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Drug Discovery Today
Journal Prestige (SJR): 2.008
Citation Impact (citeScore): 6
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ISSN (Print) 1359-6446
Published by Elsevier Homepage  [3184 journals]
  • Future unmet medical need as a guiding principle for pharmaceutical R&D
    • Abstract: Publication date: Available online 21 June 2019Source: Drug Discovery TodayAuthor(s): Matthias Vennemann, Vincent Ruland, Jan-Philip Kruse, Christine Harloff, Hubert Trübel, Heike Gielen-HaertwigIn 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 which the unmet need is addressed by the new product significantly impact its value. We have defined six dimensions as key drivers of (future) unmet medical needs of patients in a given setting. In the absence of quantifiable criteria, structured expert assessment techniques, such as the Delphi method, can guide portfolio strategies, especially for early-stage assets.
       
  • The role of molecular simulations in understanding the mechanisms of
           cell-penetrating peptides
    • Abstract: Publication date: Available online 20 June 2019Source: Drug Discovery TodayAuthor(s): Lauren M. Reid, Chandra S. Verma, Jonathan W. EssexCell-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 studies have incorporated simulation data. This review provides a critical evaluation of the current approaches that are being used to simulate CPPs interacting with artificial lipid bilayers.
       
  • Contents page 1
    • Abstract: Publication date: July 2019Source: Drug Discovery Today, Volume 24, Issue 7Author(s):
       
  • Corrigendum to “Amyloid beta modulators and neuroprotection in
           Alzheimer’s disease: a critical appraisal” [Drug Discov. Today 22
           (February (2)) (2017) 223–233]
    • Abstract: Publication date: July 2019Source: Drug Discovery Today, Volume 24, Issue 7Author(s): Chandra Sekhar Kuruva, P. Hemachandra Reddy
       
  • Contents page 2
    • Abstract: Publication date: July 2019Source: Drug Discovery Today, Volume 24, Issue 7Author(s):
       
  • Corrigendum to “Tocotrienols: the unsaturated sidekick shifting new
           paradigms in vitamin E therapeutics” [Drug Discov. Today 22 (December
           (12)) (2017) 1765–1781]
    • Abstract: Publication date: July 2019Source: Drug Discovery Today, Volume 24, Issue 7Author(s): M.M. Kanchi, M.K. Shanmugam, G. Rane, G. Sethi, A.P. Kumar
       
  • Corrigendum to “Bispecific antibodies” [Drug Discov. Today 20 (July
           (7)) (2015) 838–847]
    • Abstract: Publication date: July 2019Source: Drug Discovery Today, Volume 24, Issue 7Author(s): Roland E. Kontermann, Ulrich Brinkmann
       
  • Early Access to Medicines Scheme: real-world data collection
    • Abstract: Publication date: Available online 19 June 2019Source: Drug Discovery TodayAuthor(s): Hok Pang, Meng Wang, Christopher Kiff, Mira Soni, Dara Stein, David TyasReal-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.
       
  • LMWH and its derivatives represent new rational for cancer therapy:
           construction strategies and combination therapy
    • Abstract: Publication date: Available online 19 June 2019Source: Drug Discovery TodayAuthor(s): Shi Du, Yao Yu, Cheng Xu, Hui Xiong, Shan Yang, Jing YaoLow-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 representative drug delivery systems involving LMWH derivatives and discuss the construction principles and therapeutic effects associated with their use. We also analyze progress made in the development of antitumor combination therapies, in which LMWH has shown synergistic or combined effects with other treatment strategies.
       
  • The human endogenous metabolome as a pharmacology baseline for drug
           discovery
    • Abstract: Publication date: Available online 19 June 2019Source: Drug Discovery TodayAuthor(s): Andreu Bofill, Xavier Jalencas, Tudor I. Oprea, Jordi MestresWe 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 derived from their secondary pharmacology depend very much on that baseline. Thus, we propose a new approach for estimating safety margins.
       
  • Exosomal miRNA in chemoresistance, immune evasion, metastasis and
           progression of cancer
    • Abstract: Publication date: Available online 19 June 2019Source: Drug Discovery TodayAuthor(s): Bhagyashri Kulkarni, Prathibha Kirave, Piyush Gondaliya, Kavya Jash, Alok Jain, Rakesh K. Tekade, Kiran KaliaIn 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 progression and metastasis of cancer. Further, this review also discusses how exosomal miRNA can provide promising novel targets for the treatment and detection of cancer.
       
  • Engineering microsystems to recapitulate brain physiology on a chip
    • Abstract: Publication date: Available online 18 June 2019Source: Drug Discovery TodayAuthor(s): Kenneth Ndyabawe, William KisaalitaThe 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 challenges that we illustrate using a few neurological disorders; and we offer guidance, depending on objectives (HTS, disease modeling, etc.) for rational design of microfluidic systems and better emulation of in vivo conditions.
       
  • Mini-gut: a promising model for drug development
    • Abstract: Publication date: Available online 15 June 2019Source: Drug Discovery TodayAuthor(s): Yue-Bang Yin, Hugo R. de Jonge, Xin Wu, Yu-Long YinUntil 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 used as models to develop drugs against cystic fibrosis, cancer and infectious disease, as well as for drug screening, personalized medicine and the development of new medical tools. In this review, we highlight and discuss the importance of mini-guts for drug development and point out their limitations and future prospects.
       
  • Data science tools and applications on the way to Pharma 4.0
    • Abstract: Publication date: Available online 14 June 2019Source: Drug Discovery TodayAuthor(s): Valentin Steinwandter, Daniel Borchert, Christoph HerwigMultiple 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 nontechnical problems experienced during their development and deployment. We suggest that the establishment of development opportunity mind- and toolsets could improve this situation and would be essential cornerstones in the further development of Pharma 4.0 systems.
       
  • Hydrogels for sustained delivery of biologics to the back of the eye
    • Abstract: Publication date: Available online 13 June 2019Source: Drug Discovery TodayAuthor(s): Debby Chang, Kinam Park, Amin FamiliHydrogels 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 also provide a perspective on clinical and chemistry, manufacturing and controls (CMC) considerations that are integral to the development of an ocular hydrogel delivery system.
       
  • Protein Conjugates and Fusion Proteins as Ocular Therapeutics
    • Abstract: Publication date: Available online 13 June 2019Source: Drug Discovery TodayAuthor(s): Shrenik C. Mehta, Robert F. Kelley, Devin TesarLong-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 treatment of ocular diseases and examine the current state of LAD technologies that leverage protein engineering approaches as well as nascent technologies with potential for future impact.
       
