dose aspirin, and antiplatelet drugs associated with diverticular bleeding. This prospective study involved patients with diverticulosis who underwent colonoscopy. Alcohol and smoking, medications, and Charlson comorbidity index and Gastrointestinal Symptom Rating Scale scores were assessed. The medications evaluated were nine kinds of NSAIDs, two kinds of low-dose aspirin, 10 kinds of nonaspirin antiplatelet drugs, three kinds of anticoagulants, acetaminophen, and corticosteroids. Adjusted odds ratios (aOR) were estimated by a logistic regression model.

How does one explain these discrepant results in different studies? First, the CH5424802 supplier association of APOC3 polymorphisms and NAFLD may differ with ethnicity. Though Petersen et al.5

found this association in both Indian and non-Indian subjects, the association was weaker in the latter group. All other studies have been in non-Asian patients. To resolve this issue, one would need large studies across multiple ethnic groups. Alternatively, larger studies in the Asian Indian population should help. The APOC3 gene is located in a region that contains several genes involved in lipid transport and metabolism. The observed relationship between APOC3 gene variants and NAFLD may be predicated on another gene, which is in linkage disequilibrium with the APOC3 gene. The association of APOC3 variants with different isoforms of that gene in various ethnic groups could then account for the discrepant observations. Second, the differences could be related to the anthropometric profile of subjects included in different studies. Petersen et al.5 studied persons without any risk factor of metabolic syndrome and with relatively lower body mass index (BMI) of 24.7 ± 3.6 and 24.1 ± 2.9 kg/m2 in Indian and non-Indian groups, respectively (note that a BMI of 24.7 may indicate overweight in Indians but normal body weight in European. In comparison, other studies included

larger proportions of persons with overweight/obesity, click here dyslipidemia and even full blown metabolic syndrome. For instance, in the Finnish study under discussion,10 subjects with wild-type and variant alleles of APOC3 had mean BMI of 32 and 31.5 kg/m2, mean waist circumferences of 106 and 103 cm, and prevalence rates of metabolic syndrome of 68% and 62%, respectively. The failure to find an association between APOC3 variants and NAFLD in one large study even when only persons with BMI < 25 kg/m2 were analyzed militates against this explanation;6 however, in that study, the presence of visceral obesity, which may be present despite normal

BMI, was not specifically looked for. Several other lines of evidence suggest that the influence of APOC3 promoter variants on insulin resistance, Baf-A1 cell line type 2 diabetes mellitus and NAFLD varies with the level of adiposity. In a recent study, the APOC3 –482T allele appeared to increase the risk of type 2 diabetes in lean persons but not in overweight persons, and the –455C allele in fact appeared to protect overweight persons against diabetes.11 The APOC3 variants increased the risk of myocardial infarction only among lean and insulin sensitive subjects, and not in those with insulin resistance and visceral obesity.12 More importantly, in a recent study, minor allele (–482T) of APOC3 was associated with high liver fat only among persons in the lowest tertile of waist circumference.

44, 45 In contrast to what has been observed for CD4+CD25hi T cells RO4929097 in vivo and NKT cells, our data suggest that CD8+CD28− Tregs are unlikely to play a major role in AIH because no difference in their number was observed between patients and controls. In sharp contrast to the behavior of CD4+CD25hi T cells and NKT cells, the number of γδ T cells is elevated during the active phases of the disease. Importantly, we have demonstrated increased production of their effector molecule, granzyme B, whose level of expression correlates

with biochemical indices of liver damage such as ALT and bilirubin levels; this suggests the direct involvement of this cell population in hepatic injury. This notion is further supported by the observation that in [A] patients, there is an inversion of the physiological

