Can preclinical drug development help to predict adverse events in clinical trials?

The development of novel therapeutics is associated with high rates of attrition, with unexpected adverse events being a major cause of failure. Serious adverse events have led to organ failure, cancer development and deaths that were not expected outcomes in clinical trials. These life-threatening events were not identified during therapeutic development due to the lack of preclinical safety tests that faithfully represented human physiology. We highlight the successful application of several novel technologies, including high-throughput screening, organs-on-chips, microbiome-containing drug-testing platforms and humanised mouse models, for mechanistic studies and prediction of toxicity. We propose the incorporation of similar preclinical tests into future drug development to reduce the likelihood of hazardous therapeutics entering later-stage clinical trials.

Benchtop systems for in vivo molecular screening of labeled compounds, as a tool to speed up drug research.

BACKGROUND: For every new drug, >10,000 candidate molecules are tested for ~15 years. This is the daily mission of thousands research teams worldwide. It is well proven that small animal imaging speeds up this work, increases accuracy and decreases costs. However, commercial imaging systems have high purchase cost, require high service contracts, special facilities and trained staff. Thus, they are affordable to only few large research centres and not to the majority of small and medium research teams internationally. There are two main reasons that urge the addressing of this problem at large scale now: Firstly, small animal imaging started in 2000 and quickly research community and pharma industry understood its value, which opened preclinical imaging market (>2.5 Bil $). Continuous evolution in medicine and biology clearly shows the need to speed up research using new tools. Asian countries rapidly invest funds in drug research, enlarging existing market. Secondly, until recently such systems were based on complicated electronics and expensive components. Evolution in detector technology, electronics, software and 3D printing, made feasible the development of benchtop imaging systems, with attractive end user price. MATERIALS AND METHODS: Being an active partner of numerous international and national projects, we tried to identify the main requirements that an imaging system should have, in order to become a screening tool for daily use. Thus, we recently developed a new generation of affordable, but high-performance imaging systems, which can fulfil the daily needs of all research labs activated in preclinical research. Our technology covers the field of SPECT (Single Photon Emission Computed Tomography) and PET (Positron Emission Tomography) imaging, while an optical and x-ray imaging system is under development. The systems are based on well tested technology, including pixeliated scintillators, Position Sensitive Photomultipliers, programmable ADCs (Analog to Digital Converters) and FPGAs (Field Programmable Gate Arrays) and are connected with a standard laptop through USB and Ethernet connection. The systems are named "eyes-series" and have been already tested for fast screening of small animals injected with labeled compounds including peptides, antibodies and nanoparticles. Besides their performance, they are offered at a fraction of the cost of the commercial ones, comparable to standard lab equipment such as HPLC, gamma counter etc, opening new prospects in preclinical research. The first system is called "γ-eye™" and it is a dedicated system for imaging photons (γ-rays) which are emitted from radiolabelled biomolecules (2D-SPECT). The second system is called "ß-eye™" and detects positrons (ß-rays) from similar biomolecules (2D-PET). They both have dimensions which are 35x35x30cm and weight which is less that 30kgr. The spatial resolution of both systems is <2mm and their energy resolution <20%. Their sensitivity allows real time imaging for the first second post injection, while images are shown in real time during acquisition. They allow recording of fast frames, down to 1min, thus it is possible to perform fast kinetic studies. Finally, they are both provided along with a laptop that has preinstalled the required software, named "VISUAL-eyes". RESULTS: The technical specifications and performance evaluation of our technology will be presented. Different applications including oncology, regenerative medicine, nanomedicine and lung imaging will be given. Finally, the results of the comparison against high performance systems and a typical workflow for optimizing throughput will be demonstrated.