  • Contents page 2
    • Abstract: Publication date: June 2019Source: Drug Discovery Today, Volume 24, Issue 6Author(s):
       
  • Contents page 1
    • Abstract: Publication date: June 2019Source: Drug Discovery Today, Volume 24, Issue 6Author(s):
       
  • Machine learning on adverse drug reactions for pharmacovigilance
    • Abstract: Publication date: Available online 12 March 2019Source: Drug Discovery TodayAuthor(s): Chun Yen Lee, Yi-Ping Phoebe Chen
       
  • Drug delivery systems and novel formulations to improve treatment of rare
           corneal disease
    • Abstract: Publication date: Available online 12 March 2019Source: Drug Discovery TodayAuthor(s): Jorge Jimenez, Meera Sakthivel, Kanwal K. Nischal, Morgan V. FedorchakAs the field of ocular drug delivery grows so does the potential for novel drug discovery or reformulation in lesser-known diseases of the eye. In particular, rare corneal diseases are an interesting area of research because drug delivery is limited to the outermost tissue of the eye. This review will highlight the opportunities and challenges of drug reformulation and alternative treatment approaches for rare corneal diseases. The barriers to effective drug delivery and proposed solutions in development will be discussed along with an overview of corneal rare disease resources, their current treatments and ophthalmic drug delivery systems that could benefit such cases. The regulatory considerations for effective translation of orphan-designated products will also be discussed.
       
  • Emerging targets of inflammation and tear secretion in dry eye disease
    • Abstract: Publication date: Available online 22 February 2019Source: Drug Discovery TodayAuthor(s): Maria Markoulli, Alex HuiThe underlying mechanisms of dry eye are thought to be part of a vicious circle involving a hyperosmolarity-triggered inflammatory cascade, resulting in loss of goblet cells and glycocalyx mucin and observed corneal and conjunctival epithelial cell damage. This damage leads to increased tear film instability, further hyperosmolarity and hence perpetuating of a vicious circle. The aim of dry eye management is to restore the homeostasis of the tear film and break the perpetuation of this vicious circle. Despite the plethora of treatment options available, many of these are largely palliative, short-lived and require repeated instillations. Two emerging areas in dry eye therapy aim to promote tear secretion and to safely manage dry eye-associated inflammation and are the focus of this review.
       
  • Design principles of ocular drug delivery systems: importance of drug
           payload, release rate, and material properties
    • Abstract: Publication date: Available online 7 February 2019Source: Drug Discovery TodayAuthor(s): Astrid Subrizi, Eva M. del Amo, Viktor Korzhikov-Vlakh, Tatiana Tennikova, Marika Ruponen, Arto UrttiOcular drugs are usually delivered locally to the eye. Required drug loading, release rate, and ocular retention time of drug delivery systems depend on the potency, bioavailability, and clearance of the drug at the target site. Drug-loading capacity of the formulation is limited by the material properties and size constraints of the eye. The design aid described herein for ocular drug delivery systems guides the calculation of steady-state drug concentrations in the ocular compartments, taking into account drug dose, bioavailability, and clearance. The dosing rate can be adjusted to reach the target drug concentrations, thereby guiding the design of drug delivery systems for topical, intravitreal, and subconjunctival administration. The simple design aid can be used at early stages of drug development by investigators without expertise in pharmacokinetic and pharmacodynamic modeling.
       
  • Müller cells as a target for retinal therapy
    • Abstract: Publication date: Available online 4 February 2019Source: Drug Discovery TodayAuthor(s): Joke Devoldere, Karen Peynshaert, Stefaan C. De Smedt, Katrien RemautMüller cells are specialized glial cells that span the entire retina from the vitreous cavity to the subretinal space. Their functional diversity and unique radial morphology render them particularly interesting targets for new therapeutic approaches. In this review, we reflect on various possibilities for selective Müller cell targeting and describe how some of their cellular mechanisms can be used for retinal neuroprotection. Intriguingly, cross-species investigation of their properties has revealed that Müller cells also have an essential role in retinal regeneration. Although many questions regarding this subject remain, it is clear that Müller cells have unique characteristics that make them suitable targets for the prevention and treatment of numerous retinal diseases.
       
  • Connexin43 hemichannels: A potential drug target for the treatment of
           diabetic retinopathy
    • Abstract: Publication date: Available online 25 January 2019Source: Drug Discovery TodayAuthor(s): Odunayo O. Mugisho, Colin R. Green, Jie Zhang, Monica L. Acosta, Ilva D. RupenthalDiabetic retinopathy (DR) is a chronic vascular disease of the retina that causes vision loss in patients with type 1 and type 2 diabetes, and is associated with vascular dysfunction and occlusion, retinal oedema, haemorrhage and inadequate growth of new blood vessels. Current DR therapies primarily target downstream, later-stage vascular defects with a significant proportion of diabetic macular oedema patients being non-responders. Moreover, other evidence suggests that prolonged use of therapies targeting vascular endothelial growth factor (VEGF) might be associated with increased onset of geographic atrophy and retinal ganglion cell death. It is therefore highly desirable to prevent the onset of DR or arrest its progression at a stage preceding the appearance of more-advanced pathology by targeting upstream disease mechanisms. Connexin43 hemichannels play a part in the pathogenesis of chronic inflammatory diseases, including inflammasome pathway activation; and hemichannel block has been shown to alleviate vascular leak and inflammation. This review discusses the inflammatory changes occurring in DR as well as current therapies and their limitations. It then focuses on the role of connexin43 in DR, providing evidence for the utility of connexin43 hemichannel blockers as novel therapeutics for DR treatment.
       
  • Impact of organ-on-a-chip technology on pharmaceutical R&D costs
    • Abstract: Publication date: Available online 8 June 2019Source: Drug Discovery TodayAuthor(s): Nora Franzen, Wim H. van Harten, Valesca P. Retèl, Peter Loskill, AJM van den Eijnden-van Raaij, Maarten J. IjzermanHealthcare 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 impacting R&D costs. Here, we present an expert survey on the future role of organ-on-a-chip in drug discovery and its potential quantitative impact. We find that the technology has the potential to reduce R&D costs significantly, driven by changes in direct costs, success rates and the length of the R&D process. Finally, we discuss regulatory challenges to efficiency improvements.
       
