Beneficial drugs for liver diseases

Liver diseases are a major problem of worldwide proportions. However, the number of drugs actually used successfully in humans is very small. In this review some of the most promising/studied drugs utilized for liver diseases were chosen and analysed critically from the basic to the clinical point of view. Antiviral agents are not discussed because excellent reviews have appeared on this topic. The compounds/preparations described herein are, alphabetically: colchicine, corticosteroids, curcumin, glycyrrhizin, interferons (for their antifibrotic properties), Liv 52, nitric oxide, resveratrol, silymarin, sulfoadenosylmethionine, and thalidomide. Colchicine and corticosteroids have been studied extensively in animals and humans; most clinical studies suggest that these compounds are not useful in the treatment of liver diseases. Glycyrrhizin is an herbal medicine with several components that has interesting hepatoprotective properties in patients with subacute liver failure but deserves more prospective controlled trials. Interferon has shown interesting antifibrotic properties in animals and humans; prospective studies on their antifibrotic/fibrolytic activity are required. Curcumin, resveratrol and thalidomide are very attractive newly discovered protective and curative compounds on experimental hepatic diseases. Their mechanism of action is associated with the ability to down-regulate NF-kappaB and to decrease pronecrotic and profibrotic cytokines. Unfortunately, clinical studies are lacking. Sulfoadenosylmethionine and silymarin are also promising drugs utilized mainly in cholestasis but the benefits can be expanded if more controlled trials are performed. The future is to carry out controlled prospective double-blind multicenter studies with the newly discovered drugs with proven beneficial effects on animals. Fundamental hepatobiology should also be encouraged.     

Expectations for the pharmacists in the management of infectious diseases

In the 21 century, the management of infectious diseases has become increasingly important. Especially, the establishment of the infection prevention and control system is very important in the healthcare-settings for patient safety. And from this background, infection control teams (ICT) which perform the infectious diseases management have been organized in many institutions. These ICT members are medical doctors, nurses, medical technologists and pharmacists and the role of the pharmacist in the ICT is very important. The pharmacist should play a role as a specialist for antimicrobial agents, antiseptics and disinfectants. The roles and responsibilities of the pharmacist for infection control are leading the antimicrobial stewardship, promoting the appropriate and rational use of antimicrobial agents, advising the health system on the selection and use of appropriate antiseptics, disinfectants and sterilants, developing guidelines for risk assessment, treatment, and monitoring of patients and health care workers. Establishing internal pharmacy policies, procedures and quality control programs to prevent contamination, educating health professionals, patients, and the public activity are also included. It is expected that the infection control pharmacist should contribute to the management of infectious diseases and patient safety in the healthcare-settings.     

Cell-based therapy for liver diseases

Although liver transplantation has become standard therapy in the treatment of patients with liver failure, several problems should be considered in the management of these patients. Other approaches have been proposed, in particular cellular-based procedures. Isolated hepatocytes may be used instead of whole organ transplantation or integrated within the bioartificial devices, in order to replace the missing synthetic and metabolic liver functions. Moreover patient's own hepatocytes may be ex vivo genetically modified to provide the function of a mutant gene. However, new cell sources alternative to adult hepatocytes are actually under investigation, on the basis of recent advances in the field of liver repopulation. Xenogenic primary cells, human hepatoma cells, immortalized hepatocytes and stem cells have been testing in several experiments, even if up to now none of them represent a "gold-standard" for cell-based treatment of liver diseases. In the next future, it is possible that different clinical situations will require different therapeutic approaches, that will be finally defined from the concomitant advances in the development of artificial devices and liver cell biology.     

