Showing papers in "Expert Opinion on Drug Discovery in 2009"
TL;DR: In the era of increasing drug resistance in cancer patients, the discovery of hybrid drugs could provide an effective strategy to create chemical entities likely to be more efficacious and less prone to resistance.
Abstract: Background: Because cancer is a complex disease, it is unlikely that a single mono functional ‘targeted’ drug will be effective for treating this most advanced disease. Combined drugs that impact multiple targets simultaneously are better at controlling complex disease systems, are less prone to drug resistance and are the standard of care in cancer treatment. In order to improve the efficiency of using a two-drug cocktail, one approach involves the use of the so-called hybrid drugs, which comprises the incorporation of two drugs in a single molecule with the intention of exerting dual drug action.Objective: In the present article, we discuss the design, synthesis and various applications of anticancer hybrid agents and the developments in this field during the last few decades. Additionally, we describe different types of linkers and their role in contributing towards biological effects and the in vivo mechanism of drug release. We also depict some challenges from scientific and regulatory perspectives i...
161 citations
TL;DR: This review highlights advances in the development of FAAH inhibitors of different mechanistic classes and their in vivo efficacy, selectivity and drug-like pharmacokinetic properties.
Abstract: Background: Fatty acid amide hydrolase (FAAH) is an integral membrane enzyme that hydrolyzes the endocannabinoid anandamide and related amidated signaling lipids. Genetic or pharmacological inactivation of FAAH produces analgesic, anti-inflammatory, anxiolytic and antidepressant phenotypes without showing the undesirable side effects of direct cannabinoid receptor agonists, indicating that FAAH may be a promising therapeutic target. Objectives: This review highlights advances in the development of FAAH inhibitors of different mechanistic classes and their in vivo efficacy. Also highlighted are advances in technology for the in vitro and in vivo selectivity assessment of FAAH inhibitors using activity-based protein profiling and click chemistry-activity-based protein profiling, respectively. Recent reports on structure-based drug design for human FAAH generated by protein engineering using interspecies active site conversion are also discussed. Methods: The literature searches of Medline and SciFinder data...
159 citations
TL;DR: Polyether ionophores show a high degree of promise for the potential control of drug-resistant bacterial and parasitic infections and potential as drug candidates to combat drug- resistant infectious diseases.
Abstract: Background: As multidrug-resistant (MDR) pathogens continue to emerge, there is a substantial amount of pressure to identify new drug candidates. Carboxyl polyethers, also referred to as polyether antibiotics, are a unique class of compounds with outstanding potency against a variety of critical infectious disease targets including protozoa, bacteria and viruses. The characteristics of these molecules that are of key interest are their selectivity and high potency against several MDR etiological agents. Objective: Although many studies have been published about carboxyl polyether antibiotics, there are no recent reviews of this class of drugs. The purpose of this review is to provide the reader with an overview of the spectrum of activity of polyether antibiotics, their mechanism of action, toxicity and potential as drug candidates to combat drug-resistant infectious diseases. Conclusion: Polyether ionophores show a high degree of promise for the potential control of drug-resistant bacterial and parasitic...
155 citations
TL;DR: The past, present and future of using zebrafish to assess the impact of small molecule drugs on neural development and function are discussed, in light of understanding and treating neurodevelopmental disorders such as autism, neurodegenerative disorders including Alzheimer's, Parkinson's and Huntington's disease and neural system dysfunctions such as anxiety/depression and addiction.
Abstract: Background: Zebrafish is becoming an increasingly attractive model organism for understanding biology and developing therapeutics, because as a vertebrate, it shares considerable similarity with mammals in both genetic compositions and tissue/organ structures, and yet remains accessible to high throughput phenotype-based genetic and small molecule compound screening. Objective/method: The focus of this review is on the nervous system, which is arguably the most complex organ and known to be afflicted by > 600 disorders in humans. I discuss the past, present and future of using zebrafish to assess the impact of small molecule drugs on neural development and function, in light of understanding and treating neurodevelopmental disorders such as autism, neurodegenerative disorders including Alzheimer's, Parkinson's and Huntington's disease and neural system dysfunctions such as anxiety/depression and addiction. Conclusion: These studies hold promise to reveal fundamental mechanisms governing nervous system dev...