  • Antidepressants and nose-to-brain delivery: drivers, restraints,
           opportunities and challenges
    • Abstract: Publication date: Available online 7 June 2019Source: Drug Discovery TodayAuthor(s): Carla Vitorino, Soraia Silva, Joana Bicker, Amílcar Falcão, Ana FortunaWhy 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 antidepressants, framed within a comprehensive analysis of drivers, restraints, opportunities and challenges.Graphical abstractGraphical abstract for this article
       
  • Skin metabolism phase I and phase II enzymes in native and reconstructed
           human skin: a short review
    • Abstract: Publication date: Available online 6 June 2019Source: Drug Discovery TodayAuthor(s): Siamaque Kazem, Emma Charlotte Linssen, Susan GibbsUnderstanding 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 are reported.
       
  • Poloxamer-based in situ gelling thermoresponsive systems for ocular drug
           delivery applications
    • Abstract: Publication date: Available online 5 June 2019Source: Drug Discovery TodayAuthor(s): Karim A. Soliman, K Ullah, A. Shah, David S. Jones, Raghu R.S. ThakurIn 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 diseases of the anterior and posterior segments of the eye. Poloxamer-based ocular products have already found their way to the pharmaceutical market, but remain a potential arena for further investigation and commercial exploitation.
       
  • Challenges and opportunities for drug delivery to the posterior of the eye
    • Abstract: Publication date: Available online 5 June 2019Source: Drug Discovery TodayAuthor(s): Fernando J. Cabrera, Daniel C. Wang, Kartik Reddy, Ghanashyam Acharya, Crystal S. ShinDrug 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 release formulations, IVT implants, and preclinical topical formulations, and the challenges faced in clinical translations.
       
  • The safety evaluation of long-acting ocular delivery systems
    • Abstract: Publication date: Available online 5 June 2019Source: Drug Discovery TodayAuthor(s): Evan A. Thackaberry, Florence Lorget, Cindy Farman, Vladimir BantseevThe 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.
       
  • Ocular gene therapies in clinical practice: viral vectors and nonviral
           alternatives
    • Abstract: Publication date: Available online 5 June 2019Source: Drug Discovery TodayAuthor(s): Thierry Bordet, Francine Behar-CohenOcular 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 nongenetic retinal diseases, such as age-related macular degeneration (AMD). Here, we review current gene therapy strategies for ocular diseases, with a focus on clinical stage products.
       
  • Nitric oxide: a drug target for glaucoma revisited
    • Abstract: Publication date: Available online 4 June 2019Source: Drug Discovery TodayAuthor(s): Gerhard Garhöfer, Leopold SchmettererA 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-lowering effect of known substances with the trabecular meshwork outflow-increasing effect of NO. Here, we review the molecular mechanism of this new entity of IOP-lowering drugs.
       
  • Potential antiedematous effects of intravitreous anti-VEGF, unrelated to
           VEGF neutralization
    • Abstract: Publication date: Available online 4 June 2019Source: Drug Discovery TodayAuthor(s): Francine Behar-Cohen, Marilyn Dernigoghossian, Charlotte Andrieu-Soler, Rinath Levy, Raphaël Cohen, Min ZhaoThe 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, understanding how anti-VEGF reduces macular edema is crucial. We discuss herein how anti-VEGF exerts antiedematous effects and raise the hypothesis that mechanisms, unrelated to VEGF neutralization, might have been underestimated.
       
  • Revisiting mTOR inhibitors as anticancer agents
    • Abstract: Publication date: Available online 4 June 2019Source: Drug Discovery TodayAuthor(s): Qiu-Xu Teng, Yunali V. Ashar, Pranav Gupta, Eddie Gadee, Ying-Fang Fan, Sandra E. Reznik, John N.D. Wurpel, Zhe-Sheng ChenThe mammalian target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that regulates a variety of cellular processes, influencing diverse pathological conditions including a variety of cancers. Accordingly, therapies that target mTOR as anticancer agents benefit patients in various clinical settings. It is therefore important to fully investigate mTOR signaling at a molecular level and corresponding mTOR inhibitors to identify additional clinical opportunities of targeting mTOR in cancers. In this review, we introduce the function and regulation of the mTOR signaling pathway and organize and summarize the different roles of mTOR in cancers and a variety of mTOR inhibitors that can be used as anticancer agents. This article aims to enlighten and guide the development of mTOR-targeted anticancer agents in the future.
       
  • Pharmacological analysis of CFTR variants of cystic fibrosis using stem
           cell-derived organoids
    • Abstract: Publication date: Available online 4 June 2019Source: Drug Discovery TodayAuthor(s): Kevin G. Chen, Pingyu Zhong, Wei Zheng, Jeffrey M. BeekmanCystic 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 pharmacogenomics of diverse CFTR mutations and the emerging role of stem cell-based organoids in predicting the CF drug response. We discuss mechanisms that underlie differential CF drug responses both in organoid-based assays and in CF clinical trials, thereby facilitating the precision design of safer and more effective therapies for individual patients with CF.Graphical abstractGraphical abstract for this article
       
  • Recent advances in intraocular sustained-release drug delivery devices
    • Abstract: Publication date: Available online 4 June 2019Source: Drug Discovery TodayAuthor(s): Yiqi Cao, Karen E. Samy, Daniel A. Bernards, Tejal A. DesaiTopical 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 selection, active pharmaceutical ingredient, and implantation site.
       
  • Peptide-based protease inhibitors from plants
    • Abstract: Publication date: Available online 3 June 2019Source: Drug Discovery TodayAuthor(s): Roland Hellinger, Christian W. GruberProteases 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. In this review, we provide an overview of the diversity of plant peptide- and protein-based protease inhibitors (PIs), provide examples of such compounds that target human proteases, and discuss opportunities for these molecules in protease drug discovery and development.
       
  • Incorporating liquid biopsies into treatment decision-making: obstacles
           and possibilities
    • Abstract: Publication date: Available online 3 June 2019Source: Drug Discovery TodayAuthor(s): Nick Beije, John W.M. Martens, Stefan SleijferCirculating 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 investigating a meaningful clinical question are performed. Here, we provide an overview of the current state of liquid biopsies and make suggestions for how liquid biopsies can reach the tipping point.
       
