Metabonomics Techniques and Applications to Pharmaceutical Research & Development

In this review, the background to the approach known as metabonomics is provided, giving a brief historical perspective and summarizing the analytical and statistical techniques used. Some of the major applications of metabonomics relevant to pharmaceutical Research & Development are then reviewed including the study of various influences on metabolism, such as diet, lifestyle, and other environmental factors. The applications of metabonomics in drug safety studies are explained with special reference to the aims and achievements of the Consortium for Metabonomic Toxicology. Next, the role that metabonomics might have in disease diagnosis and therapy monitoring is provided with some examples, and the concept of pharmacometabonomics as a way of predicting an individual's response to treatment is highlighted. Some discussion is given on the strengths and weaknesses, opportunities of, and threats to metabonomics.     

NMR-based metabolic profiling and metabonomic approaches to problems in molecular toxicology

We have reviewed the main contributions to the development of NMR-based metabonomic and metabolic profiling approaches for toxicological assessment, biomarker discovery, and studies on toxic mechanisms. The metabonomic approach, (defined as the quantitative measurement of the multiparametric metabolic response of living systems to pathophysiological stimuli or genetic modification) was originally developed to assist interpretation in NMR-based toxicological studies. However, in recent years there has been extensive fusion with metabolomic and other metabolic profiling approaches developed in plant biology, and there is much wider coverage of the biomedical and environmental fields. Specifically, metabonomics involves the use of spectroscopic techniques with statistical and mathematical tools to elucidate dominant patterns and trends directly correlated with time-related metabolic fluctuations within spectral data sets usually derived from biofluids or tissue samples. Temporal multivariate metabolic signatures can be used to discover biomarkers of toxic effect, as general toxicity screening aids, or to provide novel mechanistic information. This approach is complementary to proteomics and genomics and is applicable to a wide range of problems, including disease diagnosis, evaluation of xenobiotic toxicity, functional genomics, and nutritional studies. The use of biological fluids as a source of whole organism metabolic information enhances the use of this approach in minimally invasive longitudinal studies.     

A novel therapeutic target, GPR43; Where it stands in drug discovery

With growing interest in human microbiome for its implication in metabolic disorders, inflammatory diseases, immune disorders and so forth, understanding the biology at the interface of the gut flora and the host becomes very important for identifying novel therapeutic avenues. GPR43 has been deorphanized and the metabolites of microbiome, such as short-chain fatty acids, serve as its natural ligands. There are numerous reports that GPR43 might be a crucial link to the novel therapies for the unmet medical needs and many drug discovery organizations are making their moves in response.     

The assessment of plant metabolite profiles by NMR-based methodologies

NMR-based metabolic profiling techniques can simultaneously track changes in many plant metabolites and have found a number of applications in both systems biology and biosafety. Together with multivariate statistical analyses, NMR spectroscopy has been successfully applied to the characterisation of various herbs and plant products for quality control, authentication, determining geographical origin and for detecting adulteration of products. Additionally, the metabolic consequences of plant extracts have been demonstrated in experimental animals and in man using NMR-based metabonomics approaches to characterise the response. Here the application of NMR spectroscopy and chemometric tools for analysing plant-based products and their metabolic consequences are considered with particular emphasis on deconvolving biological complexity and minimising confounding biological variability with analytical 'noise'.     

Bacterial bioactive metabolites as therapeutic agents: From production to action

Bacterial metabolites are one of the primary sources of drugs that we currently use to treat several diseases. However, bacterial drug discovery and development is a challenging and time-consuming process, and the emergence of new diseases and the development of resistance to currently available drugs demand the discovery of new metabolites with better biological activities. The new advancements in microbial technology, omics, genome and metabolic engineering, synthetic biology and the interdisciplinary approach of these fields overcome the hurdles in drug discovery and heterologous synthesis from bacteria. The gut microbiome performs a vital role in sustaining human health and aids in tackling various diseases. The metabolites produced by the gut microbiome act as an energy source for colon epithelium, maintain pH, help in cell differentiation and induces apoptosis in abnormal cells. The review discusses about the bacterial derived bioactive compounds, advancements and technologies in bacterial synthesis of bioactive sources and genomic and synthetic biology methods for the bioprospecting of bacterial metabolites. Since the gut microbiome relates to colon health, we have also discussed the techniques comprising probiotics, prebiotics, microbiome transplantation, toxins, and bacteriocins capable of preventing and managing colon associated health condition. Future directions in bacterial bioactive metabolite production are also discussed.     

