Areas covered: A literature search for studies in animal models or patients with obesity, fatty liver, non-alcoholic steatohepatitis (NASH) or NASH cirrhosis published before November 2016 was performed. After discussing epidemiology and animal models for NAFLD, we summarized both basic as well as clinical studies investigating changes in drug transport and metabolism in NAFLD. Important drug groups were assessed separately with emphasis on clinical implications for drug treatment in patients with NAFLD.
Expert opinion: Given the frequency of NAFLD even today, a high degree of drug treatment in NAFLD patients appears safe and well-tolerated despite considerable changes in hepatic uptake, distribution, metabolism and transport of drugs in these patients. NASH causes changes in biliary excretion, systemic concentrations, and renal handling of drugs leading to alterations in drug efficacy or toxicity under specific circumstances. Future clinical drug studies should focus on this special patient population in order to avoid serious adverse events in NAFLD patients. 相似文献
Areas covered: An overview is given of MSDC-0602K, a new agent in development that modulates the MPC and as such treats the symptoms of fatty liver including dysfunctional lipid metabolism, inflammation, and insulin resistance as well as the key liver pathology including fibrosis.
Methodology: The current evaluation is written from the direct experience of the authors and review of published literature using standard search techniques.
Expert Opinion: The mechanism of action of MSDC-0602K appears to be suited for treatment of the NASH pathophysiology. An ongoing phase 2b dose-ranging trial should demonstrate whether or not MSDC-0602K has the potential to be a cornerstone metabolic therapy for the treatment of NASH. 相似文献
Areas covered. The present review summarizes recent patent activity (2014-to date) filing for synthetic and natural FXR ligands, including bile acid derivatives and non-steroidal compounds, alongside their in vitro and in vivo efficacy as well as their therapeutic applications.
Expert opinion. While the first FXR agonist, obeticholic acid, has gained approval, significant safety issues have been emerged. Today is unclear whether these safety issues are class related or restricted to the bile acid scaffold of this agent. Despite the significant number of patent applications claiming steroidal and non-steroidal FXR agonists, several questions on their therapeutic potential in cholestasis and NASH remain open leaving a space for the development of novel compounds. 相似文献
Areas covered: This paper provides a comprehensive review of the main underlying mechanisms by which various drugs cause DISH, and outlines existing preclinical tools to predict it and study underlying pathways involved. The translational hurdles of these models are discussed, with the example of an organotypic liver system designed to address them. Finally, we describe the clinical assessment and management of DISH.
Expert Opinion: The complexity of the interconnected mechanistic pathways underlying DISH makes it important that preclinical evaluation of drugs is done in a physiologically and metabolically relevant context. Advanced organotypic tissue models, coupled with translational functional biomarkers and next-generational pan-omic measurements, may offer the best shot at gathering mechanistic knowledge and potential of a drug causing steatohepatitis. Ultimately this information could also help predict, detect or guide the development of specific treatments for DISH, which is an unmet need as of today. 相似文献
Areas covered: I summarize preclinical and clinical data on the efficacy and safety of the dual CCR2/CCR5 inhibitor cenicriviroc (CVC, also TBR-652 or TAK-652) for the treatment of NASH and fibrosis. In animal models of liver diseases, CVC potently inhibits macrophage accumulation in the liver and ameliorates fibrosis. In a phase 2b clinical trial (CENTAUR) on 289 patients with NASH and fibrosis, CVC consistently demonstrated liver fibrosis improvement after 1 year of therapy and had an excellent safety profile, leading to the implementation of a phase 3 trial (AURORA).
Expert opinion: Preclinical and clinical data support the development of CVC as a safe and potent antifibrotic agent. However, open questions around CVC are the durability of antifibrotic responses, divergent effects on NASH versus fibrosis, potential long-term concerns and the expected path to approval. 相似文献
Areas covered: This article reviews the safety and tolerability data of the NAFLD therapies and explains the mechanistic basis for each of the established and investigational drugs. Treatment targets include: weight loss, anti-metabolic agents such as lipid lowering and anti-diabetic drugs, inflammation, fibrosis and others such as targeting gut microbiota, immune modulation and apoptosis.
Expert opinion: Current therapies continue to remain suboptimal. Weight loss is effective but hard to achieve. Traditional and endoscopic bariatric procedures are promising although more randomized trials are needed and the long-term safety remains to be established. Clinical trials have demonstrated the efficacy of several drugs for the treatment of NASH. Of these, there remains some uncertainty about the long-term safety of vitamin E. Pioglitazone is associated with osteopenia, fluid retention and weight gain. Obeticholic acid causes pruritus in a substantial proportion of subjects and elafibranor has been associated with transient rises in creatinine. Several exciting therapies are under development and results of clinical and post-marketing trials will help elucidate their safety. 相似文献
Areas covered: In this review, we first summarize the NAFLD disease epidemiology, pathology, and diagnosis. We describe NAFLD progression with the focus on sexual and genetic differences for disease development and pharmacological treatment. Personalized treatment for multifactorial NAFLD is discussed in consideration of different factors, including genetics, gender and sex.
