Ubiquitin-proteasome system inhibitors and AMPK regulation in hepatic cold ischaemia and reperfusion injury: possible mechanisms

In the present Hypothesis article, we summarize and present data from the literature that support our hypothesis on the potential mechanisms by which UPS (ubiquitin-proteasome system) inhibitors reduce I/R (ischaemia/reperfusion) injury in the liver. I/R is the main cause of primary liver failure and, consequently, minimizing the detrimental effects of this process could increase the number of suitable transplantation grafts and also enhance the survival rate of patients after liver transplantation. A potential strategy to reduce I/R injury is the use of UPS inhibitors either as additives to preservation solutions or as drugs administered to patients. However, there is still controversy over whether the use of UPS inhibitors is beneficial or deleterious with regard to liver injury. From our experience and the few studies that have investigated the role of UPS in hepatic I/R, we believe that the use of UPS inhibitors is a potential strategy to reduce I/R injury in liver transplantation and graft preservation. We hypothesize that one of the main mechanisms of action of UPS inhibitors may be the up-regulation of AMPK (AMP-activated protein kinase) activity and the consequent down-regulation of mTOR (mammalian target of rapamycin), which may finally influence autophagy and preserve the energy state of the cell.     

Tissue selectivity of hydroxymethylglutaryl coenzyme a (HMG CoA) reductase inhibitors

Hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors are a class of lipid-lowering medications, with a major activity on plasma cholesterol levels, now enjoying a vast popularity among physicians and patients. These drugs, affecting a very early and key step of sterol biosynthesis, differ to a large extent in their physicochemical properties, tissue distribution and side effects in animals, possibly in humans. Some of these agents (namely lovastatin and simvastatin) are strikingly lipophilic and require enzymatic conversion from the lactone to the open-ring forms, whereas pravastatin, active per se, is hydrophilic. Liver uptake of pravastatin is regulated by a carrier-mediated mechanism. Other HMG CoA reductase inhibitors have been designed, with the objective of obtaining high levels of hepato-selectivity. Evaluation of available date in terms of potential advantages in tissue, namely liver selectivity, of HMG CoA reductase inhibitors, suggests, that, indeed, altered sterol biosynthesis in a number of tissues may potentially result in the appearance of significant side effects. While there is no clear-cut relationship between tissue selectivity and lipophilicity, the presence of this latter feature seems, in general, to dictate a lesser absortion to peripheral tissues vs the liver. At present, the toxicological profile of major HMG CoA reductase inhibitors appears safe; it is, however, possible that in selected patient groups liver selectivity may offer a considerable therapeutic advantage.     

Drug interactions with antilipemics

The HMG-CoA reductase inhibitors (statins) and fibrates have been associated with myotoxicity, which, in some cases, has been fatal. Rhabdomyolysis is frequently observed during drug interactions with elevated plasma concentrations. Statins have a low oral bioavailability because of their intense first-pass extraction. Cytochrome P450 3A4 (CYP3A4) is responsible for the metabolism of atorvastatin and simvastatin which present the highest risk of drug interactions with CYP3A4 inhibitors, such as macrolides, antifungal agents, protease inhibitors, calcium channel blockers, amiodarone, and grapefruit juice. Fluvastatin has a low potential for drug interactions due to its CYP2C9-dependant metabolism. Pravastatin liver extraction does not involve CYPs and presents a low potential for drug interactions. Fibrates have a high oral bioavailability (approximately 100%), and this minimises the risk of drug interactions. However, fibrates alter the pharmacokinetics of some drugs, possibly via CYP2C9 and UDP-glucuronyltransferase (UGT) inhibition. Only three cholesterol-reducing agents have demonstrated their ability to reduce the incidence of cardiovascular death in long-term follow-up randomised trials among patients with atherosclerosis. Simvastatin exhibits the highest potential for drug interactions, pravastatin and gemfibrozil the lowest.     