35 Years of Marine Natural Product Research in Sweden: Cool Molecules and Models from Cold Waters.

Currents efforts in marine biodiscovery have essentially focused on temperate to tropical shallow water organisms. With more than 6000 species of marine plants and animals, the Kosterfjord area has the richest marine biodiversity in Swedish waters, but it remains understudied. The overall objective of our marine pharmacognosy research is to explore and reveal the pharmacological potential of organisms from this poorly explored region. More generally, we wish to understand aspects of structure-activity relationships of chemical interactions in cold-water marine environment (shallow and deep). Our strategy is based on ecologically guided search for compounds through studies of physiology and organism interactions coupled to identification of bioactive molecules guided by especially in vivo assays. The research programme originated in the beginning of the 1980s with a broad screening of Swedish marine organisms using both in vitro and in vivo assays, resulting in isolation and identification of several different bioactive molecules. Two congenerous cyclopeptides, i.e. barettin and 8,9-dihydrobarettin, were isolated from the deep-sea sponge Geodia barretti, and structurally elucidated, guided by their antifouling activity and their affinity to a selection of human serotonin receptors. To optimize the activity a number of analogues of barettin were synthezised and tested for antifouling activity. Within the EU project BlueGenics, two larger homologous peptides, barrettides A and B, were isolated from G. baretti. Also, metabolic fingerprinting combined with sponge systematics was used to further study deep-sea natural product diversity in the genus Geodia. Finally, the chemical property space model 'ChemGPS-NP' has been developed and used in our research group, enabling a more efficient use of obtained compounds and exploration of possible biological activities and targets. Another approach is the broad application of phylogenetic frameworks, which can be used in prediction of where-in which organisms-to search for novel molecules or better sources of known molecules in marine organisms. In a further perspective, the deeper understanding of evolution and development of life on Earth can also provide answers to why marine organisms produce specific molecules.

Computer-Aided Drug Discovery from Marine Compounds: Identification of the Three-Dimensional Structural Features Responsible for Antimalarial Activity.

An integrated computational approach, based on molecular dynamics/mechanics, semi-empirical, and DFT calculations as well as dynamic docking studies, has been employed to gain insight into the mechanism of action of new antimalarial agents characterized by the scaffold of the marine compounds plakortin and aplidinone. The results of this approach show that these molecules, after interaction with Fe(II), likely coming from the heme molecule, give rise to the formation of radical species, that should represent the toxic intermediates responsible for subsequent reactions leading to plasmodium death. The three-dimensional structural requirements necessary for the activity of these new classes of antimalarial agents have been identified and discussed throughout the chapter.

Bluegenics: Bioactive Natural Products of Medicinal Relevance and Approaches to Their Diversification.

Nature provides a valuable resource of medicinally relevant compounds, with many antimicrobial and antitumor agents entering clinical trials being derived from natural products. The generation of analogues of these bioactive natural products is important in order to gain a greater understanding of structure activity relationships; probing the mechanism of action, as well as to optimise the natural product's bioactivity and bioavailability. This chapter critically examines different approaches to generating natural products and their analogues, exploring the way in which synthetic and biosynthetic approaches may be blended together to enable expeditious access to new designer natural products.

Discovery and Development of Novel Drugs.

Drug discovery and development process is nowadays conducted in relatively standardised sequence of phases, starting with Discovery and being followed by Preclinical, Clinical and Non-Clinical Development. Discovery phase is divided in Hit Finding, Lead generation, Lead Optimisation and Candidate Identification Phase. Main drivers of the whole process are regulatory requirements and the aim to eliminate the unnecessary spending by early elimination of unlikely drug candidates. Marine products, once purified, isolated and produced in required quantities, follow the same route as any other synthetic drug.

[Chinese medicine industry 4.0：advancing digital pharmaceutical manufacture toward intelligent pharmaceutical manufacture].

A perspective analysis on the technological innovation in pharmaceutical engineering of Chinese medicine unveils a vision on "Future Factory" of Chinese medicine industry in mind. The strategy as well as the technical roadmap of "Chinese medicine industry 4.0" is proposed, with the projection of related core technology system. It is clarified that the technical development path of Chinese medicine industry from digital manufacture to intelligent manufacture. On the basis of precisely defining technical terms such as process control, on-line detection and process quality monitoring for Chinese medicine manufacture, the technical concepts and characteristics of intelligent pharmaceutical manufacture as well as digital pharmaceutical manufacture are elaborated. Promoting wide applications of digital manufacturing technology of Chinese medicine is strongly recommended. Through completely informationized manufacturing processes and multi-discipline cluster innovation, intelligent manufacturing technology of Chinese medicine should be developed, which would provide a new driving force for Chinese medicine industry in technology upgrade, product quality enhancement and efficiency improvement.

Cheaper faster drug development validated by the repositioning of drugs against neglected tropical diseases.

