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Drug Discovery Today
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ISSN (Print) 1359-6446
Published by Elsevier Homepage  [3184 journals]
  • Animal venoms: therapeutic tools for tackling Parkinson’s disease
    • Abstract: Publication date: Available online 17 September 2019Source: Drug Discovery TodayAuthor(s): Henrique de Oliveira Amaral, Victoria Monge-Fuentes, Andréia Biolchi Mayer, Gabriel Avohay Alves Campos, Kamila Soares Lopes, Luana C. Camargo, Matheus Ferroni Schwartz, Priscilla Galante, Márcia R. MortariParkinson’s disease (PD) is a neurodegenerative pathology of the central nervous system, mainly involving the selective and progressive loss of dopaminergic neurons from the substantia nigra, resulting in motor and non-motor symptoms. PD remains an incurable ailment; thus, treatments are limited to symptom alleviation. With long-term use, conventional treatments can become inefficient, often triggering possible side effects. Considering these drawbacks, drug discovery constantly turns to nature as a source of efficient therapeutics. Thus, this review explores animal venoms as a rich source of bioactive compounds with potent neuropharmacological profiles for the development of effective adjuvant treatments with fewer side effects, ultimately aiming for the neuroprotection of dopaminergic neurons and the symptomatic relief of PD.
       
  • Design strategies for programmable oligonucleotide nanotherapeutics
    • Abstract: Publication date: Available online 13 September 2019Source: Drug Discovery TodayAuthor(s): Fitsum Feleke Sahle, Tao L. LoweDNA nanostructures have emerged as promising novel drug and gene delivery systems. Sophisticated programmable hybrid DNA nanotherapeutics have also been used for controlled and targeted drug and gene delivery. There are also numerous reports of utilizing DNA aptamers as nanomaterials targeting moieties. However, the body of literature on these DNA-based nanotherapeutics is fragmented and is not systematically reviewed. The purpose of this review is to systematically summarize the design strategy for various oligonucleotide-based programmable nanotherapeutics that are responsive to biomolecules.Graphical abstractGraphical abstract for this article
       
  • A new approach to the diagnosis and treatment of atherosclerosis: the era
           of the liposome
    • Abstract: Publication date: Available online 13 September 2019Source: Drug Discovery TodayAuthor(s): Nasim Kiaie, Armita Mahdavi Gorabi, Peter E. Penson, Gerald Watts, Thomas P. Johnston, Maciej Banach, Amirhossein SahebkarThe consequences of atherosclerotic cardiovascular disease (ASCVD) include myocardial infarction, ischemic stroke, and angina pectoris, which are major causes of mortality and morbidity worldwide. Despite current therapeutic strategies to reduce risk, patients still experience the consequences of ASCVD. Consequently, a current goal is to enhance visualization of early atherosclerotic lesions to improve residual ASCVD risk. The uses of liposomes, in the context of ASCVD, can include as contrast agents for imaging techniques, as well as for the delivery of antiatherosclerotic drugs, genes, and cells to established sites of plaque. Additionally, liposomes have a role as vaccine adjuvants against mediators of atherosclerosis. Here. we review the scientific and clinical evidence relating to the use of liposomes in the diagnosis and management of ASCVD.
       
  • Standpoint on the priority of TNTs and CNTs as targeted drug delivery
           systems
    • Abstract: Publication date: September 2019Source: Drug Discovery Today, Volume 24, Issue 9Author(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.
       
  • The current status of pharmacotherapy for the treatment of Parkinson’s
           disease: transition from single-target to multitarget therapy
    • Abstract: Publication date: September 2019Source: Drug Discovery Today, Volume 24, Issue 9Author(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.
       
  • Hot-melt extrusion in the pharmaceutical industry: toward filing a new
           drug application
    • Abstract: Publication date: September 2019Source: Drug Discovery Today, Volume 24, Issue 9Author(s): Marta F. Simões, Rui M.A. Pinto, Sérgio Simões 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 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.
       
  • Oxidative phosphorylation inducers fight pathological angiogenesis
    • Abstract: Publication date: September 2019Source: Drug Discovery Today, Volume 24, Issue 9Author(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.
       