  • Cancer cell fusion: a potential target to tackle drug-resistant and
           metastatic cancer cells
    • Abstract: Publication date: Available online 1 June 2019Source: Drug Discovery TodayAuthor(s): Clara Fernandes, Priyanka Prabhu, Kapil Juvale, Divya Suares, Mayur YCCell 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 highlight plausible mechanisms governing cell fusion with different cell types in the tumour microenvironment (TME), the clinical relevance of cancer cell fusion, its potential as a target for overcoming MDR and inhibiting metastasis, and putative modes of treatment.
       
  • Ontology mapping for semantically enabled applications
    • Abstract: Publication date: Available online 31 May 2019Source: Drug Discovery TodayAuthor(s): Ian Harrow, Rama Balakrishnan, Ernesto Jimenez-Ruiz, Simon Jupp, Jane Lomax, Jane Reed, Martin Romacker, Christian Senger, Andrea Splendiani, Jabe Wilson, Peter WoollardIn 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 capability and quality of mappings. Finally, we outline the requirements for an ontology-mapping service (OMS) and the progress being made towards implementation of a sustainable OMS.
       
  • Physicians in the pharmaceutical industry: their roles, motivations, and
           perspectives
    • Abstract: Publication date: Available online 31 May 2019Source: Drug Discovery TodayAuthor(s): Hussein Sweiti, Frank Wiegand, Christoph Bug, Martin Vogel, Frederic Lavie, Ivo Winiger-Candolfi, Maximilian SchuierAlthough 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, we outline the characteristics and skills that enable physicians to have a successful career in pharma.
       
  • Unbiased data analytic strategies to improve biomarker discovery in
           precision medicine
    • Abstract: Publication date: Available online 31 May 2019Source: Drug Discovery TodayAuthor(s): Saifur R. Khan, Yousef Manialawy, Michael B. Wheeler, Brian J. CoxOmics 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 considerations and suggest standards from an expert point-of-view to promote unbiased decision-making in biomarker discovery in precision medicine.
       
  • Standpoint on the priority of TNTs and CNTs as targeted drug delivery
           systems
    • Abstract: Publication date: Available online 31 May 2019Source: Drug Discovery TodayAuthor(s): Yasmin Ranjous, Géza Regdon, Klára Pintye-Hódi, Tamás SoványConventional 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 biocompatibility. Functionalization improves nanoparticles (NPs) via their surface modification and enables them to achieve the targeted therapy.
       
  • Cannabinoid receptors as therapeutic targets for autoimmune diseases:
           where do we stand'
    • Abstract: Publication date: Available online 31 May 2019Source: Drug Discovery TodayAuthor(s): Elaine D. Gonçalves, Rafael C. DutraDescribed 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 microglial cells, inhibiting proinflammatory cytokine expression and upregulating proresolution mediators. Thus, in this review, we summarize the mechanisms by which CBRs interact with the autoimmune environment and the potential to suppress the development and activation of autoreactive cells. Finally, we highlight how the modulation of CB1R and CB2R is advantageous in the treatment of autoimmune diseases, including multiple sclerosis (MS), type 1 diabetes mellitus (T1DM) and rheumatoid arthritis (RA).Graphical abstractGraphical abstract for this article
       
  • Raising the bar in anticancer therapy: recent advances in, and
           perspectives on, telomerase inhibitors
    • Abstract: Publication date: Available online 25 May 2019Source: Drug Discovery TodayAuthor(s): A. Prasanth Saraswati, Nicola Relitti, Margherita Brindisi, Sandra Gemma, Daniela Zisterer, Stefania Butini, Giuseppe Campiani 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 development of telomerase inhibitors as anticancer agents.Graphical abstractGraphical abstract for this article
       
  • Hot-melt extrusion in the pharmaceutical industry: toward filing a new
           drug application
    • Abstract: Publication date: Available online 25 May 2019Source: Drug Discovery TodayAuthor(s): Marta F. Simões, Rui M.A. Pinto, Sérgio SimõesThe 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 light of the current paradigm of drug development and in-line with regulatory guidelines from the ICH regions. Case studies of recently approved HME products are presented.
       
  • Success factors of crowdfunding campaigns in medical research: perceptions
           and reality
    • Abstract: Publication date: Available online 24 May 2019Source: Drug Discovery TodayAuthor(s): Anna Aleksina, Stanislau Akulenka, Ágnes LublóyCrowdfunding 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 prospective donors, we document that crowdfunding campaigns can achieve their fundraising goal regardless of the disease characteristics. Scientists could therefore request funding for any kind of project, including therapies for rare diseases and diseases with lower mortality rates.
       
  • 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: Publication date: Available online 24 May 2019Source: Drug Discovery TodayAuthor(s): Sebastian Polak, Zofia Tylutki, Mark Holbrook, Barbara WiśniowskaModel-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 the physiochemical nature of the compound. PBPK models provide a mechanistic description of individual organs and tissues to allow the prediction of the intra- and extra-cellular concentration of the parent drug and metabolites under different conditions. Information on biophase concentration enables the prediction of a drug effect in different organs and assessment of the potential for drug–drug interactions. Together, these modelling approaches can inform the exposure–response relationship and hence support hypothesis generation and testing, compound selection, hazard identification and risk assessment through to clinical proof of concept (POC) and beyond to the market.
       
  • Voltage-gated sodium channels: structures, functions, and molecular
           modeling
    • Abstract: Publication date: Available online 23 May 2019Source: Drug Discovery TodayAuthor(s): Lei Xu, Xiaoqin Ding, Tianhu Wang, Shanzhi Mou, Huiyong Sun, Tingjun HouVoltage-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 pharmacologically distinct ligand-binding sites in VGSCs and representative isoform-selective VGSC modulators in clinical trials. Finally, we review studies on molecular modeling and computer-aided drug design (CADD) for VGSCs to help understanding of biological processes involving VGSCs.
       
  • Molecular modeling approaches for the discovery of adenosine A2B receptor
           antagonists: current status and future perspectives
    • Abstract: Publication date: Available online 17 May 2019Source: Drug Discovery TodayAuthor(s): Pran Kishore Deb, Balakumar Chandrasekaran, Raghuprasad Mailavaram, Rakesh Kumar Tekade, Abdul Muttaleb Yousef JaberAdenosine 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 and interactions with various types of antagonist. The information, methods and perspectives presented here provides impetus for medicinal chemists to discover potential ligands that can bind selectively with higher affinity to A2BAR.
       
