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Photodynamic Therapy (PDT) is a clinical procedure, which utilize a photosensitive compound and light. This is a new modality of treatment for cancer, aged related macular degenerescence (AMD), psoriasis, arthritis, arterial restenosis, etc which exhibits efficiency, less traumatic effects, low recovery time and few co-lateral effects. The first officially approved drug for PDT by the Food and Drug Administration (EUA) is Photofrinâ, which is applied for cancer. A new generation drug for PDT, Visudyneâ was recently approved to treat AMD; its photoactive compound is BPDMA, a benzoporphyrin mono-acid derivative (chlorin-type molecule). A concise history, technical information and some drugs for PDT are reported.

Protective autoimmunity is the body's defense mechanism against destructive self-compounds such as those commonly associated with neurodegenerative disorders. Autoimmune disease and neurodegenerative disorders can thus be viewed as two extreme manifestations of the same process. Therefore, when designing therapy, it is important to avoid an approach that will cure the one by invoking the other. One way to stop, or at least slow down, the progression of neurodegeneration without risking development of an autoimmune disease is by boosting protective autoimmunity in a well-controlled way. Copolymer 1 (Cop-1), an approved drug for the treatment of multiple sclerosis, can be used as a treatment for autoimmune diseases and as a therapeutic vaccine for neurodegenerative diseases. We propose that the protective effect of Cop-1 vaccination is obtained through a well-controlled inflammatory reaction, and that the activity of Cop-1 in driving this reaction derives from its ability to serve as a ‘universal antigen' by weakly activating a wide spectrum of self-reactive T cells.

Objectives: This study examines the financial benefits that can accrue to drug developers from improvements in the drug development process. The effect on drug development costs from faster development, earlier decisions on project failures, and higher approval success rates are quantified. Data and Methods: The results from a recent study of research and development (R&D) costs for new drugs are used as a benchmark against which improvements in the discovery and development processes are simulated. The cost results in the benchmark study were based on a sample of 68 randomly selected investigational drugs from 10 pharmaceutical firms. Results: Simultaneous 25% reductions in phase lengths lower capitalised total cost per approved drug by 16%, or $US129 million; 50% reductions in time lower cost by 29%, or $US235 million. Earlier decisions to terminate research on drugs that will ultimately fail significantly reduce clinical costs. For example, shifting 5% of all clinical failures from phase III/regulatory review to phase I reduces out-of-pocket clinical costs by 5.5 to 7.1%; and capitalised clinical cost is lowered by 5.1 to 6.3%. If more productive discovery programmes or better preclinical screens increase success rates from 21.5% to one in three, firms can reduce capitalised total cost per approved drug by $US221 million to $US242 million. Conclusions: Whether faster development times, quicker termination decisions or higher success rates derive from public policy initiatives, better management, or new technologies, the impact on R&D costs can be substantial. Ultimately, the increased efficiency could result in more innovation and new therapies reaching patients sooner.

Tacrine (THA), the first clinically effective acetylcholinesterase (AChE) inhibitor and the first approved drug for the treatment of Alzheimer’s disease (AD), was withdrawn from the market due to its side effects, particularly its hepatotoxicity. Nowadays, THA serves as a valuable scaffold for the design of novel agents potentially applicable for AD treatment. One such compound, namely 7-methoxytacrine (7-MEOTA), exhibits an intriguing profile, having suppressed hepatotoxicity and concomitantly retaining AChE inhibition properties. Another interesting class of AChE inhibitors represents Huprines, designed by merging two fragments of the known AChE inhibitors—THA and (−)-huperzine A. Several members of this compound family are more potent human AChE inhibitors than the parent compounds. The most promising are so-called huprines X and Y. Here, we report the design, synthesis, biological evaluation, and in silico studies of 2-methoxyhuprine that amalgamates structural features of 7-MEOTA and huprine Y in one molecule.

Hepatocellular carcinoma (HCC) is often diagnosed in patients with advanced disease who are ineligible for curative surgical therapies. Sorafenib is the only approved drug for treating late stage HCC patients. However, patients rapidly become unresponsive due to inherent and acquired drug resistance. The promise of drug repurposing is that identifying new uses for existing drugs may reduce the high costs and time required for drug discovery. This is the first study employing connectivity mapping, a transcriptomics-based drug repurposing method, to identify drugs for use against sorafenib resistant (SR)-HCC via reversal of gene expression patterns. As a first step, we characterized gene expression signatures of different models of sorafenib resistance. We obtained gene expression signatures from an in vitro and an in vivo model of (SR)-HCC (publicly available microarray data) as well as from sorafenib-resistant (pool and clone) Huh7 cells generated in our lab. We determined the presence of the SR-HCC gene signatures across six patient-derived HCC gene expression datasets from the Gene Expression Omnibus (GEO) database using the nearest template method (FDR Citation Format: Kelly Regan, Ryan Reyes, Samson Jacob, Philip Payne, Tasneem Motiwala. Drug repurposing for hepatocellular carcinoma enabled via transcriptomics data from experimental models of sorafenib resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1562. doi:10.1158/1538-7445.AM2017-1562

For decades, US physicians could assume that any approved drug they prescribed would be available. However, since the turn of the 21st century, the United States now regularly experiences national drug shortages, defined by the US Food and Drug Administration (FDA) as situations in which the “total supply of all clinically interchangeable versions of an FDA-regulated drug is inadequate to meet the current or projected demand at the patient level.”1 The most challenging year so far was 2011, with 251 drug shortages, of which 73% were generic sterile injectable drugs, including many medications required to treat sepsis, cancer, and other life-threatening conditions.2 One of these drugs was norepinephrine, recommended in international guidelines as the primary vasopressor for treatment of septic shock.3 In this issue of JAMA, Vail and colleagues4 report a study examining whether the 2011 norepinephrine shortage was associated with changes in care and outcome.

