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      New IMB16-4 Hot-Melt Extrusion Preparation Improved Oral Bioavailability and Enhanced Anti-Cholestatic Effect on Rats


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          Cholestasis is challenging to treat due to lacked effective drugs. N-(3,4,5-trichlorophenyl)-2 (3-nitrobenzenesulfonamido) benzamide, abbreviated as IMB16-4, which may be effective for the treatment of cholestasis. However, its poor solubility and bioavailability seriously obstruct the research programs.


          A hot-melt extrusion (HME) preparation was first applied to increase the bioavailability of IMB16-4, the oral bioavailability, anti-cholestatic effect and vitro cytotoxicity of IMB16-4 and IMB16-4-HME were evaluated. Meanwhile, the molecular docking and qRT-PCR were used to validate the mechanism behind.


          The oral bioavailability of IMB16-4-HME improved 65-fold compared with that of pure IMB16-4. Pharmacodynamics results demonstrated that IMB16-4-HME prominently decreased the serum levels of total bile acid (TBA) and alkaline phosphatase (ALP), but elevated the level of total bilirubin (TBIL) and direct bilirubin (DBIL). Histopathology revealed that IMB16-4-HME at lower dose exhibited stronger anti-cholestatic effect compared with pure IMB16-4. In addition, molecular docking demonstrated that IMB16-4 has great affinity with PPARα, and qRT-PCR results revealed that IMB16-4-HME significantly elevated the mRNA expression level of PPARα, but decreased the mRNA level of CYP7A1. Cytotoxicity assays demonstrated that the hepatotoxicity of IMB16-4-HME was absolutely attributed to IMB16-4, and the excipients of IMB16-4-HME may increase the drug load within HepG2 cells.


          The HME preparation significantly increased the oral bioavailability and anti-cholestatic effect of pure IMB16-4, but caused liver injury at high dose, which require a dose balance between the curative effect and safety in the future research.

          Most cited references29

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          The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines

          Primary biliary cholangitis (formerly known as primary biliary cirrhosis, PBC) is an autoimmune liver disease in which a cycle of immune mediated biliary epithelial cell injury, cholestasis and progressive fibrosis can culminate over time in an end-stage biliary cirrhosis. Both genetic and environmental influences are presumed relevant to disease initiation. PBC is most prevalent in women and those over the age of 50, but a spectrum of disease is recognised in adult patients globally; male sex, younger age at onset ( 1.67 × upper limit of normal and/or elevated bilirubin) should be considered for second-line therapy, of which OCA is the only currently licensed National Institute for Health and Care Excellence recommended agent. Follow-up of patients is life-long and must address treatment of the disease and management of associated symptoms.
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            Primary biliary cholangitis

            Primary biliary cholangitis is an autoimmune liver disease that predominantly affects women. It is characterised by a chronic and destructive, small bile duct, granulomatous lymphocytic cholangitis, with typical seroreactivity for antimitochondrial antibodies. Patients have variable risks of progressive ductopenia, cholestasis, and biliary fibrosis. Considerations for the cause of this disease emphasise an interaction of chronic immune damage with biliary epithelial cell responses and encompass complex, poorly understood genetic risks and environmental triggers. Licensed disease-modifying treatment focuses on amelioration of cholestasis, with weight-dosed oral ursodeoxycholic acid. For patients who do not respond sufficiently, or patients with ursodeoxycholic acid intolerance, conditionally licensed add-on therapy is with the FXR (NR1H4) agonist, obeticholic acid. Off-label therapy is recognised as an alternative, notably with the pan-PPAR agonist bezafibrate; clinical trial agents are also under development. Baseline characteristics, such as young age, male sex, and advanced disease, and serum markers of liver injury, particularly bilirubin and ALP, are used to stratify risk and assess treatment responsiveness. Parallel attention to the burden of patient symptoms is paramount, including pruritus and fatigue.
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              Guidelines for the ethical review of laboratory animal welfare People’s Republic of China National Standard GB/T 35892‐2018 [Issued 6 February 2018 Effective from 1 September 2018]

              ABSTRACT These Chinese National Guidelines (GB/T 35892‐20181) were issued February 06, 2018 and became effective September 01, 2018. The authors recognized the urgent need for an authentic English translation to inform the international community of the compliance requirements in China. It was appreciated that the final translation must reflect the specialist understanding of those working under the Guideline whilst remaining faithful to the meaning of the original Chinese text. A three‐step translation process was therefore determined. Step 1: A professional interpretation service (KL Communications, UK) was commissioned to prepare a literal translation of the Chinese text. Supportive documents were provided which explained specialist terminology. This translation was checked by two bilingual experts. Step 2: A workshop was held in Nanjing in May 2019 to which were invited experts in laboratory animal welfare and ethical use. These included international native English‐speaking and Chinese‐speaking delegates. The delegates worked in multi‐lingual teams to review sections of the literal translation ahead of the workshop, and to agree an authentic interpretation during the workshop. Step 3: Following the workshop, three bilingual experts (two native Chinese speakers and one native English speaker) reviewed the entire document to ensure consistency of terminology and general accuracy. This document is thus not a “literal translation” but an “accurate interpretation” of the original text. Any challenge of work being performed under these Guidelines should rely on the Chinese text in the first place. However, this translation may be used as mitigating evidence, especially where those performing the work are non‐Chinese speakers.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                28 February 2023
                : 17
                : 649-657
                [1 ]Graduate School, Hebei Medical University , Shijiazhuang, People’s Republic of China
                [2 ]Hebei Key Laboratory of Metabolic Diseases, Hebei General Hospital , Shijiazhuang, People’s Republic of China
                [3 ]Department of Otolaryngology, Hebei General Hospital , Shijiazhuang, People’s Republic of China
                [4 ]Performance Assessment Department, Quality Management Department, Hebei General Hospital , Shijiazhuang, People’s Republic of China
                [5 ]Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College , Beijing, People’s Republic of China
                Author notes
                Correspondence: Hongtao Liu, Email lhtyl16@126.com
                Author information
                © 2023 Li et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                : 27 October 2022
                : 16 February 2023
                Page count
                Figures: 6, Tables: 5, References: 29, Pages: 9
                Original Research

                Pharmacology & Pharmaceutical medicine
                imb16-4,imb17-15,peroxisome proliferator activated receptor α,cholestasis,molecular docking


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