Biomarkers as a guide of medical treatment in cardiovascular diseases

There is increasing interest in utilizing novel markers of cardiovascular disease risk and consequently, there is a need to assess the value of their use. In this paper, we will review the role of biomarkers in acute coronary syndromes, heart failure and risk stratification for cardiovascular events as guide for treatment scribing. In particular, high sensitivity assays for troponin evaluation detect with greater precision patients with elevated troponin. Therefore, direct and appropriate management is succeeded in these patients with reduction of complications due to earlier treatment, as well. Regarding heart failure, randomized trials that have evaluated biomarker guided treatment approach have not succeeded in establishing specific results for natriuretic peptides (BNP, NT-proBNP) use in terms of therapy guidance. Apart from them, a variety of novel or already used biomarkers, have been tested by small trials for heart failure management, without however, managing to dominate in every day care. Finally, as far as risk stratification for cardiovascular events is concerned, hsCRP has proved to be a strong but doubted biomarker. Therefore, lifestyle and behavioral modification remain the cornerstone of primary prevention.     

Vonoprazan fumarate for the management of acid-related diseases

Introduction: Proton pump inhibitors (PPIs) display a number of limitations and unmet clinical needs that have prompted the development of novel drugs to improve the outcomes of acid-related diseases, including the eradication of H. pylori. In this context, a new synthesized potassium-competitive acid blocker (P-CAB), vonoprazan, showed higher suppression of gastric acid secretion.

Areas covered: This review discusses the current knowledge regarding the efficacy of vonoprazan in the treatment of acid-related diseases, with a particular focus on its use in Helicobacter pylori eradication.

Expert opinion: Vonoprazan showed some advantages over PPIs in terms of the pharmacokinetic and pharmacodynamic profile: fast onset of action without requiring acid activation and specific administration timing, more potent and prolonged inhibition of acid secretion, including a better nighttime acid control, and a less antisecretory variability. Recent evidence suggests that vonoprazan can be preferred to PPIs as maintenance therapy for reflux esophagitis and eradication of Helicobacter pylori owing to its stronger antisecretory effect. Moreover, vonoprazan displays favorable safety and tolerability profiles, even though long-term studies on the effects of vonoprazan are required.     

Modern trends in the management of hepatocellular carcinoma

No treatment of proven validity in hepatocellular carcinoma (HCC) has yet been found, with the exception of surgery in a small subset of patients. Furthermore, there is a paucity of phase I and II trials and of phase III prospective randomized trials. Radiation therapy is not considered very effective, even as a palliative procedure, but there has been renewed interest in this modality, with several ongoing trials attempting to establish optimal doses, fractionation and effectiveness. Chemotherapy, single or combination, has not increased the survival of patients with HCC, although there have been unquestionable, even spectacular, responses to chemotherapy. Adriamycin seems the most effective agent with approximately 25% objective responses. The regional administration of drugs and/or interruption of arterial supply, in this malignancy with a pattern of local confinement, yields quite high response rates but no increase in survival. Several trials with combined therapeutic modalities are now in progress. Furthermore, there have been important advances in nuclear medicine, in the totally implantable pump, in the understanding of pharmacokinetics and in microspheres, monoclonal antibodies, etc. It is remarkable that there have been so few randomized trials in such a common malignancy. To obtain valuable results any future studies should randomize patients into "treatment" and "no treatment" groups and stratify patients according to prognostic factors. It seems, however, that the combination of local and systemic treatment is the most promising answer to this virulent and fatal disease.     

Ursolic acid reduces hepatocellular apoptosis and alleviates alcohol-induced liver injury via irreversible inhibition of CASP3 in vivo

Alcoholic liver disease (ALD) is one of the pathogenic factors of chronic liver disease with the highest clinical morbidity worldwide. Ursolic acid (UA), a pentacyclic terpenoid carboxylic acid, has shown many health benefits including antioxidative, anti-inflammatory, anticancer, and hepatoprotective activities. We previously found that UA was metabolized in vivo into epoxy-modified UA containing an epoxy electrophilic group and had the potential to react with nucleophilic groups. In this study we prepared an alkynyl-modified UA (AM-UA) probe for tracing and capturing the target protein of UA from liver in mice, then investigated the mode by which UA bound to its target in vivo. By conducting proteome identification and bioinformatics analysis, we identified caspase-3 (CASP3) as the primary target protein of UA associated with liver protection. Molecule docking analysis showed that the epoxy group of the UA metabolite reacted with Cys-163 of CASP3, forming a covalent bond with CASP3. The binding mode of the UA metabolites (UA, CM-UA, and EM-UA) was verified by biochemical evaluation, demonstrating that the epoxy group produced by metabolism played an important role in the inhibition of CASP3. In alcohol-treated HepG2 cells, pretreatment with the UA metabolite (10 μM) irreversibly inhibited CASP3 activities, and subsequently decreased the cleavage of PARP and cell apoptosis. Finally, pre-administration of UA (20–80 mg· kg⁻¹ per day, ig, for 1 week) dose-dependently alleviated alcohol-induced liver injury in mice mainly via the inhibition of CASP3. In conclusion, this study demonstrates that UA is a valuable lead compound for the treatment of ALD.Keyword: ursolic acid, metabolite, CASP3, covalent binding, alcoholic liver disease     

