Sample records for drug development efforts
-
Federal Register 2010, 2011, 2012, 2013, 2014
2013-07-22
... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2013-N-0001] Synergizing Efforts in Standards Development for Cellular Therapies and Regenerative Medicine Products; Public Workshop AGENCY: Food and Drug Administration, HHS. ACTION: Notice of public workshop. The Food and Drug Administration (FDA), Center for...
-
Has Malaysia's antidrug effort been effective?
Scorzelli, J F
1992-01-01
It is a common belief that a massive effort in law enforcement, preventive education and rehabilitation will result in the elimination of a country's drug problem. Based on this premise. Malaysia in 1983 implemented such a multifaceted anti-drug strategy, and the results of a 1987 study by the author suggested that Malaysia's effort had begun to contribute to a steady decrease in the number of identified drug abusers. Although the number of drug-addicted individuals declined, the country's recidivism rates were still high. Because of this high relapse rate, Malaysia expanded their rehabilitation effort and developed a community transition program. In order to determine the impact of these changes on the country's battle against drug abuse, a follow-up study was conducted in 1990. The results of this study did not clearly demonstrate that the Malaysian effort had been successful in eliminating the problem of drug abuse, and raised some questions concerning the effectiveness of the country's drug treatment programs.
-
Interventions to improve the use of antimalarials in south-east Asia: an overview.
Gomes, M.; Wayling, S.; Pang, L.
1998-01-01
There are few drugs for malaria, and those which are available for use are subject to rapid development of resistance. Curiously, little effort has been made to improve drug use in malaria-endemic countries and to assess the benefits of such improvements. Advances can be made in public understanding of the value of ingesting a full regimen of antimalarials, in order to achieve complete cure, and in improving simple technologies (blister packaging) to achieve the same result. Better efforts can be made to reduce the availability of fake or substandard drugs in the marketplace. In this article, we describe the outcome of a concerted effort to improve drug compliance and drug quality in an area of multidrug resistance for malaria. These research efforts, guided by the Task Force for Improved Use of Antimalarials, characterized the problems in drug compliance in South-East Asia, and developed interventions to improve drug use in the various countries. Interventions involved drug packaging, public information campaigns, and assessments of drug quality. Results show that blister packaging worked best to improve drug compliance and that the increased cost of packaged medication did not limit its use. Drug quality was a major problem in unregulated countries and should be improved. PMID:9763718
-
Interventions to improve the use of antimalarials in south-east Asia: an overview.
Gomes, M; Wayling, S; Pang, L
1998-01-01
There are few drugs for malaria, and those which are available for use are subject to rapid development of resistance. Curiously, little effort has been made to improve drug use in malaria-endemic countries and to assess the benefits of such improvements. Advances can be made in public understanding of the value of ingesting a full regimen of antimalarials, in order to achieve complete cure, and in improving simple technologies (blister packaging) to achieve the same result. Better efforts can be made to reduce the availability of fake or substandard drugs in the marketplace. In this article, we describe the outcome of a concerted effort to improve drug compliance and drug quality in an area of multidrug resistance for malaria. These research efforts, guided by the Task Force for Improved Use of Antimalarials, characterized the problems in drug compliance in South-East Asia, and developed interventions to improve drug use in the various countries. Interventions involved drug packaging, public information campaigns, and assessments of drug quality. Results show that blister packaging worked best to improve drug compliance and that the increased cost of packaged medication did not limit its use. Drug quality was a major problem in unregulated countries and should be improved.
-
Hit Generation in TB Drug Discovery: From Genome to Granuloma
2018-01-01
Current tuberculosis (TB) drug development efforts are not sufficient to end the global TB epidemic. Recent efforts have focused on the development of whole-cell screening assays because biochemical, target-based inhibitor screens during the last two decades have not delivered new TB drugs. Mycobacterium tuberculosis (Mtb), the causative agent of TB, encounters diverse microenvironments and can be found in a variety of metabolic states in the human host. Due to the complexity and heterogeneity of Mtb infection, no single model can fully recapitulate the in vivo conditions in which Mtb is found in TB patients, and there is no single “standard” screening condition to generate hit compounds for TB drug development. However, current screening assays have become more sophisticated as researchers attempt to mirror the complexity of TB disease in the laboratory. In this review, we describe efforts using surrogates and engineered strains of Mtb to focus screens on specific targets. We explain model culture systems ranging from carbon starvation to hypoxia, and combinations thereof, designed to represent the microenvironment which Mtb encounters in the human body. We outline ongoing efforts to model Mtb infection in the lung granuloma. We assess these different models, their ability to generate hit compounds, and needs for further TB drug development, to provide direction for future TB drug discovery. PMID:29384369
-
Rational drug design paradigms: the odyssey for designing better drugs.
Kellici, Tahsin; Ntountaniotis, Dimitrios; Vrontaki, Eleni; Liapakis, George; Moutevelis-Minakakis, Panagiota; Kokotos, George; Hadjikakou, Sotiris; Tzakos, Andreas G; Afantitis, Antreas; Melagraki, Georgia; Bryant, Sharon; Langer, Thierry; Di Marzo, Vincenzo; Mavromoustakos, Thomas
2015-01-01
Due to the time and effort requirements for the development of a new drug, and the high attrition rates associated with this developmental process, there is an intense effort by academic and industrial researchers to find novel ways for more effective drug development schemes. The first step in the discovery process of a new drug is the identification of the lead compound. The modern research tendency is to avoid the synthesis of new molecules based on chemical intuition, which is time and cost consuming, and instead to apply in silico rational drug design. This approach reduces the consumables and human personnel involved in the initial steps of the drug design. In this review real examples from our research activity aiming to discover new leads will be given for various dire warnings diseases. There is no recipe to follow for discovering new leads. The strategy to be followed depends on the knowledge of the studied system and the experience of the researchers. The described examples constitute successful and unsuccessful efforts and reflect the reality which medicinal chemists have to face in drug design and development. The drug stability is also discussed in both organic molecules and metallotherapeutics. This is an important issue in drug discovery as drug metabolism in the body can lead to various toxic and undesired molecules.
-
Marinopyrroles: Unique Drug Discoveries Based on Marine Natural Products.
Li, Rongshi
2016-01-01
Natural products provide a successful supply of new chemical entities (NCEs) for drug discovery to treat human diseases. Approximately half of the NCEs are based on natural products and their derivatives. Notably, marine natural products, a largely untapped resource, have contributed to drug discovery and development with eight drugs or cosmeceuticals approved by the U.S. Food and Drug Administration and European Medicines Agency, and ten candidates undergoing clinical trials. Collaborative efforts from drug developers, biologists, organic, medicinal, and natural product chemists have elevated drug discoveries to new levels. These efforts are expected to continue to improve the efficiency of natural product-based drugs. Marinopyrroles are examined here as a case study for potential anticancer and antibiotic agents. © 2015 Wiley Periodicals, Inc.
-
Singer, Merrill
2008-12-01
Locating development efforts within the context of globalism and global drug capitalism, this article examines the significant health and social impact both legal and illegal drugs have on international development efforts. The paper takes on an issue that is generally overlooked in the development debate and is not much addressed in the current international development standard, the Millennium Development Goals, and yet is one that places serious constraints on the ability of underdeveloped nations to achieve improvement. The relationship between psychotropic or "mind/mood altering" drugs and sustainable development is rooted in the contribution that the legal and illegal drug trade makes to a set of barriers to development, including: (1) interpersonal crime and community violence; (2) the corruption of public servants and the disintegration of social institutions; (3) the emergence of new or enhanced health problems; (4) the lowering of worker productivity; (5) the ensnarement of youth in drug distribution and away from productive education or employment; (6) the skewing of economies to drug production and money laundering. The paper emphasizes the need for new approaches for diminishing the burden placed by drugs on development.
-
Tsang, Sandra K. M.
2011-01-01
The escalating youth drug abuse problem in Hong Kong has attracted intense attention from the government, schools, and youth service professionals. Most preventive efforts have focused directly on positive youth development, very often through school programs delivered to secondary school students. There have been limited efforts to engage parents even though it is obvious that the family is actually the primary context of children and youth development. This paper will assert the importance of parental engagement in youth drug-prevention work, discuss some barriers in such parental involvement, present some promising local attempts and their strengths and limitations, and propose that sustained efforts are needed to build up theory-driven and evidence-based resources for Chinese communities on the subject. PMID:22194665
-
Patel, Harshali K; Bapat, Shweta S; Bhansali, Archita H; Sansgiry, Sujit S
2018-01-01
The objective of this study was to develop a one-page (1-page) prescription drug information leaflet (PILs) and assess their impact on the information processing variables, across 2 levels of patient involvement. One-page PILs were developed using cognitive principles to lower mental effort and improve comprehension. An experimental, 3 × 2 repeated measures study was conducted to determine the impact of cognitive effort, manipulated using leaflet type on comprehension across 2 levels (high/low) of patient involvement. Adults (≥18 years) in a university setting in Houston were recruited for the study. Each participant was exposed to 3 different types of prescription drug information leaflet (the current practice, preexisting 1-page text-only, and 1-page PILs) for the 3 drugs (Celebrex, Ventolin HFA, Prezista) for a given involvement scenario. A prevalidated survey instrument was used to measure product knowledge, attitude toward leaflet, and intention to read. Multivariate analysis of variance indicated significant positive effect of cognitive effort, involvement, and their interaction effect across all measured variables. Mean scores for product knowledge, attitude toward leaflet, and intention to read were highest for PILs ( P < .001), indicating that PILs exerted lowest cognitive effort. Univariate and post hoc analysis indicate that product knowledge significantly increases with high involvement. Patients reading PILs have higher comprehension compared with the current practice and text-only prototype leaflets evaluated. Higher levels of involvement further improve participant knowledge about the drug, increase their intention to read the leaflet, and change their attitude toward the leaflet. Implementation of PILs would improve information processing for consumers by reducing their cognitive effort.
-
Drug target identification in protozoan parasites.
Müller, Joachim; Hemphill, Andrew
2016-08-01
Despite the fact that diseases caused by protozoan parasites represent serious challenges for public health, animal production and welfare, only a limited panel of drugs has been marketed for clinical applications. Herein, the authors investigate two strategies, namely whole organism screening and target-based drug design. The present pharmacopoeia has resulted from whole organism screening, and the mode of action and targets of selected drugs are discussed. However, the more recent extensive genome sequencing efforts and the development of dry and wet lab genomics and proteomics that allow high-throughput screening of interactions between micromolecules and recombinant proteins has resulted in target-based drug design as the predominant focus in anti-parasitic drug development. Selected examples of target-based drug design studies are presented, and calcium-dependent protein kinases, important drug targets in apicomplexan parasites, are discussed in more detail. Despite the enormous efforts in target-based drug development, this approach has not yet generated market-ready antiprotozoal drugs. However, whole-organism screening approaches, comprising of both in vitro and in vivo investigations, should not be disregarded. The repurposing of already approved and marketed drugs could be a suitable strategy to avoid fastidious approval procedures, especially in the case of neglected or veterinary parasitoses.
-
Fiorentino, Robert; Liu, Gumei; Pariser, Anne R; Mulberg, Andrew E
2012-09-01
Like many rare diseases, eosinophilic esophagitis (EoE) is a poorly understood disorder, and assessment tools to accurately determine disease activity, remission, and natural history have long been inadequate. Clinical outcome end points able to assess the effectiveness of candidate therapeutic agents in clinical trials have been a particular deficiency and are urgently needed. With no approved therapy available to patients and with the prevalence of EoE on the increase, collaborative approaches to drug development are becoming ever more important. We describe a collaborative effort mobilized across institutions, including both the public and private sectors, that was initiated within the past 18 months expressly to address the need for further clinical research into the cause and treatment of EoE. Collaborators include the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition; the International Gastrointestinal Eosinophilic Researchers; and the US Food and Drug Administration. This effort has resulted in the elucidation of several parameters essential for effective EoE registration trials, including the need for clinically meaningful end points that measure changes in clinical symptoms in addition to the assessment of intraepithelial mucosal eosinophilia. The development and use of biomarkers, particularly in early-phase drug development, have become an important focus for investigations that might reduce clinical reliance on serial invasive monitoring. The concerted efforts described here to develop rational therapeutics and drug development paradigms in EoE also appear to provide a model for effective collaboration in the context of drug development for rare diseases and perhaps more generally for public health initiatives. Published by Mosby, Inc.
-
Open drug discovery for the Zika virus
Ekins, Sean; Mietchen, Daniel; Coffee, Megan; Stratton, Thomas P; Freundlich, Joel S; Freitas-Junior, Lucio; Muratov, Eugene; Siqueira-Neto, Jair; Williams, Antony J; Andrade, Carolina
2016-01-01
The Zika virus (ZIKV) outbreak in the Americas has caused global concern that we may be on the brink of a healthcare crisis. The lack of research on ZIKV in the over 60 years that we have known about it has left us with little in the way of starting points for drug discovery. Our response can build on previous efforts with virus outbreaks and lean heavily on work done on other flaviviruses such as dengue virus. We provide some suggestions of what might be possible and propose an open drug discovery effort that mobilizes global science efforts and provides leadership, which thus far has been lacking. We also provide a listing of potential resources and molecules that could be prioritized for testing as in vitro assays for ZIKV are developed. We propose also that in order to incentivize drug discovery, a neglected disease priority review voucher should be available to those who successfully develop an FDA approved treatment. Learning from the response to the ZIKV, the approaches to drug discovery used and the success and failures will be critical for future infectious disease outbreaks. PMID:27134728
-
Open drug discovery for the Zika virus.
Ekins, Sean; Mietchen, Daniel; Coffee, Megan; Stratton, Thomas P; Freundlich, Joel S; Freitas-Junior, Lucio; Muratov, Eugene; Siqueira-Neto, Jair; Williams, Antony J; Andrade, Carolina
2016-01-01
The Zika virus (ZIKV) outbreak in the Americas has caused global concern that we may be on the brink of a healthcare crisis. The lack of research on ZIKV in the over 60 years that we have known about it has left us with little in the way of starting points for drug discovery. Our response can build on previous efforts with virus outbreaks and lean heavily on work done on other flaviviruses such as dengue virus. We provide some suggestions of what might be possible and propose an open drug discovery effort that mobilizes global science efforts and provides leadership, which thus far has been lacking. We also provide a listing of potential resources and molecules that could be prioritized for testing as in vitro assays for ZIKV are developed. We propose also that in order to incentivize drug discovery, a neglected disease priority review voucher should be available to those who successfully develop an FDA approved treatment. Learning from the response to the ZIKV, the approaches to drug discovery used and the success and failures will be critical for future infectious disease outbreaks.
-
Pharmacological mechanism-based drug safety assessment and prediction.
Abernethy, D R; Woodcock, J; Lesko, L J
2011-06-01
Advances in cheminformatics, bioinformatics, and pharmacology in the context of biological systems are now at a point that these tools can be applied to mechanism-based drug safety assessment and prediction. The development of such predictive tools at the US Food and Drug Administration (FDA) will complement ongoing efforts in drug safety that are focused on spontaneous adverse event reporting and active surveillance to monitor drug safety. This effort will require the active collaboration of scientists in the pharmaceutical industry, academe, and the National Institutes of Health, as well as those at the FDA, to reach its full potential. Here, we describe the approaches and goals for the mechanism-based drug safety assessment and prediction program.
-
Drug target identification in protozoan parasites
Müller, Joachim; Hemphill, Andrew
2016-01-01
Introduction Despite the fact that diseases caused by protozoan parasites represent serious challenges for public health, animal production and welfare, only a limited panel of drugs has been marketed for clinical applications. Areas covered Herein, the authors investigate two strategies, namely whole organism screening and target-based drug design. The present pharmacopoeia has resulted from whole organism screening, and the mode of action and targets of selected drugs are discussed. However, the more recent extensive genome sequencing efforts and the development of dry and wet lab genomics and proteomics that allow high-throughput screening of interactions between micromolecules and recombinant proteins has resulted in target-based drug design as the predominant focus in anti-parasitic drug development. Selected examples of target-based drug design studies are presented, and calcium-dependent protein kinases, important drug targets in apicomplexan parasites, are discussed in more detail. Expert opinion Despite the enormous efforts in target-based drug development, this approach has not yet generated market-ready antiprotozoal drugs. However, whole-organism screening approaches, comprising of both in vitro and in vivo investigations, should not be disregarded. The repurposing of already approved and marketed drugs could be a suitable strategy to avoid fastidious approval procedures, especially in the case of neglected or veterinary parasitoses. PMID:27238605
-
Nanocarriers for delivery of platinum anticancer drugs☆
Oberoi, Hardeep S.; Nukolova, Natalia V.; Kabanov, Alexander V.; Bronich, Tatiana K.
2014-01-01
Platinum based anticancer drugs have revolutionized cancer chemotherapy, and continue to be in widespread clinical use especially for management of tumors of the ovary, testes, and the head and neck. However, several dose limiting toxicities associated with platinum drug use, partial anti-tumor response in most patients, development of drug resistance, tumor relapse, and many other challenges have severely limited the patient quality of life. These limitations have motivated an extensive research effort towards development of new strategies for improving platinum therapy. Nanocarrier-based delivery of platinum compounds is one such area of intense research effort beginning to provide encouraging preclinical and clinical results and may allow the development of the next generation of platinum chemotherapy. This review highlights current understanding on the pharmacology and limitations of platinum compounds in clinical use, and provides a comprehensive analysis of various platinum–polymer complexes, micelles, dendrimers, liposomes and other nanoparticles currently under investigation for delivery of platinum drugs. PMID:24113520
-
From crystal to compound: structure-based antimalarial drug discovery.
Drinkwater, Nyssa; McGowan, Sheena
2014-08-01
Despite a century of control and eradication campaigns, malaria remains one of the world's most devastating diseases. Our once-powerful therapeutic weapons are losing the war against the Plasmodium parasite, whose ability to rapidly develop and spread drug resistance hamper past and present malaria-control efforts. Finding new and effective treatments for malaria is now a top global health priority, fuelling an increase in funding and promoting open-source collaborations between researchers and pharmaceutical consortia around the world. The result of this is rapid advances in drug discovery approaches and technologies, with three major methods for antimalarial drug development emerging: (i) chemistry-based, (ii) target-based, and (iii) cell-based. Common to all three of these approaches is the unique ability of structural biology to inform and accelerate drug development. Where possible, SBDD (structure-based drug discovery) is a foundation for antimalarial drug development programmes, and has been invaluable to the development of a number of current pre-clinical and clinical candidates. However, as we expand our understanding of the malarial life cycle and mechanisms of resistance development, SBDD as a field must continue to evolve in order to develop compounds that adhere to the ideal characteristics for novel antimalarial therapeutics and to avoid high attrition rates pre- and post-clinic. In the present review, we aim to examine the contribution that SBDD has made to current antimalarial drug development efforts, covering hit discovery to lead optimization and prevention of parasite resistance. Finally, the potential for structural biology, particularly high-throughput structural genomics programmes, to identify future targets for drug discovery are discussed.
-
Martin-Moe, Sheryl; Lim, Fredric J; Wong, Rita L; Sreedhara, Alavattam; Sundaram, Jagannathan; Sane, Samir U
2011-08-01
Quality by design (QbD) is a science- and risk-based approach to drug product development. Although pharmaceutical companies have historically used many of the same principles during development, this knowledge was not always formally captured or proactively submitted to regulators. In recent years, the US Food and Drug Administration has also recognized the need for more controls in the drug manufacturing processes, especially for biological therapeutics, and it has recently launched an initiative for Pharmaceutical Quality for the 21st Century to modernize pharmaceutical manufacturing and improve product quality. In the biopharmaceutical world, the QbD efforts have been mainly focused on active pharmaceutical ingredient processes with little emphasis on drug product development. We present a systematic approach to biopharmaceutical drug product development using a monoclonal antibody as an example. The approach presented herein leverages scientific understanding of products and processes, risk assessments, and rational experimental design to deliver processes that are consistent with QbD philosophy without excessive incremental effort. Data generated using these approaches will not only strengthen data packages to support specifications and manufacturing ranges but hopefully simplify implementation of postapproval changes. We anticipate that this approach will positively impact cost for companies, regulatory agencies, and patients, alike. Copyright © 2011 Wiley-Liss, Inc.
-
Daniel, Gregory W; Cazé, Alexis; Romine, Morgan H; Audibert, Céline; Leff, Jonathan S; McClellan, Mark B
2015-02-01
New drugs and biologics have had a tremendous impact on the treatment of many diseases. However, available measures suggest that pharmaceutical innovation has remained relatively flat, despite substantial growth in research and development spending. We review recent literature on pharmaceutical innovation to identify limitations in measuring and assessing innovation, and we describe the framework and collaborative approach we are using to develop more comprehensive, publicly available metrics for innovation. Our research teams at the Brookings Institution and Deerfield Institute are collaborating with experts from multiple areas of drug development and regulatory review to identify and collect comprehensive data elements related to key development and regulatory characteristics for each new molecular entity approved over the past several decades in the United States and the European Union. Subsequent phases of our effort will add data on downstream product use and patient outcomes and will also include drugs that have failed or been abandoned in development. Such a database will enable researchers to better analyze the drivers of drug innovation, trends in the output of new medicines, and the effect of policy efforts designed to improve innovation. Project HOPE—The People-to-People Health Foundation, Inc.
-
Investigational drugs to treat methicillin-resistant Staphylococcus aureus
Vuong, Cuong; Yeh, Anthony J; Cheung, Gordon YC; Otto, Michael
2016-01-01
Introduction Staphylococcus aureus remains one of the leading causes of morbidity and mortality worldwide. This is to a large extent due to antibiotic-resistant strains, in particular methicillin-resistant S. aureus (MRSA). While the toll of invasive MRSA infections appears to decrease in U.S. hospitals, the rate of community-associated MRSA infections remains constant and there is a surge of MRSA in many other countries. This situation calls for continuing if not increased efforts to find novel strategies to combat MRSA infections. Areas covered This review will provide an overview of current investigational antibiotics in clinical development (up to phase II), and of therapeutic antibodies and alternative drugs against S. aureus in preclinical and clinical development, including a short description of the mechanism of action and a presentation of microbiological and clinical data. Expert opinion Increased recent antibiotic development efforts and results from pathogenesis research have led to several new antibiotics and alternative drugs, as well as a more informed selection of targets for vaccination efforts against MRSA. This developing portfolio of novel anti-staphylococcal drugs will hopefully provide us with additional and more efficient ways to combat MRSA infections in the near future and prevent us from running out of treatment options, even if new resistances arise. PMID:26536498
-
Condoning Drug Education Programs at Colleges and Universities.
ERIC Educational Resources Information Center
Kaczynski, Daniel J.
This report presents the evaluation results gathered from a 2-year study of a drug prevention program involving a consortia of nine colleges and universities located in Alabama and Florida. The consortia effort was intended to: (1) strengthen their respective drug prevention activities; (2) develop policies governing alcohol and drugs; (3)…
-
Recent advances in malaria drug discovery.
Lanteri, Charlotte A; Johnson, Jacob D; Waters, Norman C
2007-06-01
Malaria is responsible for over 300 million clinical cases annually and claims the lives of approximately 1-2 million. With a disease that has plagued humanity throughout history, one would think that better control measures would be in place to decrease the mortality and morbidity associated with malaria. Due to malaria drug resistance, an increase in the number of clinical infections and deaths is soon likely to be observed. Therefore, there is a push to identify and introduce new drug entities for malaria treatment and prophylaxis. In an effort to develop new malaria drugs, several different approaches have been implemented. These include the use of drug combinations of either new or existing antimalarials, exploitation of natural products, identification of resistance reversal or sensitizing agents and the targeting of specific malarial enzymes. Past experience has shown that introduction of the same chemical entities, such as quinolines and antifolates, results in only limited efficacy with resistance developing rapidly within one year of introduction. New approaches to drug discovery should identify novel chemotypes which circumvent the parasite's disposition to drug resistance. This review summarizes current efforts in malaria drug discovery as uncovered in recent patent literature.
-
Pharmacogenomics to Revive Drug Development in Cardiovascular Disease.
Dubé, Marie-Pierre; de Denus, Simon; Tardif, Jean-Claude
2016-02-01
Investment in cardiovascular drug development is on the decline as large cardiovascular outcomes trials require considerable investments in time, efforts and financial resources. Pharmacogenomics has the potential to help revive the cardiovascular drug development pipeline by providing new and better drug targets at an earlier stage and by enabling more efficient outcomes trials. This article will review some of the recent developments highlighting the value of pharmacogenomics for drug development. We discuss how genetic biomarkers can enable the conduct of more efficient clinical outcomes trials by enriching patient populations for good responders to the medication. In addition, we assess past drug development programs which support the added value of selecting drug targets that have established genetic evidence supporting the targeted mechanism of disease. Finally, we discuss how pharmacogenomics can provide valuable evidence linking a drug target to clinically relevant outcomes, enabling novel drug discovery and drug repositioning opportunities.
-
Investigational drugs in early development for treating dengue infection.
Beesetti, Hemalatha; Khanna, Navin; Swaminathan, Sathyamangalam
2016-09-01
Dengue has emerged as the most significant arboviral disease of the current century. A drug for dengue is an urgent unmet need. As conventional drug discovery efforts have not produced any promising clinical candidates, there is a shift toward re-positioning pre-existing drugs for dengue to fast-track dengue drug development. This article provides an update on the current status of recently completed and ongoing dengue drug trials. All dengue drug trials described in this article were identified from a list of >230 trials that were returned upon searching the World Health Organization's International Clinical Trials Registry Platform web portal using the search term 'dengue' on December 31(st), 2015. None of the handful of drugs tested so far has yielded encouraging results. Early trial experience has served to emphasize the challenge of drug testing in the short therapeutic time window available, the need for tools to predict 'high-risk' patients early on and the limitations of the existing pre-clinical model systems. Significant investment of efforts and resources is a must before the availability of a safe, effective and inexpensive dengue drug becomes a reality. Currently, supportive fluid therapy remains the only option available for dengue treatment.
-
A physiome interoperability roadmap for personalized drug development
2016-01-01
The goal of developing therapies and dosage regimes for characterized subgroups of the general population can be facilitated by the use of simulation models able to incorporate information about inter-individual variability in drug disposition (pharmacokinetics), toxicity and response effect (pharmacodynamics). Such observed variability can have multiple causes at various scales, ranging from gross anatomical differences to differences in genome sequence. Relevant data for many of these aspects, particularly related to molecular assays (known as ‘-omics’), are available in online resources, but identification and assignment to appropriate model variables and parameters is a significant bottleneck in the model development process. Through its efforts to standardize annotation with consequent increase in data usability, the human physiome project has a vital role in improving productivity in model development and, thus, the development of personalized therapy regimes. Here, we review the current status of personalized medicine in clinical practice, outline some of the challenges that must be overcome in order to expand its applicability, and discuss the relevance of personalized medicine to the more widespread challenges being faced in drug discovery and development. We then review some of (i) the key data resources available for use in model development and (ii) the potential areas where advances made within the physiome modelling community could contribute to physiologically based pharmacokinetic and physiologically based pharmacokinetic/pharmacodynamic modelling in support of personalized drug development. We conclude by proposing a roadmap to further guide the physiome community in its on-going efforts to improve data usability, and integration with modelling efforts in the support of personalized medicine development. PMID:27051513
-
Dopamine, Effort-Based Choice, and Behavioral Economics: Basic and Translational Research
Salamone, John D.; Correa, Merce; Yang, Jen-Hau; Rotolo, Renee; Presby, Rose
2018-01-01
Operant behavior is not only regulated by factors related to the quality or quantity of reinforcement, but also by the work requirements inherent in performing instrumental actions. Moreover, organisms often make effort-related decisions involving economic choices such as cost/benefit analyses. Effort-based decision making is studied using behavioral procedures that offer choices between high-effort options leading to relatively preferred reinforcers vs. low effort/low reward choices. Several neural systems, including the mesolimbic dopamine (DA) system and other brain circuits, are involved in regulating effort-related aspects of motivation. Considerable evidence indicates that mesolimbic DA transmission exerts a bi-directional control over exertion of effort on instrumental behavior tasks. Interference with DA transmission produces a low-effort bias in animals tested on effort-based choice tasks, while increasing DA transmission with drugs such as DA transport blockers tends to enhance selection of high-effort options. The results from these pharmacology studies are corroborated by the findings from recent articles using optogenetic, chemogenetic and physiological techniques. In addition to providing important information about the neural regulation of motivated behavior, effort-based choice tasks are useful for developing animal models of some of the motivational symptoms that are seen in people with various psychiatric and neurological disorders (e.g., depression, schizophrenia, Parkinson’s disease). Studies of effort-based decision making may ultimately contribute to the development of novel drug treatments for motivational dysfunction. PMID:29628879
-
Dopamine, Effort-Based Choice, and Behavioral Economics: Basic and Translational Research.
Salamone, John D; Correa, Merce; Yang, Jen-Hau; Rotolo, Renee; Presby, Rose
2018-01-01
Operant behavior is not only regulated by factors related to the quality or quantity of reinforcement, but also by the work requirements inherent in performing instrumental actions. Moreover, organisms often make effort-related decisions involving economic choices such as cost/benefit analyses. Effort-based decision making is studied using behavioral procedures that offer choices between high-effort options leading to relatively preferred reinforcers vs. low effort/low reward choices. Several neural systems, including the mesolimbic dopamine (DA) system and other brain circuits, are involved in regulating effort-related aspects of motivation. Considerable evidence indicates that mesolimbic DA transmission exerts a bi-directional control over exertion of effort on instrumental behavior tasks. Interference with DA transmission produces a low-effort bias in animals tested on effort-based choice tasks, while increasing DA transmission with drugs such as DA transport blockers tends to enhance selection of high-effort options. The results from these pharmacology studies are corroborated by the findings from recent articles using optogenetic, chemogenetic and physiological techniques. In addition to providing important information about the neural regulation of motivated behavior, effort-based choice tasks are useful for developing animal models of some of the motivational symptoms that are seen in people with various psychiatric and neurological disorders (e.g., depression, schizophrenia, Parkinson's disease). Studies of effort-based decision making may ultimately contribute to the development of novel drug treatments for motivational dysfunction.
-
Strategies to support drug discovery through integration of systems and data.
Waller, Chris L; Shah, Ajay; Nolte, Matthias
2007-08-01
Much progress has been made over the past several years to provide technologies for the integration of drug discovery software applications and the underlying data bits. Integration at the application layer has focused primarily on developing and delivering applications that support specific workflows within the drug discovery arena. A fine balance between creating behemoth applications and providing business value must be maintained. Heterogeneous data sources have typically been integrated at the data level in an effort to provide a more holistic view of the data packages supporting key decision points. This review will highlight past attempts, current status, and potential future directions for systems and data integration strategies in support of drug discovery efforts.
-
The current state of GPCR-based drug discovery to treat metabolic disease.
Sloop, Kyle W; Emmerson, Paul J; Statnick, Michael A; Willard, Francis S
2018-02-02
One approach of modern drug discovery is to identify agents that enhance or diminish signal transduction cascades in various cell types and tissues by modulating the activity of GPCRs. This strategy has resulted in the development of new medicines to treat many conditions, including cardiovascular disease, psychiatric disorders, HIV/AIDS, certain forms of cancer and Type 2 diabetes mellitus (T2DM). These successes justify further pursuit of GPCRs as disease targets and provide key learning that should help guide identifying future therapeutic agents. This report reviews the current landscape of GPCR drug discovery with emphasis on efforts aimed at developing new molecules for treating T2DM and obesity. We analyse historical efforts to generate GPCR-based drugs to treat metabolic disease in terms of causal factors leading to success and failure in this endeavour. © 2018 The British Pharmacological Society.
-
ERIC Educational Resources Information Center
National Inst. on Drug Abuse (DHHS/PHS), Rockville, MD.
Research is developing a clearer picture of the dangers of mind-altering drugs. The goal of this report is to present the latest information to providers to help them strengthen their prevention and treatment efforts. A description is presented of dissociative drugs, and consideration is given as to why people take hallucinogens. The physical…
-
A Guide to Drug Abuse Education and Information Materials, 1972.