Prostate cancer (PCa) ranks second in terms of cancer-related deaths among men in the United States. The primary cause is the emergence of castration resistant prostate cancer (CRPC) and subsequent metastasis and chemoresistance. There is no known cure for CRPC with a median survival rate of about 18 months. CRPC tumors are either intrinsically resistant or rapidly develop resistance to chemotherapy. Traditional approaches to drug discovery are highly specific to single targets (molecules and indications) and are time-consuming trial-and-error approaches, which are often ineffective and unsafe for humans. This approach has resulted in a dearth of novel drugs (currently less than thirty are approved each year) and the time and costs to develop and bring one to market are prohibitive ($2.6 billion in 2013). A solution is to repurpose existing drugs with known safety profiles that interact with therapeutic targets and can be rapidly deployed for use in mono and multi-drug therapies. However, there is a problem in consistently identifying high-confidence drugs for CRPC. Many computational tools have been developed for analyses of high-throughput genomics data, and these methods have led to improved understanding of cancer biology. However, despite the generation of enormous amounts of data, improved treatments and diagnostics take a long time, and a substantial amount of research is needed to translate a genomic discovery to the bedside. We have developed an integrated drug discovery/repurposing platform that analyzes compound-protein structural interaction signatures across multiple proteomes to determine drug behavior, in contrast to traditional single (or few) target approaches. The platform implements a modeling pipeline that generates an interaction between ‘all’ (currently 3,733) human approved drugs and ‘all’ (currently 48,278) proteins using our interactome docking with dynamics program to compute ~ 1 billion proteome-compound interactions. We have prospectively validated our predictions with in vitro and in vivo preclinical studies for more than 10 different diseases including immunological, metabolic, infectious and genetic indications. Recently, we applied our integrated drug discovery pipeline and found strong relationship between CRPC with breast cancer, hypertension and inflammation to repurpose human approved drugs for CRPC. We have newly identified an FDA approved drug with IC50 less than 10nM activity on LnCaP and C4-2 cell proliferation. The repurposed lead is tissue specific and its toxicity is very less compared to other chemotherapeutic agents used for cancer. Using our computational design approach of taking into account target and anti-target binding profile we are modifying and synthesizing new analogues of this potent anti-cancer human approved drug for immunomodulation without effecting anti-cancer potency. We conclude that compared to traditional single target drug discovery that is slow and error prone, interactome based drug discovery that takes into account cancer as a heterogeneous combination of other diseases will help bring anticancer drugs faster to the clinic. Citation Format: Joydeb Majumder, Travis Lantz, Jonathan Fine, Gaurav Chopra. Drug repurposing for castration resistant prostate cancer based on disease-disease relationships. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr A35.

Over a quarter of drugs that enter clinical development fail because they are ineffective. Growing insight into genes that influence human disease may affect how drug targets and indications are selected. However, there is little guidance about how much weight should be given to genetic evidence in making these key decisions. To answer this question, we investigated how well the current archive of genetic evidence predicts drug mechanisms. We found that, among well-studied indications, the proportion of drug mechanisms with direct genetic support increases significantly across the drug development pipeline, from 2.0% at the preclinical stage to 8.2% among mechanisms for approved drugs, and varies dramatically among disease areas. We estimate that selecting genetically supported targets could double the success rate in clinical development. Therefore, using the growing wealth of human genetic data to select the best targets and indications should have a measurable impact on the successful development of new drugs.

Alzheimer's disease (AD) is a disease that threatens the elderly. No efficient therapeutic method is currently available to combat AD. Drug repurposing has provided a new route for AD drug discovery, and medical genetics has shown potential in target-based drug repurposing. We compared AD-associated genes with approved drug targets and found that three are targeted by 23 approved drugs. Thus, these drugs may be used to treat AD according to the medical genetic information of the targets. In vitro and in vivo experiments revealed that four drugs, all of which are angiotensin-converting enzyme (ACE) inhibitors, had potential to treat AD.

Jak3, together with Jak1, is involved in signal transduction initiated by cytokines signaling through the common gamma chain which are important in immune homeostasis and immune pathologies. Based on genetic evidence Jak3 has been considered to be an attractive target for immunosuppression. The Jak inhibitor tofacitinib (CP-690,550) which is an approved drug for rheumatoid arthritis was originally introduced as a selective Jak3 inhibitor, however, it also inhibits Jak1 and Jak2. The search for new selective Jak3 inhibitors has yielded several compounds whose profiles will be reviewed here. Implications on Jak3 as a therapeutic target are also discussed.