  • Contents page 2
    • Abstract: Publication date: September 2019Source: Drug Discovery Today, Volume 24, Issue 9Author(s):
       
  • Contents page 1
    • Abstract: Publication date: September 2019Source: Drug Discovery Today, Volume 24, Issue 9Author(s):
       
  • Using molecular-mimicry-inducing pathways of pathogens as novel drug
           targets
    • Abstract: Publication date: September 2019Source: Drug Discovery Today, Volume 24, Issue 9Author(s): Anjali Garg, Bandana Kumari, Neelja Singhal, Manish KumarSeveral microbial pathogens cause autoimmune diseases in humans by exhibiting molecular mimicry with the host proteins. However, the contribution of autoimmunity in microbial pathogenesis has not been evaluated critically. Clinical and experimental observations have supported and corroborated that autoimmunity was a fundamental process underlying pathology of human tuberculosis bacteria. In the current review, we propose novel drug targets based on a pathogen’s molecular-mimicry-inducing proteins. The process for identification of drug targets has been explained using Mycobacterium tuberculosis as a model organism. The procedure described here can be applied for repurposing other known drugs and/or discovery of novel therapeutics against other pathogenic bacteria that exhibit molecular mimicry with the host’s proteins.
       
  • Corrigendum to ‘Drug metabolism and pharmacokinetic strategies for
           oligonucleotide- and mRNA-based drug development’ Drug Discovery Today
           23 (2018) 1733–1745
    • Abstract: Publication date: September 2019Source: Drug Discovery Today, Volume 24, Issue 9Author(s): Shalini Andersson, Madeleine Antonsson, Marie Elebring, Rasmus Jansson-Löfmark, Lars Weidolf
       
  • Physicians in the pharmaceutical industry: their roles, motivations, and
           perspectives
    • Abstract: Publication date: September 2019Source: Drug Discovery Today, Volume 24, Issue 9Author(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.
       
  • Molecular modeling approaches for the discovery of adenosine A2B receptor
           antagonists: current status and future perspectives
    • Abstract: Publication date: September 2019Source: Drug Discovery Today, Volume 24, Issue 9Author(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.
       
  • Cannabinoid receptors as therapeutic targets for autoimmune diseases:
           where do we stand'
    • Abstract: Publication date: September 2019Source: Drug Discovery Today, Volume 24, Issue 9Author(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 Graphical abstract for this article
       
  • Nuclear G-protein-coupled receptors as putative novel pharmacological
           targets
    • Abstract: Publication date: Available online 11 September 2019Source: Drug Discovery TodayAuthor(s): Rita Ribeiro-Oliveira, Martin Vojtek, Salomé Gonçalves-Monteiro, Maria Sofia Vieira-Rocha, Joana B. Sousa, Jorge Gonçalves, Carmen DinizCell surface G-protein-coupled receptors (GPCRs) are targets for ˜30% of drugs currently on the market, and are the largest group of gene products targeted by drugs. Until recently, signaling mediated by GPCRs was thought to emanate exclusively from the cell membrane as a response to extracellular stimuli. However, recent research has revealed the existence of nuclear (n)GPCRs with the ability to trigger identical and/or distinct signaling pathways to their respective counterparts on the cell surface. Understanding of the GPCR signaling platform on the nuclear membranes and its involvement in physiology and/or pathophysiology will be important to develop selective pharmacological and pharmaceutical approaches. In this review, we summarize our current understanding of nGPCRs, with emphasis on their potential as novel pharmacological targets.
       
  • PI3K/AKT/mTOR pathway inhibitors in triple-negative breast cancer: a
           review on drug discovery and future challenges
    • Abstract: Publication date: Available online 11 September 2019Source: Drug Discovery TodayAuthor(s): Mohammad A. Khan, Vineet K. Jain, Md. Rizwanullah, Javed Ahmad, Keerti JainTriple-negative breast cancer (TNBC) is a highly malignant subtype of breast cancer associated with poor prognosis. Although conventional chemotherapy regimens have shown some effectiveness in early TNBC cases, the outcome in advanced stages is poor. The PI3K/AKT/mTOR pathway is one of the important and active pathways involved in chemoresistance and survival of TNBC. This pathway is speculated to play an important part in malignant transformation and has been considered as a potential molecular target for the design of therapeutic agents to treat TNBC. This review discusses the potentials and drug discovery perspectives of PI3K/AKT/mTOR as a therapeutic target for effective management of TNBC with anticipated challenges.
       