ERIC Educational Resources Information Center
National Inst. of Mental Health (DHEW), Rockville, MD.
This guide was developed from efforts initiated by the National Institute of Mental Health (NIMH) to inform and educate the public about drug abuse beginning in April, 1969. At that time, NIMH produced television spots, radio announcements, newspaper and magazine ads, films, and general awareness publications. This guide was developed to make…
-
Orphan drug development in the United States.
Groft, S C
1985-05-01
Drug research and development in the U.S. tends to focus on drugs to treat common diseases because of the anticipated return on investment. To stimulate pharmaceutical manufacturers to pursue the development of drugs for rare conditions, the Orphan Drug Act was enacted by Congress on January 4, 1983. Under the provisions of this Act, the FDA can make recommendations on the investigations necessary for marketing approval; exclusive marketing privileges can be obtained; tax credits for expenses incurred are allowed; availability of orphan drugs on an investigational basis is encouraged; and the Orphan Product Board is established for the coordination of research efforts and their reimbursement. The effects of this legislation are evident in the continuing increase in orphan drug designations.
-
Federal Register 2010, 2011, 2012, 2013, 2014
2012-04-19
... specific disease area during its meetings with patients? For example, who should serve as representatives of patients? (2) What methodological and practical issues should FDA consider as it develops its... Research and Center for Biologics Evaluation and Research Efforts Center for Drug Evaluation and Research...
-
Development of the NIDA-Funded Center on Substance Abuse and Mental Illness
ERIC Educational Resources Information Center
Singer, Mark I.; Kola, Lenore A.; Biegel, David E.
2008-01-01
This article describes one school's effort to establish a social work research development center in the area of coexisting drug and mental disorders (dual disorders), within the context of the social work profession's efforts to compete more effectively for federal research grants. This center was funded as part of a successful application in…
-
Anti-influenza drugs: the development of sialidase inhibitors.
von Itzstein, Mark; Thomson, Robin
2009-01-01
Viruses, particularly those that are harmful to humans, are the 'silent terrorists' of the twenty-first century. Well over four million humans die per annum as a result of viral infections alone. The scourge of influenza virus has plagued mankind throughout the ages. The fact that new viral strains emerge on a regular basis, particularly out of Asia, establishes a continual socio-economic threat to mankind. The arrival of the highly pathogenic avian influenza H5N1 heightened the threat of a potential human pandemic to the point where many countries have put in place 'preparedness plans' to defend against such an outcome. The discovery of the first designer influenza virus sialidase inhibitor and anti-influenza drug Relenza, and subsequently Tamiflu, has now inspired a number of continuing efforts towards the discovery of next generation anti-influenza drugs. Such drugs may act as 'first-line-of-defence' against the spread of influenza infection and buy time for necessary vaccine development particularly in a human pandemic setting. Furthermore, the fact that influenza virus can develop resistance to therapeutics makes these continuing efforts extremely important. An overview of the role of the virus-associated glycoprotein sialidase (neuraminidase) and some of the most recent developments towards the discovery of anti-influenza drugs based on the inhibition of influenza virus sialidase is provided in this chapter.
-
Song, Yan; Dhodda, Raj; Zhang, Jun; Sydor, Jens
2014-05-01
In the recent past, we have seen an increase in the outsourcing of bioanalysis in pharmaceutical companies in support of their drug development pipeline. This trend is largely driven by the effort to reduce internal cost, especially in support of late-stage pipeline assets where established bioanalytical assays are used to analyze a large volume of samples. This article will highlight our perspective of how bioanalytical laboratories within pharmaceutical companies can be developed into the best partner in the advancement of drug development pipelines with high-quality support at competitive cost.
-
Escolar, Diana M; Henricson, Erik K; Pasquali, Livia; Gorni, Ksenija; Hoffman, Eric P
2002-10-01
Progress in the development of rationally based therapies for Duchenne muscular dystrophy has been accelerated by encouraging multidisciplinary, multi-institutional collaboration between basic science and clinical investigators in the Cooperative International Research Group. We combined existing research efforts in pathophysiology by a gene expression profiling laboratory with the efforts of animal facilities capable of conducting high-throughput drug screening and toxicity testing to identify safe and effective drug compounds that target different parts of the pathophysiologic cascade in a genome-wide drug discovery approach. Simultaneously, we developed a clinical trial coordinating center and an international network of collaborating physicians and clinics where those drugs could be tested in large-scale clinical trials. We hope that by bringing together investigators at these facilities and providing the infrastructure to support their research, we can rapidly move new bench discoveries through animal model screening and into therapeutic testing in humans in a safe, timely and cost-effective setting.
-
Njogu, Peter M; Guantai, Eric M; Pavadai, Elumalai; Chibale, Kelly
2016-01-08
Despite the tremendous improvement in overall global health heralded by the adoption of the Millennium Declaration in the year 2000, tropical infections remain a major health problem in the developing world. Recent estimates indicate that the major tropical infectious diseases, namely, malaria, tuberculosis, trypanosomiasis, and leishmaniasis, account for more than 2.2 million deaths and a loss of approximately 85 million disability-adjusted life years annually. The crucial role of chemotherapy in curtailing the deleterious health and economic impacts of these infections has invigorated the search for new drugs against tropical infectious diseases. The research efforts have involved increased application of computational technologies in mainstream drug discovery programs at the hit identification, hit-to-lead, and lead optimization stages. This review highlights various computer-aided drug discovery approaches that have been utilized in efforts to identify novel antimalarial, antitubercular, antitrypanosomal, and antileishmanial agents. The focus is largely on developments over the past 5 years (2010-2014).
-
Yin, Liusong; Chen, Xiaoying; Vicini, Paolo; Rup, Bonita; Hickling, Timothy P
2015-06-01
Therapeutic protein products (TPPs) are of considerable value in the treatment of a variety of diseases, including cancer, hemophilia, and autoimmune diseases. The success of TPP mainly results from prolonged half-life, increased target specificity and decreased intrinsic toxicity compared with small molecule drugs. However, unwanted immune responses against TPP, such as generation of anti-drug antibody, can impact both drug efficacy and patient safety, which has led to requirements for increased monitoring in regulatory studies and clinical practice, termination of drug development, or even withdrawal of marketed products. We present an overview of current knowledge on immunogenicity of TPP and its impact on efficacy and safety. We also discuss methods for measurement and prediction of immunogenicity and review both product-related and patient-related risk factors that affect its development, and efforts that may be taken to mitigate it. Lastly, we discuss gaps in knowledge and technology and what is needed to fill these. Copyright © 2015 Elsevier Inc. All rights reserved.
-
Vizirianakis, Ioannis S; Mystridis, George A; Avgoustakis, Konstantinos; Fatouros, Dimitrios G; Spanakis, Marios
2016-04-01
The existing tumor heterogeneity and the complexity of cancer cell biology critically demand powerful translational tools with which to support interdisciplinary efforts aiming to advance personalized cancer medicine decisions in drug development and clinical practice. The development of physiologically based pharmacokinetic (PBPK) models to predict the effects of drugs in the body facilitates the clinical translation of genomic knowledge and the implementation of in vivo pharmacology experience with pharmacogenomics. Such a direction unequivocally empowers our capacity to also make personalized drug dosage scheme decisions for drugs, including molecularly targeted agents and innovative nanoformulations, i.e. in establishing pharmacotyping in prescription. In this way, the applicability of PBPK models to guide individualized cancer therapeutic decisions of broad clinical utility in nanomedicine in real-time and in a cost-affordable manner will be discussed. The latter will be presented by emphasizing the need for combined efforts within the scientific borderlines of genomics with nanotechnology to ensure major benefits and productivity for nanomedicine and personalized medicine interventions.
-
Automatic identification and normalization of dosage forms in drug monographs
2012-01-01
Background Each day, millions of health consumers seek drug-related information on the Web. Despite some efforts in linking related resources, drug information is largely scattered in a wide variety of websites of different quality and credibility. Methods As a step toward providing users with integrated access to multiple trustworthy drug resources, we aim to develop a method capable of identifying drug's dosage form information in addition to drug name recognition. We developed rules and patterns for identifying dosage forms from different sections of full-text drug monographs, and subsequently normalized them to standardized RxNorm dosage forms. Results Our method represents a significant improvement compared with a baseline lookup approach, achieving overall macro-averaged Precision of 80%, Recall of 98%, and F-Measure of 85%. Conclusions We successfully developed an automatic approach for drug dosage form identification, which is critical for building links between different drug-related resources. PMID:22336431
-
Hussong, David
2010-09-01
For several decades, the FDA has undertaken many initiatives to improve the quality and safety of sterile drug products. In recent years, efforts have also been undertaken to accelerate the rate for application approval by adding earlier involvement of microbiology reviewers in drug development. Product and manufacturing process development, as well as safe use and product design, are among the elements of enhanced technical involvement. An overview of the product quality microbiology aspects for sterile drugs is provided.
-
The practice of pre-marketing safety assessment in drug development.
Chuang-Stein, Christy; Xia, H Amy
2013-01-01
The last 15 years have seen a substantial increase in efforts devoted to safety assessment by statisticians in the pharmaceutical industry. While some of these efforts were driven by regulations and public demand for safer products, much of the motivation came from the realization that there is a strong need for a systematic approach to safety planning, evaluation, and reporting at the program level throughout the drug development life cycle. An efficient process can help us identify safety signals early and afford us the opportunity to develop effective risk minimization plan early in the development cycle. This awareness has led many pharmaceutical sponsors to set up internal systems and structures to effectively conduct safety assessment at all levels (patient, study, and program). In addition to process, tools have emerged that are designed to enhance data review and pattern recognition. In this paper, we describe advancements in the practice of safety assessment during the premarketing phase of drug development. In particular, we share examples of safety assessment practice at our respective companies, some of which are based on recommendations from industry-initiated working groups on best practice in recent years.
-
Malaria medicines to address drug resistance and support malaria elimination efforts.
Achan, Jane; Mwesigwa, Julia; Edwin, Chinagozi Precious; D'alessandro, Umberto
2018-01-01
Antimalarial drugs are essential weapons to fight malaria and have been used effectively since the 17 th century. However, P.falciparum resistance has been reported to almost all available antimalarial drugs, including artemisinin derivatives, raising concerns that this could jeopardize malaria elimination. Areas covered: In this article, we present a historical perspective of antimalarial drug resistance, review current evidence of resistance to available antimalarial drugs and discuss possible mitigating strategies to address this challenge. Expert commentary: The historical approach to drug resistance has been to change the national treatment policy to an alternative treatment. However, alternatives to artemisinin-based combination treatment are currently extremely limited. Innovative approaches utilizing available schizonticidal drugs such as triple combination therapies or multiple first line treatments could delay the emergence and spread of drug resistance. Transmission blocking drugs like primaquine may play a key role if given to a substantial proportion of malaria infected persons. Deploying antimalarial medicines in mass drug administration or mass screening and treatment campaigns could also contribute to containment efforts by eliminating resistant parasites in some settings. Ultimately, response to drug resistance should also include further investment in the development of new antimalarial drugs.
-
Thombs, Dennis L; Gonzalez, Jennifer M Reingle; Osborn, Cynthia J; Rossheim, Matthew E; Suzuki, Sumihiro
2015-05-01
In college and university residence halls, resident assistants (RAs) are expected to serve as first-aid providers to students who may have alcohol, other drug, mental health, and academic problems. Despite this responsibility, evidence-based, first-aid programs have not been developed and tested for the RA workforce. The current study examined effects of an investigational first-aid program designed specifically for RAs. The online Peer Hero Training program is a novel approach to RA training in its use of interactive video dramatizations of incidents involving substance-using or distressed residents. A 9-month randomized trial conducted on eight US campuses compared RAs who participated in the Peer Hero Training program to RAs who received training-as-usual. Participation in the Peer Hero Training program significantly increased RA first-aid efforts for residential students who may have had alcohol, other drug, mental health, or academic problems 6 months after baseline. Compared with those in the training-as-usual condition, RAs in the Peer Hero Training program made more than 10 times as many first-aid efforts for possible alcohol problems, almost 14 times the number of first-aid efforts for possible drug use, almost 3 times the number of first-aid efforts for possible mental health problems, and 3 times the number of first-aid efforts for academic problems. There was no evidence that measured RA attitudes mediated the effects of the intervention. Results of this preliminary evaluation trial suggest that online training using interactive video dramatizations is a viable approach to strengthening RAs' ability to provide alcohol, other drugs, and mental health first-aid to undergraduates.
-
Amur, S; LaVange, L; Zineh, I; Buckman-Garner, S; Woodcock, J
2015-07-01
The discovery, development, and use of biomarkers for a variety of drug development purposes are areas of tremendous interest and need. Biomarkers can become accepted for use through submission of biomarker data during the drug approval process. Another emerging pathway for acceptance of biomarkers is via the biomarker qualification program developed by the Center for Drug Evaluation and Research (CDER, US Food and Drug Administration). Evidentiary standards are needed to develop and evaluate various types of biomarkers for their intended use and multiple stakeholders, including academia, industry, government, and consortia must work together to help develop this evidence. The article describes various types of biomarkers that can be useful in drug development and evidentiary considerations that are important for qualification. A path forward for coordinating efforts to identify and explore needed biomarkers is proposed for consideration. © 2015 American Society for Clinical Pharmacology and Therapeutics.
-
Academic Patents and Access to Medicines in Developing Countries
2009-01-01
There is a widespread and growing concern that patents hinder access to life-saving drugs in developing countries. Recent student movements and legislative initiatives emphasize the potential role that research universities in developed countries could have in ameliorating this “access gap.” These efforts are based on the assumption that universities own patents on a substantial number of drugs and that patents on these drugs are currently filed in developing countries. I provide empirical evidence regarding these issues and explore the feasibility and desirability of proposals to change university patenting and licensing practices to promote access to medicines in the developing world. PMID:19008514
-
Shayman, James A
2015-12-15
Historically, most Federal Drug Administration-approved drugs were the result of "in-house" efforts within large pharmaceutical companies. Over the last two decades, this paradigm has steadily shifted as the drug industry turned to startups, small biotechnology companies, and academia for the identification of novel drug targets and early drug candidates. This strategic pivot has created new opportunities for groups less traditionally associated with the creation of novel therapeutics, including small academic laboratories, for engagement in the drug discovery process. A recent example of the successful development of a drug that had its origins in academia is eliglustat tartrate, an oral agent for Gaucher disease type 1. Copyright © 2015 the American Physiological Society.
-
One target-multiple indications: a call for an integrated common mechanisms strategy.
Nielsch, Ulrich; Schäfer, Stefan; Wild, Hanno; Busch, Andreas
2007-12-01
Ever-increasing research and development costs are putting constant pressure on the pharmaceutical industry to improve their efficiency. Efforts to increase the output of the research pipeline have yielded limited success. Traditionally, maximization of the value of a drug is attempted through life-cycle management, which is initiated late in development, or when the drug is already on the market. Validated targets can be exploited further through development of a follow-up drug, which may offer advantages regarding safety or convenience. In this article, we propose to systematically evaluate the full therapeutic potential of a drug target, proprietary chemical lead structure, or drug candidate as broad and as early as possible and we call this the 'common mechanism' approach.
-
Drugs Targeting the Dopaminergic Nervous System Alter Locomotion in Larval Zebrafish
As part of an effort at the US Environmental Protection Agency to develop a rapid in vivo screen for prioritization of toxic chemicals, we have begun to characterize the locomotor activity of zebrafish (Danio rerio) larvae. This includes assessing the acute effects of drugs that ...
-
Drugs that Target Dopamine Receptors: Changes in Locomotor Activity in Larval Zebrafish
As part of an effort at the US Environmental Protection Agency to develop a rapid in vivo screen for prioritization of toxic chemicals, we have begun to characterize the locomotor activity of zebrafish (Danio rerio) larvae. This includes assessing the acute effects of drugs known...
-
DRUG EFFECTS ON THE LOCOMOTOR ACTIVITY OF LARVAL ZEBRAFISH.
As part of an effort to develop a rapid in vivo screen for EPA’s prioritization of toxic chemicals, we have begun to characterize the locomotor activity of zebrafish (Danio rerio) larvae and the effects of prototype drugs. Zebrafish larvae (6-7 days post-fertilization) were indiv...
-
Acute neuroactive drug exposures alter locomotor activity in larval zebrafish
In an effort to develop a rapid in vivo screen for EPA's prioritization of toxic chemicals, we are characterizing the locomotor activity of zebrafish (Danio rerio) larvae after exposure to prototypic drugs that act on the central nervous system. MPTP (1-methyl-4phenyl- 1 ,2,3,6-...
-
COMPUTER-AIDED DRUG DISCOVERY AND DEVELOPMENT (CADDD): in silico-chemico-biological approach
Kapetanovic, I.M.
2008-01-01
It is generally recognized that drug discovery and development are very time and resources consuming processes. There is an ever growing effort to apply computational power to the combined chemical and biological space in order to streamline drug discovery, design, development and optimization. In biomedical arena, computer-aided or in silico design is being utilized to expedite and facilitate hit identification, hit-to-lead selection, optimize the absorption, distribution, metabolism, excretion and toxicity profile and avoid safety issues. Commonly used computational approaches include ligand-based drug design (pharmacophore, a 3-D spatial arrangement of chemical features essential for biological activity), structure-based drug design (drug-target docking), and quantitative structure-activity and quantitative structure-property relationships. Regulatory agencies as well as pharmaceutical industry are actively involved in development of computational tools that will improve effectiveness and efficiency of drug discovery and development process, decrease use of animals, and increase predictability. It is expected that the power of CADDD will grow as the technology continues to evolve. PMID:17229415
-
ERIC Educational Resources Information Center
California State Dept. of Education, Sacramento.
Although schools have the primary responsibility for educating children and adolescents, schools alone cannot prevent the use of tobacco, alcohol, and other drugs. Preventing youth from smoking, drinking, and using drugs must be a collaborative effort, jointly undertaken by the school, community, and youths themselves. This guide was developed to…
-
International epidemiology of HIV and AIDS among injecting drug users.
Des Jarlais, D C; Friedman, S R; Choopanya, K; Vanichseni, S; Ward, T P
1992-10-01
HIV/AIDS and iv drug use (IVDU) are of significant multinational scope and growing. Supporting increased IVDU in many countries are countries' geographical proximity to illicit drug trafficking distribution routes, law enforcement efforts which increase the demand for more efficient drug distribution and consumption, and countries' infrastructural and social modernization. Given the failures of intensified law enforcement efforts to thwart the use and proliferation of illegal drugs, countries with substantial IVDU should look away from preventing use to preventing HIV transmission within drug user populations. With HIV seroprevalence rates rapidly reaching 40-50% in some developing country IVDU groups, a variety of prevention programs is warranted. Such programs should be supported and implemented while prevention remains feasible. This paper examines the variation in HIV seroprevalence among IVD users, rapid HIV spread among users, HIV among IVDUs in Bangkok, emerging issues in HIV transmission among IVDUs, non-AIDS manifestations of HIV infection among IVDUs, prevention programs and effectiveness, and harm reduction.
-
Beyond hydroxyurea: new and old drugs in the pipeline for sickle cell disease
2016-01-01
Despite Food and Drug Administration (FDA) approval of hydroxyurea to reduce the frequency of vaso-occlusive episodes, sickle cell disease (SCD) has continued to be treated primarily with analgesics for pain relief. However, elucidation of the multiple pathophysiologic mechanisms leading to vaso-occlusion and tissue injury in SCD has now resulted in a burgeoning effort to identify new treatment modalities to prevent or ameliorate the consequences of the disease. Development of new drugs as well as investigation of drugs previously used in other settings have targeted cell adhesion, inflammatory pathways, upregulation of hemoglobin F, hemoglobin polymerization and sickling, coagulation, and platelet activation. Although these efforts have not yet yielded drugs ready for FDA approval, several early studies have been extremely encouraging. Moreover, the marked increase in clinical pharmaceutical research addressing SCD and the new and old drugs in the pipeline make it reasonable to expect that we will soon have new treatments for SCD. PMID:26758919
-
Gore offers to help drug companies pursue research.
1996-03-08
A meeting convened between Vice President Al Gore and executives of leading pharmaceutical companies to determine means of accelerating efforts to develop vaccines, therapeutics, and microbicides for people with HIV. Gore explained that the administration will work with pharmaceutical companies to determine the long-term effectiveness of drugs approved by the Food and Drug Administration (FDA), work with international groups to increase investment in vaccine development, help develop new microbicides for women with HIV, and identify promising areas of AIDS research. According to advocates, the Clinton Administration has made great strides in improving and accelerating the FDA's drug approval process. The next goal of the pharmaceutical research agenda should be to include consumer advocates in the decision-making process.
-
Accelerating Precision Drug Development and Drug Repurposing by Leveraging Human Genetics
Shirey-Rice, Jana K.; Lavieri, Robert R.; Jerome, Rebecca N.; Zaleski, Nicole M.; Aronoff, David M.; Bastarache, Lisa; Niu, Xinnan; Holroyd, Kenneth J.; Roden, Dan M.; Skaar, Eric P.; Niswender, Colleen M.; Marnett, Lawrence J.; Lindsley, Craig W.; Ekstrom, Leeland B.; Bentley, Alan R.; Bernard, Gordon R.; Hong, Charles C.; Denny, Joshua C.
2017-01-01
Abstract The potential impact of using human genetic data linked to longitudinal electronic medical records on drug development is extraordinary; however, the practical application of these data necessitates some organizational innovations. Vanderbilt has created resources such as an easily queried database of >2.6 million de-identified electronic health records linked to BioVU, which is a DNA biobank with more than 230,000 unique samples. To ensure these data are used to maximally benefit and accelerate both de novo drug discovery and drug repurposing efforts, we created the Accelerating Drug Development and Repurposing Incubator, a multidisciplinary think tank of experts in various therapeutic areas within both basic and clinical science as well as experts in legal, business, and other operational domains. The Incubator supports a diverse pipeline of drug indication finding projects, leveraging the natural experiment of human genetics. PMID:28379727
-
Economics of new oncology drug development.
DiMasi, Joseph A; Grabowski, Henry G
2007-01-10
Review existing studies and provide new results on the development, regulatory, and market aspects of new oncology drug development. We utilized data from the US Food and Drug Administration (FDA), company surveys, and publicly available commercial business intelligence databases on new oncology drugs approved in the United States and on investigational oncology drugs to estimate average development and regulatory approval times, clinical approval success rates, first-in-class status, and global market diffusion. We found that approved new oncology drugs to have a disproportionately high share of FDA priority review ratings, of orphan drug designations at approval, and of drugs that were granted inclusion in at least one of the FDA's expedited access programs. US regulatory approval times were shorter, on average, for oncology drugs (0.5 years), but US clinical development times were longer on average (1.5 years). Clinical approval success rates were similar for oncology and other drugs, but proportionately more of the oncology failures reached expensive late-stage clinical testing before being abandoned. In relation to other drugs, new oncology drug approvals were more often first-in-class and diffused more widely across important international markets. The market success of oncology drugs has induced a substantial amount of investment in oncology drug development in the last decade or so. However, given the great need for further progress, the extent to which efforts to develop new oncology drugs will grow depends on future public-sector investment in basic research, developments in translational medicine, and regulatory reforms that advance drug-development science.
-
Emerging and recurrent issues in drug development.
Anello, C
This paper reviews several emerging and recurrent issues relating to the drug development process. These emerging issues include changes to the FDA regulatory environment, internationalization of drug development, advances in computer technology and visualization tools, and efforts to incorporate meta-analysis methodology. Recurrent issues include: renewed interest in statistical methods for handling subgroups in the design and analysis of clinical trials; renewed interest in alternatives to the 'intention-to-treat' analysis in the presence of non-compliance in randomized clinical trials; renewed interest in methodology to address the multiplicities resulting from a variety of sources inherent in the drug development process, and renewed interest in methods to assure data integrity. These emerging and recurrent issues provide a continuing challenge to the international community of statisticians involved in drug development. Moreover, the involvement of statisticians with different perspectives continues to enrich the field and contributes to improvement in the public health.
-
Prevention of Youthful Marijuana Use.
Cermak, Timmen L; Banys, Peter
2016-01-01
Considerable money and effort have been expended in attempts to prevent drug use by youth, with disappointing results. Too often, prevention programs have singled out youth with simplistic messages of exaggerated risk and the same politically acceptable solution for all-abstinence. Historically, prevention efforts have been less effective by not being soundly based in science and failing also to address adult drug and alcohol use as part of the problem. The Institute of Medicine continuum of care model developed in 1994 offers a framework for a more sophisticated, three-tiered approach to prevention, defined as all services provided prior to a clinical diagnosis of a substance use disorder. By dividing prevention efforts into universal (delivered to broad populations without consideration of individual risk for developing substance use disorder), selected (targeting sub-groups of individuals identified on the basis of characteristics known to create an elevated risk for substance use disorder), and indicated (addressing individuals identified on the basis of manifest risk behaviors), prevention can be better tailored to meet different levels of need. Student Assistance Programs (SAPs) and community coalitions provide examples of how IOM's continuum of care model can be integrated into drug prevention programs for youth.
-
A Military-Centered Approach to Neuroprotection for Traumatic Brain Injury
Shear, Deborah A.; Tortella, Frank C.
2013-01-01
Studies in animals show that many compounds and therapeutics have the potential to greatly reduce the morbidity and post-injury clinical sequela for soldiers experiencing TBI. However, to date there are no FDA approved drugs for the treatment of TBI. In fact, expert opinion suggests that combination therapies will be necessary to treat any stage of TBI recovery. Our approach to this research effort is to conduct comprehensive pre-clinical neuroprotection studies in military-relevant animal models of TBI using the most promising neuroprotective agents. In addition, emerging efforts incorporating novel treatment strategies such as stem cell based therapies and alternative therapeutic approaches will be discussed. The development of a non-surgical, non-invasive brain injury therapeutic clearly addresses a major, unresolved medical problem for the Combat Casualty Care Research Program. Since drug discovery is too expensive to be pursued by DOD in the TBI arena, this effort capitalizes on partnerships with the Private Sector (Pharmaceutical Companies) and academic collaborations (Operation Brain Trauma Therapy Consortium) to study therapies already under advanced development. Candidate therapies selected for research include drugs that are aimed at reducing the acute and delayed effects of the traumatic incident, stem cell therapies aimed at brain repair, and selective brain cooling to stabilize cerebral metabolism. Each of these efforts can also focus on combination therapies targeting multiple mechanisms of neuronal injury. PMID:23781213
-
Preventing adolescent drug use: long-term results of a junior high program.
Ellickson, P L; Bell, R M; McGuigan, K
1993-01-01
OBJECTIVES. Although several studies have reported short-term gains for drug-use prevention programs targeted at young adolescents, few have assessed the long-term effects of such programs. Such information is essential for judging how long prevention benefits last. This paper reports results over a 6-year period for a multisite randomized trial that achieved reductions in drug use during the junior high school years. METHODS. The 11-lesson curriculum, which was tested in 30 schools in eight highly diverse West Coast communities, focused on helping 7th and 8th grade students develop the motivation and skills to resist drugs. Schools were randomly assigned to treatment and control conditions. About 4000 students were assessed in grade 7 and six times thereafter through grade 12. Program effects were adjusted for pretest covariates and school effects. RESULTS. Once the lessons stopped, the program's effects on drug use stopped. Effects on cognitive risk factors persisted for a longer time (many through grade 10), but were not sufficient to produce corresponding reductions in use. CONCLUSIONS. It is unlikely that early prevention gains can be maintained without additional prevention efforts during high school. Future research is needed to develop and test such efforts. PMID:8498624
-
The war on drugs in sport: a perspective from the front-line.
Mendoza, John
2002-07-01
Recent international developments have served to solidify the international approach to doping in sport. The development of the World Anti-Doping Agency (WADA) has resulted in new, coordinated efforts to address this important sport issue. An array of new efforts and initiatives has been initiated by the new agency. The Sydney and Salt Lake City Olympics were characterized by intensive efforts to minimize doping. The antidoping environment is evolving rapidly, and several profoundly important developments will take place in the immediate future. To outline the challenges, opportunities, and changing circumstances of the current antidoping environment so that sport medicine practitioners might understand the context in which a variety of new initiatives and approaches will develop. At the same time, to ensure that practitioners understand the importance of appropriately developed and delivered antidoping policies, programs, and procedures, and the need for their harmonization. To ensure that sport medicine practitioners appreciate the need for a comprehensive approach to doping control, i.e., programs that include much more than drug testing. A review of relevant policy documents derived from a variety of sport and antidoping organizations; selected references drawn from MEDLINE; and materials prepared by colleagues drawn from the international antidoping community. The increased global effort to address doping is welcome. It will require that several critical issues be addressed that will test the resolve of all involved.
-
Application of liposomal technologies for delivery of platinum analogs in oncology
Liu, Demin; He, Chunbai; Wang, Andrew Z; Lin, Wenbin
2013-01-01
Platinum-based chemotherapy, such as cisplatin, oxaliplatin, and carboplatin, is one of the most widely utilized classes of cancer therapeutics. While highly effective, the clinical applications of platinum-based drugs are limited by their toxicity profiles as well as suboptimal pharmacokinetic properties. Therefore, one of the key research areas in oncology has been to develop novel platinum analog drugs and engineer new platinum drug formulations to improve the therapeutic ratio further. Such efforts have led to the development of platinum analogs including nedaplatin, heptaplatin, and lobaplatin. Moreover, reformulating platinum drugs using liposomes has resulted in the development of L-NDPP (Aroplatin™), SPI-77, Lipoplatin™, Lipoxal™, and LiPlaCis®. Liposomes possess several attractive biological activities, including biocompatibility, high drug loading, and improved pharmacokinetics, that are well suited for platinum drug delivery. In this review, we discuss the various platinum drugs and their delivery using liposome-based drug delivery vehicles. We compare and contrast the different liposome platforms as well as speculate on the future of platinum drug delivery research. PMID:24023517
-
Nano anti-cancer drugs: pros and cons and future perspectives.
Ali, Imran
2011-02-01
For last one decade, scientists are working for developing nano anti-cancer drugs with claim of ideal ones due to their targeted chemotherapic nature. These drugs have many beneficial properties such as targeted drug delivery and gene therapy modalities with minimum side effects. This article describes pros and cons and future perspectives of nano anti-cancer drugs. Efforts have been made to address importance, special features, toxicities (general, blood identities, immune system and environmental) and future perspectives of nano anti-cancer drugs. It was concluded that nano anti-cancer drugs may be magic bullet drugs for cancer treatment leading to bright future of the whole world.
-
In Silico Chemogenomics Drug Repositioning Strategies for Neglected Tropical Diseases.
Andrade, Carolina Horta; Neves, Bruno Junior; Melo-Filho, Cleber Camilo; Rodrigues, Juliana; Silva, Diego Cabral; Braga, Rodolpho Campos; Cravo, Pedro Vitor Lemos
2018-03-08
Only ~1% of all drug candidates against Neglected Tropical Diseases (NTDs) have reached clinical trials in the last decades, underscoring the need for new, safe and effective treatments. In such context, drug repositioning, which allows finding novel indications for approved drugs whose pharmacokinetic and safety profiles are already known, is emerging as a promising strategy for tackling NTDs. Chemogenomics is a direct descendent of the typical drug discovery process that involves the systematic screening of chemical compounds against drug targets in high-throughput screening (HTS) efforts, for the identification of lead compounds. However, different to the one-drug-one-target paradigm, chemogenomics attempts to identify all potential ligands for all possible targets and diseases. In this review, we summarize current methodological development efforts in drug repositioning that use state-of-the-art computational ligand- and structure-based chemogenomics approaches. Furthermore, we highlighted the recent progress in computational drug repositioning for some NTDs, based on curation and modeling of genomic, biological, and chemical data. Additionally, we also present in-house and other successful examples and suggest possible solutions to existing pitfalls. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
-
Combination Approaches to Combat Multi-Drug Resistant Bacteria
Worthington, Roberta J.; Melander, Christian
2013-01-01
The increasing prevalence of infections caused by multi-drug resistant bacteria is a global health problem that is exacerbated by the dearth of novel classes of antibiotics entering the clinic over the past 40 years. Herein we describe recent developments toward combination therapies for the treatment of multi-drug resistant bacterial infections. These efforts include antibiotic-antibiotic combinations, and the development of adjuvants that either directly target resistance mechanisms such as the inhibition of β-lactamase enzymes, or indirectly target resistance by interfering with bacterial signaling pathways such as two-component systems. We also discuss screening of libraries of previously approved drugs to identify non-obvious antimicrobial adjuvants. PMID:23333434
-
The Effects of Acute Exposure to Neuroactive Drugs on the Locomotor Activity of Larval Zebrafish
In an effort to develop a rapid in vivo screen for EPA’s prioritization of toxic chemicals, we have begun to characterize the locomotor activity of zebrafish (Danio rerio) larvae using prototypic drugs that act on the central nervous system. Initially, we chose to define the beh...
