Regulatory sanctions for ethically relevant GCP violations.
Abstract Although EU inspectors and clinical assessors are mandated to identify and act upon ethical issues, regulators lack guidance on how this can be done. Hence, we propose a four-step regulatory approach on ethically relevant GCP violation findings. The first step is identification of the ethical issue. Next is analysis [i.e., identifying the gravity (intensity or severity) and the magnitude (amount and duration) of the ethics violation as well as the responsible person(s) or entity or entities]. The third step is evaluation, (i.e., the process of deliberating to determine the significance of the ethics viola...
Source: Drug Discovery Today - July 6, 2019 Category: Drugs & Pharmacology Authors: de la Cruz Bernabe R, van Thiel GJMW, Breekveldt NS, Gispen CC, van Delden JJM Tags: Drug Discov Today Source Type: research

Target 2035: probing the human proteome.
Abstract Biomedical scientists tend to focus on only a small fraction of the proteins encoded by the human genome despite overwhelming genetic evidence that many understudied proteins are important for human disease. One of the best ways to interrogate the function of a protein and to determine its relevance as a drug target is by using a pharmacological modulator, such as a chemical probe or an antibody. If these tools were available for most human proteins, it should be possible to translate the tremendous advances in genomics into a greater understanding of human health and disease, and catalyze the creation of...
Source: Drug Discovery Today - July 3, 2019 Category: Drugs & Pharmacology Authors: Carter AJ, Kraemer O, Zwick M, Mueller-Fahrnow A, Arrowsmith CH, Edwards AM Tags: Drug Discov Today Source Type: research

Nucleolin-based targeting strategies for cancer therapy: from targeted drug delivery to cytotoxic ligands.
Moreira JN Abstract Cancer is currently the second leading cause of death worldwide and current therapeutic approaches remain ineffective in several cases. Therefore, there is a need to develop more efficacious therapeutic agents, especially for subtypes of cancer lacking targeted therapies. Limited drug penetration into tumors impairs the efficacy of therapies targeting cancer cells. One of the strategies to overcome this problem is targeting the more accessible tumor vasculature via molecules such as nucleolin, which is expressed at the surface of cancer and angiogenic endothelial cells, thus enabling a dual ce...
Source: Drug Discovery Today - July 1, 2019 Category: Drugs & Pharmacology Authors: Romano S, Fonseca N, Simões S, Gonçalves J, Moreira JN Tags: Drug Discov Today Source Type: research

Toward a repositioning of the antibacterial drug nifuroxazide for cancer treatment.
Abstract Nifuroxazide (NFX) is a broad-spectrum antibacterial drug that has been used for the treatment of infectious diarrhoea since 1966. In 2008, the discovery of potent inhibition of the transcription factor signal transducer and activator of transcription (STAT)3 by NFX prompted studies as a potential anticancer agent. Subsequently, it was shown that NFX induces cancer cell apoptosis and inhibits tumour growth. Recently, NFX was identified as a potent inhibitor of aldehyde dehydrogenase (ALDH)1 that selectively kills ALDHhigh cancer-initiating cells. These two landmark discoveries - STAT3 and ALDH1 inhibition...
Source: Drug Discovery Today - June 28, 2019 Category: Drugs & Pharmacology Authors: Bailly C Tags: Drug Discov Today Source Type: research

Are we ready to close the discussion on the interchangeability of biosimilars?
Abstract Since the introduction of the first biosimilar the discussion about their interchangeability has persisted. The body of evidence gathered for biosimilars provides reassurance that they are approved based on a rigorous comparability exercise and do not show clinically meaningful differences to their reference products. There are no data suggesting that the risk of switching to a biosimilar in terms of increased immunogenicity is greater than switching between two batches of any biologic. The key concern around switching biosimilars is the nocebo effect, which reinforces the need for physician involvement w...
Source: Drug Discovery Today - June 26, 2019 Category: Drugs & Pharmacology Authors: Ebbers HC, Schellekens H Tags: Drug Discov Today Source Type: research

Potential effects of increased openness in pharma: the original knowledge behind new drugs.
This study seeks to determine potential changes in the degree of openness in pharmaceutical R&D by investigating where the knowledge behind new molecular entities (NMEs) comes from in terms of type of organization, geography and time. We find that the organizations granted NMEs increasingly rely on external knowledge sources but that these are increasingly shared among NME grantees. Universities are the most important indirect knowledge contributor and their relative importance has increased with time. NME grantees are increasingly relying on knowledge from different countries and the age of the knowledge sources confi...
Source: Drug Discovery Today - June 26, 2019 Category: Drugs & Pharmacology Authors: Bignami F, Mattsson P Tags: Drug Discov Today Source Type: research