  • Serendipitous drug repurposing through social media
    • Abstract: Publication date: Available online 16 May 2019Source: Drug Discovery TodayAuthor(s): Daniel P. Kelly, Julie Blatt
       
  • Intravitreal nanoparticles for retinal delivery
    • Abstract: Publication date: Available online 16 May 2019Source: Drug Discovery TodayAuthor(s): Xiaonan Huang, Ying ChauTeaser: Recent findings regarding utilization of intravitreally injected nanoparticles for the retinal-targeted delivery of all types of therapeutics are summarized. The respective pharmacokinetic model for intravitreal nanoparticles was also developed.Intravitreal injection is one of the major administration routes for the treatment of posterior ocular diseases. Intravitreal therapeutics usually suffer from unsatisfactory efficacy owing to fast clearance from the vitreous humour and insufficient distribution into the retina. Engineered nanoparticles have been applied for specific tissue targeting over the past decades. In this review, we summarize the most recent research utilizing intravitreal nanoparticles to deliver therapeutics to the retina. Herein, the achievement made in preclinical research and challenges remaining in the field are highlighted. Parameters including size, charge, stability and choice of modified ligand on intraocular distribution and transport are also systematically discussed based on a proposed pharmacokinetic model. We provide insights for rational design principles for intravitreal nanoparticles for targeted retinal delivery.
       
  • The current status of pharmacotherapy for the treatment of Parkinson’s
           disease: transition from single-target to multitarget therapy
    • Abstract: Publication date: Available online 16 May 2019Source: Drug Discovery TodayAuthor(s): Siew L. Cheong, Stephanie Federico, Giampiero Spalluto, Karl-Norbert Klotz, Giorgia PastorinParkinson’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 provide an overview of the pathogenesis of PD and the current pharmacotherapies. Furthermore, rationales and examples of multitarget approaches that have been tested in preclinical trials for the treatment of PD are also discussed.
       
  • Bicyclic peptides: types, synthesis and applications
    • Abstract: Publication date: Available online 15 May 2019Source: Drug Discovery TodayAuthor(s): Shahrzad Ahangarzadeh, Mohammad M. Kanafi, Simzar Hosseinzadeh, Ahad Mokhtarzadeh, Mahmood Barati, Javad Ranjbari, Lobat TayebiBicyclic peptides form one of the most promising platforms for drug development owing to their biocompatibility, similarity and chemical diversity to proteins, and they are considered as a possible practical tool in various therapeutic and diagnostic applications. Bicyclic peptides are known to have the capability of being employed as an effective alternative to complex molecules, such as antibodies, or small molecules. This review provides a summary of the recent progress on the types, synthesis and applications of bicyclic peptides. More specifically, natural and synthetic bicyclic peptides are introduced with their different production methods and relevant applications, including drug targeting, imaging and diagnosis. Their uses as antimicrobial agents, as well as the therapeutic functions of different bicyclic peptides, are also discussed.
       
  • Current potential and challenges in the advances of liquid crystalline
           nanoparticles as drug delivery systems
    • Abstract: Publication date: Available online 15 May 2019Source: Drug Discovery TodayAuthor(s): Thiagarajan Madheswaran, Murugesh Kandasamy, Rajendran J.C. Bose, Vengadeshprabhu KaruppagounderLyotropic nonlamellar liquid crystalline nanoparticles (NPs) (LCN), such as cubosomes and hexosomes, are useful tools for applications in drug delivery because of their unique structural properties. LCNs are highly versatile carriers that can be applied for use with topical, oral, and intravenous treatments. In recent years, significant research has focused on improving their preparation and characterization, including controlling drug release and enhancing the efficacy of loaded bioactive molecules. Nevertheless, the clinical translation of LCN-based carriers has been slow. In this review, we highlight recent advances and challenges in the development and application of LCN, providing examples of their topical, oral, and intravenous drug delivery applications, and discussing translational obstacles to LCN as a NP technology.
       
  • Therapeutic implications of nanomedicine for ocular drug delivery
    • Abstract: Publication date: Available online 15 May 2019Source: Drug Discovery TodayAuthor(s): Tuo Meng, Vineet Kulkarni, Russell Simmers, Vikram Brar, Qingguo XuTeaserOcular nanomedicine poses a promising therapeutic potential and offers many advantages over conventional ophthalmic medications for effective ocular drug delivery; because nanomedicine can overcome ocular barriers, improve drug-release profiles and reduce potential drug toxicity.Delivering therapeutics to the eye is challenging on multiple levels: rapid clearance of eyedrops from the ocular surface requires frequent instillation, which is difficult for patients; transport of drugs across the blood–retinal barrier when drugs are administered systemically, and the cornea when drugs are administered topically, is difficult to achieve; limited drug penetration to the back of the eye owing to the cornea, conjunctiva, sclera and vitreous barriers. Nanomedicine offers many advantages over conventional ophthalmic medications for effective ocular drug delivery because nanomedicine can increase the therapeutic index by overcoming ocular barriers, improving drug-release profiles and reducing potential drug toxicity. In this review, we highlight the therapeutic implications of nanomedicine for ocular drug delivery.
       
  • Current outlook on drug resistance in chronic myeloid leukemia (CML) and
           potential therapeutic options
    • Abstract: Publication date: Available online 15 May 2019Source: Drug Discovery TodayAuthor(s): Daniel Nisakar Meenakshi Sundaram, Xiaoyan Jiang, Joseph M. Brandwein, Juliana Valencia-Serna, K.C. Remant, Hasan UludağChronic myeloid leukemia (CML) is a myeloproliferative neoplasm the hallmark of which, the breakpoint cluster region-Abelson (BCR-ABL) oncogene, has been the target of tyrosine kinase inhibitors (TKIs), which have significantly improved the survival of patients with CML. However, because of an increase in TKI resistance, it is becoming imperative to identify resistance mechanisms so that drug therapies can be better prescribed and new agents developed. In this review, we discuss the various BCR-ABL-dependent and -independent mechanisms of resistance observed in CML, and the range of therapeutic solutions available to overcome such resistance and to ultimately improve the survival of patients with CML.
       