Expert opinion: The livers of female and male NAFLD patients have different metabolic capacities which influence the metabolism of all drugs applied to such patients. This aspect is not yet sufficiently taken into account. The liver computational models might quicken the pace toward assessing personalized disease progression and treatment options. 相似文献
Areas covered: Here, we review the current knowledge of PGRN physiological functions and GRN mutations associated with FTD; we also summarize state of the art clinical trials and those compounds able to replace PGRN loss in preclinical models.
Expert opinion: PGRN represents a promising therapeutic target for FTD. Cohorts suitable for treatment, ideally at the preclinical stage, where pathogenic mechanisms ongoing in the brain are targeted, are available. However, PGRN may have side effects, such as the risk of tumorigenesis, and the risk/benefit ratio of any intervention cannot be predicted. Furthermore, at present, the situation is complicated by the absence of adequate outcome measures. 相似文献
Experimental approach: To assess drug proarrhythmic risk, we used a set of in vitro electrophysiological measurements describing ion channel inhibition triggered by the investigated drugs. The Cardiac Safety Simulator version 2.0 (CSS; Simcyp, Sheffield, UK) platform was used to simulate human left ventricular cardiac myocyte action potential models.
Results: This study shows the impact of drug concentration changes on particular ionic currents by using available experimental data. The simulation results display safety threshold according to drug concentration threshold and log (threshold concentration/ effective therapeutic plasma concentration (ETPC)).
Conclusion and implications: We reproduced the underlying biophysical characteristics of cardiac cells resulted in effects of drugs associated with cardiac arrhythmias (action potential duration (APD) and QT prolongation and TdP) which were observed in published 3D simulations, yet with much less computational burden. 相似文献
Area covered: We describe the clinicopathological significance of MUC4, summarize mechanisms contributing to its deregulated expression, review preclinical studies aimed at inhibiting MUC4, and discuss how MUC4 overexpression provides opportunities for developing targeted therapies. Finally, we discuss the challenges for developing MUC4-based therapeutics, and identify areas where efforts should be directed to effectively exploit MUC4 as a therapeutic target for PC.
Expert opinion: Studies demonstrating that abrogation of MUC4 expression reduces proliferation and metastasis of PC cells and enhances sensitivity to therapeutic agents affirm its utility as a therapeutic target. Emerging evidence also supports the suitability of MUC4 as a potential immunotherapy target. However, these studies have been limited to in vitro, ex vivo or in vivo approaches using xenograft tumors in immunodeficient murine models. For translational relevance, MUC4-targeted therapies should be evaluated in murine models with intact immune system and accurate tumor microenvironment. Additionally, future studies evaluating MUC4 as a target for immunotherapy must entail characterization of immune response in PC patients and investigate its association with immunosuppression and survival. 相似文献
Objective: This review aims to synthesize recent developments in Echinacea biotechnology and to identify promising applications for these advances in the industry.
Methods: A comprehensive survey of peer-reviewed publications was carried out, focusing on Echinacea biotechnology and impacts on phytochemistry. This article primarily covers research findings since 2007 and builds on earlier reviews on the biotechnology of Echinacea.
Results: Bioreactors, genetic engineering and controlled biotic or abiotic elicitation have the potential to significantly improve the yield, consistency and overall quality of Echinacea products. Using these technologies, a variety of new applications for Echinacea can be realized, such as the use of seed oil and antimicrobial and immune boosting feed additives for livestock.
Conclusions: New applications can take advantage of the well-established popularity of Echinacea as a NHP. Echinacea presents a myriad of potential health benefits, including anti-inflammatory, anxiolytic and antibiotic activities that have yet to be fully translated into new applications. The distinct chemistry and bioactivity of different Echinacea species and organs, moreover, can lead to interesting and diverse commercial opportunities. 相似文献
Areas covered: This review summarizes the available data for orally administered antimicrobials routinely used as monotherapy for MRSA infections. We make recommendations and highlight the current gaps in the literature. A PubMed (1966 – Present) search was performed to identify relevant literature for this review.
Expert commentary: There is a vast divide in the amount of pharmacokinetic/pharmacodynamic data to guide dosing decisions for older MRSA agents compared with the oxazolidenones.
Five-year view: Additional retrospective data will become available for the older MRSA agents in severe MRSA infections. 相似文献
Research design and methods: Multicenter survey, open-label study of 49 Japanese COPD patients aged ≥ 40 years; outpatients with >10 pack years of smoking history; ratio of forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < 70%; predicted FEV1 < 80%; treated with bronchodilators and/or inhaled corticosteroids as maintenance therapy until week 48.
Main outcome measures: The primary endpoint was change in pulmonary function (trough FEV1, trough FVC); secondary endpoints were QOL and physical activity at 48 weeks after initiation of therapy.
Results: Airway reversibility was confirmed in untreated patients. Significant changes over time were not observed for FEV1 and FVC, indicating lung function at initiation of treatment was maintained during the observation period. COPD assessment test scores showed statistical and clinical improvements. Cough, sputum, breathlessness, and shortness of breath were significantly improved.