I. INTRODUCTIONAs of 2002, the Federal Food and Drug Administration (FDA) had approved Neurontin, a drug developed by the pharmaceutical company Pfizer, for two uses, the treatment of epilepsy and pain related to shingles. 1 A staggering ninety-four percent of Neurontin prescriptions in the prior five years, however, were for other (non-FDA) approved uses.2 These other uses effectively tripled Medicaid's costs for the drug between 1998 and 2003.3 Insurance companies covered the off-label uses because they appeared in the Drugdex compendium, a federally authorized listing of drugs that includes evidence regarding the drug's effe ctiveness, clinical indications, and proper dosing.4 Drugdex included an additional forty-eight uses for Neurontin, ranging from bipolar disorder to the hiccups.5 Two other federally approved compendia existed at that time; one listed seven uses for Neuron tin while the other listed only one.6A 2003 Wall Street Journal article identified several concerns with Drugdex's off-label listing standards.7 First, Drugdex did not adhere to strict FDA protocols. Instead, it often relied on one-patient observations for evidence of efficacy, and sometimes even disregarded studies showing that certain off -label uses were ineffective.8 Second, Drugdex publisher Thomson ran "continuing medical education" seminars for the pharmaceutical industry. 9 Thomson's customers included companies whose drugs are listed in Drugdex, such as Pfizer, GlaxoSmithKline, and Eli Lilly. 10 Third, one of the six authors of the Neurontin section in Drugdex had a financial relationship with Parke -Davis, the company that initially manufactured Neurontin, which Pfizer subsequently acquired.11 This author received at least $75,000 for speaking engagements on the uses of Neurontin. 12 The article cited concerns with this compendium that spanned from personal conflicts of interest that could affect the interpretation of clinical evidence to corporate conflicts of interest that could produce an overall desire to please the pharmaceutical industry.13Concerns still exist about conflicts of interest, relationships with the pharmaceutical industry, and a lack of transparency in the creation of the drug compendia. These concerns are especially rampant in the field of oncology, which features one of the highest rates of prescriptions for off -label drugs.14 For instance, in 2006 the American Society of Clinical Oncol ogy estimated that fifty percent of cancer treatment drugs are prescribed off-label.15 Concerns about the integrity of the four federally authorized drug compendia that provide cancer treatment information are substantial. Problems such as a lack of transparency and a failure to employ systematic methods for determining which drug indications to include are particularly prevalent in the oncology compendia. 16 Furthermore, the steep costs of oncology drugs coupled with favorable reimbursement policies for off -label uses listed in the compendia provide added encouragement for drug manufacturers to go to great lengths to have multiple indications listed for their oncology drugs. 17Not only do these conflicts of interest have the potential to harm patients by condoning dangerous off-label uses, but they also provide a de facto safe harbor for pharmaceutical companies engaged in illegal off-label marketing when the federal government brings actions under the False Claims Act (FCA). 18 Pharmaceutical companies that influence off-label compendia listings can increase drug reimbursement while protecting themselves from false claims liability; federal prosecutors are unlikely to bring actions if the federal health insurance programs already are reimbursing for a drug use listed in the compendia.Part II of this Note explains the relevant legal and factual background for off - label drug approval and marketing under the Food, Drug, and Cosmetic Act (FDCA). It also details Medicare and Medicaid reimbursement for off -label uses and liability for off-label marketing under the False Claims Act. …

The unique morphological characteristics, capacity of manipulating host cell function and association with chronic inflammatory diseases represent the features of Chlamydia pneumoniae that have fascinated scientists and medical professionals for several decades.In this paper, the authors review the current status of attempts to discover and develop drugs against C. pneumoniae, including: the discovery of non-conventional antichlamydial agents, targeting chlamydial type 3 secretion system, approved drug repositioning and combination therapies. In addition, the authors discuss the recent advances in C. pneumoniae-related genomics and proteomics research and genetic manipulation technologies.Based on current knowledge, it is important for researchers to continue to focus on phenotypic assays on persistent infections. There should also be a careful evaluation of the physicochemical properties of the lead candidates and attempts toward more narrow-spectrum antibacterial agents. All these elements are important for successful lead generation. The recent advances in understanding C. pneumoniae biology and breakthroughs in genetic transformation are likely to improve the potential for identifying and validating therapeutic targets within both the bacterium and its host cells.

The high cost and slow pace of the pharmaceutical industry in bringing novel anti-cancer drugs for waiting patients indicates that the current business model for drug development needs innovation. We assumed that studying anticancer activities from approved disease modifying medicines might provide a possible way to lower the cost and speed up anti-cancer drug development. To test the idea, we studied the molecular mechanisms of anticancer effect of Total Glucosides of Paeony (TGP), a Chinese State Food and Drug Administration approved drug, in non-small cell lung cancer (NSCLC) cell-based systems. NSCLC is the leading cause of death from all cancers. Epidermal growth factor receptor (EGFR) is a major and effective molecular target of anti-NSCLC therapy because EGFR is over-expressed in 50-80 percent of NSCLC. We discovered that TGP inhibited phosphorylation of two most prominent members of EGFR family, EGFR and HER-2, in addition to suppressing EGFR and HER-2 expression in lung cancer cell lines tested. Subsequently, TGP showed expected anti-cellular proliferation, pro-apoptosis, and cell cycle arrest properties of EGFR inhibition in the cancer cell lines tested. Therefore, searching anti-EGFR and HER-2 activities among approved medicines might be a reasonable approach for novel anti-NSCLC drug discovery.

Systemic inflammation associated with diverse clinical conditions is a vital problem in critical care medicine with significant morbidity and mortality. In this chapter, we describe exclusively on systemic inflammation caused by sepsis, ischemia and reperfusion injury, and trauma hemorrhagic shock. Despite all efforts in the clinical arena treatment for these indications remain limited. The only FDA approved drug as a treatment for sepsis, Xigris (drotrecogin alfa [activated]) has recently been voluntarily withdrawn by Eli Lily. There is an unmet and urgent clinical need exists for novel therapies for these conditions. There are pathological similarities as well as differences exist among these conditions. Even though all three pathologies are initiated by different means, all leads to exaggerated inflammatory response and multi-organ failure. Therefore, therapies developed to dampen the exaggerated systemic inflammation could be beneficial for all three pathologies. Milk fat globule-epidermal growth factor-factor 8 (MFG-E8) is first identified as a bridging molecule that accelerated the interaction between apoptotic cells and phagocytes and facilitates the engulfment of apoptotic cells. We then, demonstrated that MFG-E8 plays a significant role in sepsis, ischemia and reperfusion injury, and trauma hemorrhagic shock. In this chapter, we will briefly review the different systemic inflammatory conditions and describe the key evidence for the role of MFG-E8 and highlight the notion that MFG-E8 could be developed as a potential therapeutic for these indications.

Since HCC is caused by the activation and aberrant expression of various proteins, development of any effective treatment requires targeting multiple signaling cascades simultaneously. Sorafenib, the first FDA approved drug in the United States for the treatment of HCC, was successful because it targets kinases of different signaling pathways at the same time. This approach has led to the development of a number of drugs, which target various growth factor receptors and other signaling pathways, which are currently undergoing clinical trials. In addition, owing to the success of miR-26a, different miRNAs are also being tested in clinical trials to treat HCC. Stem cell therapy is also being developed as a HCC therapy.

