- Email: [email protected]
1136 HOMA-IR VS HOMA-AD AND LIVER AND LEUKOCYTES IRS1 IN ASSESSING INSULIN RESISTANCE (IR) IN LEAN NAÏVE HCV-INFECTED PATIENTS: MORE THAN LIPID METABOLISM IS INVOLVED
POSTERS Conclusions: These results indicated miR-449a promotes cell differentiation and restore partially the hepatocyte phenotype, which is apparently beneficial for HBV replication. Our findings provide a new concept to understand the role of miRNAs in HBV replication and present a useful way to identify host factors involved in HBV infection.
08b: VIRAL HEPATITIS C: CLINICAL (EXCEPT THERAPY)
1135 A STUDY OF UNIPEG® IN HEALTHY HUMAN SUBJECTS TO EVALUATE ITS SAFETY AND PHARMACOKINETIC BEHAVIOUR T. Ahmad1 , R. Ahsan2 , M.R. Raza3 , G. Saba4 . 1 Center for Bioequivalence Studies and Bioassay Research (CBSBR), International Center for Chemical and Biological Sciences, University of Karachi (ICCBS), Karachi, Pakistan; 2 Clinical Trial Labs, London, UK; 3 National Institute of Child Health (NICH), 4 CBSBR at ICCBS, University of Karachi, Karachi, Pakistan E-mail: [email protected] Background and Purpose: Peginterferon alfa 2a (20 kDa) derived from E. coli is a distinct variety of peginterferons. A pilot study of this drug (UNIPEG® ) was conducted on healthy human subjects to evaluate its safety and pharmacokinetic behavior in local population. Experimental: With due approval of the IEC operating under ICHICP guidelines ten healthy male subjects (Age: Years 25.2±5.33 (20–32); Weight: Kg 59.60±7.71 (60–74) were selected randomly from the Pakistani population after thorough screening and signing of the Informed Consent Document for an Open label, Single Dose study. Each subject received a subcutaneous injection of the drug (180 mg) in abdominal skin and blood samples were collected at 0 (predose) and 1, 2, 3, 6, 12, 24, 36, 60, 84, 108, 132 and 156 hours, and analyzed by a validated ELISA for Unipeg® . The assay with a dynamic range of 900 to 7 pg/mL gave an inter assay mean accuracy of 98.31% and precision of 8.59%. (n = 18). The safety and tolerance of the drug was evaluated by observation of Adverse Events and evaluating the change in general health parameters, hematological and biochemical test results during and after the study. Results: Pharmacokinetics: Presented as Mean±SEM (range). Cmax: 18.67±2.92 ng/ml (7.05–34.51); AUC0–∞ : 1440±113 h.mg/l] (969–2101); Absorption Half-Life: 17.02±2.06 h (10.37–29.26); Volume of Distribution: 8.933±1.72 L (4.81–18.34); Clearance: 0.112±8.21 ml/.h (71.96–155.96). Safety: No Sever Adverse Effect was observed however the most common Adverse Event (AE) was the fever; observed in all volunteers (n = 10), headache (6), Fatigue (5), Vomiting (4) and diarrhea, loss of appetite, body ache was observed in 3 volunteers. Three out of ten volunteers demonstrated decrease in WBC and platelets count. Insignificant changes in hematology returned to normal values within 16 days. Conclusions: The pharmacokinetic results of UNIPEG® correlate very well with those found for other pegylated interferons generally used in therapy. The safety profile of UNIPEG® was found very similar to those of reported in literature for unmodified IFNs and other pegylated interferons generally used in therapy. Future clinical trials are recommended to further establish the safety profile and pharmacokinetics.