Vδ1/Vδ2 ratio in favor of Vδ1 cells, which have an enhanced ability to produce the proinflammatory cytokine IFN-γ. This finding is similar to what we have observed in patients with hepatitis C virus–related chronic liver disease, in which an inverted Vδ1/Vδ2 ratio is associated with active hepatitis with markedly elevated aminotransferase levels.46 Disruption of the physiological γδ T cell balance has also been linked to the inflammatory process in other autoimmune diseases.31, 32 In conclusion, our data show that a profound impairment of T cell regulation characterizes the adult form of AIH and is not confined to classical CD4+CD25hi T cells, in that it also involves NKT cells. Moreover, we have demonstrated that γδ T cells, normally Amino acid PLX4032 cell line able to perform both regulatory and effector functions, in AIH are skewed toward the latter and are likely to be involved in the pathogenesis of liver damage. Further studies are needed

to dissect the complex interplay between regulatory and effector cell functions in the circulation and in the livers of patients with AIH. This knowledge is essential for the establishment of cell-based immunotherapies aimed at restraining the inflammatory autoimmune attack while reconstituting tolerance to liver autoantigens. The authors are grateful to Dr. Alberto Quaglia for his assistance with the photography. Additional Supporting Information may be found in the online version of this article. “
“Aim:  To investigate direct effects of hepatitis B virus (HBV) on collagen type I in vitro. Methods:  Collagen type I were measured after LX-2 cell cultured with purified or serum HBV for 12, 24 and 48 h. Furthermore, evidence of HBV infection to LX-2 were detected, and different inhibitors were used to identify pathways regulating collagen I expression. Results:  The 3 × 105 IU/mL purified/serum HBV increased collagen type I mRNA expression by 2.2-/3.2- and 1.3-/1.

44, 45 In contrast to what has been observed for CD4+CD25hi T cells BMS-354825 manufacturer and NKT cells, our data suggest that CD8+CD28− Tregs are unlikely to play a major role in AIH because no difference in their number was observed between patients and controls. In sharp contrast to the behavior of CD4+CD25hi T cells and NKT cells, the number of γδ T cells is elevated during the active phases of the disease. Importantly, we have demonstrated increased production of their effector molecule, granzyme B, whose level of expression correlates

with biochemical indices of liver damage such as ALT and bilirubin levels; this suggests the direct involvement of this cell population in hepatic injury. This notion is further supported by the observation that in [A] patients, there is an inversion of the physiological

Vδ1/Vδ2 ratio in favor of Vδ1 cells, which have an enhanced ability to produce the proinflammatory cytokine IFN-γ. This finding is similar to what we have observed in patients with hepatitis C virus–related chronic liver disease, in which an inverted Vδ1/Vδ2 ratio is associated with active hepatitis with markedly elevated aminotransferase levels.46 Disruption of the physiological γδ T cell balance has also been linked to the inflammatory process in other autoimmune diseases.31, 32 In conclusion, our data show that a profound impairment of T cell regulation characterizes the adult form of AIH and is not confined to classical CD4+CD25hi T cells, in that it also involves NKT cells. Moreover, we have demonstrated that γδ T cells, normally Selleck Ponatinib Tofacitinib datasheet able to perform both regulatory and effector functions, in AIH are skewed toward the latter and are likely to be involved in the pathogenesis of liver damage. Further studies are needed

to dissect the complex interplay between regulatory and effector cell functions in the circulation and in the livers of patients with AIH. This knowledge is essential for the establishment of cell-based immunotherapies aimed at restraining the inflammatory autoimmune attack while reconstituting tolerance to liver autoantigens. The authors are grateful to Dr. Alberto Quaglia for his assistance with the photography. Additional Supporting Information may be found in the online version of this article. “
“Aim:  To investigate direct effects of hepatitis B virus (HBV) on collagen type I in vitro. Methods:  Collagen type I were measured after LX-2 cell cultured with purified or serum HBV for 12, 24 and 48 h. Furthermore, evidence of HBV infection to LX-2 were detected, and different inhibitors were used to identify pathways regulating collagen I expression. Results:  The 3 × 105 IU/mL purified/serum HBV increased collagen type I mRNA expression by 2.2-/3.2- and 1.3-/1.

2A, Supporting Table 2). Analysis of cyclin B1 and Cdk1 expression by western blot confirmed mitotic delay. These results clearly demonstrate dysregulated cell cycle progression in the hepatocytes of β2SP+/− mice and suggest that, whereas mutant hepatocytes