A new series of benzopolycyclic amines active as NMDA receptor antagonists were synthesized. Most of them exhibited increased activity compared with related analogues previously published. All the tested compounds were more potent than clinically approved amantadine and one of them displayed a lower IC50 value than memantine, an anti-Alzheimer’s approved drug.

Fungal infections constitute some of the most difficult clinical management problems encountered after solid organ transplantation. Although the predominant pathogens continue to be Candida species followed by Aspergillus species, emerging fungal pathogens including azole-resistant yeast, Fusarium, and dematiaceous fungi are becoming more significant. Identification of novel risk factors has expanded traditional concepts of the epidemiology of these infections. Optimal prophylaxis of fungal infections constitutes an area of active research. Diagnosis continues to be a challenge, but newer methods including antigen assays and panfungal or specific fungal polymerase chain reaction methodology are promising. Advances in therapy include lipid amphotericin formulations, newer azoles such as voriconazole, ravuconazole, and posaconazole, and echinocandins such as the recently approved drug caspofungin, as well as immunomodulatory therapy.

Beta-adrenergic receptor agonists have been used for tocolysis in the setting of preterm labor for more than three decades. One of these agents, ritodrine hydrochloride, is the only Federal Drug Administration (FDA) approved drug for the treatment of preterm labor. Despite their widespread use, only a few prospective randomized placebo-controlled trials have been performed. These agents have been shown to have more patients deliver beyond 48 hours after the onset of treatment as compared with controls, but have never shown a difference in neonatal outcomes. Because they are one of the few tocolytic agents to have been shown to make a difference when compared with controls, the beta-agonists are commonly used as the control groups in studies examining the efficacy of newer tocolytic agents. In general, agents such as nifedipine, magnesium sulfate, and atosiban have not been shown to be more efficacious than the beta-agonists. However, several studies have shown these agents to have less side effects and lower discontinuation rates than the beta-agonists.

The introduction of typical antipsychotics over six decades ago signaled an important milestone in psychiatry. However, second-generation antipsychotics ameliorated the positive symptoms of schizophrenia but displayed limited effectiveness for the negative and cognitive symptoms. In addition, while the newer antipsychotics produced fewer motor side effects, the atypical antipsychotics still induced weight gain and endocrinopathies. In recent years, a third generation of antipsychotics was identified. Aripiprazole was the first approved drug acting as a D2 partial agonist/functionally selective ligand. This review presents the state of the development of novel antipsychotic dopaminergic and non-dopaminergic agents, supported by an overview of the compounds evaluated under advanced preclinical and clinical development (e.g., cariprazine and brexpiprazole). In line with the recent trends in the development of modern atypical antipsychotics, we present our strategic development of long-chain arylpiperazine-derived quinoline- and isoquinoline-sulfonamide displaying a multireceptor binding profile and partial D2 receptor agonism.

1Region North America, Fresenius Kabi USA, Three Corporate Drive, Lake Zurich, IL 60047, USA 2Goodwin Procter LLP The New York Times Building 620 Eighth Avenue New York, NY 10018, USA *Author for correspondence: Tel.: +1 212 459 7015 Fax: +1 212 355 3333 E-mail: jhanish@goodwinprocter.com Two recent decisions of the Federal Circuit applied differing interpretations to specific fact patterns, leading to substantial ambiguity regarding whether research related to an already approved drug, or research that is not required by the US FDA to gain approval, is exempt from patent infringement. Despite the Federal Circuit’s differing interpretations, the Supreme Court is unlikely to straighten out the confusion in the foreseeable future, which likely will result in increased risk and uncertainty in the pharmaceutical industry.

There has been increased concern that the current "blockbuster" model of drug discovery and development practiced by "Big Pharma" are unsustainable in terms of cost (> $1 billion/approved drug) and time to market (10 - 15 years). The recent mergers and acquisitions (M&A), shuttering of internal research programs, closure of "redundant" sites of operations, senior management turnover and continued workforce reductions among the top 10 major pharmaceutical companies reflect draconian responses to reduce costs. However, the resultant exodus of intellectual capital, loss in motivation and momentum, and exit from early stage discovery programs by pharmaceutical companies has contributed to an "innovation deficit". Disease advocacy groups, investment communities and the government are calling for new innovative business models to address this deficit. In particular they are looking towards academia and clinical trials centers to catalyze new innovations in translational research. Indeed over the last decade many academic institutions have launched drug discovery centers largely comprising high-throughput screening (HTS) to accelerate "translational" research. A major impetus for this "open innovation" effort has been the National Institutes of Health (NIH) "Roadmap" and Molecular Libraries Initiative/Program (MLI/MLP), which is in its last year, and will be transitioned into the National Center for the Advancement of Translational Sciences (NCATS). With the end of Roadmap funding, general reduction in Federal government funding and its recent sequestration, academic drug discovery centers are being challenged to become selfsustaining, adding financial value, while remaining aligned with the missions of their respective academic non-profit institutions. We describe herein, a brief history of our bi-coastal Conrad Prebys Center for Chemical Genomics (Prebys Center) at the Sanford|Burnham Medical Research Institute (SBMRI), the key components of its infrastructure, core competencies of its fully integrated drug discovery expertise, best practices adopted in our day-to-day operations, and finally some of our current funding and collaboration and/or strategic alliance models for pre-competitive drug discovery with other academic/clinical partners, other governmental agencies, and with pharmaceutical and biotechnology companies.