Application of metabonomics in drug development

Metabolic profiling (metabonomics/metabolomics) is the untargeted analysis of metabolic composition in a biological sample, and is principally aimed at biomarker discovery. The frequent use of noninvasive biofluid analysis in metabonomics is suited to the clinic and facilitates dynamic monitoring. Analytical protocols for metabolic biomarkers are potentially robust because a metabolite is the same chemical entity irrespective of its origin, facilitating 'bench-to-bedside' translational research. Metabonomics can make an impact at several points in the drug-development process: target identification; lead discovery and optimization; preclinical efficacy and safety assessment; mode-of-action and mechanistic toxicology; patient stratification; and clinical pharmacological monitoring. This review describes and exemplifies the latest developments in each of these areas, including the impact of new data and chemical analytical techniques. The future goals for metabonomics are the validation of existing biomarkers, in terms of mechanism and translation to man, together with a focus on characterizing the individual ('personalized healthcare').     

Identification of end points relevant to detection of potentially adverse drug reactions

Expectations are high that the use of proteomics, gene arrays and metabonomics will improve risk assessment and enable prediction of toxicity early in drug development. These molecular profiling techniques may be used to classify compounds and to identify predictive markers that can be used to screen large numbers of chemicals. One of the challenges for the scientific community is to discriminate between changes in gene/protein expression and metabolic profiles reflecting physiological/adaptive responses, and changes related to pathology and toxicology. In these proceedings we provide a brief overview of the technologies with focus on proteomics and the possible applications to mechanistic and predictive toxicology. The discussion also includes strengths and limitations of molecular profiling technologies.     

The Role of Dietary Fiber and Gut Microbiome Modulation in Progression of Chronic Kidney Disease

Nutrition is one of the fundamental approaches to promoting and preventing all kinds of diseases, especially kidney diseases. Dietary fiber forms a significant aspect of renal nutrition in treating chronic kidney disease (CKD). Dietary fiber intake influences the composition and metabolism of the gut microbiome with proven roles in reducing uremic toxin production, preserving kidney function, and retarding the progression of CKD through mechanisms of regulating metabolic, immunological, and inflammatory processes. Understanding dietary fiber’s pathogenesis and mechanistic action in modulating host and microbiome interactions provides a potential adjunct therapeutic target for preventing, controlling, and treating CKD patients. In this regard, a recommendation of adequate and appropriate dietary fiber intake to restore beneficial gut microbiota composition would reduce the risks and complications associated with CKD. This mini review summarizes current evidence of the role of dietary fiber intake in modulating the gut microbiome to improve kidney health.     

Pharmacometabonomics as an effector for personalized medicine

This article introduces and reviews the concept of pharmacometabonomics, with recent experimental exemplifications of the approach being described and discussed. Pharmacometabonomics seeks to predict the response of an individual to a stimulus (e.g., drug, toxin, surgery, nutrition and so on) prior to the stimulus or other perturbation. It is an integral part of top-down systems biology which aims to improve understanding of phenotypic differences and the impact of beneficial and pathological interventions. The pharmacometabonomic concept is also integral to the understanding of mammalian-gut microbiome cometabolic interactions and their consequences, including the impact on disease and therapy. Although the subject is only at an early stage and requires further exemplification and validation, the approach has major implications for improved efficiency in drug discovery efforts, for example, by enabling more careful selection of animals in preclinical studies, for better stratification of patients in drug clinical trials and for individualized therapies. It could also find application in population-wide large cohort studies and in studies of nutrition where it would allow the elucidation of health risk factors and provide easily measured surrogate biomarkers.     

Metabonomics in toxicology: a review.