seem to have an accelerated G1/S phase, there is a definite delay in progression through the G2 and M phases. Given evidence of dysregulated cell cycle in β2SP+/− mice following PHx, we then assessed the expression of the checkpoint proteins p53 and p21 in wildtype and mutant mouse livers. Analysis of Roxadustat nmr p53 and p21 expression by western blot demonstrated a significant impairment in their expressions at different timepoints post-PHx in β2SP+/− mouse livers in comparison to wildtype mouse livers (Fig. 3, Supporting Table 2). Moreover, the peak in p53 and p21 expression in mutant mice correlated with diminished levels of cyclin A and Cdk1 and delayed expression of p-histone (Ser10) (Fig. 2), suggesting that p53 and p21 may activate the G2/M-phase cell cycle checkpoint following PHx. To evaluate whether elevated p53 expression in mutant mice was secondary to impaired p53 regulation, we assessed transformed 3T3 cell double minute 2 (MDM2) and phosphatase and tensin homolog (PTEN) expression by western blot. PTEN may protect p53 from MDM2-mediated degradation and enhance p53 stability, whereas p53 can enhance

the transcription of PTEN.19 We demonstrated identical levels of PTEN and significantly BMS907351 lower expression of MDM2 in mutant mice at 24 and 48 hours post-PHx (Supporting Fig. 1), suggesting enhanced p53 expression secondary to cellular or genotoxic stress and the DNA-damage response. G2/M-phase delay was further confirmed by analysis of phosphorylated Cdk1 (Thr14) (Fig.

2B, Supporting Table 2) and pSTAT3 (Tyr705) (Fig. 3, Supporting Table 2) expression. We then performed the Transferase-Mediated dUTP Nick-End Labeling (TUNEL) assay to determine whether p53 may mediate increased apoptosis leading to impaired regeneration. Cleaved caspase expression was virtually absent or significantly reduced in mutant mice compared with wildtype mice, particularly VAV2 at 48 hours post-PHx. There was no evidence of correlating cleaved caspase-3 expression with either elevated p53 or p21 in mutant mice (Fig. 3). Similarly, results for the TUNEL assay were also negative at 48 hours (Supporting Fig. 2). These results further confirm a temporary p53-p21-mediated G2/M-phase arrest leading to delayed liver regeneration in β2SP+/− mice. Activation of p53 in response to DNA damage is mediated by phosphorylation on serine 15 and 20 by the kinases ATM/ATR and Chk2. Phosphorylation of p53 then results in an activated protein with numerous transcriptional targets necessary for cell cycle arrest, DNA repair, or apoptosis.

The PVX-CP gene was amplified by reverse transcription-polymerase chain reaction, cloned and expressed in Escherichia coli. For immunization, the CP fractions from bacterial lysate were purified either by simple fractionation or by excision from sodium buy Tanespimycin dodecyl sulphate gels. The PVX-CP was injected into rabbits for antibody production. The PVX-CP antibodies reacted in an indirect plate trapped antigen enzyme-linked immunosorbent assay and immunoblot assay and were useful for the detection

of a broad spectrum of isolates of PVX. “
“During 2010, a new foliar blight was detected on potted Dodonaea viscosa cv. Purpurea plants in two nurseries in Catania (Italy). On the basis of morphological and cultural features, the pathogen was identified as Phytophthora palmivora. The internal transcribed spacer (ITS)-rDNA sequence of a representative Phytophthora isolate from hopbush showed 99% identity with other ITS sequences of different P. palmivora isolates available in GenBank, thus confirming the morpho-cultural identification. Koch’s postulates were fulfilled by pathogenicity

tests on potted EGFR cancer D. viscosa cv. Purpurea seedlings. To our knowledge, this is the first report of P. palmivora foliar blight disease on D. viscosa. “
“The anthracnose pathogen, Colletotrichum gloeosporioides (Penz.) Penz. & Sacc., is a major cause of disease in the avocado industry, causing significant economic losses, and infects all cultivars. In South Africa, cvs Fuerte and Hass are the most widely grown. Identification of genes differentially expressed in avocado during infection with the fungus represents an important step towards understanding the plants defence responses and would assist in designing appropriate intervention strategies. In this study, 454 sequencing and analysis of the transcriptome of infected cv. Fuerte avocado fruits were performed using the second Roche 454 GS FLX Titanium platform. cDNA libraries enriched for differentially

expressed genes were constructed from unharvested and harvested avocado fruit tissues collected after 1, 4 and 24 h postinfection (early response) and after 3, 4, 5 and 7 days postinfection (late response), then sequenced. RT-PCR was used to validate the sequencing results. The single sequencing run produced 215 781 reads from the transcriptome with an average sequence length of 252–300 nucleotides. A total of 70.6 megabases of sequence data were generated and subjected to BLAST searches from which 639 genes encoding proteins functioning in metabolism, signal transduction, transcriptional control, defence, stress, transportation processes and some genes with unknown functions were identified. Avocado is able to respond to C. gloeosporioides infection by exhibiting a sophisticated molecular system for pathogen recognition and by activating structural and biochemical defence mechanisms.