Neurobiology and therapeutic utility of neurotoxins targeting postsynaptic mechanisms of neuromuscular transmission.
Abstract The neuromuscular junction (NMJ) is the principal site for the translation of motor neurochemical signals to muscle activity. Therefore, the release and sensing machinery of acetylcholine (ACh) along with muscle contraction are two of the principal targets of natural toxins and pathogens, causing paralysis. Given pharmacology and medical advances, the active ingredients of toxins that target postsynaptic mechanisms have become of major interest, showing promise as drug leads. Herein, we review key facets of prevalent toxins modulating the mechanisms of ACh sensing and generation of the postsynaptic respon...
Source: Drug Discovery Today - June 24, 2019 Category: Drugs & Pharmacology Authors: Ayvazyan NM, O'Leary VB, Dolly JO, Ovsepian SV Tags: Drug Discov Today Source Type: research

Drug repurposing: a promising tool to accelerate the drug discovery process.
Abstract Traditional drug discovery and development involves several stages for the discovery of a new drug and to obtain marketing approval. It is necessary to discover new strategies for reducing the drug discovery time frame. Today, drug repurposing has gained importance in identifying new therapeutic uses for already-available drugs. Typically, repurposing can be achieved serendipitously (unintentional fortunate observations) or through systematic approaches. Numerous strategies to discover new indications for FDA-approved drugs are discussed in this article. Drug repurposing has therefore become a productive ...
Source: Drug Discovery Today - June 22, 2019 Category: Drugs & Pharmacology Authors: Parvathaneni V, Kulkarni NS, Muth A, Gupta V Tags: Drug Discov Today Source Type: research

Future unmet medical need as a guiding principle for pharmaceutical R & D.
Future unmet medical need as a guiding principle for pharmaceutical R&D. Drug Discov Today. 2019 Jun 21;: Authors: Vennemann M, Ruland V, Kruse JP, Harloff C, Trübel H, Gielen-Haertwig H Abstract In pharmaceutical R&D the strategic focus is on addressing areas of high unmet medical need. 'Unmet medical need' is a widely used term in the healthcare sector but a common definition does not exist. The current standard of care determines the current unmet medical need, whereas the future unmet medical need (i.e., the unmet medical need when a new product reaches the market) and the extent to w...
Source: Drug Discovery Today - June 21, 2019 Category: Drugs & Pharmacology Authors: Vennemann M, Ruland V, Kruse JP, Harloff C, Trübel H, Gielen-Haertwig H Tags: Drug Discov Today Source Type: research

The role of molecular simulations in understanding the mechanisms of cell-penetrating peptides.
Abstract Cell-penetrating peptides (CPPs) offer an exciting approach to tackle the pharmacokinetic challenges associated with the delivery of large, polar molecules to intracellular targets. Since the discovery of the first CPPs in the early 1990s, vast amounts of research have been undertaken to characterise their cellular uptake mechanisms. Despite this, the precise mechanisms of cellular internalisation of many CPPs remain elusive owing to inconsistent experimental results. Molecular dynamics (MD) simulations provide an approach to probe specific aspects of the internalisation process and many published CPP stu...
Source: Drug Discovery Today - June 20, 2019 Category: Drugs & Pharmacology Authors: Reid LM, Verma CS, Essex JW Tags: Drug Discov Today Source Type: research

LMWH and its derivatives represent new rational for cancer therapy: construction strategies and combination therapy.
Abstract Low-molecular-weight heparin (LMWH) has attracted increasing attention as a tumor treatment because of its board range of physiological functions. Over the past decade, diverse LMWH derivatives have increased the variety of antitumor strategies available, serving not only as anti-tumor agents, but also as drug delivery platforms. In this review, we introduce the basic strategy for structural modification of LMWH to attenuate its antitumor activity while reducing its risk of bleeding and immune responses, as well as highlighting current applications of LMWH and its derivatives in cancer therapy. We select ...
Source: Drug Discovery Today - June 19, 2019 Category: Drugs & Pharmacology Authors: Du S, Yu Y, Xu C, Xiong H, Yang S, Yao J Tags: Drug Discov Today Source Type: research

Exosomal miRNA in chemoresistance, immune evasion, metastasis and progression of cancer.
Abstract In the treatment of cancer, there are three significant limitations causing high mortality and recurrence rates among cancer patients. First, the escape of tumor cells from the immune system; second, the development of multi-drug resistance (MDR) to chemotherapeutic drugs; and, third, the noxious metastases of cancer cells. Exosomes are vesicular cargos involved in the transportation of miRNA, mRNA and proteins from one cell to another cell. This review details the current understanding of the exosomal transmission of miRNA and crosstalk with the downstream consequences, ultimately leading to the progress...
Source: Drug Discovery Today - June 19, 2019 Category: Drugs & Pharmacology Authors: Kulkarni B, Kirave P, Gondaliya P, Jash K, Jain A, Tekade RK, Kalia K Tags: Drug Discov Today Source Type: research

