Synthetic cannabinoids: Analysis and metabolites

Cannabimimetics (commonly referred to as synthetic cannabinoids), a group of compounds encompassing a wide range of chemical structures, have been developed by scientists with the hope of achieving selectivity toward one or the other of the cannabinoid receptors CB1 and CB2. The goal was to have compounds that could possess high therapeutic activity without many side effects. However, underground laboratories have used the information generated by the scientific community to develop these compounds for illicit use as marijuana substitutes. This chapter reviews the different classes of these “synthetic cannabinoids” with particular emphasis on the methods used for their identification in the herbal products with which they are mixed and identification of their metabolites in biological specimens.     

全球寡核苷酸类药物开发现状与趋势

从产品开发角度分析寡核苷酸类药物的发展现状和未来趋势。     

Propolis characterization and antimicrobial activities against Staphylococcus aureus and Candida albicans: A review

Propolis is a plant-based sticky substance that is produced by honeybees. It has been used traditionally by ancient civilizations as a folk medicine, and is known to have many pharmaceutical properties including antioxidant, antibacterial, antifungal, anti-inflammatory, antiviral, and antitumour effects. Worldwide, researchers are still studying the complex composition of propolis to unveil its biological potential, and especially its antimicrobial activity against a variety of multidrug-resistant microorganisms. This review explores scientific reports published during the last decade on the characterization of different types of propolis, and evaluates their antimicrobial activities against Staphylococcus aureus and Candida albicans. Propolis can be divided into different types depending on their chemical composition and physical properties associated with geographic origin and plant sources. Flavonoids, phenols, diterpenes, and aliphatic compounds are the main chemicals that characterize the different types of propolis (Poplar, Brazilian, and Mediterranean), and are responsible for their antimicrobial activity. The extracts of most types of propolis showed greater antibacterial activity against Gram-positive bacteria: particularly on S. aureus, as well as on C. albicans, as compared to Gram-negative pathogens. Propolis acts either by directly interacting with the microbial cells or by stimulating the immune system of the host cells. Some studies have suggested that structural damage to the microorganisms is a possible mechanism by which propolis exhibits its antimicrobial activity. However, the mechanism of action of propolis is still unclear, due to the synergistic interaction of the ingredients of propolis, and this natural substance has multi-target activity in the cell. The broad-spectrum biological potentials of propolis present it as an ideal candidate for the development of new, potent, and cost-effective antimicrobial agents.     

A decade of marketing approval of gene and cell-based therapies in the United States,European Union and Japan: An evaluation of regulatory decision-making

There is a widely held expectation of clinical advance with the development of gene and cell-based therapies (GCTs). Yet, establishing benefits and risks is highly uncertain. We examine differences in decision-making for GCT approval between jurisdictions by comparing regulatory assessment procedures in the United States (US), European Union (EU) and Japan. A cohort of 18 assessment procedures was analyzed by comparing product characteristics, evidentiary and non-evidentiary factors considered for approval and post-marketing risk management. Product characteristics are very heterogeneous and only three products are marketed in multiple jurisdictions. Almost half of all approved GCTs received an orphan designation. Overall, confirmatory evidence or indications of clinical benefit were evident in US and EU applications, whereas in Japan approval was solely granted based on non-confirmatory evidence. Due to scientific uncertainties and safety risks, substantial post-marketing risk management activities were requested in the EU and Japan. EU and Japanese authorities often took unmet medical needs into consideration in decision-making for approval. These observations underline the effects of implemented legislation in these two jurisdictions that facilitate an adaptive approach to licensing. In the US, the recent assessments of two chimeric antigen receptor-T cell (CAR-T) products are suggestive of a trend toward a more permissive approach for GCT approval under recent reforms, in contrast to a more binary decision-making approach for previous approvals. It indicates that all three regulatory agencies are currently willing to take risks by approving GCTs with scientific uncertainties and safety risks, urging them to pay accurate attention to post-marketing risk management.     