-
Tobbell, Dominique A
2008-01-01
During the 1960s, the drug industry was the subject of two congressional investigations into its business practices and pricing policies, and in 1962, passage of the Drug Amendments mandated greater Food and Drug Administration authority over pharmaceutical development. In this article, I examine the industry's efforts to circumvent these political challenges by drawing on its longstanding relationship with academic physicians and the American Medical Association. Using the medical profession's shared concern about expanding government oversight over therapeutic practice, the industry called on academic physicians to join forces with it and establish an expert advisory body to guide government officials on pharmaceutical policy. Drawing on research in the archives of the University of Pennsylvania and the National Academy of Sciences and a careful reading of the trade and biomedical literature and congressional documents, I argue that by positioning themselves as pharmaceutical experts, the members of this industry-academic alliance gave industry a seat at the policy table and enabled it to challenge the efforts of pharmaceutical reformers to further increase the government's role in drug development.
-
The role of academic institutions in the development of drugs for rare and neglected diseases.
Coles, L D; Cloyd, J C
2012-08-01
There are approximately 7,000 rare disorders, many of which are life-threatening. Diagnosis is often problematic, and therapies are few. Before the passage of the Orphan Drug Act in 1983, neither the pharmaceutical industry nor universities devoted much effort to research on rare diseases. Important changes have occurred within and outside universities that position them to play a significant role in developing orphan drugs. Several models are being employed to promote drug-related research, including disease-focused, discovery-focused, development-focused, and industry-partnership-focused approaches. However, significant barriers challenge universities' ability to fully contribute to orphan drug development. Academic institutions, along with industry, government, and not-for-profit organizations, must address these issues in order to advance the field. New initiatives designed to increase university-based orphan drug research include creating mechanisms to ensure program continuity, building research and regulatory support infrastructure, facilitating commercialization, expanding government support, and developing mutually beneficial partnerships among academe, industry, and government.
-
Fujie, Akihiko
2017-01-01
To actualize the invention of all-Japanese medicines, the Department of Innovative Drug Discovery and Development (iD3) in the Japan Agency for Medical Research and Development (AMED) serves as the headquarters for the Drug Discovery Support Network. iD3 assists with creating research strategies for the seeds of medicines discovered by academia and provides technological support, intellectual property management, and aid for applying the seeds through industry-led efforts. In this review, from the perspective of a science coordinator, I will describe the current activities of the drug discovery support network and iD3 as well as the challenges and future developments of pharmaceutical research and development using the natural product drug discovery method.
-
Ramamoorthi, Roopa; Graef, Katy M; Dent, Jennifer
2015-01-01
Schistosomiasis, one of 17 diseases deemed to be neglected by the World Health Organization, has received little attention from the biopharmaceutical industry. Due to this, only a handful of drugs have been developed to treat schistosomiasis, with only one, praziquantel, used in most endemic regions. Growing concern over resistance coupled with praziquantel's incomplete efficacy across all stages of the Schistosoma platyhelminth life cycle highlights the urgent need for new drugs. The WIPO Re:Search consortium is a platform whereupon biopharmaceutical company compounds are being repurposed to efficiently and cost-effectively develop new drugs for neglected diseases such as schistosomiasis. This article summarizes recent clinical-stage efforts to identify new antischistosomals and highlights biopharmaceutical company compounds with potential for repurposing to treat schistosomiasis.
-
[Nanoscale drug carriers for traditional Chinese medicine research and development].
Yi, Cheng-xue; Yu, Jiang-nan; Xu, Xi-ming
2008-08-01
Nanocarriers generally made of natural or artificial polymers ranging in size from about 10-1 000 nm, possess versatile properties suitable for drug delivery, including good biocompatibility and biodegradability, potential capability of targeted delivery and controlled release of incorporated drugs, and have been extensively used in the development of new drug delivery systems (DDS). These types of nano-DDS have considerable potential to traditional Chinese medicine (TCM), and recently have attracted increasing efforts on the TCM research and development. In this review, the recently published literature worldwide is covered to describe the latest advances in the applications as TCM delivery carriers, and to highlight the characteristics and preparation methods of some selected examples of promising nanocarriers such as nanoparticles, lipid nanoparticles, nanoemulsions, nanomicelles and nanoliposomes.
-
A community effort to assess and improve drug sensitivity prediction algorithms
Costello, James C; Heiser, Laura M; Georgii, Elisabeth; Gönen, Mehmet; Menden, Michael P; Wang, Nicholas J; Bansal, Mukesh; Ammad-ud-din, Muhammad; Hintsanen, Petteri; Khan, Suleiman A; Mpindi, John-Patrick; Kallioniemi, Olli; Honkela, Antti; Aittokallio, Tero; Wennerberg, Krister; Collins, James J; Gallahan, Dan; Singer, Dinah; Saez-Rodriguez, Julio; Kaski, Samuel; Gray, Joe W; Stolovitzky, Gustavo
2015-01-01
Predicting the best treatment strategy from genomic information is a core goal of precision medicine. Here we focus on predicting drug response based on a cohort of genomic, epigenomic and proteomic profiling data sets measured in human breast cancer cell lines. Through a collaborative effort between the National Cancer Institute (NCI) and the Dialogue on Reverse Engineering Assessment and Methods (DREAM) project, we analyzed a total of 44 drug sensitivity prediction algorithms. The top-performing approaches modeled nonlinear relationships and incorporated biological pathway information. We found that gene expression microarrays consistently provided the best predictive power of the individual profiling data sets; however, performance was increased by including multiple, independent data sets. We discuss the innovations underlying the top-performing methodology, Bayesian multitask MKL, and we provide detailed descriptions of all methods. This study establishes benchmarks for drug sensitivity prediction and identifies approaches that can be leveraged for the development of new methods. PMID:24880487
-
A community effort to assess and improve drug sensitivity prediction algorithms.
Costello, James C; Heiser, Laura M; Georgii, Elisabeth; Gönen, Mehmet; Menden, Michael P; Wang, Nicholas J; Bansal, Mukesh; Ammad-ud-din, Muhammad; Hintsanen, Petteri; Khan, Suleiman A; Mpindi, John-Patrick; Kallioniemi, Olli; Honkela, Antti; Aittokallio, Tero; Wennerberg, Krister; Collins, James J; Gallahan, Dan; Singer, Dinah; Saez-Rodriguez, Julio; Kaski, Samuel; Gray, Joe W; Stolovitzky, Gustavo
2014-12-01
Predicting the best treatment strategy from genomic information is a core goal of precision medicine. Here we focus on predicting drug response based on a cohort of genomic, epigenomic and proteomic profiling data sets measured in human breast cancer cell lines. Through a collaborative effort between the National Cancer Institute (NCI) and the Dialogue on Reverse Engineering Assessment and Methods (DREAM) project, we analyzed a total of 44 drug sensitivity prediction algorithms. The top-performing approaches modeled nonlinear relationships and incorporated biological pathway information. We found that gene expression microarrays consistently provided the best predictive power of the individual profiling data sets; however, performance was increased by including multiple, independent data sets. We discuss the innovations underlying the top-performing methodology, Bayesian multitask MKL, and we provide detailed descriptions of all methods. This study establishes benchmarks for drug sensitivity prediction and identifies approaches that can be leveraged for the development of new methods.
-
Ekins, Sean; Williams, Antony J
2014-03-01
There are many funded efforts going on focused on tuberculosis research and drug or vaccine development. There is little if any global coordination or collaboration and subsequently there are likely to be huge data silos and duplication of efforts. We now propose steps to remedy this by fostering more open science in TB research. Copyright © 2013 Elsevier Ltd. All rights reserved.
-
Three-Dimensional Cell Cultures in Drug Discovery and Development
Fang, Ye; Eglen, Richard M.
2017-01-01
The past decades have witnessed significant efforts toward the development of three-dimensional (3D) cell cultures as systems that better mimic in vivo physiology. Today, 3D cell cultures are emerging, not only as a new tool in early drug discovery but also as potential therapeutics to treat disease. In this review, we assess leading 3D cell culture technologies and their impact on drug discovery, including spheroids, organoids, scaffolds, hydrogels, organs-on-chips, and 3D bioprinting. We also discuss the implementation of these technologies in compound identification, screening, and development, ranging from disease modeling to assessment of efficacy and safety profiles. PMID:28520521
-
Molecular dynamics-driven drug discovery: leaping forward with confidence.
Ganesan, Aravindhan; Coote, Michelle L; Barakat, Khaled
2017-02-01
Given the significant time and financial costs of developing a commercial drug, it remains important to constantly reform the drug discovery pipeline with novel technologies that can narrow the candidates down to the most promising lead compounds for clinical testing. The past decade has witnessed tremendous growth in computational capabilities that enable in silico approaches to expedite drug discovery processes. Molecular dynamics (MD) has become a particularly important tool in drug design and discovery. From classical MD methods to more sophisticated hybrid classical/quantum mechanical (QM) approaches, MD simulations are now able to offer extraordinary insights into ligand-receptor interactions. In this review, we discuss how the applications of MD approaches are significantly transforming current drug discovery and development efforts. Copyright © 2016 Elsevier Ltd. All rights reserved.
-
Drug-conjugated polymers as gene carriers for synergistic therapeutic effect.
Pofali, P A; Singh, B; Dandekar, P; Jain, R D; Maharjan, S; Choi, Y J; Arote, R B; Cho, C S
2016-05-01
The ability to safely and effectively transfer gene into cells is the fundamental goal of gene delivery. In spite of the best efforts of researchers around the world, gene therapy has limited success. This may be because of several limitations of delivering gene which is one of the greatest technical challenges in the modern medicine. To address these issues, many efforts have been made to bind drugs and genes together by polymers for co-delivery to achieve synergistic effect. Usually, binding interaction of drugs with polymers is either physical or chemical. In case of drug-polymer physical interaction, the efficiency of drugs generally decreases because of separation of drugs from polymers in vivo whenever it comes in contact with charged biofluid/s or cells. While chemical interaction of drug-polymer overcomes the aforementioned obstacle, several problems such as steric hindrance, solubility, and biodegradability hinder it to develop as gene carrier. Considering these benefits and pitfalls, the objective of this review is to discuss the possible extent of drug-conjugated polymers as safe and efficient gene delivery carriers for achieving synergistic effect to combat various genetic disorders. © 2015 Wiley Periodicals, Inc.
-
Molecularly Imprinted Polymers: Novel Discovery for Drug Delivery.
Dhanashree, Surve; Priyanka, Mohite; Manisha, Karpe; Vilasrao, Kadam
2016-01-01
Molecularly imprinted polymers (MIP) are novel carriers synthesized by imprinting of a template over a polymer. This paper presents the recent application of MIP for diagnostic and therapeutic drug delivery. MIP owing to their 3D polymeric structures and due to bond formation with the template serves as a reservoir of active causing stimuli sensitive, enantioselective, targetted and/or controlled release. The review elaborates about key factors for optimization of MIP, controlled release by MIP for various administration routes various forms like patches, contact lenses, nanowires along with illustrations. To overcome the limitation of organic solvent usage causing increased cost, water compatible MIP and use of supercritical fluid technology for molecular imprinting were developed. Novel methods for developing water compatible MIP like pickering emulsion polymerization, co-precipitation method, cyclodextrin imprinting, surface grafting, controlled/living radical chain polymerization methods are described with illustration in this review. Various protein imprinting methods like bulk, epitope and surface imprinting are described along with illustrations. Further, application of MIP in microdevices as biomimetic sensing element for personalized therapy is elaborated. Although development and application of MIP in drug delivery is still at its infancy, constant efforts of researchers will lead to a novel intelligent drug delivery with commercial value. Efforts should be directed in developing solid oral dosage forms consisting of MIP for therapeutic protein and peptide delivery and targeted release of potent drugs addressing life threatening disease like cancer. Amalgamation of bio-engineering and pharmaceutical techniques can make these future prospects into reality.
-
Parriot, Sandi; Hudson, Thomas H.; Lang, Thierry; Ngundam, Franklyn; Leed, Susan; Sena, Jenell; Harris, Michael; O'Neil, Michael; Sciotti, Richard; Read, Lisa; Lecoeur, Herve; Grogl, Max
2017-01-01
ABSTRACT In any drug discovery and development effort, a reduction in the time of the lead optimization cycle is critical to decrease the time to license and reduce costs. In addition, ethical guidelines call for the more ethical use of animals to minimize the number of animals used and decrease their suffering. Therefore, any effort to develop drugs to treat cutaneous leishmaniasis requires multiple tiers of in vivo testing that start with higher-throughput efficacy assessments and progress to lower-throughput models with the most clinical relevance. Here, we describe the validation of a high-throughput, first-tier, noninvasive model of lesion suppression that uses an in vivo optical imaging technology for the initial screening of compounds. A strong correlation between luciferase activity and the parasite load at up to 18 days postinfection was found. This correlation allows the direct assessment of the effects of drug treatment on parasite burden. We demonstrate that there is a strong correlation between drug efficacy measured on day 18 postinfection and the suppression of lesion size by day 60 postinfection, which allows us to reach an accurate conclusion on drug efficacy in only 18 days. Compounds demonstrating a significant reduction in the bioluminescence signal compared to that in control animals can be tested in lower-throughput, more definitive tests of lesion cure in BALB/c mice and Golden Syrian hamsters (GSH) using Old World and New World parasites. PMID:28137819
-
van Rijt, Sabine H.; Sadler, Peter J.
2010-01-01
This review illustrates notable recent progress in the field of medicinal bioinorganic chemistry with many new approaches to the design of innovative metal-based anticancer drugs emerging. Current research addressing the problems associated with platinum drugs has focused on other metal-based therapeutics that have different modes of action, and on prodrug and targeting strategies in an effort to diminish the side-effects of cisplatin chemotherapy. PMID:19782150
-
Is the GAIN Act a turning point in new antibiotic discovery?
Brown, Eric D
2013-03-01
The United States GAIN (Generating Antibiotic Incentives Now) Act is a call to action for new antibiotic discovery and development that arises from a ground swell of concern over declining activity in this therapeutic area in the pharmaceutical sector. The GAIN Act aims to provide economic incentives for antibiotic drug discovery in the form of market exclusivity and accelerated drug approval processes. The legislation comes on the heels of nearly two decades of failure using the tools of modern drug discovery to find new antibiotic drugs. The lessons of failure are examined herein as are the prospects for a renewed effort in antibiotic drug discovery and development stimulated by new investments in both the public and private sector.
-
ERIC Educational Resources Information Center
Hawkins, J. David; Nederhood, Britt
This handbook was developed for the purpose of providing drug and alcohol prevention program managers with a comprehensive yet easy-to-use tool to help their evaluation efforts. The handbook emphasizes program staff members working together as a team. It provides instruments and activities for determining program effectiveness, as well as…
-
2010-01-01
Despite increasing efforts and support for anti-malarial drug R&D, globally anti-malarial drug discovery and development remains largely uncoordinated and fragmented. The current window of opportunity for large scale funding of R&D into malaria is likely to narrow in the coming decade due to a contraction in available resources caused by the current economic difficulties and new priorities (e.g. climate change). It is, therefore, essential that stakeholders are given well-articulated action plans and priorities to guide judgments on where resources can be best targeted. The CRIMALDDI Consortium (a European Union funded initiative) has been set up to develop, through a process of stakeholder and expert consultations, such priorities and recommendations to address them. It is hoped that the recommendations will help to guide the priorities of the European anti-malarial research as well as the wider global discovery agenda in the coming decade. PMID:20626844
-
Rosenfeldt, Hans; Kropp, Timothy; Benson, Kimberly; Ricci, M Stacey; McGuinn, W David; Verbois, S Leigh
2010-03-01
The drug development of new anti-cancer agents is streamlined in response to the urgency of bringing effective drugs to market for patients with limited life expectancy. FDA's regulation of oncology drugs has evolved from the practices set forth in Arnold Lehman's seminal work published in the 1950s through the current drafting of a new International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) safety guidance for anti-cancer drug nonclinical evaluations. The ICH combines the efforts of the regulatory authorities of Europe, Japan, and the United States and the pharmaceutical industry from these three regions to streamline the scientific and technical aspects of drug development. The recent development of new oncology drug classes with novel mechanisms of action has improved survival rates for some cancers but also brings new challenges for safety evaluation. Here we present the legacy of Lehman and colleagues in the context of past and present oncology drug development practices and focus on some of the current issues at the center of an evolving harmonization process that will generate a new safety guidance for oncology drugs, ICH S9. The purpose of this new guidance will be to facilitate oncology drug development on a global scale by standardizing regional safety requirements.
-
Otic drug delivery systems: formulation principles and recent developments.
Liu, Xu; Li, Mingshuang; Smyth, Hugh; Zhang, Feng
2018-04-25
Disorders of the ear severely impact the quality of life of millions of people, but the treatment of these disorders is an ongoing, but often overlooked challenge particularly in terms of formulation design and product development. The prevalence of ear disorders has spurred significant efforts to develop new therapeutic agents, but perhaps less innovation has been applied to new drug delivery systems to improve the efficacy of ear disease treatments. This review provides a brief overview of physiology, major diseases, and current therapies used via the otic route of administration. The primary focuses are on the various administration routes and their formulation principles. The article also presents recent advances in otic drug deliveries as well as potential limitations. Otic drug delivery technology will likely evolve in the next decade and more efficient or specific treatments for ear disease will arise from the development of less invasive drug delivery methods, safe and highly controlled drug delivery systems, and biotechnology targeting therapies.
-
[Challenges and strategies of drug innovation].
Guo, Zong-Ru; Zhao, Hong-Yu
2013-07-01
Drug research involves scientific discovery, technological inventions and product development. This multiple dimensional effort embodies both high risk and high reward and is considered one of the most complicated human activities. Prior to the initiation of a program, an in-depth analysis of "what to do" and "how to do it" must be conducted. On the macro level, market prospects, capital required, risk assessment, necessary human resources, etc. need to be evaluated critically. For execution, drug candidates need to be optimized in multiple properties such as potency, selectivity, pharmacokinetics, safety, formulation, etc., all with the constraint of finite amount of time and resources, to maximize the probability of success in clinical development. Drug discovery is enormously complicated, both in terms of technological innovation and organizing capital and other resources. A deep understanding of the complexity of drug research and our competitive edge is critical for success. Our unique government-enterprise-academia system represents a distinct advantage. As a new player, we have not heavily invested in any particular discovery paradigm, which allows us to select the optimal approach with little organizational burden. Virtue R&D model using CROs has gained momentum lately and China is a global leader in CRO market. Essentially all technological support for drug discovery can be found in China, which greatly enables domestic R&D efforts. The information technology revolution ensures the globalization of drug discovery knowledge, which has bridged much of the gap between China and the developed countries. The blockbuster model and the target-centric drug discovery paradigm have overlooked the research in several important fields such as injectable drugs, orphan drugs, and following high quality therapeutic leads, etc. Prejudice against covalent ligands, prodrugs, nondrug-like ligands can also be taken advantage of to find novel medicines. This article will discuss the current challenges and future opportunities for drug innovation in China.
-
Drug discovery for neglected tropical diseases at the Sandler Center.
Robertson, Stephanie A; Renslo, Adam R
2011-08-01
The Sandler Center's approach to target-based drug discovery for neglected tropical diseases is to focus on parasite targets that are homologous to human targets being actively investigated in the pharmaceutical industry. In this way we attempt to use both the know-how and actual chemical matter from other drug-development efforts to jump start the discovery process for neglected tropical diseases. Our approach is akin to drug repurposing, except that we seek to repurpose leads rather than drugs. Medicinal chemistry can then be applied to optimize the leads specifically for the desired antiparasitic indication.
-
The Next Wave of Influenza Drugs.
Shaw, Megan L
2017-10-13
Options for influenza therapy are currently limited to one class of drug, the neuraminidase inhibitors. Amidst concerns about drug resistance, much effort has been placed on the discovery of new drugs with distinct targets and mechanisms of action, with great success. There are now several candidates in late stage development which include small molecules targeting the three subunits of the viral polymerase complex and monoclonal antibodies targeting the hemagglutinin, as well as host-directed therapies. The availability of drugs with diverse mechanisms now opens the door to exploring combination therapies for influenza, and the range of administration routes presents more opportunities for treating hospitalized patients.
-
Drug discovery for neglected tropical diseases at the Sandler Center
Robertson, Stephanie A; Renslo, Adam R
2011-01-01
The Sandler Center’s approach to target-based drug discovery for neglected tropical diseases is to focus on parasite targets that are homologous to human targets being actively investigated in the pharmaceutical industry. In this way we attempt to use both the know-how and actual chemical matter from other drug-development efforts to jump start the discovery process for neglected tropical diseases. Our approach is akin to drug repurposing, except that we seek to repurpose leads rather than drugs. Medicinal chemistry can then be applied to optimize the leads specifically for the desired antiparasitic indication. PMID:21859302
-
Human neuroscience at National Institute on Drug Abuse: Implications for genetics research
DOE Office of Scientific and Technical Information (OSTI.GOV)
Gordon, H.W.
It is becoming clear that there is a genetic component to drug abuse. Family studies, adoption studies, and critical twin studies have all pointed to some genetic vulnerability or risk factors for an individual to abuse psychoactive drugs depending on certain psychopathologies in the biological parents and/or parents` own drug use. The question for the next generation of research at the National Institute on Drug Abuse (NIDA) is to apply the rapidly developing technology in molecular genetics in an effort to determine the candidate genes contributing to the risk. 19 refs.
-
[Smuggling of illegal drugs by body suffers].
Aksnes, Tonje Amb; Jacobsen, Dag
2004-07-01
Body packers are persons who smuggle illegal drugs by swallowing condoms or plastic cylinders containing such substances. Body stuffers are drug dealers or drug abusers who swallow illegal drugs in an effort to conceal evidence during an arrest or in fear of being arrested. We report four cases and discuss management. Asymptomatic body packers may be managed conservatively with laxatives and water-soluble contrast medium. This method allows an accurate follow-up with abdominal radiography. If patients develop abdominal pain or signs and symptoms of intoxication, surgical intervention should be considered. Both types of patients should be monitored carefully.
-
Open Drug Discovery Toolkit (ODDT): a new open-source player in the drug discovery field.
Wójcikowski, Maciej; Zielenkiewicz, Piotr; Siedlecki, Pawel
2015-01-01
There has been huge progress in the open cheminformatics field in both methods and software development. Unfortunately, there has been little effort to unite those methods and software into one package. We here describe the Open Drug Discovery Toolkit (ODDT), which aims to fulfill the need for comprehensive and open source drug discovery software. The Open Drug Discovery Toolkit was developed as a free and open source tool for both computer aided drug discovery (CADD) developers and researchers. ODDT reimplements many state-of-the-art methods, such as machine learning scoring functions (RF-Score and NNScore) and wraps other external software to ease the process of developing CADD pipelines. ODDT is an out-of-the-box solution designed to be easily customizable and extensible. Therefore, users are strongly encouraged to extend it and develop new methods. We here present three use cases for ODDT in common tasks in computer-aided drug discovery. Open Drug Discovery Toolkit is released on a permissive 3-clause BSD license for both academic and industrial use. ODDT's source code, additional examples and documentation are available on GitHub (https://github.com/oddt/oddt).
-
National Guard Counterdrug Operations: A Case Study for Greater Participation
2003-04-01
Executive Branch responsible for developing, coordinating, and overseeing the implementation of the National Drug Control Strategy ( NDCS ). ONDCP oversees...It is the Drug Czar’s responsibility to ensure that the efforts of both departments are consolidated and support the overall NDCS . The 2002 NDCS ...priority, as it was in the 1999 NDCS . The president’s NDCS seeks to reduce use of illegal drugs by 10 percent over two years and 25 percent over five
-
Khleif, Samir N; Doroshow, James H; Hait, William N
2010-07-01
Recent discoveries in cancer biology have greatly increased our understanding of cancer at the molecular and cellular level, but translating this knowledge into safe and effective therapies for cancer patients has proved to be challenging. There is a growing imperative to modernize the drug development process by incorporating new techniques that can predict the safety and effectiveness of new drugs faster, with more certainty, and at lower cost. Biomarkers are central to accelerating the identification and adoption of new therapies, but currently, many barriers impede their use in drug development and clinical practice. In 2007, the AACR-FDA-NCI Cancer Biomarkers Collaborative stepped into the national effort to bring together disparate stakeholders to clearly delineate these barriers, to develop recommendations for integrating biomarkers into the cancer drug development enterprise, and to set in motion the necessary action plans and collaborations to see the promise of biomarkers come to fruition, efficiently delivering quality cancer care to patients.
-
The interaction between intellectual property and drug regulatory systems: global perspectives.
Madden, Edward A
2007-02-01
Regulatory compliance in the development, production and sale of new drugs accounts for the largest single expense in bringing a drug product to market. To justify developmental and regulatory compliance costs, drug innovators turn to the intellectual property (IP) system to provide a means for securing returns on investment. Because the drug regulatory system in most countries operates in isolation of the IP system, one of the greatest challenges facing the pharmaceutical industry is the extent to which IP rights can be managed against an independent drug regulatory system. Many regulatory bodies in developed countries have sought to ensure a compromise between the rights of generic companies and IP owners by including safeguards in the regulatory framework, such as patent linking and data protection; however, these efforts are yet to be applied in some of the biggest potential drug markets in emerging economies.
-
Qi, Sheng; McAuley, William J; Yang, Ziyi; Tipduangta, Pratchaya
2014-07-01
Use of the amorphous state is considered to be one of the most effective approaches for improving the dissolution and subsequent oral bioavailability of poorly water-soluble drugs. However as the amorphous state has much higher physical instability in comparison with its crystalline counterpart, stabilization of amorphous drugs in a solid-dosage form presents a major challenge to formulators. The currently used approaches for stabilizing amorphous drug are discussed in this article with respect to their preparation, mechanism of stabilization and limitations. In order to realize the potential of amorphous formulations, significant efforts are required to enable the prediction of formulation performance. This will facilitate the development of computational tools that can inform a rapid and rational formulation development process for amorphous drugs.
-
NASA Astrophysics Data System (ADS)
Patel, Anant A.
As a result of tremendous efforts in past few decades, various techniques have been developed in order to resolve solubility issues associated with class II and IV drugs, However, majority of these techniques offer benefits associated with certain drawbacks; majorly including low drug loading, physical instability on storage and excessive use of environmentally challenging organic solvents. Hence, current effort was to develop an eco-friendly technique using liquid salt as green solvent, which can offer improvement in dissolution while maintaining long term stability. The liquid salt formulations (LSF) of poorly soluble model drugs ibuprofen, gemfibrozil and indomethacin were developed using 1-Ethyl-3-methylimidazolium ethyl sulfate (EMIM ES) as a non-toxic and environmentally friendly alternate to organic solvents. Liquid medications containing clear solutions of drug, EMIM ES and polysorbate 20, were adsorbed onto porous carrier Neusilin US2 to form free flowing powder. The LSF demonstrated greater rate and extent of dissolution compared to crystalline drugs. The dissolution data revealed that more than 80% drug release from LSF within 20 mins compared to less than 18% release from pure drugs. As high as 70% w/w liquid loading was achieved while maintaining good flowability and compressibility. In addition, the LSF samples exposed to high temperature and high humidity i.e. 40°C/80% RH for 8 weeks, demonstrated excellent physical stability without any signs of precipitation or crystallization. As most desirable form of administration is tablet, the developed liquid salt formulations were transformed into tablets using design of experiment approach by Design Expert Software. The tablet formulation composition and critical parameter were optimized using Box-Behnken Design. This innovative liquid salt formulation technique offered improvement in dissolution rate and extent as well as contributed to excellent physical stability on storage. Moreover, this formulation approach served as eco-friendly compelling alternate to conventional techniques involving organic solvents.
-
Discovery of Bioactive Compounds by the UIC-ICBG Drug Discovery Program in the 18 Years Since 1998.
Zhang, Hong-Jie; Li, Wan-Fei; Fong, Harry H S; Soejarto, Djaja Doel
2016-10-31
The International Cooperative Biodiversity Groups (ICBG) Program based at the University of Illinois at Chicago (UIC) is a program aimed to address the interdependent issues of inventory and conservation of biodiversity, drug discovery and sustained economic growth in both developing and developed countries. It is an interdisciplinary program involving the extensive synergies and collaborative efforts of botanists, chemists and biologists in the countries of Vietnam, Laos and the USA. The UIC-ICBG drug discovery efforts over the past 18 years have resulted in the collection of a cumulative total of more than 5500 plant samples (representing more than 2000 species), that were evaluated for their potential biological effects against cancer, HIV, bird flu, tuberculosis and malaria. The bioassay-guided fractionation and separation of the bioactive plant leads resulted in the isolation of approximately 300 compounds of varying degrees of structural complexity and/or biological activity. The present paper summarizes the significant drug discovery achievements made by the UIC-ICBG team of multidisciplinary collaborators in the project over the period of 1998-2012 and the projects carried on in the subsequent years by involving the researchers in Hong Kong.
-
Alam, Fahmida; Islam, Md Asiful; Kamal, M A; Gan, Siew Hua
2016-08-13
Over the years, natural products have shown success as antidiabetics in vitro, in vivo and in clinical trials. Because natural product-derived drugs are more affordable and effective with fewer side-effects compared to conventional therapies, pharmaceutical research is increasingly leaning towards the discovery of new antidiabetic drugs from natural products targeting pathways or components associated with type 2 diabetes mellitus (T2DM) pathophysiology. However, the drug discovery process is very lengthy and costly with significant challenges. Therefore, various techniques are currently being developed for the preclinical research phase of drug discovery with the aim of drug development with less time and efforts from natural products. In this review, we have provided an update on natural products including fruits, vegetables, spices, nuts, beverages and mushrooms with potential antidiabetic activities from in vivo, in vitro and clinical studies. Synergistic interactions between natural products and antidiabetic drugs; and potential antidiabetic active compounds from natural products are also documented to pave the way for combination treatment and new drug discovery, respectively. Additionally, a brief idea of the drug discovery process along with the challenges that arise during drug development from natural products and the methods to conquer those challenges are discussed to create a more convenient future drug discovery process.
-
Natural products and drug discovery: a survey of stakeholders in industry and academia.
Amirkia, Vafa; Heinrich, Michael
2015-01-01
In recent decades, natural products have undisputedly played a leading role in the development of novel medicines. Yet, trends in the pharmaceutical industry at the level of research investments indicate that natural product research is neither prioritized nor perceived as fruitful in drug discovery programmes as compared with incremental structural modifications and large volume HTS screening of synthetics. We seek to understand this phenomenon through insights from highly experienced natural product experts in industry and academia. We conducted a survey including a series of qualitative and quantitative questions related to current insights and prospective developments in natural product drug development. The survey was completed by a cross-section of 52 respondents in industry and academia. One recurrent theme is the dissonance between the perceived high potential of NP as drug leads among individuals and the survey participants' assessment of the overall industry and/or company level strategies and their success. The study's industry and academic respondents did not perceive current discovery efforts as more effective as compared with previous decades, yet industry contacts perceived higher hit rates in HTS efforts as compared with academic respondents. Surprisingly, many industry contacts were highly critical to prevalent company and industry-wide drug discovery strategies indicating a high level of dissatisfaction within the industry. These findings support the notion that there is an increasing gap in perception between the effectiveness of well established, commercially widespread drug discovery strategies between those working in industry and academic experts. This research seeks to shed light on this gap and aid in furthering natural product discovery endeavors through an analysis of current bottlenecks in industry drug discovery programmes.
