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Drug Discovery Today

Gerhard Prinsloo, Georgia Papadi, Mebrahtom G Hiben, Laura de Haan, Jochem Louisse, Karsten Beekmann, Jacques Vervoort, Ivonne M C M Rietjens
This review provides an update on the promises and pitfalls when using in vitro bioassays to evaluate beneficial and adverse health effects of botanicals and botanical preparations. Important issues addressed in the paper are: (i) the type of assays and biological effects available; (ii) false-positives, false-negatives and confounding factors; (iii) matrix and combination effects; (iv) extrapolation of in vitro data to the in vivo situation; (v) when (not) to use bioassays; and (vi) identification of active constituents...
May 19, 2017: Drug Discovery Today
Barbara Pavan, Antonio Capuzzo, Alessandro Dalpiaz
Several olfactory receptors (ORs) have been characterized outside the olfactory neuroepithelium in neuronal and non-neuronal tissues, where they were implicated in the recognition of diverse chemical signals. ORs have been found to regulate melanogenesis in skin melanocytes, and OR expression has been found in the human brain nigrostriatal dopaminergic neurons, where production of melanin occurs as neuromelanin and can change with age; OR expression is downregulated in Parkinson's disease. Therefore, we propose several odorants as new functional ligands to ORs expressed in non-olfactory pigmented cells as dopaminergic neurons and melanocytes, where, by acting on cAMP-induced melanin production, they could help to counteract melanogenic and neurodegenerative dysfunctions, including melanoma and Parkinson's disease...
May 19, 2017: Drug Discovery Today
Mirae Kim, Jinhyeong Jang, Chaenyung Cha
Theranostic nanomedicine, utilizing state-of-the-art, multifaceted nanomaterials and devices with therapeutic and diagnostic dual functions, has emerged as a highly attractive and promising new field of medicine. The theory behind the use of nanomaterials for theranostic applications is to impart multifunctionality by applying various engineering strategies to combine different modalities on a nanoscale. Carbon nanomaterials, which have been a subject of intense scientific research and industrial applications in recent years, have also found their way into theranostic nanomedicine owing to their innate multifunctionality...
May 19, 2017: Drug Discovery Today
Arnaud Machelart, Ok-Ryul Song, Eik Hoffmann, Priscille Brodin
Tuberculosis (TB) remains a leading global health problem that is exacerbated by the emergence of multidrug and extensively drug-resistant Mycobacterium tuberculosis strains. Control of the disease requires novel therapeutic strategies. Modulating host homeostasis appears to be a promising approach, and recent studies have identified novel potential host targets and compounds that could be investigated for host-directed therapies (HDTs). Moreover, the recent development of intracellular high-throughput phenotypic assays makes it possible to screen large libraries of compounds to identify more rapidly new effectors for mycobacterial elimination...
May 19, 2017: Drug Discovery Today
Pallabita Chowdhury, Allison M Roberts, Sheema Khan, Bilal B Hafeez, Subhash C Chauhan, Meena Jaggi, Murali M Yallapu
Magnetic nanoparticles (MNPs) play a vital role for improved imaging applications. Recently, a number of studies demonstrate MNPs can be applied for targeted delivery, sustained release of therapeutics, and hyperthermia. Based on stable particle size and shape, biocompatibility, and inherent contrast enhancement characteristics, MNPs have been encouraged for pre-clinical studies and human use. As a theranostic platform development, MNPs need to balance both delivery and imaging aspects. Thus, this review provides significant insight and advances in the theranostic role of MNPs through the documentation of unique magnetic nanoparticles used in prostate cancer, their interaction with prostate cancer cells, in vivo fate, targeting, and biodistribution...
May 16, 2017: Drug Discovery Today
Barbara Wiƛniowska, Zofia Tylutki, Sebastian Polak
Since 2005, when the International Conference on Harmonisation (ICH) E14 guideline was adopted, no drug has been withdrawn because of QTc prolongation or torsade de pointes arrhythmia. There are, however, costs associated with this success. In addition to the time and money invested, thorough QT (TQT) studies have limited the efficiency of the drug development pipeline. In this paper, we discuss the relevance of TQT trials as a tool for proarrhythmic risk prediction as a part of the debate regarding their usefulness...
May 13, 2017: Drug Discovery Today
Pallabi Sengupta, Samit Chattopadhyay, Subhrangsu Chatterjee
BCL-2 overexpression promotes neoplastic cell expansion in cancers. Multiple noncanonical B-DNA motifs in the BCL-2 gene regulate selective modulation of its expression in normal and cancer cells. Three G-quadruplex topologies and one i-motif, in the vicinity of the P1 (major) promoter, stringently control its transcription. RNA quadruplexes and Z-DNA elements within translocation breakpoints of noncoding regions affect translation and promote oncogenic transformation of BCL-2 [e.g., t(14;18) translocation]...