21 Together, these observations 17-AAG concentration suggest that catabolism of existing adipose stores may be essential for

normal hepatic regeneration. To address this possibility, regeneration was examined in fld mice.22 The fld mice are homozygous for a mutation in Lpin1, which results in markedly diminished adipose tissue depot size throughout the body.22 Strain-matched wild-type and heterozygous mice appear identical to each other and exhibit comparable amounts of total body fat (18% ± 2% and 18% ± 1%, respectively, versus 13% ± 1% in fld mice; assessed by MR spectroscopy). Wild-type and heterozygous mice also demonstrate equivalent hepatocellular proliferation 36 hours after two-thirds partial hepatectomy, the time of peak proliferation in this model (Fig. 4C). Therefore,

heterozygous mice were used as controls for analyses of liver regeneration in fld animals. These experiments showed that the regenerative response to partial hepatectomy was significantly impaired in fld mice, with reduced hepatocellular BrdU incorporation (Fig. 4A-C) and cyclin D1 mRNA and protein expression (Fig. 5A-C) compared to controls. The fld mice also exhibited diminished hepatocellular mitotic frequency (Fig. 2D-F; *P = 0.11 at 48 hours; P = 0.06 at 72 hours) and delayed recovery of liver mass (57% ± 5% versus 62% ± 1% in controls at 72 hours after partial hepatectomy, P = 0.2); SCH 900776 however, these differences were not significant. Postoperative mortality was modestly increased in fld mice with 3 of 42 animals dying within 24 hours after partial hepatectomy compared to 0 of 44 heterozygous controls (P = 0.08). There was no increase in hepatic tissue necrosis in surviving P-type ATPase null mice compared to controls (Fig. 4D,E). The hepatic regenerative response to CCl4 administration was also investigated, with administration of CCl4 at a dose sufficient to induce robust regeneration in wild-type mice (Fig. 2) resulting in lethality in four of four fld mice versus one of

four controls. Together, these data show that liver regeneration is impaired in lipodystrophic fld mice. Next, changes in systemic metabolism after partial hepatectomy were examined in fld mice. The results showed that regenerating liver from fld mice contained significantly less triglyceride than controls (Fig. 6A). Triglyceride content was also reduced in quiescent fld liver, which likely reflects both the systemic adipose deficiency of fld mice and the increased hepatic triglyceride content at baseline in the BALBc genetic background.23fld mice exhibited less severe hypoglycemia 12-24 hours after partial hepatectomy (Fig. 6B) and higher plasma insulin levels 48-72 hours after surgery (Fig. 6C) compared to controls.

There are studies indicating that they have increased vascular resistances in nonsplanchnic vascular territories, such as the brain, kidneys, muscle, and skin.[27, 28] The percentage of patients with grade 1 and 2 LVDD was more significant in the group of patients with ascites and increased PRA than those with ascites, but normal PRA, or without ascites. Patients with cirrhosis with significant effective arterial blood volume showed arterial hypotension and reduced left

ventricular systolic function (CO and LV stroke work) and cardiac chronotropic function, as compared Small molecule high throughput screening to the other two groups. These data indicate that cardiac dysfunction plays an important role in the pathogenesis of the impairment of effective arterial blood volume in cirrhosis. Our results indicate that nonazotemic patients with cirrhosis with LVDD are specially predisposed to develop HRS. During follow-up, HRS type 1 was diagnosed in 14 of 80 (17%) patients. Patients who went on to develop HRS type 1 were clearly at a more advanced stage of LVDD and lower effective arterial blood volume than patients who did not develop type 1 HRS. The categorization of patients