-
Johnstone, Timothy C.; Suntharalingam, Kogularamanan; Lippard, Stephen J.
2016-01-01
The platinum drugs, cisplatin, carboplatin, and oxaliplatin, prevail in the treatment of cancer,, but new platinum agents have been very slow to enter the clinic. Recently, however, there has been a surge of activity, based on a great deal of mechanistic information, aimed at developing non-classical platinum complexes that operate via mechanisms of action distinct from those of the approved drugs. The use of nanodelivery devices has also grown and many different strategies have been explored to incorporate platinum warheads into nanomedicine constructs. In this review, we discuss these efforts to create the next generation of platinum anticancer drugs. The introduction provides the reader with a brief overview of the use, development, and mechanism of action of the approved platinum drugs to provide the context in which more recent research has flourished. We then describe approaches that explore non-classical platinum(II) complexes with trans geometry and with a monofunctional coordination mode, polynuclear platinum(II) compounds, platinum(IV) prodrugs, dual-treat agents, and photoactivatable platinum(IV) complexes. Nanodelivery particles designed to deliver platinum(IV) complexes will also be discussed, including carbon nanotubes, carbon nanoparticles, gold nanoparticles, quantum dots, upconversion nanoparticles, and polymeric micelles. Additional nanoformulations including supramolecular self-assembled structures, proteins, peptides, metal-organic frameworks, and coordination polymers will then be described. Finally, the significant clinical progress made by nanoparticle formulations of platinum(II) agents will be reviewed. We anticipate that such a synthesis of disparate research efforts will not only help to generate new drug development ideas and strategies, but also reflect our optimism that the next generation of platinum cancer drugs is about to arrive. PMID:26865551
-
A long and winding road; evolution of antimicrobial drug development - crisis management.
Echols, Roger M
2012-11-01
The development of antimicrobial drugs has evolved from observational case reports to complex randomized prospective clinical trials in specific treatment indications. Beginning around the year 2000, the US FDA has evolved its approach on study design and other study characteristics, which has made the conduct of these studies more difficult and the outcomes for sponsors more risky. This has contributed to the decline in the discovery and development of new antimicrobials, which are needed to address the increasing problem of bacterial resistance to existing marketed products. This study reviews the historical basis for the current regulatory climate including the various crises that have led to considerable political pressures on the agency. Recent efforts to resolve development uncertainties and to provide economic incentives for future antimicrobial drug development are presented.
-
The Tuberculosis Drug Discovery and Development Pipeline and Emerging Drug Targets
Mdluli, Khisimuzi; Kaneko, Takushi; Upton, Anna
2015-01-01
The recent accelerated approval for use in extensively drug-resistant and multidrug-resistant-tuberculosis (MDR-TB) of two first-in-class TB drugs, bedaquiline and delamanid, has reinvigorated the TB drug discovery and development field. However, although several promising clinical development programs are ongoing to evaluate new TB drugs and regimens, the number of novel series represented is few. The global early-development pipeline is also woefully thin. To have a chance of achieving the goal of better, shorter, safer TB drug regimens with utility against drug-sensitive and drug-resistant disease, a robust and diverse global TB drug discovery pipeline is key, including innovative approaches that make use of recently acquired knowledge on the biology of TB. Fortunately, drug discovery for TB has resurged in recent years, generating compounds with varying potential for progression into developable leads. In parallel, advances have been made in understanding TB pathogenesis. It is now possible to apply the lessons learned from recent TB hit generation efforts and newly validated TB drug targets to generate the next wave of TB drug leads. Use of currently underexploited sources of chemical matter and lead-optimization strategies may also improve the efficiency of future TB drug discovery. Novel TB drug regimens with shorter treatment durations must target all subpopulations of Mycobacterium tuberculosis existing in an infection, including those responsible for the protracted TB treatment duration. This review summarizes the current TB drug development pipeline and proposes strategies for generating improved hits and leads in the discovery phase that could help achieve this goal. PMID:25635061
-
Microfluidics-assisted in vitro drug screening and carrier production
Tsui, Jonathan H.; Lee, Woohyuk; Pun, Suzie H.; Kim, Jungkyu; Kim, Deok-Ho
2013-01-01
Microfluidic platforms provide several unique advantages for drug development. In the production of drug carriers, physical properties such as size and shape, and chemical properties such as drug composition and pharmacokinetic parameters, can be modified simply and effectively by tuning the flow rate and geometries. Large numbers of carriers can then be fabricated with minimal effort and with little to no batch-to-batch variation. Additionally, cell or tissue culture models in microfluidic systems can be used as in vitro drug screening tools. Compared to in vivo animal models, microfluidic drug screening platforms allow for high-throughput and reproducible screening at a significantly lower cost, and when combined with current advances in tissue engineering, are also capable of mimicking native tissues. In this review, various microfluidic platforms for drug and gene carrier fabrication are reviewed to provide guidelines for designing appropriate carriers. In vitro microfluidic drug screening platforms designed for high-throughput analysis and replication of in vivo conditions are also reviewed to highlight future directions for drug research and development. PMID:23856409
-
National Drug Control Strategy.
ERIC Educational Resources Information Center
Office of National Drug Control Policy, Washington, DC.
This report presents a comprehensive blueprint for new direction and effort in the national fight against illegal drug use. It is the result of an intensive review of federal anti-drug efforts to date and incorporates advice and recommendations from hundreds of interested and involved anti-drug leaders outside the federal government. The…
-
Organ-on-a-Chip Technology for Reproducing Multiorgan Physiology.
Lee, Seung Hwan; Sung, Jong Hwan
2018-01-01
In the drug development process, the accurate prediction of drug efficacy and toxicity is important in order to reduce the cost, labor, and effort involved. For this purpose, conventional 2D cell culture models are used in the early phase of drug development. However, the differences between the in vitro and the in vivo systems have caused the failure of drugs in the later phase of the drug-development process. Therefore, there is a need for a novel in vitro model system that can provide accurate information for evaluating the drug efficacy and toxicity through a closer recapitulation of the in vivo system. Recently, the idea of using microtechnology for mimicking the microscale tissue environment has become widespread, leading to the development of "organ-on-a-chip." Furthermore, the system is further developed for realizing a multiorgan model for mimicking interactions between multiple organs. These advancements are still ongoing and are aimed at ultimately developing "body-on-a-chip" or "human-on-a-chip" devices for predicting the response of the whole body. This review summarizes recently developed organ-on-a-chip technologies, and their applications for reproducing multiorgan functions. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
-
Research, public policy and drug abuse: current approaches and new directions.
Smith, J P
This article examines current U.S. research policy in the drug abuse field and comments on future directions. It discusses three main themes: (1) the relationship of national policy and research on drug abuse; (2) how research is planned and priorities are set at the National Institute on Drug Abuse; and (3) the need for a variety of policy studies on drug abuse to help develop more effective national prevention and control efforts. Examination of national policy statements on drug abuse supply and demand reduction issued by administrations from John F. Kennedy to Ronald W. Reagan suggests a lack of appreciation of the potential that research offers to aid public policy and an underutilization of research as a response to gaps in our knowledge of how to deal with drug problems. This paper proposes development of a National Research Strategy on Drug Abuse to identify research goals that reflect national policy needs. The importance and contribution of policy studies, as part of the National Research Strategy, are discussed with a plea for research to improve policy analysis and development.
-
Kumar Kakkar, Ashish; Dahiya, Neha
2014-06-01
Strategy, Management and Health Policy Large pharmaceutical companies have traditionally focused on the development of blockbuster drugs that target disease states with large patient populations. However, with large-scale patent expirations and competition from generics and biosimilars, anemic pipelines, escalating clinical trial costs, and global health-care reform, the blockbuster model has become less viable. Orphan drug initiatives and the incentives accompanied by these have fostered renewed research efforts in the area of rare diseases and have led to the approval of more than 400 orphan products. Despite targeting much smaller patient populations, the revenue-generating potential of orphan drugs has been shown to be huge, with a greater return on investment than non-orphan drugs. The success of these "niche buster" therapeutics has led to a renewed interest from "Big Pharma" in the rare disease landscape. This article reviews the key drivers for orphan drug research and development, their profitability, and issues surrounding the emergence of large pharmaceutical firms into the orphan drug space. © 2014 Wiley Periodicals, Inc.
-
Advances in MRSA drug discovery: where are we and where do we need to be?
Kurosu, Michio; Siricilla, Shajila; Mitachi, Katsuhiko
2013-09-01
Methicillin-resistant Staphylococcus aureus (MRSA) have been on the increase during the past decade, due to the steady growth of the elderly and immunocompromised patients, and the emergence of multidrug-resistant (MDR) bacterial strains. Although there are a limited number of anti-MRSA drugs available, a number of different combination antimicrobial drug regimens have been used to treat serious MRSA infections. Thus, the addition of several new antistaphylococcal drugs into clinical practice should broaden clinician's therapeutic options. As MRSA is one of the most common and problematic bacteria associated with increasing antimicrobial resistance, continuous efforts for the discovery of lead compounds as well as development of alternative therapies and faster diagnostics are required. This article summarizes the FDA-approved drugs to treat MRSA infections, the drugs in clinical trials, and the drug leads for MRSA and related Gram-positive bacterial infections. In addition, the article discusses the mode of action of antistaphylococcal molecules and the resistant mechanisms of some molecules. The number of pipeline drugs presently undergoing clinical trials is not particularly encouraging. There are limited and rather expensive therapeutic options for MRSA infections in the critically ill. Further research efforts are required for effective phage therapy on MRSA infections in clinical use, which seem to be attractive therapeutic options for the future.
-
Multidrug Efflux Systems in Microaerobic and Anaerobic Bacteria
Xu, Zeling; Yan, Aixin
2015-01-01
Active drug efflux constitutes an important mechanism of antibiotic and multidrug resistance in bacteria. Understanding the distribution, expression, and physiological functions of multidrug efflux pumps, especially under physiologically and clinically relevant conditions of the pathogens, is the key to combat drug resistance. In animal hosts, most wounded, infected and inflamed tissues display low oxygen tensions. In this article, we summarize research development on multidrug efflux pumps in the medicinally relevant microaerobic and anaerobic pathogens and their implications in the effort to combat drug-resistant infections. PMID:27025630
-
Hanna, Debra; Romero, Klaus; Schito, Marco
2017-03-01
The development of novel tuberculosis (TB) multi-drug regimens that are more efficacious and of shorter duration requires a robust drug development pipeline. Advances in quantitative modeling and simulation can be used to maximize the utility of patient-level data from prior and contemporary clinical trials, thus optimizing study design for anti-TB regimens. This perspective article highlights the work of seven project teams developing first-in-class translational and quantitative methodologies that aim to inform drug development decision-making, dose selection, trial design, and safety assessments, in order to achieve shorter and safer therapies for patients in need. These tools offer the opportunity to evaluate multiple hypotheses and provide a means to identify, quantify, and understand relevant sources of variability, to optimize translation and clinical trial design. When incorporated into the broader regulatory sciences framework, these efforts have the potential to transform the development paradigm for TB combination development, as well as other areas of global health. Copyright © 2016. Published by Elsevier Ltd.
-
The worldwide trend of using botanical drugs and strategies for developing global drugs.
Ahn, Kyungseop
2017-03-01
Natural product drugs, or botanical drugs, are drugs composed of natural substances which have constituents with healthenhancing or medicinal activities. In Korea, government-led projects brought attention to botanical drugs invigorating domestic botanical drug industry. Foreign markets, as well, are growing bigger as the significance of botanical drugs stood out. To follow along with the tendency, Korea puts a lot of effort on developing botanical drugs suitable for global market. However, standards for approving drug sales vary by countries. And also, thorough standardization, certification, clinical studies and data of these will be required as well as data confirming safety and effectiveness. Meanwhile, as an international exchange in botanical drug market continues, the importance of plant resources was emphasized. Thus countries' ownership of domestic natural resources became vital. Not only establishing a systematic method to secure domestic plant resources, but also cooperation with other countries on sharing natural resources is essential to procure natural resources effectively. Korea started to show visible results with botanical drugs, and asthma/COPD treatment made out of speedwell is one example. Sufficient investment and government's active support for basic infrastructure for global botanical drugs will bring Korea to much higher level of botanical drug development. [BMB Reports 2017; 50(3): 111-116].
-
Alcohol and Drug Abuse Intervention and Prevention Program. Annual Report 1988-89.
ERIC Educational Resources Information Center
Rapaport, Ross J.
Institutions of higher learning are taking responsibility for and becoming part of the societal effort to combat alcohol/drug problems. There are a number of national and state efforts which specifically target higher education for prevention, education, intervention, treatment, and referral efforts. Considerable efforts are currently underway to…
-
Vaccine and Drug Ontology Studies (VDOS 2014).
Tao, Cui; He, Yongqun; Arabandi, Sivaram
2016-01-01
The "Vaccine and Drug Ontology Studies" (VDOS) international workshop series focuses on vaccine- and drug-related ontology modeling and applications. Drugs and vaccines have been critical to prevent and treat human and animal diseases. Work in both (drugs and vaccines) areas is closely related - from preclinical research and development to manufacturing, clinical trials, government approval and regulation, and post-licensure usage surveillance and monitoring. Over the last decade, tremendous efforts have been made in the biomedical ontology community to ontologically represent various areas associated with vaccines and drugs - extending existing clinical terminology systems such as SNOMED, RxNorm, NDF-RT, and MedDRA, developing new models such as the Vaccine Ontology (VO) and Ontology of Adverse Events (OAE), vernacular medical terminologies such as the Consumer Health Vocabulary (CHV). The VDOS workshop series provides a platform for discussing innovative solutions as well as the challenges in the development and applications of biomedical ontologies for representing and analyzing drugs and vaccines, their administration, host immune responses, adverse events, and other related topics. The five full-length papers included in this 2014 thematic issue focus on two main themes: (i) General vaccine/drug-related ontology development and exploration, and (ii) Interaction and network-related ontology studies.
-
Drug companies cut HIV drug prices in the developing world.
Yamey, G
2000-05-20
The UN has reported that five multinational pharmaceutical companies would cut down HIV drug prices in the developing world. One of these drug companies is GlaxoWellcome, which has promised to reduce the price of zidovudine and lamivudine to US$2 in the poorest nations, a fifth of its price in the US. Although Peter Piot, director of the UN Program on HIV/AIDS, welcomed the companies' promises, he warned that price cuts alone will not curb the epidemic. He stated that this initiative is only one critical factor in what must become a much broader and more urgent effort to help people living with HIV/AIDS. Moreover, health and development agencies expressed concern that AIDS drugs will still be unaffordable for the vast majority of those in need in developing countries. In addition, poor countries lack the infrastructure to deliver these drugs safely and effectively. During the time of the UN announcement, US President Bill Clinton also signed an executive order allowing sub-Saharan Africa to adopt legal measures to obtain cheap HIV drugs. Meanwhile, South Africa's reaction to the offer to cut antiretroviral drug prices has been lukewarm.
-
Advantages of Structure-Based Drug Design Approaches in Neurological Disorders
Aarthy, Murali; Panwar, Umesh; Selvaraj, Chandrabose; Singh, Sanjeev Kumar
2017-01-01
Objective: The purpose of the review is to portray the theoretical concept on neurological disorders from research data. Background: The freak changes in chemical response of nerve impulse causes neurological disorders. The research evidence of the effort done in the older history suggests that the biological drug targets and their effective feature with responsive drugs could be valuable in promoting the future development of health statistics structure for improved treatment for curing the nervous disorders. Methods: In this review, we summarized the most iterative theoretical concept of structure based drug design approaches in various neurological disorders to unfathomable understanding of reported information for future drug design and development. Results: On the premise of reported information we analyzed the model of theoretical drug designing process for understanding the mechanism and pathology of the neurological diseases which covers the development of potentially effective inhibitors against the biological drug targets. Finally, it also suggests the management and implementation of the current treatment in improving the human health system behaviors. Conclusion: With the survey of reported information we concluded the development strategies of diagnosis and treatment against neurological diseases which leads to supportive progress in the drug discovery. PMID:28042767
-
Drug Discovery and Development of Antimalarial Agents: Recent Advances.
Thota, Sreekanth; Yerra, Rajeshwar
2016-01-01
Malaria, a deadly infectious parasitic disease, is a major issue of public health in the world today and already produces serious economic constraints in the endemic countries. Most of the malarial infections and deaths are due to Plasmodium falciparum and Plasmodium vivax species. The recent emergence of resistance necessitates the search for new antimalarial drugs, which overcome the resistance and act through new mechanisms. Although much effort has been directed towards the discovery of novel antimalarial drugs. 4-anilino quinolone triazines as potent antimalarial agents, their in silico modelling and bioevaluation as Plasmodium falciparum transketolase and β-hematin inhibitors has been reported. This review is primarily focused on the drug discovery of the recent advances in the development of antimalarial agents and their mechanism of action.
-
New approaches to structure-based discovery of dengue protease inhibitors.
Tomlinson, S M; Malmstrom, R D; Watowich, S J
2009-06-01
Dengue virus (DENV), a member of the family Flaviviridae, presents a tremendous threat to global health since an estimated 2.5 billion people worldwide are at risk for epidemic transmission. DENV infections are primarily restricted to sub-tropical and tropical regions; however, there is concern that the virus will spread into new regions including the United States. There are no approved antiviral drugs or vaccines to combat dengue infection, although DENV vaccines have entered Phase 3 clinical trials. Drug discovery and development efforts against DENV and other viral pathogens must overcome specificity, efficacy, safety, and resistance challenges before the shortage of licensed drugs to treat viral infections can be relieved. Current drug discovery methods are largely inefficient and thus relatively ineffective at tackling the growing threat to public health presented by emerging and remerging viral pathogens. This review discusses current and newly implemented structure-based computational efforts to discover antivirals that target the DENV NS3 protease, although it is clear that these computational tools can be applied to most disease targets.
-
Concepts and challenges in quantitative pharmacology and model-based drug development.
Zhang, Liping; Pfister, Marc; Meibohm, Bernd
2008-12-01
Model-based drug development (MBDD) has been recognized as a concept to improve the efficiency of drug development. The acceptance of MBDD from regulatory agencies, industry, and academia has been growing, yet today's drug development practice is still distinctly distant from MBDD. This manuscript is aimed at clarifying the concept of MBDD and proposing practical approaches for implementing MBDD in the pharmaceutical industry. The following concepts are defined and distinguished: PK-PD modeling, exposure-response modeling, pharmacometrics, quantitative pharmacology, and MBDD. MBDD is viewed as a paradigm and a mindset in which models constitute the instruments and aims of drug development efforts. MBDD covers the whole spectrum of the drug development process instead of being limited to a certain type of modeling technique or application area. The implementation of MBDD requires pharmaceutical companies to foster innovation and make changes at three levels: (1) to establish mindsets that are willing to get acquainted with MBDD, (2) to align processes that are adaptive to the requirements of MBDD, and (3) to create a closely collaborating organization in which all members play a role in MBDD. Pharmaceutical companies that are able to embrace the changes MBDD poses will likely be able to improve their success rate in drug development, and the beneficiaries will ultimately be the patients in need.
-
Fusion of nonclinical and clinical data to predict human drug safety.
Johnson, Dale E
2013-03-01
Adverse drug reactions continue to be a major cause of morbidity in both patients receiving therapeutics and in drug R&D programs. Predicting and possibly eliminating these adverse events remains a high priority in industry, government agencies and healthcare systems. With small molecule candidates, the fusion of nonclinical and clinical data is essential in establishing an overall system that creates a true translational science approach. Several new advances are taking place that attempt to create a 'patient context' mechanism early in drug research and development and ultimately into the marketplace. This 'life-cycle' approach has as its core the development of human-oriented, nonclinical end points and the incorporation of clinical knowledge at the drug design stage. The next 5 years should witness an explosion of what the author views as druggable and safe chemical space, pharmacosafety molecular targets and the most important aspect, an understanding of unique susceptibilities in patients developing adverse drug reactions. Our current knowledge of clinical safety relies completely on pharmacovigilance data from approved and marketed drugs, with a few exceptions of drugs failing in clinical trials. Massive data repositories now and soon to be available via cloud computing should stimulate a major effort in expanding our view of clinical drug safety and its incorporation into early drug research and development.
-
Detection of illicit drugs in impaired driver saliva by a field-usable SERS analyzer
NASA Astrophysics Data System (ADS)
Shende, Chetan; Huang, Hermes; Farquharson, Stuart
2014-05-01
One of the greatest dangers of drug use is in combination with driving. According to the most recent National Highway Traffic Safety Administration (NHTSA) studies, more than 11% of drivers tested positive for illicit drugs, while 18% of drivers killed in accidents tested positive for illicit, prescription or over-the-counter drugs. Consequently, there is a need for a rapid, noninvasive, roadside drug testing device, similar to the breathalyzers used by law enforcement officials to estimate blood alcohol levels of impaired drivers. In an effort to satisfy this need we have been developing a sampling kit that allows extraction of drugs from 1 mL of saliva and detection by surfaceenhanced Raman spectroscopy using a portable Raman analyzer. Here we describe the development of the sampling kit and present measurements of diazepam at sub μg/mL concentrations measured in ~15 minutes.
-
Mechler, Konstantin; Mountford, William K; Hoffmann, Georg F; Ries, Markus
2015-04-18
Lysosomal storage disorders are a heterogeneous group of approximately 50 monogenically inherited orphan conditions. A defect leads to the storage of complex molecules in the lysosome, and patients develop a complex multisystemic phenotype of high morbidity often associated with premature death. More than 30 years ago the Orphan Drug Act of 1983 passed the United States legislation intended to facilitate the development of drugs for rare disorders. We directed our efforts in assessing which lysosomal diseases had drug development pressure and what distinguished those with successful development and approvals from diseases not treated or without orphan drug designation. Analysis of the FDA database for orphan drug designations through descriptive and comparative statistics. Between 1983 and 2013, fourteen drugs for seven conditions received FDA approval. Overall, orphan drug status was designated 70 times for 20 conditions. Approved therapies were enzyme replacement therapies (N = 10), substrate reduction therapies (N = 1), small molecules facilitating lysosomal substrate transportation (N = 3). FDA approval was significantly associated with a disease prevalence higher than 0.5/100,000 (p = 0.00742) and clinical development programs that did not require a primary neurological endpoint (p = 0.00059). Orphan drug status was designated for enzymes, modified enzymes, fusion proteins, chemical chaperones, small molecules leading to substrate reduction, or facilitating subcellular substrate transport, stem cells as well as gene therapies. Drug development focused on more common diseases. Primarily neurological diseases were neglected. Small clinical trials with either somatic or biomarker endpoints were successful. Enzyme replacement therapy was the most successful technology. Four factors played a key role in successful orphan drug development or orphan drug designations: 1) prevalence of disease 2) endpoints 3) regulatory precedent, and 4) technology platform. Successful development seeded further innovation.
-
Molecular targets for flavivirus drug discovery
Sampath, Aruna; Padmanabhan, R.
2009-01-01
Flaviviruses are a major cause of infectious disease in humans. Dengue virus causes an estimated 50 million cases of febrile illness each year, including an increasing number of cases of hemorrhagic fever. West Nile virus, which recently spread from the Mediterranean basin to the Western Hemisphere, now causes thousands of sporadic cases of encephalitis annually. Despite the existence of licensed vaccines, yellow fever, Japanese encephalitis and tick-borne encephalitis also claim many thousands of victims each year across their vast endemic areas. Antiviral therapy could potentially reduce morbidity and mortality from flavivirus infections, but no effective drugs are currently available. This article introduces a collection of papers in Antiviral Research on molecular targets for flavivirus antiviral drug design and murine models of dengue virus disease that aims to encourage drug development efforts. After reviewing the flavivirus replication cycle, we discuss the envelope glycoprotein, NS3 protease, NS3 helicase, NS5 methyltransferase and NS5 RNA-dependent RNA polymerase as potential drug targets, with special attention being given to the viral protease. The other viral proteins are the subject of individual articles in the journal. Together, these papers highlight current status of drug discovery efforts for flavivirus diseases and suggest promising areas for further research. PMID:18796313
-
Druggable orthosteric and allosteric hot spots to target protein-protein interactions.
Ma, Buyong; Nussinov, Ruth
2014-01-01
Drug designing targeting protein-protein interactions is challenging. Because structural elucidation and computational analysis have revealed the importance of hot spot residues in stabilizing these interactions, there have been on-going efforts to develop drugs which bind the hot spots and out-compete the native protein partners. The question arises as to what are the key 'druggable' properties of hot spots in protein-protein interactions and whether these mimic the general hot spot definition. Identification of orthosteric (at the protein- protein interaction site) and allosteric (elsewhere) druggable hot spots is expected to help in discovering compounds that can more effectively modulate protein-protein interactions. For example, are there any other significant features beyond their location in pockets in the interface? The interactions of protein-protein hot spots are coupled with conformational dynamics of protein complexes. Currently increasing efforts focus on the allosteric drug discovery. Allosteric drugs bind away from the native binding site and can modulate the native interactions. We propose that identification of allosteric hot spots could similarly help in more effective allosteric drug discovery. While detection of allosteric hot spots is challenging, targeting drugs to these residues has the potential of greatly increasing the hot spot and protein druggability.
-
SFINX-a drug-drug interaction database designed for clinical decision support systems.
Böttiger, Ylva; Laine, Kari; Andersson, Marine L; Korhonen, Tuomas; Molin, Björn; Ovesjö, Marie-Louise; Tirkkonen, Tuire; Rane, Anders; Gustafsson, Lars L; Eiermann, Birgit
2009-06-01
The aim was to develop a drug-drug interaction database (SFINX) to be integrated into decision support systems or to be used in website solutions for clinical evaluation of interactions. Key elements such as substance properties and names, drug formulations, text structures and references were defined before development of the database. Standard operating procedures for literature searches, text writing rules and a classification system for clinical relevance and documentation level were determined. ATC codes, CAS numbers and country-specific codes for substances were identified and quality assured to ensure safe integration of SFINX into other data systems. Much effort was put into giving short and practical advice regarding clinically relevant drug-drug interactions. SFINX includes over 8,000 interaction pairs and is integrated into Swedish and Finnish computerised decision support systems. Over 31,000 physicians and pharmacists are receiving interaction alerts through SFINX. User feedback is collected for continuous improvement of the content. SFINX is a potentially valuable tool delivering instant information on drug interactions during prescribing and dispensing.
-
Private versus social incentives for pharmaceutical innovation.
González, Paula; Macho-Stadler, Inés; Pérez-Castrillo, David
2016-12-01
We provide a theoretical framework to contribute to the current debate regarding the tendency of pharmaceutical companies to direct their R&D toward marketing products that are "follow-on" drugs of already existing drugs, rather than toward the development of breakthrough drugs. We construct a model with a population of patients who can be treated with drugs that are horizontally and vertically differentiated. In addition to a pioneering drug, a new drug can be marketed as the result of an innovative process. We analyze physician prescription choices and the optimal pricing decision of an innovative firm. We also characterize the incentives of the innovative firm to conduct R&D activities, disentangling the quest for breakthrough drugs from the firm effort to develop follow-on drugs. Our results offer theoretical support for the conventional wisdom that pharmaceutical firms devote too many resources to conducting R&D activities that lead to incremental innovations. Copyright © 2016 Elsevier B.V. All rights reserved.
-
Ferlini, Cristiano; Gallo, Daniela; Scambia, Giovanni
2008-03-01
Taxanes are presently widely employed for the medical treatment of cancer. However, despite the huge clinical success, these agents exhibit clinical problems related to poor drug solubility, toxicity and, in particular, drug resistance. To identify the critical points related to the process of development of novel taxanes. Publicly available data on the paclitaxel and docetaxel analogues, which have entered a clinical development phase in the last 2 years have been taken into consideration. The development involved novel formulations of paclitaxel and novel chemical entities. For each agent in each category the development phase is analysed and a synthetic comment for each category is included. Despite all the efforts, until now clinical success with the new development of taxanes has been limited. Moreover, the expected clinical introduction of epothilones could further restrict the space for development of novel taxanes. Despite these facts, some interesting concepts emerged during the process of development and could lead to successful drugs in the forthcoming years.
-
"Who's winning the human race?"Cold war as pharmaceutical political strategy.
Tobbell, Dominique A
2009-10-01
Between 1959 and 1962, Senator Estes Kefauver led a congressional investigation into the pricing practices of U.S. drug firms. As part of its defense, the industry mobilized the rhetoric of cold war and promoted the industry as a critical national asset in the global war against communism. The industry argued that any effort to undermine corporate innovation by inviting, as Kefauver proposed, greater government involvement in drug development threatened the public's health and invited socialism-in the form of socialized medicine-into the domestic political economy. This strategy proved critical to the industry's efforts to build political support for itself, particularly among the medical profession, and undermine Kefauver's reform agenda.
-
Recent Progress in Nanomedicine: Therapeutic, Diagnostic and Theranostic Applications
Rizzo, Larissa Y.; Theek, Benjamin; Storm, Gert; Kiessling, Fabian; Lammers, Twan
2013-01-01
In recent years, the use of nanomedicine formulations for therapeutic and diagnostic applications has increased exponentially. Many different systems and strategies have been developed for drug targeting to pathological sites, as well as for visualizing and quantifying important (patho-) physiological processes. In addition, ever more efforts have been undertaken to combine diagnostic and therapeutic properties within a single nanomedicine formulation. These so-called nanotheranostics are able to provide valuable information on drug delivery, drug release and drug efficacy, and they are considered to be highly useful for personalizing nanomedicine-based (chemo-) therapeutic interventions. PMID:23578464
-
Modular reservoir concept for MEMS-based transdermal drug delivery systems
NASA Astrophysics Data System (ADS)
Cantwell, Cara T.; Wei, Pinghung; Ziaie, Babak; Rao, Masaru P.
2014-11-01
While MEMS-based transdermal drug delivery device development efforts have typically focused on tightly-integrated solutions, we propose an alternate conception based upon a novel, modular drug reservoir approach. By decoupling the drug storage functionality from the rest of the delivery system, this approach seeks to minimize cold chain storage volume, enhance compatibility with conventional pharmaceutical practices, and allow independent optimization of reservoir device design, materials, and fabrication. Herein, we report the design, fabrication, and preliminary characterization of modular reservoirs that demonstrate the virtue of this approach within the application context of transdermal insulin administration for diabetes management.
-
[Computational chemistry in structure-based drug design].
Cao, Ran; Li, Wei; Sun, Han-Zi; Zhou, Yu; Huang, Niu
2013-07-01
Today, the understanding of the sequence and structure of biologically relevant targets is growing rapidly and researchers from many disciplines, physics and computational science in particular, are making significant contributions to modern biology and drug discovery. However, it remains challenging to rationally design small molecular ligands with desired biological characteristics based on the structural information of the drug targets, which demands more accurate calculation of ligand binding free-energy. With the rapid advances in computer power and extensive efforts in algorithm development, physics-based computational chemistry approaches have played more important roles in structure-based drug design. Here we reviewed the newly developed computational chemistry methods in structure-based drug design as well as the elegant applications, including binding-site druggability assessment, large scale virtual screening of chemical database, and lead compound optimization. Importantly, here we address the current bottlenecks and propose practical solutions.
-
Implications of HLA-allele associations for the study of type IV drug hypersensitivity reactions.
Sullivan, A; Watkinson, J; Waddington, J; Park, B K; Naisbitt, D J
2018-03-01
Type IV drug hypersensitivity remains an important clinical problem and an obstacle to the development of new drugs. Several forms of drug hypersensitivity are associated with expression of specific HLA alleles. Furthermore, drug-specific T-lymphocytes have been isolated from patients with reactions. Despite this, controversy remains as to how drugs interact with immune receptors to stimulate a T-cell response. Areas covered: This article reviews the pathways of T-cell activation by drugs and how the ever increasing number of associations between expression of HLA alleles and susceptibility to hypersensitivity is impacting on our research effort to understanding this form of iatrogenic disease. Expert opinion: For a drug to activate a T-cell, a complex is formed between HLA molecules, an HLA binding peptide, the drug and the T-cell receptor. T-cell responses can involve drugs and stable or reactive metabolites bound covalently or non-covalently to any component of this complex. Recent research has linked the HLA associations to the disease through the characterization of drug-specific T-cell responses restricted to specific alleles. However, there is now a need to identify the additional genetic or environment factors that determine susceptibility and use our increased knowledge to develop predictive immunogenicity tests that offer benefit to Pharma developing new drugs.