1136 HOMA-IR VS HOMA-AD AND LIVER AND LEUKOCYTES IRS1 IN ASSESSING INSULIN RESISTANCE (IR) IN LEAN NAIVE HCV-INFECTED PATIENTS: MORE THAN LIPID METABOLISM IS INVOLVED M. Michalczuk1 , C.R. Kappel2 , M.R. Alvares-da-Silva3 . 1 Hospital de Clinicas de Porto Alegre, 2 Universidade Federal do Rio Grande do Sul, 3 Gastroenterology Division Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil E-mail: [email protected] Aims: HCV can induce IR, often assessed by HOMA-IR, which is subject of growing criticism. The novel index HOMA-AD, adiponectin-based, is suggested to be superior to HOMA-IR. This study was designed to compare for the first time HOMA-IR and HOMA-AD in HCV infected patients. Also we tried to examine the relationship between insulin receptors (IRS1) and adiponectin, an anti-inflammatory adipokyne, down-regulated in non-alcoholic fatty liver disease-related IR. Methods: 94 naive, non-obese (BMI < 30), non-diabetics, nondyslipidemics, and non-transplanted HCV infected patients were prospectively included and compared to 29 age-matched controls. Blood samples were taken to determine HOMA-IR and HOMA-AD. HCV genotype and viral load, and liver fibrosis were also evaluated. The study was approved by the Ethical Committee. All patients gave their written consent. Results: Mean glucose was higher in HCV (94.4±10.1) than controls (90.5±9.78) – P = 0.07, as well as median insulin (25th -75th percentiles) – HCV (8.62; 6.52–13.7) and controls (7.33; 4.74–10.7) – P = 0.004. HOMA-IR was higher in HCV patients – P = 0.002, and was related to the viral load above than 400,000 UI/mL (P = 0.02), but was not related to the fibrosis (P = 0.21) or the genotype (P = 0.89). Adiponectin and HOMA-AD were similar in the both groups – P = 0.29 and 0.45, respectively. HOMA-IR and HOMA-AD had a significant correlation either in cases (Spearman’s rho = 0.605; P < 0.001) and controls (p = 0.753; P < 0.001). There was no correlation between IRS-1 both in leukocytes and liver and serum adiponectin (Spearman’s rho=0.212 and 0.06; P = 0.22 and 0.734, respectively). Conclusions: 1. even in a low risk population, HCV is able to induce IR, as assessed by HOMA-IR, but HOMA-AD was not a useful tool in evaluating IR; 2. there was no relationship between leukocytes and liver IRS1 and adiponectin, suggesting that IR is not related to the lipid metabolism in HCV patients. 1137 LOW SERUM LEVELS OF LDL-CHOLESTEROL INVERSELY CORRELATE WITH OXYSTEROLS PLASMA LEVELS IN HCV INFECTED PATIENTS M. Arciello1,2 , S. Petta3 , B. Conti1 , V. Leoni4 , G. Iannucci5 , G. Labbadia5 , S. Sofia2 , C. Camma` 3 , A. Craxì3 , C. Balsano1,2 . 1 Andrea Cesalpino Foundation, Rome, 2 Internal Medicine and Public Health, University of L’Aquila, L’Aquila, 3 Cattedra & Unit` a Operativa di Gastroenterologia, Di.Bi.M.I.S., University of Palermo, Palermo, 4 Genetic Unit of Neurodegenerative and Metabolic Diseases, IRCCS National Institute of Neurology “C. Besta” Milan, Milan, 5 Internal Medicine, University of Rome “La Sapienza”, Roma, Italy E-mail: [email protected] Background and Aims: Hepatitis C virus (HCV) infection is characterized by increased oxidative stress (OS). This pathological condition can be appreciated through the evaluation of oxysterols plasma concentrations. Oxysterols are products of cholesterol peroxidation and may potentially interfering with several cellular functions. Furthermore may affect lipid metabolism modulating the Liver X Receptors (LXRs) activities. HCV exploits host lipid
Journal of Hepatology 2011 vol. 54 | S363–S534
S449
08b: VIRAL HEPATITIS C: CLINICAL (EXCEPT THERAPY)
1135 A STUDY OF UNIPEG® IN HEALTHY HUMAN SUBJECTS TO EVALUATE ITS SAFETY AND PHARMACOKINETIC BEHAVIOUR T. Ahmad1 , R. Ahsan2 , M.R. Raza3 , G. Saba4 . 1 Center for Bioequivalence Studies and Bioassay Research (CBSBR), International Center for Chemical and Biological Sciences, University of Karachi (ICCBS), Karachi, Pakistan; 2 Clinical Trial Labs, London, UK; 3 National Institute of Child Health (NICH), 4 CBSBR at ICCBS, University of Karachi, Karachi, Pakistan E-mail: [email protected] Background and Purpose: Peginterferon alfa 2a (20 kDa) derived from E. coli is a distinct variety of peginterferons. A pilot study of this drug (UNIPEG® ) was conducted on healthy human subjects to evaluate its safety and pharmacokinetic behavior in local population. Experimental: With due approval of the IEC operating under ICHICP guidelines ten healthy male subjects (Age: Years 25.2±5.33 (20–32); Weight: Kg 59.60±7.71 (60–74) were selected randomly from the Pakistani population after thorough screening and signing of the Informed Consent Document for an Open label, Single Dose study. Each subject received a subcutaneous injection of the drug (180 mg) in abdominal skin and blood samples were collected at 0 (predose) and 1, 2, 3, 6, 12, 24, 36, 60, 84, 108, 132 and 156 hours, and analyzed by a validated ELISA for Unipeg® . The assay with a dynamic range of 900 to 7 pg/mL gave an inter assay mean accuracy of 98.31% and precision of 8.59%. (n = 18). The safety and tolerance of the drug was evaluated by observation of Adverse Events and evaluating the change in general health parameters, hematological and biochemical test results during and after the study. Results: Pharmacokinetics: Presented as Mean±SEM (range). Cmax: 18.67±2.92 ng/ml (7.05–34.51); AUC0–∞ : 1440±113 h.mg/l] (969–2101); Absorption Half-Life: 17.02±2.06 h (10.37–29.26); Volume of Distribution: 8.933±1.72 L (4.81–18.34); Clearance: 0.112±8.21 ml/.h (71.96–155.96). Safety: No Sever Adverse Effect was observed however the most common Adverse Event (AE) was the fever; observed in all volunteers (n = 10), headache (6), Fatigue (5), Vomiting (4) and diarrhea, loss of appetite, body ache was observed in 3 volunteers. Three out of ten volunteers demonstrated decrease in WBC and platelets count. Insignificant changes in hematology returned to normal values within 16 days. Conclusions: The pharmacokinetic results of UNIPEG® correlate very well with those found for other pegylated interferons generally used in therapy. The safety profile of UNIPEG® was found very similar to those of reported in literature for unmodified IFNs and other pegylated interferons generally used in therapy. Future clinical trials are recommended to further establish the safety profile and pharmacokinetics.