A case of interstitial lung disease with atorvastatin (Tahor) and a review of the literature about these effects observed under statins

The 3-Hydroxy-3-methyl-glutaryl coenzyme A (HGM-CoA) reductase inhibitors, or statins, are competitive inhibitors of the rate-limiting enzyme in cholesterol synthesis. Generally, statins have an excellent safety profile. Elevations of liver transaminases and creatine phosphokinase with myalgia have been associated with the use of HGM-Co A reductase inhibitors, case reports of rhabdomyolysis are rare, most occurring with concomitant use with other drugs such as cyclosporin, fusidic acid and gemfibrozil. We describe here the clinical case of a patient who developed interstitial lung disease as probably a result of the use of statins which particularly increased with long-term atorvastatin treatment. The present review details some case-reports of interstitial lung disease reported under statins in the literature. Few systemic adverse effects such as lupus-like-syndromes and polymyositis have been reported. Recent experimentations have demonstrated that cholesterol is not the only intracellular target of statins but that they also have a potential role in atherosclerosis and in organ transplantation as immunosuppressor agents.     

Calcineurin inhibitor-induced headache: clinical characteristics and possible mechanisms

OBJECTIVE: To classify the headache syndromes under treatment with calcineurin inhibitors and to investigate whether the latter influence the nitric oxide production of human brain microvascular cells (HBMEC). BACKGROUND: Single cases of cyclosporine-induced headaches have been reported. Since calcineurin inhibitors are known to influence the renal metabolism of NO, a key molecule in tension-type headache and migraine, we were interested whether calcineurin inhibitors might change NO metabolism in HBMEC as well. DESIGN AND METHODS: Headache symptoms of 74 patients receiving cyclosporine and/or tacrolimus for organ transplantation were retrospectively assessed. Furthermore, the effect of cyclosporine and tacrolimus on nitric oxide production in human brain microvascular endothelial cells was investigated after incubation. RESULTS: Only 18 of the 74 patients reported no headache 1-36 months after liver, lung, or bone-marrow transplantation, 28 reported a new headache, and 17 an increase in the frequency or intensity of a pre-existing headache. The headache was generally classified as migraine without aura (IHS 1.1) or migraine-like headache (IHS 1.6). Furthermore, we found significantly increased NO production after co-incubation of calcineurin inhibitors with human brain microvascular endothelial cells. CONCLUSION: The pathophysiological mechanism of these headaches may be connected with an endothelial dysfunction in terms of increased production of NO.     

Serine protease inhibitors as anti-hepatitis C virus agents

Approximately 3% of the worldwide population (i.e., more than 170 million people) are chronically infected with the hepatitis C virus (HCV). An estimated 20% of these patients will develop liver cirrhosis within a mean of 20 years, and 2–5% of cirrhotic patients will die of end-stage liver disease or hepatocellular carcinoma. The currently approved antiviral therapy with pegylated interferon (pegIFN) and ribavirin induces a sustained virological response (SVR) in 40–50% of patients infected with genotype 1, the most prevalent HCV type. In this review, we focus on the development and clinical application of serine protease inhibitors as anti-HCV agents. Although highly active in inducing a significant decline of serum HCV RNA, the rapid development of resistance must be counteracted in combination with other antiviral agents, currently pegIFN-α and ribavirin. Two serine protease inhibitors have reached clinical Phase III trials, increasing SVR rates and shortening treatment duration when combined with pegIFN and ribavirin. Trials of interferon-free targeted combination therapies are currently underway.     

