Do We have a Satisfactory Cell Viability Assay? Review of the Currently Commercially-Available Assays.

Cell-based assays are an important part of the drug discovery process and clinical research. One of the main hurdles is to design sufficiently robust assays with adequate signal to noise parameters while maintaining the inherent physiology of the cells and not interfering with the pharmacology of target being investigated. A plethora of assays that assess cell viability (or cell heath in general) are commercially available and can be classified under different categories according to their concepts and principle of reactions. The assays are valuable tools, however, suffer from a large number of limitations. Some of these limitations can be procedural or operational, but others can be critical as those related to a poor concept or the lack of proof of concept of an assay, e.g. those relying on differential permeability of dyes in-and-out of viable versus compromised cell membranes. While the assays can differentiate between dead and live cells, most, if not all, of them can just assess the relative performance of cells rather than providing a clear distinction between healthy and dying cells. The possible impact of relatively high molecular weight dyes, used in most of the assay, on cell viability has not been addressed. More innovative assays are needed, and until better alternatives are developed, setup of current cell-based studies and data interpretation should be made with the limitations in mind. Negative and positive control should be considered whenever feasible. Also, researchers should use more than one orthogonal method for better assessment of cell health.

Research Techniques Made Simple: An Introduction to Drug Discovery for Dermatology.

This article aims to provide an overview of drug discovery with a focus on application within dermatology. The term "drug" can be used to describe a wide variety of agents, including small molecules, cell therapies, and antibodies, which may be dosed intravenously, orally, topically, or by other routes of administration. We summarize the economics and risks involved in drug discovery. Understanding the needs of patients and clinicians through use of a target product profile before initiating drug discovery can reduce time and effort spent developing a poor or unneeded drug. For small molecule drug discovery, a chemical starting point is then required. We present four options for finding a chemical starting point for drug discovery projects: screening libraries of compounds or modifying, reformulating, or repositioning a known drug. Examples of each technique's use in dermatology are provided. We also describe the subsequent steps involved in discovery of a new drug. To help interested readers, we provide information on how to engage with academic drug discovery centers or industrial partners.

Predicting the Risk of Phospholipidosis with in Silico Models and an Image-Based in Vitro Screen.

The drug-induced accumulation of phospholipids in lysosomes of various tissues is predominantly observed in regular repeat dose studies, often after prolonged exposure, and further investigated in mechanistic studies prior to candidate nomination. The finding can cause delays in the discovery process inflicting high costs to the affected projects. This article presents an in vitro imaging-based method for early detection of phospholipidosis liability and a hybrid approach for early detection and risk mitigation of phospolipidosis utilizing the in vitro readout with in silico model prediction. A set of reference compounds with phospolipidosis annotation was used as an external validation set yielding accuracies between 77.6% and 85.3% for various in vitro and in silico models, respectively. By means of a small set of chemically diverse known drugs with in vivo phospholipidosis annotation, the advantages of combining different prediction methods to reach an overall improved phospholipidosis prediction will be discussed.

Mitigating risk in academic preclinical drug discovery.

The number of academic drug discovery centres has grown considerably in recent years, providing new opportunities to couple the curiosity-driven research culture in academia with rigorous preclinical drug discovery practices used in industry. To fully realize the potential of these opportunities, it is important that academic researchers understand the risks inherent in preclinical drug discovery, and that translational research programmes are effectively organized and supported at an institutional level. In this article, we discuss strategies to mitigate risks in several key aspects of preclinical drug discovery at academic drug discovery centres, including organization, target selection, assay design, medicinal chemistry and preclinical pharmacology.

Middle East respiratory syndrome: obstacles and prospects for vaccine development.