Early Access to Medicines Scheme: real-world data collection.
Abstract Real-world data (RWD) generated during the preapproval phase could be supplementary to primary clinical trial outcomes; however, as we discuss here, a data collection framework is needed to ensure the validity and applicability of these data. PMID: 31228615 [PubMed - as supplied by publisher] (Source: Drug Discovery Today)
Source: Drug Discovery Today - June 19, 2019 Category: Drugs & Pharmacology Authors: Pang H, Wang M, Kiff C, Soni M, Stein D, Tyas D Tags: Drug Discov Today Source Type: research

The human endogenous metabolome as a pharmacology baseline for drug discovery.
Abstract We have limited understanding of the variation in in vitro affinities of drugs for their targets. An analysis of a highly curated set of 442 interactions between 293 drugs and 79 primary targets reveals that 67% of drug-target affinities have values above that of the corresponding endogenous ligand, 96% of them fitting within a range of two orders of magnitude. Our findings suggest that the evolutionary optimised affinity of endogenous ligands for their native proteins can serve as a baseline for the primary pharmacology of drugs. We show that the degree of off-target selectivity and safety risks of drugs...
Source: Drug Discovery Today - June 18, 2019 Category: Drugs & Pharmacology Authors: Bofill A, Jalencas X, Oprea TI, Mestres J Tags: Drug Discov Today Source Type: research

Engineering microsystems to recapitulate brain physiology on a chip.
Abstract The structural and functional organization of the human brain consists of 52 regions with distinct cellular organization. In vitro models for normal and pathological states using isolated brain-region-specific 3D engineered tissues fail to recapitulate information integration and/or transfer that arises from connectivity among neuroanatomical structures. Therefore, development of brain-on-a-chip microsystems must shift to multiple region neuron network designs to be relevant in brain functionality and deficit modeling. However, in vitro formation of multiregional networks on microdevices presents several ...
Source: Drug Discovery Today - June 18, 2019 Category: Drugs & Pharmacology Authors: Ndyabawe K, Kisaalita W Tags: Drug Discov Today Source Type: research

Mini-gut: a promising model for drug development.
Abstract Until recently, major advances in drug development have been hampered by a lack of proper cell and tissue models; but the introduction of organoid technology has revolutionized this field. At the level of the gastrointestinal tract, the so-called mini-gut comprises all major cell types of native intestine and recapitulates the composition and function of native intestinal epithelium. The mini-gut can be classified as an intestinal organoid (IO), derived from pluripotent stem cells, or as an enteroid, consisting only of epithelial cells and generated from adult stem cells. Both classifications have been us...
Source: Drug Discovery Today - June 15, 2019 Category: Drugs & Pharmacology Authors: Yin YB, de Jonge HR, Wu X, Yin YL Tags: Drug Discov Today Source Type: research

Data science tools and applications on the way to Pharma 4.0.
Abstract Multiple obstacles are driving the digital transformation of the biopharmaceutical industry. Novel digital techniques, often marketed as 'Pharma 4.0', are thought to solve some long-existing obstacles in the biopharma life cycle. Pharma 4.0 concepts, such as cyberphysical systems and dark factories, require data science tools as technological core components. Here, we review current data science applications at various stages of the bioprocess life cycle, including their scopes and data sources. We are convinced that the scope and usefulness of these tools are currently limited by technical and nontechnic...
Source: Drug Discovery Today - June 14, 2019 Category: Drugs & Pharmacology Authors: Steinwandter V, Borchert D, Herwig C Tags: Drug Discov Today Source Type: research

Hydrogels for sustained delivery of biologics to the back of the eye.
Abstract Hydrogels are water-laden polymer networks that have been used for myriad biological applications. By controlling the chemistry through which a hydrogel is constructed, a wide range of chemical and physical properties can be accessed, making them an attractive class of biomaterials. In this review, we cover the application of hydrogels for sustained delivery of biologics to the back of the eye. In adapting hydrogels to this purpose, success is dependent on careful consideration of material properties, route of administration, means of injection, and control of drug efflux, all of which are addressed. We a...
Source: Drug Discovery Today - June 13, 2019 Category: Drugs & Pharmacology Authors: Chang D, Park K, Famili A Tags: Drug Discov Today Source Type: research

Protein Conjugates and Fusion Proteins as Ocular Therapeutics.
Abstract Long-acting delivery (LAD) of ocular therapeutics has substantial potential to improve the standard of care for ocular diseases such as age-related macular degeneration (AMD) by increasing patient compliance and reducing overall treatment burden on patients and healthcare providers. While relatively few ocular LAD technologies are currently on the market, a variety of emergent and novel protein engineering-based technologies are being investigated in both the laboratory and clinical settings. Here, we review some of the key indications and treatments which would benefit from the development of LAD for the...
Source: Drug Discovery Today - June 13, 2019 Category: Drugs & Pharmacology Authors: Mehta SC, Kelley RF, Tesar D Tags: Drug Discov Today Source Type: research