  • Applying drug synergy metrics to oncology combination screening data:
           agreements, disagreements and pitfalls
    • Abstract: Publication date: Available online 10 September 2019Source: Drug Discovery TodayAuthor(s): Anna H.C. Vlot, Natalia Aniceto, Michael P. Menden, Gudrun Ulrich-Merzenich, Andreas BenderSynergistic drug combinations are commonly sought to overcome monotherapy resistance in cancer treatment. To identify such combinations, high-throughput cancer–cell-line combination screens are performed; and synergy is quantified using competing models based on fundamentally different assumptions. Here, we compare the behaviour of four synergy models, namely Loewe additivity, Bliss independence, highest single agent and zero interaction potency, using the Merck oncology combination screen. We evaluate agreements and disagreements between the models and investigate putative artefacts of each model’s assumptions. Despite at least moderate concordance between scores (Pearson’s r>0.32, Spearman’s ρ > 0.34), multiple instances of strong disagreement were observed. Those disagreements are driven by, among others, large differences in tested concentrations, maximum response values and median effective concentrations.
       
  • Understanding the variability of the S1′ pocket to improve matrix
           metalloproteinase inhibitor selectivity profiles
    • Abstract: Publication date: Available online 9 September 2019Source: Drug Discovery TodayAuthor(s): Aleix Gimeno, Raúl Beltrán-Debón, Miquel Mulero, Gerard Pujadas, Santiago Garcia-VallvéMatrix metalloproteinases (MMPs) are a family of proteins involved in a range of pathologies. Given that MMP broad-spectrum inhibition is associated with severe adverse effects, selectivity has become a priority in the design of MMP inhibitors, and is often achieved by targeting the variable S1′ pocket. However, the specific characteristics of the S1′ pocket that determine inhibitor selectivity are often not described and, in many cases, challenging to identify. In this review, we investigate the variability of the S1′ pocket across the MMP family, and propose explanations for the selectivity of previously described inhibitors. These analyses provide valuable insights into how to design novel inhibitors selective for a given MMP.TeaserInspecting the structures of selective MMP inhibitors and the nature and variability of the S1 pocket across the MMP family has provided valuable information on selective MMP inhibition.
       
  • Cholinergic muscarinic M1 and M4 receptors as therapeutic targets for
           cognitive, behavioural, and psychological symptoms in psychiatric and
           neurological disorders
    • Abstract: Publication date: Available online 6 September 2019Source: Drug Discovery TodayAuthor(s): Daniel Erskine, John-Paul Taylor, Geor Bakker, Alastair J.H. Brown, Tim Tasker, Pradeep J. NathanCholinergic dysfunction is involved in a range of neurological and psychiatric disorders, including schizophrenia, dementia and Lewy body disease (LBD), leading to widespread use of cholinergic therapies. However, such drugs have focussed on increasing the availability of acetylcholine (ACh) generally, with relatively little work done on the muscarinic system and specific muscarinic receptor subtypes. In this review, we provide an overview of the major cholinergic pathways and cholinergic muscarinic receptors in the human brain and evidence for their dysfunction in several neurological and psychiatric disorders. We discuss how the selectivity of cholinergic system dysfunction suggests that targeted cholinergic therapeutics to the muscarinic receptor subtypes will be vital in treating several disorders associated with cognitive dysfunction and behavioural and psychological symptoms.
       
  • Learning and augmenting natural processes: potential means of combating
           antimicrobial resistance from a drug R&D perspective
    • Abstract: Publication date: Available online 6 September 2019Source: Drug Discovery TodayAuthor(s): Charles Oo, Sherwin K.B. Sy
       
  • Moving beyond the current limits of data analysis in longevity and healthy
           lifespan studies
    • Abstract: Publication date: Available online 6 September 2019Source: Drug Discovery TodayAuthor(s): Wilson Wen Bin Goh, Subhash Thalappilly, Guillaume ThibaultLiving longer with sustainable quality of life is becoming increasingly important in aging populations. Understanding associative biological mechanisms have proven daunting, because of multigenicity and population heterogeneity. Although Big Data and Artificial Intelligence (AI) could help, naïve adoption is ill advised. We hold the view that model organisms are better suited for big-data analytics but might lack relevance because they do not immediately reflect the human condition. Resolving this hurdle and bridging the human–model organism gap will require some finesse. This includes improving signal:noise ratios by appropriate contextualization of high-throughput data, establishing consistency across multiple high-throughput platforms, and adopting supporting technologies that provide useful in silico and in vivo validation strategies.
       