-
A class of tricyclic compounds blocking malaria parasite oocyst development and transmission.
Eastman, Richard T; Pattaradilokrat, Sittiporn; Raj, Dipak K; Dixit, Saurabh; Deng, Bingbing; Miura, Kazutoyo; Yuan, Jing; Tanaka, Takeshi Q; Johnson, Ronald L; Jiang, Hongying; Huang, Ruili; Williamson, Kim C; Lambert, Lynn E; Long, Carole; Austin, Christopher P; Wu, Yimin; Su, Xin-Zhuan
2013-01-01
Malaria is a deadly infectious disease in many tropical and subtropical countries. Previous efforts to eradicate malaria have failed, largely due to the emergence of drug-resistant parasites, insecticide-resistant mosquitoes and, in particular, the lack of drugs or vaccines to block parasite transmission. ATP-binding cassette (ABC) transporters are known to play a role in drug transport, metabolism, and resistance in many organisms, including malaria parasites. To investigate whether a Plasmodium falciparum ABC transporter (Pf14_0244 or PfABCG2) modulates parasite susceptibility to chemical compounds or plays a role in drug resistance, we disrupted the gene encoding PfABCG2, screened the recombinant and the wild-type 3D7 parasites against a library containing 2,816 drugs approved for human or animal use, and identified an antihistamine (ketotifen) that became less active against the PfABCG2-disrupted parasite in culture. In addition to some activity against asexual stages and gametocytes, ketotifen was highly potent in blocking oocyst development of P. falciparum and the rodent parasite Plasmodium yoelii in mosquitoes. Tests of structurally related tricyclic compounds identified additional compounds with similar activities in inhibiting transmission. Additionally, ketotifen appeared to have some activity against relapse of Plasmodium cynomolgi infection in rhesus monkeys. Further clinical evaluation of ketotifen and related compounds, including synthetic new derivatives, in blocking malaria transmission may provide new weapons for the current effort of malaria eradication.
-
Military Infectious Diseases Update on Vaccine Development
2011-01-24
Research Program (MIDRP) Insect Vector ControlDiagnostics Prevention Treatment Infectious diseases adversely impact military operations. Vaccines...appropriate treatment and aids commanders in the field. Most militarily relevant infectious diseases are transmitted by biting insects and other...based Insect Repellent (1946) Vaccines Protectants Antiparasitic Drugs Research Effort Advanced Development Fielded Products Malaria Rapid
-
Carpentier, Francesca Renee Dillman
2016-02-09
This commentary explores the implications of increased social media marketing by drug manufacturers, based on findings in Hyosun Kim's article of the major themes in recent Food and Drug Administration (FDA) warning letters and notices of violation regarding online direct-to-consumer promotions of pharmaceuticals. Kim's rigorous analysis of FDA letters over a 10-year span highlights a relative abundance of regulatory action toward marketer-controlled websites and sponsored advertisements, compared to branded and unbranded social media messaging. However, social media marketing efforts are increasing, as is FDA attention to these efforts. This commentary explores recent developments and continuing challenges in the FDA's attempts to provide guidance and define pharmaceutical company accountability in marketer-controlled and -uncontrolled claims disseminated through social media. © 2016 by Kerman University of Medical Sciences.
-
NASA Astrophysics Data System (ADS)
Singh, R. K.; Kim, W.-S.; Ollinger, M.; Craciun, V.; Coowantwong, I.; Hochhaus, G.; Koshizaki, N.
2002-09-01
There is an urgent need to develop controlled drug release systems for the delivery of drugs via the pulmonary route. A key issue in pulmonary dry delivery systems is to reduce the amount of biodegradable polymers that are added to control the drug release. We have synthesized nanofunctionalized drug particles using the pulsed laser deposition on particles (PLDP) (e.g. budesonide) in an effort to control the architecture and thickness of a nanoscale polymer coating on the drug particles. In vitro studies indicated that the dry half-life release for budesonide can be enhanced from 1.2 to over 60 min by a nanoscale coating on the drug particle. Extensive studies have been conducted to characterize the bonding and composition of the polymer film deposited on drug particles.
-
Dudley, Dawn M.; Chin, Emily N.; Bimber, Benjamin N.; Sanabani, Sabri S.; Tarosso, Leandro F.; Costa, Priscilla R.; Sauer, Mariana M.; Kallas, Esper G.; O.’Connor, David H.
2012-01-01
Background Great efforts have been made to increase accessibility of HIV antiretroviral therapy (ART) in low and middle-income countries. The threat of wide-scale emergence of drug resistance could severely hamper ART scale-up efforts. Population-based surveillance of transmitted HIV drug resistance ensures the use of appropriate first-line regimens to maximize efficacy of ART programs where drug options are limited. However, traditional HIV genotyping is extremely expensive, providing a cost barrier to wide-scale and frequent HIV drug resistance surveillance. Methods/Results We have developed a low-cost laboratory-scale next-generation sequencing-based genotyping method to monitor drug resistance. We designed primers specifically to amplify protease and reverse transcriptase from Brazilian HIV subtypes and developed a multiplexing scheme using multiplex identifier tags to minimize cost while providing more robust data than traditional genotyping techniques. Using this approach, we characterized drug resistance from plasma in 81 HIV infected individuals collected in São Paulo, Brazil. We describe the complexities of analyzing next-generation sequencing data and present a simplified open-source workflow to analyze drug resistance data. From this data, we identified drug resistance mutations in 20% of treatment naïve individuals in our cohort, which is similar to frequencies identified using traditional genotyping in Brazilian patient samples. Conclusion The developed ultra-wide sequencing approach described here allows multiplexing of at least 48 patient samples per sequencing run, 4 times more than the current genotyping method. This method is also 4-fold more sensitive (5% minimal detection frequency vs. 20%) at a cost 3–5× less than the traditional Sanger-based genotyping method. Lastly, by using a benchtop next-generation sequencer (Roche/454 GS Junior), this approach can be more easily implemented in low-resource settings. This data provides proof-of-concept that next-generation HIV drug resistance genotyping is a feasible and low-cost alternative to current genotyping methods and may be particularly beneficial for in-country surveillance of transmitted drug resistance. PMID:22574170
-
Emerging approaches for histone deacetylase inhibitor drug discovery.
Zwergel, Clemens; Valente, Sergio; Jacob, Claus; Mai, Antonello
2015-06-01
Histone deacetylases (HDACs) are key players in the mediation of gene expression for both cancerous and noncancerous malignancies. Overexpression of these enzymes has been demonstrated in numerous types of cancer with some enzyme isoforms also involved in neurological, inflammatory and viral pathologies. Hence, the development of HDAC inhibitors (HDACis) represents a promising approach for their treatment. Numerous chemical entities have been studied in the recent years and some of them have reached clinical trials. This review summarizes the recent efforts in the drug development of HDACis and their potential application as therapeutic agents in cancerous, neurological, inflammatory and viral diseases. The development of novel potent and selective HDACis is ongoing. However, increased scientific effort is needed to aid the fight of specific types of cancerous or noncancerous disease with more selective agents required to avoid side effects during therapy. An interesting therapeutic approach is the use of HDACis in combination with other epigenetic target modulators to combine their therapeutic potential for a synergistic effect.
-
Salter, H; Holland, R
2014-09-01
In the last decade, there have been intensive efforts to invent, qualify and use novel biomarkers as a means to improve success rates in drug discovery and development. The biomarkers field is maturing and this article considers whether these research efforts have brought about the expected benefits. The characteristics of a clinically useful biomarker are described and the impact this area of research has had is evaluated by reviewing a few, key examples of emerging biomarkers. There is evidence that the impact has been genuine and is increasing in both the drug and the diagnostic discovery and development processes. Beneficial impact on patient health outcomes seems relatively limited thus far, with the greatest impact in oncology (again, both in terms of novel drugs and in terms of more refined diagnoses and therefore more individualized treatment). However, the momentum of research would indicate that patient benefits are likely to increase substantially and to broaden across multiple therapeutic areas. Even though this research was originally driven by a desire to improve the drug discovery and development process, and was therefore funded with this aim in mind, it seems likely that the largest impact may actually come from more refined diagnosis. Refined diagnosis will facilitate both better allocation of healthcare resources and the use of treatment regimens which are optimized for the individual patient. This article also briefly reviews emerging technological approaches and how they relate to the challenges inherent in biomarker discovery and validation, and discusses the role of public/private partnerships in innovative biomarker research. © 2014 The Association for the Publication of the Journal of Internal Medicine.
-
From Composition to Cure: A Systems Engineering Approach to Anticancer Drug Carriers.
MacEwan, Sarah R; Chilkoti, Ashutosh
2017-06-06
The molecular complexity and heterogeneity of cancer has led to a persistent, and as yet unsolved, challenge to develop cures for this disease. The pharmaceutical industry focuses the bulk of its efforts on the development of new drugs, but an alternative approach is to improve the delivery of existing drugs with drug carriers that can manipulate when, where, and how a drug exerts its therapeutic effect. For the treatment of solid tumors, systemically delivered drug carriers face significant challenges that are imposed by the pathophysiological barriers that lie between their site of administration and their site of therapeutic action in the tumor. Furthermore, drug carriers face additional challenges in their translation from preclinical validation to clinical approval and adoption. Addressing this diverse network of challenges requires a systems engineering approach for the rational design of optimized carriers that have a realistic prospect for translation from the laboratory to the patient. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
-
The Drug Discovery and Development Industry in India—Two Decades of Proprietary Small‐Molecule R&D
2017-01-01
Abstract This review provides a comprehensive survey of proprietary drug discovery and development efforts performed by Indian companies between 1994 and mid‐2016. It is based on the identification and detailed analysis of pharmaceutical, biotechnology, and contract research companies active in proprietary new chemical entity (NCE) research and development (R&D) in India. Information on preclinical and clinical development compounds was collected by company, therapeutic indication, mode of action, target class, and development status. The analysis focuses on the overall pipeline and its evolution over two decades, contributions by type of company, therapeutic focus, attrition rates, and contribution to Western pharmaceutical pipelines through licensing agreements. This comprehensive analysis is the first of its kind, and, in our view, represents a significant contribution to the understanding of the current state of the drug discovery and development industry in India. PMID:28464443
-
The Drug Discovery and Development Industry in India-Two Decades of Proprietary Small-Molecule R&D.
Differding, Edmond
2017-06-07
This review provides a comprehensive survey of proprietary drug discovery and development efforts performed by Indian companies between 1994 and mid-2016. It is based on the identification and detailed analysis of pharmaceutical, biotechnology, and contract research companies active in proprietary new chemical entity (NCE) research and development (R&D) in India. Information on preclinical and clinical development compounds was collected by company, therapeutic indication, mode of action, target class, and development status. The analysis focuses on the overall pipeline and its evolution over two decades, contributions by type of company, therapeutic focus, attrition rates, and contribution to Western pharmaceutical pipelines through licensing agreements. This comprehensive analysis is the first of its kind, and, in our view, represents a significant contribution to the understanding of the current state of the drug discovery and development industry in India. © 2017 The Author. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
-
ERIC Educational Resources Information Center
Jones, Virginia H.; Hutchins, Ellen
This manual assists state agencies in developing public policy and programs to address prevention and treatment for the abuse of alcohol and other drugs by women during pregnancy. It stresses the importance of collaborative action among the many agencies involved. The first chapter is a specific call for collaboration, noting several federal…
-
Drug Delivery for Peripheral Nerve Regeneration
2014-09-01
1. Introduction 4 2. Keywords 4 3. Accomplishments 4 4. Impact 15 5. Changes/Problems 16 6. Products 17 7. Participants & Other... enzymatically and under adverse pH levels • Diffusion dropped dramatically after 6 days Figure 8 shows that the diffusion rate is independent of loaded...efficacy of the device using in-vitro and DRG studies. This data will help researchers/ industry to further develop drug delivery efforts in other areas
-
Ebola vaccine, therapeutics, and diagnostics.
Furuyama, Wakako; Takada, Ayato
2016-01-01
Ebolaviruses, members of the family Filoviridae, cause severe hemorrhagic fever in humans and nonhuman primates, with human case fatality rates of up to 90%. No effective prophylaxis or treatment for Ebola virus disease (EVD) is yet commercially available. During the latest outbreak of EVD in West Africa, several unapproved drugs were used for the treatment of patients. This outbreak has indeed accelerated efforts to develop antiviral strategies and some of the vaccine and drug candidates have undergone clinical trials. This article reviews previous researches and recent advances on the development of vaccine, therapeutics, and diagnostics for EVD.
-
Advanced Research Projects Agency counterdrug program
NASA Astrophysics Data System (ADS)
Pennella, John J.
1994-03-01
The Department of Defense (DoD), in support of the National Drug Control Strategy, has designated that detecting and countering the production, trafficking and use of illegal drugs is a high priority national security mission. The Advanced Research Projects Agency (ARPA) Counterdrug Program is assisting DoD in this objective by developing technology and prototype systems to enhance the capabilities of the DoD and civilian law enforcement agencies, consistent with the DoD mission and the supply reduction goals of the National Drug Control Strategy. The objective of this paper is to summarize the current ARPA Counterdrug Program, with special emphasis on the current efforts and future plans for developing technology to meet the National needs for Non-Intrusive Inspection.
-
Combination therapeutics in complex diseases.
He, Bing; Lu, Cheng; Zheng, Guang; He, Xiaojuan; Wang, Maolin; Chen, Gao; Zhang, Ge; Lu, Aiping
2016-12-01
The biological redundancies in molecular networks of complex diseases limit the efficacy of many single drug therapies. Combination therapeutics, as a common therapeutic method, involve pharmacological intervention using several drugs that interact with multiple targets in the molecular networks of diseases and may achieve better efficacy and/or less toxicity than monotherapy in practice. The development of combination therapeutics is complicated by several critical issues, including identifying multiple targets, targeting strategies and the drug combination. This review summarizes the current achievements in combination therapeutics, with a particular emphasis on the efforts to develop combination therapeutics for complex diseases. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
-
[In silico, in vitro, in omic experimental models and drug safety evaluation].
Claude, Nancy; Goldfain-Blanc, Françoise; Guillouzo, André
2009-01-01
Over the last few decades, toxicology has benefited from scientific, technical, and bioinformatic developments relating to patient safety assessment during clinical and drug marketing studies. Based on this knowledge, new in silico, in vitro, and "omic" experimental models are emerging. Although these models cannot currently replace classic safety evaluations performed on laboratory animals, they allow compounds with unacceptable toxicity to be rejected in the early stages of drug development, thereby reducing the number of laboratory animals needed. In addition, because these models are particularly adapted to mechanistic studies, they can help to improve the relevance of the data obtained, thus enabling better prevention and screening of the adverse effects that may occur in humans. Much progress remains to be done, especially in the field of validation. Nevertheless, current efforts by industrial, academic laboratories, and regulatory agencies should, in coming years, significantly improve preclinical drug safety evaluation thanks to the integration of these new methods into the drug research and development process.
-
Preclinical models used for immunogenicity prediction of therapeutic proteins.
Brinks, Vera; Weinbuch, Daniel; Baker, Matthew; Dean, Yann; Stas, Philippe; Kostense, Stefan; Rup, Bonita; Jiskoot, Wim
2013-07-01
All therapeutic proteins are potentially immunogenic. Antibodies formed against these drugs can decrease efficacy, leading to drastically increased therapeutic costs and in rare cases to serious and sometimes life threatening side-effects. Many efforts are therefore undertaken to develop therapeutic proteins with minimal immunogenicity. For this, immunogenicity prediction of candidate drugs during early drug development is essential. Several in silico, in vitro and in vivo models are used to predict immunogenicity of drug leads, to modify potentially immunogenic properties and to continue development of drug candidates with expected low immunogenicity. Despite the extensive use of these predictive models, their actual predictive value varies. Important reasons for this uncertainty are the limited/insufficient knowledge on the immune mechanisms underlying immunogenicity of therapeutic proteins, the fact that different predictive models explore different components of the immune system and the lack of an integrated clinical validation. In this review, we discuss the predictive models in use, summarize aspects of immunogenicity that these models predict and explore the merits and the limitations of each of the models.
-
Recent advances in malaria drug discovery
Biamonte, Marco A.; Wanner, Jutta; Le Roch, Karine G.
2013-01-01
This digest covers some of the most relevant progress in malaria drug disco very published betwe en 2010 and 2012. There is an urgent need to develop new antimalarial drugs. Such drugs can target the blood stage of the disease to alleviate the symptoms, the liver stage to prevent relapses, and the transmission stage to protect other humans. The pipeline for the blood stage is becoming robust, but this should not be a source of complacency, as the current therapies set a high standard. Drug disco very efforts directed towards the liver and transmission stages are in their infancy but are receiving increasing attention as targeting these stages could be instrumental in eradicating malaria. PMID:23587422
-
Delayed access to treatments for rare diseases: who's to blame?
Feltmate, Karen; Janiszewski, Peter M; Gingerich, Sheena; Cloutier, Michael
2015-04-01
The development and commercialization of drugs for rare diseases, termed 'orphan drugs', has historically been economically unattractive. However, because of the introduction of legislation that provides financial and regulatory incentives for the development of orphan drugs, new developments are making their way through the regulatory approval processes. Unfortunately, delays in availability of new drugs for treating rare disease continue to persist. This paper reviews the approach of several regulatory jurisdictions to orphan drugs in an effort to determine their relative effectiveness in providing patient access. Generally speaking, regulatory authorities across jurisdictions have recognized the need to enhance timely access to safe, effective treatment for patients with rare diseases and have been able to shift the approval timelines for access to new care. The greater impediment to orphan drug access appears to be funding, particularly in publicly sponsored health-care systems. Redundancies in federal and provincial reviews of orphan drugs can result in significant delays in access to new drugs. Clearly, more must be done to accelerate access to the treatments so desperately needed by patients. Public payers must be held accountable for their process and decisions--especially for rare disease therapies. © 2015 Asian Pacific Society of Respirology.
-
Ethical framework for resource allocation during a drug supply shortage.
Gibson, Jennifer L; Bean, Sally; Chidwick, Paula; Godkin, Dianne; Sibbald, Robert W; Wagner, Frank
2012-01-01
Drug supply shortages are common in health systems due to manufacturing and other delays. Frequently, shortages are successfully addressed through conservation and redistribution efforts, with limited impact on patient care. However, when Sandoz Canada Inc. announced in February 2012 that it was reducing production of a number of generic injectable drugs at its Quebec facility, the scope and magnitude of the drug supply shortage were unprecedented in Canada. The potential for an extreme scarcity of some drugs raised ethical concerns about patient care, including the need to limit access to some health services. In this article, the authors describe the development and implementation of an ethical framework to promote equitable access to drugs and healthcare services in the context of a drug supply shortage within and across health systems.
-
Prediction of Metabolism of Drugs using Artificial Intelligence: How far have we reached?
Kumar, Rajnish; Sharma, Anju; Siddiqui, Mohammed Haris; Tiwari, Rajesh Kumar
2016-01-01
Information about drug metabolism is an essential component of drug development. Modeling the drug metabolism requires identification of the involved enzymes, rate and extent of metabolism, the sites of metabolism etc. There has been continuous attempts in the prediction of metabolism of drugs using artificial intelligence in effort to reduce the attrition rate of drug candidates entering to preclinical and clinical trials. Currently, there are number of predictive models available for metabolism using Support vector machines, Artificial neural networks, Bayesian classifiers etc. There is an urgent need to review their progress so far and address the existing challenges in prediction of metabolism. In this attempt, we are presenting the currently available literature models and some of the critical issues regarding prediction of drug metabolism.
-
An update on applications of nanostructured drug delivery systems in cancer therapy: a review.
Aberoumandi, Seyed Mohsen; Mohammadhosseini, Majid; Abasi, Elham; Saghati, Sepideh; Nikzamir, Nasrin; Akbarzadeh, Abolfazl; Panahi, Yunes; Davaran, Soodabeh
2017-09-01
Cancer is a main public health problem that is known as a malignant tumor and out-of-control cell growth, with the potential to assault or spread to other parts of the body. Recently, remarkable efforts have been devoted to develop nanotechnology to improve the delivery of anticancer drug to tumor tissue as minimizing its distribution and toxicity in healthy tissue. Nanotechnology has been extensively used in the advance of new strategies for drug delivery and cancer therapy. Compared to customary drug delivery systems, nano-based drug delivery method has greater potential in different areas, like multiple targeting functionalization, in vivo imaging, extended circulation time, systemic control release, and combined drug delivery. Nanofibers are used for different medical applications such as drug delivery systems.
-
Brazil: An emerging partner in drug R&D.
Rodrigues, Debora G
2009-08-01
With the need for innovation in drug discovery and development and changes to patent laws that are enabling greater IP protection, many pharmaceutical companies are pursuing international cooperation agreements with foreign companies as part of a global development strategy to enhance product pipelines. Brazil, the largest pharmaceutical market in Latin America, has improved its infrastructure, scientific and technological capabilities and has created a sustainable strategy to promote drug discovery research activities. Positive economic growth, a stable political structure, expanding patient populations an increasing governmental, private and foreign investments are creating a new landscape for drug R&D in the country. As Brazilian-based pharmaceutical companies become further established, new opportunities for partnerships and collaborative alliances are becoming available for the drug discovery process, as well as for co-manufacturing and co-marketing efforts. This feature review provides an overview of the Brazilian pharmaceutical market and discusses current opportunities, emerging trends and challenges for this expanding market.
-
Raising awareness of the importance of funding for tuberculosis small-molecule research.
Riccardi, Giovanna; Old, Iain G; Ekins, Sean
2017-03-01
Tuberculosis (TB) drug discovery research is hampered by several factors, but as in many research areas, the available funding is insufficient to support the needs of research and development. Recent years have seen various large collaborative efforts involving public-private partnerships, mimicking the situation during the golden age of antibiotic drug discovery during the 1950s and 1960s. The large-scale collaborative efforts funded by the European Union (EU) are now subject to diminishing financial support. As a result, TB researchers are increasingly looking for novel forms of funding, such as crowdfunding, to fill this gap. Any potential solution will require a careful reassessment of the incentives to encourage additional organizations to provide funding. Copyright © 2016 Elsevier Ltd. All rights reserved.
-
The Secret Lives of Neurotrophin Receptors | Center for Cancer Research
Neurotrophins are a family of growth factors that are critical to the proper development and functioning of the nervous system. Neurotrophins activate a family of tyrosine receptor kinases (Trk), which typically initiate signaling cascades through phosphorylation. This axis is important for central nervous system (CNS) drug development efforts, ranging from pain management to
-
Behavioral repertoire of larval zebrafish: Baseline activity and response to drug treatment.
As part of the EPA’s effort to develop an in vivo, vertebrate screen for toxic chemicals, we have begun to characterize basic behaviors of 6-day post-fertilization (dpf) zebrafish (Danio rerio) larvae in a microtiter plate format. Our main goal is to develop a method for rapidly ...
-
Luepke, Katherine H; Suda, Katie J; Boucher, Helen; Russo, Rene L; Bonney, Michael W; Hunt, Timothy D; Mohr, John F
2017-01-01
Growing antimicrobial resistance and a dwindling antibiotic pipeline have resulted in an emerging postantibiotic era, as patients are now dying from bacterial infections that were once treatable. The fast-paced "Golden Age" of antibiotic development that started in the 1940s has lost momentum; from the 1980s to the early 2000s, there was a 90% decline in the approval of new antibiotics as well as the discovery of few new novel classes. Many companies have shifted away from development due to scientific, regulatory, and economic hurdles that proved antibiotic development to be less attractive compared with more lucrative therapeutic areas. National and global efforts are focusing attention toward potential solutions for reinvigorating the antibiotic pipeline and include "push" incentives such as public-private partnerships and "pull" incentives such as reimbursement reform and market exclusivity. Hybrid models of incentives, global coordination among stakeholders, and the appropriate balance of antibiotic pricing, volume of drug used, and proper antimicrobial stewardship are key to maximizing efforts toward drug development to ensure access to patients in need of these therapies. © 2016 Pharmacotherapy Publications, Inc.
-
Human engineered heart tissue as a model system for drug testing.
Eder, Alexandra; Vollert, Ingra; Hansen, Arne; Eschenhagen, Thomas
2016-01-15
Drug development is time- and cost-intensive and, despite extensive efforts, still hampered by the limited value of current preclinical test systems to predict side effects, including proarrhythmic and cardiotoxic effects in clinical practice. Part of the problem may be related to species-dependent differences in cardiomyocyte biology. Therefore, the event of readily available human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CM) has raised hopes that this human test bed could improve preclinical safety pharmacology as well as drug discovery approaches. However, hiPSC-CM are immature and exhibit peculiarities in terms of ion channel function, gene expression, structural organization and functional responses to drugs that limit their present usefulness. Current efforts are thus directed towards improving hiPSC-CM maturity and high-content readouts. Culturing hiPSC-CM as 3-dimensional engineered heart tissue (EHT) improves CM maturity and anisotropy and, in a 24-well format using silicone racks, enables automated, multiplexed high content readout of contractile function. This review summarizes the principal technology and focuses on advantages and disadvantages of this technology and its potential for preclinical drug screening. Copyright © 2015 Elsevier B.V. All rights reserved.
-
Barriers to the Preclinical Development of Therapeutics that Target Aging Mechanisms
Burd, Christin E.; Gill, Matthew S.; Niedernhofer, Laura J.; Robbins, Paul D.; Austad, Steven N.; Barzilai, Nir
2016-01-01
Through the progress of basic science research, fundamental mechanisms that contribute to age-related decline are being described with increasing depth and detail. Although these efforts have identified new drug targets and compounds that extend life span in model organisms, clinical trials of therapeutics that target aging processes remain scarce. Progress in aging research is hindered by barriers associated with the translation of basic science discoveries into the clinic. This report summarizes discussions held at a 2014 Geroscience Network retreat focused on identifying hurdles that currently impede the preclinical development of drugs targeting fundamental aging processes. From these discussions, it was evident that aging researchers have varied perceptions of the ideal preclinical pipeline. To forge a clear and cohesive path forward, several areas of controversy must first be resolved and new tools developed. Here, we focus on five key issues in preclinical drug development (drug discovery, lead compound development, translational preclinical biomarkers, funding, and integration between researchers and clinicians), expanding upon discussions held at the Geroscience Retreat and suggesting areas for further research. By bringing these findings to the attention of the aging research community, we hope to lay the foundation for a concerted preclinical drug development pipeline. PMID:27535964
-
Schneider, Lon S
2014-03-01
The February 2013 Food and Drug Administration (FDA) draft guidance for developing drugs for early-stage Alzheimer's disease (AD) creates certain challenges as they guide toward the use of one cognitive outcome to gain accelerated marketing approval for preclinical AD drugs, and a composite clinical scale - the Clinical Dementia Rating Scale in particular - for the primary outcome for prodromal AD clinical trials. In light of the developing knowledge regarding early stage diagnoses and clinical trials outcomes, we recommend that FDA describe its requirements for validating preclinical AD diagnoses for drug development purposes, maintain the principle for requiring coprimary outcomes, and encourage the advancement of outcomes for early stage AD trials. The principles for drug development for early stage AD should not differ from those for clinical AD, especially as the diagnoses of prodromal and early AD impinge on each other. The FDA should not recommend that a composite scale be used as a sole primary efficacy outcome to support a marketing claim unless it requires that the cognitive and functional components of such a scale are demonstrated to be individually meaningful. The current draft guidelines may inadvertently constrain efforts to better assess the clinical effects of new drugs and inhibit innovation in an area where evidence-based clinical research practices are still evolving. Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
-
ALS Biomarkers for Therapy Development: State of the Field & Future Directions
Benatar, Michael; Boylan, Kevin; Jeromin, Andreas; Rutkove, Seward B.; Berry, James; Atassi, Nazem; Bruijn, Lucie
2015-01-01
Biomarkers have become the focus of intense research in the field of amyotrophic lateral sclerosis (ALS), with the hope that they might aid therapy development efforts. Notwithstanding the discovery of many candidate biomarkers, none have yet emerged as validated tools for drug development. In this review we present a nuanced view of biomarkers based on the perspective of the FDA; highlight the distinction between discovery and validation; describe existing and emerging resources; review leading biological fluid-based, electrophysiological and neuroimaging candidates relevant to therapy development efforts; discuss lessons learned from biomarker initiatives in related neurodegenerative diseases; and outline specific steps that we, as a field, might take in order to hasten the development and validation of biomarkers that will prove useful in enhancing efforts to develop effective treatments for ALS patients. Most important among these perhaps is the proposal to establish a federated ALS Biomarker Consortium (ABC) in which all interested and willing stakeholders may participate with equal opportunity to contribute to the broader mission of biomarker development and validation. PMID:26574709
-
Recent approaches in design of peptidomimetics for antimicrobial drug discovery research.
Lohan, Sandeep; Bisht, Gopal Singh
2013-06-01
Resistant pathogenic microbial strains are emerging at a rate that far exceeds the pace of new anti-infective drug development. In order to combat resistance development, there is pressing need to develop novel class of antibiotics having different mechanism of action in comparison to existing antibiotics. Antimicrobial peptides (AMPs) have been identified as ubiquitous components of innate immune system and widely regarded as a potential source of future antibiotics owing to a remarkable set of advantageous properties ranging from broad spectrum of activity to low propensity of resistance development. However, AMPs present several drawbacks that strongly limit their clinical applicability as ideal drug candidates such as; poor bioavailability, potential immunogenicity and high production cost. Thus, to overcome the limitations of native peptides, peptidomimetic becomes an important and promising approach. The different research groups worldwide engaged in antimicrobial drug discovery over the past decade have paid tremendous effort to design peptidomimetics. This review will focus on recent approaches in design of antimicrobial peptidomimetics their structure-activity relationship studies, mode of action, selectivity & toxicity.
-
2000-01-01
To address important problems and needed changes in online and retrospective drug utilization review (DUR) programs. Emphasis is placed on reliability of DUR criteria and the shift of traditional retrospective DUR programs toward disease management and health care outcomes. Published literature evaluating the role of online and retrospective DUR programs. Particular attention was given to studies assessing DUR criteria reliability and new interventions with retrospective DUR programs. A literature review was conducted along with an expert summary from the U.S. Pharmacopeia Drug Utilization Review Advisory Panel. Studies have revealed variations in DUR criteria that could be affecting clinical practice and patient care. Appropriate formal methodologies and use of consistent procedures in developing online prospective DUR programs and systems could help resolve these problems. Traditional retrospective DUR is also shifting to incorporate disease management and methodologies from health outcomes and pharmacoeconomics studies. Refinements are needed to improve the reliability and validity of online DUR criteria and to minimize false positive messages. Databases created as a result of DUR efforts have been used in new and innovative ways to incorporate health outcomes data and disease management interventions. Additional outcomes data, combined with quality assurance efforts, should increase the utility of DUR/disease management efforts in evaluating health systems while improving the effectiveness and efficiency of pharmacists' health care interventions.