Metabonomics and its many pseudonyms (metabolomics, metabolic profiling, etc.) have exploded onto the scientific scene in the past 2 to 3 years. Nowhere has the impact been more profound than within the toxicology community. Within this community there exists a great deal of uncertainty about whether metabonomics is something to count on or just the most recent technological flash in the pan. Much of the uncertainty is due to unfamiliarity with analytical and chemometric facets of the technology and the attendant fear of any "black-box." With those fears in mind, metabonomics technology is reviewed with particular emphasis on toxicologic applications in preclinical drug development. The jargon, logistics, and applications of the technology are covered in some detail with emphasis on recent work in the field.     

Anti-IL-4/-13 based therapy in asthma

It is recognised that airway inflammation is key to asthma pathogenesis. Biopharmaceutical approaches have identified new therapies that target key cells and mediators that drive the inflammatory responses in the asthmatic lung. Such an approach resulted in the development of biologics targeted at inhibition of IL-4, IL-5 and IL-13. However, early clinical trials with these biologics in patients with asthma were for the most part disappointing even though they were highly effective in animal models of asthma. It is becoming apparent that significant clinical effects with anti-cytokine-based biologic therapies are more likely in carefully selected patient populations that take asthma phenotypes into account. The development of discriminatory biomarkers and genetic profiling may aid identification of such patients with asthma. This review is an update of the evidence demonstrating the effectiveness or otherwise of the targeting of the T_H2 cytokines IL-4 and IL-13 with biologics in patients with asthma.     

肠道菌群与放疗敏感性及放射性黏膜炎关系的研究进展

肠道菌群在肿瘤治疗中的作用在近几年受到广泛关注，包括化疗及免疫治疗在内的抗肿瘤治疗疗效均受到肠道菌群的调节。放疗是抗肿瘤中的重要组成部分，其疗效及不良反应发生风险受到多种因素的影响。近期研究表明，肠道菌群通过调节机体免疫系统影响放疗敏感性以及放射性黏膜炎的严重程度。该文系统地回顾了描述肠道菌群调节放疗疗效及其黏膜毒性的研究，希望通过调节肠道菌群以提高放疗疗效并减轻放疗副反应。     

Targeted microbiome-sparing antibiotics

A factor in our inability to meet the challenge of clinical antibiotic resistance has been the low productivity of research and development (R&D) efforts, with only incremental improvements on existing broad-spectrum classes coming into clinical use recently. The disappointing returns from this approach have focussed attention on narrower-spectrum antibiotics; such new agents are directed against the pathogen of relevance with the additional benefit of preserving the human microbiome(s). Our knowledge of the gut microbiome and its contribution to health homeostasis increases yearly and suggests that broad-spectrum treatments incur health costs beyond the initial infection. Improved diagnostics, antibiotic stewardship, and the crucial role of the gut microbiome in health indicate targeted agents as a more viable approach for future antibiotic R&D.     

The human gut microbiome – a new and exciting avenue in cardiovascular drug discovery

ABSTRACT

Introduction: Over the past decade, numerous research efforts have identified the gut microbiota as a novel regulator of human metabolic syndrome and cardiovascular disease (CVD). With the elucidation of underlying molecular mechanisms of the gut microbiota and its metabolites, the drug-discovery process of CVD therapeutics might be expedited.

Areas covered: The authors describe the evidence concerning the impact of gut microbiota on metabolic disorders and CVD and summarize the current knowledge of the gut microbial mechanisms that underlie CVD with a focus on microbial metabolites. In addition, they discuss the potential impact of the gut microbiota on the drug efficacy of available cardiometabolic therapeutic agents. Most importantly, the authors review the role of the gut microbiome as a promising source of potential drug targets and novel therapeutics for the development of new treatment modalities for CVD. This review also presents the various effective strategies to investigate the gut microbiome for CVD drug-discovery approaches.

Expert opinion: With the elucidation of its causative role in cardiometabolic disease and atherosclerosis, the human gut microbiome holds promises as a reservoir of novel potential therapeutic targets as well as novel therapeutic agents, paving a new and exciting avenue in cardiovascular drug discovery.     