  • Advances in differentiation therapy for osteosarcoma
    • Abstract: Publication date: Available online 6 September 2019Source: Drug Discovery TodayAuthor(s): Yingqian Chen, Ji Cao, Ning Zhang, Bo Yang, Qiaojun He, Xuejing Shao, Meidan YingDifferentiation therapy involves the use of agents that can induce differentiation in cancer cells, with the irreversible loss of tumour phenotype. The application of differentiation therapy in osteosarcoma has made progress because of a better understanding of the potential links between differentiation defects and tumorigenesis. Here, we review recent studies on differentiation therapy for osteosarcoma, describing a variety of differentiation inducers. By highlighting these examples of drug-induced osteosarcoma cell differentiation, we can acquire unique insights into not only osteosarcoma treatment, but also novel approaches to transform differentiating drugs into more effective therapies for other solid tumours.
       
  • Soft drugs for dermatological applications: recent trends
    • Abstract: Publication date: Available online 5 September 2019Source: Drug Discovery TodayAuthor(s): Silvio Aprile, Marta Serafini, Tracey PiraliA soft drug (SD) displays a metabolically labile spot and, after having exerted its activity in the site of action, undergoes a fast metabolism, leading to inactive metabolites. The SD approach has recently found widespread application in the dermatological field because it provides a means of localising the therapeutic effect in skin, while minimising systemic exposure. The literature is rapidly growing of successful examples of compounds targeting sphingosine-1-phosphate receptor 1 (S1PR1), transient receptor potential vanilloid 1 (TRPV1), Janus kinase (JAK), caspase 1, and histone deacetylase (HDAC), for the treatment of skin inflammatory, autoimmune, and oncological diseases. As a demonstration of the potential of this strategy, the SD approach recently led to the approval of crisaborole, a soft phosphodiesterase 4 (PDE4) inhibitor, for atopic dermatitis, while other agents are in clinical development.
       
  • DNA methyltransferases: emerging targets for the discovery of inhibitors
           as potent anticancer drugs
    • Abstract: Publication date: Available online 5 September 2019Source: Drug Discovery TodayAuthor(s): Jie Yu, Tianli Xie, Zhe Wang, Xuwen Wang, Su Zeng, Yu Kang, Tingjun HouDNA methyltransferases (DNMTs) are a conserved family of cytosine methylases with crucial roles in epigenetic regulation. They have been considered as promising therapeutic targets for the epigenetic treatment of cancer. Therefore, DNMT inhibitors (DNMTis) have attracted considerable interest in recent years for the modulation of the aberrant DNA methylation pattern in a reversible way. In this review, we provide a structure-based overview of the therapeutic importance of DNMTs against different cancer types, and then summarize recently investigated DNMTis as well as their inhibitory mechanisms, focusing on recent advances in the development of DNMTis with specificity and/or selectivity developed through computational approaches.
       
  • In vivo imaging of TGFβ signalling components using positron
           emission tomography
    • Abstract: Publication date: Available online 5 September 2019Source: Drug Discovery TodayAuthor(s): Lonneke Rotteveel, Alex J. Poot, Harm Jan Bogaard, Peter ten Dijke, Adriaan A. Lammertsma, Albert D. WindhorstThe transforming growth factor β (TGFβ) family of cytokines achieves homeostasis through a careful balance and crosstalk with complex signalling pathways. Inappropriate activation or inhibition of this pathway and mutations in its components are related to diseases such as cancer, vascular diseases, and developmental disorders. Quantitative imaging of expression levels of key regulators within this pathway using positron emission tomography (PET) can provide insights into the role of this pathway in vivo, providing information on underlying pathophysiological processes. PET imaging can also be used to study the drug targeting of this pathway and to detect diseases in which this pathway is disturbed. In this review, we provide an overview of PET tracers available to study the TGFβ signalling pathway. In addition, we discuss future imaging targets for this pathway and possible leads for new PET tracers.
       
  • Causative glaucoma treatment: promising targets and delivery systems
    • Abstract: Publication date: August 2019Source: Drug Discovery Today, Volume 24, Issue 8Author(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
       
  • Drug delivery systems and novel formulations to improve treatment of rare
           corneal disease
    • Abstract: Publication date: August 2019Source: Drug Discovery Today, Volume 24, Issue 8Author(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.
       
  • Müller cells as a target for retinal therapy
    • Abstract: Publication date: August 2019Source: Drug Discovery Today, Volume 24, Issue 8Author(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.
       
  • Design principles of ocular drug delivery systems: importance of drug
           payload, release rate, and material properties
    • Abstract: Publication date: August 2019Source: Drug Discovery Today, Volume 24, Issue 8Author(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.
       
