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      Single and multiple dose pharmacokinetics and tolerability of HX-1171, a novel antioxidant, in healthy volunteers


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          HX-1171 (1-O-hexyl-2,3,5-trimethylhydroquinone) is a promising antioxidant with therapeutic potential for hepatic fibrosis. The aim of this study was to investigate the tolerability and pharmacokinetics of HX-1171 in healthy volunteers.


          A randomized, single-blind, placebo-controlled, dose escalation study was conducted in 83 subjects. In the single ascending dose study, 20, 40, 80, 160, 300, 600, 1,200, 1,500 or 2,000 mg of HX-1171 was administered to 67 subjects. In the multiple ascending dose study, 500 or 1,000 mg was administered to 16 subjects for 14 days. The plasma and urine concentrations of HX-1171 were determined by using a validated liquid chromatography-mass spectrometry method. Pharmacokinetic parameters were obtained by non-compartmental analysis. Tolerability was assessed based on physical examinations, vital signs, clinical laboratory tests, and electrocardiograms.


          Adverse events reported in the study were all mild in intensity and resolved without any sequelae. HX-1171 was rapidly and minimally absorbed with a median time at maximal concentration of 0.63–1.50 hours and slowly eliminated with a terminal half-life of 21.12–40.96 hours. Accumulation index ranged from 2.0 to 2.2 after repeated dosing for 14 days. For both the single and multiple doses administrations, urinary concentrations indicated that less than 0.01% of the HX-1171 administered was excreted in urine.


          HX-1171 was well tolerated and minimally absorbed in healthy volunteers. The pharmacokinetic profile of HX-1171 was consistent with once-a-day dosing.

          Most cited references13

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          Confidence interval criteria for assessment of dose proportionality.

          The aim of this work was a pragmatic, statistically sound and clinically relevant approach to dose-proportionality analyses that is compatible with common study designs. Statistical estimation is used to derive a (1-alpha)% confidence interval (CI) for the ratio of dose-normalized, geometric mean values (Rdnm) of a pharmacokinetic variable (PK). An acceptance interval for Rdnm defining the clinically relevant, dose-proportional region is established a priori. Proportionality is declared if the CI for Rdnm is completely contained within the critical region. The approach is illustrated with mixed-effects models based on a power function of the form PK = beta0 x Dose(beta1); however, the logic holds for other functional forms. It was observed that the dose-proportional region delineated by a power model depends only on the dose ratio. Furthermore, a dose ratio (rho1) can be calculated such that the CI lies entirely within the pre-specified critical region. A larger ratio (rho2) may exist such that the CI lies completely outside that region. The approach supports inferences about the PK response that are not constrained to the exact dose levels studied. The proposed method enhances the information from a clinical dose-proportionality study and helps to standardize decision rules.
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            Risk factors of fibrosis in alcohol-induced liver disease.

            In patients with nonalcoholic steatohepatitis (NASH), age, obesity, and diabetes mellitus are independent predictors of the degree of fibrosis. The relative risk for fibrosis adjusted for sex was also associated with increasing grade of Perls stain. The aim of this study was to determine whether the risk factors for fibrosis described in NASH are also risk factors in alcohol-induced liver disease. A total of 268 alcoholic patients with negative hepatitis B virus and hepatitis C virus serology underwent liver biopsy. Fibrosis was assessed semiquantitatively by a score fluctuating between 0 to 8. Liver iron overload was assessed by Perls staining and graded in 4 classes. We have used multivariate regression with partial correlation analysis to assess the variability of fibrosis score according to the value of 7 variables: sex, age, body mass index (BMI) in the past year before the hospitalization when the patient was asymptomatic, daily alcohol intake over the past 5 years, total duration of alcohol abuse, Perls grade, and blood glucose level. In the multivariate regression, fibrosis score was positively correlated with age (P =.001), BMI (P =.002), female sex (P <.05), Perls grade (P <.05), and blood glucose level (P <.05). Twenty percent of the variability of fibrosis score was explained by the 7 variables. In conclusion, after adjustment for daily alcohol intake and total duration of alcohol abuse, BMI, Perls grade, and blood glucose are also independent risk factors for fibrosis in alcohol-induced liver disease, raising therapeutic implications for the management of these patients.
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              Non-alcoholic fatty liver disease in older people.

              Non-alcoholic fatty liver disease (NAFLD) is principally a disease of middle and old age. Previous studies reported it to be benign in old age, however more recent studies suggest an increased mortality in the >60-year-olds. To define the prevalence of risk factors and the laboratory and histological differences between different age groups with NAFLD, in order to confirm/refute findings in previous smaller studies. Retrospective, cohort study set in a tertiary liver clinic in the UK. 351 consecutive patients with biopsy-proven NAFLD were divided into an older (> or =60), a middle-aged (> or =50 to <60) and a younger (<50) group. Blood pressure, body mass index, serum lipids, glucose, HbA1C, albumin, liver enzymes, bilirubin, mean cell volume (MCV), platelets, and insulin resistance were recorded. In addition, liver biopsy was analyzed for steatosis, inflammation and fibrosis. Older patients had significantly more risk factors (hypertension, obesity, diabetes, hyperlipidaemia). Albumin, alanine aminotransferase (ALT), ALT/aspartate aminotransferase ratio and platelets significantly reduced with advancing age. MCV and alkaline phosphatase significantly increased with increasing age. Older patients had significantly greater fibrosis on biopsy with less percentage fat, with the cirrhotic patients being significantly older than non-cirrhotics. Insulin resistance was similar in younger and older groups. NAFLD affects mainly the middle-aged and the elderly. With advancing age come more risk factors for its development. Older patients show more severe biochemical, haematological and histological changes, with cirrhotics having a significantly greater age than those with milder disease.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                23 March 2015
                : 9
                : 1735-1742
                [1 ]Department of Clinical Pharmacology and Therapeutics, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, Republic of Korea
                [2 ]Nippon Hypox Laboratories Inc., Yamanashi, Japan
                [3 ]College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea
                [4 ]Biotoxtech Co., Ltd, Cheongju, Republic of Korea
                Author notes
                Correspondence: Kyun-Seop Bae, Department of Clinical Pharmacology and Therapeutics, College of Medicine, University of Ulsan, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Republic of Korea, Tel +82 2 3010 4623, Fax +82 2 3010 4622, Email ksbae@ 123456amc.seoul.kr
                © 2015 Kim et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research

                Pharmacology & Pharmaceutical medicine
                hx-1171,antioxidant,pharmacokinetics,tolerability,healthy subjects


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