The recent emergence of Middle East respiratory syndrome (MERS) highlights the need to engineer new methods for expediting vaccine development against emerging diseases. However, several obstacles prevent pursuit of a licensable MERS vaccine. First, the lack of a suitable animal model for MERS complicates the in vivo testing of candidate vaccines. Second, due to the low number of MERS cases, pharmaceutical companies have little incentive to pursue MERS vaccine production as the costs of clinical trials are high. In addition, the timeline from bench research to approved vaccine use is 10 years or longer. Using novel methods and cost-saving strategies, genetically engineered vaccines can be produced quickly and cost-effectively. Along with progress in MERS animal model development, these obstacles can be circumvented or at least mitigated.

Futurescapes: evidence expectations in the USA for comparative effectiveness research for drugs in 2020.

AIM: Explore key factors influencing future expectations for the production of evidence from comparative effectiveness research for drugs in the USA in 2020 and construct three plausible future scenarios. MATERIALS & METHODS: Semistructured key informant interviews and three rounds of modified Delphi with systematic scenario-building methods. RESULTS & CONCLUSION: Most influential key factors were: health delivery system integration; electronic health record development; exploitation of very large databases and mixed data sources; and proactive patient engagement in research. The scenario deemed most likely entailed uneven development of large integrated health systems with pockets of increased provider risk for patient care, enhanced data collection systems, changing incentives to do comparative effectiveness research and new opportunities for evidence generation partnerships.

Novel approaches are needed to develop tomorrow's antibacterial therapies.

Society faces a crisis of rising antibiotic resistance even as the pipeline of new antibiotics has been drying up. Antibiotics are a public trust; every individual's use of antibiotics affects their efficacy for everyone else. As such, responses to the antibiotic crisis must take a societal perspective. The market failure of antibiotics is due to a combination of scientific challenges to discovering and developing new antibiotics, unfavorable economics, and a hostile regulatory environment. Scientific solutions include changing the way we screen for new antibiotics. More transformationally, developing new treatments that seek to disarm pathogens without killing them, or that modulate the host inflammatory response to infection, will reduce selective pressure and hence minimize resistance emergence. Economic transformation will require new business models to support antibiotic development. Finally, regulatory reform is needed so that clinical development programs are feasible, rigorous, and clinically relevant. Pulmonary and critical care specialists can have tremendous impact on the continued availability of effective antibiotics. Encouraging use of molecular diagnostic tests to allow pathogen-targeted, narrow-spectrum antibiotic therapy, using short rather than unnecessarily long course therapy, reducing inappropriate antibiotic use for probable viral infections, and reducing infection rates will help preserve the antibiotics we have for future generations.

[Present situation and development strategies of Chinese medicine preparation in medical institutions].

As the actual clinical reflecting of transform Chinese medicine special curative effect, Chinese medicine preparation not only satisfies the need of hospital clinic, scientific research and teaching, but also plays an important role in deepening medical and health system reform, improving people's health level and contributing to the economic growth. However, some problems about administration and approval (tending to western medicine), contraction of the scale, lack of synchronization for clinic and scientific research, and the imbalance of regional development make Chinese medicine preparation move forwards slowly in contradiction. It has not only reduced the effectiveness of the Chinese medicine preparation in hospital clinic, but also brought bad effect on modernized development of Chinese medicine preparation. Research shows that main influencing factors of status quo of Chinese medicine preparation in medical institution include imperfect laws and regulations, high cost than income, and shortage of talents in preparation research. The analysis indicated that the necessary measures to break the contradiction, improve clinical effect of Chinese medicine, and promote the modernization development of Chinese drugs preparation were as follows: government and related departments should strengthen the supporting force in policy by adjusting the examination and approval policy, speeding up dispensing use, reforming pricing system, including into medicare reimbursement, integrating advantage resources and so on; medical institution should actively carry out research and development of traditional Chinese Medicine through drawing the traditional and modern essence, reserving professional talents, and developing characteristic preparation; companies cooperate with hospitals for complementary advantages, which can rapidly transform Chinese medicine preparation into clinical practice.

Lessons learned from the fate of AstraZeneca's drug pipeline: a five-dimensional framework.