  • The gap between the need for novel retinal drug delivery methods,
           
    • Abstract: Publication date: August 2019Source: Drug Discovery Today, Volume 24, Issue 8Author(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.
       
  • Emerging targets of inflammation and tear secretion in dry eye disease
    • Abstract: Publication date: August 2019Source: Drug Discovery Today, Volume 24, Issue 8Author(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.
       
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    • Abstract: Publication date: August 2019Source: Drug Discovery Today, Volume 24, Issue 8Author(s):
       
  • Contents page 1
    • Abstract: Publication date: August 2019Source: Drug Discovery Today, Volume 24, Issue 8Author(s):
       
  • Drug delivery to retinal photoreceptors
    • Abstract: Publication date: August 2019Source: Drug Discovery Today, Volume 24, Issue 8Author(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.
       
  • Connexin43 hemichannels: A potential drug target for the treatment of
           diabetic retinopathy
    • Abstract: Publication date: August 2019Source: Drug Discovery Today, Volume 24, Issue 8Author(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.
       
  • Modified cells as potential ocular drug delivery systems
    • Abstract: Publication date: August 2019Source: Drug Discovery Today, Volume 24, Issue 8Author(s): Tatiana Tennikova, Arto UrttiDrug delivery to ocular targets is problematic, especially in retinal disease treatment. Therefore, targeted drug delivery, prolonged drug action, and minimally invasive treatments are needed. In this review, we describe cell technologies for drug delivery. These technologies are based on genetic engineering and nongenetic-based approaches for cell modification. In principle, cell technologies enable targeted delivery, long drug action, and minimally invasive administration, but they have only been sparsely studied for ocular drug delivery. Herein, these technologies are discussed in the ocular context.
       
  • ER stress response mediates diabetic microvascular complications
    • Abstract: Publication date: Available online 17 August 2019Source: Drug Discovery TodayAuthor(s): Himanshu Sankrityayan, Manisha J. Oza, Yogesh A. Kulkarni, Shrikant R. Mulay, Anil Bhanudas GaikwadEndoplasmic reticulum (ER) homeostasis orchestrates the folding, modification, and trafficking of secretory and membrane proteins to the Golgi compartment, thus governing cellular functions. Alterations in ER homeostasis result in the activation of signaling pathways, such as the unfolded protein response (UPR), to regain ER homeostasis. Nevertheless, failure of UPR leads to activation of autophagy-mediated cell death. Several recent studies emphasized the association of the ER stress (ERS) response with the initiation and progression of diabetes. In this review, we highlight the contribution of the ERS response, such as UPR and autophagy, in the initiation and progression of diabetes and associated microvascular complications, including diabetic nephropathy (DN), retinopathy, and neuropathy, in various experimental models, as well as in humans. We highlight the ERS as a putative therapeutic target for the treatment of diabetic microvascular complications and, thus, the urgent need for the development of improved synthetic and natural inhibitors of ERS.
       
  • Novel insights into the role of urotensin II in cardiovascular disease
    • Abstract: Publication date: Available online 17 August 2019Source: Drug Discovery TodayAuthor(s): João Pereira-Castro, Carmen Brás-Silva, Ana Patrícia Fontes-SousaUrotensin II (UII) is a vasoactive peptide that interacts with a specific receptor called the UT receptor. UII has been implicated in cardiovascular regulation, with promising therapeutic applications based on UT receptor antagonism. The endogenous ligands of the UT receptor: UII and urotensin-related peptide (URP), differentially bind and activate this receptor. Also, the receptor localization is not restricted to the plasma membrane, possibly inducing different physiological responses that could support its inconsistent, but potent, vasoactive activity. These properties could explain the disappointing outcomes in clinical studies, in contrast to the positive preclinical results regarding heart failure, pulmonary hypertension, atherosclerosis and diabetes mellitus. These aspects should be considered in future investigations to a better comprehension of the role of UII as a potential therapeutic target.
       