Impact of organ-on-a-chip technology on pharmaceutical R & D costs.
Impact of organ-on-a-chip technology on pharmaceutical R&D costs. Drug Discov Today. 2019 Jun 08;: Authors: Franzen N, van Harten WH, Retèl VP, Loskill P, van den Eijnden-van Raaij A, Ijzerman MJ Abstract Healthcare systems are faced with the challenge of providing innovative treatments, while shouldering high drug costs that pharmaceutical companies justify by the high costs of R&D. An emergent technology that could transform R&D efficiency is organ-on-a-chip. The technology bridges the gap between preclinical testing and human trials through better predictive models, significantly...
Source: Drug Discovery Today - June 8, 2019 Category: Drugs & Pharmacology Authors: Franzen N, van Harten WH, Retèl VP, Loskill P, van den Eijnden-van Raaij A, Ijzerman MJ Tags: Drug Discov Today Source Type: research

Antidepressants and nose-to-brain delivery: drivers, restraints, opportunities and challenges.
una A Abstract Why is nose-to-brain delivery considered to be a strategy that directly allows the access of antidepressants to the brain? In which circumstances can the intranasal pathway be applicable? Are there any requirements to follow? What triggers the antidepressant market? Which constraints are imposed during discovery programs? What opportunities can arise and what is their current status of development? Are they already translated into clinical practice? Which challenges are expected from recent development strategies? This review aims at providing a critical appraisal of nose-to-brain delivery of antide...
Source: Drug Discovery Today - June 7, 2019 Category: Drugs & Pharmacology Authors: Vitorino C, Silva S, Bicker J, Falcão A, Fortuna A Tags: Drug Discov Today Source Type: research

Skin metabolism phase I and phase II enzymes in native and reconstructed human skin: a short review.
Abstract Understanding skin metabolism is important when considering drug discovery and safety assessment. This review compares xenobiotic skin metabolism in ex vivo skin to reconstructed human skin and reconstructed human epidermis models, concentrating on phase I and phase II enzymes. Reports on phase I enzymes are more abundant than for phase II enzymes with mRNA and protein expression far more reported than enzyme activity. Almost all of the xenobiotic metabolizing enzymes detected in human skin are also present in liver. However, in general the relative levels are lower in skin than in liver and fewer enzymes...
Source: Drug Discovery Today - June 6, 2019 Category: Drugs & Pharmacology Authors: Kazem S, Linssen EC, Gibbs S Tags: Drug Discov Today Source Type: research

Challenges and opportunities for drug delivery to the posterior of the eye.
Abstract Drug delivery to the posterior of the eye remains challenging even though the eye is readily accessible. Its unique and complex anatomy and physiology contribute to the limited drug delivery via non-invasive topical treatment, which is the prevalent ophthalmic treatment. To treat the most common retinal diseases, intravitreal (IVT) injection has been a common and effective therapy. With the advancement of nanotechnologies, novel formulations and drug delivery systems are being developed to treat posterior diseases. Here, we discuss the recent advancement in ocular delivery systems, including-sustained rel...
Source: Drug Discovery Today - June 5, 2019 Category: Drugs & Pharmacology Authors: Cabrera FJ, Wang DC, Reddy K, Acharya G, Shin CS Tags: Drug Discov Today Source Type: research

Poloxamer-based in situ gelling thermoresponsive systems for ocular drug delivery applications.
Abstract In situ gels have recently received interest as ocular drug delivery vehicles because they combine the merits of easy instillation and sustained drug release. In this review, we focus on the use of poloxamers as in situ gelling systems in ocular drug delivery because of their thermoresponsive gelling behaviour, biocompatibility, and ease of sterilisation. Furthermore, the sol-gel transition temperature, mucoadhesive properties, and drug release profiles of poloxamer-based in situ gels can be finely tuned, enabling them to be used as vehicles for the delivery of small and large drug molecules to treat dise...
Source: Drug Discovery Today - June 5, 2019 Category: Drugs & Pharmacology Authors: Soliman KA, Ullah K, Shah A, Jones DS, Thakur RRS Tags: Drug Discov Today Source Type: research

The safety evaluation of long-acting ocular delivery systems.
Abstract The safety evaluation of ocular long-acting delivery (LAD) technologies is a nascent field. Here, we detail the challenges in assessing the safety of novel LAD technologies, and well as the most common types of toxicity encountered during early toxicity testing. A detailed understanding of the route of administration, pharmacology, and functionality and/or pharmacokinetics (PK) of LAD, along with all of its component parts, including the active pharmaceutical ingredient and excipients, is crucial for the successful development of next-generation long-acting ocular therapeutics. PMID: 31173909 [PubMed...
Source: Drug Discovery Today - June 4, 2019 Category: Drugs & Pharmacology Authors: Thackaberry EA, Lorget F, Farman C, Bantseev V Tags: Drug Discov Today Source Type: research