135 citations
TL;DR: The role and specific characteristics of dorsal root ganglia (DRG) derived sensory neuron culture system as a useful model in evaluating the pathogenic mechanisms of peripheral neuropathies and examination and validation of potential therapeutic compounds are addressed.
Abstract: BACKGROUND: Peripheral neuropathies affect many people worldwide and are caused by or associated with a wide range of conditions, both genetic and acquired. Current therapies are directed at symptomatic control because no effective regenerative treatment exists. Primary challenge is that mechanisms that lead to distal axonal degeneration, a common feature of all peripheral neuropathies, are largely unknown. OBJECTIVE/METHODS: To address the role and specific characteristics of dorsal root ganglia (DRG) derived sensory neuron culture system as a useful model in evaluating the pathogenic mechanisms of peripheral neuropathies and examination and validation of potential therapeutic compounds. A thorough review of the recent literature was completed and select examples of the use of DRG neurons in different peripheral neuropathy models were chosen to highlight the utility of these cultures. CONCLUSION: Many useful models of different peripheral neuropathies have been developed using DRG neuronal culture and potential therapeutic targets have been examined, but so far none of the potential therapeutic compounds have succeeded in clinical trials. In recent years, focus has changed to evaluation of axon degeneration as the primary outcome measure advocating a drug development strategy starting with phenotypic drug screening, followed by validation in primary complex co-cultures and animal models.
129 citations
TL;DR: Findings on alternative non-lytic modes of antimicrobial action that go beyond membrane disruption are summarized, with an emphasis on the specific interaction with microbial cell wall/membrane components, signaling of AMP exposure and intracellular targets of peptide action.
Abstract: Background: Antimicrobial peptides (AMP) are widely recognized as promising alternatives to the current use of antibiotics and fungicides. Amino-acid sequences of a vast majority of AMP share cationic and amphipathic biophysical properties that allow their insertion into lipid bilayers and can lead to alteration of biological membrane functions. Initial characterization studies linked these properties to antimicrobial killing activity. However, further data indicate that this is not the sole mode of action and that more subtle mechanisms might mediate the interaction with and effect to target microbes, as well as the specificity and toxicity of peptides. As such, AMP are increasingly viewed as powerful multifunctional drugs. Objective: This review summarizes findings on these alternative non-lytic modes of antimicrobial action that go beyond membrane disruption, with an emphasis on the specific interaction with microbial cell wall/membrane components, signaling of AMP exposure and intracellular targets of...
87 citations
TL;DR: This review provides a succinct overview and comparison of experimental and in silico screening techniques, selected case studies where both methods were used in concert to investigate their performance and complementary nature and a statement on the developments in experimental andIn silico approaches in the near future.
Abstract: Background: In the current situation of weak drug pipelines, impending patent expiration of several blockbuster drugs, industry consolidation and changing business models that target special diseases like cancer, diabetes, Alzheimer's and obesity, the pharmaceutical industry is under intense pressure to generate a strong drug pipeline distinguished by better productivity, diversity and cost effectiveness. The goal is discovering high-quality leads in the initial stages of the development cycle, to minimize the costs associated with failures at later ones. Objective: Thus, there is a great amount of interest in further developing and optimizing high-throughput screening and in silico screening, the two methods responsible for generating most of the lead compounds. Although high-throughput screening is the predominant starting point for discovery programs, in silico methods have gradually made inroads by their more rational approach, to expedite the drug discovery and development process. Conclusion: Modern...
77 citations
TL;DR: Given the dire clinical need for effective treatments of cachexia, animal models will continue to play a vital role in assessing the efficacy and safety of potential treatments prior to testing in humans.
