- Email: [email protected]
405 SERUM LEVELS OF CHEMERIN, VASPIN, VISFATIN AND SPECAM-1 IN PATIENTS WITH CHRONIC HEPATITIS C
05f: VIRAL HEPATITIS − f) HEPATITIS C − CLINICAL (EXCEPT THERAPY) injury in hepatitis C and non-alcoholic steatohepatitis patients. The safety, tolerability, and pharmacokinetics (PK) of single and multiple oral dose administration of GS-9450 in healthy volunteers were studied. Gender and food effects were also evaluated. Methods: Two Phase I, randomized, double-blind, placebo-controlled studies were conducted to evaluate the PK of GS-9450 following single and multiple dose administration. Single ascending oral doses of 0, 5, 10, 20, 40, 80 and 120 mg of GS-9450 were administered to 48 healthy male volunteers. Volunteers in the 40 mg cohort who received the single dose in a fasted state also received GS-9450 after a high fat breakfast. Six female volunteers received GS-9450, 40 mg, to evaluate the effect of gender on GS-9450 PK. In the second study, 24 volunteers received multiple daily doses of 0, 40, 80 and 120 mg of GS-9450 over 15 days. Results: GS-9450 reached peak plasma concentrations (Cmax ) at 0.5−3 hours (hrs) post-dose. GS-9450 was eliminated with median elimination half-lives (T1/ 2 ) of approximately 10 to 16 hrs across all dose levels. Systemic exposure to GS-9450 increased in a dose-proportional manner over the range of single and multiple doses. Only 2−4% of the dose was excreted unchanged as GS-9450 in urine consistent with metabolism of GS-9450 in the liver. Neither food nor gender had a significant effect on the PK of GS-9450. GS-9450 was well tolerated without serious or severe adverse events (AEs). The most frequently reported AE was headache. There was no clear relationship between dose and incidence, frequency, onset or duration of treatment-related AEs, which were transient and mild in nature. One male volunteer discontinued dosing due to development of a rash of mild severity. No clinically significant changes in laboratory data, vital signs, and ECG values were observed. Conclusions: The half-life of GS-9450 supports once-daily dosing and no evidence was found for a significant gender or food effect on GS-9450 PK. GS-9450 was well tolerated by healthy male and female volunteers. 405 SERUM LEVELS OF CHEMERIN, VASPIN, VISFATIN AND SPECAM-1 IN PATIENTS WITH CHRONIC HEPATITIS C 1 , A. Gabriel2 , M. Waluga3 , W. Mazur4 , ˙ M. Kukla1 , K. Zwirska-Korczala A. Berdowska5 , B. Rybus-Kalinowska6 , M. Kalinowski7 , E. Wo´zniakGrygiel1 , R. Bułdak1 . 1 Physiology, 2 Pathomorphology, Medical University of Silesia in Katowice, Zabrze, 3 Gastroenterology, Medical University of Silesia in Katowice, Katowice, 4 Infectious Diseases, Medical University of Silesia in Katowice, Chorz´ow, 5 Microbiology and Biotechnology, Jan Długosz University, Czestochowa, 6 Basic Sciences, Medical University of Silesia in Katowice, Bytom, 7 First Department of Cardiology, Medical University of Silesia in Katowice, Zabrze, Poland E-mail: [email protected]
Introduction: The adipocytokine profile seems to play a distinct role in the pathogenesis of chronic hepatitis C (CHC). Chemerin, vaspin and visfatin are new adipokines with various suggested function which may modulate inflammatory reaction and insulin sensitivity. Platelet endothelial cell adhesion molecule (PECAM)-1 is adhesion molecule which plays a putative role in leukocyte-endothelial interaction and formation of new blood vessels. Aims and Methods: To assess adipokines and sPECAM-1 serum concentration and its association with biochemical parameters and morphological features and to evaluate relationship between adipokines and sPECAM-1 in CHC. 40 patients with CHC (Group 1) and 20 healthy volunteers (Group 2), similar in age and BMI [43.6(11.6) vs 40.9(11.8) years and 24.3(3.1) vs 23.9(3.3) kg/M2 , respectively] with normal fasting glucose and lipid profile were included. Results: Serum chemerin and visfatin levels were significantly higher in Group 1 compared to Group 2 [31.1(20.0) vs 6.1(2.4) ng/mL, p = 0.018 and 50.9(13.8) vs 23.7(3.8) ng/mL; p < 0.001] whereas vaspin level significantly decreased in CHC patients [0.72(0.4) vs 1.6(0.8) ng/mL, p = 0.01]. sPECAM-1 levels were higher in Group 1 but not significantly [8.4(1.6) vs 7.0(0.6) ng/mL, p = 0.22). Chemerin and visfatin were negatively associated with necro-inflammatory grade (r = −0.49, p = 0.01; r = −0.36, p = 0.007; respectively). The lowest levels of chemerin and visfatin were found in patients with moderate/severe inflammatory reaction: grade 3/4 − 14.4(10.9) and 39.2(15.0), grade 2 − 38.5(20.0)