Nitric oxide: a drug target for glaucoma revisited.
r L Abstract A reduction in intraocular pressure (IOP) is the only recognized therapy for glaucoma. Hence, drugs exhibiting ocular hypotensive effects are important targets for antiglaucomatous drug development. IOP is determined by the equilibrium of aqueous humor production and outflow through either the trabecular meshwork or the uveoscleral outflow pathway. There is increasing evidence that nitric oxide (NO) has a major role in the regulation of IOP by directly acting on the trabecular meshwork and thereby lowering IOP. Taking advantage of this mechanism, newly designed NO-donating drugs combine the IOP-loweri...
Source: Drug Discovery Today - June 4, 2019 Category: Drugs & Pharmacology Authors: Garhöfer G, Schmetterer L Tags: Drug Discov Today Source Type: research

Pharmacological analysis of CFTR variants of cystic fibrosis using stem cell-derived organoids.
Abstract Cystic fibrosis (CF) is a life-shortening genetic disease caused by mutations of CFTR, the gene encoding cystic fibrosis transmembrane conductance regulator. Despite considerable progress in CF therapies, targeting specific CFTR genotypes based on small molecules has been hindered because of the substantial genetic heterogeneity of CFTR mutations in patients with CF, which is difficult to assess by animal models in vivo. There are broadly four classes (e.g., II, III, and IV) of CF genotypes that differentially respond to current CF drugs (e.g., VX-770 and VX-809). In this review, we shed light on the phar...
Source: Drug Discovery Today - June 4, 2019 Category: Drugs & Pharmacology Authors: Chen KG, Zhong P, Zheng W, Beekman JM Tags: Drug Discov Today Source Type: research

Revisiting mTOR inhibitors as anticancer agents.
This article aims to enlighten and guide the development of mTOR-targeted anticancer agents in the future. PMID: 31173912 [PubMed - as supplied by publisher] (Source: Drug Discovery Today)
Source: Drug Discovery Today - June 4, 2019 Category: Drugs & Pharmacology Authors: Teng QX, Ashar YV, Gupta P, Gadee E, Fan YF, Reznik SE, Wurpel JND, Chen ZS Tags: Drug Discov Today Source Type: research

Potential antiedematous effects of intravitreous anti-VEGF, unrelated to VEGF neutralization.
Abstract The intravitreous injection of therapeutic proteins that neutralize vascular endothelial growth factor (VEGF) family members is efficient to reduce macular edema associated with wet age-related macular degeneration (AMD), retinal vein occlusion (RVO) and diabetic retinopathy (DR). It has revolutionized the visual prognosis of patients with macular edema. The antiedematous effect is dependent on an intravitreous dose of drug, which varies between patients and requires frequent and repeated injections to maintain its effects. At the time when optimizing the duration of anti-VEGF effects is a major challenge...
Source: Drug Discovery Today - June 4, 2019 Category: Drugs & Pharmacology Authors: Behar-Cohen F, Dernigoghossian M, Andrieu-Soler C, Levy R, Cohen R, Zhao M Tags: Drug Discov Today Source Type: research

Ocular gene therapies in clinical practice: viral vectors and nonviral alternatives.
Abstract Ocular gene therapy has entered into clinical practice. Although viral vectors are currently the best option to replace and/or correct genes, the optimal method to deliver these treatments to the retinal pigment epithelial (RPE) cells and/or photoreceptor cells remains to be improved to increase transduction efficacy and reduce iatrogenic risks. Beyond viral-mediated gene replacement therapies, nonviral gene delivery approaches offer the promise of sustained fine-tuned expression of secreted therapeutic proteins that can be adapted to the evolving stage of the disease course and can address more common no...
Source: Drug Discovery Today - June 4, 2019 Category: Drugs & Pharmacology Authors: Bordet T, Behar-Cohen F Tags: Drug Discov Today Source Type: research

Recent advances in intraocular sustained-release drug delivery devices.
Abstract Topical eye-drop administration and intravitreal injections are the current standard for ocular drug delivery. However, patient adherence to the drug regimen and insufficient administration frequency are well-documented challenges to this field. In this review, we describe recent advances in intraocular implants designed to deliver therapeutics for months to years, to obviate the issues of patient adherence. We highlight recent advances in monolithic ocular implants in the literature, the commercialization pipeline, and approved for the market. We also describe design considerations based on material sele...
Source: Drug Discovery Today - June 4, 2019 Category: Drugs & Pharmacology Authors: Cao Y, Samy KE, Bernards DA, Desai TA Tags: Drug Discov Today Source Type: research