  • Superbugs but no drugs: steps in averting a post-antibiotic era
    • Abstract: Publication date: Available online 16 August 2019Source: Drug Discovery TodayAuthor(s): Mohamad Hamad, Farah Al-Marzooq, Orive Gorka, Taleb H. Al‐Tel
       
  • Immunotherapy for treating methamphetamine, heroin and cocaine use
           disorders
    • Abstract: Publication date: Available online 13 August 2019Source: Drug Discovery TodayAuthor(s): Tang Xiaoshan, Yang Junjie, Wang Wenqing, Zeng Yunong, Li Jiaping, Lin Shanshan, Selva Nandakumar Kutty, Cheng KuiDrug addiction is a serious health problem prevalent worldwide. Currently available therapies including pharmacotherapy and psychotherapy are insufficient to meet the clinical needs for treating drug abuse. Recently, immunotherapy has emerged as a promising approach to treat such drug-use disorders. Pharmacokinetic antagonists are used in immunotherapy, functioning by sequestering the drugs in the periphery but without allowing the drug to cross the blood–brain barrier. This can reduce the toxic and rewarding effects of the drugs, while preventing addiction and facilitating reduced relapse rates. Herein, we update recent developments in the immunotherapeutic strategies to treat abuse of drugs like methamphetamine, heroin and cocaine. In addition, we summarize the drug design used so far and its optimization strategies. Further, we document the efficacy of anti-drug vaccines and monoclonal antibodies, with an aim to promote development of new anti-drug immunotherapies.
       
  • Can we use Nature’s Structure-Activity-Relationships to Make Better
           Drugs'
    • Abstract: Publication date: Available online 13 August 2019Source: Drug Discovery TodayAuthor(s): Terry Kenakin
       
  • A human-on-a-chip approach to tackling rare diseases
    • Abstract: Publication date: Available online 11 August 2019Source: Drug Discovery TodayAuthor(s): Camilly P. Pires de Mello, John Rumsey, Victoria Slaughter, James J. HickmanDrug development for rare diseases, classified as diseases with a prevalence of
       
  • Cervical cancer and HPV infection: ongoing therapeutic research to
           counteract the action of E6 and E7 oncoproteins
    • Abstract: Publication date: Available online 6 August 2019Source: Drug Discovery TodayAuthor(s): Ana M. Almeida, João A. Queiroz, Fani Sousa, Ângela SousaCervical cancer is the fourth most common cancer among women worldwide and its development is mainly associated with human papillomavirus infection, a highly sexually transmissible virus. The expression of E6 and E7 viral oncoproteins deregulates cell repairing mechanisms through impairment of tumor suppressor protein functions, such as p53 or retinoblastoma protein. Although the implementation of new preventive vaccines has decreased the infection rate and cervical cancer progression, there are still many women who are affected by this pathology. Nowadays, the main treatment often requires the use of invasive techniques. From well-established strategies, like DNA vaccines and gene therapy, to innovative gene silencing technologies; different methodologies are currently under scrutiny that target the E6 and E7 oncoproteins and/or their modes of action.
       
  • Targeted Cell Delivery for Articular Cartilage Regeneration and
           Osteoarthritis Treatment
    • Abstract: Publication date: Available online 6 August 2019Source: Drug Discovery TodayAuthor(s): Nahid Nasiri, Samaneh Hosseini, Mauro Alini, Ali Khademhosseini, Mohamadreza Baghaban EslaminejadOsteoarthritis (OA) is one of the main causes of pain and disability worldwide. In recent years, numerous efforts have been made in pharmaceutical and surgical therapies for management of OA. The therapeutic features of mesenchymal stem cells (MSCs), have led to numerous preclinical and clinical trials that confirmed the efficacy of cell therapy as treatment for OA. Recent works have attempted to customize cell participation in tissue regeneration using site specific targeting approaches. Targeting approaches are based on direct modifications to the surface of MSCs or indirect modifications on an engineered nano-mediator. Here, we provide a comprehensive review of the advances in targeted cell delivery and define the priorities for future work in terms of OA and cartilage regeneration
       
  • Endothelin-1 traps as a potential therapeutic tool: from diabetes to
           beyond'
    • Abstract: Publication date: Available online 5 August 2019Source: Drug Discovery TodayAuthor(s): Arjun Jain, Charles Coffey, Vidhi Mehrotra, Josef FlammerThere is substantial research on the vasoactive peptide endothelin (ET)-1 in physiology, as well as in pathology. In fact, pathologically elevated levels of ET-1 have been found in several disease states, such as various cardiovascular diseases, different cancers, some neurodegenerative disorders, as well as in diabetes. Here, we describe and discuss ET-1, its importance in different diseases, and the potential therapeutic effects of ET-traps in the treatment of these diseases. Previous in vitro and in vivo research (in the diabetes disease space) demonstrated that ET-traps potently and significantly prevent the induction of different markers of diabetes-related pathology. This included induction of extracellular matrix (ECM) proteins (collagen 4α1 and fibronectin), which are pathologically elevated in diabetes. The ET-traps prevented induction of these and brought a significant return to non-diabetic levels. We also discuss the merits of using ET-traps over the currently used endothelin receptor antagonists (ERAs) and previously used therapeutic antibodies.
       