Abstract: BACKGROUND: Cachexia is a devastating syndrome of body wasting that worsens quality of life and survival for patients suffering from diseases such as cancer, chronic kidney disease and chronic heart failure Successful treatments have been elusive in humans, leaving a clear need for the development of new treatment compounds Animal models of cachexia are able to recapitulate the clinical findings from human disease and have provided a much-needed means of testing the efficacy of prospective therapies OBJECTIVE: This review focuses on animal models of cachexia caused by cancer, chronic heart failure and chronic kidney disease, including the features of these models, their implementation, and commonly-followed outcome measures CONCLUSION: Given a dire clinical need for effective treatments of cachexia, animal models will continue a vital role in assessing the efficacy and safety of potential treatments prior to testing in humans Also important in the future will be the use of animal models to assess the durability of effect from anti-cachexia treatments and their effect on prognosis of the underlying disease states
66 citations
TL;DR: This review describes utilization of literature-derived protein and chemical functional knowledge bases in drug development, which can rationalize many aspects of drug development process including drug repositioning and biomarker design.
Abstract: Importance of the field: Drug discovery and development is a very complex and costly process Understanding the detailed molecular mechanisms of a disease and drug actions can make it more efficient not only for new target discovery but also for lead prioritization, drug repositioning and development of biomarkers for drug efficacy and safety Access to formalized knowledge about functions of proteins and small molecules is crucial for rationalization of the drug development process, and scientific publications are the main source of this knowledge Protein knowledge networks capturing protein functions, protein–protein relations and organization of proteins in complex cellular sub-systems are making their way into modern drug discovery Chemical networks representing multiple aspects of chemical functional information integrated into a protein systems biology network is even more advanced and promising paradigmAreas covered in this review: This review describes utilization of literature-derived protein
60 citations
TL;DR: Possible ways of exploring molecular hybridization strategies to plan new effective dual or symbiotic drug candidates are described.
Abstract: The molecular hybridization approach is one of the most valuable structural modification tools useful for the discovery of ligands and prototypes presenting either optimized affinity for one bioreceptor or the ability to modulate more than one bioreceptor associated with the target disease. The growing efforts to discover hybrid drugs resulting from the combination of pharmacophoric moieties of different known lead compounds have brought a new hope for the treatment of multifactorial diseases in recent years. This editorial describes possible ways of exploring molecular hybridization strategies to plan new effective dual or symbiotic drug candidates.
57 citations
TL;DR: The design of non-peptidic BACE1 inhibitors is described from a historical perspective and not by the inhibitor's category, suggesting that the respective methods have both merits and demerits and should be used in a mutually complementary manner.
Abstract: Background: β-Secretase, also called BACE1, is a promising molecular target for developing anti-Alzheimer's disease drugs. Several approaches of drug discovery for this therapy have been attempted, for example, substrate-based and structure-based designs, high-throughput screening, fragment-based lead generation and in silico screening. Method: In this review, we describe the design of non-peptidic BACE1 inhibitors from a historical perspective and not by the inhibitor's category. Conclusion: The respective methods have both merits and demerits and should be used in a mutually complementary manner.
TL;DR: NMR is a critical component of the drug discovery process, where the versatility of the technique enables it to continually expand and evolve its role, and NMR is expected to maintain this growth over the next decade with advancements in automation, speed of structure calculation, in-cell imaging techniques and the expansion of NMR amenable targets.
Abstract: Background: Drug discovery is a complex and unpredictable endeavor with a high failure rate Current trends in the pharmaceutical industry have exacerbated these challenges and are contributing to the dramatic decline in productivity observed over the last decade The industrialization of science by forcing the drug discovery process to adhere to assembly-line protocols is imposing unnecessary restrictions, such as short project timelines Recent advances in NMR are responding to these self-imposed limitations and are providing opportunities to increase the success rate of drug discovery Objective/method: A review of recent advancements in NMR technology that have the potential of significantly impacting and benefiting the drug discovery process is presented These include fast NMR data collection protocols and high-throughput protein structure determination, rapid protein–ligand co-structure determination, lead discovery using fragment-based NMR affinity screens, NMR metabolomics to monitor in vivo effi
TL;DR: An encouraging advance is the dissection of therapeutic efficacy of antagonists from induction of hyperthermia, a side effect that initially had raised concerns about the suitability of systemically administered TRPV1 antagonists for therapy.
