MedWorm.com provides a medical RSS filtering service. Over 6000 RSS medical sources are combined and output via different filters. This feed contains the latest items from the 'Drug Discovery Today' source. Wed, 08 Feb 2012 14:04:12 +0100 http://www.medworm.com/index.php?rid=5626015&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22265918%26dopt%3DAbstract Authors: Robson T, James IF Abstract The immunophilin family of proteins has a vast number of roles regulating a variety of biological processes through protein-protein interactions. A relatively new and divergent member of this family, FK506-binding protein like (FKBPL), is emerging as a key player in the DNA damage response, steroid receptor signalling and more recently, control of tumour growth where it regulates response to endocrine therapy in addition to acting as a novel antiangiogenic protein. As a new therapeutic peptide based on FKBPL approaches clinical trials. In this article we highlight a unique approach to targeting tumours that are resistant to current antiangiogenic therapies and we support the role of FKBPL as a novel prognostic and predictive biomarker, distinct ... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5626015 Mon, 16 Jan 2012 05:00:00 +0100 5626015 http://www.medworm.com/index.php?rid=5626014&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22269133%26dopt%3DAbstract Authors: Mullane K, Williams M Abstract The successful transition of drug-like new chemical entities from discovery to clinical trials coupled with real-time feedback from the latter represents a key element for success in drug discovery. Now designated as T1 translational medicine, this process has, similar to other recent solutions to improve productivity, been hyped as a novel discipline, despite the fact that many of its component activities have existed in the pharmacological sciences for many decades. Instead of proselytizing translational medicine, the priority is to improve the quality of the science and decision-making processes involved in advancing compounds to ensure that what is translated has value. PMID: 22269133 [PubMed - as supplied by publisher] (Source: Drug ... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5626014 Mon, 16 Jan 2012 05:00:00 +0100 5626014 http://www.medworm.com/index.php?rid=5626013&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22269134%26dopt%3DAbstract Authors: Pang MH, Kim Y, Jung KW, Cho S, Lee DH Abstract Since the introduction of drug discovery based on single targets, the number of newly developed drugs has steadily declined, and the reliablility of the current drug-discovery paradigm has been unceasingly questioned. As an alternative, an emerging approach pursuing multi-targeting drugs has arisen to reflect multifactorial diseases caused by the complex networks of various mechanisms. The purpose of this paper is to review multi-target drugs and introduce our progress in establishing a practical methodology for identifying antinociceptive multi-target drugs. We have adopted a system of ex vivo efficacy screening using long-term potentiation in rat spinal cord as a surrogate biomarker for neuropathic pain. A bait-target appro... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5626013 Mon, 16 Jan 2012 05:00:00 +0100 5626013 http://www.medworm.com/index.php?rid=5626012&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22269135%26dopt%3DAbstract We describe how best this can be implemented, the potential benefits that can be obtained and the pitfalls that are often encountered. PMID: 22269135 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5626012 Mon, 16 Jan 2012 05:00:00 +0100 5626012 http://www.medworm.com/index.php?rid=5626011&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22269136%26dopt%3DAbstract Authors: Peters JU, Hert J, Bissantz C, Hillebrecht A, Gerebtzoff G, Bendels S, Tillier F, Migeon J, Fischer H, Guba W, Kansy M Abstract The term 'pharmacological promiscuity' describes the activity of a single compound against multiple targets. When undesired, promiscuity is a major safety concern that needs to be detected as early as possible in the drug discovery process. The analysis of large datasets reveals that the majority of promiscuous compounds are characterized by recognizable molecular properties and structural motifs, the most important one being a basic center with a pK(a)(B)>6. These compounds interact with a small set of targets such as aminergic GPCRs; some of these targets attract surprisingly high hit rates. In this review, we discuss current trends in the as... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5626011 Mon, 16 Jan 2012 05:00:00 +0100 5626011 http://www.medworm.com/index.php?rid=5626016&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22245656%26dopt%3DAbstract Authors: Travers J, Sharp S, Workman P PMID: 22245656 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5626016 Fri, 30 Dec 2011 05:00:00 +0100 5626016 http://www.medworm.com/index.php?rid=5580063&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22222943%26dopt%3DAbstract Authors: Wild DJ, Ding Y, Sheth AP, Harland L, Gifford EM, Lajiness MS Abstract Systems chemical biology, the integration of chemistry, biology and computation to generate understanding about the way small molecules affect biological systems as a whole, as well as related fields such as chemogenomics, are central to emerging new paradigms of drug discovery such as drug repurposing and personalized medicine. Recent Semantic Web technologies such as RDF and SPARQL are technical enablers of systems chemical biology, facilitating the deployment of advanced algorithms for searching and mining large integrated datasets. In this paper, we aim to demonstrate how these technologies together can change the way that drug discovery is accomplished. PMID: 22222943 [PubMed - as supplied by p... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5580063 Thu, 29 Dec 2011 05:00:00 +0100 5580063 http://www.medworm.com/index.php?rid=5580062&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22227532%26dopt%3DAbstract Authors: Morgan P, Van Der Graaf PH, Arrowsmith J, Feltner DE, Drummond KS, Wegner CD, Street SD Abstract In an effort to uncover systematic learnings that can be applied to improve compound survival, an analysis was performed on data from Phase II decisions for 44 programs at Pfizer. It was found that not only were the majority of failures caused by lack of efficacy but also that, in a large number of cases (43%), it was not possible to conclude whether the mechanism had been tested adequately. A key finding was that an integrated understanding of the fundamental pharmacokinetic/pharmacodynamic principles of exposure at the site of action, target binding and expression of functional pharmacological activity (termed together as the 'three Pillars of survival') all determine the lik... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5580062 Thu, 29 Dec 2011 05:00:00 +0100 5580062 http://www.medworm.com/index.php?rid=5567008&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22210121%26dopt%3DAbstract Authors: Zhang F, Xue J, Shao J, Jia L Abstract The binding of a drug to plasma protein reduces free drug in the blood circulation that would otherwise be available for penetration into tissues to reach the therapeutic target or the kidney for elimination. Therefore, the binding event affects drug elimination from the body, efficacy, duration of action and toxicity. Co-administration of other drugs, food and pathological conditions of patients can significantly change percentage binding of the drug and result in serious consequences. Here, we present the largest and newest information on plasma protein binding for 222 drugs, of which 50% show 90-100% binding, a range that could be considered as a favorable element for future lead selection. We also provide critical and comprehensiv... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5567008 Fri, 23 Dec 2011 05:00:00 +0100 5567008 http://www.medworm.com/index.php?rid=5567012&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22207221%26dopt%3DAbstract Authors: Jones NP, Schulze A Abstract Targeting cancer metabolism has emerged as a hot topic for drug discovery. Most cancers have a high demand for metabolic inputs (i.e. glucose/glutamine), which aid proliferation and survival. Interest in targeting cancer metabolism has been renewed in recent years with the discovery that many cancer-related (e.g. oncogenic and tumour suppressor) pathways have a profound effect on metabolism and that many tumours become dependent on specific metabolic processes. Considering the recent increase in our understanding of cancer metabolism and the increasing knowledge of the enzymes and pathways involved, the question arises: could metabolism be cancer's Achilles heel? During recent years, interest into the possible therapeutic benefit of targeting m... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5567012 Thu, 22 Dec 2011 05:00:00 +0100 5567012 http://www.medworm.com/index.php?rid=5567011&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22207222%26dopt%3DAbstract Authors: Jones PS, Jones D Abstract Recent changes to non-clinical cancer guidelines offer a golden opportunity to expedite the translation of new anticancer drugs into the clinic. In this review we look at how these guidelines can be implemented and how they can be integrated with non-clinical and clinical study design to produce robust and safe clinical trials. PMID: 22207222 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5567011 Thu, 22 Dec 2011 05:00:00 +0100 5567011 http://www.medworm.com/index.php?rid=5567010&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22210119%26dopt%3DAbstract Authors: Bhunia A, Bhattacharjya S, Chatterjee S Abstract The method of saturation transfer difference (STD) nuclear magnetic resonance (NMR) is an indispensable NMR tool in drug discovery. It identifies binding epitope(s) at the atomic resolution of small molecule ligands (e.g. organic drugs, peptides and oligosaccharides), while interacting with their receptors, such as proteins and/or nucleic acids. The method is widely used to screen active drug molecules, simultaneously ranking them in a qualitative way. STD NMR is highly successful for a variety of high molecular weight systems, such as whole viruses, platelets, intact cells, lipopolysaccharide micelles, membrane proteins, recombinant proteins and dispersion pigments. Modifications of STD pulse programs using (13)C and (15)N ... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5567010 Thu, 22 Dec 2011 05:00:00 +0100 5567010 http://www.medworm.com/index.php?rid=5567009&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22210120%26dopt%3DAbstract Authors: Lev D, Thorat C, Phillips I, Thomas M, Imoisili MA PMID: 22210120 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5567009 Thu, 22 Dec 2011 05:00:00 +0100 5567009 http://www.medworm.com/index.php?rid=5552325&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22198298%26dopt%3DAbstract Authors: Esmail H, Barry CE, Wilkinson RJ Abstract Treatment of latent tuberculosis (LTBI) is a vital component of tuberculosis (TB) elimination but is not efficiently implemented with currently available diagnostics and therapeutics. The tuberculin skin test and interferon-γ release assays can inform that infection has occurred, but do not prove that it persists. Treatment of LTBI with isoniazid targets actively replicating bacilli but not non-replicating populations, prolonging treatment duration. Developing more predictive diagnostic tests and treatments of shorter duration requires a greater understanding of the biology of LTBI, from both host and bacillary perspectives. In this article, we discuss the basis of current diagnosis and treatment of LTBI and review recent developm... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5552325 Tue, 20 Dec 2011 05:00:00 +0100 5552325 http://www.medworm.com/index.php?rid=5552327&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22198164%26dopt%3DAbstract Authors: Pezaro CJ, Mukherji D, De-Bono JS Abstract Prostate cancer has long since been recognised as being hormonally driven via androgen receptor signalling. Abiraterone acetate (AA) is a rationally designed CYP17 inhibitor that blocks the conversion of androgens from non-gonadal precursors effectively, thus reducing testosterone to undetectable levels. AA has recently been proved to extend survival for men with metastatic castration-resistant prostate cancer who have progressive disease after first-line chemotherapy treatment. In addition, it is currently being tested in a Phase III trial in the pre-chemotherapy setting. This paper will review the preclinical discovery and clinical development of AA and will outline the strategy of parallel translational research. PMID: 2219... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5552327 Mon, 19 Dec 2011 05:00:00 +0100 5552327 http://www.medworm.com/index.php?rid=5552326&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22198165%26dopt%3DAbstract Authors: Tedcastle A, Cawood R, Di Y, Fisher K, Seymour L Abstract Building on their success in vaccination, many groups are now exploring the use of viruses as anticancer agents. In general, viral therapeutics provide the possibility to express anticancer proteins directly at the tumour site, decreasing exposure to normal tissue during delivery and maximising therapeutic index. Some viruses are also 'oncolytic', either naturally or by design, and these agents function to kill cancer cells selectively before spreading to infect adjacent cells and repeat the process. This whole field of cancer 'virotherapy' is moving forward rapidly at the moment, with notable clinical successes demonstrated with a range of oncolytic agents developed as directly oncolytic and also as oncolytic cance... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5552326 Fri, 16 Dec 2011 05:00:00 +0100 5552326 http://www.medworm.com/index.php?rid=5537901&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22192884%26dopt%3DAbstract Authors: Cvek B Abstract The effort to repurpose old drugs for new uses is not sufficient; even drugs that have been used clinically for decades must undergo expensive clinical trials. This process requires the pharmaceutical industry to fund the repatenting of old drugs. Because inexpensive drugs are necessary for people around the world, attempts should be made to develop nonprofit drugs through clinical trials of generic drugs that are funded by governments and charities. Evidence supports the use the old anti-alcoholic drug Antabuse as a new nonprofit drug for cancer. PMID: 22192884 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5537901 Fri, 16 Dec 2011 05:00:00 +0100 5537901 http://www.medworm.com/index.php?rid=5537904&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22178890%26dopt%3DAbstract Authors: Yang Y, Adelstein SJ, Kassis AI Abstract Data mining of available biomedical data and information has greatly boosted target discovery in the 'omics' era. Target discovery is the key step in the biomarker and drug discovery pipeline to diagnose and fight human diseases. In biomedical science, the 'target' is a broad concept ranging from molecular entities (such as genes, proteins and miRNAs) to biological phenomena (such as molecular functions, pathways and phenotypes). Within the context of biomedical science, data mining refers to a bioinformatics approach that combines biological concepts with computer tools or statistical methods that are mainly used to discover, select and prioritize targets. In response to the huge demand of data mining for target discovery in the 'o... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5537904 Thu, 15 Dec 2011 05:00:00 +0100 5537904 http://www.medworm.com/index.php?rid=5537902&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22192883%26dopt%3DAbstract Authors: Chen T, Stephens PA, Middleton FK, Curtin NJ Abstract Cell survival following DNA damage depends on activating checkpoints to arrest proliferation. Most cancer cells have dysregulated G1 checkpoints making them dependent on their S and G2 checkpoints, which are activated by ATR/Chk1 signalling. Thus, inhibiting ATR or Chk1 should selectively sensitise cancer cells to DNA damage. Genetic inactivation of ATR and Chk1 abrogates cell cycle arrest and enhances cytotoxicity following exposure to DNA-damaging agents. Similar effects were seen with small-molecule Chk1 inhibitors in preclinical studies, and clinical trial data are starting to emerge. Recently, potent ATR inhibitors have been identified that also sensitise cancer cells in vitro. ATR and Chk1 inhibitors might also ca... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5537902 Thu, 15 Dec 2011 05:00:00 +0100 5537902 http://www.medworm.com/index.php?rid=5537906&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22155646%26dopt%3DAbstract This article defines key properties of a good drug target from the perspective of a pharmaceutical company. PMID: 22155646 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5537906 Sun, 11 Dec 2011 05:00:00 +0100 5537906 http://www.medworm.com/index.php?rid=5537905&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22178889%26dopt%3DAbstract Authors: Bennani YL Abstract Pharmaceutical companies must find a better way to increase their output of truly new drugs for the benefit of patients and for their business survival. Here, I highlight a general perspective from within pharmaceutical research as it pertains to research advances in chemistry, biology, pharmacology, pharmacokinetics and toxicology that, if well integrated, stands to put the industry on a productive path. In addition, I provide a complementary perspective on the corporate culture aspect of innovation. I also introduce a new concept, termed 'innovation ASAP' (iASAP; asking powerful questions, seeking the outliers, accepting defeat and populating astutely) and provide support for it using examples of several successful drugs. PMID: 22178889 [PubMed - ... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5537905 Sat, 10 Dec 2011 05:00:00 +0100 5537905 http://www.medworm.com/index.php?rid=5537903&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22178891%26dopt%3DAbstract Authors: Campbell SJ, Gaulton A, Marshall J, Bichko D, Martin S, Brouwer C, Harland L Abstract Generating new therapeutic hypotheses for human disease requires the analysis and interpretation of many different experimental datasets. Assembling a holistic picture of the current landscape of drug discovery activity remains a challenge, however, because of the lack of integration between biological, chemical and clinical resources. Although tools designed to tackle the interpretation of individual data types are abundant, systems that bring together multiple elements to directly enable decision making within drug discovery programmes are rare. In this article, we review the path that led to the development of a knowledge system to tackle this problem within our organization and highli... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5537903 Wed, 07 Dec 2011 05:00:00 +0100 5537903 http://www.medworm.com/index.php?rid=5537909&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22155223%26dopt%3DAbstract Authors: Melzer MS Abstract In this article a new class of anticancer and antiviral drugs is discussed. These new drugs consist of small di- and tri-peptides, designed to bind to single-stranded (ss) regions that are crucial for the expression of genes such as the c-myc oncogene in cancers and start sites (and other ss regions) of viral pathogenic genes. The components (i.e. the amino acids and the sequences they form) of these peptides could be dictated by the specific binding of amino acids to their ss anticodons in tRNA. Cancer cell viability depends on the continued overexpression of the c-myc oncogene, and thus this gene is a target of opportunity for anticancer agents. Sharply reducing the overexpression of c-myc leads to the death of cancer cells. To achieve this end the fol... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5537909 Fri, 02 Dec 2011 05:00:00 +0100 5537909 http://www.medworm.com/index.php?rid=5537908&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22155224%26dopt%3DAbstract Authors: Hoeng J, Deehan R, Pratt D, Martin F, Sewer A, Thomson TM, Drubin DA, Waters CA, de Graaf D, Peitsch MC PMID: 22155224 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5537908 Fri, 02 Dec 2011 05:00:00 +0100 5537908 http://www.medworm.com/index.php?rid=5537907&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22155225%26dopt%3DAbstract Authors: Carney S PMID: 22155225 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5537907 Wed, 30 Nov 2011 05:00:00 +0100 5537907 http://www.medworm.com/index.php?rid=5537912&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22138262%26dopt%3DAbstract Authors: Blundy K PMID: 22138262 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5537912 Sat, 26 Nov 2011 05:00:00 +0100 5537912 http://www.medworm.com/index.php?rid=5537910&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22138563%26dopt%3DAbstract Authors: Di L, Fish PV, Mano T Abstract Solubility has a crucial role in the success of a drug candidate. Compounds with low solubility not only cause problems for in vitro and in vivo assays, but also add significant burdens to drug development. Drug discovery and drug development often have different solubility screening requirements and methodologies have been developed to meet the needs of these different stages. PMID: 22138563 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5537910 Sat, 26 Nov 2011 05:00:00 +0100 5537910 http://www.medworm.com/index.php?rid=5537913&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22134007%26dopt%3DAbstract This article provides an overview on recent developments and is an update to the article of Green et al. that was published in 2004. As this article is a comprehensive review we divided it in two parts. In this Part A of our review, recent developments in acute stroke treatment and in stroke prevention are described. In Part B we will reflect on neuroprotection. PMID: 22134007 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5537913 Wed, 23 Nov 2011 05:00:00 +0100 5537913 http://www.medworm.com/index.php?rid=5537915&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22119310%26dopt%3DAbstract Authors: Malerba M, Radaeli A, Morjaria JB Abstract Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow limitation. In moderate-to-severe COPD, long-acting bronchodilators are the basis of therapy. Inhaled long-acting β(2)-agonists (LABAs) are used for the treatment of COPD. LABAs have been in use since the 1990s enabling persistent bronchodilation for 12 hours; however, sustained bronchodilation is desirable. Compared with twice-daily LABAs, new LABAs with ultra-long duration (ultra-LABAs) could provide improvements in efficacy and compliance with fast onset of action, 24-hour bronchodilation and a good safety profile. Several novel ultra-LABAs showing once-daily delivery profiles are in development. In this article, we discuss these novel agents'... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5537915 Fri, 18 Nov 2011 05:00:00 +0100 5537915 http://www.medworm.com/index.php?rid=5537914&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22119877%26dopt%3DAbstract Authors: Chen L, Li Y, Yu H, Zhang L, Hou T Abstract The impact of P-glycoprotein (P-gp) on the multidrug resistance and pharmacokinetics of clinically important drugs has been widely recognized. Here, we review in silico approaches and computational models for identifying substrates or inhibitors of P-gp. The advances in the datasets for model building and available computational models are summarized and the advantages and drawbacks of these models are outlined. We also discuss the impact of the recently reported crystal structures of P-gp on potential breakthroughs in the computational modeling of P-gp substrates. Finally, the challenges of developing reliable prediction models for P-gp inhibitors or substrates, as well as the strategies to surmount these challenges, are reviewe... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5537914 Fri, 18 Nov 2011 05:00:00 +0100 5537914 http://www.medworm.com/index.php?rid=5537911&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22138380%26dopt%3DAbstract Authors: Jones N PMID: 22138380 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5537911 Fri, 18 Nov 2011 05:00:00 +0100 5537911 http://www.medworm.com/index.php?rid=5537916&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22100998%26dopt%3DAbstract Authors: Hook LA Abstract Stem cells have enormous potential to revolutionise the drug discovery process at all stages, from target identification through to toxicology studies. Their ability to generate physiologically relevant cells in limitless supply makes them an attractive alternative to currently used recombinant cell lines or primary cells. However, realisation of the full potential of stem cells is currently hampered by the difficulty in routinely directing stem cell differentiation to reproducibly and cost effectively generate pure populations of specific cell types. In this article we discuss how stem cells have already been used in the drug discovery process and how novel technologies, particularly in relation to stem cell differentiation, can be applied to attain wides... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5537916 Mon, 07 Nov 2011 05:00:00 +0100 5537916 http://www.medworm.com/index.php?rid=5427042&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22094242%26dopt%3DAbstract Authors: Suresh B, Ramakrishna S, Baek KH Abstract Ran-binding protein microtubule-organizing center (RanBPM) appears to function as a scaffolding protein in several signal transduction pathways. RanBPM is a crucial component of multiprotein complexes that regulate the cellular function by modulating and/or assembling with a wide range of proteins in different intracellular regions and thereby mediate diverse cellular functions. This suggests a role for RanBPM as a scaffolding protein. In this article, we have summarized the diverse functions of RanBPM and its interacting partners that have been investigated to date. Also, we have categorized the role of RanBPM into four divisions: RanBPM as a modulator/protein stabilizer, regulator of transcription activity, cell cycle and neurolo... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5427042 Mon, 07 Nov 2011 05:00:00 +0100 5427042 http://www.medworm.com/index.php?rid=5427041&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22094243%26dopt%3DAbstract Authors: Dorożyński PP, Kulinowski P, Stanisz GJ, Młynarczyk A Abstract The magnetic resonance imaging (MRI) studies of controlled-release (CR) dosage forms can be roughly divided into two groups. The first comprises studies performed in static conditions (small solvent volumes and ambient temperature). Such studies have provided insight into molecular phenomena in hydrating polymeric matrices. The second group covers research performed in dynamic conditions (medium flow or stirring) related to drug dissolution. An important issue is supplementation of the MRI results with data obtained by complementary techniques, such as X-ray microtomography (μCT). As we discuss here, an understanding of the mechanism underlying the release of the drug from the dosage form will lead to the d... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5427041 Mon, 07 Nov 2011 05:00:00 +0100 5427041 http://www.medworm.com/index.php?rid=5427040&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22094244%26dopt%3DAbstract In this study we assessed possible determinants of applications for OMPs in the EU since 2000 that are associated with a successful marketing authorisation. Our analysis shows that clinical trial characteristics such as demonstrating convincing evidence of a beneficial effect on the primary endpoint, the selection of a clinically relevant endpoint, providing RCT data as pivotal study evidence and the submission of sound dose finding data are critical success factors. In addition, high medical need seems to counterweigh uncertainties about the scientific evidence in the benefit-risk assessment of OMPs. PMID: 22094244 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5427040 Mon, 07 Nov 2011 05:00:00 +0100 5427040 http://www.medworm.com/index.php?rid=5427039&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22094245%26dopt%3DAbstract Authors: Ghaemmaghami AM, Hancock MJ, Harrington H, Kaji H, Khademhosseini A Abstract Developing biologically relevant models of human tissues and organs is an important enabling step for disease modeling and drug discovery. Recent advances in tissue engineering, biomaterials and microfluidics have led to the development of microscale functional units of such models also referred to as 'organs on a chip'. In this review, we provide an overview of key enabling technologies and highlight the wealth of recent work regarding on-chip tissue models. In addition, we discuss the current challenges and future directions of organ-on-chip development. PMID: 22094245 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5427039 Mon, 07 Nov 2011 05:00:00 +0100 5427039 http://www.medworm.com/index.php?rid=5427038&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22094246%26dopt%3DAbstract Authors: Costantino L, Boraschi D Abstract Injectable nanosized carriers (5-250nm) are actively studied as anticancer drug delivery agents for targeted drug delivery to the brain. Among these, polymeric nanoparticles (Np) have been studied since 1995, but only five of them recently started Phase I clinical trials, and none of these targets brain pathologies. To date, clinical trials for brain drug delivery have started for macromolecular- and nanocarrier-based systems in the treatment of brain tumors. This review, on the basis of the results obtained so far from preclinical studies, will critically consider the possibilities that polymeric Np have to reach the clinic as drug delivery agents for the brain, in comparison with other platforms. PMID: 22094246 [PubMed - as supplied ... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5427038 Mon, 07 Nov 2011 05:00:00 +0100 5427038 http://www.medworm.com/index.php?rid=5427043&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22079191%26dopt%3DAbstract Authors: Bader MA, Gassmann O, Ziegler N, Ruether F Abstract Effectively managing and optimizing the value of the patent portfolio is a major challenge for many firms, especially those in knowledge intensive industries, such as the pharmaceutical, biotechnological and chemical industry. However, insights on effective patent portfolio strategies are rare. Therefore, in this article we investigate in detail how firms successfully manage and optimize their patent portfolios to increase their overall competitiveness. We discover that successful patent portfolio management is rooted in managing the patents along their life cycles. Based on the findings of ten case studies, we develop a holistic patent life cycle management model reflecting five distinctive phases of patent management: e... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5427043 Thu, 03 Nov 2011 04:00:00 +0100 5427043 http://www.medworm.com/index.php?rid=5427045&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22056716%26dopt%3DAbstract Authors: Moroy G, Martiny VY, Vayer P, Villoutreix BO, Miteva MA Abstract Quantitative structure-activity relationship (QSAR) methods and related approaches have been used to investigate the molecular features that influence the absorption, distribution, metabolism, excretion and toxicity (ADMET) of drugs. As the three-dimensional structures of several major ADMET proteins become available, structure-based (docking-scoring) computations can be carried out to complement or to go beyond QSAR studies. Applying docking-scoring methods to ADMET proteins is a challenging process because they usually have a large and flexible binding cavity; however, promising results relating to metabolizing enzymes have been reported. After reviewing current trends in the field we applied structure-base... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5427045 Sat, 29 Oct 2011 04:00:00 +0100 5427045 http://www.medworm.com/index.php?rid=5427046&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22056715%26dopt%3DAbstract Authors: Sun H, Tawa G, Wallqvist A Abstract The general goal of drug discovery is to identify novel compounds that are active against a preselected biological target with acceptable pharmacological properties defined by marketed drugs. Scaffold hopping has been widely applied by medicinal chemists to discover equipotent compounds with novel backbones that have improved properties. In this article we classify scaffold hopping into four major categories, namely heterocycle replacements, ring opening or closure, peptidomimetics and topology-based hopping. We review the structural diversity of original and final scaffolds with respect to each category. We discuss the advantages and limitations of small, medium and large-step scaffold hopping. Finally, we summarize software that is fre... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5427046 Wed, 26 Oct 2011 04:00:00 +0100 5427046 http://www.medworm.com/index.php?rid=5427044&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22063083%26dopt%3DAbstract Authors: Modi S, Hughes M, Garrow A, White A Abstract In silico toxicology prediction is an extremely challenging area because many toxicological effects are a result of changes in multiple physiological processes. In this article we discuss limitations and strengths of these in silico tools. Additionally, we look at different parameters that are necessary to make the best use of these tools, and also how to gain acceptance outside the modelling community and into the regulatory arena. As a solution, we propose an integrated workflow for combined use of data extraction, quantitative structure activity relationships and read-across methods. We also discuss how the recent advances in this field can enable transition to a new paradigm of the discovery process, as exemplified by the To... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5427044 Tue, 25 Oct 2011 04:00:00 +0100 5427044 http://www.medworm.com/index.php?rid=5382951&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22033197%26dopt%3DAbstract Authors: Vandenhaute E, Sevin E, Hallier-Vanuxeem D, Dehouck MP, Cecchelli R Abstract Several parameters influencing the brain distribution of compounds must be considered when designing potential neuropharmaceuticals in early-stage drug discovery. The blood-brain barrier (BBB) represents an obstacle for drug penetration into the brain. Many in vitro BBB models have proven useful for predicting the BBB permeation rate, but do not meet all criteria for use in early-stage drug discovery: feasibility, rapidity, reliability and a low requirement for human resources. To meet this demand, we have developed a robust, higher-throughout, cell-based model exhibiting BBB features (low paracellular permeability, functional efflux pumps and the correct endothelial phenotype). This system comes ... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5382951 Thu, 20 Oct 2011 04:00:00 +0100 5382951 http://www.medworm.com/index.php?rid=5382950&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22033198%26dopt%3DAbstract Authors: Fishman P, Bar-Yehuda S, Liang BT, Jacobson KA Abstract The G(i)-coupled A(3) adenosine receptor (A(3)AR) mediates anti-inflammatory, anticancer and anti-ischemic protective effects. The receptor is overexpressed in inflammatory and cancer cells, while low expression is found in normal cells, rendering the A(3)AR as a potential therapeutic target. Highly selective A(3)AR agonists have been synthesized and molecular recognition in the binding site has been characterized. In this article, we summarize preclinical and clinical human studies that demonstrate that A(3)AR agonists induce specific anti-inflammatory and anticancer effects through a molecular mechanism that entails modulation of the Wnt and the NF-κB signal transduction pathways. At present, A(3)AR agonists are de... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5382950 Wed, 19 Oct 2011 04:00:00 +0100 5382950 http://www.medworm.com/index.php?rid=5382954&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22020052%26dopt%3DAbstract Authors: John JE PMID: 22020052 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5382954 Fri, 14 Oct 2011 04:00:00 +0100 5382954 http://www.medworm.com/index.php?rid=5382952&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22024215%26dopt%3DAbstract Authors: Muresan S, Petrov P, Southan C, Kjellberg MJ, Kogej T, Tyrchan C, Varkonyi P, Xie PH Abstract The increase in drug research output from patent applications, together with the expansion of public data collections, such as ChEMBL and PubChem BioAssay, has made it essential for pharmaceutical companies to integrate both internal and external 'SAR estate'. The AstraZeneca response has been the development of an enterprise application, Chemistry Connect, containing 45 million unique chemical structures from 18 internal and external data sources. It includes merged compound-to-assay-to-result-to-target relationships extracted from patents, papers and internal data. Users can explore connections between these by searching using drug names or synonyms, chemical structures, patent ... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5382952 Fri, 14 Oct 2011 04:00:00 +0100 5382952 http://www.medworm.com/index.php?rid=5382957&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22016086%26dopt%3DAbstract Authors: Savino R, Terracciano R Abstract Mass spectrometry (MS)-profiling of human bodily fluids is a new approach for the discovery of novel disease biomarkers and, consequently, of new druggable targets. However, the complexity and the high dynamic range of biological samples make the characterization of endogenous peptides and/or proteins a challenging task. To this end, the introduction of new technologies, enabling sample pre-fractionation and/or pre-treatment before MS, could be useful. Progress in the field of nanostructured materials has provided innovative devices, particularly those based on mesoporous silica, which have proved to be successful. The ability to address new emerging material-based MS-profiling platforms will ultimately determine how deeply nanotechnology a... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5382957 Thu, 13 Oct 2011 04:00:00 +0100 5382957 http://www.medworm.com/index.php?rid=5382956&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22016087%26dopt%3DAbstract Authors: Lötsch J, Geisslinger G Abstract Increasing knowledge of molecular signaling processes has enabled the identification of drug targets that synergistically address multifactorial symptoms along several contributing pathways. The idea behind 'polypills' is that minor doses of pharmacodynamically interacting drugs would selectively achieve intended clinical effects. Analogously, monofactorial symptoms could be addressed vertically along their main pathway. Clinical selectivity follows from successive incomplete inhibitions of the pathological pathway at several steps. Here, we discuss and exemplify of how successive inhibitions in the prostaglandin E2 (PGE(2)) signaling pathway could achieve anti-inflammatory and analgesic effects while preserving physiological PGE(2) signal... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5382956 Thu, 13 Oct 2011 04:00:00 +0100 5382956 http://www.medworm.com/index.php?rid=5382953&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22020181%26dopt%3DAbstract Authors: Agoram BM, Demin O Abstract Quantitative and systems pharmacology (QSP) is an emerging modelling technique that combines the flexibility of systems biology and tractability of compartmental pharmacokinetic-pharmacodynamic modelling techniques. Historically, there has been extensive use of QSP within the field of pharmacokinetics to optimise drug biopharmaceutical properties. However, application to target and biomarker selection, and design of preclinical and clinical studies is limited, but growing rapidly. In this article we highlight the impact of QSP within drug discovery and development by citing examples from within the field of pharmacology and we argue for a more systematic integration of QSP within the drug discovery and development paradigm. PMID: 22020181 [P... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5382953 Thu, 13 Oct 2011 04:00:00 +0100 5382953 http://www.medworm.com/index.php?rid=5382955&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22016088%26dopt%3DAbstract Authors: Polich GR Abstract In the face of inadequate treatments, rare disease patients have begun acting like scientists and studying themselves. Through online networks, patient groups transform disease experiences into novel research data: exchanging therapeutic anecdotes, willingly self-testing treatments and compiling outcomes into preliminary research hypotheses which are subsequently relayed to professionals. Through such efforts, rare disease patient groups have helped evaluate and validate several new therapeutic modalities. In this article, I specifically explore the process of patient-driven research while considering broader implications of the trend. While issues regarding methodological quality and patient safety must not be overlooked, through future partnerships wit... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5382955 Wed, 12 Oct 2011 04:00:00 +0100 5382955 http://www.medworm.com/index.php?rid=5332080&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22001144%26dopt%3DAbstract We present examples of drug repurposing by retrospective clinical trial analysis and suggest that this strategy presents a promising way of rescuing failed developmental candidates. We contend that the commercial barriers to successful drug rescue are less problematic than for drug repurposing. We indicate practical means for mining data from past clinical trials, either for new indications or for specific patient groups. PMID: 22001144 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5332080 Fri, 07 Oct 2011 04:00:00 +0100 5332080 http://www.medworm.com/index.php?rid=5332079&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22001600%26dopt%3DAbstract Authors: Ebbers HC, Pieters T, Leufkens HG, Schellekens H Abstract Concerns emanating from the medical community about the safety and efficacy of biosimilars indicate an increasing distrust of the outcome of the drug regulatory process. To illustrate this, we analysed the creation of the European biosimilar regulatory framework, specifically focussing on the guidelines outlining approval criteria for biosimilar erythropoietins, which have been recently adopted. We observed an absence of the organised medical community in the public process of creating and updating the guidelines. In this article we argue that, to ensure that innovative medicines continue to find their way to the patients who might benefit from them, a closer collaboration between the organised medical community and... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5332079 Thu, 06 Oct 2011 04:00:00 +0100 5332079 http://www.medworm.com/index.php?rid=5332078&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22001601%26dopt%3DAbstract Authors: D'Alessandro A, Zolla L Abstract Recent developments in cancer research have led to reconsiderations regarding metabolic dysfunctions in cancer cell proliferation and differentiation. The original concept stemmed from the observation that, even in presence of oxygen, highly proliferating cells tend to generate energy strictly from the glycolytic pathway, through a process called aerobic glycolysis, also known as the Warburg effect. More recently, advances in the field of metabolomics applied to cancer research enabled the documenting of the generality of the Warburg effect in a broad variety of tumors. Through metabolomics, cancer cells told us that oxidative stress, while representing one leading cause of genetic instability underpinning carcinogenesis, could also deliver... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5332078 Tue, 04 Oct 2011 04:00:00 +0100 5332078 http://www.medworm.com/index.php?rid=5332081&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21986108%26dopt%3DAbstract Authors: Xia Y, Rocchi P, Iovanna JL, Peng L Abstract Pancreatic cancer belongs to the group of extremely aggressive human cancers; conventional cancer treatments have little impact. Increasing understanding of the pathways associated with pancreatic cancer progression has enabled the development of targeted therapy on this cancer. Heat shock proteins (HSPs) and related heat shock response (HSR) pathways control multiple important oncogenic pathways for pancreatic cancer development. Consequently, they represent promising novel targets for pancreatic cancer therapy. Various strategies have been proposed and elaborated to target HSPs/HSR in pancreatic cancer with the corresponding modulators, the details of which are highlighted in this review. PMID: 21986108 [PubMed - as suppli... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5332081 Sat, 01 Oct 2011 04:00:00 +0100 5332081 http://www.medworm.com/index.php?rid=5332083&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21978988%26dopt%3DAbstract Authors: Calabrese G, Nesnas JJ, Barbu E, Fatouros D, Tsibouklis J Abstract The early promise of boron neutron capture therapy as a method for the treatment of cancer has been inhibited by the inherent toxicity associated with therapeutically useful doses of (10)B-containing pharmacophores, the need for target-tissue specificity and the challenges imposed by biological barriers. Although developments in the synthetic chemistry of polyhedral boranes have addressed issues of toxicity to a considerable extent, the optimisation of the transport and the delivery of boronated agents to the site of action - the subject of this review - is a challenge that is addressed by the development of innovative formulation strategies. PMID: 21978988 [PubMed - as supplied by publisher] (Source: D... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5332083 Thu, 29 Sep 2011 04:00:00 +0100 5332083 http://www.medworm.com/index.php?rid=5332082&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21983329%26dopt%3DAbstract Authors: Slingerland M, Guchelaar HJ, Gelderblom H Abstract Liposomes as pharmaceutical drug carriers were developed to increase antitumour efficacy and decrease drug toxicity. Doxorubicin HCl liposomal injection was the first liposomal encapsulated anticancer drug to receive clinical approval. To date, virtually all traditional anticancer drugs have been encapsulated in liposomes. The majority of clinical studies only support the concept of a decreased toxicity and better tolerability of the liposomal anticancer drug. Although liposomal anticancer drugs have grown to maturity in several indications and are now in widespread further development programmes using their theoretical advantages to fulfil the high expectations, further studies are warranted - including the development of... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5332082 Thu, 29 Sep 2011 04:00:00 +0100 5332082 http://www.medworm.com/index.php?rid=5283924&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21963522%26dopt%3DAbstract Authors: Harland L, Larminie C, Sansone SA, Popa S, Marshall MS, Braxenthaler M, Cantor M, Filsell W, Forster MJ, Huang E, Matern A, Musen M, Saric J, Slater T, Wilson J, Lynch N, Wise J, Dix I Abstract The life science industries (including pharmaceuticals, agrochemicals and consumer goods) are exploring new business models for research and development that focus on external partnerships. In parallel, there is a desire to make better use of data obtained from sources, such as human clinical samples to inform and support early research programmes. Success in both areas depends upon the successful integration of heterogeneous data from multiple providers and scientific domains, something that is already a major challenge within the industry. This issue is exacerbated by the absence ... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5283924 Fri, 23 Sep 2011 04:00:00 +0100 5283924 http://www.medworm.com/index.php?rid=5283923&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21963616%26dopt%3DAbstract Authors: Plowright AT, Johnstone C, Kihlberg J, Pettersson J, Robb G, Thompson RA Abstract In drug discovery, the central process of constructing and testing hypotheses, carefully conducting experiments and analysing the associated data for new findings and information is known as the design-make-test-analyse cycle. Each step relies heavily on the inputs and outputs of the other three components. In this article we report our efforts to improve and integrate all parts to enable smooth and rapid flow of high quality ideas. Key improvements include enhancing multi-disciplinary input into 'Design', increasing the use of knowledge and reducing cycle times in 'Make', providing parallel sets of relevant data within ten working days in 'Test' and maximising the learning in 'Analyse'. ... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5283923 Thu, 22 Sep 2011 04:00:00 +0100 5283923 http://www.medworm.com/index.php?rid=5283925&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21959306%26dopt%3DAbstract Authors: Yallapu MM, Jaggi M, Chauhan SC Abstract Curcumin, a natural diphenolic compound derived from turmeric Curcuma longa, has proven to be a modulator of intracellular signaling pathways that control cancer cell growth, inflammation, invasion, apoptosis and cell death, revealing its anticancer potential. In this review, we focus on the design and development of nanoparticles, self-assemblies, nanogels, liposomes and complex fabrication for sustained and efficient curcumin delivery. We also discuss the anticancer applications and clinical benefits of nanocurcumin formulations. Only a few novel multifunctional and composite nanosystem strategies offer simultaneous therapy as well as imaging characteristics. We also summarize the challenges to developing curcumin delivery platfor... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5283925 Sun, 18 Sep 2011 04:00:00 +0100 5283925 http://www.medworm.com/index.php?rid=5267008&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21945860%26dopt%3DAbstract Authors: Jørgensen JT Abstract After years of hesitation a larger number of pharmaceutical and biotech companies are now supporting the idea of a more individualized pharmacotherapy. The companies that are now involved in this research-demanding area will have to face several challenges. The key factor for success will be an in-depth molecular understanding of the pathophysiology and the mechanism of the drug under development. The one-disease-one-drug-one-target paradigm that has been prevailing for decades is history. Most diseases are heterogeneous and based on molecular profiling. They can be divided into biological subgroups that each requires a specific pharmacological intervention. PMID: 21945860 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5267008 Sun, 18 Sep 2011 04:00:00 +0100 5267008 http://www.medworm.com/index.php?rid=5267006&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21946060%26dopt%3DAbstract Authors: Tong W, Zhang L Abstract Fetal hypoxia adversely affects the brain and heart development, yet the mechanisms responsible remain elusive. Recent studies indicate an important role of the extracellular matrix in fetal development and tissue remodeling. The matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs) have been implicated in a variety of physiological and pathological processes in the cardiovascular and central nervous systems. This review summarizes current knowledge of the mechanisms by which fetal hypoxia induces the imbalance of MMPs, TIMPs and collagen expression patterns, resulting in growth restriction and aberrant tissue remodeling in the developing heart and brain. Collectively, this information cou... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5267006 Sun, 18 Sep 2011 04:00:00 +0100 5267006 http://www.medworm.com/index.php?rid=5267009&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21945859%26dopt%3DAbstract Authors: Chen M, Zhang L Abstract Adverse insults during intrauterine life can result in permanent changes in the physiology and metabolism of the offspring, which in turn leads to an increased risk of disease in adulthood. This is an adaptational response by the fetus to changes in the environmental signals that it receives during early life to ensure its survival and prepare itself for postnatal life. Increasing evidence suggests that the epigenetic regulation of gene expression patterns has a crucial role in the developmental programming of adult disease. This review summarizes recent studies of epigenetic mechanisms and focuses particularly on studies that explore identifiable epigenetic biomarkers in the promoters of specific disease-associated genes. Such biomarkers would ena... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5267009 Fri, 16 Sep 2011 04:00:00 +0100 5267009 http://www.medworm.com/index.php?rid=5267007&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21945861%26dopt%3DAbstract This article defines key properties of a good drug target from the perspective of a pharmaceutical company. PMID: 21945861 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5267007 Fri, 16 Sep 2011 04:00:00 +0100 5267007 http://www.medworm.com/index.php?rid=5267010&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21930234%26dopt%3DAbstract Authors: Montuschi P, Barnes PJ Abstract Until the relationship between symptoms, lung function tests, airway inflammation, airway hyper-responsiveness (AHR), exacerbations and remodelling is clarified, regular treatment seems to enable a greater disease control than on-demand therapy in most patients with mild persistent asthma. Current guideline classification based on disease severity remains a cornerstone in asthma management. However, the heterogeneity of asthma, the growing emphasis on subphenotypes, including molecular phenotypes identified by -omics technologies, and their possible implications in terms of different asthma severity, progression and therapeutic response, are changing current asthma treatment mainly based on disease severity classification to a pharmacologica... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5267010 Sat, 10 Sep 2011 04:00:00 +0100 5267010 http://www.medworm.com/index.php?rid=5267005&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21946261%26dopt%3DAbstract Authors: Holdgate GA, Gill AL Abstract The kinetics of ligand-target interactions have been recognised as being instrumental in dictating the efficacy of drug action. Increased focus on kinetic signatures in drug discovery has concincided with improvements in label free methodology for measuring kinetic parameters. Simultaneously, focus has also been applied to increasing the quality of compounds, in terms of their physicochemical properties. To facilitate this drive towards higher compound quality, metrics such as ligand efficiency and enthalpic efficiency have been employed. We propose another metric, kinetic efficiency, that may be used pragmatically to help identify those compounds displaying differentiated kinetic behaviour. The combination of these metrics has the potential t... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5267005 Sat, 10 Sep 2011 04:00:00 +0100 5267005 http://www.medworm.com/index.php?rid=5234774&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21920452%26dopt%3DAbstract This report discusses the general principle and development of PDs-based GWAS, highlights the practical use of this approach in addressing various pharmacogenomic problems, and suggests that this approach will be an important method to study the genetic architecture of drug responses or reactions. PMID: 21920452 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5234774 Tue, 06 Sep 2011 04:00:00 +0100 5234774 http://www.medworm.com/index.php?rid=5234773&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21920453%26dopt%3DAbstract Authors: Sen E Abstract A network of activated signaling cascades, transcription factors and their coordinated interactions promote tumorigenesis. In addition, the role of inflammation in tumor evolution is certain. Inflammatory mediators working via intracellular signaling cascades regulate hubs of transcriptional networks that are required for the survival and rapid growth of malignant cells, and number of inflammatory stimuli far exceeds the limited list of transcription factors that they activate. Therefore, inhibiting transcription factors that act at the intersections of several deregulated signaling pathways should hold promise for generating anticancer agents. This review aims to discuss how inflammation-mediated transcription-factor interplay could be targeted to develop a... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5234773 Tue, 06 Sep 2011 04:00:00 +0100 5234773 http://www.medworm.com/index.php?rid=5234772&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21920454%26dopt%3DAbstract Authors: Prasad K, Breckenridge A Abstract Are regulatory agencies and processes up to speed? This is an often asked question. Recent advances in science and the improved knowledge of the human genome have a considerable influence on drug development and their impact on the regulatory aspect is also significant for several reasons, including changing stakeholder expectations and treatment paradigms. One of the challenges faced by the regulators is the need to adapt regulatory processes to accommodate the newer methodologies and techniques while ensuring that the biomarkers, tests and/or diagnostics, and the clinical trials are appropriate and fit for purpose. The change in emphasis in pharmacological treatment from a phenotype-based approach to newer methods is attractive but is it... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5234772 Tue, 06 Sep 2011 04:00:00 +0100 5234772 http://www.medworm.com/index.php?rid=5234771&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21920455%26dopt%3DAbstract Authors: Foot E PMID: 21920455 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5234771 Tue, 06 Sep 2011 04:00:00 +0100 5234771 http://www.medworm.com/index.php?rid=5234770&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21920456%26dopt%3DAbstract Authors: Suen CS, Burn P Abstract Finding a cure for type 1 diabetes (T1D) has been elusive. Incretin-based therapies, since their approval, have demonstrated their clinical utilities in type 2 diabetes (T2D). Yet, their potential clinical benefits in T1D remain to be appraised. GLP-1, in addition to its insulinotropic action in alleviating hyperglycemia, possesses beneficial effects in protecting progressive impairment of pancreatic β-cell function, preservation of β-cell mass and suppression of glucagon secretion, gastric emptying and appetite. Preclinical data using incretin-based therapies in diabetic NOD mice demonstrated additional effects including immuno-modulation, anti-inflammation and β-cell regeneration. Thus, data accumulated hold the promise that incretin-based the... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5234770 Tue, 06 Sep 2011 04:00:00 +0100 5234770 http://www.medworm.com/index.php?rid=5234769&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21924376%26dopt%3DAbstract Authors: Williams AJ, Ekins S, Clark AM, Jack JJ, Apodaca RL Abstract Mobile hardware and software technology continues to evolve very rapidly and presents drug discovery scientists with new platforms for accessing data and performing data analysis. Smartphones and tablet computers can now be used to perform many of the operations previously addressed by laptops or desktop computers. Although the smaller screen sizes and requirements for touch-screen manipulation can present user-interface design challenges, especially with chemistry-related applications, these limitations are driving innovative solutions. In this early review of the topic, we collectively present our diverse experiences as software developer, chemistry database expert and naïve user, in terms of what mobile platf... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5234769 Tue, 06 Sep 2011 04:00:00 +0100 5234769 http://www.medworm.com/index.php?rid=5221299&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21903176%26dopt%3DAbstract Authors: Chalkidou K, Rawlins M Abstract Genetic and proteomic information can be used to identify those patient groups who are most susceptible to a disease and those who are most likely to respond to particular pharmacological treatments. In this review we discuss the impact of cost-effectiveness analysis (CEA) regarding the way pharmacogenetics are adopted by healthcare systems and also, the potential impact of pharmacogenetics about the way CEA is conducted. We conclude that, although CEA can help incentivise the development of appropriate pharmacogenetic tests, when used inappropriately by payers or when ignored by developers, it can act as an obstacle to the adoption of health and efficiency improving technologies. In addition, although economic incentives for payers and deve... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5221299 Tue, 30 Aug 2011 04:00:00 +0100 5221299 http://www.medworm.com/index.php?rid=5221298&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21906694%26dopt%3DAbstract Authors: Keeling P PMID: 21906694 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5221298 Tue, 30 Aug 2011 04:00:00 +0100 5221298 http://www.medworm.com/index.php?rid=5221301&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21889604%26dopt%3DAbstract Authors: Chhatbar C, Mishra R, Kumar A, Singh SK Abstract The AIDS vaccine development effort has already been facing various scientific and economic challenges. The fundamental challenge resides at the level of understanding the basic biology of HIV-1 infection and an effective antiviral immune response. There is a need to design immunogens that can elicit cross-clade neutralizing antibodies (NAbs) along with effective T-cell responses against a wide variety of primary HIV isolates. We must exploit the capabilities of the vaccine-elicited cytotoxic T cells and the NAb responses in controlling HIV-1 replication. A coordinated approach is required to understand the intricacies involved in the basic immune responses against HIV infection as well as the cross-clade effectiveness of an... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5221301 Fri, 26 Aug 2011 04:00:00 +0100 5221301 http://www.medworm.com/index.php?rid=5221300&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21889605%26dopt%3DAbstract Authors: Higgs G PMID: 21889605 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5221300 Thu, 25 Aug 2011 04:00:00 +0100 5221300 http://www.medworm.com/index.php?rid=5221304&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21888986%26dopt%3DAbstract Authors: Nohaile M Abstract As drug discovery and translational scientists think about using stratification with biomarkers to improve the chances of getting medicines to patients, several areas of expertise need to be considered. These include analytical validation, clinical validation, regulatory affairs and intellectual property. Getting the right input from the right expert at the right time can make or break an effort to bring a biomarker-based companion diagnostic successfully into clinical practice. PMID: 21888986 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5221304 Wed, 24 Aug 2011 04:00:00 +0100 5221304 http://www.medworm.com/index.php?rid=5221303&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21888987%26dopt%3DAbstract Authors: Blair ED, Blakemore JA Abstract Some years ago, we developed a value assessment process that was predicated on certain assumptions about how valuation might be influenced by drug development and marketing factors. Here, we discuss how our assumptions have held up particularly in light of regulatory and reimbursement changes. In addition, we assess how the relationship models derived from the value-assessment process have been substantiated by reviewing some recent cases of testing and stratification. PMID: 21888987 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5221303 Wed, 24 Aug 2011 04:00:00 +0100 5221303 http://www.medworm.com/index.php?rid=5221302&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21888988%26dopt%3DAbstract Authors: Frueh FW Abstract The focus of treating an individual patient is the identification of the individual's specific needs. The measurement of the patient's characteristics, such as blood pressure or body temperature, and also the measurement of biomarkers, such as cholesterol or hemoglobin A1C help to assess the health of the patient. The deeper the insights into the phenotypic and molecular characteristics of the patient, the better we are positioned to treat a patient. Increasingly, this assessment includes testing for certain pharmacologically relevant genetic variations (pharmacogenetics). Evaluating how the patient's genetic makeup combined with the patient's exposure to environmental influences could impact disease and treatment decisions is becoming the cornerstone of ... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5221302 Wed, 24 Aug 2011 04:00:00 +0100 5221302 http://www.medworm.com/index.php?rid=5221305&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21884816%26dopt%3DAbstract Authors: Pirmohamed M Abstract The subject area of pharmacogenetics, also known as pharmacogenomics, has a long history. Research in this area has led to fundamental discoveries, which have helped our understanding of the reasons why individuals differ in the way they handle drugs, and ultimately in the way they respond to drugs, either in terms of efficacy or toxicity. However, not much of this knowledge has been translated into clinical practice, most drug-gene associations that have some evidence of clinical validity have not progressed to clinical settings. Advances in genomics since 2000, including the ready availability of data on the variability of the human genome, have provided us with unprecedented opportunities to understand variability in drug responses, and the opportu... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5221305 Mon, 22 Aug 2011 04:00:00 +0100 5221305 http://www.medworm.com/index.php?rid=5180202&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21875682%26dopt%3DAbstract Authors: Bertolini F, Marighetti P, Martin-Padura I, Mancuso P, Hu-Lowe DD, Shaked Y, D'Onofrio A Abstract The anti-angiogenic class of drugs is one of the few where representatives have gained international approval for use in oncology clinical trials during the past decade. Most of the biological and clinical activity of the currently available generation of anti-angiogenic drugs targets vascular endothelial growth factor (VEGF) and its related pathways. However, the clinical benefits associated with the use of these drugs have, so far, been limited. There is, therefore, an unmet need for biomarkers that can be used to identify patients who are most likely to benefit therapeutically and also to predict the best schedule and dosage for these drugs. Here, we discuss some of the eme... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5180202 Sun, 21 Aug 2011 23:00:00 +0100 5180202 http://www.medworm.com/index.php?rid=5180190&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21875683%26dopt%3DAbstract Authors: Flynn AA Abstract Pharmacogenetics (PGx) is increasingly used as a way to target treatment to patients who are most likely to benefit. To date, PGx has shown clinical significance across a few applications but widespread use has been limited by the need for further technical, methodological and practical advances and for educating clinical researchers on the value of PGx. Here, I describe the current scope of PGx research, including recent contributions to prospective study design. A case study is included to demonstrate the limitations of current practice and to describe some practical steps for improving the chances of identifying genetic effects. Additionally, I describe some opportunities for the integration and application of disparate data sources in exploratory PGx ... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5180190 Sun, 21 Aug 2011 23:00:00 +0100 5180190 http://www.medworm.com/index.php?rid=5180185&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21875684%26dopt%3DAbstract Authors: Buckland GL Abstract The incidence of asthma is on the increase and calls for research are growing, yet asthma is a disease that scientists are still trying to come to grips with. Asthma research has relied heavily on animal use; however, in light of increasingly robust in vitro and computational models and the need to more fully incorporate the 'Three Rs' principles of Replacement, Reduction and Refinement, is it time to reassess the asthma research paradigm? Progress in non-animal research techniques is reaching a level where commitment and integration are necessary. Many scientists believe that progress in this field rests on linking disciplines to make research directly translatable from the bench to the clinic; a '21st-century' scientific approach to address age-old q... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5180185 Sun, 21 Aug 2011 23:00:00 +0100 5180185 http://www.medworm.com/index.php?rid=5180209&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21872676%26dopt%3DAbstract Authors: Manetti F Abstract LIM kinases (LIMK) exert their functions by recruiting many macromolecular partners that could contribute to modulate LIMK activity in a positive or negative manner. In addition to proteins that interact with LIMK in human or animal cells and tissues, recent data show that LIMK activity is also influenced by HIV-1 viral proteins. These results suggest new strategies for the treatment of HIV-1 infection, based on the inhibition of LIMK-mediated cofilin inactivation and consequent actin depolymerization. Further efforts are however required to unravel the mechanism by which the virus interferes with LIMK activity and with the right balance of actin remodeling. PMID: 21872676 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5180209 Wed, 17 Aug 2011 23:00:00 +0100 5180209 http://www.medworm.com/index.php?rid=5160221&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21864709%26dopt%3DAbstract Authors: Singh D, Kashyap A, Pandey RV, Saini KS Abstract The cytochrome P450 (CYP) enzymes, involved in the metabolism of therapeutic drugs, are the major determinants of the half-life of a drug. From a drug industry perspective, variability in drug response owing to CYP polymorphisms makes CYP profiling a commercially interesting option for diagnosis, prognosis and predicting response to drug treatment. Recent studies highlighting microRNA-mediated regulation of CYP genes represents a major advance in our understanding of variations in individual drug responses. Herein we review new perspectives on the molecular mechanisms of CYP regulation and genotyping technologies. Together, these developments present novel therapeutic opportunities and help to explain the integrated response... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5160221 Mon, 15 Aug 2011 23:00:00 +0100 5160221 http://www.medworm.com/index.php?rid=5160220&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21864710%26dopt%3DAbstract Authors: Bottegoni G, Favia AD, Recanatini M, Cavalli A Abstract Polypharmacology-based strategies are gaining increased attention as a novel approach to obtaining potentially innovative medicines for multifactorial diseases. However, some within the pharmaceutical community have resisted these strategies because they can be resource-hungry in the early stages of the drug discovery process. Here, we report on fragment-based and computational methods that might accelerate and optimize the discovery of multitarget drugs. In particular, we illustrate that fragment-based approaches can be particularly suited for polypharmacology, owing to the inherent promiscuous nature of fragments. In parallel, we explain how computer-assisted protocols can provide invaluable insights into how to unv... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5160220 Mon, 15 Aug 2011 23:00:00 +0100 5160220 http://www.medworm.com/index.php?rid=5160222&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21856438%26dopt%3DAbstract Authors: Minghetti P, Rocco P, Cilurzo F, Del Vecchio L, Locatelli F Abstract In the European Union (EU), the regulatory policy for biosimilars has enabled different biosimilar products to be marketed through an abridged application, which allows the applicant to submit a reduced dossier. Nevertheless, some manufacturers of biological products that share some characteristics with copies have opted for a full application; therefore, the number and extent of clinical studies required in these cases is increased. Here, we focus on a comparison of recombinant human erythropoietin medicinal products. We analyse and discuss clinical studies submitted to the European Medicines Agency that relate to available biosimilars and biological medicinal products that are authorised with a full dos... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5160222 Thu, 11 Aug 2011 23:00:00 +0100 5160222 http://www.medworm.com/index.php?rid=5142581&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21839183%26dopt%3DAbstract Authors: Kawasaki Y, Freire E Abstract Extremely high affinity and selectivity are two of the most sought-after properties of drug molecules. Selectivity has been difficult to achieve, especially for targets that belong to large families of structurally and functionally related proteins. There are essentially two ways by which selectivity can be improved during lead optimization: a chemical modification of the lead compound that improves the affinity towards the target to a higher extent than to off-target molecules; and a chemical modification that lowers the affinity of the lead compound towards off-target molecules. Maximal selectivity is achieved when both mechanisms can be combined synergistically. As we discuss here, analysis of several protease inhibitors that vary in a sing... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5142581 Mon, 01 Aug 2011 23:00:00 +0100 5142581 http://www.medworm.com/index.php?rid=5108516&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21824528%26dopt%3DAbstract Authors: Peng LH, Fung KP, Leung PC, Gao JQ New knowledge of the signal controls and activities of adult stem cells (ASCs) involved in wound repair have led to extensive investigation of the topical delivery of biomacromolecules and multipotent stem cells to injured tissues for scar-less regeneration. The transplantation of genetically recombinant stem cells, which have roles as both therapeutics and carriers for gene delivery to wound sites, represents an attractive strategy for wound treatment. Here, we compare viral and non-viral vectors and three-dimensional scaffold-based transfection strategies in terms of their biosafety, recombinant efficiency and influence on the differentiation of ASCs, to indicate the future direction of the application of recombinant ASCs in wound treatment... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5108516 Fri, 29 Jul 2011 23:00:00 +0100 5108516 http://www.medworm.com/index.php?rid=5108529&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21820527%26dopt%3DAbstract Authors: Wehling M Approximately a decade ago, translational medicine was invented both as a catchword and as a novel approach to improve success in drug development and ameliorate the low-output syndrome from collapsing pipelines. However, no major breakthroughs regarding rates of expensive late attrition or market approvals have been detected, and drug industry condensation continues to accelerate. Here, I discuss what went wrong: namely the fact that the concept does not exist apart from general claims and attributes, and no robust structures, such as toolboxes, algorithms, reproducible standards and procedures, and assessment tools have been developed and/or implemented. Translational medicine might be a clue to the survival of biomedical research, but it needs to be filled with sc... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5108529 Wed, 27 Jul 2011 23:00:00 +0100 5108529 http://www.medworm.com/index.php?rid=5108548&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21803170%26dopt%3DAbstract Authors: Mah JT, Low ES, Lee E SNPs can alter protein function and phenotype, leading to altered pharmacogenomic drug profiles. The exponential number of SNPs makes it impossible to perform wet laboratory experiments to determine the biological significance of each one. However, bioinformatics tools can be used to screen for potentially deleterious SNPs that might affect important drug targets before further investigation by wet laboratory techniques. As there are numerous web-based bioinformatics tools, much time and effort is needed to select the most appropriate tool to use. Here, we review state-of-the-art bioinformatics tools to help researchers analyze and select the most promising SNPs for drug discovery in the shortest time possible. PMID: 21803170 [PubMed - as supplied by ... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5108548 Fri, 22 Jul 2011 23:00:00 +0100 5108548 http://www.medworm.com/index.php?rid=5108535&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21810482%26dopt%3DAbstract Authors: Kalyaanamoorthy S, Chen YP Several technology-based strategies have been developed to address the significance of the two phases of drug discovery: hit identification and lead identification. Structure-based drug design (SBDD), a method that depends on possessing the knowledge of 3D structures of biological targets, is growing swiftly with the development of new technologies for searching potential ways to combat disease. The past decade has evidenced a threefold increase in the amount of software and tools in the online repositories. Herein, we review the in silico strategies and modules applied at the level of hit identification and confer the different challenges with possible solutions in enhancing the success rate of the 'hit-to-lead' phase that could eventually help the ... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5108535 Thu, 21 Jul 2011 23:00:00 +0100 5108535 http://www.medworm.com/index.php?rid=5108551&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21784168%26dopt%3DAbstract Authors: Anderson AC, Pollastri MP, Schiffer CA, Peet NP Drug resistance is problematic in microbial disease, viral disease and cancer. Understanding at the outset that resistance will impact the effectiveness of any new drug that is developed for these disease categories is imperative. In this Feature, we detail approaches that have been taken with selected drug targets to reduce the susceptibility of new drugs to resistance mechanisms. We will also define the concepts of robust drugs and resilient targets, and discuss how the design of robust drugs and the selection of resilient targets can lead to successful strategies for combating resistance. PMID: 21784168 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5108551 Mon, 18 Jul 2011 23:00:00 +0100 5108551 http://www.medworm.com/index.php?rid=5108598&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21782967%26dopt%3DAbstract Authors: Faller B, Ottaviani G, Ertl P, Berellini G, Collis A A set of diverse bioactive molecules, relevant from a medicinal chemistry viewpoint, was assembled and used to navigate the physicochemical property space of new and old, or traditional drugs against a larger set of 12,000 diverse bioactive small molecules. Most drugs on the market only occupy a fraction of the property space of the bioactive molecules, whereas new molecular entities (NMEs) approved since 2002 are moving away from this traditional drug space. In this new territory, semi-empirical rules derived from knowledge accumulated from historic, older molecules are not necessarily valid and different liabilities become more prominent. PMID: 21782967 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5108598 Sun, 17 Jul 2011 23:00:00 +0100 5108598 http://www.medworm.com/index.php?rid=5108592&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21782968%26dopt%3DAbstract Authors: Watkins F, Pendry B, Corcoran O, Sanchez-Medina A Three of the four major Anglo-Saxon collections reporting medicinal formulations in England from the 10th century, the Old English Herbarium, Bald's Leechbook and the Lacnunga, could contain leads and insights into new medicinal uses. Previous pharmacological studies of medicinal plants mentioned in Anglo-Saxon medical texts suggested that some were effective and led to the identification and isolation of natural compounds. For example, matricin from yarrow Achillea millefolium L., is a proprionic acid analogue that yields chamazulene carboxylic acid with cyclooxygenase-2 activity similar to that of ibuprofen. As we discuss here, multidisciplinary projects could further explore historical texts to discover additional plant meta... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5108592 Sun, 17 Jul 2011 23:00:00 +0100 5108592 http://www.medworm.com/index.php?rid=5108581&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21782969%26dopt%3DAbstract Authors: Hegde NR, Kaveri SV, Bayry J Despite remarkable progress in the control of infectious diseases through vaccination, better delivery systems have been poorly explored. There is renewed interest in the discovery of novel vaccines and adjuvants owing to emerging and reemerging diseases and the burden and complexity of chronic infectious diseases. Conversely, the need for rapid local, regional, mucosal or parenteral bioavailability has led to advances in delivery systems and devices. Here, we present recent developments in the field of non-invasive cutaneous delivery of vaccines for infectious diseases. Transdermal delivery using microneedles could revolutionize the way prophylactic interventions for infectious diseases are carried out in the future. PMID: 21782969 [PubMed - a... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5108581 Sun, 17 Jul 2011 23:00:00 +0100 5108581 http://www.medworm.com/index.php?rid=5108613&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21777691%26dopt%3DAbstract Authors: Núñez S, Venhorst J, Kruse CG In this review, we begin by introducing the basic principles of kinetics and thermodynamics of target-drug binding within the context of drug discovery. In addition, we present a meta-analysis of the recent literature describing the kinetic and thermodynamic resolution of successful clinical candidates with diverse mechanisms of action. We finish by discussing the best practices in the triage and chemical optimization towards clinical candidates with maximal in vivo efficacy devoid of adverse events. PMID: 21777691 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5108613 Mon, 11 Jul 2011 23:00:00 +0100 5108613 http://www.medworm.com/index.php?rid=5108658&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21745584%26dopt%3DAbstract Authors: Henriksen K, Christiansen C, Karsdal MA How do pharmaceutical companies find new uses for old or failed drugs? Is there a way to 'manage serendipity' at the very first stage of identifying compounds that could be developed into new drugs? Several approaches are now being pursued by various companies that are dedicated to drug repositioning cross a spectrum of technologies and scientific bases. Biochemical markers could provide significant shortcuts for drug development. In this review, we introduce drug repositioning, approaches to it and their associated challenges. We also highlight a novel class of serological biomarkers, namely neo-epitopes, which have proven successful in repositioning drugs in clinical settings. PMID: 21745584 [PubMed - as supplied by publisher] (Sou... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5108658 Fri, 01 Jul 2011 23:00:00 +0100 5108658 http://www.medworm.com/index.php?rid=5108654&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21745585%26dopt%3DAbstract Authors: Bunin BA, Ekins S PMID: 21745585 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5108654 Fri, 01 Jul 2011 23:00:00 +0100 5108654 http://www.medworm.com/index.php?rid=5108650&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21745586%26dopt%3DAbstract Authors: Dejonckheere E, Vandenbroucke RE, Libert C Deficient blood supply (ischemia) is a common consequence of some surgical procedures and certain pathologies. Once blood circulation is re-established (reperfusion), a complex series of events results in recruitment of inflammatory cells, rearrangement of the extracellular matrix and induction of cell death, which lead to organ dysfunction. Although ischemia/reperfusion (I/R) injury is an important cause of death, there is no effective therapy targeting the molecular mechanism of disease progression. Matrix metalloproteinases (MMPs), which are important regulators of many cellular activities, have a central role in disease progression after I/R injury, as suggested by numerous studies using MMP inhibitors or MMP-deficient mice. Here,... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5108650 Fri, 01 Jul 2011 23:00:00 +0100 5108650 http://www.medworm.com/index.php?rid=5108646&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21745587%26dopt%3DAbstract Authors: Hudson J, Orviska M Views on pharmacogenetics and gene therapy systematically differ across European countries. But despite a complex regulatory regime there is a balance of support, albeit laced with considerable uncertainty. PMID: 21745587 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5108646 Fri, 01 Jul 2011 23:00:00 +0100 5108646 http://www.medworm.com/index.php?rid=5108627&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21757026%26dopt%3DAbstract Authors: Baell JB PMID: 21757026 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5108627 Fri, 01 Jul 2011 23:00:00 +0100 5108627 http://www.medworm.com/index.php?rid=5012249&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21741495%26dopt%3DAbstract This article addresses the question about whether informed consent (IC) can be waived in Phase IV randomized observational drug studies (P4RODSs). To do this, it was first necessary to establish that the term P4RODS is a contradiction precisely because randomization necessarily makes a study 'interventional', hence P4RIDS. Once this was established we argued that, based on the right and the harm principles, universally waiving IC in P4RIDS is ethically unjustifiable. Looking into public health and the nature of equipotent and bioequivalent drugs were also insufficient rationale to justify circumstantial waiving of IC. We conclude that IC can never be waived in P4RIDS, although an opt-out procedure in minimal risk studies could be ethically acceptable. PMID: 21741495 [PubMed - as suppli... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5012249 Tue, 28 Jun 2011 23:00:00 +0100 5012249 http://www.medworm.com/index.php?rid=5012251&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21718797%26dopt%3DAbstract Authors: Edwards PJ PMID: 21718797 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5012251 Mon, 27 Jun 2011 23:00:00 +0100 5012251 http://www.medworm.com/index.php?rid=5012250&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21723955%26dopt%3DAbstract Authors: Holmes AM, Solari R, Holgate ST Asthma remains an area of considerable unmet medical need. Few new drugs have made it to the clinic during the past 50 years, with many that perform well in preclinical animal models of asthma, failing in humans owing to lack of safety and efficacy. The failure to translate promising drug candidates from animal models to humans has led to questions about the utility of in vivo studies and to demand for more predictive models and tools based on the latest technologies. Following a workshop with experts from academia and the pharmaceutical industry, we suggest here a disease modelling framework designed to better understand human asthma, and accelerate the development of safe and efficacious new asthma drugs that go beyond symptomatic relief. ... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5012250 Wed, 22 Jun 2011 23:00:00 +0100 5012250 http://www.medworm.com/index.php?rid=5012252&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21708279%26dopt%3DAbstract This article provides new insights into the different strategy paths or business models currently being implemented by Canadian biopharma companies. Through a case-study methodology, seven biopharma companies pertaining to three business models were analyzed, leading to a broad set of results emerging from the following areas: activity, business model and strategy; management and human resources; and R&D, technology and innovation strategy. The three business models represented were: model 1 (conventional biotech oriented to new drug development, radical innovation and search for discoveries); model 2 (development of a technology platform, usually in proteomics and bioinformatics); and model 3 (incremental innovation, with shorter and less risky development timelines). PMID: 217082... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5012252 Thu, 16 Jun 2011 23:00:00 +0100 5012252 http://www.medworm.com/index.php?rid=5012256&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21704182%26dopt%3DAbstract Authors: Zagozdzon R, Gallagher WM, Crown J The HER2 receptor is currently one of the flagship therapeutic targets in clinical oncology. Trastuzumab, an antibody targeting HER2, has become a foundation of care in women with HER2-positive breast cancer. However, many women with metastatic breast cancer do not respond to trastuzumab-based therapy. One possible source of trastuzumab resistance is the presence of truncated forms of HER2 in the tumor. Numerous studies suggest that detection of truncated HER2 in the tumor should result in modification of the classical therapeutic approach. Recent development of several promising compounds brings hope that a generation of novel therapeutic modalities against HER2-positive cancers will be delivered in the future. PMID: 21704182 [PubMed - a... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5012256 Wed, 15 Jun 2011 23:00:00 +0100 5012256 http://www.medworm.com/index.php?rid=5012254&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21704184%26dopt%3DAbstract Authors: Young RJ, Green DV, Luscombe CN, Hill AP Here, we review the performance of chromatographic hydrophobicity measurements in a data set of 100000 GlaxoSmithKline compounds, demonstrating the advantages of the method over octanol-water partitioning and highlighting new insights for drug discovery. The value of chromatographic measurements, versus other hydrophobicity estimates, was supported by improved relationships with solubility, permeation, cytochrome P450s, intrinsic clearance, hERG binding and promiscuity. We also observed marked differentiation of the relative influence of intrinsic and effective hydrophobicity. The summing of hydrophobicity values plus aromatic ring count [logD(pH7.4) (or logP)+#Ar], indicated a wide relevance for simplistic 'property forecast indices' i... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5012254 Wed, 15 Jun 2011 23:00:00 +0100 5012254 http://www.medworm.com/index.php?rid=5012255&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21704183%26dopt%3DAbstract Authors: Cheshire DR To an outsider, the exploration of thousands of molecules to find a small number of potential candidate drugs must appear enormously wasteful, but many medicinal chemists would defend this waste as unavoidable. Here, I provide evidence that suggests that modern medicinal chemists are overproductive in that they synthesise many more compounds than are required to achieve the objectives of the project. The difficulties encountered in finding the data for the analysis presented here prompted the design and implementation of a more rigorous approach to capture the essence of a medicinal chemistry program. The result, medicinal chemistry knowledge sharing (MeCKS), was designed to capture and communicate emerging issues and their solutions to the medicinal chemistry comm... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5012255 Tue, 14 Jun 2011 23:00:00 +0100 5012255 http://www.medworm.com/index.php?rid=5012253&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21704185%26dopt%3DAbstract Authors: Bennani YL Pharmaceutical companies must find a better way to increase their output of truly new drugs for the benefit of patients and for their business survival. Here, I highlight a general perspective from within pharmaceutical research as it pertains to research advances in chemistry, biology, pharmacology, pharmacokinetics and toxicology that, if well integrated, stands to put the industry on a productive path. In addition, I provide a complementary perspective on the corporate culture aspect of innovation. I also introduce a new concept, termed 'innovation ASAP' (iASAP; asking powerful questions, seeking the outliers, accepting defeat and populating astutely) and provide support for it using examples of several successful drugs. PMID: 21704185 [PubMed - as supplied b... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=5012253 Tue, 14 Jun 2011 23:00:00 +0100 5012253 http://www.medworm.com/index.php?rid=4969221&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21683153%26dopt%3DAbstract Authors: Teutonico D, Ponchel G The oral route is probably the preferred method for drug administration, owing to simplicity and positive safety aspects. Despite these advantages, this route of administration presents limitations relating to difficult absorption for some molecules, such as peptides, proteins and nucleic acids. Numerous approaches have been proposed to circumvent this drawback and improve the absorption of these active substances, but, today, these approaches offer an inefficient solution. Therefore, the use of patches for oral delivery was proposed, realized by using traditional techniques or microfabrication procedures. This review will focus on the rationale underlying the development of these dosage forms, critically discussing their performance and potential. P... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4969221 Sat, 11 Jun 2011 23:00:00 +0100 4969221 http://www.medworm.com/index.php?rid=4969222&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21664485%26dopt%3DAbstract Authors: Kwa FA, Balcerczyk A, Licciardi P, El-Osta A, Karagiannis TC Chromatin modifying compounds are emerging as the next generation of anticancer therapies. By altering gene expression they could be able to correct uncontrolled proliferation and, in certain cases, aberrant apoptotic pathways, which are hallmarks of malignant cells. The modulation of gene expression is regulated via chromatin remodelling processes that include DNA methylation and chromatin modifications. The identification of aberrant methylation of genes and dysregulated histone acetylation status in cancer cells provides a basis for novel epigenetic therapies. Currently available chromatin modifying agents, a group that includes DNA methyltransferase and histone deacetylase inhibitors, exert anticancer effects by ... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4969222 Tue, 31 May 2011 23:00:00 +0100 4969222 http://www.medworm.com/index.php?rid=4922426&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21658467%26dopt%3DAbstract Authors: Giordanetto F, Boström J, Tyrchan C A major remark made by observers relates to the focus of the pharmaceutical industry on 'me-too' drugs rather than 'first-in-class' drugs, the latter are considered to be 'truly' innovative medicines. Although the subject is heavily debated, chemists in project teams around the globe are routinely following up compounds from competitors. An important strategic consideration is the degree of chemical modification of the original structure required for success. Here, we present an analysis of the DiMasi and Faden set of first-in-class and follow-on drug pairs (n=74); showing that 70% of them are structurally very similar, meaning that they are characterized by minimal structural variations. This highlights the fact that even simple atomic var... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4922426 Thu, 26 May 2011 23:00:00 +0100 4922426 http://www.medworm.com/index.php?rid=4922427&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21635967%26dopt%3DAbstract Authors: Schwarz AJ, Becerra L, Upadhyay J, Anderson J, Baumgartner R, Coimbra A, Evelhoch J, Hargreaves R, Robertson B, Iyengar S, Tauscher J, Bleakman D, Borsook D There is increasing interest in the application of quantitative magnetic resonance imaging (MRI) methods to drug development, but as yet little standardization or best practice guidelines for its use in this context. Pharmaceutical trials are subject to regulatory constraints and sponsor company processes, including site qualification and expectations around study oversight, blinding, quality assurance and quality control (QA/QC), analysis and reporting of results. In this article, we review the processes on the sponsor side and also the procedures involved in data acquisition at the imaging site. We then propose summary r... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4922427 Mon, 23 May 2011 23:00:00 +0100 4922427 http://www.medworm.com/index.php?rid=4922431&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21624498%26dopt%3DAbstract Authors: Kell DB, Dobson PD, Oliver SG All cells necessarily contain tens, if not hundreds, of carriers for nutrients and intermediary metabolites, and the human genome codes for more than 1000 carriers of various kinds. Here, we illustrate using a typical literature example the widespread but erroneous nature of the assumption that the 'background' or 'passive' permeability to drugs occurs in the absence of carriers. Comparison of the rate of drug transport in natural versus artificial membranes shows discrepancies in absolute magnitudes of 100-fold or more, with the carrier-containing cells showing the greater permeability. Expression profiling data show exactly which carriers are expressed in which tissues. The recognition that drugs necessarily require carriers for uptake into cell... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4922431 Sun, 22 May 2011 23:00:00 +0100 4922431 http://www.medworm.com/index.php?rid=4922430&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21624499%26dopt%3DAbstract Authors: Yao L, Zhang Y, Li Y, Sanseau P, Agarwal P Electronic health records (EHRs) have increased in popularity in many countries. Pushed by legal mandates, EHR systems have seen substantial progress recently, including increasing adoption of standards, improved medical vocabularies and enhancements in technical infrastructure for data sharing across healthcare providers. Although the progress is directly beneficial to patient care in a hospital or clinical setting, it can also aid drug discovery. In this article, we review three specific applications of EHRs in a drug discovery context: finding novel relationships between diseases, re-evaluating drug usage and discovering phenotype-genotype associations. We believe that in the near future EHR systems and related databases will impac... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4922430 Sun, 22 May 2011 23:00:00 +0100 4922430 http://www.medworm.com/index.php?rid=4922428&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21624501%26dopt%3DAbstract Authors: Nicoletti F, Fagone P, Meroni P, McCubrey J, Bendtzen K Patients undergoing long-term highly active antiretroviral therapy treatment are probably at a higher risk of various HIV-related complications. Hyperactivation of The mammalian target of rapamycin (mTOR) has been found to contribute to dysregulated apoptosis and autophagy which determine CD4(+)-T-cell loss, impaired function of innate immunity and development of neurocognitive disorders. Dysregulated mTOR activation has also been shown to play a key part in the development of nephropathy and in the pathogenesis of HIV-associated malignancies. These studies strongly support a multifunctional key role for mTOR in the pathogenesis of HIV-related disorders and suggest that specific mTOR inhibitors could represent a novel app... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4922428 Sun, 22 May 2011 23:00:00 +0100 4922428 http://www.medworm.com/index.php?rid=4922429&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21624500%26dopt%3DAbstract Authors: Chen M, Vijay V, Shi Q, Liu Z, Fang H, Tong W Drug-induced liver injury (DILI) is a leading cause of drugs failing during clinical trials and being withdrawn from the market. Comparative analysis of drugs based on their DILI potential is an effective approach to discover key DILI mechanisms and risk factors. However, assessing the DILI potential of a drug is a challenge with no existing consensus methods. We proposed a systematic classification scheme using FDA-approved drug labeling to assess the DILI potential of drugs, which yielded a benchmark dataset with 287 drugs representing a wide range of therapeutic categories and daily dosage amounts. The method is transparent and reproducible with a potential to serve as a common practice to study the DILI of marketed drugs for su... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4922429 Thu, 19 May 2011 23:00:00 +0100 4922429 http://www.medworm.com/index.php?rid=4876636&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21601650%26dopt%3DAbstract Authors: McInnes C, Wyatt MD The Polo-like kinases (PLKs) have been investigated as oncology targets for several years; however, only recently have potent inhibitors been described. Here, we report on progress in the clinical validation of the PLKs as antitumor drug targets as well as recent understanding gained regarding their synergistic roles in the context of other molecular defects occurring in tumors. Also relevant to the development of PLK inhibitors as therapeutics are the putative roles of other members of this family as tumor suppressors. The resulting potential drawbacks of non-isoform selective compounds are presented. As an alternative approach to achieving PLK1 specificity, we discuss prospects for developing small molecule inhibitors of the crucial regulatory and subcell... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4876636 Thu, 12 May 2011 23:00:00 +0100 4876636 http://www.medworm.com/index.php?rid=4876635&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21601651%26dopt%3DAbstract Authors: Carey N, Marques CJ, Reik W DNA methylation is one of the most extensively studied, and one of the most stable, of all epigenetic modifications. Two drugs that target DNA methyltransferase enzymes are licensed for clinical use in oncology but relatively little attention has focused on the enzymatic pathways by which DNA methylation can be reversed. Recent breakthroughs have identified at least two classes of enzymes that can achieve functional reversal. This review discusses the significance of DNA demethylation in a range of human diseases, the candidate proteins that mediate the demethylation and the opportunities and challenges in targeting these candidates to develop new therapeutics. PMID: 21601651 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4876635 Thu, 12 May 2011 23:00:00 +0100 4876635 http://www.medworm.com/index.php?rid=4876633&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21605697%26dopt%3DAbstract Authors: Loughney D, Claus BL, Johnson SR With the financial and productivity challenges currently facing the pharmaceutical industry, there is constant pressure to justify resources and improve efficiency. With process-driven activities, understanding the contribution of these resources is reasonably straightforward. By contrast, measuring the contribution of knowledge workers is less obvious. Here, we present an impact-oriented approach to assessing the performance of an industrial computer-assisted drug design group. We discuss how these metrics are used to understand and optimize resource allocation in support of drug discovery programs. PMID: 21605697 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4876633 Thu, 12 May 2011 23:00:00 +0100 4876633 http://www.medworm.com/index.php?rid=4876632&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21605698%26dopt%3DAbstract We present here some of the basic requirements of multi-parameter drug design, the crucial role of informatics and examples of favorable practice. The most crucial of these best practices are the need for informaticians to align their technologies and insights directly to discovery projects and for all scientists in drug discovery to become more proficient in the use of in silico methods. PMID: 21605698 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4876632 Thu, 12 May 2011 23:00:00 +0100 4876632 http://www.medworm.com/index.php?rid=4876637&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21600301%26dopt%3DAbstract Authors: Betz UA Portfolio management in drug development has become a best practice in the pharmaceutical industry. By contrast, early on in the value chain - the discovery phase - portfolio management is still in its infancy. Nevertheless, owing to the attrition of R&D projects from phase to phase and the cost of capital involved, these early phases of drug discovery play a significant part for the overall cost of bringing new, innovative drugs to the market. This paper describes various approaches to manage a portfolio of projects in early-stage drug discovery and provides crucial factors that determine the success of such an approach. PMID: 21600301 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4876637 Tue, 10 May 2011 23:00:00 +0100 4876637 http://www.medworm.com/index.php?rid=4876634&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21601652%26dopt%3DAbstract Authors: Vanderwall DE, Yuen N, Al-Ansari M, Bailey J, Fram D, Green DV, Pickett S, Vitulli G, Luengo J, Almenoff JS Drug toxicity is a major cause of late-stage product attrition. During lead identification and optimization phases little information is typically available about which molecules might have safety concerns. A system was built linking chemistry, preclinical and human safety information, enabling scientists to lever safety knowledge across multiple disciplines. The system consists of a data warehouse with chemical structures and chemical and biological properties for ∼80000 compounds and tools to access and analyze clinical data, toxicology, in vitro pharmacology and drug metabolism data. Tapping into this safety knowledge enables rapid clinically focused risk assessment... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4876634 Tue, 10 May 2011 23:00:00 +0100 4876634 http://www.medworm.com/index.php?rid=4876639&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21570476%26dopt%3DAbstract Authors: Matheis K, Laurie D, Andriamandroso C, Arber N, Badimon L, Benain X, Bendjama K, Clavier I, Colman P, Firat H, Goepfert J, Hall S, Joos T, Kraus S, Kretschmer A, Merz M, Padro T, Planatscher H, Rossi A, Schneiderhan-Marra N, Schuppe-Koistinen I, Thomann P, Vidal JM, Molac B The importance of using translational safety biomarkers that can predict, detect and monitor drug-induced toxicity during human trials is becoming increasingly recognized. However, suitable processes to qualify biomarkers in clinical studies have not yet been established. There is a need to define clear scientific guidelines to link biomarkers to clinical processes and clinical endpoints. To help define the operational approach for the qualification of safety biomarkers the IMI SAFE-T consortium has establi... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4876639 Thu, 05 May 2011 23:00:00 +0100 4876639 http://www.medworm.com/index.php?rid=4876638&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21570477%26dopt%3DAbstract Authors: Hamm CA, Costa FF Future drug design and development relies on an ability to unravel the complexities of the epigenome in normal and disease states. Proper epigenetic regulation is essential for normal differentiation in embryogenesis and development. Conversely, abnormal epigenetic regulation is a feature of complex diseases, including cancer, diabetes, and heart disease. Epigenetic therapies hold promise for a wide range of biological applications, from cancer treatment to the development of induced pluripotent stem cells. The development of more specific and effective epigenetic therapies, however, requires a more complete understanding of epigenomic landscapes. Here, we give a historical overview of the epigenomic field and how epigenetic modifications can affect embryo de... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4876638 Wed, 04 May 2011 23:00:00 +0100 4876638 http://www.medworm.com/index.php?rid=4876640&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21570475%26dopt%3DAbstract Authors: De Temmerman ML, Rejman J, Demeester J, Irvine DJ, Gander B, De Smedt SC Subunit vaccines offer a safer alternative to traditional organism-based vaccines, but their immunogenicity is impaired. This hurdle might be overcome by the use of micro- and nanodelivery systems carrying the antigen(s). This review discusses the rationale for the use of particulate vaccines and provides an overview of antigen-delivery vehicles currently under investigation. It further highlights the cellular uptake, antigen processing and the presentation by antigen-presenting cells because these processes are partially governed by particle characteristics and eventually determine the immunological outcome. Finally, we address the attractive concept of concomitant delivery of antigens and immunopotentia... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4876640 Tue, 03 May 2011 23:00:00 +0100 4876640 http://www.medworm.com/index.php?rid=4823915&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21558017%26dopt%3DAbstract Authors: Cunningham MR PMID: 21558017 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4823915 Sat, 30 Apr 2011 23:00:00 +0100 4823915 http://www.medworm.com/index.php?rid=4768659&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21511051%26dopt%3DAbstract Authors: Kanwar JR, Kamalapuram SK, Kanwar RK Survivin, a prominent anticancer target, is ubiquitously expressed in a plethora of cancers and the evolving complexity in functional regulation of survivin is yet to be deciphered. However, pertaining to the recent studies, therapeutic modulation of survivin is critically regulated by interaction with prominent cell-signalling pathways [HIF-1α, HSP90, PI3K/AKT, mTOR, ERK, tumour suppressor genes (p53, PTEN), oncogenes (Bcl-2, Ras)] and a wide range of growth factors (EGFR, VEGF, among others). In our article we discuss, in detail, an overview of the recent developments in the pharmacological modulation of survivin via cell-signalling paradigms and antisurvivin therapeutics, along with an outlook on therapeutic management of survivin in dr... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4768659 Mon, 11 Apr 2011 23:00:00 +0100 4768659 http://www.medworm.com/index.php?rid=4768658&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21511052%26dopt%3DAbstract Authors: Choudhary S, Mathew M, Verma RS Immunotoxins are chimeric proteins consisting of a tumor-specific ligand (antibody, growth factor or peptide) linked to a modified toxin. These molecules bind to cell surface receptors and are subsequently internalized by endocytosis, resulting in cell death. Advances in protein engineering and phage display have enabled the selection of high-affinity targeting moieties. Denileukin diftitox is the only FDA-approved immunotoxin, although others such as BL22 are currently in different phases of development. This review elaborates the key findings of the important clinical studies relating to various chimeric toxins. PMID: 21511052 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4768658 Mon, 11 Apr 2011 23:00:00 +0100 4768658 http://www.medworm.com/index.php?rid=4768657&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21513815%26dopt%3DAbstract Authors: Nielsen PA, Andersson O, Hansen SH, Simonsen KB, Andersson G The endothelial blood-brain barrier (BBB) ensures an optimal environment for proper neural function in vertebrates; however, it also creates a major obstacle for the medical treatment of brain diseases. Despite significant progress in the development of various in vitro and in silico models for predicting BBB permeation, many challenges remain and, so far, no model is able to meet the early drug discovery demands of the industry for reliability and time and cost efficiency. Recently, it was found that the grasshopper (Locusta migratoria) brain barrier has similar functionality as the vertebrate BBB. The insect model can thus be used as a surrogate for the vertebrate BBB as it meets the demands required during the dru... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4768657 Mon, 11 Apr 2011 23:00:00 +0100 4768657 http://www.medworm.com/index.php?rid=4768660&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21504798%26dopt%3DAbstract Authors: Knutsen LJ This review provides an account of why more companies involved in drug discovery fail than succeed at releasing the creative energy of gifted scientists, whose invention of new drugs they rely upon to remain at the forefront of the biopharma industry. Initiatives aimed at improving output of new chemical entities often have the opposite effect from that intended and scientists become demotivated. Those with drive, vision and enthusiasm move to smaller companies to rediscover the spirit of discovery. Some executives fail to understand the psyche of researchers; an applied understanding of the intrinsic motivation of scientists would improve research performance. Entities that focus on smaller autonomous units and sound ethical values will discover the most innovative... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4768660 Fri, 08 Apr 2011 23:00:00 +0100 4768660 http://www.medworm.com/index.php?rid=4768663&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21477662%26dopt%3DAbstract Authors: Ghizzoni M, Haisma HJ, Maarsingh H, Dekker FJ Post-translational modifications of proteins, such as acetylation, are important regulatory events in eukaryotic cells. Reversible acetylations of histones and non-histone proteins regulate gene expression and protein activity. Acetylation levels of proteins are regulated by a dynamic equilibrium between acetylation by (histone) acetyltransferases and deacetylation by (histone) deacetylases. Alterations in this equilibrium can result in pathological states. Inflammation is a physiological response that, under certain conditions, turns into a disease. This review focuses on the crucial regulatory roles of protein acetylation in NF-κB-mediated inflammation and the potential applications of small-molecule inhibitors of acetylation fo... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4768663 Tue, 05 Apr 2011 23:00:00 +0100 4768663 http://www.medworm.com/index.php?rid=4768662&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21477663%26dopt%3DAbstract Authors: Pavan B, Paganetto G, Dalpiaz A Pharmacological studies of molecular mechanisms leading to the differentiation of neurons with retained dopaminergic fate and function suggest that such differentiation could be a form of treatment of neurodegenerative disorders, such as Parkinson's disease (PD) and schizophrenia. This goal could be achieved by neuronal replacement therapies based upon the manipulation of endogenous precursors in situ or by transplantation-based approaches. Signals conveyed by the adenylyl cyclase (AC) pathway appear to be crucial for the suitable differentiation of neurons. Here, we discuss dopamine (DA)-sensitive isoforms of AC as key cues for dopaminergic neuronal patterning and as interesting therapeutic targets for the induction of regenerative processes or... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4768662 Tue, 05 Apr 2011 23:00:00 +0100 4768662 http://www.medworm.com/index.php?rid=4768661&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21477664%26dopt%3DAbstract Authors: Schwarz AJ, Becerra L, Upadhyay J, Anderson J, Baumgartner R, Coimbra A, Evelhoch J, Hargreaves R, Robertson B, Iyengar S, Tauscher J, Bleakman D, Borsook D Functional magnetic resonance imaging (fMRI) experiments are more complex compared with standard radiological imaging, involving additional data streams and hardware along with complex analysis methods. Here, we propose guidelines based around mitigating risks associated with the complexities of the technique at the level of the individual imaging protocol, including workable and effective quality assurance/quality control procedures and rigorous, predefined, analysis pipelines. Our aim is to provide a framework for 'good imaging practice' (GIP), enabling these requirements to be addressed at an appropriate level of detail... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4768661 Mon, 04 Apr 2011 23:00:00 +0100 4768661 http://www.medworm.com/index.php?rid=4768664&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21458592%26dopt%3DAbstract Authors: Bondaryev TB, Verba OV PMID: 21458592 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4768664 Wed, 30 Mar 2011 23:00:00 +0100 4768664 http://www.medworm.com/index.php?rid=4664806&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21443967%26dopt%3DAbstract Authors: Walker SM, Davies BJ In addressing the challenges facing pharmaceutical R&D one question is frequently asked: how can continuous improvement, delivered through a Lean Sigma approach, be applied in a research environment to deliver overall benefit? We show that taking a value chain approach to improvement projects in a discovery research organization, initially focusing on the drug discovery project delivery level (i.e. middle layer of the value chain), provides the foundation for an effective continuous improvement programme. The adaptation of Lean Sigma principles and methodology, combined with the tenacity and creativity of scientists, enabled the delivery of significant improvements in challenging areas, including target selection, project decision making and the compou... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4664806 Fri, 25 Mar 2011 00:00:00 +0100 4664806 http://www.medworm.com/index.php?rid=4664808&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21440664%26dopt%3DAbstract Authors: Woollard PM, Mehta NA, Vamathevan JJ, Van Horn S, Bonde BK, Dow DJ PMID: 21440664 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4664808 Thu, 24 Mar 2011 00:00:00 +0100 4664808 http://www.medworm.com/index.php?rid=4664811&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21414418%26dopt%3DAbstract Authors: Teague SJ Which projects in the drug discovery field are most likely to be successful? In this article, I provide guidelines for answering this question by examining recent drug market entrants in detail, in particular their route of administration, trial design, novelty, therapeutic target and toxicities. I identify targets, trials and organizations as the key issues that are currently leading to the poor productivity in the pharmaceutical industry. Here, I outline some solutions and reasons for optimism, and suggest that the key determinants for success in drug discovery can be defined by studying recently launched drugs. PMID: 21414418 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4664811 Tue, 22 Mar 2011 00:00:00 +0100 4664811 http://www.medworm.com/index.php?rid=4664810&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21414419%26dopt%3DAbstract Authors: Yallapu MM, Jaggi M, Chauhan S Here, we provide a comprehensive insight into current advances in the use of nanogel-mediated chemotherapy for cancer treatment. Nanogels are composed of cross-linked three-dimensional polymer chain networks that are formed via covalent linkages or self-assembly processes. The porosity between the cross-linked networks of nanogels not only provides an ideal reservoir for loading drugs, oligonucleotides and imaging agents, but also protects them from environmental degradation and hazards. Here, we focus mainly on novel synthetic strategies and key considerations in the design of nanogel-based drug delivery systems for controlled and targeted cancer therapeutic applications. PMID: 21414419 [PubMed - as supplied by publisher] (Source: Drug Disco... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4664810 Tue, 22 Mar 2011 00:00:00 +0100 4664810 http://www.medworm.com/index.php?rid=4664809&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21439402%26dopt%3DAbstract Authors: Mayweg A, Hofer U, Schnider P, Agnetti F, Galley G, Mattei P, Lucas M, Boehm HJ Medicinal chemistry is a complex science that lies at the interface of many fields of research and at the very heart of drug discovery, with property relationships based on chemical structure at its core. It is clear that the effective capture and dissemination of medicinal chemistry knowledge and experience will be a key differentiator among pharmaceutical organizations and crucial for the future success in delivering effective and safe drug candidates. Therefore, in 2005 we developed ROCK (Roche medicinal chemistry knowledge), an internal user-friendly and peer-reviewed Wiki-like application to capture, browse and search tacit knowledge, key discoveries and property effects related to chemical st... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4664809 Tue, 22 Mar 2011 00:00:00 +0100 4664809 http://www.medworm.com/index.php?rid=4605293&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21402166%26dopt%3DAbstract Authors: Buchan NS, Rajpal DK, Webster Y, Alatorre C, Gudivada RC, Zheng C, Sanseau P, Koehler J The application of translational approaches (e.g. from bed to bench and back) is gaining momentum in the pharmaceutical industry. By utilizing the rapidly increasing volume of data at all phases of drug discovery, translational bioinformatics is poised to address some of the key challenges faced by the industry. Indeed, computational analysis of clinical data and patient records has informed decision-making in multiple aspects of drug discovery and development. Here, we review key examples of translational bioinformatics approaches to emphasize its potential to enhance the quality of drug discovery pipelines, reduce attrition rates and, ultimately, lead to more effective treatments. PMI... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4605293 Fri, 11 Mar 2011 00:00:00 +0100 4605293 http://www.medworm.com/index.php?rid=4605294&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21397037%26dopt%3DAbstract Authors: Erden Z, von Krogh G Clusters are groups of co-located and interconnected firms and institutions linked by commonalities in their strategies and complementarities in their activities and resources. There are several reasons for the geographical clustering of firms in the biopharmaceutical industry. This review unpacks some advantages and disadvantages of cluster participation, and proposes a new method to enable managers and researchers to identify clusters in the biopharmaceutical industry. PMID: 21397037 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4605294 Wed, 09 Mar 2011 00:00:00 +0100 4605294 http://www.medworm.com/index.php?rid=4605297&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21376135%26dopt%3DAbstract Authors: Vet NJ, de Hoog M, Tibboel D, de Wildt SN PMID: 21376135 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4605297 Tue, 01 Mar 2011 00:00:00 +0100 4605297 http://www.medworm.com/index.php?rid=4605296&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21376136%26dopt%3DAbstract Authors: Ekins S, Williams AJ, Krasowski MD, Freundlich JS One approach to speed up drug discovery is to examine new uses for existing approved drugs, so-called 'drug repositioning' or 'drug repurposing', which has become increasingly popular in recent years. Analysis of the literature reveals many examples of US Food and Drug Administration-approved drugs that are active against multiple targets (also termed promiscuity) that can also be used to therapeutic advantage for repositioning for other neglected and rare diseases. Using proof-of-principle examples, we suggest here that with current in silico technologies and databases of the structures and biological activities of chemical compounds (drugs) and related data, as well as close integration with in vitro screening data, improved ... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4605296 Tue, 01 Mar 2011 00:00:00 +0100 4605296 http://www.medworm.com/index.php?rid=4605295&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21376137%26dopt%3DAbstract Authors: Zhang YF, Tang XD, Gao JH, Fang DC, Yang SM Heparanase has been identified as a particularly important player in metastasis, and its expression directly correlates with the metastatic spread of various tumors. Ideal targets for immunotherapy are gene products that are silenced in normal tissues but overexpressed in cancer, and that are directly involved in tumor cell survival and progression. Metastasis is the culmination of neoplastic progression. The importance of the role of heparanase in metastasis implies that immune escape by downregulation of heparanase expression could reduce the mortality of the cancer. These characteristics of heparanase make it an attractive universal target for cancer immunotherapy. Here, we review current knowledge about heparanase and its involve... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4605295 Tue, 01 Mar 2011 00:00:00 +0100 4605295 http://www.medworm.com/index.php?rid=4543472&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21354326%26dopt%3DAbstract Authors: Giri S, Bader A Hepatotoxicity is often unpredictable in the early phase of drug discovery and leads to drug attrition in preclinical and clinical development. Here, we discuss the conventional preclinical liver models that do not mimic in vivo livers[1. AU: OK? Or would the use of the word sometimes be applicable here, before the word: do?]. We focus on key components such as new sources of hepatocyte-derived human stem cells, enhanced direct oxygenation, defined biocompatibility nanoscaffolds, organotypical cellular models, dynamic culture, and metabolite status inside and outside the cell for effective configuration for the development of a bioartificial liver (BAL) device to mimic the in vivo liver microenvironment. The potential for development of BAL devices could open u... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4543472 Thu, 24 Feb 2011 00:00:00 +0100 4543472 http://www.medworm.com/index.php?rid=4543471&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21354473%26dopt%3DAbstract Authors: Uitdehaag JC Given the stakes that industry and society have in making drug discovery more successful, we need to find solutions to the productivity gap with any method imaginable. In this light, the application of methods adopted from manufacturing, such as lean thinking, kaizen and six sigma, is imperative, because they represent a rational approach to productivity increase [1-3]. For those who have not (yet) heard of these methods: kaizen focuses on continuous improvement, six sigma on minimizing defects and variability. The lean method attempts to improve processes by focusing on customer value and eliminating any activity that does not contribute [1]. PMID: 21354473 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4543471 Thu, 24 Feb 2011 00:00:00 +0100 4543471 http://www.medworm.com/index.php?rid=4543474&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21349346%26dopt%3DAbstract Authors: Ripphausen P, Nisius B, Bajorath J Virtual screening is a much discussed topic in chemoinformatics and medicinal chemistry, and widely applied in pharmaceutical research. Here, we provide an in-depth analysis of currently available ligand-based virtual screening applications. We formulate a number of scientific quality criteria for prospective ligand-based virtual screens and analyze, in detail, the information provided by currently available peer-reviewed publications. The results presented herein provide a detailed view of the current state-of-the-art in this field and point at a number of problematic issues but also opportunities for further advances. PMID: 21349346 [PubMed - as supplied by publisher] (Source: Drug Discovery Today) Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4543474 Mon, 21 Feb 2011 00:00:00 +0100 4543474 http://www.medworm.com/index.php?rid=4543473&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21349347%26dopt%3DAbstract Authors: Koenig J R&D expenditures in the pharmaceutical industry have been increasing, whereas the number of new drugs has stagnated. The patent cliff and increasing pricing pressure from payers urge for greater effectiveness and efficiency throughout the industry, including R&D. Good processes are at the heart of increased efficiency, while carefully maintaining and expanding freedom for scientific exploration and innovation. Primary targets for process improvement are service platforms, administration and interactions with suppliers, which are already applicable during the early research phase for new products. Further down the value stream, developments such as quality by design promise increased flexibility in manufacturing processes on the condition of increased process u... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4543473 Mon, 21 Feb 2011 00:00:00 +0100 4543473 http://www.medworm.com/index.php?rid=4543477&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21333749%26dopt%3DAbstract Authors: Zhang YJ, Duan Y, Zheng XF The mTOR signaling pathway is dysregulated in ∼50% of all human malignancies and is a major cancer drug target. Although rapamycin analogs (rapalogs) have shown clinical efficacy in a subset of cancers, they do not fully exploit the antitumor potential of mTOR targeting. Because the mTOR kinase domain is important for rapamycin-sensitive and -insensitive functions, mTOR catalytic inhibitors have been developed recently as the second generation of anti-mTOR agents. Importantly, they have shown marked improvement of antitumor activity in vivo and in vitro. This review will detail the potential therapeutic value and issues of these novel antineoplastic agents, with emphasis placed on those that have already entered clinical trials. PMID: 21333749 ... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4543477 Thu, 17 Feb 2011 00:00:00 +0100 4543477 http://www.medworm.com/index.php?rid=4543476&cid=s_35525_13_f&fid=35525&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21335100%26dopt%3DAbstract Authors: Paolino D, Cosco D, Molinaro R, Celia C, Fresta M The blood-brain barrier (BBB) hinders the accumulation of active compounds in the central nervous system, thus decreasing their therapeutic effectiveness. To overcome this obstacle, interesting supramolecular nanodevices are herein considered. These systems have many advantages over the conventional formulations, such as having structures made up of biocompatible and biodegradable materials, the possibility of bypassing the BBB in a non-invasive manner (without structural modifications) and the possibility of being structurally modified to modulate the biopharmaceutical properties of the encapsulated compounds. Polymolecular (liposomes, niosomes, nanogels) and oligomolecular (cyclodextrins) devices have potential clinical appli... Drug Discovery Today journals http://www.medworm.com/rss/comments.php?id=4543476 Tue, 15 Feb 2011 00:00:00 +0100 4543476