  • Repurposing multiple sclerosis drugs: a review of studies in other
           neurological and psychiatric conditions
    • Abstract: Publication date: Available online 14 May 2019Source: Drug Discovery TodayAuthor(s): Paulus Stefan Rommer, Johann SellnerTreatment options for multiple sclerosis (MS) have improved in the past 20 years, with new oral disease-modifying drugs and monoclonal antibodies becoming available. The success seen with these drugs in MS, and their various mechanisms of action, has led to them being investigated in other neurological and psychiatric disorders. This review article summarises the ongoing and completed studies of MS drugs in neurological and psychiatric conditions other than MS. The most promising results are for interferon beta in human T cell leukaemia virus 1 associated myelopathy/tropical spastic paraparesis and glioma, and for fingolimod in acute ischaemic stroke and intracerebral haemorrhage. The coming years could see the arrival of exciting new therapies for disorders that neurologists have historically found difficult to treat and that represent a significant unmet clinical need.
       
  • Methods for exploring and eliciting patient preferences in the medical
           product lifecycle: a literature review
    • Abstract: Publication date: Available online 8 May 2019Source: Drug Discovery TodayAuthor(s): Vikas Soekhai, Chiara Whichello, Bennett Levitan, Jorien Veldwijk, Cathy Anne Pinto, Bas Donkers, Isabelle Huys, Eline van Overbeeke, Juhaeri Juhaeri, Esther W. de Bekker-GrobPreference studies are becoming increasingly important within the medical product decision-making context. Currently, there is limited understanding of the range of methods to gain insights into patient preferences. We developed a compendium and taxonomy of preference exploration (qualitative) and elicitation (quantitative) methods by conducting a systematic literature review to identify these methods. This review was followed by analyzing prior preference method reviews, to cross-validate our results, and consulting intercontinental experts, to confirm our outcomes. This resulted in the identification of 32 unique preference methods. The developed compendium and taxonomy can serve as an important resource for assessing these methods and helping to determine which are most appropriate for different research questions at varying points in the medical product lifecycle.
       
  • Drug discovery: a research sector stricken in France that can sometimes
           pay off
    • Abstract: Publication date: Available online 7 May 2019Source: Drug Discovery TodayAuthor(s): Jean-Louis Kraus
       
  • Retinal cell regeneration using tissue engineered polymeric scaffolds
    • Abstract: Publication date: Available online 30 April 2019Source: Drug Discovery TodayAuthor(s): Maria Abedin Zadeh, Mouhamad Khoder, Ali A. Al-Kinani, Husam M. Younes, Raid G. AlanyDegenerative retinal diseases, such as age-related macular degeneration (AMD), can lead to permanent sight loss. Although intravitreal anti-vascular endothelial growth factor (VEGF) and steroid injections are effective for the management of early stages of wet and/or neovascular AMD (nAMD), no proven treatments currently exist for dry AMD or for the advanced geographic atrophy of the retina that follows. Tissue engineering (TE) has recently emerged as a promising alternative to repair retinal damaged and restore its functions. Here, we review recent advances in TE, with a particular emphasis on retinal regeneration. We provide an overview of retinal diseases, followed by a comprehensive review of TE techniques, cells, and polymers used in the fabrication of scaffolds for retinal cell regenerations, in particular the retinal pigment epithelium (RPE).
       
  • The Horizon Scanning System at The Italian Medicines Agency
    • Abstract: Publication date: Available online 30 April 2019Source: Drug Discovery TodayAuthor(s): Michele Marangi, Jelena Ivanovic, Giuseppa PistrittoThe new era of medical innovation is a great opportunity for healthcare; but it poses new challenges for affordability of healthcare systems. To enable timely implementation of value-based clinical care and payment approaches, it is important to look beyond usual timescales to inform decision makers about forthcoming disruptive technologies early. Horizon scanning could represent an efficient tool in support of decision making and rational use of available resources. Different horizon scanning programmes exist in Europe and there is a need for further international cooperation between competent authorities. In relation to this, the present review aims to highlight the importance of early information availability and illustrates the Italian Medicines Agency Horizon Scanning System in the context of the European regulatory network.
       
  • Drug resistance: origins, evolution and characterization of genomic clones
           and the tumor ecosystem to optimize precise individualized therapy
    • Abstract: Publication date: Available online 19 April 2019Source: Drug Discovery TodayAuthor(s): Ioannis D. Kyrochristos, Demosthenes E. Ziogas, Dimitrios H. RoukosProgress in understanding and overcoming fatal intrinsic and acquired resistance is slow, with only a few exceptions. Despite advances in modern genome and transcriptome analysis, the controversy of the three different theories on drug resistance and tumor progression, namely dynamic intratumor heterogeneity, pre-existing minor genomic clones and tumor ecosystem, is unresolved. Moreover, evidence on transcriptional heterogeneity suggests the necessity of a drug bank for individualized, precise drug-sensitivity prediction. We propose a cancer type- and stage-specific clinicogenomic and tumor ecosystemic concept toward cancer precision medicine, focusing on early therapeutic resistance and relapse.
       
  • Collaborative drug discovery and the Tres Cantos Antimalarial Set (TCAMS)
    • Abstract: Publication date: Available online 10 April 2019Source: Drug Discovery TodayAuthor(s): Lucia Fusani, Alvaro Cortes CabreraMalaria affects a population of over 200 million people worldwide. New drugs are needed because of widespread resistance, and the hunt for such drugs involves a coordinated research effort from the scientific community. The release of the Tres Cantos Antimalarial Set (TCAMS) in 2010 represented a landmark in the field of collaborative drug discovery for malaria. This set of>13 000 molecules with confirmed activity against several strains of Plasmodium falciparum was publicly released with the goal of fostering additional research beyond the GlaxoSmithKline (GSK) network of collaborators. Here, we examine the outcomes realized from TCAMS over the past 8 years and whether the expectations surrounding this initiative have become a reality.
       