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and 46.8(10.8), grade 1 − 52.4(26.2) and 65.1(27.8) ng/mL, p = 0.03 and p = 0.03, respectively. Vaspin and sPECAM-1 were higher, but not significantly in the case of more advanced fibrosis: stage 1 − 0.6(0.4) and 7.0(1.9), stage 2 − 1.0(0.4) and 7.9(1.6), stage 3/4 − 1.0(0.6) and 9.6(1.3), p = 0.80 and p = 0.24, respectively). Vaspin serum concentration was positively associated with sPECAM-1 (r = 0.38, p = 0.03). ROC curve analysis showed a fair discriminant power of serum chemerin and visfatin concentrations for detection of moderate/severe inflammatory activity with an area under curve (AUC) 0.78 and 0.63, respectively. Conclusions: Our findings support a complex interaction between analyzed adipokines and pathogenesis of inflammatory process in CHC. Further investigations on a greater number of patients are necessary to better determine the exact role of these adipokines in CHC pathogenesis. 406 HEPATITIS C VIRUS INFECTION AND CEREBROVASCULAR DISEASE MORTALITY M.-H. Lee1,2 , H.-I. Yang1 , C.-L. Jen1 , C.-H. Wang3 , Y.-M. Chiou4 , S.-L. You1 , C.-J. Chen1,2 . 1 The Genomics Research Center, Academia Sinica, 2 Graduate Institute of Epidemiology, College of Public Health National Taiwan University, Taipei, 3 Cardinal Tien Hospital, Taipei, 4 Taichung Veterans General Hospital, Taichung, Taiwan E-mail: [email protected] Background and Aims: Cerebrovascular disease is one of the leading causes of death worldwide. Hepatitis C virus (HCV) infection has been reported to be associated with the risk of carotid atherosclerosis, but the association between HCV infection and cerebrovascular diseases remains inconclusive. This prospective study was conducted to evaluate cerebrovascular disease mortality associated with HCV infection after adjustment for other traditional risk factors. Methods: This study enrolled 23,820 residents living in seven townships in Taiwan between 1991 and 1992. Participants were interviewed personally by structured questionnaires to collect information including demographic characteristics, cigarettes smoking, alcohol consumption, and history of diseases. They also provided blood samples for various serological and biochemical tests. There were 1,313 anti-HCV seropositives who were further examined for HCV RNA by polymerase chain reaction. National death certification profiles from 1991 to 2007 were utilized for computerized linkage to ascertain deaths from cerebrovascular diseases (ICD-9: 430–438). Person-years at risk were calculated for each person as time from enrollment date to either the date of death or to the end of 2007. Cox’s proportional hazard models were used to estimates of relative risks of dying from cerebrovascular diseases after adjustment for age, sex, smoking, alcohol consumption, educational levels, body mass index, serum levels of triglycerides and cholesterol, history of diabetes and hypertension, and glomerular filtration rate. Results: The mortality rate per 100,000 person-years was 66 and 171, respectively, for anti-HCV seronegative and seropositive participants. Compared with the anti-HCV-seronegative participants as the referent group, the multivariate-adjusted relative risk (95% confidence interval) of dying from cerebrovascular diseases was 1.39 (0.65−2.95) for anti-HCVseropositive and HCV RNA-seronegative participants and 2.82 (1.83−4.36) for anti-HCV-seropositive and HCV RNA-seropositive participants. Conclusions: Active HCV infection may be an independent risk predictor of cerebrovascular diseases.