1136 HOMA-IR VS HOMA-AD AND LIVER AND LEUKOCYTES IRS1 IN ASSESSING INSULIN RESISTANCE (IR) IN LEAN NAIVE HCV-INFECTED PATIENTS: MORE THAN LIPID METABOLISM IS INVOLVED M. Michalczuk1 , C.R. Kappel2 , M.R. Alvares-da-Silva3 . 1 Hospital de Clinicas de Porto Alegre, 2 Universidade Federal do Rio Grande do Sul, 3 Gastroenterology Division Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil E-mail: [email protected] Aims: HCV can induce IR, often assessed by HOMA-IR, which is subject of growing criticism. The novel index HOMA-AD, adiponectin-based, is suggested to be superior to HOMA-IR. This study was designed to compare for the first time HOMA-IR and HOMA-AD in HCV infected patients. Also we tried to examine the relationship between insulin receptors (IRS1) and adiponectin, an anti-inflammatory adipokyne, down-regulated in non-alcoholic fatty liver disease-related IR. Methods: 94 naive, non-obese (BMI < 30), non-diabetics, nondyslipidemics, and non-transplanted HCV infected patients were prospectively included and compared to 29 age-matched controls. Blood samples were taken to determine HOMA-IR and HOMA-AD. HCV genotype and viral load, and liver fibrosis were also evaluated. The study was approved by the Ethical Committee. All patients gave their written consent. Results: Mean glucose was higher in HCV (94.4±10.1) than controls (90.5±9.78) – P = 0.07, as well as median insulin (25th -75th percentiles) – HCV (8.62; 6.52–13.7) and controls (7.33; 4.74–10.7) – P = 0.004. HOMA-IR was higher in HCV patients – P = 0.002, and was related to the viral load above than 400,000 UI/mL (P = 0.02), but was not related to the fibrosis (P = 0.21) or the genotype (P = 0.89). Adiponectin and HOMA-AD were similar in the both groups – P = 0.29 and 0.45, respectively. HOMA-IR and HOMA-AD had a significant correlation either in cases (Spearman’s rho = 0.605; P < 0.001) and controls (p = 0.753; P < 0.001). There was no correlation between IRS-1 both in leukocytes and liver and serum adiponectin (Spearman’s rho=0.212 and 0.06; P = 0.22 and 0.734, respectively). Conclusions: 1. even in a low risk population, HCV is able to induce IR, as assessed by HOMA-IR, but HOMA-AD was not a useful tool in evaluating IR; 2. there was no relationship between leukocytes and liver IRS1 and adiponectin, suggesting that IR is not related to the lipid metabolism in HCV patients. 1137 LOW SERUM LEVELS OF LDL-CHOLESTEROL INVERSELY CORRELATE WITH OXYSTEROLS PLASMA LEVELS IN HCV INFECTED PATIENTS M. Arciello1,2 , S. Petta3 , B. Conti1 , V. Leoni4 , G. Iannucci5 , G. Labbadia5 , S. Sofia2 , C. Camma` 3 , A. Craxì3 , C. Balsano1,2 . 1 Andrea Cesalpino Foundation, Rome, 2 Internal Medicine and Public Health, University of L’Aquila, L’Aquila, 3 Cattedra & Unit` a Operativa di Gastroenterologia, Di.Bi.M.I.S., University of Palermo, Palermo, 4 Genetic Unit of Neurodegenerative and Metabolic Diseases, IRCCS National Institute of Neurology “C. Besta” Milan, Milan, 5 Internal Medicine, University of Rome “La Sapienza”, Roma, Italy E-mail: [email protected] Background and Aims: Hepatitis C virus (HCV) infection is characterized by increased oxidative stress (OS). This pathological condition can be appreciated through the evaluation of oxysterols plasma concentrations. Oxysterols are products of cholesterol peroxidation and may potentially interfering with several cellular functions. Furthermore may affect lipid metabolism modulating the Liver X Receptors (LXRs) activities. HCV exploits host lipid
Journal of Hepatology 2011 vol. 54 | S363–S534
S449