in three groups according to diastolic function has prognostic relevance. Patients without LVDD had the longest and those with grade 2 LVDD the shortest probability of survival. Cardiac dysfunction were related to degree of liver failure, as indicated see more by a higher prevalence of ascites and HE and higher Child-Pugh and MELD scores in patients with grade 2 LVDD than in those with grade 0 LVDD. This observation has also been reported by other studies.[2, 4, 10] However, our data indicate that the E/e′ ratio is an independent prognostic factor of survival. In addition, the accuracy of the E/e’ ratio in the prediction of survival was not modified by severity

of liver function estimated by MELD >15. Previous studies have also demonstrated that an E/A ratio ≤1 was an independent predictor of death in patients with cirrhosis who are treated with TIPS.[35, 36] These data indicate that the increased mortality risk in LVDD could be related to a more deteriorated cardiocirculatory function that occurs simultaneously and in Sclareol parallel with the progression of liver failure. The current investigation shows that cardiac dysfunction in cirrhosis is the result of several primary cardiac disorders, which correlated with the impairment of effective arterial blood volume and degree of liver failure. Our results suggest that LVDD and its severity is a sensitive marker of advanced cirrhosis, type 1 HRS development, and mortality. Therefore, the examination of any patient with cirrhosis and PH and normal creatinine should include an echocardiographic study with TDI, and when an E/e’ ratio >10 is diagnosed, it should be necessary to carry out a careful follow-up of patients who are candidates for LT.

The EC50 against key variants, Gt1a_Q30R and Gt1a_Y93H, observed frequently in patients

who fail NS5A inhibitor-based therapy are 3 and 6 pM respectively. The potency against all tested commonly observed Gt1 NS5A resistant variants resulting from a single nucleotide change is < 10 pM. MK-8408 is also pan-genotype; notably, the EC50 in the RG7204 order more difficult-to-in-hibit Gt3a replicons, NC009824 and S52, are 0.3 and 3 pM respectively. De novo resistance selection studies in Gt1 replicon cells demonstrated that two or more mutations at positions 28, 30, 31 and 93 were required to elicit resistance consistent with a high genetic barrier to resistance for the compound. No resistant Acalabrutinib variants were selected with MK-8408 in Gt1b_(con1) at ≥10X EC90. MK-8408 inhibited replicons bearing signature RAVs selected with NS3 protease and NS5B nucleotide and non-nucleotide inhibitors with no shift in potency relative to its wild-type activity. Preclinical studies support a once-daily oral administration of MK-8408 in patients chronically infected with HCV. Conclusions: We have identified a potent, pan-genotype NS5A inhibitor with activity against resistant variants

selected with previous inhibitors in the class. MK-8408 does not display evidence of cross-resistance when tested against RAVs from other HCV DAA classes and therefore provides an attractive alternative to patients who fail these www.selleck.co.jp/products/sorafenib.html therapies. Disclosures: Ernest Asante-Appiah – Employment: Merck Stephanie Curry -

Employment: Merck Patricia McMonagle – Employment: Merck and Co. Donna Carr – Employment: merck sharpe and dohme, merck research laboratory Frederick Lahser – Employment: Merck Robert Chase – Employment: Merck, Inc Stuart Black – Employment: Merck Eric B. Ferrari – Employment: Merck Paul Ingravallo – Employment: Merck & Co Wensheng Yu – Employment: Merck Joseph Kozlowski – Employment: Merck The following people have nothing to disclose: Rong Liu, Sony Agrawal, Laura Rokosz, Karin Bystol, Shiying Chen, Ling Tong Methods: A randomized, placebo-controlled, dose-escalation FTIH study was conducted in healthy volunteers (HV) to evaluate safety and pharmacokinetics (PK) of single dose (SD) and repeat doses (RD) of GSK175. A randomized, placebo-controlled, dose-escalation POC study is ongoing to evaluate safety, PK, and antiviral activity of GSK175 in chronic hepatitis C (CHC) subjects with HCV genotype (GT) 1, 2, or 3. Results: In the completed FTIH study, GSK175 SD (Fasted: 5, 15, 30, 60mg; Fed: 30mg) was given orally to 17 HV (13 active, 4 placebo). RD (Fasted: 10, 30, 60mg) was given to 30 HV (24 active, 6 placebo) once daily (QD) for 14 days. No drug-related adverse events (AEs) leading to discontinuation of drug or SAEs were reported. Treatment-related AEs were infrequent across the dose groups.