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Background & Aims: One major cause of hepatic sinusoidal obstruction syndrome (HSOS) is the intake of pyrrolizidine alkaloid (PA)-containing products. Over 8000 PA-induced HSOS cases have been reported worldwide and at least 51 among them were suspected to be attributed to exposure to the Chinese medicine ‘Tusanqi’. PA-induced hepatotoxicity involves cytochrome P450-mediated metabolic activation of PAs to electrophilic pyrrolic metabolites which react with macromolecules, such as proteins. However, no studies have found such protein adduction in HSOS patients. We report one HSOS case confirmed by liver biopsy, where the patient claimed taking ‘Tusanqi’ as self-medication. Methods: The herb was analyzed by HPLC–MS, and its induced hepatotoxicity in rats was assessed by monitoring the alteration of serum ALT level and liver morphology. Blood pyrrole–protein adducts were determined by UPLC–MS. Results: The herb the patient consumed was identified as Gynura segetum, an erroneous substitute of non-PA-containing Sedum aizoon, called ‘Tusanqi’. Hepatotoxic PAs senecionine and seneciphylline were detected in G. segetum. In the PA-exposed patient, serum pyrrole–protein adducts were detected by a newly developed analytical approach. The animal study showed a good correlation of liver injury with the ingestion of G. segetum. Conclusions: For the first time, serum pyrrole–protein adducts were unequivocally detected in a PA-induced HSOS patient, and such adducts show a potential to be developed as a biomarker for the assessment of PA-induced HSOS. Similar to the well-known case of aristolochic acid-poisoning, the observed HSOS was confirmed to arise from the consumption of PA-containing G. segetum, an erroneous substitute of non-PA-containing S. aizoon. [ABSTRACT FROM AUTHOR]

Abstract: No drugs have been approved clinically for the therapy of hepatic fibrosis. Though interferon-γ (IFN-γ) is a highly effective anti-fibrotic agent in vitro and in some animal models in vivo, its anti-fibrotic potential in clinical trials has been disappointing, due to unwanted off-target effects and a short half-life period which results in poor efficacy. The aims of this study are to develop a new targeted drug delivery system to selectively deliver IFN-γ to hepatic stellate cells (HSCs) and to investigate whether it will improve the anti-fibrotic effect of IFN-γ and reduce its side effects in fibrotic livers. Sterically stable liposomes (SSLs) were modified by cyclic peptides (pPB) with a specific affinity for platelet-derived growth factor receptor-β (PDGFR-β), and then IFN-γ was encapsulated in the targeted liposomes (pPB-SSL-IFN-γ). In vitro, pPB-SSL was found to be taken up and internalized by cultured activated HSCs. The binding of FITC-labeled pPB-SSL to activated HSCs was in a time-dependent and concentration-dependent manner, which could be inhibited by excess unlabelled pPB-SSL, PDGF-BB, suramin or monensin. The inhibitory effect of pPB-SSL-IFN-γ on the proliferation of activated HSCs was respectively 7.24-fold and 2.95-fold higher than that of free IFN-γ and IFN-γ encapsulated in untargeted SSLs. In healthy rats, the tissue distribution, living-body tracing image analyses and pharmacokinetics study showed that pPB-SSL-IFN-γ accumulated mainly in the livers and had a longer half-life than free IFN-γ (3.98±0.52h vs. 0.21±0.03h). Furthermore, in rats with hepatic fibrosis induced by thioacetamide injection, FITC-labeled pPB-SSL was found to predominantly localize in activated HSCs by immunofluorescent double staining for FITC and albumin or α-smooth muscle actin (α-SMA). The enhanced anti-fibrotic effect of pPB-SSL-IFN-γ treatnment was indicated by significant decreases in the histologic Ishak stage, collagen I-staining positive areas, and α-SMA expression levels in fibrotic livers. In addition, pPB-SSL-IFN-γ treatment improved the leukopenia caused by low- and high-dosage free IFN-γ treatments. In conclusion, IFN-γ encapsulated in pPB-SSL had an extended circulation half-life and was selectively delivered to activated HSCs, which enhanced the anti-fibrotic effect of IFN-γ and reduced its side-effects in rats with hepatic fibrosis. Thus, pPB-SSL-IFN-γ may be an effective agent for the therapy of hepatic fibrosis. [Copyright &y& Elsevier]

Abstract: Background and aims: Few drugs have been confirmed to be effective for fulminant hepatic failure (FHF). The purpose of this study was to prepare sterically stable liposomes (SSL) encapsulating hepatic stimulator substance (HSS) and determine their therapeutic effect on FHF. Methods: HSS were encapsulated into SSL (HSS-SSL). FHF was induced in rats by thioacetamide (TAA) injection (400mg/kg, three times with a 24-h interval). The agents, including HSS-SSL, SSL, HSS, and sodium chloride (NS), were each injected intravenously 2h after the second and the third TAA injection. Results: Freshly prepared HSS-SSL had a mean size of 93.59nm and the average encapsulation efficiency was 37.20%. HSS encapsulated in SSL showed a longer half life and more potent target to injured livers than free HSS. Twenty-four hours after the third TAA-injection, the survival rate of HSS-SSL-treated rats (80%) was significantly higher than that of rats treated with NS (20%), SSL (25%), or HSS (50%). Histopathologic examination showed that there was the least necrosis and inflammation in the livers of HSS-SSL-treated rats. The incidence of stage 3 or 4 hepatic encephalopathy in HSS-SSL-treated rats was significantly lower than that in rats treated with other agents. The serum pro-inflammatory cytokine levels and hepatic lipid peroxidation levels were both markedly reduced, while hepatocyte proliferative rate was markedly increased after HSS-SSL treatment. Conclusion: Encapsulation by SSL markedly improved the therapeutic effect of HSS on FHF in rats. Encapsulation by SSL may be an effective approach to enhance the therapeutic potency of drugs for FHF. [Copyright &y& Elsevier]