The development of obesity is related to the regulation of energy intake, energy expenditure, and energy storage in the body. Increasing energy expenditure by inducing lipolysis followed by fat oxidation is one of the alternatives which could help to reverse this increasingly widespread condition. Currently, there is no approved drug targeting on stimulation of energy expenditure available. The use of herbal medicines has become a preferred alternative, supported by the classical consensus on the innocuity of herbal medicine vs synthetic drugs, something that often lacks a scientific basis (ban on Ephedra, for example). The inclusion of functional food in the daily diet has also been promoted although its efficacy requires further investigation. This review summarizes the results of recent work focused on the investigation of edible plant materials targeted at various important pathways related to stimulation of energy expenditure. The aim is to evaluate a number of plants that may be of interest for further studies because of their potential to provide novel lead compounds or functional foods which may be used to combat obesity, but require further studies to evaluate their antiobesity activity in humans.

In the first place, let us agree that the word poison does not exist, because in medicine use is made of the most violent poisons, which become, according as they are employed, most salutary remedies .—"THE COUNT OF MONTE CRISTO," ALEXANDRE DUMAS A TOXIC DRUG WAS A VALUABLE asset to the Count of Monte Cristo. In the novel of that name by Alexandre Dumas, the count uses a potentially toxic medication in a revenge plot against a public prosecutor who had sentenced him unjustly to life in prison. But to the modern drug industry, toxic medications are not assets at all but instead major liabilities. Toxicity prevents many compounds from being developed and approved. And it occasionally forces withdrawal of an approved drug from the market, a recent notable example being Merck's withdrawal of the arthritis drug Vioxx in 2004 owing to cardiovascular side effects. The drug industry expends considerable time and effort trying to ...

Motivation: The discovery of therapeutic targets is important for cancer treatment. Although dozens of targets have been used in cancer therapies, cancer remains a serious disease with a high mortality rate. Owing to the expansion of cancer-related data, we now have the opportunity to infer therapeutic targets using computational biology methods. Results: Here, we describe a method, termed anticancer activity enrichment analysis, used to determine genes that could be used as therapeutic targets. The results show that these genes have high likelihoods of being developed into clinical targets (>60%). Combined with gene expression data, we predicted 50 candidate targets for lung cancer, of which 19 of the top 20 genes are targeted by approved drugs or drugs used in clinical trials. A hexokinase family member, hexokinase domain-containing protein 1 (HKDC1), is the only one of the top 20 genes that has not been targeted by either an approved drug or one being used in clinical trials. Further investigations indicate that HKDC1 is a novel potential therapeutic target for lung cancer. Conclusion: We developed a protocol to identify potential therapeutic targets from heterogeneous data. We suggest that HKDC1 is a novel potential therapeutic target for lung cancer. Contact: huangjf@mail.kiz.ac.cn Supplementary Information: Supplementary data are available at Bioinformatics online.

Access to drugs for rare diseases varies considerably, not only in terms of which drugs are reimbursed but also which patients get access. Five-year-old Luc has been diagnosed with MPS II (Hunter’s Syndrome), a genetic disorder with progressive debilitating symptoms affecting the joints and major organs and, in some children, cognitive functioning. The good news is that there is an approved drug treatment that is effective in “slowing the progression of symptoms”; however, the pivotal clinical trials were only conducted with children over the age of five who had no cognitive impairment. While disease severity is hard to diagnose at an early age, his physician believes Luc has some cognitive impairment. Luc’s ability to get access to treatment depends on where he lives.

Pharmaceutical nanomaterials (NMs) encompass a wide variety of materials including drug nanoparticles (NPs), which can be amorphous or crystalline; or nanoparticulate drug delivery systems, such as micelles, microemulsions, liposomes, drug-polymer conjugates, and antibody-drug conjugates. These NMs are either transient or persistent—depending on whether the integrity of their structure and size is maintained until reaching the site of drug action. Examples of several approved drug products are included as pharmaceutical nanoparticulate systems along with a commentary on the current development issues and paradigms for various categories of NPs. This commentary discusses the preparation of nanoparticulate systems for commercial development, and the biopharmaceutical and pharmacokinetic advantages of these systems. A criterion of criticality is defined that incorporates the structure, in addition to size requirement of pharmaceutical NPs to identify systems that may require special development and regulatory considerations. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3867–3882, 2013

Hollow microcapsules capable of disintegrating in response to dual biological stimuli have been synthesized from two FDA approved drug molecules. The capsules fabricated from protamine and chondroitin sulphate disintegrate in the presence of either trypsin or hyaluronidase enzymes, which are documented to be simultaneously over-expressed under some pathological conditions.

A generic method describes advanced tailoring of polymer drug carriers based on polymer-block-peptides. Combinatorial means are used to select suitable peptide segments to specifically complex small-molecule drugs. The resulting specific drug formulation agents render insoluble drugs water-soluble and enable precise adjustment of drug-release profiles beyond established block-copolymer carriers. While proof of principle is shown on chlorin as a partially approved drug for photodynamic cancer therapy, the concept is universal and applies to a broad spectrum of difficult drugs.

Idiopathic pulmonary fibrosis (IPF) is one of the major challenges for respiratory medicine, since prognosis is particularly poor and few therapeutic options are available – in fact, at present the only approved drug is pirfenidone. Overcoming this challenge will be dependent on successful design and completion of randomized clinical trials. The last decade witnessed an unprecedented increase in quality and quantity of trials in IPF; however, most have been negative and potential obstacles have emerged. In particular, the choice of the best end point; that is, one that is both clinically meaningful and at the same time feasible, as well as the management of missing data still represent issues are not fully resolved. The increasingly competitive environment and the heterogeneity in approach by different regulatory agencies also need to be considered. During the next few years, more and more trials will be designed and completed in the hope of developing quicker and safer treatments to IPF patients.

A Risk Evaluation and Mitigation Strategies (REMS) program is a risk management plan that uses risk minimization strategies beyond approved drug labeling to manage serious risks associated with a medication.