  • Targeting mRNA translation in Parkinson’s disease
    • Abstract: Publication date: Available online 8 April 2019Source: Drug Discovery TodayAuthor(s): Danilo Correddu, Ivanhoe K.H. LeungParkinson’s disease (PD) is one of the most common neurodegenerative disorders. The exact cause(s) of PD is not well understood, although genetic mutations are associated with some forms of the disease. Many of these mutations, in particular those that are found in LRRK2, DJ1, PINK1, and Parkin, are linked to the deregulation of mRNA translation, suggesting that this process is important for the onset of PD. Herein, we highlight recent studies that provide insights into the molecular mechanisms that relate mRNA translation to PD. These studies confirm the central role of translation in PD, emphasising the potential of restoring mRNA translation functionality as a new therapeutic treatment against PD, and providing novel targets for developing new chemical agents to target this disease.Graphical abstractGraphical abstract for this article
       
  • Ocular biopharmaceutics: impact of modeling and simulation on topical
           ophthalmic formulation development
    • Abstract: Publication date: Available online 5 April 2019Source: Drug Discovery TodayAuthor(s): Hovhannes J. Gukasyan, Shumet Hailu, Thomas K. Karami, Richard GrahamThe estimation of ocular pharmacokinetics (PK) in various eye tissues is limited because of sampling challenges. Computational modeling and simulation tools underpinning the elucidation of drug access routes and prediction of ocular exposure are essential for the mechanistic assessment of biopharmaceutics in the eye. Therefore, theoretical and experimental evaluation of ocular absorption and transit models is necessary. Biopharmaceutical parameter sensitivity analysis based on permeability and drug dose illustrates utility in ocular drug delivery assessment, which could have innovative and cost-saving impacts on ophthalmic product development and therapeutic bioequivalence (BE) evaluations.
       
  • Recent developments in liposomal drug delivery systems for the treatment
           of retinal diseases
    • Abstract: Publication date: Available online 5 April 2019Source: Drug Discovery TodayAuthor(s): Andrew J. Urquhart, Anne Z. EriksenDiseases of the retina cause vision loss and blindness, which have a profound impact on an individual’s quality of life. The number of therapies available to treat retinal diseases is limited. Nanoparticle (NP)-based medicines represent one strategy to expand both the number of available therapies and the range of retinal diseases treated. Liposomes, phospholipid vesicles that frequently contain cholesterol and/or modified surface chemistries, have already had minor success in retinal disease treatment and hold significant promise. Here, we provide a snapshot of recent research developments in liposomal drug delivery systems for retinal diseases and discuss the challenges associated with liposomal systems in the context of recent developments.
       
  • Recent advances in the management of diabetic retinopathy
    • Abstract: Publication date: Available online 4 April 2019Source: Drug Discovery TodayAuthor(s): Nabeela Dulull, Faith Kwa, Narin Osman, Uma Rai, Bilal Shaikh, Thilini R. ThrimawithanaDiabetic retinopathy (DR) is a microvascular complication of diabetes and is the leading cause of vision loss in people with diabetes. The current treatments do not target early stages of disease or impede disease progression. Therefore, the identification of new therapeutic targets, the development of novel therapies targeting early stages of the disease and accurate models that simulate pathological characteristics of this disorder are crucial. This review provides an overview of the pathological mechanisms underlying the development of DR, highlighting the recent advances in current and emerging treatments for DR.
       
  • Targeting P2X7 receptors as a means for treating retinal disease
    • Abstract: Publication date: Available online 4 April 2019Source: Drug Discovery TodayAuthor(s): Erica L. Fletcher, Anna Y. Wang, Andrew I. Jobling, Matthew V. Rutar, Ursula Greferath, Ben Gu, Kirstan A. VesseyAge-related macular degeneration and glaucoma are the commonest causes of irreversible vision loss in industrialized countries. The purine ATP is known to regulate a range of cellular functions in the retina via its action on P2 receptors, especially the P2X7 receptor. Although agents that attenuate P2X7 receptor function have been in development for many years, no compound is currently approved for the treatment of eye disease. However, newer compounds that cross the blood–brain barrier could have potential to reduce vision loss. This review will outline recent information relating to the role of P2X7 in age-related macular degeneration and glaucoma and, subsequently, we will discuss recent developments for attenuating P2X7 receptor function.
       
  • Alternative splicing, RNA-seq and drug discovery
    • Abstract: Publication date: Available online 4 April 2019Source: Drug Discovery TodayAuthor(s): Shanrong ZhaoAlternative splicing, hereafter referred to as AS, is an essential component of gene expression regulation that contributes to the diversity of proteomes. Recent developments in RNA sequencing (RNA-seq) technologies, combined with the advent of computational tools, have enabled transcriptome-wide studies of AS at an unprecedented scale and resolution. RNA mis-splicing can cause human disease, and to target alternative splicing has led to the development of novel therapeutics. Splice variants diversify the repertoire of biomarkers and functionally contribute to drug resistance. Our expanding knowledge of AS variation in human populations holds great promise for improving disease diagnoses and ultimately patient care in the era of sequencing and precision medicine.
       
  • Targeting drug delivery within the suprachoroidal space
    • Abstract: Publication date: Available online 3 April 2019Source: Drug Discovery TodayAuthor(s): Jae Hwan Jung, J. Jeremy Chae, Mark R. PrausnitzThe suprachoroidal space (SCS), a potential anatomical space between the sclera and choroid, is a novel route for drug delivery targeting the chorioretinal layers of the eye. The safety and efficacy of SCS drug delivery have been shown in multiple clinical trials. Recent studies have developed methods for more precise targeting within the SCS at sites of action at the posterior pole (e.g., macula), near the limbus (e.g., ciliary body), and throughout the SCS using iontophoresis, swollen hydrogels, high-density particle emulsions, highly viscous and non-Newtonian fluids, and microstents. Here, we review novel technologies targeting the posterior, anterior, or entire SCS.
       
  • Accelerated drug discovery by rapid candidate drug identification
    • Abstract: Publication date: Available online 1 April 2019Source: Drug Discovery TodayAuthor(s): Fredrik Bergström, Bo LindmarkThe eventual candidate drug (CD) is often already synthesized during early drug discovery but not nominated until much later. To facilitate the rapid identification of a potential CD, a thoroughly worked-out CD target profile (CDTP) with criteria acceptable for the disease target product profile (TPP) is required at the start of lead generation (LG). In addition to driving the compound property optimization, the preclinical project team has to understand the ultimate goal to be able to rapidly identify and progress a potential CD. A screening cascade with meaningful and well-balanced progression criteria based on the CDTP is required to rapidly filter out unwanted compounds and to progress a potential CD through the cascade to candidate selection.
       