Incorporating liquid biopsies into treatment decision-making: obstacles and possibilities.
Abstract Circulating tumor cells (CTCs) and cell-free DNA (cfDNA) together with newer emerging liquid biopsies have a unique potential to deal with key issues in oncology. For example, they can be used to assess prognosis, direct treatment with certain kinds of drug, or provide information about response to treatment. However, despite an overflow of literature on the subject, clinical implementation of these liquid biopsies has been scarce. This is mainly because there is a lack of preanalytical standardization, multiple different techniques or platforms are being used, and a lack of prospective studies investigat...
Source: Drug Discovery Today - June 3, 2019 Category: Drugs & Pharmacology Authors: Beije N, Martens JWM, Sleijfer S Tags: Drug Discov Today Source Type: research

Correlates of time to approval and other clinical development periods.
Abstract The drug development cycle is classically divided into a clinical phase and review phase, with the clinical phase typically being further partitioned based on the planning and conduct of adequate and well controlled trials. Factors affecting the duration of the development intervals have not previously been systematically investigated. Here, we analyze a large population (N = 825) of New Drug Applications (NDAs) approved between 2008 and 2017 to characterize the typical duration of these intervals and the development factors associated with their duration. These data and analyses will help t...
Source: Drug Discovery Today - June 3, 2019 Category: Drugs & Pharmacology Authors: Breder CD, Vanheusen M, Chang LC Tags: Drug Discov Today Source Type: research

Peptide-based protease inhibitors from plants.
Abstract Proteases have an important role in homeostasis, and dysregulation of protease function can lead to pathogenesis. Therefore, proteases are promising drug targets in cancer, inflammation, and neurodegenerative diseases. Although there are well-established pharmaceuticals on the market, drug development for proteases is challenging. This is often caused by the limited selectivity of currently available lead compounds. Proteinaceous plant protease inhibitors are a diverse family of (poly)peptides that are important to maintain physiological homeostasis and to serve the innate defense machinery of the plant. ...
Source: Drug Discovery Today - June 3, 2019 Category: Drugs & Pharmacology Authors: Hellinger R, Gruber CW Tags: Drug Discov Today Source Type: research

Cancer cell fusion: a potential target to tackle drug-resistant and metastatic cancer cells.
Abstract Cell fusion is an integral, established phenomenon underlying various physiological processes in the cell cycle. Although research in cancer metastasis has hypothesised numerous molecular mechanisms and signalling pathways responsible for invasion and metastasis, the origin and progression of metastatic cells within primary tumours remains unclear. Recently, the role of cancer cell fusion in cancer metastasis and development of multidrug resistance (MDR) in tumours has gained prominence. However, evidence remains lacking to justify the role of cell fusion in cancer metastasis and drug resistance. Here, we...
Source: Drug Discovery Today - June 1, 2019 Category: Drugs & Pharmacology Authors: Fernandes C, Prabhu P, Juvale K, Suares D, Yc M Tags: Drug Discov Today Source Type: research

Physicians in the pharmaceutical industry: their roles, motivations, and perspectives.
Abstract Although physicians occupy a significant number of key positions in the pharmaceutical industry, practicing clinicians are often unaware of the variety of career paths within this industry, or of the structure of a pharmaceutical company. Here, we address questions that practicing clinicians frequently ask their colleagues in the pharmaceutical industry. In addition to providing an overview of the common roles occupied by physicians in pharma, we also describe the various motivations for transitioning into the industry and discuss different scenarios regarding the timing of the career change. Furthermore,...
Source: Drug Discovery Today - May 31, 2019 Category: Drugs & Pharmacology Authors: Sweiti H, Wiegand F, Bug C, Vogel M, Lavie F, Winiger-Candolfi I, Schuier M Tags: Drug Discov Today Source Type: research

2018 in review: FDA approvals of new molecular entities.
Abstract 2018 was a remarkable year, both in terms of the number of new molecular entities (NMEs) approved and the organizations developing them. In total, 59 NMEs received a nod from the US Food and Drug Administration (FDA), most of which were approved using a priority or breakthrough designation. Orphan drugs accounted for more than half of new approvals, only the second time in history that level has been achieved. Moreover, the net number of organizations that received an FDA approval and remain active in new drug research surged in 2018, reflecting both an increase in new organizations and lower levels of in...
Source: Drug Discovery Today - May 31, 2019 Category: Drugs & Pharmacology Authors: Kinch MS, Griesenauer RH Tags: Drug Discov Today Source Type: research

Unbiased data analytic strategies to improve biomarker discovery in precision medicine.
Abstract Omics technologies promised improved biomarker discovery for precision medicine. The foremost problem of discovered biomarkers is irreproducibility between patient cohorts. From a data analytics perspective, the main reason for these failures is bias in statistical approaches and overfitting resulting from batch effects and confounding factors. The keys to reproducible biomarker discovery are: proper study design, unbiased data preprocessing and quality control analyses, and a knowledgeable application of statistics and machine learning algorithms. In this review, we discuss study design and analysis cons...
Source: Drug Discovery Today - May 31, 2019 Category: Drugs & Pharmacology Authors: Khan SR, Manialawy Y, Wheeler MB, Cox BJ Tags: Drug Discov Today Source Type: research