Pharmaceutical products must undergo a battery of preclinical general toxicology studies to provide information regarding the safety of a potential new drug prior to initiation of the various clinical trials in humans, which are necessary before a molecule can become an approved drug. The order of the general toxicology studies begins with acute screening and progresses through longer durations of exposure up to as much as 1 year in length. In this chapter, numerous regional and global considerations regarding the influence rendered on the types of general toxicology study designs needed for regulatory submission will be discussed. Practical knowledge on how to integrate general toxicology assessments into the preclinical program is shared herein. By understanding the intricacies of the general toxicology plan, the hope is that it will facilitate smoother milestone transitions as the potential drug candidate moves forward in development.

We wished to determine the extent to which drugs used to treat HIV disease and its clinical manifestations are prescribed for conditions other than those listed on the U.S. Food and Drug Administration's approved drug label, how such "off-label" use varies by patient characteristics and type of HIV-related medical condition, and the extent to which physicians alter the way they treat HIV-related conditions because of reimbursement problems associated with off-label drug use. We surveyed 1,530 primary care providers for people with HIV disease between February and May 1993. A three-part survey instrument was used to obtain data on the drugs prescribed for the last three patients with HIV disease treated by the provider, the preferred choice of therapy for 32 specific HIV-related conditions, and the extent to which providers faced reimbursement problems regarding the use of drugs for off-label indications. Three drug compendia were used as cited sources of off-label drug uses. In all, 387 (32%) evaluable surveys were returned, yielding data on 1,148 patients. The majority (81%) of patients received at least one drug off-label, and almost half (40%) of all reported drug therapy was off-label. Most off-label drug use was for treatment and prevention of HIV-related opportunistic infections, which frequently represented the community standard of practice (e.g., trimethoprim/sulfamethoxazole for prevention of Pneumocystis carinii pneumonia), or the de facto standard of practice when no licensed therapies were available (e.g., drugs for treatment of Mycobacterium avium complex, MAC). More than 75% of off-label usage was cited in at least one of the three authoritative medical compendia. The use of drugs for off-label indications in HIV care is common and frequently represents community standards of care. Reliance on drug compendia for support of off-label drug use accounts for the majority of such uses, although many legitimate off-label uses may not be included because of compendia publication lag. The prevalence of off-label drug use in routine clinical practice and the development of newer and more costly drugs for treatment of HIV and its medical complications argues for the articulation of an explicit national reimbursement policy for off-label uses of prescription drugs so that medically appropriate therapies will be available to those with insurance in a rational, consistent way.

Drug action is the result of interaction with target sites, for both desired (pharmacological) and undesired (toxic) actions, modulated by the transfer processes, the pharmacokinetic variables of absorption, distribution, metabolism and elimination, by which the drug enters and leaves the body. There exist in general better relationships between effect and internal exposure, i.e. target concentrations, most frequently related to plasma concentration, than with the external dose offered. Drug metabolism and pharmacokinetic studies have essential roles to play in all stages of the research and development process, ideally being involved from the pre-nomination phase in drug discovery through to post-marketing surveillance. There occurs far more inter and intraspecies variation, in animals and humans, in the factors influencing the nature and extent of internal exposure, than in the sensitivity of drug targets and this pharmacokinetic variability is the cause of major problems in drug development. The origins of this may be termed “pharmacokinetic defects” and include, inter alia, poor absorption, very short or very long half-life, enzyme induction and high first pass effect. Failure to take these into consideration can cause expensive delay and/or failure during development and make an approved drug vulnerable in the marketplace. It will be argued that the thoughtful inclusion of new feedback loops will improve decision making at various stages during drug development. These should be based on quality metabolic and pharmacokinetic data and exploit the opportunities which the new biology offers for predicting metabolic pathways, anticipating kinetic variability and understanding mechanisms of toxicity. Such improved decision making should contribute to enhanced time- and cost-efficiency of development and ultimately lead to safer, more easily used, drugs.

The danger to the health of patients taking drugs) recently on the market after being approved by the Food and Drug Administration (FDA) is well documented. While there may be problems inherent to the drug itself, what is emerging as a more serious issue is possible “drug-drug interactions (DDIs)” between a newly approved drug and the drugs already being taken by the patient. Researchers at Stanford University recently noted that “DDIs cause nearly 74,000 emergency room visits and 195,000 hospitalizations in the USA.” This situation is not due to laxity by the FDA so much as it reflects the current state of health care. As Professor Barbara Evans explains, the FDA plays the role as “gatekeeper” in assessing the safety and efficacy of drugs, and other products, before they go on the market but as a matter of “realism” because “[t]he gate is intrinsically porous, and safety cannot be achieved by fighting that fact but rather by responding to it.” Indeed, concerns about the problem resulted in Congress extending the FDA’s ability to require manufacturers to conduct their own research studies to assess the safety and efficacy of the drugs they sell not just before seeking FDA approval but afterwards as well. Yet despite the awarding of these new powers, there is still no comprehensive mechanism in place to gather the information needed to protect or warn patients who receive these prescriptions. So although the FDAA gives the FDA the authority to require sponsors to conduct post-market clinical trials if it is aware of “a known serious risk related to the use of the drug involved” it also authorizes the FDA to “[a]ssess signals of serious risk related to the use of the drug.” This article proposes ways in which the FDA can use this power to promote and protect the public’s health. There have been numerous reports by or commissioned by the FDA or other government and private entities. The goal of this article is to gather this information, re-affirm why change is necessary, suggest two additional measures that so far have not been proposed, the addition of whistleblower protection and greater use of electronic medical and pharmaceutical records, and explain why the FDA could make these changes itself rather than await action from Congress. It is the claim of this article that although the phenomena of the emergence of post- approval hazards is inevitable, the FDA can do far more to protect patients by using its legal authority to require post- market surveillance for all, not some, newly approved products. Moreover, it can increase the likelihood of relevant information coming to its attention sooner by targeting the specific groups who are likely to have early knowledge of harms caused by new drugs: the sponsors, health care providers, patients, and the FDA itself.