  • Microfluidic bioprinting for organ-on-a-chip models
    • Abstract: Publication date: Available online 30 March 2019Source: Drug Discovery TodayAuthor(s): Fang Yu, Deepak ChoudhuryBioprinting is a revolutionary technology to assemble scaffolds for growing tissues. Microfluidic organs-on-a-chip is a useful platform with widespread applications mainly in drug screening and pathological studies. Organ-on-a-chip models are created to recapitulate the structural, microenvironmental and physiological functions of human organs. Recently, bioprinting has been applied to fabricate organ-on-a-chip models owing to its ability to print multiple materials and cell types simultaneously with good spatial resolution and reproducibility. This enables the creation of a biomimetic microenvironment with heterogeneous 3D structures. Functional vascularized tissue structure can be printed directly enabling fluid flow for transport of nutrition, gaseous exchange and removal of waste. We examine the integration of microfluidic and bioprinting technologies for organ-on-a-chip applications and discuss the future trends and challenges.
       
  • Pathway analysis of GWAS loci identifies novel drug targets and
           repurposing opportunities
    • Abstract: Publication date: Available online 29 March 2019Source: Drug Discovery TodayAuthor(s): Deepali Jhamb, Michal Magid-Slav, Mark R. Hurle, Pankaj AgarwalGenome-wide association studies (GWAS) have made considerable progress and there is emerging evidence that genetics-based targets can lead to 28% more launched drugs. We analyzed 1589 GWAS across 1456 pathways to translate these often imprecise genetic loci into therapeutic hypotheses for 182 diseases. These pathway-based genetic targets were validated by testing whether current drug targets were enriched in the pathway space for the same indication. Remarkably, 30% of diseases had significantly more targets in these pathways than expected by chance; the comparable number for GWAS alone (without pathway analysis) was zero. This study shows that a systematic global pathway analysis can translate genetic findings into therapeutic hypotheses for both new drug discovery and repositioning opportunities for current drugs.
       
  • Depot formulations to sustain periocular drug delivery to the posterior
           eye segment
    • Abstract: Publication date: Available online 28 March 2019Source: Drug Discovery TodayAuthor(s): Yosra Agban, Sachin S. Thakur, Odunayo O. Mugisho, Ilva D. RupenthalThe periocular space is a promising alternative route for the delivery of drugs to the posterior eye segment, especially when treating conditions in the outer ocular layers. In this review, we discuss the different periocular routes as well as the physiological barriers and elimination mechanisms limiting drug bioavailability at the back of the eye. We then highlight various types of depot formulation, including particulate delivery systems, semisolid formulations, and implants, used to increase the contact time with the ocular tissues. With the additional advantage of sustaining drug release, such depot formulations could enhance periocular drug delivery to the posterior eye segment.
       
  • Combination therapy and co-delivery strategies to optimize treatment of
           posterior segment neurodegenerative diseases
    • Abstract: Publication date: Available online 27 March 2019Source: Drug Discovery TodayAuthor(s): Alicia Arranz-Romera, Sergio Esteban-Pérez, David Garcia-Herranz, Alba Aragón-Navas, Irene Bravo-Osuna, Rocio Herrero-VanrellNeurodegenerative diseases affecting the posterior segment of the eye are one of the major causes of irreversible blindness worldwide. The pathogenesis of these retinal pathologies is characterized by a multifactorial etiology, involving the complex interaction of different apoptotic mechanisms, suggesting that effective treatments will require a multimodal approach. Thus, combination therapy based on the potential synergistic activities of drugs with different mechanisms of action is currently receiving considerable attention. Here, we summarize several kinds of strategy for the co-administration of different drugs to the posterior segment of the eye, highlighting those that involve co-delivery from multiloaded drug delivery systems.Graphical abstractGraphical abstract for this article
       
  • Causative glaucoma treatment: promising targets delivery systems
    • Abstract: Publication date: Available online 21 March 2019Source: Drug Discovery TodayAuthor(s): Raphael Mietzner, Miriam BreunigGlaucoma is one of the most common causes of blindness worldwide. Elevated intraocular pressure (IOP) is the major modifiable risk factor of the disease. Conventional therapy suffers from poor compliance, low bioavailability, and the lack of causative treatment options. To improve therapeutic success, it is crucial to identify major mediators of pathological changes associated with elevated IOP and to intervene at the molecular level. Here, we discuss relevant key functions of transforming growth factor-β2 (TGF-β2), connective tissue growth factor (CTGF), integrins, Rho-associated kinase (ROCK), and nitric oxide (NO) with regard to the onset of glaucoma, highlighting new drug delivery approaches for causative treatment.Graphical abstractGraphical abstract for this article
       
  • The gap between the need for novel retinal drug delivery methods,
           
    • Abstract: Publication date: Available online 20 March 2019Source: Drug Discovery TodayAuthor(s): Ron Neumann, Dana BarequetThe past four decades were marked by the realization that the delivery of drugs into the eye is a crucial step in the development and utilization of new ocular drugs. This realization led to vast efforts and investments in research and development (R&D) to improve and approve new technologies. The realization of intravitreal injections and the vast utilization of this methodology in retinal disease management deepened the need for new drug delivery methods for drugs already approved safe and effective. Yet, there are only a handful of technologies approved and in clinical use today. Here, we focus on this gap by highlighting bottlenecks and by encouraging creative thinking for solutions.
       
  • Oxidative phosphorylation inducers fight pathological angiogenesis
    • Abstract: Publication date: Available online 14 March 2019Source: Drug Discovery TodayAuthor(s): M.Pilar Bayona-Bafaluy, Olivia Esteban, Javier Ascaso, Julio Montoya, Eduardo Ruiz-PesiniPathological mutations in subunits of the oxidative phosphorylation (OXPHOS) system, or inhibitors of this biochemical pathway, increase the production of vascular endothelial growth factor (VEGF) and pathological angiogenesis. In many angiogenesis-related diseases, such as retinal, rheumatoid diseases, or cancer, OXPHOS dysfunction can be found. Thus, enhancing OXPHOS might be a promising therapeutic approach for pathologic angiogenesis.
       
  • Drug delivery to retinal photoreceptors
    • Abstract: Publication date: Available online 13 March 2019Source: Drug Discovery TodayAuthor(s): Erico Himawan, Per Ekström, Matej Buzgo, Pieter Gaillard, Einar Stefánsson, Valeria Marigo, Thorsteinn Loftsson, François Paquet-DurandThe photoreceptors of the retina are afflicted by diseases that still often lack satisfactory treatment options. Although suitable drugs might be available in some cases, the delivery of these compounds into the eye and across the blood–retinal barrier remains a significant challenge for therapy development. Here, we review the routes of drug administration to the retina and highlight different options for drug delivery to the photoreceptor cells.
       
 
 
JournalTOCs
School of Mathematical and Computer Sciences
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