Ontology mapping for semantically enabled applications.
Abstract In this review, we provide a summary of recent progress in ontology mapping at a crucial time when biomedical research is under a deluge of an increasing amount and variety of data. This is particularly important for realising the full potential of semantically enabled or enriched applications and for meaningful insights, such as drug discovery, using machine-learning technologies. We discuss challenges and solutions for better ontology mappings, as well as how to select ontologies before their application. In addition, we describe tools and algorithms for ontology mapping, including evaluation of tool ca...
Source: Drug Discovery Today - May 31, 2019 Category: Drugs & Pharmacology Authors: Harrow I, Balakrishnan R, Jimenez-Ruiz E, Jupp S, Lomax J, Reed J, Romacker M, Senger C, Splendiani A, Wilson J, Woollard P Tags: Drug Discov Today Source Type: research

Standpoint on the priority of TNTs and CNTs as targeted drug delivery systems.
aacute;ny T Abstract Conventional drug delivery systems have limitations according to their toxicity and poor solubility, bioavailability, stability, and pharmacokinetics (PK). Here, we highlight the importance of functionalized titanate nanotubes (TNTs) as targeted drug delivery systems. We discuss the differences in the physicochemical properties of TNTs and carbon nanotubes (CNTs) and focus on the use of functionalization to improve their characteristics. TNTs are promising materials for drug delivery systems because of their superb properties compared with CNTs, such as their processability, wettability, and b...
Source: Drug Discovery Today - May 31, 2019 Category: Drugs & Pharmacology Authors: Ranjous Y, Regdon G, Pintye-Hódi K, Sovány T Tags: Drug Discov Today Source Type: research

Cannabinoid receptors as therapeutic targets for autoimmune diseases: where do we stand?
ra RC Abstract Described during the late 1980s and 1990s, cannabinoid receptors (CB1R and CB2R) are G-protein-coupled receptors (GPCRs) activated by endogenous ligands and cannabinoid drug compounds, such as Δ9-THC. Whereas CB1R has a role in the regulation of neurotransmission in different brain regions and mainly mediates the psychoactive effects of cannabinoids, CB2R is found predominantly in the cells and tissues of the immune system and mediates anti-inflammatory and immunomodulatory processes. Studies have demonstrated that CB1R and CB2R can affect the activation of T cells, B cells, monocytes, and mic...
Source: Drug Discovery Today - May 31, 2019 Category: Drugs & Pharmacology Authors: Gonçalves ED, Dutra RC Tags: Drug Discov Today Source Type: research

Advances and challenges in developing andrographolide and its analogues as cancer therapeutic agents.
Abstract Andrographolide (AGP), a naturally occurring bioactive compound, has been investigated as a lead compound in cancer drug development. Its multidimensional therapeutic effects have raised interest among medicinal chemists, which has led to extensive structural modification of the compound, resulting in analogues with improved pharmacological and pharmaceutical properties. Nevertheless, the analogues with the improved properties need to be rigorously studied to identify drug-like lead compounds. We scrutinised articles published from 2012 to 2018, to objectively provide opinions on the mechanisms of action ...
Source: Drug Discovery Today - May 30, 2019 Category: Drugs & Pharmacology Authors: Liong SH, Ying QS, Sulaiman I, Sagineedu SR, Woei JLC, Stanslas J Tags: Drug Discov Today Source Type: research

Raising the bar in anticancer therapy: recent advances in, and perspectives on, telomerase inhibitors.
Abstract Telomerase is a ribonucleic reverse transcriptase enzyme that uses an integral RNA component as a template to add tandem telomeric DNA repeats, TTAGGG, at the 3' end of the chromosomes. However, 85-90% of human tumors and their derived cell lines predominantly express high levels of telomerase, therefore contributing to cancer cell development. However, in normal cells, telomerase activity is almost always absent except in germ cells and stem cells. This differential expression has been exploited to develop highly specific and potent cancer therapeutics. In this review, we outline recent advances in the d...
Source: Drug Discovery Today - May 25, 2019 Category: Drugs & Pharmacology Authors: Saraswati AP, Relitti N, Brindisi M, Gemma S, Zisterer D, Butini S, Campiani G Tags: Drug Discov Today Source Type: research