Abstract: Background: The capsaicin receptor TRPV1, a polymodal nociceptor whose expression is up-regulated in a number of painful inflammatory disorders, represents a promising therapeutic target for pain relief. Potent small molecule TRPV1 antagonists are now undergoing clinical trials in patients with inflammatory or neuropathic pain. This review focuses on the multiplicity of factors regulating this channel and on their contributions to the emerging complexity of responses to TRPV1 and partial antagonists. For example, it is now clear that antagonists of capsaicin response can also antagonize, have no effect, or stimulate response to heat or protons. The complexity of TRPV1 regulation affords the potential to optimize agents for a specific therapeutic indication. An encouraging advance is the dissection of therapeutic efficacy of antagonists from induction of hyperthermia, a side effect that initially had raised concerns about the suitability of systemically administered TRPV1 antagonists for therapy. Objective...
TL;DR: Comment on various factors involved in the creation of structurally, and most crucially, functionally diverse compound libraries highlight the central role played by organic synthesis and discuss the value of diversity-driven synthetic approaches in the search for new biologically active molecules.
Abstract: Background: ‘Diversity’ is often cited as a crucial consideration when generating compound collections for biological screening. However, what exactly does one mean by ‘diversity’ and why is it important? Objective: How can diversity be incorporated into compound collections and what are the theoretical and technical challenges this poses? In this editorial, we comment on various factors involved in the creation of structurally, and most crucially, functionally diverse compound libraries. Conclusions: In particular, we highlight the central role played by organic synthesis and discuss the value of diversity-driven synthetic approaches in the search for new biologically active molecules with potentially exciting and unusual biological properties.
TL;DR: Clinical experience with approved TNF antagonists shows that there is a demand for minimizing risks associated with persistent blocking of TNF action, and it is foreseeable that efficacy and safety will be further improved and that TNF-targeting strategies will be exploited in further inflammatory and other diseases, including metabolic diseases and cancer.
Abstract: Background: TNF is a central mediator of inflammation and key target for intervention in inflammatory diseases such as rheumatoid arthritis, psoriasis and Crohn's disease. The four at present approved protein therapeutics directly target TNF and inhibit binding to its two TNF receptors. Treatment with TNF antagonists results in significant clinical responses and is generally well tolerated. Objective: Ten years of clinical experience with 1 million patients treated also revealed the limits of the available antagonists and potential therapy-associated risks, foremost being tuberculosis reactivation, but also neurologic and hematologic events, and even malignancies. These findings ask for improvement of established therapies. Method: We here review published literature on strategies interfering with TNF action and provide an overview of the now approved antagonists of TNF action as well as new reagents under development. Conclusion: Clinical experience with approved TNF antagonists shows that there is a dem...
TL;DR: In this paper, the authors proposed a method to find new antimalarials from medicinal and randomly collected plants, crude extracts are screened against P. falciparum in cultures and in malaria animal models, following bioassays of purified fractions, and cytotoxicity tests.
Abstract: Background: Malaria is the most important parasitic disease and its control depends on specific chemotherapy, now complicated by Plasmodium falciparum that has become resistant to most commonly available antimalarials. Treatment of the disease requires quinine or drug combinations of artemisinin derivatives and other antimalarials. Further drug resistance is expected. New active compounds need to be discovered. Objective/method: To find new antimalarials from medicinal and randomly collected plants, crude extracts are screened against P. falciparum in cultures and in malaria animal models, following bioassays of purified fractions, and cytotoxicity tests. Conclusion: For antimalarial research, screening medicinal plants is more efficient than screening randomly chosen plants. Biomonitored fractionation allows selection of new active molecules identified as potential antimalarials in multidisciplinary projects in Brazil; no new molecule is available for human testing. The advantages of projects based on et...
TL;DR: Assessment of the degree of renal dysfunction is not enough as a single end point, and should be complemented by the evaluation of parameters such as renal microcirculation, oxygenation, cellular adaptive response and morphology, according to the perspective of the compound pathogenesis of ARF.