May 12, 2017: Drug Discovery Today
Satya K Kota, Savithri B Kota
Kidneys have a major role in normal physiology and metabolic homeostasis. Loss or impairment of kidney function is a common occurrence in several metabolic disorders, including hypertension and diabetes. Chronic kidney disease (CKD) affect nearly 10% of the population worldwide; ranks 18th in the list of causes of death; and contributes to a significant proportion of healthcare costs. The tissue repair and regenerative potential of kidneys are limited and they decline during aging. Recent studies have demonstrated a key role for epigenetic processes and players, such as DNA methylation, histone modifications, noncoding (nc)RNA, and so on, in both kidney development and disease...
May 6, 2017: Drug Discovery Today
Hao Cheng, Aditya Chawla, Yafeng Yang, Yuxiao Li, Jin Zhang, Hae Lin Jang, Ali Khademhosseini
Bone is one of the major organs of the human body; it supports and protects other organs, produces blood cells, stores minerals, and regulates hormones. Therefore, disorders in bone can cause serious morbidity, complications, or mortality of patients. However, despite the significant occurrence of bone diseases, such as osteoarthritis (OA), osteoporosis (OP), non-union bone defects, bone cancer, and myeloma-related bone disease, their effective treatments remain a challenge. In this review, we highlight recent progress in the development of nanotechnology-based drug delivery for bone treatment, based on its improved delivery efficiency and safety...
May 6, 2017: Drug Discovery Today
Libin Ye, Suvrajit Maji, Narinder Sanghera, Piraveen Gopalasingam, Evgeniy Gorbunov, Sergey Tarasov, Oleg Epstein, Judith Klein-Seetharaman
Recently, major progress has been made in uncovering the mechanisms of how insulin engages its receptor and modulates downstream signal transduction. Here, we present in detail the current structural knowledge surrounding the individual components of the complex, binding sites, and dynamics during the activation process. A novel kinase triggering mechanism, the 'bow-arrow model', is proposed based on current knowledge and computational simulations of this system, in which insulin, after its initial interaction with binding site 1, engages with site 2 between the fibronectin type III (FnIII)-1 and -2 domains, which changes the conformation of FnIII-3 and eventually translates into structural changes across the membrane...
May 3, 2017: Drug Discovery Today
Harvey Wong, Tonika Bohnert, Valeriu Damian-Iordache, Christopher Gibson, Cheng-Pang Hsu, Anu Shilpa Krishnatry, Bianca M Liederer, Jing Lin, Qiang Lu, Jerome T Mettetal, Daniel R Mudra, Marjoleen J M A Nijsen, Patricia Schroeder, Edgar Schuck, Satyendra Suryawanshi, Patrick Trapa, Alice Tsai, Haiqing Wang, Fan Wu
With inadequate efficacy being the primary cause for the attrition of drug candidates in clinical development, the need to better predict clinical efficacy earlier in the drug development process has increased in importance in the pharmaceutical industry. Here, we review current applications of translational pharmacokinetic-pharmacodynamic (PK-PD) modeling of preclinical data in the pharmaceutical industry, including best practices. Preclinical translational PK-PD modeling has been used in many therapeutic areas and has been impactful to drug development...
May 2, 2017: Drug Discovery Today
Gordon Munro, Inger Jansen-Olesen, Jes Olesen
Preclinical research activities in relation to pain typically involve the 'holy trinity' of nociceptive, inflammatory and neuropathic pain for purposes of target validation and defining target product profiles of novel analgesic compounds. For some reason it seems that headache or migraine are rarely considered as additional entities to explore. Frontline medications used in the treatment of, for example, inflammatory pain, neuropathic pain and migraine (NSAIDs versus pregabalin/duloxetine versus triptans) reveal distinct differences in pathophysiology that partially explain this approach...
May 2, 2017: Drug Discovery Today
John C Talpos
Research indicates that relieving the cognitive and negative symptoms of schizophrenia is crucial for improving patient quality of life. However effective pharmacotherapies for cognitive and negative symptoms do not currently exist. A review of ongoing Phase III clinical trials indicates that, despite numerous compounds being investigated for cognition in schizophrenia, few are actually novel and most are not backed by empirically driven preclinical research efforts. Based on these trials, and a general disinvestment in development of novel therapies for schizophrenia, the likelihood of a major advancement in treating cognitive differences in schizophrenia does not look promising...