Introduction: The adipocytokine profile seems to play a distinct role in the pathogenesis of chronic hepatitis C (CHC). Chemerin, vaspin and visfatin are new adipokines with various suggested function which may modulate inflammatory reaction and insulin sensitivity. Platelet endothelial cell adhesion molecule (PECAM)-1 is adhesion molecule which plays a putative role in leukocyte-endothelial interaction and formation of new blood vessels. Aims and Methods: To assess adipokines and sPECAM-1 serum concentration and its association with biochemical parameters and morphological features and to evaluate relationship between adipokines and sPECAM-1 in CHC. 40 patients with CHC (Group 1) and 20 healthy volunteers (Group 2), similar in age and BMI [43.6(11.6) vs 40.9(11.8) years and 24.3(3.1) vs 23.9(3.3) kg/M2 , respectively] with normal fasting glucose and lipid profile were included. Results: Serum chemerin and visfatin levels were significantly higher in Group 1 compared to Group 2 [31.1(20.0) vs 6.1(2.4) ng/mL, p = 0.018 and 50.9(13.8) vs 23.7(3.8) ng/mL; p < 0.001] whereas vaspin level significantly decreased in CHC patients [0.72(0.4) vs 1.6(0.8) ng/mL, p = 0.01]. sPECAM-1 levels were higher in Group 1 but not significantly [8.4(1.6) vs 7.0(0.6) ng/mL, p = 0.22). Chemerin and visfatin were negatively associated with necro-inflammatory grade (r = −0.49, p = 0.01; r = −0.36, p = 0.007; respectively). The lowest levels of chemerin and visfatin were found in patients with moderate/severe inflammatory reaction: grade 3/4 − 14.4(10.9) and 39.2(15.0), grade 2 − 38.5(20.0)
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and 46.8(10.8), grade 1 − 52.4(26.2) and 65.1(27.8) ng/mL, p = 0.03 and p = 0.03, respectively. Vaspin and sPECAM-1 were higher, but not significantly in the case of more advanced fibrosis: stage 1 − 0.6(0.4) and 7.0(1.9), stage 2 − 1.0(0.4) and 7.9(1.6), stage 3/4 − 1.0(0.6) and 9.6(1.3), p = 0.80 and p = 0.24, respectively). Vaspin serum concentration was positively associated with sPECAM-1 (r = 0.38, p = 0.03). ROC curve analysis showed a fair discriminant power of serum chemerin and visfatin concentrations for detection of moderate/severe inflammatory activity with an area under curve (AUC) 0.78 and 0.63, respectively. Conclusions: Our findings support a complex interaction between analyzed adipokines and pathogenesis of inflammatory process in CHC. Further investigations on a greater number of patients are necessary to better determine the exact role of these adipokines in CHC pathogenesis. 406 HEPATITIS C VIRUS INFECTION AND CEREBROVASCULAR DISEASE MORTALITY M.-H. Lee1,2 , H.-I. Yang1 , C.-L. Jen1 , C.-H. Wang3 , Y.-M. Chiou4 , S.-L. You1 , C.-J. Chen1,2 . 1 The Genomics Research Center, Academia Sinica, 2 Graduate Institute of Epidemiology, College of Public Health National Taiwan University, Taipei, 3 Cardinal Tien Hospital, Taipei, 4 Taichung Veterans General Hospital, Taichung, Taiwan E-mail: [email protected] Background and Aims: Cerebrovascular disease is one of the leading causes of death worldwide. Hepatitis C virus (HCV) infection has been reported to be associated with the risk of carotid atherosclerosis, but the association between HCV infection and cerebrovascular diseases remains inconclusive. This prospective study was conducted to evaluate cerebrovascular disease mortality associated with HCV infection after adjustment for other traditional risk factors. Methods: This study enrolled 23,820 residents living in seven townships in Taiwan between 1991 and 1992. Participants were interviewed personally by structured questionnaires to collect information including demographic characteristics, cigarettes smoking, alcohol consumption, and history of diseases. They also provided blood samples for various serological and biochemical tests. There were 1,313 anti-HCV seropositives who were further examined for HCV RNA by polymerase chain reaction. National death certification profiles from 1991 to 2007 were utilized for computerized linkage to ascertain deaths from cerebrovascular diseases (ICD-9: 430–438). Person-years at risk were calculated for each person as time from enrollment date to either the date of death or to the end of 2007. Cox’s proportional hazard models were used to estimates of relative risks of dying from cerebrovascular diseases after adjustment for age, sex, smoking, alcohol consumption, educational levels, body mass index, serum levels of triglycerides and cholesterol, history of diabetes and hypertension, and glomerular filtration rate. Results: The mortality rate per 100,000 person-years was 66 and 171, respectively, for anti-HCV seronegative and seropositive participants. Compared with the anti-HCV-seronegative participants as the referent group, the multivariate-adjusted relative risk (95% confidence interval) of dying from cerebrovascular diseases was 1.39 (0.65−2.95) for anti-HCVseropositive and HCV RNA-seronegative participants and 2.82 (1.83−4.36) for anti-HCV-seropositive and HCV RNA-seropositive participants. Conclusions: Active HCV infection may be an independent risk predictor of cerebrovascular diseases.