Hemophagocytic syndrome due to Epstein-Barr virus and cytomegalovirus coinfection in a patient on adalimumab

IntroductionHemophagocytic syndrome (HPS) is a rare but potentially fatal complication of viral infections. Epstein-Barr virus (EBV) and cytomegalovirus (CMV) often infect patients receiving TNF-alpha inhibitors (TNF-α inhibitors). While EBV and CMV are well established infections for the development of infectious mononucleosis, coinfection with EBV and CMV is common among immunosuppressed patients and can result in a fatal course. In addition, such viral infections can cause HPS. To the best of our knowledge, we present here the first report of HPS induced by EBV and CMV coinfection during anti-TNFα inhibitor use.Case reportA 23-year-old man hospitalized with fever, elevated liver enzymes, lymphadenopathy, and hepatosplenomegaly was diagnosed with HPS associated with EBV and CMV coinfection while using adalimumab. No clinical improvement was observed after discontinuation of adalimumab. HPS complicated by EBV and CMV coinfection was finally diagnosed, and immediate administration of ganciclovir and prednisone was considered to have prevented a lethal clinical outcome.ConclusionFor cases showing unexplained fever, elevated liver enzymes, and lymphadenopathy while using anti-TNFα inhibitors, screening for EBV and CMV coinfection should be encouraged. In addition, HPS should be considered in patients with EBV and/or CMV infection receiving anti-TNFα inhibitors to facilitate early definitive therapy.     

The Dipeptidyl Peptidase (DPP)-4 Inhibitors for Type 2 Diabetes Mellitus in Challenging Patient Groups

Treating hyperglycemia is a critical aspect of managing type 2 diabetes mellitus (T2DM), but can be especially challenging in patients from vulnerable groups such as those with chronic kidney disease, African Americans, and older people. The dipeptidyl peptidase (DPP)-4 inhibitors are relatively new oral antidiabetes drugs that have been incorporated into treatment algorithms over the past few years and have also been studied in these vulnerable patients. Clinical trials with DPP-4 inhibitors have now been reported for all these patient groups and have demonstrated significant improvements in measures of hyperglycemia, with a good safety profile. Based on the current evidence, it appears that the DPP-4 inhibitors are worthy of consideration not only for the most straightforward patients with T2DM, but also for these vulnerable patients.     

免疫治疗相关肝毒性的诊断与管理

免疫检查点抑制剂开启了肿瘤治疗的新时代，但随着临床应用的增加，免疫治疗相关不良反应亦不断被报道并逐渐引发关注。肝毒性是其中较常发生且具有一定致死性的严重不良反应，及早识别、诊断并对其进行恰当管理非常重要。目前国内外临床指南均对免疫治疗相关肝毒性的管理发布了指导性建议，但在肝毒性分级、激素使用剂量、激素治疗无效的后线治疗以及免疫治疗再挑战方面，仍存有较多争议和商榷空间。此外，早期识别肝毒性的发生、发现兼具灵敏度和特异度的预测指标具有重要意义。     

Transfusion medicine service policies for recombinant factor VIIa administration

Recombinant FVIIa (rFVIIa) has been approved for treatment of bleeding in hemophilia patients with inhibitors. It has also been successfully used in nonhemophilia patients with acquired antibodies against FVIII (acquired hemophilia). Pharmacological doses of rFVIIa have been found to enhance the thrombin generation on already activated platelets and, therefore, may also likely be of benefit in providing hemostasis in other situations characterized by profuse bleeding and impaired thrombin generation, such as patients with thrombocytopenia and in those with functional platelet defects. Additionally, it has been used successfully in a variety of less well-characterized bleeding situations, as well as in patients with impaired liver function. To date, case reports, anecdotal experience, and limited clinical trials describe these uses; data from randomized clinical trials are limited. Because of the recent trends in rFVIIa usage in non-approved settings among physicians from various disciplines, significant concerns about its safety, efficacy, and costs have arisen. Additionally, dosing of rFVIIa for these potentially broad clinical applications is not standardized. Currently, the decision on when and where to use rFVIIa for patients with uncontrolled bleeding continues to be one that must be made by individual physicians, assisted by their hospital pharmacotherapeutics and transfusion committees.     