Maintaining research and development (R&D) productivity at a sustainable level is one of the main challenges currently facing the pharmaceutical industry. In this article, we discuss the results of a comprehensive longitudinal review of AstraZeneca's small-molecule drug projects from 2005 to 2010. The analysis allowed us to establish a framework based on the five most important technical determinants of project success and pipeline quality, which we describe as the five 'R's: the right target, the right patient, the right tissue, the right safety and the right commercial potential. A sixth factor - the right culture - is also crucial in encouraging effective decision-making based on these technical determinants. AstraZeneca is currently applying this framework to guide its R&D teams, and although it is too early to demonstrate whether this has improved the company's R&D productivity, we present our data and analysis here in the hope that it may assist the industry overall in addressing this key challenge.

Potential strategies for increasing drug-discovery productivity.

The productivity challenge facing the pharmaceutical industry is well documented. Strategies to improve productivity have mainly focused on enhancing efficiency, such as the application of Lean Six Sigma process improvement methods and the introduction of modeling and simulation in place of 'wet' experiments. While these strategies have their benefits, the real challenge is to improve effectiveness by reducing clinical failure rates. We advocate redesigning the screening cascade to identify and optimize novel compounds with improved efficacy against disease, not just with improved potency against the target. There should be greater use of disease-relevant phenotypic screens in conjunction with target-based assays to drive medicinal chemistry optimization. An opportunistic approach to polypharmacology is recommended. There should also be more emphasis on optimization of the molecular mechanism of action incorporating understanding of binding kinetics, consideration of covalent drug strategies and targeting allosteric modulators.

Drug discovery alliances in India--indications, targets, and new chemical entities.

Global pharmaceutical and biotechnology companies have been building increasingly on the skills and services offered by Indian biotech companies through strategic collaborative partnerships and alliances to fuel their in-house discovery and development pipelines. With the exception of generic press releases, however, very little has been published on the process and progress of drug discovery itself, such as the targets or modes of action involved, nor on the scientific output of such collaborations, and therefore on new chemical entities coming out of India through research collaborations. This Essay provides an analytical review of recent patents, patent applications, and peer-reviewed publications of major research alliances. It aims at highlighting their scientific output as well as the considerable bandwidth of targets and therapeutic areas involved.

[Dynamic monitoring risk of anti-hepatoma new drug development].

Risk monitoring of new Chinese patent anti-hepatoma drugs is tracking recognized risks and residual risks, identifying emerging risk and ensure the implementation of the plan, estimating the process of reducing effectiveness. The paper is mainly through understanding the status of Chinese patent anti-hepatoma drugs, the content, characteristic and analysis method of dynamic risk monitoring, and then select the risk control indicators, collect risk information. Finally, puts forward the thought of anti-hepatoma drugs listed evaluation in our country, and try to establish the model of dynamic risk management of anti-hepatoma drugs.

Analysis of Pogostemon cablin from pharmaceutical research to market performances.

INTRODUCTION: Pogostemon cablin (P. cablin), called Ciruicao or Guanghuoxiang, is a well-known Chinese materia medica in southeast Asia that is widely used in gastrointestinal disease and exterior syndromes, being confirmed by both in vitro and in vivo studies. To exploit this traditional medicine that adequately fits modern drugs, however, a comprehensive review about its pharmacy research and market performance is extremely necessary. AREAS COVERED: This article reviews various components extracted from this plant as well as the biological activities derived from those chemical compositions. The authors summarize the quality evaluation and highlight the therapeutic effects of P. cablin, such as antiviral activities, antioxidation effect, antiinflammatory, analgesic activities, and intestinal barrier function protection. The preparation profile of P. cablin and some future related research were also described in this review. Last but not least, a market performance analysis was conducted. EXPERT OPINION: P. cablin has beneficial therapeutic potential as an effective adaptogenic herbal remedy in clinic. Molecular mechanisms and active targets of P. cablin compounds, the qualitative and quantitative standard of P. cablin, as well as novel drug delivery systems of P. cablin, would be developed.