Abstract: Background: Acute renal failure (ARF) is a broad clinical entity, encompassing diverse pathophysiologies, with heterogeneous functional and morphological features. In the same fashion, various animal models of ARF differ in their mechanisms, distribution and type of injury, cellular responses and outcome. Objective: To appraise available animal models of ARF used for the assessment of potential therapeutic interventions, providing their basic pathophysiologies. Methods: Review of literature and summaries of expert opinion discussion forums. Results/conclusions: Various animal models of ARF are used for the development of therapeutic/preventive interventions, including toxic, hypoxic and septic models. Incomplete understanding of the outstanding complexity of human ARF often leads to too simplistic interventional concepts or to misconceptions, based on models with limited clinical relevance. Thus, for the appropriateness of animal models, the use of models inflicting severe injury, though highly reproducib...
TL;DR: Under the FBDD approach, both identifying the starting fragment hit to be developed and generating the drug lead from that starting fragmenthit are important.
Abstract: Background: Fragment-based drug discovery (FBDD) has been established as a powerful alternative and complement to traditional high-throughput screening techniques for identifying drug leads. At present, this technique is widely used among academic groups as well as small biotech and large pharmaceutical companies. In recent years, > 10 new compounds developed with FBDD have entered clinical development, and more and more attention in the drug discovery field is being focused on this technique. Objective: Under the FBDD approach, a fragment library of relatively small compounds (molecular mass = 100 – 300 Da) is screened by various methods and the identified fragment hits which normally weakly bind to the target are used as starting points to generate more potent drug leads. Because FBDD is still a relatively new drug discovery technology, further developments and optimizations in screening platforms and fragment exploitation can be expected. This review summarizes recent advances in FBDD platforms and dis...
TL;DR: In this article, the authors present the current knowledge about QSAR studies of diverse groups of molecules with free radical scavenging activity, which can help to understand the proper mechanism underlying the interaction between the free radicals and antioxidant molecules.
Abstract: Background: During the past decade a large number of reports described the roles of active oxygen species in the development or exacerbation of various kinds of diseases. The systemic antioxidant defense system often fails to control the excess free radicals. Such a condition necessitates external antioxidant supplementation either in the form of drugs or vitamins. Quantitative structure–activity relationship (QSAR) serves as an effective computational tool for search and design of active molecules that may eventually be synthesized and assayed. Objective/method: This review presents the current knowledge about QSAR studies of diverse groups of molecules with free radical scavenging activity. The QSAR studies summarized here would help to understand the proper mechanism underlying the interaction between the free radicals and antioxidant molecules. Conclusion: The primary determinant factors for potent antioxidant activity include the electronic distribution of the molecules together with their lipophilic...
TL;DR: A useful, integrated network can be built from various databases and networks by resolving several issues, such as limited coverage and inconsistency, and can be completed by the prediction of missing links, biological network comparison and drug target identification.
Abstract: Background: One of the most recent and important developments in drug discovery is a new drug development approach of building and analyzing networks that contain relationships among drugs and targets, diseases, genes and other components. These networks and their integrations provide useful information for finding new targets as well as new drugs. Objective: This review article aims to review recent developments in various types of networks and suggest the future direction of these network studies for drug discovery. Methods: Databases and networks are integrated into a more complete network to better present the relationships among drugs, targets, genes, phenotypes and diseases. After discussing the limitations and obstacles of the recent research, we suggest several strategies to build a successful and practical drug–target network. Results/conclusion: A useful, integrated network can be built from various databases and networks by resolving several issues, such as limited coverage and inconsistency. T...
TL;DR: Despite the plethora of cell types potentially suitable for HCS, so far only a handful of cellular models account for the great majority of HCS assays, and the introduction of novel cell types, including engineered and primary cells, will further expand the potential of H CS for systems biology and drug discovery.
Abstract: Background: High-content screening (HCS) defines a series of cell-based multiparametric approaches for analysis at the single-cell level. In recent years, HCS has been increasingly pursued in the d...
TL;DR: Although in vitro models of pancreatic cancer are of tremendous value for genetic studies and for initial functional screenings in drug discovery, they carry several immanent drawbacks and are often poor in predicting therapeutic response in humans.