GROWTH INHIBITION BY SUBSTANCES IN LIVER

Certain tissue constituents inhibitory to cell growth, extracted from liver, are described. The findings indicate that inhibitory material is adsorbed to colloids in the native state and is freed from them by alcohol extraction. One inhibitor, ethanolamine, has been isolated. This substance differs in its biological properties from the bulk of the inhibitory material present in liver. Progress in purification of other inhibitors is described, and it is shown that inhibition by these extracts is not correlated with surface activity or with the presence of pigmented constituents. The inhibitors have common properties which suggest that they are of physiological significance in the regulation of growth: action over a wide range of concentrations at which other cell functions are undamaged; reversibility of action; presence in adult liver in concentrations near those which inhibit growth in vitro, while in embryo liver they are found only in much lower concentrations.     

Nucleotide prodrugs for HCV therapy

HCV infection is a significant worldwide health problem and is a major cause of hepatocellular carcinoma. The current standard of care, interferon and ribavirin, is only effective against a proportion of the patient population infected with HCV. To address the shortcomings of existing therapy, the development of direct acting antiviral agents is under investigation. The HCV RNA dependent RNA polymerase is an essential enzyme for viral replication and is therefore a logical target against which to develop novel anti-HCV agents. Nucleosides have been shown to be effective as antiviral agents for other viral diseases and therefore, have been investigated as inhibitors of HCV replication. The development of prodrugs of nucleoside 5'-monophosphates has been pursued to address limitations associated with poor nucleoside phosphorylation. This is required to produce the nucleoside 5'-triphosphate which is the anabolite that is the actual inhibitor of the polymerase enzyme. Prodrugs of nucleoside 5'-monophosphates have been developed that enable their delivery into cells and in vivo into the liver. The implementation of these prodrug strategies has ultimately led to the identification of several prodrugs of nucleoside 5'-monophosphates that are potent inhibitors of HCV replication in vitro. They have progressed into the clinic and the early data demonstrate greatly reduced viral load levels in HCV-infected patients. This review will survey the state of nucleotide prodrugs for the treatment of HCV.     

Immunotherapy in hepatocellular carcinoma: Combination strategies

Liver cancer is one of the most common causes of cancer death globally, and its incidence in the United States is increasing. Patients with advanced hepatocellular carcinoma (HCC) who are not candidates for surgical resection, liver transplant, or locoregional therapies can be treated with systemic therapies. Multiple agents, including sorafenib, lenvatinib, and regorafenib are approved for use as either first- or second-line therapy in this patient population, but all have relatively modest survival benefits. HCC is potentially susceptible to therapy with checkpoint inhibitors, including agents such as nivolumab and pembrolizumab, which are both approved by the Food and Drug Administration for patients previously treated with sorafenib but have not demonstrated superior overall survival in phase III trials. It is clear that more effective approaches are needed to potentiate the effects of checkpoint inhibitors in patients with HCC. This review will outline and appraise the current literature on the use of checkpoint inhibitors in HCC as part of a combination treatment involving an additional mode of therapy. The list of agents that can be paired with checkpoint inhibitors includes an additional checkpoint inhibitor, vascular endothelial growth factor or vascular endothelial growth factor receptor inhibitors, tyrosine kinase inhibitors, OX-40 agonists, and PT-112 inhibitors. The main non-pharmacologic therapies currently being studied for inclusion in a combination strategy include radiation therapy, trans-arterial chemoembolization, and ablation.     

The effect of liver cirrhosis on activation of the coagulation and fibrinolysis system and on coagulation inhibitors

The activation of coagulation and fibrinolysis as well as coagulation inhibitors in the blood of patients with compensated (n = 25) and decompensated (n = 25) liver cirrhosis were studied. Protein C (PC) was decreased in a more pronounced manner than antithrombin III (AT III) in liver cirrhosis. Thereby, PC proved to be a highly sensible indicator of liver cell dysfunction. Decreased levels of PC activity (PC ratio activity/antigen 0.82) in decompensated liver cirrhosis suggest production of dysfunctional, undercarboxylated PC. We observed increased blood concentrations of fibrinopeptide A (FPA) (p less than 0.05) in both groups of patients compared to healthy volunteers (n = 25), while D-Dimer was increased only in patients with decompensated liver cirrhosis (p less than 0.01). Comparing both groups of patients. D-Dimer was significantly different with higher levels in decompensated liver cirrhosis (p less than 0.01). The ratio D-Dimer/FPA was significantly increased in decompensated liver cirrhosis compared to both other groups. These observations indicate that efflux from the extravascular space, e.g. ascitic fluid, contributes to the high contents of fibrin degradation products (D-Dimer) in patients with decompensated liver cirrhosis. In summary we conclude that patients with liver cirrhosis have enhanced activation of both coagulation and fibrinolysis but that the balance is not significantly displaced.     