There is an urgent need to make drug discovery cheaper and faster. This will enable the development of treatments for diseases currently neglected for economic reasons, such as tropical and orphan diseases, and generally increase the supply of new drugs. Here, we report the Robot Scientist 'Eve' designed to make drug discovery more economical. A Robot Scientist is a laboratory automation system that uses artificial intelligence (AI) techniques to discover scientific knowledge through cycles of experimentation. Eve integrates and automates library-screening, hit-confirmation, and lead generation through cycles of quantitative structure activity relationship learning and testing. Using econometric modelling we demonstrate that the use of AI to select compounds economically outperforms standard drug screening. For further efficiency Eve uses a standardized form of assay to compute Boolean functions of compound properties. These assays can be quickly and cheaply engineered using synthetic biology, enabling more targets to be assayed for a given budget. Eve has repositioned several drugs against specific targets in parasites that cause tropical diseases. One validated discovery is that the anti-cancer compound TNP-470 is a potent inhibitor of dihydrofolate reductase from the malaria-causing parasite Plasmodium vivax.

[Advanced in solubilization methods of water-insoluble natural drugs].

With the development of natural products, the research activities on the solubilization methods of water-insoluble natural products have been carried out worldwide. Big molecular weight and poor solubility of most natural active ingredients lead to a very poor oral absorption and low bioavailability, which has extremely limited their development in pharmaceutical fields and clinical application. As a result, it is necessary to find out a suitable technique to improve the solubility and enhance the oral bioavailability of insoluble natural drugs. Based on the related references published in these years, this review introduced some new techniques to improve the solubility and bioavailability of natural drugs, including prodrugs, inclusion complex, solid dispersion, cocrystals, osmotic pump, liquisolid compacts, micronization, self-microemulsifying, nanosuspensions, lipsomes, polymeric micelles and so on, and summarized the theory, characteristics, application range, application examples, problems and development direction of each technique.

[SCHWABE Company's patent portfolio of Ginkgo biloba preparation].

SCHWABE Company in German is the first and largest manufacturer of Ginkgo biloba preparation. The company not only has leading technology in this field, but also protects its own market effectively through the high quality of patent drafting and exactly patent layout. Based on multi-angle analysis for patent portfolio of G. biloba preparation at application time, legal status, globally layout, Chinese layout, the article provides technical reference of research and development of G. biloba, also provides valuable experience of traditonal Chinese medicine patent portfolio layout for Chinese enterprises.

[Discussion on polysaccharide determination methods in new Chinese drug research].

According to existing problems in polysaccharide determination methods in new Chinese drug applications, the method suitability, chemical reference selection, components interference and method research were introduced. The author suggests that suitable determination method should be selected according to the structure and property of the polysaccharide, and validated. Some influent factors should be examined to assure the accuracy of the method, such as the stability and using amount of the visualizing reagent, visualizing time, maximum detection wavelength etc. Monosaccharide and other water soluble components should be removed from polysaccharide sample, and suitable reference substance and detection wavelength should be selected. It should pay attention to mutual interference of neutral and acidic saccharide, and use inhibitor to eliminate the interference. Because the slopes of the standard curves are different for different monosaccharide, it is proposed that the types and ratios of the monosaccharide in heteroglycan should be understood, and mixed reference substance solution in the ratio is prepared for determination.

[Optimization theory and practical application of membrane science technology based on resource of traditional Chinese medicine residue].

Resource of traditional Chinese medicine residue is an inevitable choice to form new industries characterized of modem, environmental protection and intensive in the Chinese medicine industry. Based on the analysis of source and the main chemical composition of the herb residue, and for the advantages of membrane science and technology used in the pharmaceutical industry, especially membrane separation technology used in improvement technical reserves of traditional extraction and separation process in the pharmaceutical industry, it is proposed that membrane science and technology is one of the most important choices in technological design of traditional Chinese medicine resource industrialization. Traditional Chinese medicine residue is a very complex material system in composition and character, and scientific and effective "separation" process is the key areas of technology to re-use it. Integrated process can improve the productivity of the target product, enhance the purity of the product in the separation process, and solve many tasks which conventional separation is difficult to achieve. As integrated separation technology has the advantages of simplified process and reduced consumption, which are in line with the trend of the modern pharmaceutical industry, the membrane separation technology can provide a broad platform for integrated process, and membrane separation technology with its integrated technology have broad application prospects in achieving resource and industrialization process of traditional Chinese medicine residue. We discuss the principles, methods and applications practice of effective component resources in herb residue using membrane separation and integrated technology, describe the extraction, separation, concentration and purification application of membrane technology in traditional Chinese medicine residue, and systematically discourse suitability and feasibility of membrane technology in the process of traditional Chinese medicine resource industrialization in this paper.