Abstract: Background: Pancreatic cancer is a disease of near uniform fatality and the overwhelming majority of patients succumb to their advanced malignancy in a few months of diagnosis. Despite considerable advances in our understanding of molecular mechanisms underlying pancreatic carcinogenesis, this knowledge has not yet been fully translated into clinically available treatment strategies that yield significant improvements in disease free or overall survival. Objective: Cell line-based in vitro model systems provide powerful tools to identify potential molecular targets for therapeutic intervention as well as for initial preclinical evaluation of novel drug candidates. Here, we provide a brief overview of recent literature on cell line-based model systems of pancreatic cancer and their application in the search for novel therapeutics against this vicious disease. Conclusion: Although in vitro models of pancreatic cancer are of tremendous value for genetic studies and for initial functional screenings in drug d...
TL;DR: The cantilever biosensors provide an extraordinarily sensitive method for binding affinity measurement using label-free reagents and are anticipated that they will be cost-competitive and easy to use in a research bioanalytical laboratory.
Abstract: Importance of the field: There is a growing need for inexpensive and highly sensitive methods in high-throughput format for measuring drug–target interactions. Cantilever biosensors are ultra-high sensitive electromechanical sensors that have been successfully used for label-free detection of a large number of biological entities. They are emerging as a technology that appears attractive for high-throughput drug discovery applications. Therefore, a brief description of this technology is provided here.Areas covered in this review: The objective of this review is to present an overview of the development in cantilever biosensor field reported to date and examine applications of cantilever biosensors for biomolecular interaction characterization and drug discovery. The subareas included in the review are: cantilever measurement principles, various interactions measured such as DNA–DNA, protein–protein, membrane protein–ligand and DNA–protein. Discussion on biomarker detection is also included.What the reade...
TL;DR: Systems thinking has now come of age enabling a ‘bird's eye view’ of the biological systems under study, at the same time allowing us to ‘zoom in’, where necessary, for a detailed description of individual components.
Abstract: Importance of the field: The shift in focus from ligand based design approaches to target based discovery over the last two to three decades has been a major milestone in drug discovery research. Currently, it is witnessing another major paradigm shift by leaning towards the holistic systems based approaches rather the reductionist single molecule based methods. The effect of this new trend is likely to be felt strongly in terms of new strategies for therapeutic intervention, new targets individually and in combinations, and design of specific and safer drugs. Computational modeling and simulation form important constituents of new-age biology because they are essential to comprehend the large-scale data generated by high-throughput experiments and to generate hypotheses, which are typically iterated with experimental validation.Areas covered in this review: This review focuses on the repertoire of systems-level computational approaches currently available for target identification. The review starts with...
TL;DR: Only model-based methodologies, able to integrate the diverse characteristics of a compound, can provide a rational approach to increase efficiency in drug development in this area, through the development of pharmacokinetic–pharmacodynamics models able to integrating quantitative descriptions of Pharmacokinetics, desired and unwanted effects.
Abstract: Background: Schizophrenia is a severe mental disorder characterized by definite specificities and complexities (heterogeneity of the disease symptoms, large between-subject variability in disease progression and response to therapeutic agents, placebo response, dropout, questionable preclinical models, importance of market differentiation, etc.) that make drug development in this field particularly difficult when compared to the other therapeutic areas. However, drug receptor binding (especially to D2, 5-HT2 and H1 receptors) can provide a useful quantitative framework that can be related to the downstream clinical (amelioration of disease-related scores) and unwanted (neurological effects and metabolic disregulation) effects. Objective: This paper reviews the pharmacokinetic, pharmacodynamic and disease progression approaches applied to the development of new drugs for the treatment of schizophrenia. Conclusions: Only model-based methodologies, able to integrate the diverse characteristics of a compound,...
TL;DR: This review contextualises many ERS and UPR client proteins that are deregulated or mutated in cancers and shows links between E RS and the UPR, their implication in oncogenic transformation, tumour progression and escape from immune surveillance, apoptosis inhibition, angiogenesis, metastasis, acquired drug resistance and poor cancer prognosis.