221 Background: To our knowledge, no study has examined adherence to antiemetic guidelines with soon-to-be-approved or newly approved chemotherapy agents. In 2015, the Food and Drug Administration approved 18 cancer drugs, underscoring the timeliness of this topic. Here, we hypothesize that patients prescribed new drugs are at risk for poor guideline adherence, and we report on antiemetic prescribing practices and outcomes with TAS-102, a recently approved drug for metastatic colorectal cancer. Methods: This study focused on all patients prescribed TAS-102 in 2015 at the Mayo Clinic in Rochester, MN for compassionate use or routine care within 3 months of FDA approval. First-cycle antiemetic prophylaxis was examined for adherence to National Comprehensive Cancer Network Guidelines, version 1.2015, for chemotherapy of low emetogenic potential based on TAS-102 phase 3 data. Results: Among 44 patients, 28 (64%) had nausea and vomiting with prior chemotherapy. With the first cycle of TAS-102, 25 (57%) were prescribed antiemetics in a guideline-adherent manner; 15 (34%) in a non-guideline-adherent/more aggressive manner; and 4 (9%) in a non-guideline-adherent/less aggressive manner. In guideline-adherent patients, rates of nausea and vomiting were 52% and 24%, respectively, with one patient requiring an unscheduled clinic visit and another an emergency department visit and hospital admission - all for nausea and vomiting. In non-guideline-adherent/more aggressive patients (who received more prophylaxis than called for), these rates were 33% and 27%, respectively, with one patient requiring a clinic visit and emergency department visit and another an emergency department visit. In non-guideline-adherent/less aggressive patients, no nausea or vomiting was reported. Conclusions: Poor adherence to antiemetic guidelines occurred often. However, because adherence was not associated with better control of nausea and vomiting, clinical judgment should complement guidelines in patients about to receive new cancer drugs, particularly with drugs of low emetogenic potential and also in patients with a history of chemotherapy-induced nausea and vomiting.

A newly approved drug to treat Duchenne muscular dystrophy seems likely to be used by most US neurologists, even though its benefit has yet to be proved, treatment costs $300 000 (£230 000; €270 000) a year, and the head of the Food and Drug Administration has said that the main clinical study on which it rests “should probably be retracted by its authors.” Eteplirsen, made by Sarepta Therapeutics and marketed as Exondys 51, was approved in the United States this month after a long internal battle between FDA scientists who doubted its efficacy and the director of the FDA’s Center for Drug Evaluation and Research, Janet Woodcock. The details of this dispute, which led to formal complaints against Woodcock from several top agency scientists, are laid out in an unusually frank report by the FDA’s commissioner, Robert Califf.1 The drug’s approval has been widely interpreted as a victory for Woodcock’s vision of an FDA that is more responsive to patients’ demands, especially those with …

This article provides pharmacists and other health professionals with a practical guide to using FDA's Orange Book, the authoritative source for FDA approved products and their respective therapeutic equivalence ratings. Copyright © 1995 by W.B. Saunders Company

Basic scientific research generates knowledge that has intrinsic value which is independent of future applications. Basic research may also lead to practical benefits, such as a new drug or diagnostic method. Building on our previous study of basic biomedical and biological researchers at Harvard, we present findings from a new survey of similar scientists from three countries. The goal of this study was to design policies to enhance both the public health potential and the work satisfaction and test scientists’ attitudes towards these factors. The present survey asked about the scientists’ motivations, goals and perspectives along with their attitudes concerning policies designed to increase both the practical (i.e. public health) benefits of basic research as well as their own personal satisfaction. Close to 900 basic investigators responded to the survey; results corroborate the main findings from the previous survey of Harvard scientists. In addition, we find that most bioscientists disfavor present policies that require a discussion of the public health potential of their proposals in grants but generally favor softer policies aimed at increasing the quality of work and the potential practical benefits of basic research. In particular, bioscientists are generally supportive of those policies entailing the organization of more meetings between scientists and the general public, the organization of more academic discussion about the role of scientists in the society, and the implementation of a “basic bibliography” for each new approved drug.

Venetoclax is a BH3 mimetic approved for treating chronic lymphocytic leukemia. Cancer cells are resistant to apoptosis but "primed for death" by elevated BCL-2, which binds to pro-apoptotic proteins and holds them in check. Venetoclax releases this antagonism and is the first approved drug to target a protein-protein interaction.

e15604Background: Hepatocellular carcinoma (HCC) is the fourth commonest solid cancer in males in Saudi Arabia. Sorafenib is the only FDA approved drug for advanced unresectable HCC. In this study,...

Fragment screening, an emerging approach for hit finding in drug discovery, has recently been proven effective by its first approved drug, vemurafenib, for cancer treatment. Techniques such as nuclear magnetic resonance, surface plasmon resonance, and isothemal titration calorimetry, with their own pros and cons, have been employed for screening fragment libraries. As an alternative approach, screening based on high-performance liquid chromatography separation has been developed. In this work, we present weak affinity LC/MS as a method to screen fragments under high-throughput conditions. Affinity-based capillary columns with immobilized thrombin were used to screen a collection of 590 compounds from a fragment library. The collection was divided into 11 mixtures (each containing 35 to 65 fragments) and screened by MS detection. The primary screening was performed in4 h (corresponding to3500 fragments per day). Thirty hits were defined, which subsequently entered a secondary screening using an active site-blocked thrombin column for confirmation of specificity. One hit showed selective binding to thrombin with an estimated dissociation constant (K (D)) in the 0.1 mM range. This study shows that affinity LC/MS is characterized by high throughput, ease of operation, and low consumption of target and fragments, and therefore it promises to be a valuable method for fragment screening.