-
Mansbach, Robert S; Schoedel, Kerri A; Kittrelle, Jeffrey P; Sellers, Edward M
2010-12-01
The scientific and regulatory assessment of abuse and dependence potential of drugs involves a multi-layered evaluation of its properties related to chemistry, formulation, pharmacology, animal behavior and clinical response. In addition to the primary laboratory-based assessment in experienced drug users, data are also reviewed from studies in healthy volunteers and in the patient population. Much of the emphasis in these latter studies is placed on adverse events that are reported by the subject or observed by the investigator. Unlike other aspects of abuse potential assessment, the evaluation of abuse- and dependence-related events has not been the subject of scholarly research. The present commentary presents recommendations for several areas that would benefit from a consensus review to result in greater standardization for the analysis and presentation of abuse- and dependence-related data from clinical trials. These include special investigator training, a system of weighted primary and secondary terms, adjudication of individual events, case report management, organization of integrated safety data, and protocols for drug accountability. Such an effort would aid in implementing the evolving efforts of health authorities to guide drug developers in the collection and presentation of data needed for the regulation of drugs with the potential for abuse and dependence. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
-
Tanguay, Pascal; Kamarulzaman, Adeeba; Aramrattana, Apinun; Wodak, Alex; Thomson, Nicholas; Ali, Robert; Vumbaca, Gino; Lai, Gloria; Chabungbam, Anand
2015-10-16
Evidence indicates that detention of people who use drugs in compulsory centers in the name of treatment is common in Cambodia, China, Indonesia, Lao PDR, Malaysia, Myanmar, Philippines, Thailand, and Vietnam. The expansion of such practices has been costly, has not generated positive health outcomes, and has not reduced supply or demand for illicit drugs. United Nations agencies have convened several consultations with government and civil society stakeholders in order to facilitate a transition to voluntary evidence- and community-based drug dependence treatment and support services. In an effort to support such efforts, an informal group of experts proposes a three-step process to initiate and accelerate national-level transitions. Specifically, the working group recommends the establishment of a national multisectoral decision-making committee to oversee the development of national transition plans, drug policy reform to eliminate barriers to community-based drug dependence treatment and support services, and the integration of community-based drug dependence treatment in existing national health and social service systems.In parallel, the working group recommends that national-level transitions should be guided by overarching principles, including ethics, human rights, meaningful involvement of affected communities, and client safety, as well as good governance, transparency, and accountability. The transition also represents an opportunity to review the roles and responsibilities of various agencies across the public health and public security sectors in order to balance the workload and ensure positive results. The need to accelerate national-level transitions to voluntary community-based drug dependence treatment and support services is compelling--on economic, medical, sustainable community development, and ethical grounds--as extensively documented in the literature. In this context, the expert working group fully endorses initiation of a transition towards voluntary evidence- and community-based drug dependence treatment and support services across the region, as well as the steady scale-down of compulsory centers for drug users.Components of voluntary community-based drug dependence treatment and support services are being implemented in Cambodia, China, Indonesia, Malaysia, and Thailand. However, significant technical and financial support will be required to be allocated from national budgets and by international development agencies in order to complete the transition and reduce the reliance on detention of people who use drugs in Asia.
-
Chemical Informatics and the Drug Discovery Knowledge Pyramid
Lushington, Gerald H.; Dong, Yinghua; Theertham, Bhargav
2012-01-01
The magnitude of the challenges in preclinical drug discovery is evident in the large amount of capital invested in such efforts in pursuit of a small static number of eventually successful marketable therapeutics. An explosion in the availability of potentially drug-like compounds and chemical biology data on these molecules can provide us with the means to improve the eventual success rates for compounds being considered at the preclinical level, but only if the community is able to access available information in an efficient and meaningful way. Thus, chemical database resources are critical to any serious drug discovery effort. This paper explores the basic principles underlying the development and implementation of chemical databases, and examines key issues of how molecular information may be encoded within these databases so as to enhance the likelihood that users will be able to extract meaningful information from data queries. In addition to a broad survey of conventional data representation and query strategies, key enabling technologies such as new context-sensitive chemical similarity measures and chemical cartridges are examined, with recommendations on how such resources may be integrated into a practical database environment. PMID:23782037
-
Waging the Wrong War: Drug War Strategy and Issues
1992-04-15
their success. Unfortunately, this simple division of mission orientation (different ends) has led to a kind of "body count" mentality among the...chemicals necessary to sustain illegal drug enterprises."" Department of Defense officials report that efforts have led to successes not only against...support marijuana and coca eradication under the host country’s Internal Defense and Development umbrella. Subchapter I of the Foreign Assistance Act also
-
Singh, Vijay K; Hanlon, Briana K; Santiago, Paola T; Seed, Thomas M
2017-09-01
Terrorist attacks, with their intent to maximize psychological and economic damage as well as inflicting sickness and death on given targeted populations, are an ever-growing worldwide concern in government and public sectors as they become more frequent, violent, and sensational. If given the chance, it is likely that terrorists will use radiological or nuclear weapons. To thwart these sinister efforts, both physical and medical countermeasures against these weapons are currently being researched and developed so that they can be utilized by the first responders, military, and medical providers alike. This is the third article of a three-part series in which we have reviewed additional radiation countermeasures that are currently under early preclinical phases of development using largely animal models and have listed and discussed clinical support measures, including agents used for radiation-induced emesis, as well as countermeasures not requiring Food and Drug Administration approval. Despite the significant progress that has been made in this area during the last several years, additional effort is needed in order to push promising new agents, currently under development, through the regulatory pipeline. This pipeline for new promising drugs appears to be unreasonably slow and cumbersome; possible reasons for this inefficiency are briefly discussed. Significant and continued effort needs to be afforded to this research and development area, as to date, there is no approved radioprotector that can be administered prior to high dose radiation exposure. This represents a very significant, unmet medical need and a significant security issue. A large number of agents with potential to interact with different biological targets are under development. In the next few years, several additional radiation countermeasures will likely receive Food and Drug Administration approval, increasing treatment options for victims exposed to unwanted ionizing irradiation.
-
Literature-based prediction of novel drug indications considering relationships between entities.
Jang, Giup; Lee, Taekeon; Lee, Byung Mun; Yoon, Youngmi
2017-06-27
There have been many attempts to identify and develop new uses for existing drugs, which is known as drug repositioning. Among these efforts, text mining is an effective means of discovering novel knowledge from a large amount of literature data. We identify a gene regulation by a drug and a phenotype based on the biomedical literature. Drugs or phenotypes can activate or inhibit gene regulation. We calculate the therapeutic possibility that a drug acts on a phenotype by means of these two types of regulation. We assume that a drug treats a phenotype if the genes regulated by the phenotype are inversely correlated with the genes regulated by the drug. Based on this hypothesis, we identify drug-phenotype associations with therapeutic possibility. To validate the drug-phenotype associations predicted by our method, we make an enrichment comparison with known drug-phenotype associations. We also identify candidate drugs for drug repositioning from novel associations and thus reveal that our method is a novel approach to drug repositioning.
-
Analytical surveillance of emerging drugs of abuse and drug formulations
Thomas, Brian F.; Pollard, Gerald T.; Grabenauer, Megan
2012-01-01
Uncontrolled recreational drugs are proliferating in number and variety. Effects of long-term use are unknown, and regulation is problematic, as efforts to control one chemical often lead to several other structural analogs. Advanced analytical instrumentation and methods are continuing to be developed to identify drugs, chemical constituents of products, and drug substances and metabolites in biological fluids. Several mass spectrometry based approaches appear promising, particularly those that involve high resolution chromatographic and mass spectrometric methods that allow unbiased data acquisition and sophisticated data interrogation. Several of these techniques are shown to facilitate both targeted and broad spectrum analysis, which is often of particular benefit when dealing with misleadingly labeled products or assessing a biological matrix for illicit drugs and metabolites. The development and application of novel analytical approaches such as these will help to assess the nature and degree of exposure and risk and, where necessary, inform forensics and facilitate implementation of specific regulation and control measures. PMID:23154240
-
Hernandez, J. Javier; Pryszlak, Michael; Smith, Lindsay; Yanchus, Connor; Kurji, Naheed; Shahani, Vijay M.; Molinski, Steven V.
2017-01-01
The repositioning or “repurposing” of existing therapies for alternative disease indications is an attractive approach that can save significant investments of time and money during drug development. For cancer indications, the primary goal of repurposed therapies is on efficacy, with less restriction on safety due to the immediate need to treat this patient population. This report provides a high-level overview of how drug developers pursuing repurposed assets have previously navigated funding efforts, regulatory affairs, and intellectual property laws to commercialize these “new” medicines in oncology. This article provides insight into funding programs (e.g., government grants and philanthropic organizations) that academic and corporate initiatives can leverage to repurpose drugs for cancer. In addition, we highlight previous examples where secondary uses of existing, Food and Drug Administration- or European Medicines Agency-approved therapies have been predicted in silico and successfully validated in vitro and/or in vivo (i.e., animal models and human clinical trials) for certain oncology indications. Finally, we describe the strategies that the pharmaceutical industry has previously employed to navigate regulatory considerations and successfully commercialize their drug products. These factors must be carefully considered when repurposing existing drugs for cancer to best benefit patients and drug developers alike. PMID:29184849
-
Hernandez, J Javier; Pryszlak, Michael; Smith, Lindsay; Yanchus, Connor; Kurji, Naheed; Shahani, Vijay M; Molinski, Steven V
2017-01-01
The repositioning or "repurposing" of existing therapies for alternative disease indications is an attractive approach that can save significant investments of time and money during drug development. For cancer indications, the primary goal of repurposed therapies is on efficacy, with less restriction on safety due to the immediate need to treat this patient population. This report provides a high-level overview of how drug developers pursuing repurposed assets have previously navigated funding efforts, regulatory affairs, and intellectual property laws to commercialize these "new" medicines in oncology. This article provides insight into funding programs (e.g., government grants and philanthropic organizations) that academic and corporate initiatives can leverage to repurpose drugs for cancer. In addition, we highlight previous examples where secondary uses of existing, Food and Drug Administration- or European Medicines Agency-approved therapies have been predicted in silico and successfully validated in vitro and/or in vivo (i.e., animal models and human clinical trials) for certain oncology indications. Finally, we describe the strategies that the pharmaceutical industry has previously employed to navigate regulatory considerations and successfully commercialize their drug products. These factors must be carefully considered when repurposing existing drugs for cancer to best benefit patients and drug developers alike.
-
The impact of the written request process on drug development in childhood cancer.
Snyder, Kristen M; Reaman, Gregory; Avant, Debbie; Pazdur, Richard
2013-04-01
The Food and Drug Administration (FDA) Modernization Act, enacted in 1997, created a pediatric exclusivity incentive allowing sponsors to qualify for an additional 6 months of marketing exclusivity after satisfying the requirements outlined in the Written Request (WR). This review evaluates the impact of the WR mechanism on the development of oncology drugs in children. A search of the FDA document archiving, reporting, and regulatory tracking system was performed for January 1, 2000 to December 31, 2010. Drugs were identified and pediatric-specific labeling information was obtained from Drugs@fda.gov and FDA Pediatric Labeling Changes Table. Fifty WRs have been issued for oncology drugs. Pediatric studies have been submitted for 14 drugs. Thirteen received pediatric exclusivity. As of December 31, 2010, labeling changes have been made for 11 drugs. Three drugs were approved for pediatric use. WRs have provided a mechanism to promote the study of drugs in pediatric malignancies. Information from studies resulting from the WRs regarding safety, pharmacokinetics, and tolerability of oncology drugs has been incorporated into pediatric labeling for 11/14 of the drugs. Earlier communication and collaboration between the FDA, National Cancer Institute, clinical investigators, and commercial sponsors are envisioned to facilitate the identification and prioritization of emerging new drugs of interest for WR consideration. Since this is the only regulatory mechanism, resulting from specific legislative initiatives relevant to cancer drug development for children, efforts to enhance its impact on increasing drug approval for pediatric cancer indications are warranted. Copyright © 2013 Wiley Periodicals, Inc.
-
Unifying Theories of Psychedelic Drug Effects
Swanson, Link R.
2018-01-01
How do psychedelic drugs produce their characteristic range of acute effects in perception, emotion, cognition, and sense of self? How do these effects relate to the clinical efficacy of psychedelic-assisted therapies? Efforts to understand psychedelic phenomena date back more than a century in Western science. In this article I review theories of psychedelic drug effects and highlight key concepts which have endured over the last 125 years of psychedelic science. First, I describe the subjective phenomenology of acute psychedelic effects using the best available data. Next, I review late 19th-century and early 20th-century theories—model psychoses theory, filtration theory, and psychoanalytic theory—and highlight their shared features. I then briefly review recent findings on the neuropharmacology and neurophysiology of psychedelic drugs in humans. Finally, I describe recent theories of psychedelic drug effects which leverage 21st-century cognitive neuroscience frameworks—entropic brain theory, integrated information theory, and predictive processing—and point out key shared features that link back to earlier theories. I identify an abstract principle which cuts across many theories past and present: psychedelic drugs perturb universal brain processes that normally serve to constrain neural systems central to perception, emotion, cognition, and sense of self. I conclude that making an explicit effort to investigate the principles and mechanisms of psychedelic drug effects is a uniquely powerful way to iteratively develop and test unifying theories of brain function. PMID:29568270
-
Lost but making progress—Where will new analgesic drugs come from?
Borsook, David; Hargreaves, Richard; Bountra, Chas; Porreca, Frank
2015-01-01
There is a critical need for effective new pharmacotherapies for pain. The paucity of new drugs successfully reaching the clinic calls for a reassessment of current analgesic drug discovery approaches. Many points early in the discovery process present significant hurdles, making it critical to exploit advances in pain neurobiology to increase the probability of success. In this review, we highlight approaches that are being pursued vigorously by the pain community for drug discovery, including innovative preclinical pain models, insights from genetics, mechanistic phenotyping of pain patients, development of biomarkers, and emerging insights into chronic pain as a disorder of both the periphery and the brain. Collaborative efforts between pharmaceutical, academic, and public entities to advance research in these areas promise to de-risk potential targets, stimulate investment, and speed evaluation and development of better pain therapies. PMID:25122640
-
Gold-Based Medicine: A Paradigm Shift in Anti-Cancer Therapy?
Yeo, Chien Ing; Ooi, Kah Kooi; Tiekink, Edward R T
2018-06-11
A new era of metal-based drugs started in the 1960s, heralded by the discovery of potent platinum-based complexes, commencing with cisplatin [(H₃N)₂PtCl₂], which are effective anti-cancer chemotherapeutic drugs. While clinical applications of gold-based drugs largely relate to the treatment of rheumatoid arthritis, attention has turned to the investigation of the efficacy of gold(I) and gold(III) compounds for anti-cancer applications. This review article provides an account of the latest research conducted during the last decade or so on the development of gold compounds and their potential activities against several cancers as well as a summary of possible mechanisms of action/biological targets. The promising activities and increasing knowledge of gold-based drug metabolism ensures that continued efforts will be made to develop gold-based anti-cancer agents.
-
New Therapeutic Uses for Existing Drugs.
Austin, Bobbie Ann; Gadhia, Ami D
2017-01-01
Eighty percent of drugs that enter human clinical testing are never approved for use. This means that for every five drugs that make it into the clinic, there are four that failed to show effectiveness for treating the disease or condition the drug was designed to treat.This high failure rate means there are many existing, partially developed therapeutic candidates with known pharmacology, formulation, and potential toxicity. Finding new uses for existing experimental drugs or biologics "repositioning" builds upon previous research and development efforts, so new candidate therapies can be advanced to clinical trials for a new use more quickly than starting from scratch.Federal funding initiatives in the U.S. and UK started to support pre-clinical /or early stage trials for repositioning existing experimental drugs or biologics (therapies). This chapter covers some of the process issues that have been solved and the remaining challenges that are still in need of solutions. The chapter is primarily written from a U.S. federal funding perspective. The general concepts could be applied more globally to benefit rare and neglected disease populations. The drug development and process bottlenecks are the same for both rare and common disease.
-
Microfabrication for Drug Delivery
Koch, Brendan; Rubino, Ilaria; Quan, Fu-Shi; Yoo, Bongyoung; Choi, Hyo-Jick
2016-01-01
This review is devoted to discussing the application of microfabrication technologies to target challenges encountered in life processes by the development of drug delivery systems. Recently, microfabrication has been largely applied to solve health and pharmaceutical science issues. In particular, fabrication methods along with compatible materials have been successfully designed to produce multifunctional, highly effective drug delivery systems. Microfabrication offers unique tools that can tackle problems in this field, such as ease of mass production with high quality control and low cost, complexity of architecture design and a broad range of materials. Presented is an overview of silicon- and polymer-based fabrication methods that are key in the production of microfabricated drug delivery systems. Moreover, the efforts focused on studying the biocompatibility of materials used in microfabrication are analyzed. Finally, this review discusses representative ways microfabrication has been employed to develop systems delivering drugs through the transdermal and oral route, and to improve drug eluting implants. Additionally, microfabricated vaccine delivery systems are presented due to the great impact they can have in obtaining a cold chain-free vaccine, with long-term stability. Microfabrication will continue to offer new, alternative solutions for the development of smart, advanced drug delivery systems. PMID:28773770
-
Genomics, systems biology and drug development for infectious diseases.
Sakata, Tomoyo; Winzeler, Elizabeth A
2007-12-01
Although a variety of drugs are available for many infectious diseases that predominantly affect the developing world reasons remain for continuing to search for new chemotherapeutics. First, the development of microbial resistance has made some of the most effective and inexpensive drug regimes unreliable and dangerous to use on severely ill patients. Second, many existing antimicrobial drugs show toxicity or are too expensive for countries where the per capita income is in the order of hundreds of dollars per year. In recognition of this, new publicly and privately financed drug discovery efforts have been established to identify and develop new therapies for diseases such as tuberculosis, malaria and AIDS. This in turn, has intensified the need for tools to facilitate drug identification for those microbes whose molecular biology is poorly understood, or which are difficult to grow in the laboratory. While much has been written about how functional genomics can be used to find novel protein targets for chemotherapeutics this review will concentrate on how genome-wide, systems biology approaches may be used following whole organism, cell-based screening to understand the mechanism of drug action or to identify biological targets of small molecules. Here we focus on protozoan parasites, however, many of the approaches can be applied to pathogenic bacteria or parasitic helminths, insects or disease-causing fungi.
-
Polypharmacology of Approved Anticancer Drugs.
Amelio, Ivano; Lisitsa, Andrey; Knight, Richard A; Melino, Gerry; Antonov, Alexey V
2017-01-01
The major drug discovery efforts in oncology have been concentrated on the development of selective molecules that are supposed to act specifically on one anticancer mechanism by modulating a single or several closely related drug targets. However, a bird's eye view on data from multiple available bioassays implies that most approved anticancer agents do, in fact, target many more proteins with different functions. Here we will review and systematize currently available information on the targets of several anticancer drugs along with revision of their potential mechanisms of action. Polypharmacology of the current antineoplastic agents suggests that drug clinical efficacy in oncology can be achieved only via modulation of multiple cellular mechanisms. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
-
Bioreactor Technologies to Support Liver Function In Vitro
Ebrahimkhani, Mohammad R; Neiman, Jaclyn A Shepard; Raredon, Micah Sam B; Hughes, David J; Griffith, Linda G
2014-01-01
Liver is a central nexus integrating metabolic and immunologic homeostasis in the human body, and the direct or indirect target of most molecular therapeutics. A wide spectrum of therapeutic and technological needs drive efforts to capture liver physiology and pathophysiology in vitro, ranging from prediction of metabolism and toxicity of small molecule drugs, to understanding off-target effects of proteins, nucleic acid therapies, and targeted therapeutics, to serving as disease models for drug development. Here we provide perspective on the evolving landscape of bioreactor-based models to meet old and new challenges in drug discovery and development, emphasizing design challenges in maintaining long-term liver-specific function and how emerging technologies in biomaterials and microdevices are providing new experimental models. PMID:24607703
-
Miyamoto, Yukiko; Eckmann, Lars
2015-01-01
Diarrheal diseases are among the leading causes of morbidity and mortality in the world, particularly among young children. A limited number of infectious agents account for most of these illnesses, raising the hope that advances in the treatment and prevention of these infections can have global health impact. The two most important parasitic causes of diarrheal disease are Cryptosporidium and Giardia. Both parasites infect predominantly the small intestine and colonize the lumen and epithelial surface, but do not invade deeper mucosal layers. This review discusses the therapeutic challenges, current treatment options, and drug development efforts against cryptosporidiosis and giardiasis. The goals of drug development against Cryptosporidium and Giardia are different. For Cryptosporidium, only one moderately effective drug (nitazoxanide) is available, so novel classes of more effective drugs are a high priority. Furthermore, new genetic technology to identify potential drug targets and better assays for functional evaluation of these targets throughout the parasite life cycle are needed for advancing anticryptosporidial drug design. By comparison, for Giardia, several classes of drugs with good efficacy exist, but dosing regimens are suboptimal and emerging resistance begins to threaten clinical utility. Consequently, improvements in potency and dosing, and the ability to overcome existing and prevent new forms of drug resistance are priorities in antigiardial drug development. Current work on new drugs against both infections has revealed promising strategies and new drug leads. However, the primary challenge for further drug development is the underlying economics, as both parasitic infections are considered Neglected Diseases with low funding priority and limited commercial interest. If a new urgency in medical progress against these infections can be raised at national funding agencies or philanthropic organizations, meaningful and timely progress is possible in treating and possibly preventing cryptosporidiosis and giardiasis. PMID:26635732
-
Sustainability: Building Program and Coalition Support. A Prevention 101 Series Publication
ERIC Educational Resources Information Center
Glider, Peggy
2010-01-01
Given the prevalence of alcohol and other drug abuse and violence on campuses and in communities, programs and coalitions developed to prevent or intervene in these problems are faced with a challenging and long-term task. While the development of coalitions or campus-based prevention programs is a healthy start, these efforts must be sustained…
-
DOT National Transportation Integrated Search
1996-05-01
This paper describes a new single extraction screening procedure that was developed to identify as many drugs as possible in urine, with minimal effort and cost. Urine specimens are hydrolyzed and the specimen is then extracted using commercially pur...
-
Collaborative drug discovery for More Medicines for Tuberculosis (MM4TB)
Ekins, Sean; Spektor, Anna Coulon; Clark, Alex M.; Dole, Krishna; Bunin, Barry A.
2016-01-01
Neglected disease drug discovery is generally poorly funded compared with major diseases and hence there is an increasing focus on collaboration and precompetitive efforts such as public–private partnerships (PPPs). The More Medicines for Tuberculosis (MM4TB) project is one such collaboration funded by the EU with the goal of discovering new drugs for tuberculosis. Collaborative Drug Discovery has provided a commercial web-based platform called CDD Vault which is a hosted collaborative solution for securely sharing diverse chemistry and biology data. Using CDD Vault alongside other commercial and free cheminformatics tools has enabled support of this and other large collaborative projects, aiding drug discovery efforts and fostering collaboration. We will describe CDD's efforts in assisting with the MM4TB project. PMID:27884746
-
Jaffe, Jerome H; O'Keeffe, Charles
2003-05-21
The practice of prescribing opioid drugs for opioid dependent patients in the U.S. has been subjected to special government scrutiny for almost 100 years. From 1920 until 1964, doctors who used opioids to treat addicts risked federal and/or state criminal prosecution. Although that period ended when oral methadone maintenance was established as legitimate medical practice, public concern about methadone diversion and accidental overdose fatalities, combined with political pressure from both hostile bureaucracies and groups committed to drug-free treatments, led to the development of unprecedented and detailed Food and Drug Administration (FDA) regulations that specified the manner in which methadone (and later, levo-alpha-acetyl methadol, or levomethadyl acetate, (LAAM)) could be provided. In 1974, Congress gave the Drug Enforcement Administration (DEA) additional oversight of methadone treatment programs. Efforts to liberalize the FDA regulations over the past 30 years have been resisted by both the DEA and existing treatment providers. Additional flexibility for clinicians may evolve from the most recent effort to create an accreditation system to replace some of the FDA regulations. The development of buprenorphine, a partial opioid agonist, as an effective treatment for opioid addiction reopened the possibility for having a less burdensome oversight process, especially because of its reduced toxicity if ingested by non-tolerant individuals. New legislation, the Drug Addiction Treatment Act (DATA) of 2000, created an opportunity for clinicians with special training to be exempted from both federal methadone regulations and the requirement to obtain a special DEA license when using buprenorphine to treat addicts. Some details of how the DATA was developed, moved through Congress, and signed into law are described.
-
Inconsistencies in the drug use process.
Hutchinson, R A; Lewis, R K; Hatoum, H T
1990-06-01
Rational drug therapy has historically been viewed as the right drug, in the right dose, at the right time, for the right patient. Today, the emphasis on cost containment has added an extra dimension: cost-effective therapeutic regimens. Most stages of the DUP have not been extensively studied. Evidence presented to date reflects duplication of efforts and suboptimal decisions, with little concerted effort to identify means for improvements that may have a favorable impact on cost and patient outcome. The increasing use of drugs as the primary mode to treat diseases, the reduction in the number of hospital employees at a time increased severity of patient illness, the nursing shortage, and the increasing cost and complexity of drugs, along with the inconsistencies that exist in drug use, demonstrate a need for a complete review of the DUP. The DUP, as it currently operates, is not conducive to the provision of a systematic approach to therapy. The stages in this process are often independent of each other and poorly performed by a variety of health professionals. The subsequent development of strategies for improving the chance for optimal drug therapy through the use of pharmacists as drug therapy experts is needed. The pharmacy profession is in a prime position where expanded patient care services and supervision of the entire DUP may actually decrease the total cost of health care. This expansion represents the key to increasing acceptance of pharmacists' clinical role and for ensuring long-term survival of the profession.
-
Counter - Drug: Mandate for the Army.
1991-03-01
this comprehensive review will provide a basis for responding to new missions assigned...observations for determining the short-, mid-, and long-term direction of Army support to the national counter-drug effort. Also, this comprehensive review will provide...and long-term direction of Army support to the national counter-drug effort. Also, this comprehensive review will provide a basis for responding
-
Travels with Chairman of the Joint Chiefs of Staff, Marine General Peter
that time. Story Counter-drug Efforts May Aid Afghanistan BOGOTA, Colombia, Jan. 20, 2007 Â The long experience in its counter-drug effort to help the Afghan government fight a similar battle. " has working the counter-drug (issue)," Marine Gen. Peter Pace said. "It's been a very
-
Treatment utilization among persons with opioid use disorder in the United States.
Wu, Li-Tzy; Zhu, He; Swartz, Marvin S
2016-12-01
The United States is experiencing an opioid overdose epidemic. Treatment use data from diverse racial/ethnic groups with opioid use disorder (OUD) are needed to inform treatment expansion efforts. We examined demographic characteristics and behavioral health of persons aged ≥12 years that met criteria for past-year OUD (n=6,125) in the 2005-2013 National Surveys on Drug Use and Health (N=503,101). We determined the prevalence and correlates of past-year use of alcohol/drug use treatment and opioid-specific treatment to inform efforts for improving OUD treatment. Among persons with OUD, 81.93% had prescription (Rx) OUD only, 9.75% had heroin use disorder (HUD) only, and 8.32% had Rx OUD+HUD. Persons with Rx OUD+HUD tended to be white, adults aged 18-49, males, or uninsured. The majority (80.09%) of persons with OUD had another substance use disorder (SUD), and major depressive episode (MDE) was common (28.74%). Of persons with OUD, 26.19% used any alcohol or drug use treatment, and 19.44% used opioid-specific treatment. Adolescents, the uninsured, blacks, native-Hawaiians/Pacific-Islanders/Asian-Americans, persons with Rx OUD only, and persons without MDE or SUD particularly underutilized opioid-specific treatment. Among alcohol/drug use treatment users, self-help group and outpatient rehabilitation treatment were commonly used services. Most people with OUD report no use of OUD treatment. Multifaceted interventions, including efforts to access insurance coverage, are required to change attitudes and knowledge towards addiction treatment in order to develop a supportive culture and infrastructure to enable treatment-seeking. Outreach efforts could target adolescents, minority groups, and the uninsured to improve access to treatment. Copyright © 2016 The Author(s). Published by Elsevier Ireland Ltd.. All rights reserved.
-
Kline, Neal D; Tripathi, Ashish; Mirsafavi, Rustin; Pardoe, Ian; Moskovits, Martin; Meinhart, Carl; Guicheteau, Jason A; Christesen, Steven D; Fountain, Augustus W
2016-11-01
A microfluidic device is being developed by University of California-Santa Barbara as part of a joint effort with the United States Army to develop a portable, rapid drug detection device. Surface-enhanced Raman spectroscopy (SERS) is used to provide a sensitive, selective detection technique within the microfluidic platform employing metallic nanoparticles as the SERS medium. Using several illicit drugs as analytes, the work presented here describes the efforts of the Edgewood Chemical Biological Center to optimize the microfluidic platform by investigating the role of nanoparticle material, nanoparticle size, excitation wavelength, and capping agents on the performance, and drug concentration detection limits achievable with Ag and Au nanoparticles that will ultimately be incorporated into the final design. This study is particularly important as it lays out a systematic comparison of limits of detection and potential interferences from working with several nanoparticle capping agents-such as tannate, citrate, and borate-which does not seem to have been done previously as the majority of studies only concentrate on citrate as the capping agent. Morphine, cocaine, and methamphetamine were chosen as test analytes for this study and were observed to have limits of detection (LOD) in the range of (1.5-4.7) × 10 -8 M (4.5-13 ng/mL), with the borate capping agent having the best performance.
-
The Internet as a source of drugs of abuse.
Forman, Robert F; Marlowe, Douglas B; McLellan, A Thomas
2006-10-01
The Internet is a vital medium for communication, entertainment, and commerce, with more than 1 billion individuals connected worldwide. In addition to the many positive functions served by the Internet, it also has been used to facilitate the illicit sale of controlled substances. No-prescription websites (NPWs) offer--and then actually sell--controlled substances over the Internet without a valid prescription. NPW monitoring studies have focused primarily on the availability of prescription opioid medications, although many other drugs of abuse also are available online. Research indicates that these NPW sites are prevalent. Google or Yahoo searches simply using the term "Vicodin" return 40% to 50% NPWs in the top 100 sites. Thus, NPWs represent an important development in the sale of illicit drugs because of the ease with which controlled substances can be sold with relative anonymity. The emergence of NPWs requires new law enforcement and public health initiatives; continued monitoring efforts will determine whether efforts to reduce the availability of NPWs are successful.
-
Discovery and Characterization of ACT-451840: an Antimalarial Drug with a Novel Mechanism of Action.
Boss, Christoph; Aissaoui, Hamed; Amaral, Nathalie; Bauer, Aude; Bazire, Stephanie; Binkert, Christoph; Brun, Reto; Bürki, Cédric; Ciana, Claire-Lise; Corminboeuf, Olivier; Delahaye, Stephane; Dollinger, Claire; Fischli, Christoph; Fischli, Walter; Flock, Alexandre; Frantz, Marie-Céline; Girault, Malory; Grisostomi, Corinna; Friedli, Astrid; Heidmann, Bibia; Hinder, Claire; Jacob, Gael; Le Bihan, Amelie; Malrieu, Sophie; Mamzed, Saskia; Merot, Aurelien; Meyer, Solange; Peixoto, Sabrina; Petit, Nolwenn; Siegrist, Romain; Trollux, Julien; Weller, Thomas; Wittlin, Sergio
2016-09-20
More than 40 % of the world's population is at risk of being infected with malaria. Most malaria cases occur in the countries of sub-Saharan Africa, Central and South America, and Asia. Resistance to standard therapy, including artemisinin combinations, is increasing. There is an urgent need for novel antimalarials with new mechanisms of action. In a phenotypic screen, we identified a series of phenylalanine-based compounds that exhibit antimalarial activity via a new and yet unknown mechanism of action. Our optimization efforts culminated in the selection of ACT-451840 [(S,E)-N-(4-(4-acetylpiperazin-1-yl)benzyl)-3-(4-(tert-butyl)phenyl)-N-(1-(4-(4-cyanobenzyl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl)acrylamide] for clinical development. Herein we describe our optimization efforts from the screening hit to the potential drug candidate with respect to antiparasitic activity, drug metabolism and pharmacokinetics (DMPK) properties, and in vivo pharmacological efficacy. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
-
Considering the Future of Pharmaceutical Promotions in Social Media
Carpentier, Francesca Renee Dillman
2016-01-01
This commentary explores the implications of increased social media marketing by drug manufacturers, based on findings in Hyosun Kim’s article of the major themes in recent Food and Drug Administration (FDA) warning letters and notices of violation regarding online direct-to-consumer promotions of pharmaceuticals. Kim’s rigorous analysis of FDA letters over a 10-year span highlights a relative abundance of regulatory action toward marketer-controlled websites and sponsored advertisements, compared to branded and unbranded social media messaging. However, social media marketing efforts are increasing, as is FDA attention to these efforts. This commentary explores recent developments and continuing challenges in the FDA’s attempts to provide guidance and define pharmaceutical company accountability in marketer-controlled and -uncontrolled claims disseminated through social media. PMID:27239874
-
Novel cephalosporins for the treatment of MRSA infections.
