Efficacy and safety of entecavir plus carnitine complex (GODEX®) compared to entecavir monotherapy in patient with ALT elevated chronic hepatitis B: randomized, multicenter open-label trials. The GOAL study

Jun, Dae Won; Kim, Byung Ik; Cho, Yong Kyun; Kim, Hong Ju; Kwon, Young Oh; Park, Soo Young; Han, Sang Young; Baek, Yang Hyun; Jung, Yong Jin; Kim, Hwi Young; Kim, Won; Heo, Jeong; Woo, Hyun Young; Hwang, Seong Gyu; Rim, Kyu Sung; Choi, Jong Young; Bae, Si Hyun; Lee, Young Sang; Lim, Y.-S.; Cheong, Jae Youn; Cho, Sung Won; Lee, Byung Seok; Kim, Seok Hyun; Sohn, Joo Hyun; Kim, Tae Yeob; Paik, Yong Han; Kim, Ja Kyung; Lee, Kwan Sik

doi:10.3350/cmh.2013.19.2.165

Cited by 26 publications

(20 citation statements)

References 15 publications

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“…Several reports have revealed that carnitine supplementation has a positive effect on various liver diseases. Carnitine supplementation reportedly improves liver steatosis and fibrosis in patients with NASH and decreases alanine aminotransferase levels in patients infected with hepatitis B virus . In addition, we revealed that carnitine supplementation suppresses hepatitis C virus (HCV) replication and HCV‐induced oxidant stress .…”

Section: Discussionmentioning

confidence: 86%

L‐Carnitine Suppresses Loss of Skeletal Muscle Mass in Patients With Liver Cirrhosis

Ohara

Ogawa

Suda

et al. 2018

Hepatology Communications

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Liver cirrhosis (LC) is a major cause of secondary sarcopenia. Sarcopenia makes the prognosis worse; thus, novel therapeutic options for sarcopenia in patients with LC are urgently required as they are currently limited. In this retrospective study, 158 patients with LC were screened, and 35 of those patients who were treated with L‐carnitine for more than 6 months and for whom skeletal muscle mass changes could be evaluated by computer tomography were enrolled. Of the 158 patients, 79 patients who did not receive L‐carnitine supplementation served as controls. Cases and controls were propensity score matched for age, sex, presence of hepatocellular carcinoma, and branched chain amino acid administration, and changes in skeletal muscle mass and clinical data were compared. The 35 patients who received L‐carnitine supplementation and 35 propensity score‐matched patients who did not receive carnitine supplementation comprised the final enrollment. Compared with control patients, patients who received L‐carnitine had significantly worse liver function, which is associated with rapid progress of skeletal muscle depletion. However, loss of skeletal muscle mass was significantly suppressed in patients receiving L‐carnitine, and a significant effect was observed in patient subgroups stratified by age, sex, presence of hepatocellular carcinoma, and branched chain amino acid administration. The change ratios of most laboratory data, including vitamin D and insulin‐like growth factor 1 levels, were similar in the two groups, but ammonia levels were significantly less in those receiving L‐carnitine. However, even in patients receiving L‐carnitine but not showing an ammonia decrease, loss of skeletal muscle was significantly suppressed. Conclusion: L‐carnitine suppresses loss of skeletal muscle mass and may therefore be a novel therapeutic option for sarcopenia in patients with LC. (Hepatology Communications 2018; 00:000‐000)

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Section: Discussionmentioning

confidence: 86%

L‐Carnitine Suppresses Loss of Skeletal Muscle Mass in Patients With Liver Cirrhosis

Ohara

Ogawa

Suda

et al. 2018

Hepatology Communications

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“…Interestingly, among the NTCP inhibitors identified, indomethacin was also previously shown to reduce hepatitis B e antigen (HBeAg) and HBV-DNA in sera of silent HBV carriers (Bahrami et al, 2005; Kapicioğlu et al, 2000). Also, the known NTCP inhibitor L-carnitine showed higher ALT normalization rate in chronic HBV patients (Jun et al, 2013). In addition, a recent in vitro study showed that ezetimibe blocks hepatitis B virus infection by targeting a post-entry step(s) in the HBV life cycle, although minor effects on binding and uptake of viral particles were also observed (Lucifora et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Quantitative NTCP pharmacophore and lack of association between DILI and NTCP Inhibition