Neurodegenerative diseases affect the lives of millions of patients and their families. Due to the complexity of these diseases and our limited understanding of their pathogenesis, the design of therapeutic agents that can effectively treat these diseases has been challenging. Huntington disease (HD) is one of several neurological disorders with few therapeutic options. HD, like numerous other neurodegenerative diseases, involves extensive neuronal cell loss. One potential strategy to combat HD and other neurodegenerative disorders is to intervene in the execution of neuronal cell death. Inhibiting neuronal cell death pathways may slow the development of neurodegeneration. However, discovering small molecule inhibitors of neuronal cell death remains a significant challenge. Here, we review candidate therapeutic targets controlling cell death mechanisms that have been the focus of research in HD, as well as an emerging strategy that has been applied to developing small molecule inhibitors—fragment-based drug discovery (FBDD). FBDD has been successfully used in both industry and academia to identify selective and potent small molecule inhibitors, with a focus on challenging proteins that are not amenable to traditional high-throughput screening approaches. FBDD has been used to generate potent leads, pre-clinical candidates, and has led to the development of an FDA approved drug. This approach can be valuable for identifying modulators of cell-death-regulating proteins; such compounds may prove to be the key to halting the progression of HD and other neurodegenerative disorders.

In a recent study, a currently approved drug, bexarotene, rapidly cleared s-amyloid plaques in a murine model of Alzheimer's disease. The rate of clearance was dramatic, although plaques returned over time.

Background The FDA approved drug Efavirenz is a Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) successful first line drug of choice in Highly Active Anti-Retroviral Therapy (HAART) for treatment of HIV and AIDS. It is poorly water soluble drug (10 g/ml) with 40-45% of bioavailability and administered as high doses 600-800 mg/day. Increase in solubility can enhance bioavailability; providing reduction of dose, resistance and harmful side effects.

Drug shortages and discontinuations can present a dangerous if not deadly scenario for our pediatric patients. The inability of a provider to prescribe the indicated and approved drug for an illness often can adversely affect therapy, compromise or delay medical procedures, and result in medication errors and less than therapeutic treatment outcome (Jensen, Kimzey, & Saliba, 2005). A survey of 311 pharmacy experts representing 228 hospitals and other health care sites over a 6-month period showed that 89% experienced shortages that could have caused a medication safety issue or error in patient care, and 80% experienced shortages resulting in a delay or cancellation of a patient care intervention. In addition, 98% experienced shortages resulting in increased costs. Providers pay an average of 11%more for shortage products. If these products cannot be obtained, providers can turn to generic medications (if available) or more costly therapeutic substitutes. This could result in at least $200 million annually, not including indirect costs, such as the added labor needed to manage shortages and secure alternative supplies (Cherici et al., 2011).

Trypanosoma brucei is a parasite that causes African sleeping sickness in humans and nagana in livestock and is transmitted by the tsetse fly. There is an urgent need for the development of new drugs against African trypanosomiasis due to the lack of vaccines and effective drugs. Orlistat (also called tetrahydrolipstatin or THL) is an FDA-approved antiobesity drug targeting primarily the pancreatic and gastric lipases within the gastrointestinal tract. It shows potential activities against tumors, mycobacteria, and parasites. Herein, we report the synthesis and evaluation of an expanded set of orlistat-like compounds, some of which showed highly potent trypanocidal activities in both the bloodstream form (BSF) and the procyclic form (PCF) of T. brucei. Subsequent in situ parasite based proteome profiling was carried out to elucidate potential cellular targets of the drug in both forms. Some newly identified targets were further validated by the labeling of recombinantly expressed enzymes in Escherichia coli lysates. Bioimaging experiments with a selected compound were carried out to study the cellular uptake of the drug in T. brucei. Results indicated that orlistat is much more efficiently taken up by the BSF than the PCF of T. brucei and has clear effects on the morphology of mitochondria, glycosides, and the endoplasmic reticulum in both BSF and PCF cells. These results support specific effects of orlistat on these organelles and correlate well with our in situ proteome profiling. Given the economic challenges of de novo drug development for neglected diseases, we hope that our findings will stimulate further research towards the conversion of orlistat-like compounds into new trypanocidal drugs.

Of great interest in recent years has been computationally predicting the novel polypharmacology of drug molecules. Here, we applied an "induced-fit" protocol to improve the homology models of 5-HT(2A) receptor, and we assessed the quality of these models in retrospective virtual screening. Subsequently, we computationally screened the FDA approved drug molecules against the best induced-fit 5-HT(2A) models and chose six top scoring hits for experimental assays. Surprisingly, one well-known kinase inhibitor, sorafenib, has shown unexpected promiscuous 5-HTRs binding affinities, K(i) = 1959, 56, and 417 nM against 5-HT(2A), 5-HT(2B), and 5-HT(2C), respectively. Our preliminary SAR exploration supports the predicted binding mode and further suggests sorafenib to be a novel lead compound for 5HTR ligand discovery. Although it has been well-known that sorafenib produces anticancer effects through targeting multiple kinases, carefully designed experimental studies are desirable to fully understand whether its "off-target" 5-HTR binding activities contribute to its therapeutic efficacy or otherwise undesirable side effects.

Amyotrophic Lateral Sclerosis (ALS) is a progressive and disabling neurodegenerative disorder characterized by upper and lower motor neuron loss, leading to respiratory insufficiency and death after 3-5 years. Riluzole is currently the only FDA approved drug for ALS, but it has only modest effects on survival. The majority of ALS cases are sporadic and probably associated to a multifactorial etiology. With the completion of genome sequencing in humans and model organisms, together with the advent of DNA microarray technology, the transcriptional cascades and networks underlying neurodegeneration in ALS are being elucidated providing new potential pharmacological targets. The main challenge now is the effective screening of the myriad of targets to identify those with the most therapeutic utility. The present review will illustrate how the identification, prioritization and validation of preclinical therapeutics can be achieved through genomic analysis of critical pathways and networks deregulated in ALS pathology.