Conclusions: Lung function and QOL of untreated Japanese COPD patients improved and improvements were maintained by performing a therapeutic intervention that conformed to published guidelines. 相似文献
Methods: In a randomized clinical trial 44 patients with acute bacterial meningitis were randomly assigned to the conventional- or high-dose vancomycin groups. Clinical and laboratory parameters were used for evaluation of response to the treatment regimens.
Results: In the high-dose group, leukocytosis and fever resolved significantly faster than those in the conventional group. Furthermore, the length of hospitalization was shorter and Glasgow Coma Scale at the end of 10th day was significantly lower in the high dose compared to the conventional group. Trend of creatinine clearance changes did not differ significantly between the two groups.
Conclusion: In comparison to the conventional-dose regimen, the high-dose vancomycin regimen was associated with significantly more favorable clinical response without increase in the incidence of nephrotoxicity in patients with acute bacterial meningitis. 相似文献
Objective: The present review compiles and summarizes the chemical compositions, biological properties and clinical efficacy of mulberry leaves that are related to the amelioration of cardiometabolic risks.
Methods: Published English literature from the PubMed, Science Direct and Google Scholar databases was searched by using ‘mulberry leaves’ ‘Morus spp.’, ‘hyperglycemia’, ‘hyperlipidemia’, ‘obesity’, ‘hypertension’, ‘oxidative stress’, ‘atherosclerosis’ and ‘cardiovascular diseases’ as the keywords. The relevant articles published over the past two decades were identified and reviewed.
Results: Mulberry leaves contain numerous chemical constituents. 1-Deoxynojirimycin (DNJ), phenolics and flavonoids are the prominent functional compounds. Preclinical and clinical studies showed that mulberry leaves possessed various beneficial effects against cardiometabolic risks, including antihyperglycaemic, antihyperlipidaemic, antiobesity, antihypertensive, antioxidative, anti-inflammatory, anti-atherosclerotic and cardioprotective effects.
Conclusions: Mulberry leaves could be a promising therapeutic option for modulating cardiometabolic risks. However, further investigations should be performed to substantiate the potential of mulberry leaves in practical uses. 相似文献
Areas covered: This article reviews the pathophysiology as well as pharmacological aspects of PONV prophylaxis and treatment. Relevant strategic aspects for pharmacological prophylaxis of PONV are discussed and clinical standard operating procedures are presented.
Expert opinion: The expert opinion focuses on poor implementation of actual PONV guidelines and future considerations. 相似文献
Areas covered: This review details the history and epidemiology of CA-MRSA, while covering both current and future treatment options that are and may be available to clinicians. The authors reviewed both historic and more recent literature on this ever-evolving topic.
Expert opinion: While development of new anti-MRSA agents should be encouraged, the importance of antimicrobial stewardship in the battle to stay ahead of the curve with regards to the ongoing control of the MRSA epidemic should be emphasised. 相似文献
The objective of this study was to assess the timely disclosure of results of company-sponsored clinical trials related to all new medicines approved by the European Medicines Agency (EMA) during 2012. This is an extension of the previously reported study of trials related to all new medicines approved in Europe in 2009, 2010 and 2011, which found that over three-quarters of all these trials were disclosed within 12 months and almost 90% were disclosed by the end of the study.
Methods:
The methodology used was exactly as previously reported. Various publicly available information sources were searched for both clinical trial registration and disclosure of results. All completed company-sponsored trials related to each new medicine approved for marketing by the EMA in 2012, carried out in patients and recorded on a clinical trials registry and/or included in an EMA European Public Assessment Report (EPAR), were included. Information sources were searched between 1 May and 31 July 2014.
Outcome measures and results:
The main outcome measure was the proportion of trials for which results had been disclosed on a registry or in the scientific literature either within 12 months of the later of either first regulatory approval or trial completion, or by 31 July 2014 (end of survey). Of the completed trials associated with 23 new medicines licensed to 17 different companies in 2012, results of 90% (307/340) had been disclosed within 12 months, and results of 92% (312/340) had been disclosed by 31 July 2014.
Conclusions:
The disclosure rate within 12 months of 90% suggests the industry is now achieving disclosure in a timely manner more consistently than before. The overall disclosure rate at study end of 92% indicates that the improvement in transparency amongst company-sponsored trials has been maintained in the trials associated with new medicines approved in 2012. 相似文献
Areas covered: This review focuses on the clinical development of several emerging drugs for the treatment of NASH and the impact of these drugs on current treatment standards.
Expert opinion: Four drug classes (FXR agonists, CCR2/CCR5 antagonists, ASK1 inhibitors, and PPARα/δ agonists) have moved into phase 3 trials for their investigation as NASH treatments. Results from phase 2 trials of other therapeutic agents with other pharmacological actions are also expected. The importance of combinational therapies with synergistic benefits engaging different targets, is now understood. Furthermore, studies have determined that the Mediterranean diet is beneficial for patients with NAFLD, while the traditional Okinawan diet is also considered useful. In the future, it will be important to establish new biomarkers to assess NAFLD activity, furthermore non-invasive diagnostic methods will promote the development of new drugs for NASH. 相似文献