A novel herbal product based on Piper betle and Sphaeranthus indicus essential oils: Toxicity,repellent activity and impact on detoxifying enzymes GST and CYP450 of Aedes aegypti Liston (Diptera: Culicidae)

Fresh leaves of Piper betle Linn. (Piperales: Piperaceae) and Sphaeranthus indicus Linn. (Asterales: Asteraceae), commonly known as betel leaves and East Indian globe thistle, respectively, were harvested and steam distilled for the extraction of P. betle and S. indicus crude volatile oils (Pb-CVO and Si-CVO, respectively). LC₅₀ calculated on 3^rd instar larvae of dengue mosquito Aedes aegypti Linn. (Diptera: Culicidae) was 42.17?ppm for PbSi-CVO (i.e., herbal formulation based on the EOs of P. betle and S. indicus). The larval and pupal duration were significantly longer post-treatment with 100?ppm of PbSi-CVO, if compared to control. We observed that PbSi-CVO significantly altered the detoxifying enzymes GST and CYP450 compared to the expression of control. Sub-lethal concentrations of PbSi-CVO showed strong repellent properties against dengue mosquitoes, without adverse reactions on the volunteers experiencing the repellent assays. Lastly, the adulticidal activity of PbSi-CVO was studied. Overall, our study outlined that this herbal product represents a promising candidate for the development of botanical based adulticidal agents.     

Standardized programming to reduce the burden of inappropriate therapies in implantable cardioverter defibrillators - Single centre follow up results

Background

Current algorithms and device morphology templates have been proposed in current Implantable Cardioverter-Defibrillators (ICDs) to minimize inappropriate therapies (ITS), but this has not been completely successful.

Are we prepared for animal cell technology in the 21st century?

Large scale animal cell culture for the production of complex therapeutic proteins has been a major success of the biotechnology industry. Today, approximately half of the $ 5 billion annual turnover of the biotechnology industry is based upon this technology, in many cases with reactors of more than 10 m³. As we look towards the 21 st century, however, we can see novel approaches to the production of therapeutic proteins, by means of gene and cellular therapies. These technologies present new engineering challenges to the animal cell technologist. Are we prepared to meet these challenges? The needs include: small-scale reactors for the preparation of autologous cell lines, methods for the production of viruses to be used as vectors in gene therapy, artificial organ and the processing of xenogenic cell lines and tissues for cellular implants in humans. More attention should be given to three-dimensional cell cultures. Mass transfer considerations need to be extended beyond just oxygen transfer, to include cellular communication in small systems; this is becoming increasingly important for the control and optimise growth and product formation. Apart from improvements of large-scale systems, substantial advantages could be gained by studying new methods for the production and delivery of therapeutic proteins, using small-scale cell culture systems. We should adapt teaching, regulatory, patent and clinical infrastructure to meet this challenge in a harmonious way.     

Application of diffusion‐edited and solvent suppression 1H‐NMR to the direct analysis of markers in valerian‐hop liquid herbal products

Introduction – The rising trend to consume herbal products for the treatment and/or prevention of minor ailments together with their chemical and pharmacological complexity means there is an urgent need to develop new approaches to their quality and stability. Objectives – This work looks at the application of one‐dimensional diffusion‐edited ¹H‐NMR spectroscopy (1D DOSY) and ¹H‐NMR with suppression of the ethanol and water signals to the characterisation of quality and stability markers in multi‐component herbal medicines/food supplements. Material and Methods – The experiments were performed with commercial tinctures of Valeriana officinalis L. (valerian), expired and non‐expired, as well as its combination with Hummulus lupulus L. (hops), which is one of the most popular blends of relaxant herbs. These techniques did not require purification or evaporation of components for the qualitative analysis of the mixture, but only the addition of D₂O and TSP. Results – The best diagnostic signals were found at δ 7 ppm (H‐11, valerenic acid), δ 4.2 ppm (H‐1, hydroxyvalerenic acid) and δ 1.5‐1.8 ppm (methyl groups in prenylated moieties, α‐acids/prenylated flavones). Conclusion – This work concludes on the potential value of 1D DOSY ¹H‐NMR to provide additional assurance of quality in complex natural mixtures. Copyright © 2016 John Wiley & Sons, Ltd.     

Multiomics Reveals Ectopic ATP Synthase Blockade Induces Cancer Cell Death via a lncRNA-mediated Phospho-signaling Network

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Highlights

• •Ectopic ATP synthase as a therapeutic target for gefitinib-resistant NSCLC.
• •Multiomics uncovers the dynamic network in response to ecto-ATP synthase blockade.
• •Ecto-ATP synthase blockade induces cytotoxicity by CK2/phospho-topo IIα/GAS5 axis.
• •A positive feedforward circuit between phospho-topo IIα and lncRNA-GAS5.