Abstract: Background: In eukaryotes, endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) are coordinately regulated to maintain steady-state levels and activities of various cellular proteins to ensure cell survival. Objective: This review (Part I of II) focuses on specific ERS and UPR signalling regulators, their expression in the cancer phenotype and apoptosis, and proposes how their implication in these processes can be rationalised into proteasome inhibition, apoptosis induction and the development of more efficacious targeted molecular cancer therapies. Method: In this review, we contextualise many ERS and UPR client proteins that are deregulated or mutated in cancers and show links between ERS and the UPR, their implication in oncogenic transformation, tumour progression and escape from immune surveillance, apoptosis inhibition, angiogenesis, metastasis, acquired drug resistance and poor cancer prognosis. Conclusion: Evasion of programmed cell death or apoptosis is a hallmark of cancer ...
TL;DR: Although drug throughput is modest, the high quality of the information allows in-depth evaluation and the possibility of analyzing later after effects and/or recovery after drug treatment is notable.
Abstract: Background: The Bionas 2500® analyzing system is an advanced label-free technology using a cell-based multi-sensor array, which is commercially available. Data on metabolism, respiration, adhesion, cell proliferation and cell death rates, as well as ligand–receptor interactions (multi-parametric) can be acquired and statistically evaluated. Noteworthy is the possibility of analyzing later after effects and/or recovery after drug treatment. In addition, Bionas supports all conceivable drug application modes (one, two or more drugs). Specimens for drug screening with Bionas consist of human permanent cell lines, primary cell cultures as well as ‘tumor slices’ obtained from biopsies and surgery material. Objective/methods: Examples of measurements are presented and discussed. Conclusion: Although drug throughput is modest, the high quality of the information allows in-depth evaluation.
TL;DR: While angiogenic inhibitors are now in clinical use, their limited benefits mean they must urgently develop strategies to improve the efficacy of this approach.
Abstract: Background: Angiogenesis is essential for tumour growth and development and since the pioneering work of Judah Folkman several anti-angiogenic strategies have now been successfully employed. Objective: This article aims to present a detailed review of current knowledge of the main pathways involved in angiogenesis, the strategies employed for inhibition and the current status of angiogenesis inhibitors in therapeutic use. Methods: A systematic review of the literature was undertaken including angiogenesis in cancer and angiogenesis inhibitors in pre-clinical and clinical trials. Conclusion: While angiogenic inhibitors are now in clinical use, their limited benefits mean we must urgently develop strategies to improve the efficacy of this approach.
TL;DR: An attempt has been made through this article to review the most potential medicinal plants with pharmacologically established hepatoprotective activity and finds the effective leads from natural resources for the desired therapeutic benefit.
Abstract: Background: Several lead compounds have been developed from natural resources as hepatoprotective. The hepatotoxic nature of the drugs, industrial toxins and drug-induced hepatotoxicity has been recognized as the major problem associated with liver diseases. Natural products including herbs have great potential in treating liver disorders. Objective: Botanicals have been used traditionally by herbalists and indigenous healers worldwide for several years for the prevention and treatment of liver disease and clinical research in this century has confirmed the efficacy of several plants in the treatment of liver disease. Many herbs used in several systems of alternative medicines have a long history of traditional use in revitalizing the liver and treating liver dysfunction and disease. Many of these herbs have been evaluated in clinical studies and are now being investigated phytochemically to understand their actions in a better way. Conclusion: An attempt has been made through this article to review the m...
TL;DR: It is concluded that human stem cells offer a source of physiologically relevant cells that show great potential as a future tool in cardiac drug discovery, but some technical challenges related to cell differentiation and production remain and must be overcome before successful application can become a reality.
Abstract: Background: The pharmaceutical industry suffers from high attrition rates during late phases of drug development. Improved models for early evaluation of drug efficacy and safety are needed to address this problem. Recent developments have illustrated that human stem cell-derived cardiomyocytes are attractive for using as a model system for different cardiac diseases and as a model for screening, safety pharmacology and toxicology. Objective: In this review, we discuss contemporary drug discovery models and their characteristics for cardiac efficacy testing and safety assessment. Additionally, we evaluate various sources of stem cells and how these cells could potentially improve early screening and safety models. Conclusion: We conclude that human stem cells offer a source of physiologically relevant cells that show great potential as a future tool in cardiac drug discovery. However, some technical challenges related to cell differentiation and production and also to validation of improved platforms rema...