Biomarkers for methotrexate-induced liver injury: Urinary protein profiling of psoriasis patients

Hepatic fibrosis is an adverse drug reaction of methotrexate (MTX) seen after long-term use in psoriasis patients. Currently, patients are monitored for MTX-induced hepatic fibrosis by performing liver biopsy, which is risky and burdensome for the patient, or by measuring plasma procollagen type III aminopeptide (PIIINP), which is not conclusive. The objective of this study was to identify novel predictive and preferably non-invasive biomarkers to monitor psoriasis patients for MTX-induced hepatic fibrosis.     

溶血磷脂酰胆碱在肝脏疾病中的研究进展

溶血磷脂酰胆碱(lysophosphatidylcholines,LPCs)是磷脂的一种,具有多种生理功能,与糖尿病、动脉粥样硬化、血脂异常等代谢性疾病和心血管疾病密切相关。LPCs主要在肝脏代谢,在肝脏疾病和肝毒性中可发生明显变化;近年来,学者们对多种肝脏疾病和化学性肝毒性模型的大量研究均涉及了LPCs。该文针对LPCs作为生物标志物与肝癌、胆汁淤积、肝硬化、肝炎等肝脏疾病和化学性肝损伤模型的关系进行综述,为肝脏疾病和肝毒性的基础研究与临床治疗提供参考。     

Review article: liver transplantation for hepatocellular carcinoma

Despite recent advances in techniques of in situ tumour ablation, surgical therapy remains at present the mainstay treatment for primary hepatic malignancies. After an initial endeavour in the establishment of liver transplantation as a treatment option, in particular for unresectable liver tumours, only a few indications, for example early hepatocellular carcinoma in cirrhosis, are currently agreed upon. Other indications, such as peripheral cholangiocarcinoma and hepatocellular carcinoma in noncirrhotics have largely been abandoned or are still under debate, as is the case with fibrolamellar carcinoma. The selection of patients suffering from hepatocellular carcinoma in cirrhosis for liver transplantation is still based on tumour size and node number, because the current state of diagnostic imaging fails to reliably predict the most important prognostic parameter: vascular infiltration. Other selection criteria are under investigation. Studies on multimodal therapy are also underway but have not yet demonstrated a clear benefit.     

Toxicological effects of cationic nanobubbles on the liver and kidneys: Biomarkers for predicting the risk

Nanobubbles with acoustical activity are used as both diagnostic and therapeutic carriers for detecting and treating diseases. We aimed to prepare nanobubbles and assess toxic responses to them in the liver and kidneys. The cytotoxicity of nanobubbles was determined by examining the viability of liver (HepG2) and kidney (293T) cell lines after a 24-h treatment at various concentrations (0.01–2%). Toxic effects of different formulations were compared by determining functional markers such as γ-glutamyl transferase (γ-GT) and blood urea nitrogen (BUN) after intravenous administration of nanobubbles. Cationic nanobubbles caused concentration-dependent cytotoxicity against cultured cells with a more significant effect in the liver than in the kidneys. A significant reduction of viability was revealed at a concentration as low as 0.1%. Cational systems with soyaethyl morpholinium ethosulfate (SME) exhibited the greatest γ-GT level at 6-fold higher than the control. Immunohistochemistry detected liver fibrosis and inflammation with nanobubbles treatment, especially SME-containing ones at higher doses. According to plasma proteomic profiles, gelsolin and fetuin-B were significantly downregulated 3-fold in the high-dose SME-treated group. Transthyretin decreased by 6-fold in this group. The fibrinogen gamma chain expression was highly elevated. The results suggest that these protein biomarkers are sensitive for assessing the risk of nanobubble exposure. This study is the first to systematically evaluate the possible toxicity of nanobubbles in the liver and kidneys.     