April 29, 2017: Drug Discovery Today
Ram Prasad Bhusal, Ghader Bashiri, Brooke X C Kwai, Jonathan Sperry, Ivanhoe K H Leung
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis that can remain dormant for many years before becoming active. One way to control and eliminate TB is the identification and treatment of latent TB, preventing infected individuals from developing active TB and thus eliminating the subsequent spread of the disease. Isocitrate lyase (ICL) is involved in the mycobacterial glyoxylate and methylisocitrate cycles. ICL is important for the growth and survival of M. tuberculosis. ICL is not present in humans and is therefore a potential therapeutic target for the development of anti-TB agents...
April 27, 2017: Drug Discovery Today
Asier Antoranz, Theodore Sakellaropoulos, Julio Saez-Rodriguez, Leonidas G Alexopoulos
Biomarkers are cornerstones of healthcare spanning a spectrum of applications, such as disease diagnosis and stratification of patient populations. Despite significant efforts that have identified thousands of potential biomarkers, their translation into clinical practice remains poor: less than two approvals per year across all diseases. In part, this inefficiency arises from experimental limitations of the biomarker discovery pipeline. Widely used mass-spectrometry (MS) approaches suffer from sample throughput, whereas targeted approaches, such as immunoassays, suffer from low multiplexability...
April 27, 2017: Drug Discovery Today
Shadab Md, Shadabul Haque, Thiagarajan Madheswaran, Farrukh Zeeshan, Venkata Srikanth Meka, Ammu K Radhakrishnan, Prashant Kesharwani
Topical photodynamic therapy (PDT) is a non-invasive technique used in the treatment of malignant and non-malignant skin diseases. It offers great promise because of its simplicity, enhanced patient compliance, localisation of the photosensitizer, as well as the use of light and oxygen to achieve photocytotoxicity. Despite progress in photosensitizer-mediated topical PDT, its clinical application is limited by poor penetration of photosensitizers through the skin. Therefore, much effort has been made to develop nanocarriers that can tackle the challenges of conventional photosensitizer-mediated PDT for topical delivery...
April 27, 2017: Drug Discovery Today
Esther Kim, Paige M C Omura, Andrew W Lo
Translating academic medical research into new therapies is an important challenge for the biopharmaceutical industry and investment communities, which have historically favored later-stage assets with lower risk and clearer commercial value. The Stanford SPARK program is an innovative model for addressing this challenge. The program was created in 2006 to educate students and faculty about bringing academic research from bench to bedside. Every year, the program provides mentorship and funding for approximately a dozen SPARK 'scholars', with a focus on impacting patient lives, regardless of economic factors...
April 26, 2017: Drug Discovery Today
Kai Li, Hossein Nejadnik, Heike E Daldrup-Link
Superparamagnetic iron oxide (SPIO) nanoparticles have been intensively studied for the development of contrast agents in MRI. First-generation SPIO nanoparticles had diagnostic capabilities only, whereas a new generation of SPIO nanoparticle has multifunctional characteristics for combined therapeutic and diagnostic applications. These theranostic nanoparticles hold great potential for image-guided cancer therapies. In particular, polymer-coated theranostic SPIO nanoparticles have enjoyed increasing attention as a result of good biocompatibility, biodegradability and versatile functionality endowed by polymeric matrices...
April 26, 2017: Drug Discovery Today
Deepika Singh, Aliva Prity Minz, Sanjeeb Kumar Sahoo
Tumors are heterogeneous and contain a small population of cells that has a crucial role in tumor progression, metastasis, drug resistance, and relapse as a result of their self-renewal, proliferation, and differentiation properties. These cells are known as cancer stem cells (CSCs) and accumulating evidence suggests that they show significant resistance to conventional chemotherapy. Thus, various antitumor strategies have been developed to eliminate therapeutic-resistant CSCs by targeting the molecular differences between CSCs and bulk cancer cells...
April 21, 2017: Drug Discovery Today
Jing Zhao, Guorui Jin, Guojun Weng, Jianjun Li, Jian Zhu, Junwu Zhao
Fluorescence imaging is superior in sensitivity and resolution compared with other imaging modalities; however, its application is hindered by high background noise. Tissue-selective strategies, such as passive, active, and activatable targeting, hold great promise in accelerating clinical translation by significantly improving the tumor:background ratio (TBR) and, in turn, the sensitivity and contrast of fluorescence imaging. Compared with the 'always on' contrast agents, activatable probes, which remain nonfluorescent until being activated by tumor-specific molecular targets, further enhance TBR and at the same time provide additional molecular information that can be related to tumor staging and therapy response...
April 20, 2017: Drug Discovery Today
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