Metabolic profiling technologies for biomarker discovery in biomedicine and drug development

The state-of-the-art of nuclear magnetic resonance spectroscopy, mass spectrometry and statistical tools for the acquisition and evaluation of complex multidimensional spectroscopic data in metabolic profiling is reviewed in this article. The continuous evolution of the sensitivity, precision and throughput has made these technologies powerful and extremely robust tools for application in systems biology, pharmaceutical and diagnostics research. Particular emphasis is also given to the collection and storage of biological samples that are subjected to metabolite profiling. Selected examples from preclinical and clinical applications are paradigmatically shown. These illustrate the power of the profiling technologies for characterizing the metabolic phenotype of healthy, diseased and treated subjects. The complexity of disease and drug treatment is asking for an adequate response by integrated and comprehensive metabolite profiling approaches that allow the discovery of new combinations of metabolic biomarkers.     

Docetaxel in the management of prostate cancer: current standard of care and future directions

Background: Advanced and metastatic prostate cancer continues to represent a significant healthcare burden. Since the publication of two randomized trials that showed significant survival and palliative benefits for men treated with docetaxel, this drug has become the treatment of choice for patients with metastatic castration resistant prostate cancer (CRPC). Objective: This review discusses the development and current use of docetaxel in metastatic CRPC, as well as future clinical applications. Methods: The current literature, meeting abstracts and ClinicalTrials.gov have been reviewed. The most relevant studies involving patients with prostate cancer receiving therapy with docetaxel, alone or in combination with other agents, have been summarised. Conclusion: Docetaxel monotherapy is the approved treatment for patients with metastatic CRPC, and its association with other agents, such as targeted therapies, is currently under study. Several trials are currently ongoing to investigate the use of docetaxel in the early stages of disease, particularly in the neoadjuvant and adjuvant settings for patients with high-risk disease.     

Novel inhibitors in development for hepatocellular carcinoma

Importance of the field: The multikinase inhibitor sorafenib was the first agent to demonstrate a survival benefit for patients with locally advanced or metastatic hepatocellular carcinoma (HCC). Although sorafenib represents a landmark in the treatment of HCC and proved molecularly targeted therapy to be effective in this disease, it represents just the first step towards an improvement in systemic therapy. Since then, novel inhibitors have been evaluated in early clinical trials, showing potential activity.

Areas covered in this review: This article aims to review novel inhibitors emerging in the field of advanced HCC. An Internet-based search was performed to identify abstracts, clinical trials (www.clinicaltrials.gov, last accessed 30 November 2009), and original research and review articles.

What the reader will gain: Readers will gain a comprehensive survey of current molecularly targeted therapy approaches in advanced HCC. In addition, challenges such as the design of clinical trials, the assessment of radiological response, the role of combination therapy, and future developments in molecularly targeted therapy are discussed.

Take home message: Sorafenib is the standard of care in patients with advanced HCC. However, promising novel inhibitors are under investigation. Combined molecularly targeted therapies according to an individual genomic and proteomic profiling will probably lead to more personalised medicine in advanced HCC.     

Recent developments in the pharmacological treatment of Crohn's disease

Therapy for Crohn's disease (CD) is rapidly evolving with the emergence of new discoveries in disease pathogenesis. Since the approval of the first biological agent, infliximab, there have been several others that have been studied and are available for use within the context of clinical trials, in CD patients who do not respond to conventional medications or whose disease cannot be maintained in remission with the use of infliximab. The number of available drugs that have focused on the inhibition of TNF is growing. To avoid the injectable route of administering biologicals, several oral agents, such as thalidomide analogues, nonabsorbable antibiotics, such as rifaximin, and specific antibiotics, such as ornidazole, are being studied and considered for patients with CD. Hormonal therapies, such as growth hormone, coherin, medroxyprogesterone acetate and dehydroepiandrosterone, are other novel therapies for CD. Immunomodulators in use in other fields of medicine, including tacrolimus, 6-thioguanine and leflunomide, are being evaluated for the treatment of patients with CD and are also discussed. Several other promising therapies, such as cyclophosphamide, extracorporeal photochemotherapy, stem cell transplantation and the use of porcine whipworm, add to the available therapeutic armamentarium of this life-long remitting and relapsing disease. The future for CD patients is promising with the ever-expanding repertoire of drugs that are being studied.