  • The influence of ketamine on drug discovery in depression
    • Abstract: Publication date: Available online 2 August 2019Source: Drug Discovery TodayAuthor(s): Christoph Kraus, Daniel Wasserman, Ioline D. Henter, Elia Acevedo-Diaz, Bashkim Kadriu, Carlos A. ZarateRecent research demonstrating that the glutamatergic modulator ketamine has rapid, robust and sustained antidepressant effects has been a turning point in drug discovery for depression. The recent FDA approval of esketamine for adults with treatment-resistant major depressive disorder (MDD) has further underscored the relevance of this agent in spurring investigation into novel and mechanistically distinct agents for use in depression. Over the past two decades, ketamine research has ushered in a new wave of studies seeking to not only identify its mechanism of action but also to examine the antidepressant potential of novel or repurposed agents. This article reviews the approaches that have proven particularly fruitful for the field of neuropsychiatry.
       
  • Deep learning in drug discovery: opportunities, challenges and future
           prospects
    • Abstract: Publication date: Available online 1 August 2019Source: Drug Discovery TodayAuthor(s): Antonio LavecchiaArtificial Intelligence (AI) is an area of computer science that simulates the structures and operating principles of the human brain. Machine learning (ML) belongs to the area of AI and endeavors to develop models from exposure to training data. Deep Learning (DL) is another subset of AI, where models represent geometric transformations over many different layers. This technology has shown tremendous potential in areas such as computer vision, speech recognition and natural language processing. More recently, DL has also been successfully applied in drug discovery. Here, I analyze several relevant DL applications and case studies, providing a detailed view of the current state-of-the-art in drug discovery and highlighting not only the problematic issues, but also the successes and opportunities for further advances.
       
  • Methods to identify and optimize small molecules interacting with RNA
           (SMIRNAS)
    • Abstract: Publication date: Available online 26 July 2019Source: Drug Discovery TodayAuthor(s): Andrei Ursu, Simon Vézina-Dawod, Matthew D. DisneyRNAs, particularly noncoding (nc)RNAs, are becoming increasingly important therapeutic targets, because they are causative and antagonists of human disease. Indeed, aberrant RNA structural elements and expression deregulate biological processes. In this review, we describe methodologies to discover and optimize small molecules interacting with RNA (SMIRNAS), including the evaluation of direct target engagement and the rescue of RNA-mediated phenotypes in vitro and in vivo. Such studies are essential to fully characterize the mode of action of SMIRNAS and advance our understanding of rationally and efficiently drugging RNAs for therapeutic benefit.
       
  • Ocular drugs and drug delivery systems – Current trends and future
           perspectives
    • Abstract: Publication date: Available online 19 July 2019Source: Drug Discovery TodayAuthor(s): Ilva D. Rupenthal, Ann Daugherty
       
  • Sharpening the focus on cancer tumours
    • Abstract: Publication date: Available online 17 July 2019Source: Drug Discovery TodayAuthor(s): Josephine Bunch
       
  • The Art of Virtualizing Pharma R&D
    • Abstract: Publication date: Available online 16 July 2019Source: Drug Discovery TodayAuthor(s): Alexander Schuhmacher, Oliver Gassmann, Michael Kuss, Markus Hinder
       
  • Physiologically based ocular pharmacokinetic modeling using computational
           methods
    • Abstract: Publication date: Available online 15 July 2019Source: Drug Discovery TodayAuthor(s): Paul J. Missel, Ramesh SarangapaniHere, we apply physiologically based models to simulate ocular drug administration. A non-anatomical model is used that applies a simple theorem for calculating ocular bioavailability from a topical dose. A computational fluid dynamic model is also described that incorporates ocular physiology in anatomical models for rabbit, monkey and man. This second method applies material properties and boundary conditions for various tissues enabling simulation of fluid flows, pressures, temperatures, convection, and drug advection following various modes of administration. The method provides a regional distribution with a given tissue not available using standard compartmental models, and enables translation of results from animal experiments into predictions for human ocular pharmacokinetics (PK).
       