Glinka, Tomasz W
2002-02-01
Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are among the most difficult to treat, Efforts toward the development of cephalosporin antimicrobial agents with activity against MRSA have been ongoing for the last decade. In spite of advancement of several potential drugs into clinical trials no such drugs are available for anti-MRSA therapy yet. The recent emergence of MRSA strains resistant to vancomycin, which is the treatment of choice for MRSA infection, has made the clinical need for new effective drugs even more pressing. In the present review structure-activity relationships are discussed with an emphasis on anti-MRSA activity, pharmacokinetics and efficacy in animal models. Clinical trial status of promising drug candidates is also provided where available.
-
Porous Carriers for Controlled/Modulated Drug Delivery
Ahuja, G.; Pathak, K.
2009-01-01
Considerable research efforts have been directed in recent years towards the development of porous carriers as controlled drug delivery matrices because of possessing several features such as stable uniform porous structure, high surface area, tunable pore size and well-defined surface properties. Owing to wide range of useful properties porous carriers have been used in pharmaceuticals for many purposes including development of floating drug delivery systems, sustained drug delivery systems. Various types of pores like open, closed, transport and blind pores in the porous solid allow them to adsorb drugs and release them in a more reproducible and predictable manner. Pharmaceutically exploited porous adsorbents includes, silica (mesoporous), ethylene vinyl acetate (macroporous), polypropylene foam powder (microporous), titanium dioxide (nanoporous). When porous polymeric drug delivery system is placed in contact with appropriate dissolution medium, release of drug to medium must be preceded by the drug dissolution in the water filled pores or from surface and by diffusion through the water filled channels. The porous carriers are used to improve the oral bioavailability of poorly water soluble drugs, to increase the dissolution of relatively insoluble powders and conversion of crystalline state to amorphous state. PMID:20376211
-
Drug repurposing in malignant pleural mesothelioma: a breath of fresh air?
Boyer, Arnaud; Pasquier, Eddy; Tomasini, Pascale; Ciccolini, Joseph; Greillier, Laurent; Andre, Nicolas; Barlesi, Fabrice; Mascaux, Celine
2018-03-31
Drug repurposing is the use of known drugs for new indications. Malignant pleural mesothelioma (MPM) is a rare cancer with a poor prognosis. So far, few treatments have been approved in this disease. However, its incidence is expected to increase significantly, particularly in developing countries. Consequently, drug repurposing appears as an attractive strategy for drug development in MPM, since the known pharmacology and safety profile based on previous approvals of repurposed drugs allows for faster time-to-market for patients and lower treatment cost. This is critical in low- and middle-income countries where access to expensive drugs is limited. This review assesses the published preclinical and clinical data about drug repurposing in MPM.In this review, we identified 11 therapeutic classes that could be repositioned in mesothelioma. Most of these treatments have been evaluated in vitro , half have been evaluated in vivo in animal models of MPM and only three ( i.e. valproate, thalidomide and zoledronic acid) have been investigated in clinical trials, with limited benefits so far. Efforts could be coordinated to pursue further investigations and test promising drugs identified in preclinical experiments in appropriately designed clinical trials. Copyright ©ERS 2018.
-
Inhibiting the Epidermal Growth Factor Receptor | Center for Cancer Research
The Epidermal Growth Factor Receptor (EGFR) is a widely distributed cell surface receptor that responds to several extracellular signaling molecules through an intracellular tyrosine kinase, which phosphorylates target enzymes to trigger a downstream molecular cascade. Since the discovery that EGFR mutations and amplifications are critical in a number of cancers, efforts have been under way to develop and use targeted EGFR inhibitors. These efforts have met with some spectacular successes, but many patients have not responded as expected, have subsequently developed drug-resistant tumors, or have suffered serious side effects from the therapies to date. CCR Investigators are studying EGFR from multiple vantage points with the goal of developing even better strategies to defeat EGFR-related cancers.
-
Gavande, Navnath S; VanderVere-Carozza, Pamela; Mishra, Akaash K; Vernon, Tyler L; Pawelczak, Katherine S; Turchi, John J
2017-10-12
XPA is a unique and essential protein required for the nucleotide excision DNA repair pathway and represents a therapeutic target in oncology. Herein, we are the first to develop novel inhibitors of the XPA-DNA interaction through structure-guided drug design efforts. Ester derivatives of the compounds 1 (X80), 22, and 24 displayed excellent inhibitory activity (IC 50 of 0.82 ± 0.18 μM and 1.3 ± 0.22 μM, respectively) but poor solubility. We have synthesized novel amide derivatives that retain potency and have much improved solubility. Furthermore, compound 1 analogs exhibited good specificity for XPA over RPA (replication protein A), another DNA-binding protein that participates in the nucleotide excision repair (NER) pathway. Importantly, there were no significant interactions observed by the X80 class of compounds directly with DNA. Molecular docking studies revealed a mechanistic model for the interaction, and these studies could serve as the basis for continued analysis of structure-activity relationships and drug development efforts of this novel target.
-
Nwaka, Solomon
2011-09-01
Solomon Nwaka was born in Nigeria and grew up seeing at first hand the impact of neglected diseases. His research efforts have taken him across the globe, in both the developed and developing world. Following posts in academia, industry and at the Medicines for Malaria Venture, he is now at the WHO where he is engaged in initiating schemes to support research into neglected diseases in developing countries, notably the African Network for Drugs and Diagnostics Innovation, which is now an organization under the United Nations Economic Commission for Africa. He speaks to Future Medicinal Chemistry about what inspired him to take up a career in neglected disease research and how the developing world should lead the effort to tackle some of the diseases that most affect them.
-
Cooperative research and development opportunities with the National Cancer Institute
NASA Technical Reports Server (NTRS)
Sybert, Kathleen
1991-01-01
The Office of Technology Development (OTD) of the National Cancer Institute (NCI) is responsible for negotiating Cooperative Research and Development Agreements (CRADAs), whereby the knowledge resulting from NCI investigators' government-sponsored research is developed in collaboration with universities and/or industry into new products of importance for the diagnosis and treatment of cancer and acquired immunodeficiency syndrome (AIDS). The NCI has recently executed a unique 'clinical trials' CRADA and is developing a model agreement based upon it for the development and commercialization of products for the diagnosis and treatment of cancer and AIDS. NCI drug screening, preclinical testing, clinical trials, and AIDS program capabilities form the basis for this new technology development/technology transfer vehicle. NCI's extensive drug screening program and 'designer foods' program serve as potential sources of investigational new drugs (INDs) and cancer preventatives. Collaborations between NCI and pharmaceutical companies having the facilities, experience, and expertise necessary to develop INDs into approved drugs available to the public are being encouraged where the companies have proprietary rights to INDs, or where NCI has proprietary rights to INDs and invites companies to respond to a collaborator announcement published in the Federal Register. The joint efforts of the NCI and the chosen collaborator are designed to generate the data necessary to obtain pharmaceutic regulatory approval from the Food and Drug Administration (FDA) to market the drugs developed, and thereby make them available to health care providers for the diagnosis and treatment of cancer and AIDS.
-
Huang, Shijie; Zhu, Xuechen; Melançon, Charles E
2016-01-15
The ribosome is the quintessential antibacterial drug target, with many structurally and mechanistically distinct classes of antibacterial agents acting by inhibiting ribosome function. Detecting and quantifying ribosome inhibition by small molecules and investigating their binding modes and mechanisms of action are critical to antibacterial drug discovery and development efforts. To develop a ribosome inhibition assay that is operationally simple, yet provides direct information on the drug target and the mechanism of action, we have developed engineered E. coli strains harboring an orthogonal ribosome-controlled green fluorescent protein (GFP) reporter that produce fluorescent signal when the orthogonal ribosome is inhibited. As a proof of concept, we demonstrate that these strains, when coexpressing homogeneous populations of aminoglycoside resistant ribosomes, act as sensitive and quantitative detectors of ribosome inhibition by a set of 12 structurally diverse aminoglycoside antibiotics. We suggest that this strategy can be extended to quantifying ribosome inhibition by other drug classes.
-
Small, Will; Fast, Danya; Krusi, Andrea; Wood, Evan; Kerr, Thomas
2009-01-01
Background Street-involved youth are a population at risk of adopting injection as a route of administration, and preventing the transition to injection drug use among street youth represents a public health priority. In order to inform epidemiological research and prevention efforts, we conducted a qualitative study to investigate the initiation of injection drug use among street-involved youth in Vancouver, Canada. Methods Qualitative interviews with street youth who inject drugs elicited descriptions of the adoption of injection as a route of administration. Interviewees were recruited from the At-Risk Youth Study (ARYS), a cohort of street-involved youth who use illicit drugs in Vancouver, Canada. Audio recorded interviews were transcribed verbatim and a thematic analysis was conducted. Results 26 youth aged 16 to 26 participated in this study, including 12 females. Among study participants the first injection episode frequently featured another drug user who facilitated the initiation of injecting. Youth narratives indicate that the transition into injecting is influenced by social interactions with drug using peers and evolving perceptions of injecting, and rejecting identification as an injector was important among youth who did not continue to inject. It appears that social conventions discouraging initiating young drug users into injection exist among established injectors, although this ethic is often ignored. Conclusion The importance of social relationships with other drug users within the adoption of injection drug use highlights the potential of social interventions to prevent injection initiation. Additionally, developing strategies to engage current injectors who are likely to initiate youth into injection could also benefit prevention efforts. PMID:19405977
-
Carpenter, Kenneth M.; Bedi, Gillinder; Vadhan, Nehal P.
2015-01-01
While substance use is common, only a minority of individuals who use drugs or alcohol develop problematic use. An understanding of the factors underlying the transition from substance use to misuse may improve prevention and intervention efforts. A key feature of substance misuse is ongoing decisions to use drugs or alcohol despite escalating negative consequences. Research findings highlight the importance of both relatively automatic, associative cognitive processes and relatively controlled, deliberative, and rational-analytic cognitive processes, for understanding situational decisions to use drugs. In this review, we discuss several cognitive component processes that may contribute to decision-making that promotes substance use and misuse, with a focus on more automatic processes. A growing body of evidence indicates that relative differences in the strength of these component processes can account for individual differences in the transition from substance use to misuse, and may offer important avenues for developing novel intervention strategies. PMID:26084667
-
Carpenter, Kenneth M; Bedi, Gillinder; Vadhan, Nehal P
2015-08-01
While substance use is common, only a minority of individuals who use drugs or alcohol develop problematic use. An understanding of the factors underlying the transition from substance use to misuse may improve prevention and intervention efforts. A key feature of substance misuse is ongoing decisions to use drugs or alcohol despite escalating negative consequences. Research findings highlight the importance of both relatively automatic, associative cognitive processes and relatively controlled, deliberative, and rational-analytic cognitive processes, for understanding situational decisions to use drugs. In this review, we discuss several cognitive component processes that may contribute to decision-making that promotes substance use and misuse, with a focus on more automatic processes. A growing body of evidence indicates that relative differences in the strength of these component processes can account for individual differences in the transition from substance use to misuse and may offer important avenues for developing novel intervention strategies.
-
Barriers to the Preclinical Development of Therapeutics that Target Aging Mechanisms.
Burd, Christin E; Gill, Matthew S; Niedernhofer, Laura J; Robbins, Paul D; Austad, Steven N; Barzilai, Nir; Kirkland, James L
2016-11-01
Through the progress of basic science research, fundamental mechanisms that contribute to age-related decline are being described with increasing depth and detail. Although these efforts have identified new drug targets and compounds that extend life span in model organisms, clinical trials of therapeutics that target aging processes remain scarce. Progress in aging research is hindered by barriers associated with the translation of basic science discoveries into the clinic. This report summarizes discussions held at a 2014 Geroscience Network retreat focused on identifying hurdles that currently impede the preclinical development of drugs targeting fundamental aging processes. From these discussions, it was evident that aging researchers have varied perceptions of the ideal preclinical pipeline. To forge a clear and cohesive path forward, several areas of controversy must first be resolved and new tools developed. Here, we focus on five key issues in preclinical drug development (drug discovery, lead compound development, translational preclinical biomarkers, funding, and integration between researchers and clinicians), expanding upon discussions held at the Geroscience Retreat and suggesting areas for further research. By bringing these findings to the attention of the aging research community, we hope to lay the foundation for a concerted preclinical drug development pipeline. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America.
-
Pharmacogenetics of drug response in Parkinson's disease.
Džoljić, Eleonora; Novaković, Ivana; Krajinovic, Maja; Grbatinić, Ivan; Kostić, Vladimir
2015-01-01
Parkinson's disease (PD) is a debilitating, demoralizing and financially devastating condition affecting 1% of population at the age of 60 years. Thus, very important issue to address is individual therapy optimization. Recent results have shown evidence that variable efficacy of treatment and risk of motor and mental complications could have genetic origin. Significant roles in that process play (pharmaco)genomic/genetic studies of PD. Variability in genes coding for drug-metabolizing enzymes, drug receptors and proteins involved in drug pathway signaling is an important factor determining inter-individual variability in drug responses. Interpersonal differences in drug responses are clearly documented although individualized treatment of PD is not widely known. Treatment with antiparkinsonian drugs is associated with the development of complications, such as L-DOPA-induced dyskinesia (LID), hallucinations and excessive daytime sleepiness. Carriers of specific genetic polymorphisms are particularly susceptible to development of some of these drug adverse effects. Pharmacogenomics aims to understand the relationship between genetic factors and inter-individual variations in drug responses, and to translate this information in therapy tailored to individual patient genetics. Relatively few efforts have been made to investigate the role of pharmacogenetics in the individual response to anti-PD drugs. Thus, many genetic variations and polymorphisms in myriad of different proteins can influence individual response to anti-PD drugs.
-
Ocular delivery of macromolecules
Kim, Yoo-Chun; Chiang, Bryce; Wu, Xianggen; Prausnitz, Mark R.
2014-01-01
Biopharmaceuticals are making increasing impact on medicine, including treatment of indications in the eye. Macromolecular drugs are typically given by physician-administered invasive delivery methods, because non--invasive ocular delivery methods, such as eye drops, and systemic delivery, have low bioavailability and/or poor ocular targeting. There is a need to improve delivery of biopharmaceuticals to enable less-invasive delivery routes, less-frequent dosing through controlled-release drug delivery and improved drug targeting within the eye to increase efficacy and reduce side effects. This review discusses the barriers to drug delivery via various ophthalmic routes of administration in the context of macromolecule delivery and discusses efforts to develop controlled-release systems for delivery of biopharmaceuticals to the eye. The growing number of macromolecular therapies in the eye needs improved drug delivery methods that increase drug efficacy, safety and patient compliance. PMID:24998941
-
Industry funding of the FDA: effects of PDUFA on approval times and withdrawal rates.
Berndt, Ernst R; Gottschalk, Adrian H B; Philipson, Tomas J; Strobeck, Matthew W
2005-07-01
The development of new therapies is a crucial component of efforts to improve healthcare. Because drug development and FDA regulatory review have historically been lengthy and costly processes, the US Congress passed a series of legislative acts, beginning in 1992, known collectively as the Prescription Drug User Fee Acts (PDUFA), which sought to expedite the FDA drug-review process. Here, we review data on drug approvals and drug-approval times, both as a whole and by therapeutic class, which demonstrate that implementation of the PDUFAs led to substantial incremental reductions in approval times beyond what would have been observed in the absence of these legislative acts. In addition, our preliminary examination of the trends in the number of new molecular entity withdrawals, frequently used as a proxy to assess the FDA's safety record, suggests that the proportion of approvals ultimately leading to safety withdrawals prior to PDUFA and during PDUFA I and II were not statistically different.
-
Perspectives on Advances in Tuberculosis Diagnostics, Drugs, and Vaccines
Schito, Marco; Migliori, Giovanni Battista; Fletcher, Helen A.; McNerney, Ruth; Centis, Rosella; D'Ambrosio, Lia; Bates, Matthew; Kibiki, Gibson; Kapata, Nathan; Corrah, Tumena; Bomanji, Jamshed; Vilaplana, Cris; Johnson, Daniel; Mwaba, Peter; Maeurer, Markus; Zumla, Alimuddin
2015-01-01
Despite concerted efforts over the past 2 decades at developing new diagnostics, drugs, and vaccines with expanding pipelines, tuberculosis remains a global emergency. Several novel diagnostic technologies show promise of better point-of-care rapid tests for tuberculosis including nucleic acid–based amplification tests, imaging, and breath analysis of volatile organic compounds. Advances in new and repurposed drugs for use in multidrug-resistant (MDR) or extensively drug-resistant (XDR) tuberculosis have focused on development of several new drug regimens and their evaluation in clinical trials and now influence World Health Organization guidelines. Since the failure of the MVA85A vaccine 2 years ago, there have been no new tuberculosis vaccine candidates entering clinical testing. The current status quo of the lengthy treatment duration and poor treatment outcomes associated with MDR/XDR tuberculosis and with comorbidity of tuberculosis with human immunodeficiency virus and noncommunicable diseases is unacceptable. New innovations and political and funder commitment for early rapid diagnosis, shortening duration of therapy, improving treatment outcomes, and prevention are urgently required. PMID:26409271
-
Malaria in South America: a drug discovery perspective.
Cruz, Luiza R; Spangenberg, Thomas; Lacerda, Marcus V G; Wells, Timothy N C
2013-05-24
The challenge of controlling and eventually eradicating malaria means that new tools are urgently needed. South America's role in this fight spans both ends of the research and development spectrum: both as a continent capable of discovering and developing new medicines, and also as a continent with significant numbers of malaria patients. This article reviews the contribution of groups in the South American continent to the research and development of new medicines over the last decade. Therefore, the current situation of research targeting malaria control and eradication is discussed, including endemicity, geographical distribution, treatment, drug-resistance and diagnosis. This sets the scene for a review of efforts within South America to discover and optimize compounds with anti-malarial activity.
-
ERIC Educational Resources Information Center
Gandhi, Allison Gruner; Murphy-Graham, Erin; Petrosino, Anthony; Chrismer, Sara Schwartz; Weiss, Carol H.
2007-01-01
In an effort to promote evidence-based practice, government officials, researchers, and program developers have developed lists of model programs in the prevention field. This article reviews the evidence used by seven best-practice lists to select five model prevention programs. The authors' examination of this research raises questions about the…
-
Nachman, Sharon; Ahmed, Amina; Amanullah, Farhana; Becerra, Mercedes C; Botgros, Radu; Brigden, Grania; Browning, Renee; Gardiner, Elizabeth; Hafner, Richard; Hesseling, Anneke; How, Cleotilde; Jean-Philippe, Patrick; Lessem, Erica; Makhene, Mamodikoe; Mbelle, Nontombi; Marais, Ben; McIlleron, Helen; Mc Neeley, David F; Mendel, Carl; Murray, Stephen; Navarro, Eileen; Oramasionwu, Gloria E; Porcalla, Ariel R; Powell, Clydette; Powell, Mair; Rigaud, Mona; Rouzier, Vanessa; Samson, Pearl; Schaaf, H. Simon; Shah, Seema; Starke, Jeff; Swaminathan, Soumya; Wobudeya, Eric; Worrell, Carol
2015-01-01
Children represent a significant proportion of the global tuberculosis (TB) burden, and may be disproportionately more affected by its most severe clinical manifestations. Currently available treatments for pediatric drug-susceptible (DS) and drug-resistant (DR) TB, albeit generally effective, are hampered by high pill burden, long duration of treatment, coexistent toxicities, and an overall lack of suitable, child-friendly formulations. The complex and burdensome nature of administering the existing regimens to treat DS TB also contributes to the rise of DR TB strains. Despite the availability and use of these therapies for decades, a dearth of dosing evidence in children underscores the importance of sustained efforts for TB drug development to better meet the treatment needs of children with TB. Several new TB drugs and regimens with promising activity against both DS and DR TB strains have recently entered clinical development and are in various phases of clinical evaluation in adults or have received marketing authorization for adults. However, initiation of clinical trials to evaluate these drugs in children is often deferred, pending the availability of complete safety and efficacy data in adults or after drug approval. This document summarizes consensus statements from an international panel of childhood TB opinion leaders which support the initiation of evaluation of new TB drugs and regimens in children at earlier phases of the TB Drug development cycle. PMID:25957923
-
Deren, Sherry; Gelpí-Acosta, Camila; Albizu-García, Carmen E; González, Ángel; Des Jarlais, Don C; Santiago-Negrón, Salvador
2014-11-01
High levels of HIV risk behaviors and prevalence have been reported among Puerto Rican people who inject drugs (PRPWID) since early in the HIV epidemic. Advances in HIV prevention and treatment have reduced HIV among people who inject drugs (PWID) in the United States. We examined HIV-related data for PRPWID in Puerto Rico and the US Northeast to assess whether disparities continue. Injection drug use as a risk for HIV is still overrepresented among Puerto Ricans. Lower availability of syringe exchanges, drug abuse treatment, and antiretroviral treatment for PWID in Puerto Rico contribute to higher HIV risk and incidence. These disparities should be addressed by the development of a federally supported Northeast-Puerto Rico collaboration to facilitate and coordinate efforts throughout both regions.
-
Public-private partnerships as driving forces in the quest for innovative medicines
2013-01-01
Background Despite progress in translational research, we are still falling short in developing the innovative medicines required to address major public health needs. Furthermore, the failure rate, time, and cost required for registration of a new drug are pushing the economics of the industry to the breaking point. New models of drug development based on collaborative endeavours are badly needed to improve this dire situation. Findings In 2004, the US Food and Drug Administration (FDA) introduced the Critical Path Initiative with the intent of modernizing drug development by implementing public-private partnerships (PPP) to share data, expertise, and resources. In response to FDA’s initiative, in the following year the non-profit Critical Path Institute (C-Path) was formed. At the same time, the National Institutes of Health (NIH) Public-Private Partnership program was established. In Europe, the Innovative Medicines Initiative (IMI) supported jointly by the European Union and the European Federation of Pharmaceutical Industries and Associations was launched in 2008. These independent efforts have a common long-term objective, namely to facilitate the emergence of innovative medicines by developing new tools for drug discovery, new indicators for drug efficacy or safety, and new approaches for patient stratification. Herein, we present evidence that PPP already exert a positive impact on the drug development process. Conclusions Public-private partnerships represent attractive means to leverage resources dispersed across industry, academia, and voluntary health organizations in order to address multiple challenges of drug development in an era of constrained resources and increased regulatory pressure. PMID:23369569
-
Advances in targeting strategies for nanoparticles in cancer imaging and therapy.
Yhee, Ji Young; Lee, Sangmin; Kim, Kwangmeyung
2014-11-21
In the last decade, nanoparticles have offered great advances in diagnostic imaging and targeted drug delivery. In particular, nanoparticles have provided remarkable progress in cancer imaging and therapy based on materials science and biochemical engineering technology. Researchers constantly attempted to develop the nanoparticles which can deliver drugs more specifically to cancer cells, and these efforts brought the advances in the targeting strategy of nanoparticles. This minireview will discuss the progress in targeting strategies for nanoparticles focused on the recent innovative work for nanomedicine.
-
2006-11-01
humans. Of these, Plasmodium falciparum is the most deadly. P . vivax, although it rarely causes death, is a constant annoyance and the leading...liver hepatocytes. Both P . vivax and P . falciparum have developed resistance to numerous antimalarial drugs, which has undermined the available...assay in our own laboratory. P . falciparum strains D6 and W2 were treated with a panel of known anti-malarial drugs and their respective IC50s were
-
Private Military Firms as Instruments of U.S. Foreign Policy: The Case of Columbia
2007-06-01
left a “power vacuum ” in many countries. Internal power struggles and ethnic conflicts broke out and led to a kind of warfare which is...the foundation for the increase of the private military sector.3 In many developing countries, private military firms (PMFs) have filled the vacuum ...efforts to dismantle the Medellín cartel in 1993 and the Cali cartel in 1995. With the drug organizations destroyed there was a vacuum in the drug
-
Han, Bumsoo; Qu, Chunjing; Park, Kinam; Konieczny, Stephen F.; Korc, Murray
2016-01-01
Targeted delivery aims to selectively distribute drugs to targeted tumor tissue but not to healthy tissue. This can address many of clinical challenges by maximizing the efficacy but minimizing the toxicity of anti-cancer drugs. However, complex tumor microenvironment poses various barriers hindering the transport of drugs and drug delivery systems. New tumor models that allow for the systematic study of these complex environments are highly desired to provide reliable test beds to develop drug delivery systems for targeted delivery. Recently, research efforts have yielded new in vitro tumor models, the so called tumor-microenvironment-on-chip, that recapitulate certain characteristics of the tumor microenvironment. These new models show benefits over other conventional tumor models, and have the potential to accelerate drug discovery and enable precision medicines. However, further research is warranted to overcome their limitations and to properly interpret the data obtained from these models. In this article, key features of the in vivo tumor microenvironment that are relevant to drug transport processes for targeted delivery was discussed, and the current status and challenges for developing in vitro transport model systems was reviewed. PMID:26688098
-
Supercritical fluid processing of drug nanoparticles in stable suspension.
Pathak, Pankaj; Meziani, Mohammed J; Desai, Tarang; Foster, Charles; Diaz, Julian A; Sun, Ya-Ping
2007-07-01
Significant effort has been directed toward the development of drug formulation and delivery techniques, especially for the drug of no or poor aqueous solubility. Among various strategies to address the solubility issue, the reduction of drug particle sizes to the nanoscale has been identified as a potentially effective and broadly applicable approach. Complementary to traditional methods, supercritical fluid techniques have found unique applications in the production and processing of drug particles. Here we report the application of a newly developed supercritical fluid processing technique, Rapid Expansion of a Supercritical Solution into a Liquid Solvent, to the nanosizing of potent antiparasitic drug Amphotericin B particles. A supercritical carbon dioxide-cosolvent system was used for the solubilization and processing of the drug. The process produced well-dispersed nanoscale Amphotericin B particles suspended in an aqueous solution, and the suspension was intrinsically stable or could be further stabilized in the presence of water-soluble polymers. The properties of the drug nanoparticles were found to be dependent on the type of cosolvent used. The results on the use of dimethyl sulfoxide and methanol as cosolvents and their effects on the properties of nanosized Amphotericin B particles are presented and discussed.
-
Lopez, Felipe L; Ernest, Terry B; Tuleu, Catherine; Gul, Mine Orlu
2015-01-01
Introduction: Most conventional drug delivery systems are not acceptable for pediatric patients as they differ in their developmental status and dosing requirements from other subsets of the population. Technology platforms are required to aid the development of age-appropriate medicines to maximize patient acceptability while maintaining safety, efficacy, accessibility and affordability. Areas covered: The current approaches and novel developments in the field of age-appropriate drug delivery for pediatric patients are critically discussed including patient-centric formulations, administration devices and packaging systems. Expert opinion: Despite the incentives provided by recent regulatory modifications and the efforts of formulation scientists, there is still a need for implementation of pharmaceutical technologies that enable the manufacture of licensed age-appropriate formulations. Harmonization of endeavors from regulators, industry and academia by sharing learning associated with data obtained from pediatric investigation plans, product development pathways and scientific projects would be the way forward to speed up bench-to-market age appropriate formulation development. A collaborative approach will benefit not only pediatrics, but other patient populations such as geriatrics would also benefit from an accelerated patient-centric approach to drug delivery. PMID:26165848
-
Federal Register 2010, 2011, 2012, 2013, 2014
2012-05-07
... year, FDA speakers provide updates on current efforts affecting the development of global regulatory strategies, while industry professionals from some of today's leading pharmaceutical companies present case... hear directly from FDA experts and representatives of global regulatory authorities on best practices...
-
Media Advocacy. Technical Assistance Packet.
ERIC Educational Resources Information Center
Join Together, Boston, MA.
Media advocacy is an environmental strategy that can be used to support alcohol and other drug prevention and policy development efforts. It helps shift the focus from understanding public health issues as individual problems to understanding them as social conditions that require collective behavior changes. Successful media advocacy uses the…
-
Parsing interindividual drug variability: an emerging role for systems pharmacology
Turner, Richard M; Park, B Kevin; Pirmohamed, Munir
2015-01-01
There is notable interindividual heterogeneity in drug response, affecting both drug efficacy and toxicity, resulting in patient harm and the inefficient utilization of limited healthcare resources. Pharmacogenomics is at the forefront of research to understand interindividual drug response variability, but although many genotype-drug response associations have been identified, translation of pharmacogenomic associations into clinical practice has been hampered by inconsistent findings and inadequate predictive values. These limitations are in part due to the complex interplay between drug-specific, human body and environmental factors influencing drug response and therefore pharmacogenomics, whilst intrinsically necessary, is by itself unlikely to adequately parse drug variability. The emergent, interdisciplinary and rapidly developing field of systems pharmacology, which incorporates but goes beyond pharmacogenomics, holds significant potential to further parse interindividual drug variability. Systems pharmacology broadly encompasses two distinct research efforts, pharmacologically-orientated systems biology and pharmacometrics. Pharmacologically-orientated systems biology utilizes high throughput omics technologies, including next-generation sequencing, transcriptomics and proteomics, to identify factors associated with differential drug response within the different levels of biological organization in the hierarchical human body. Increasingly complex pharmacometric models are being developed that quantitatively integrate factors associated with drug response. Although distinct, these research areas complement one another and continual development can be facilitated by iterating between dynamic experimental and computational findings. Ultimately, quantitative data-derived models of sufficient detail will be required to help realize the goal of precision medicine. WIREs Syst Biol Med 2015, 7:221–241. doi: 10.1002/wsbm.1302 PMID:25950758
-
Hit and lead criteria in drug discovery for infectious diseases of the developing world.
Katsuno, Kei; Burrows, Jeremy N; Duncan, Ken; Hooft van Huijsduijnen, Rob; Kaneko, Takushi; Kita, Kiyoshi; Mowbray, Charles E; Schmatz, Dennis; Warner, Peter; Slingsby, B T
2015-11-01
Reducing the burden of infectious diseases that affect people in the developing world requires sustained collaborative drug discovery efforts. The quality of the chemical starting points for such projects is a key factor in improving the likelihood of clinical success, and so it is important to set clear go/no-go criteria for the progression of hit and lead compounds. With this in mind, the Japanese Global Health Innovative Technology (GHIT) Fund convened with experts from the Medicines for Malaria Venture, the Drugs for Neglected Diseases initiative and the TB Alliance, together with representatives from the Bill &Melinda Gates Foundation, to set disease-specific criteria for hits and leads for malaria, tuberculosis, visceral leishmaniasis and Chagas disease. Here, we present the agreed criteria and discuss the underlying rationale.
-
Pant, Saumya; Weiner, Russell; Marton, Matthew J.