Better prediction of the local concentration-effect relationship: the role of physiologically based pharmacokinetics and quantitative systems pharmacology and toxicology in the evolution of model-informed drug discovery and development.
Abstract Model-informed drug discovery and development (MID3) is an umbrella term under which sit several computational approaches: quantitative systems pharmacology (QSP), quantitative systems toxicology (QST) and physiologically based pharmacokinetics (PBPK). QSP models are built using mechanistic knowledge of the pharmacological pathway focusing on the putative mechanism of drug efficacy; whereas QST models focus on safety and toxicity issues and the molecular pathways and networks that drive these adverse effects. These can be mediated through exaggerated on-target or off-target pharmacology, immunogenicity or...
Source: Drug Discovery Today - May 24, 2019 Category: Drugs & Pharmacology Authors: Polak S, Tylutki Z, Holbrook M, Wiśniowska B Tags: Drug Discov Today Source Type: research

Hot-melt extrusion in the pharmaceutical industry: toward filing a new drug application.
otilde;es S Abstract The pharmaceutical development of amorphous solid dispersions (ASDs) by hot-melt extrusion (HME) is briefly reviewed. A systematic step-by-step approach is presented, where thermodynamics, polymer screening, multivariate statistics and process optimization are combined, to increase the success of HME-based drug product development. The quality by design (QbD) concept is introduced and applied to HME. Steps and tools for its effective implementation are provided, including risk assessment highlighting crucial points. The technical and scientific specificities of HME-based ASDs are discussed in ...
Source: Drug Discovery Today - May 24, 2019 Category: Drugs & Pharmacology Authors: Simões MF, Pinto RMA, Simões S Tags: Drug Discov Today Source Type: research

Success factors of crowdfunding campaigns in medical research: perceptions and reality.
;y Á Abstract Crowdfunding in medical research is becoming more popular owing to increasing competition for the shrinking amount of government funding. To inform researchers applying for this complementary source of research funding, we investigate the determinants of successful crowdfunding campaigns in medical research. We find that establishing and maintaining professional contacts through social media is of major importance for successful crowdfunding campaigns; an additional tweet or retweet significantly increases the success of crowdfunding campaigns. In contrast to the stated preferences of prospect...
Source: Drug Discovery Today - May 24, 2019 Category: Drugs & Pharmacology Authors: Aleksina A, Akulenka S, Lublóy Á Tags: Drug Discov Today Source Type: research

Voltage-gated sodium channels: structures, functions, and molecular modeling.
Abstract Voltage-gated sodium channels (VGSCs), formed by 24 transmembrane segments arranged into four domains, have a key role in the initiation and propagation of electrical signaling in excitable cells. VGSCs are involved in a variety of diseases, including epilepsy, cardiac arrhythmias, and neuropathic pain, and, therefore, have been regarded as appealing therapeutic targets for the development of anticonvulsant, antiarrhythmic, and local anesthetic drugs. In this review, we discuss recent advances in understanding the structures and biological functions of VGSCs. In addition, we systematically summarize eight...
Source: Drug Discovery Today - May 23, 2019 Category: Drugs & Pharmacology Authors: Xu L, Ding X, Wang T, Mou S, Sun H, Hou T Tags: Drug Discov Today Source Type: research

Molecular modeling approaches for the discovery of adenosine A2B receptor antagonists: current status and future perspectives.
Abstract Adenosine receptors (ARs) are classified as A1, A2A, A2B, and A3 subtypes belonging to the superfamily of G-protein-coupled receptors (GPCRs). Several molecular modeling approaches have been developed for A2BAR and its antagonists, from the construction of a homology model, molecular docking, molecular dynamics (MD) simulations, and 3D quantitative structure-activity relationship (QSAR) modeling to pharmacophore modeling, each of which has different objectives and outcomes. In this review, we provide a systematic outline of advances in molecular modeling approaches towards A2BAR for deducing its structure...
Source: Drug Discovery Today - May 16, 2019 Category: Drugs & Pharmacology Authors: Deb PK, Chandrasekaran B, Mailavaram R, Tekade RK, Jaber AMY Tags: Drug Discov Today Source Type: research

The current status of pharmacotherapy for the treatment of Parkinson's disease: transition from single-target to multitarget therapy.
Abstract Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons. Motor features such as tremor, rigidity, bradykinesia and postural instability are common traits of PD. Current treatment options provide symptomatic relief to the condition but are unable to reverse disease progression. The conventional single-target therapeutic approach might not always induce the desired effect owing to the multifactorial nature of PD. Hence, multitarget strategies have been proposed to simultaneously target multiple proteins involved in the development of PD. Herein, we prov...
Source: Drug Discovery Today - May 15, 2019 Category: Drugs & Pharmacology Authors: Cheong SL, Federico S, Spalluto G, Klotz KN, Pastorin G Tags: Drug Discov Today Source Type: research

Serendipitous drug repurposing through social media.
PMID: 31102729 [PubMed - as supplied by publisher] (Source: Drug Discovery Today)
Source: Drug Discovery Today - May 15, 2019 Category: Drugs & Pharmacology Authors: Kelly DP, Blatt J Tags: Drug Discov Today Source Type: research