Medical management of chronic liver diseases in children (part I): focus on curable or potentially curable diseases

The management of children with chronic liver disease (CLD) mandates a multidisciplinary approach. CLDs can be classified into 'potentially' curable, treatable non-curable, and end-stage diseases. Goals pertaining to the management of CLDs can be divided into prevention or minimization of progressive liver damage in curable CLD by treating the primary cause; prevention or control of complications in treatable CLD; and prediction of the outcome in end-stage CLD in order to deliver definitive therapy by surgical procedures, including liver transplantation. Curative, specific therapies aimed at the primary causes of CLDs are, if possible, best considered by a pediatric hepatologist. Medical management of CLDs in children will be reviewed in two parts, with part I (this article) specifically focusing on 'potentially' curable CLDs. Dietary modification is the cornerstone of management for galactosemia, hereditary fructose intolerance, and certain glycogen storage diseases, as well as non-alcoholic steatohepatitis. It is also essential in tyrosinemia, in addition to nitisinone [2-(nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione] therapy, as well as in Wilson disease along with copper-chelating agents such as D-penicillamine, triethylenetetramine dihydrochloride, and ammonium tetrathiomolybdate. Zinc and antioxidants are adjuvant drugs in Wilson disease. New advances in chronic viral hepatitis have been made with the advent of oral antivirals. In children, currently available drugs for the treatment of chronic hepatitis B virus infection are standard interferon (IFN)-α-2, pegylated IFN-α-2 (PG-IFN), and lamivudine. In adults, adefovir and entecavir have also been licensed, whereas telbivudine, emtricitabine, tenofovir disoproxil fumarate, clevudine, and thymosin α-1 are currently undergoing clinical testing. For chronic hepatitis C virus infection, the most accepted treatment is PG-IFN plus ribavirin. Corticosteroids, with or without azathioprine, remain the basic strategy for inducing remission in autoimmune hepatitis. Ciclosporin (cyclosporine) and other immune suppressants may be used for patients who do not achieve remission, or who have significant side effects, with corticosteroid/azathioprine therapy. The above therapies can prevent, or at least minimize, progression of liver damage, particularly if started early, leading to an almost normal quality of life in affected children.     

Manipulating thymic apoptosis for future therapy of autoimmune diseases

In humans, T-cell development takes place in the thymus, which contains an external cortical region and an inner medulla. The skeleton of the thymus consists of stromal cells and is filled with thymocytes in different stages of differentiation. Thymocytes undergo to a development process before becoming mature T lymphocytes ready for export to the peripheral lymphoid organs. Classically, T-cell development has been reported to occur in four steps. First, bone marrow derived thymocytes that express neither CD4 nor CD8 surface antigens (double negative [DN] thymocytes) undergo an extensive phase of proliferation and differentiation and begin to express CD4 and CD8 (step 2: double positive [DP] thymocytes). During a subsequent negative selection process, approximately 5% of these DP cells undergo apoptosis. If these cells are not eliminated, they could differentiate into autoreactive lymphocytes, leading to the development of peripheral autoimmune diseases. In the thymus, a particular population of T regulatory (Treg) cells also develops. These Treg cells migrate to the periphery and are capable of suppressing autoreactive lymphocytes that may have escaped from the negative selection process. Autoimmune diseases are generally the result of insufficient negative selection of autoreactive cells in the thymus or a deficiency in Treg cell production or function. Future therapeutic strategies for autoimmune diseases should exploit manipulations in the negative selection process and/or the differentiation of Treg cells in the thymus.     

传染病医院药房管理初探

为促进和完善传染病医院药房管理工作提供参考。了解传染病医院药房在管理过程中存在的一些问题,分析和探讨其原因。传染病医院不同于各大综合性医院,应该建立适合自身发展需求的药房管理模式。