Recent trends in the pharmacological activity of isoprenyl phenolics.

A number of prenylated phenols, mainly flavonoids, have been identified as active constituents of medicinal plants. Due to their beneficial effects on human health, this class of compounds has received a great deal of attention, not only from the pharmaceutical industry, but also from other areas of applied sciences, including the food, brewing, and cosmetics industries. The addition of prenyl residues through the activity of isoprenyltransferases, the key biosynthetic enzymes for these plant metabolites, endows flavonoids with a variety of biological activities, mostly due to improved interaction with membranes and proteins. The role of prenylated flavonoids in plants correlates with their activities as antioxidant or anti-infectious agents. In connection with these effects, these compounds have been evaluated for multiple potential uses, e.g. as antibacterial, antiprotozoal, antifungal, anti-inflammatory, antitumor, estrogenic, antidiabetic, or antithrombotic agents, among others. The present review, in principle focused on phenolic derivatives containing a non-cyclized isoprenyl chain, discusses the most relevant pharmacological reports for the period 2005-2012.

Al2O3 nanoparticles induce mitochondria-mediated cell death and upregulate the expression of signaling genes in human mesenchymal stem cells.

An increase in the broad usage of Al2O3 nanoparticles (ANPs) in the food and agricultural sectors may produce rare hazards for human health. The objective of this study was to assess the acute toxicity of ANPs in human mesenchymal stem cells (hMSCs) in vitro. Cell viability, cellular uptake, morphology, and gene expression using quantitative real-time polymerase chain reaction (qRT-PCR) were analyzed. The results indicate that ANPs have a significant and dose-dependent effect on cytotoxicity. Control cells showed a characteristic, homogeneous nuclear staining pattern, whereas ANP-exposed cells showed abnormal nuclear morphological changes such as condensation or fragmentation. An early characteristic of apoptosis was observed in ANP-treated cells. Further confirmation of cell death in hMSCs was observed through increased expression of chosen signaling genes and also decreased expression of Bcl-2 during mitochondria-mediated cell death. Although they provide great advantages in food and agricultural products, the chronic and acute toxicity of ANPs still needs to be assessed carefully.

[Industry of traditional Chinese patent medicine science and technology development and review].

"Fifteen" since, our country Chinese traditional medicine industry science and technology has made remarkable achievements. In this paper, the development of science and technology policy, Chinese medicine industry, platform construction and other aspects were analyzed, showing 10 years of Chinese traditional medicine industry development of science and technology innovation achievement and development, and on the current development of traditional Chinese medicine industry facing the main tasks and guarantee measures are analyzed.

Melt extrusion: process to product.

INTRODUCTION: Niche applicability and industrial adaptability have led hot melt extrusion (HME) techniques to gain wide acceptance and have, therefore, solidified their place in the array of pharmaceutical research and manufacturing operations. Melt extrusion's momentum has resulted in extensive research publications, reviews and patents on the subject for over a decade. Currently, > 50% of the new drug candidates are speculated to be highly lipophilic and thus poorly bioavailable. HME is a key technology for these and other formulation and processing issues. AREAS COVERED: Various approaches have been addressed using HME in developing solid molecular dispersions and have demonstrated viability to provide sustained, modified and targeted drug delivery resulting in improved bioavailability. This review provides a holistic perspective on HME from equipment, processing and materials to its varied applications in oral delivery (immediate release, sustained release, taste masking, enteric and targeted release, as well as trans-drug delivery), oral mucosal, dermal, ungual and intravaginal systems. EXPERT OPINION: Interest in HME as a pharmaceutical process continues to grow and the potential of automation and reduction of capital investment and labor costs has earned this technique a necessary consideration as a drug delivery solution.