Dong

Ekins

Polli

2015

European Journal of Pharmaceutical Sciences

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The human sodium taurocholate cotransporting polypeptide (NTCP) is a hepatic bile acid transporter. Inhibition of NTCP uptake may potentially also prevent hepatitis B virus (HBV) infection. The first objective was to develop a quantitative pharmacophore for NTCP inhibition. Recent studies showed that hepatotoxic drugs could inhibit bile acid uptake into hepatocytes, without inhibiting canalicular efflux, and cause bile acid elevation in plasma. Hence, a second objective was to examine whether NTCP inhibition is associated with drug induced liver injury (DILI). Twenty-seven drugs from our previous study were used as the training set to develop a quantitative pharmacophore. From secondary screening from a drug database, six retrieved drugs and three drugs not retrieved by the model were tested for NTCP inhibition. Tertiary screening involved drugs known to cause DILI and not cause DILI. Overall, ninety-four drugs were assessed for hepatotoxicity and were assessed relative to NTCP inhibition. The quantitative pharmacophore possessed one hydrogen bond acceptor, one hydrogen bond donor, a hydrophobic feature, and excluded volumes. From 94 drugs, NTCP inhibitors and non-inhibitors were approximately equally distributed across the drugs of most DILI concern, less DILI concern, and no DILI concern, indicating no relationship between NTCP inhibition and DILI risk. Hence, an approach to treat HBV via NTCP inhibition is not expected to be associated with DILI.

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“…Besides, it has been shown that L-Cn displays immune suppressive properties in Crohn’s disease ( 13 , 14 ). On the contrary, previous studies demonstrated the protective effect of carnitine supplementation on ALT normalization in patients with CHB when combined with entecavir, improvement in sarcopenia and hyperammonemia in patients with liver cirrhosis, and hospital admissions reduction in patients with hepatic encephalopathy ( 15 – 18 ). However, available findings regarding plasma L-Cn levels in patients with chronic HBV infection remain somewhat contradictory, and the effect of L-Cn on the expression of inhibitory receptors and the production of suppressive cytokines by immune cells have not yet been fully elucidated.…”

Section: Introductionmentioning

confidence: 83%

High L-Carnitine Levels Impede Viral Control in Chronic Hepatitis B Virus Infection

et al. 2021

Front. Immunol.

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Persistent antigen exposure during chronic hepatitis B infection leads to exhausted immune responses, thus impeding viral control. In recent years, immunometabolism opens new therapeutic possibilities for the modulation of immune responses. Herein, we investigated the immunomodulatory effect of L-carnitine (L-Cn) on immune cells in chronic HBV infection. In this study, 141 treatment-naïve patients with chronic HBV infection, 38 patients who achieved HBsAg loss following antiviral treatment, and 47 patients who suffered from HBV-related HCC from real-life clinical practice were recruited. The plasma L-Cn levels were measured by ELISA. RNA sequencing was conducted to define the transcriptional profiles of peripheral blood mononuclear cells after L-Cn stimulation. In vitro assays were performed to assess the effect of L-Cn on immune cells; the frequencies and function of immune cells were analyzed by flow cytometry. We found that compared with patients with HBsAg loss, patients with HBsAg positivity and patients who suffered from HBV-related HCC had higher levels of L-Cn, and the plasma levels of L-Cn in the HBeAg-positive chronic hepatitis patients who had elevated ALT were significantly higher than that of HBeAg-negative chronic infection and HBsAg loss groups. Moreover, a positive correlation between plasma levels of L-Cn and HBsAg levels was found. Additionally, RNA sequencing analysis demonstrated that L-Cn altered the transcriptional profiles related to immune response. In vitro assays revealed that L-Cn suppressed the proliferation of and IFN-γ production by CD4+ and CD8+ T cells. It also down-regulated the proliferation and IgG production of B cells. Notably, L-Cn enhanced IL-10 secretion from regulatory T cells and up-regulated the expression of inhibitory receptors on T cells. Moreover, a variant in CPT2 (rs1799821) was confirmed to be associated with L-Cn levels as well as complete response in CHB patients following Peg-IFNα antiviral therapy. Taken together, the immunosuppressive properties of L-Cn may hinder the control of HBV in chronic HBV infection, implicating that L-Cn manipulation might influence the prognosis of patients with HBV infection.

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Efficacy and safety of entecavir plus carnitine complex (GODEX®) compared to entecavir monotherapy in patient with ALT elevated chronic hepatitis B: randomized, multicenter open-label trials. The GOAL study

Cited by 26 publications

References 15 publications

L‐Carnitine Suppresses Loss of Skeletal Muscle Mass in Patients With Liver Cirrhosis

L‐Carnitine Suppresses Loss of Skeletal Muscle Mass in Patients With Liver Cirrhosis

Quantitative NTCP pharmacophore and lack of association between DILI and NTCP Inhibition

High L-Carnitine Levels Impede Viral Control in Chronic Hepatitis B Virus Infection

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