Treatment of diabetes mellitus with oral hypoglycemic agents

As the number of type 2 diabetes patients is still increasing in Japan, careful management and appropriate treatment of diabetes with oral hypoglycemic agents are required for all general physicians. Ultimate aim of treatment should be maintenance of a quality of life not different from that of persons without diabetes. Recently various new oral hypoglycemic agents have been developed and six different classes of agents are available now: sulfonylureas, biguanides, alpha-glucosidase inhibitors, glinides, thiazolidinediones, and dipeptidyl peptidase-4 inhibitors. In this article we describe the specific mechanisms of actions, side effects, and important points in clinical usage. Every drug therapy should be supported by lifestyle changes and the agents to be used should be selected after consideration of patient's patho-physiological state of diabetes, the presence of any complications, age, functional disorders of the liver, kidney, heart and lung, and the risk for hypoglycemia.     

Spironolactone in heart failure – a revived role for an old drug

Spironolactone is an aldosterone antagonist which has been used as a mild potassium-sparing diuretic and in treatment of ascites in liver failure. Recent studies have shown that it has an additive effect to those of ACE inhibitors in heart failure treatment.     

MR imaging features of focal liver lesions in Wilson disease

Hepatic involvement in Wilson disease (WD) manifests as a diffuse chronic disease in the majority of patients. However, in a subset of patients focal liver lesions may develop, presenting with a wide range of imaging features. The majority of focal liver lesions in patients with WD are benign nodules, but there are reports that have described malignant liver tumors or dysplastic nodules in these patients. Because of the possibility of malignant transformation of liver nodules, major concerns have been raised with respect to the management and follow-up of patients with WD in whom focal liver lesions have been identified. The assessment of liver involvement in patients with WD is generally performed with ultrasonography. However, ultrasonography conveys limited specificity so that magnetic resonance (MR) imaging is often performed to improve lesion characterization. This review was performed to illustrate the spectrum of MR imaging features of focal liver lesions that develop in patients with WD. It is assumed that familiarity with the MR imaging presentation of focal liver lesions in WD may help clarify the actual nature of hepatic nodules in patients with this condition.     

Progression of liver fibrosis in patients coinfected with hepatitis C virus and human immunodeficiency virus undergoing antiretroviral therapy

As the immunosuppression caused by human immunodeficiency virus (HIV) accelerates the progression of hepatitis C virus (HCV)-related liver fibrosis, the immune reconstitution associated with highly active antiretroviral therapy (HAART) may have the opposite effect. However, hepatotoxicity related to HAART could enhance the progression of liver fibrosis. Some retrospective studies have shown that therapy with the protease inhibitors may be associated with less severe liver fibrosis, whereas nevirapine use seems to correlate with faster progression. Low-grade liver toxicity associated with nevirapine could account for this effect. However, other studies have not confirmed these findings. Long-term prospective studies are needed to analyse the impact of antiretroviral drugs on the progression of HCV-related liver disease. Meanwhile, no specific recommendations can be made on the use of individual drugs or drug classes in HIV/HCV-coinfected patients. Most importantly however, the inherent benefits of HAART largely outweigh the risk of enhancing fibrosis progression. Additionally, in coinfected patients, other factors that promote fibrogenesis, such as alcohol consumption, should be avoided. Antiviral treatment of chronic hepatitis C could also reduce the risk of liver damage associated with HAART.