  • CDx, NGS and regulation: five perspectives from the Pistoia Alliance
    • Abstract: Publication date: Available online 12 July 2019Source: Drug Discovery TodayAuthor(s): John Wise, Mike Furness, Stewart McWilliams, Simon PattonCompanion diagnostics (CDx) are essential to the practice of precision medicine. Next-generation sequencing is an increasingly important tool in the development of CDx. However, for CDx to be deployed, many different biopharma industry sectors need to collaborate. This paper outlines some of the challenges and opportunities perceived by the biopharmaceutical industry, the Europe Molecular Quality Network, a regulatory agency, a notified body and a CDx service provider.
       
  • Regulatory sanctions for ethically relevant GCP violations
    • Abstract: Publication date: Available online 6 July 2019Source: Drug Discovery TodayAuthor(s): Rosemarie de la Cruz Bernabe, Ghislaine J.M.W. van Thiel, Nancy S. Breekveldt, Christine C. Gispen, Johannes J.M. van DeldenAlthough 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 violation, with the intention of identifying the most reasonable sanction and/or corrective or reparative action). Last is decision-making or the process of choosing and implementing a regulatory course of action.
       
  • Target 2035: probing the human proteome
    • Abstract: Publication date: Available online 3 July 2019Source: Drug Discovery TodayAuthor(s): Adrian J. Carter, Oliver Kraemer, Matthias Zwick, Anke Mueller-Fahrnow, Cheryl H. Arrowsmith, Aled M. EdwardsBiomedical 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 innovative new medicines. Target 2035 is a global federation for developing and applying new technologies with the goal of creating chemogenomic libraries, chemical probes, and/or functional antibodies for the entire proteome.
       
  • Nucleolin-based targeting strategies for cancer therapy: from targeted
           drug delivery to cytotoxic ligands
    • Abstract: Publication date: Available online 2 July 2019Source: Drug Discovery TodayAuthor(s): Sofia Romano, Nuno Fonseca, Sérgio Simões, João Gonçalves, João Nuno MoreiraCancer 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 cellular targeting strategy. In this review, we present and discuss nucleolin-based targeting strategies that have been developed for cancer therapy, with a special focus on recent antibody-based approaches.
       
  • Toward a repositioning of the antibacterial drug nifuroxazide for cancer
           treatment
    • Abstract: Publication date: Available online 28 June 2019Source: Drug Discovery TodayAuthor(s): Christian BaillyNifuroxazide (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 – strongly support the potential repositioning of NFX as a targeted anticancer agent. The related antiparasitic drug nifurtimox is undergoing clinical development for the treatment of paediatric tumours. The anticancer potential of NFX is highlighted here.Graphical Graphical abstract for this article
       
  • Potential effects of increased openness in pharma: the original knowledge
           behind new drugs
    • Abstract: Publication date: Available online 26 June 2019Source: Drug Discovery TodayAuthor(s): Francesca Bignami, Pauline MattssonThis 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 confirms that recent NMEs are mostly follow-on drugs. This work provides evidence of the increasing openness of pharma to new knowledge sources as a means to improving the drug discovery and development process.
       
  • Are we ready to close the discussion on the interchangeability of
           biosimilars'
    • Abstract: Publication date: Available online 26 June 2019Source: Drug Discovery TodayAuthor(s): Hans C. Ebbers, Huub SchellekensSince 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 when switching. Whereas this might argue against automatic substitution of biosimilars, it is not a biosimilars-specific concern. To increase physician confidence in biosimilars, regulators should acknowledge that biosimilars are interchangeable.
       
  • Neurobiology and therapeutic utility of neurotoxins targeting postsynaptic
           mechanisms of neuromuscular transmission
    • Abstract: Publication date: Available online 24 June 2019Source: Drug Discovery TodayAuthor(s): Naira M. Ayvazyan, Valerie B. O’Leary, J. Oliver Dolly, Saak V. OvsepianThe 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 response, with muscle contraction. We consider the correlation between their outstanding selectivity and potency and their effects on motor function, and discuss emerging data advocating their usage for the development of therapies alleviating neuromuscular dysfunction.
       
  • Drug repurposing: a promising tool to accelerate the drug discovery
           process
    • Abstract: Publication date: Available online 22 June 2019Source: Drug Discovery TodayAuthor(s): Vineela Parvathaneni, Nishant S. Kulkarni, Aaron Muth, Vivek GuptaTraditional 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 approach for drug discovery because it provides a novel way to explore old drugs for new use but encounters several challenges. Some examples of different approaches are reviewed here.
       
  • 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.
       
  • 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.
       
  • 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.
       
  • 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.
       
  • 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.
       
  • 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.
       
  • 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.
       
  • 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).
       
  • 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.
       
  • 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.
       
  • 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
       
 
 
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