2014-01-01
Over the past decade, next-generation sequencing (NGS) technology has experienced meteoric growth in the aspects of platform, technology, and supporting bioinformatics development allowing its widespread and rapid uptake in research settings. More recently, NGS-based genomic data have been exploited to better understand disease development and patient characteristics that influence response to a given therapeutic intervention. Cancer, as a disease characterized by and driven by the tumor genetic landscape, is particularly amenable to NGS-based diagnostic (Dx) approaches. NGS-based technologies are particularly well suited to studying cancer disease development, progression and emergence of resistance, all key factors in the development of next-generation cancer Dxs. Yet, to achieve the promise of NGS-based patient treatment, drug developers will need to overcome a number of operational, technical, regulatory, and strategic challenges. Here, we provide a succinct overview of the state of the clinical NGS field in terms of the available clinically targeted platforms and sequencing technologies. We discuss the various operational and practical aspects of clinical NGS testing that will facilitate or limit the uptake of such assays in routine clinical care. We examine the current strategies for analytical validation and Food and Drug Administration (FDA)-approval of NGS-based assays and ongoing efforts to standardize clinical NGS and build quality control standards for the same. The rapidly evolving companion diagnostic (CDx) landscape for NGS-based assays will be reviewed, highlighting the key areas of concern and suggesting strategies to mitigate risk. The review will conclude with a series of strategic questions that face drug developers and a discussion of the likely future course of NGS-based CDx development efforts. PMID:24860780
-
Gathering and Exploring Scientific Knowledge in Pharmacovigilance
Lopes, Pedro; Nunes, Tiago; Campos, David; Furlong, Laura Ines; Bauer-Mehren, Anna; Sanz, Ferran; Carrascosa, Maria Carmen; Mestres, Jordi; Kors, Jan; Singh, Bharat; van Mulligen, Erik; Van der Lei, Johan; Diallo, Gayo; Avillach, Paul; Ahlberg, Ernst; Boyer, Scott; Diaz, Carlos; Oliveira, José Luís
2013-01-01
Pharmacovigilance plays a key role in the healthcare domain through the assessment, monitoring and discovery of interactions amongst drugs and their effects in the human organism. However, technological advances in this field have been slowing down over the last decade due to miscellaneous legal, ethical and methodological constraints. Pharmaceutical companies started to realize that collaborative and integrative approaches boost current drug research and development processes. Hence, new strategies are required to connect researchers, datasets, biomedical knowledge and analysis algorithms, allowing them to fully exploit the true value behind state-of-the-art pharmacovigilance efforts. This manuscript introduces a new platform directed towards pharmacovigilance knowledge providers. This system, based on a service-oriented architecture, adopts a plugin-based approach to solve fundamental pharmacovigilance software challenges. With the wealth of collected clinical and pharmaceutical data, it is now possible to connect knowledge providers’ analysis and exploration algorithms with real data. As a result, new strategies allow a faster identification of high-risk interactions between marketed drugs and adverse events, and enable the automated uncovering of scientific evidence behind them. With this architecture, the pharmacovigilance field has a new platform to coordinate large-scale drug evaluation efforts in a unique ecosystem, publicly available at http://bioinformatics.ua.pt/euadr/. PMID:24349421
-
Targeted drug delivery for cancer therapy: the other side of antibodies
2012-01-01
Therapeutic monoclonal antibody (TMA) based therapies for cancer have advanced significantly over the past two decades both in their molecular sophistication and clinical efficacy. Initial development efforts focused mainly on humanizing the antibody protein to overcome problems of immunogenicity and on expanding of the target antigen repertoire. In parallel to naked TMAs, antibody-drug conjugates (ADCs) have been developed for targeted delivery of potent anti-cancer drugs with the aim of bypassing the morbidity common to conventional chemotherapy. This paper first presents a review of TMAs and ADCs approved for clinical use by the FDA and those in development, focusing on hematological malignancies. Despite advances in these areas, both TMAs and ADCs still carry limitations and we highlight the more important ones including cancer cell specificity, conjugation chemistry, tumor penetration, product heterogeneity and manufacturing issues. In view of the recognized importance of targeted drug delivery strategies for cancer therapy, we discuss the advantages of alternative drug carriers and where these should be applied, focusing on peptide-drug conjugates (PDCs), particularly those discovered through combinatorial peptide libraries. By defining the advantages and disadvantages of naked TMAs, ADCs and PDCs it should be possible to develop a more rational approach to the application of targeted drug delivery strategies in different situations and ultimately, to a broader basket of more effective therapies for cancer patients. PMID:23140144
-
Clulow, Andrew J; Salim, Malinda; Hawley, Adrian; Gilbert, Elliot P; Boyd, Ben J
2018-05-07
Efforts to develop orally administered drugs tend to place an exceptional focus on aqueous solubility as this is an essential criterion for their absorption in the gastrointestinal tract. In this work we examine the solid state behavior and solubility of OZ439, a promising single-dose cure for malaria being developed as the highly water-soluble mesylate salt. The aqueous phase behavior of the OZ439 mesylate salt was determined using a combination of small angle neutron and X-ray scattering (SANS and SAXS, respectively). It was found that this salt has low solubility at low concentrations with the drug largely precipitated in free base aggregates. However, with increasing concentration these crystalline aggregates were observed to dissociate into cationic micelles and lamellar phases, effectively increasing the dissolved drug concentration. It was also found that the dissolved OZ439 spontaneously precipitated in the presence of biologically relevant anions, which we attribute to the high lattice energies of most of the salt forms of the drug. These findings show that aqueous solubility is not always what it seems in the context of amphiphilic drug molecules and highlights that its use as the principal metric in selecting drug candidates for development can be perilous.
-
Use and reimbursement of off-label drugs in pediatric anesthesia: the Italian experience.
Salvo, Ida; Landoni, Giovanni; Mucchetti, Marta; Cabrini, Luca; Pani, Luca
2014-06-01
Most of the drugs used in anesthesia are off-label in children even if they present solid clinical evidence in adults. This lack of authorization is caused by multiple factors including the difficulty in conducting research in this area (due to the ethical concerns and/or the low number of available participants, the high variability of the outcome measures) and the lack of economic interest of the pharmaceutical companies (due to the limited market). Define a list of medicinal products commonly used off-label in pediatrics anesthesia to be reimbursed by Italian National Health System. We hereby describe the methodological framework used to allow reimbursed use of a list of medicinal products, widely used off-label in pediatric patients, ensuring the best therapeutic results with the lowest possible risk for children. A task force of pediatric anesthesiologists from Italy petitioned the Italian Medicines Agency (AIFA) to allow a number of commonly utilized but off-label drugs for pediatric anesthesia to be reimbursed for specific indications. For each drug, both the supporting literature and expert opinion were used, and the resulting list of drugs allowed to be used/reimbursed officially by AIFA was significantly expanded. This paper documents one approach to the problem of off-label use of drugs for pediatric patients that can be a model for future efforts. Continuous efforts are needed from government institutions and sponsors on drug development and on drug approval process in pediatrics, as research on drug effectiveness and safety is mandatory in children as in adults. At the same time, clinicians must become more familiar with the drug-approval process, participate to sponsored trials, and perform ztrials themselves. © 2014 John Wiley & Sons Ltd.
-
Drugs for neglected diseases: a failure of the market and a public health failure?
Trouiller, P; Torreele, E; Olliaro, P; White, N; Foster, S; Wirth, D; Pécoul, B
2001-11-01
Infectious diseases cause the suffering of hundreds of millions of people, especially in tropical and subtropical areas. Effective, affordable and easy-to-use medicines to fight these diseases are nearly absent. Although science and technology are sufficiently advanced to provide the necessary medicines, very few new drugs are being developed. However, drug discovery is not the major bottleneck. Today's R&D-based pharmaceutical industry is reluctant to invest in the development of drugs to treat the major diseases of the poor, because return on investment cannot be guaranteed. With national and international politics supporting a free market-based world order, financial opportunities rather than global health needs guide the direction of new drug development. Can we accept that the dearth of effective drugs for diseases that mainly affect the poor is simply the sad but inevitable consequence of a global market economy? Or is it a massive public health failure, and a failure to direct economic development for the benefit of society? An urgent reorientation of priorities in drug development and health policy is needed. The pharmaceutical industry must contribute to this effort, but national and international policies need to direct the global economy to address the true health needs of society. This requires political will, a strong commitment to prioritize health considerations over economic interests, and the enforcement of regulations and other mechanisms to stimulate essential drug development. New and creative strategies involving both the public and the private sector are needed to ensure that affordable medicines for today's neglected diseases are developed. Priority action areas include advocating an essential medicines R&D agenda, capacity-building in and technology transfer to developing countries, elaborating an adapted legal and regulatory framework, prioritizing funding for essential drug development and securing availability, accessibility, distribution and rational use of these drugs.
-
PROGRESS AND PROBLEMS IN THE APPLICATION OF FOCUSED ULTRASOUND FOR BLOOD-BRAIN BARRIER DISRUPTION
Vykhodtseva, Natalia; McDannold, Nathan; Hynynen, Kullervo
2008-01-01
Advances in neuroscience have resulted in the development of new diagnostic and therapeutic agents for potential use in the central nervous system (CNS). However, the ability to deliver the majority of these agents to the brain is limited by the blood–brain barrier (BBB), a specialized structure of the blood vessel wall that hampers transport and diffusion from the blood to the brain. Many CNS disorders could be treated with drugs, enzymes, genes, or large-molecule biotechnological products such as recombinant proteins, if they could cross the BBB. This article reviews the problems of the BBB presence in treating the vast majority of CNS diseases and the efforts to circumvent the BBB through the design of new drugs and the development of more sophisticated delivery methods. Recent advances in the development of noninvasive, targeted drug delivery by MRI-guided ultrasound-induced BBB disruption are also summarized. PMID:18511095
-
Le, Tuan-Anh; Amin, Faiz Ul; Kim, Myeong Ok
2017-01-01
The blood–brain barrier (BBB) hinders drug delivery to the brain. Despite various efforts to develop preprogramed actuation schemes for magnetic drug delivery, the unmodeled aggregation phenomenon limits drug delivery performance. This paper proposes a novel scheme with an aggregation model for a feed-forward magnetic actuation design. A simulation platform for aggregated particle delivery is developed and an actuation scheme is proposed to deliver aggregated magnetic nanoparticles (MNPs) using a discontinuous asymmetrical magnetic actuation. The experimental results with a Y-shaped channel indicated the success of the proposed scheme in steering and disaggregation. The delivery performance of the developed scheme was examined using a realistic, three-dimensional (3D) vessel simulation. Furthermore, the proposed scheme enhanced the transport and uptake of MNPs across the BBB in mice. The scheme presented here facilitates the passage of particles across the BBB to the brain using an electromagnetic actuation scheme. PMID:29271927
-
Single dose treatment of malaria - current status and perspectives.
Mischlinger, Johannes; Agnandji, Selidji T; Ramharter, Michael
2016-07-01
Despite increased international efforts for control and ultimate elimination, malaria remains a major health problem. Currently, artemisinin-based combination therapies are the treatment of choice for uncomplicated malaria exhibiting high efficacy in clinical trial settings in sub-Saharan Africa. However, their administration over a three-day period is associated with important problems of treatment adherence resulting in markedly reduced effectiveness of currently recommended antimalarials under real world settings. Antimalarial drug candidates and antimalarial drug combinations currently under advanced clinical development for the indication as single dose antimalarial therapy. Expert commentary: Several new drug candidates and combinations are currently undergoing pivotal proof-of-concept studies or clinical development programmes. The development of a single dose combination therapy would constitute a breakthrough in the control of malaria. Such an innovative treatment approach would simultaneously close the effectiveness gap of current three-day therapies and revolutionize population based interventions in the context of malaria elimination campaigns.
-
Hoshiar, Ali Kafash; Le, Tuan-Anh; Amin, Faiz Ul; Kim, Myeong Ok; Yoon, Jungwon
2017-12-22
The blood-brain barrier (BBB) hinders drug delivery to the brain. Despite various efforts to develop preprogramed actuation schemes for magnetic drug delivery, the unmodeled aggregation phenomenon limits drug delivery performance. This paper proposes a novel scheme with an aggregation model for a feed-forward magnetic actuation design. A simulation platform for aggregated particle delivery is developed and an actuation scheme is proposed to deliver aggregated magnetic nanoparticles (MNPs) using a discontinuous asymmetrical magnetic actuation. The experimental results with a Y-shaped channel indicated the success of the proposed scheme in steering and disaggregation. The delivery performance of the developed scheme was examined using a realistic, three-dimensional (3D) vessel simulation. Furthermore, the proposed scheme enhanced the transport and uptake of MNPs across the BBB in mice. The scheme presented here facilitates the passage of particles across the BBB to the brain using an electromagnetic actuation scheme.
-
Diverse targeted approaches to battle multidrug resistance in cancer.
Shankaraiah, Nagula; Nekkanti, Shalini; Ommi, Ojaswitha; Lakshmi, P S Soukya
2018-04-09
The efficacy of successful cancer therapies is frequently hindered by the development of drug resistance in the tumor. The term 'drug resistance' is used to illustrate the decreased effectiveness of a drug in curing a disease or alleviating the symptoms of the patient. This phenomenon helps tumors to survive the damage caused by a specific drug or group of drugs. In this context, studying the mechanisms of drug resistance and applying this information to design customized treatment regimens can improve therapeutic efficacy as well as the curative outcome. Over the years, numerous multidrug resistance (MDR) mechanisms have been recognized and tremendous effort has been put into developing agents to address them. The integration of data emerging from the elucidation of molecular and biochemical pathways and specific tumor-associated factors has shown tremendous promise within the oncology community for improving patient outcomes. In this review, we provide an overview of the utility of these molecular and biochemical signaling processes as well as tumor-associated factors associated with MDR, for the rational selection of cancer treatment strategies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
-
Using Computational Toxicology to Enable Risk-Based ...
presentation at Drug Safety Gordon Research Conference 2016 on research efforts in NCCT to enable Computational Toxicology to support risk assessment. Slide presentation at Drug Safety Gordon Research Conference 2016 on research efforts in NCCT to enable Computational Toxicology to support risk assessment.
-
ERIC Educational Resources Information Center
Whitlatch, Jo Bell
1977-01-01
This essay lists resources on drug information. Topics include classes of drugs, drugs which are abused, identification of drug abusers, drug education, national patterns of abuse and treatment, drug toxicity and poisoning, federal regulations, federal enforcement efforts and strategies, and the relationship of drugs and crime. (JAB)
-
Tonge, Peter J.; Xie, Lei; Bourne, Philip E.
2009-01-01
The rise of multi-drug resistant (MDR) and extensively drug resistant (XDR) tuberculosis around the world, including in industrialized nations, poses a great threat to human health and defines a need to develop new, effective and inexpensive anti-tubercular agents. Previously we developed a chemical systems biology approach to identify off-targets of major pharmaceuticals on a proteome-wide scale. In this paper we further demonstrate the value of this approach through the discovery that existing commercially available drugs, prescribed for the treatment of Parkinson's disease, have the potential to treat MDR and XDR tuberculosis. These drugs, entacapone and tolcapone, are predicted to bind to the enzyme InhA and directly inhibit substrate binding. The prediction is validated by in vitro and InhA kinetic assays using tablets of Comtan, whose active component is entacapone. The minimal inhibition concentration (MIC99) of entacapone for Mycobacterium tuberculosis (M.tuberculosis) is approximately 260.0 µM, well below the toxicity concentration determined by an in vitro cytotoxicity model using a human neuroblastoma cell line. Moreover, kinetic assays indicate that Comtan inhibits InhA activity by 47.0% at an entacapone concentration of approximately 80 µM. Thus the active component in Comtan represents a promising lead compound for developing a new class of anti-tubercular therapeutics with excellent safety profiles. More generally, the protocol described in this paper can be included in a drug discovery pipeline in an effort to discover novel drug leads with desired safety profiles, and therefore accelerate the development of new drugs. PMID:19578428
-
Drugs foresight 2020: a Delphi expert panel study.
Lintonen, Tomi; Konu, Anne; Rönkä, Sanna; Kotovirta, Elina
2014-05-03
Historically substance misuse has been relatively common in western countries, but comparatively few Finns report drug use. The Drugs 2020 study aimed at foreseeing changes in the drug situation in Finland by the year 2020. The Delphi method was used, utilizing drug experts of the EU national network in Finland. Marked growth was foreseen in drug use, especially in synthetic designer drugs and misuse of medicinal drugs. Significant increase was also expected in growing cannabis at home. However, the control of drug market was expected to shift more into the hands of organized crime. No consensus was reached on how drug prices will develop in the time period. Drug use is likely to remain punishable although the use and possession of cannabis may be treated less severely. It seems likely that health and social services resources will be directed towards medicinal treatment. Foresight can be utilized in preparing for the future; desirable developments can be fostered, and measures can be taken to curb probable but undesirable lines of development. Based on the results of this study, the experts' view is that it is highly likely that the Finnish society will have to prepare for an increase in the demand for drug-related care, both in terms of content of the care and financing the services. Also, the forecasted increase in the role of legal prescription medicine used as intoxicants will call for efforts not only in changing prescription practices but in border and police control measures, as well. Parallel developments have been foreseen in the UK and Sweden, and it is likely that similar trends will actualize also in other western countries.
-
Abarro, P A
1987-01-01
The Colombo Plan was established in 1950 as a regional intergovernmental organization for co-operative economic and social development in Asia and the Pacific comprising 26 member States. The permanent secretariat is the Colombo Plan Bureau to which is attached the Drug Advisory Programme (DAP) headed by a drug adviser, who consults with Governments and helps develop co-operative programmes for drug abuse prevention and control. DAP functions in close liaison and co-operation with organizations of the United Nations system and other regional and international organizations in pursuing activities in line with the international strategy and policies for drug control of the United Nations. DAP assists member States in creating public awareness of the dangers of drug abuse and drug trafficking through the use of mass media, seminars, workshops and conferences and study exchange programmes. It assists Governments in updating their drug laws and in establishing special drug units and national co-ordinating bodies on drug abuse control. DAP encourages and supports the utilization of community resources and the activities of non-governmental organizations and voluntary bodies for the prevention and reduction of drug abuse, as well as the use of mass media for more co-ordinated efforts in this area. It assists member States in developing human resources and technical expertise of personnel in the various disciplines of law enforcement, prevention, treatment and rehabilitation, through training, seminars, study exchange fellowship programmes and research. DAP also assists in promoting co-operation at the regional and interregional levels, and is involved in developing and strengthening co-operation between agencies of member States that deal with drug problems.
-
Subtype and pathway specific responses to anticancer compounds in breast cancer.
Heiser, Laura M; Sadanandam, Anguraj; Kuo, Wen-Lin; Benz, Stephen C; Goldstein, Theodore C; Ng, Sam; Gibb, William J; Wang, Nicholas J; Ziyad, Safiyyah; Tong, Frances; Bayani, Nora; Hu, Zhi; Billig, Jessica I; Dueregger, Andrea; Lewis, Sophia; Jakkula, Lakshmi; Korkola, James E; Durinck, Steffen; Pepin, François; Guan, Yinghui; Purdom, Elizabeth; Neuvial, Pierre; Bengtsson, Henrik; Wood, Kenneth W; Smith, Peter G; Vassilev, Lyubomir T; Hennessy, Bryan T; Greshock, Joel; Bachman, Kurtis E; Hardwicke, Mary Ann; Park, John W; Marton, Laurence J; Wolf, Denise M; Collisson, Eric A; Neve, Richard M; Mills, Gordon B; Speed, Terence P; Feiler, Heidi S; Wooster, Richard F; Haussler, David; Stuart, Joshua M; Gray, Joe W; Spellman, Paul T
2012-02-21
Breast cancers are comprised of molecularly distinct subtypes that may respond differently to pathway-targeted therapies now under development. Collections of breast cancer cell lines mirror many of the molecular subtypes and pathways found in tumors, suggesting that treatment of cell lines with candidate therapeutic compounds can guide identification of associations between molecular subtypes, pathways, and drug response. In a test of 77 therapeutic compounds, nearly all drugs showed differential responses across these cell lines, and approximately one third showed subtype-, pathway-, and/or genomic aberration-specific responses. These observations suggest mechanisms of response and resistance and may inform efforts to develop molecular assays that predict clinical response.
-
Andrews, A B; Patterson, E G
1995-01-01
Recent efforts to develop legal mechanisms to detect prenatal substance abuse and force pregnant women into drug-free conditions have precipitated ethical struggles for social workers. This article reviews relevant social work values and ethical issues, particularly the need to balance obligations to promote client self-determination, privacy, and access to chosen services with professional values that support coercive intervention to aid vulnerable people and to protect life. The constitutional principles that most affect coercive interventions--due process and equal protection--are reviewed. Recommendations are offered to guide ethical and legal social work for case interventions and policy development.
-
Brazilian Federal Police drug chemical profiling - the PeQui project.
Zacca, Jorge J; Botelho, Elvio Dias; Vieira, Maurício L; Almeida, Fernanda L A; Ferreira, Luciana S; Maldaner, Adriano O
2014-07-01
Over the past six years the Brazilian Federal Police has undertaken major efforts in order to implement and to develop its own drug chemical profiling program. This paper aims to provide a broad perspective regarding the managerial strategies and some examples of subsequent technical issues involved in the implementation of such a project. Close collaboration with local drug enforcement and investigation teams, establishment of proper worldwide partnerships with well recognized institutions in the field of drug analysis and the attainment of suitable funding and human resources are shown to be key success factors. Some preliminary results concerning the chemical profile of cocaine seizures in Brazil during this process are presented. Copyright © 2014 Forensic Science Society. Published by Elsevier Ireland Ltd. All rights reserved.
-
Introducing new contraceptives.
Segal, S J; Coutinho, E
1986-12-01
At this time, private research efforts to discover new contraceptives are threatened. Drug companies, particularly in the US, have reduced their interest in contraceptive development due to concern over the rising cost of product liability insurance, the cost of lawsuits in defense of liability claims, and the fear of extremely high awards by juries in product liability cases. The current form of private-public collaboration, now threatened by the liability crisis, works under a few simple principles of agreement. Private industry agrees to supply its patented chemical compounds for assessment as contraceptive agents, to be willing to enter into negotiations with public sector organizations to develop the contraceptive drugs if initial tests warrant it, and to release compounds to another company if the patent-holder declines to proceed with contraceptive development. The public-sector program agrees to fund the studies, keep the industry informed, and maintain confidentiality. When the technology is discovered by the public sector and is of potential interest to private industry, the collaboration involves other issues. The public agency agrees to supply manufacturing know-how and all biological and clinical information, to license under applicable patents, and to permit cross reference to regulatory agency filings. Private industry agrees to use its best efforts to bring the product to market, to manufacture the product at reduced cost for public sector use, or to provide know-how for others to do so. It also agrees to assume product liability and to grant the public sector agency licenses to any patented improvement in its product. Contraceptive research both within and outside the US is feeling the effects of the US litigious atmosphere. Companies from abroad now wish to steer clear of contraceptive research, even though these companies would be prepared to meet the requirements of the Food and Drug Administration. Contraceptives, considered to be high risk targets for lawsuits, are receiving little of the research budgets of pharmaceutical companies. Opposition anti-abortion forces also has had an effect. When the Population Council received new drug approval for the Copper-T-200, it was the 1st time the FDA had issued approval to a noncommercial sponsor. This unprecedented event established a new phase in the cooperative efforts between industry and the nonprofit sector to develop contraceptive products. It showed that given adequate funding, nonprofit agencies can carry out full product development, including the initial regulatory agency clearances.
-
Developing New Treatments for Heart Failure: Focus on the Heart.
Gheorghiade, Mihai; Larson, Christopher J; Shah, Sanjiv J; Greene, Stephen J; Cleland, John G F; Colucci, Wilson S; Dunnmon, Preston; Epstein, Stephen E; Kim, Raymond J; Parsey, Ramin V; Stockbridge, Norman; Carr, James; Dinh, Wilfried; Krahn, Thomas; Kramer, Frank; Wahlander, Karin; Deckelbaum, Lawrence I; Crandall, David; Okada, Shunichiro; Senni, Michele; Sikora, Sergey; Sabbah, Hani N; Butler, Javed
2016-05-01
Compared with heart failure (HF) care 20 to 30 years ago, there has been tremendous advancement in therapy for ambulatory HF with reduced ejection fraction with the use of agents that block maladaptive neurohormonal pathways. However, during the past decade, with few notable exceptions, the frequency of successful drug development programs has fallen as most novel therapies have failed to offer incremental benefit or raised safety concerns (ie, hypotension). Moreover, no therapy has been approved specifically for HF with preserved ejection fraction or for worsening chronic HF (including acutely decompensated HF). Across the spectrum of HF, preliminary results from many phase II trials have been promising but are frequently followed by unsuccessful phase III studies, highlighting a disconnect in the translational process between basic science discovery, early drug development, and definitive clinical testing in pivotal trials. A major unmet need in HF drug development is the ability to identify homogeneous subsets of patients whose underlying disease is driven by a specific mechanism that can be targeted using a new therapeutic agent. Drug development strategies should increasingly consider therapies that facilitate reverse remodeling by directly targeting the heart itself rather than strictly focusing on agents that unload the heart or target systemic neurohormones. Advancements in cardiac imaging may allow for more focused and direct assessment of drug effects on the heart early in the drug development process. To better understand and address the array of challenges facing current HF drug development, so that future efforts may have a better chance for success, the Food and Drug Administration facilitated a meeting on February 17, 2015, which was attended by clinicians, researchers, regulators, and industry representatives. The following discussion summarizes the key takeaway dialogue from this meeting. © 2016 American Heart Association, Inc.
-
[Activity of NTDs Drug-discovery Research Consortium].
Namatame, Ichiji
2016-01-01
Neglected tropical diseases (NTDs) are an extremely important issue facing global health care. To improve "access to health" where people are unable to access adequate medical care due to poverty and weak healthcare systems, we have established two consortiums: the NTD drug discovery research consortium, and the pediatric praziquantel consortium. The NTD drug discovery research consortium, which involves six institutions from industry, government, and academia, as well as an international non-profit organization, is committed to developing anti-protozoan active compounds for three NTDs (Leishmaniasis, Chagas disease, and African sleeping sickness). Each participating institute will contribute their efforts to accomplish the following: selection of drug targets based on information technology, and drug discovery by three different approaches (in silico drug discovery, "fragment evolution" which is a unique drug designing method of Astellas Pharma, and phenotypic screening with Astellas' compound library). The consortium has established a brand new database (Integrated Neglected Tropical Disease Database; iNTRODB), and has selected target proteins for the in silico and fragment evolution drug discovery approaches. Thus far, we have identified a number of promising compounds that inhibit the target protein, and we are currently trying to improve the anti-protozoan activity of these compounds. The pediatric praziquantel consortium was founded in July 2012 to develop and register a new praziquantel pediatric formulation for the treatment of schistosomiasis. Astellas Pharma has been a core member in this consortium since its establishment, and has provided expertise and technology in the area of pediatric formulation development and clinical development.
-
USDA-ARS?s Scientific Manuscript database
Foodborne pathogens remain global health problems despite concerted efforts to control the transmission of these microorganisms through food. The resurgence of drug resistant bacteria has renewed interest in developing and testing new sources of antimicrobial agents to control foodborne illness. Thi...
-
Regulation of Hexose and Pentose Metabolism by "Escherichia coli"
ERIC Educational Resources Information Center
Desai, Tasha A.
2009-01-01
Microorganisms can be used to produce a variety of chemicals such as drugs, enzymes, and fuels from different sugars. Traditionally, these processes have involved a single feedstock, most often glucose. More recently, significant effort has been devoted towards developing processes that directly use plant-based material as the feedstock. One…
-
The common participation of oncogenic KRAS proteins in many of the most lethal human cancers, together with the ease of detecting somatic KRAS mutant alleles in patient samples, has spurred persistent and intensive efforts to develop drugs that inhibit KRAS activity.
-
In an effort to develop a rapid in vivo screen for EPA’s prioritization of toxic chemicals, we are characterizing the locomotor activity of zebrafish (Danio rerio) larvae after developmental exposure to various classes of prototypic drugs that act on the central nervous system. ...
-
Mental Health Counseling and Specialty Courts
ERIC Educational Resources Information Center
Davis, Toni O.; Cates, Keith A.
2017-01-01
Specialty courts, such as mental health courts, drug courts, and veterans treatment courts, were developed with the intention of reducing recidivism and obtaining better outcomes for participants selected from the particular populations served by each court. Efforts to improve the public good have produced a reimagining of the justice system with…
-
Discovery of new antimalarial chemotypes through chemical methodology and library development.
Brown, Lauren E; Chih-Chien Cheng, Ken; Wei, Wan-Guo; Yuan, Pingwei; Dai, Peng; Trilles, Richard; Ni, Feng; Yuan, Jing; MacArthur, Ryan; Guha, Rajarshi; Johnson, Ronald L; Su, Xin-zhuan; Dominguez, Melissa M; Snyder, John K; Beeler, Aaron B; Schaus, Scott E; Inglese, James; Porco, John A
2011-04-26
In an effort to expand the stereochemical and structural complexity of chemical libraries used in drug discovery, the Center for Chemical Methodology and Library Development at Boston University has established an infrastructure to translate methodologies accessing diverse chemotypes into arrayed libraries for biological evaluation. In a collaborative effort, the NIH Chemical Genomics Center determined IC(50)'s for Plasmodium falciparum viability for each of 2,070 members of the CMLD-BU compound collection using quantitative high-throughput screening across five parasite lines of distinct geographic origin. Three compound classes displaying either differential or comprehensive antimalarial activity across the lines were identified, and the nascent structure activity relationships (SAR) from this experiment used to initiate optimization of these chemotypes for further development.
-
Development of an in vitro cell culture model to study milk to plasma ratios of therapeutic drugs.
Athavale, Maithili A; Maitra, Anurupa; Patel, Shahnaz; Bhate, Vijay R; Toddywalla, Villi S
2013-01-01
To create an in vitro cell culture model to predict the M/P (concentration of drug in milk/concentration in maternal plasma) ratios of therapeutic drugs viz. rifampicin, theophylline, paracetamol, and aspirin. An in vitro cell culture model using CIT3 cells (mouse mammary epithelial cells) was created by culturing the cells on transwells. The cells formed an integral monolayer, allowing only transcellular transport as it happens in vivo. Functionality of the cells was confirmed through scanning electron microscopy. Time wise transfer of the study drugs from plasma to milk was studied and compared with actual (in vivo) M/P ratios obtained at reported tmax for the respective drugs. The developed model mimicked two important intrinsic factors of mammary epithelial cells viz. secretory and tight-junction properties and also the passive route of drug transport. The in vitro M/P ratios at reported tmax were 0.23, 0.61, 0.87, and 0.03 respectively, for rifampicin, theophylline, paracetamol, and salicylic acid as compared to 0.29, 0.65, 0.65, and 0.22, respectively, in vitro. Our preliminary effort to develop an in vitro physiological model showed promising results. Transfer rate of the drugs using the developed model compared well with the transfer potential seen in vivo except for salicylic acid, which was transferred in far lower concentration in vitro. The model has a potential to be developed as a non-invasive alternative to the in vitro technique for determining the transfer of therapeutic drugs into breast milk.
-
Huang, Shiew-Mei; Strong, John M; Zhang, Lei; Reynolds, Kellie S; Nallani, Srikanth; Temple, Robert; Abraham, Sophia; Habet, Sayed Al; Baweja, Raman K; Burckart, Gilbert J; Chung, Sang; Colangelo, Philip; Frucht, David; Green, Martin D; Hepp, Paul; Karnaukhova, Elena; Ko, Hon-Sum; Lee, Jang-Ik; Marroum, Patrick J; Norden, Janet M; Qiu, Wei; Rahman, Atiqur; Sobel, Solomon; Stifano, Toni; Thummel, Kenneth; Wei, Xiao-Xiong; Yasuda, Sally; Zheng, Jenny H; Zhao, Hong; Lesko, Lawrence J
2008-06-01
Predicting clinically significant drug interactions during drug development is a challenge for the pharmaceutical industry and regulatory agencies. Since the publication of the US Food and Drug Administration's (FDA's) first in vitro and in vivo drug interaction guidance documents in 1997 and 1999, researchers and clinicians have gained a better understanding of drug interactions. This knowledge has enabled the FDA and the industry to progress and begin to overcome these challenges. The FDA has continued its efforts to evaluate methodologies to study drug interactions and communicate recommendations regarding the conduct of drug interaction studies, particularly for CYP-based and transporter-based drug interactions, to the pharmaceutical industry. A drug interaction Web site was established to document the FDA's current understanding of drug interactions (http://www.fda.gov/cder/drug/drugInteractions/default.htm). This report provides an overview of the evolution of the drug interaction guidances, includes a synopsis of the steps taken by the FDA to revise the original drug interaction guidance documents, and summarizes and highlights updated sections in the current guidance document, Drug Interaction Studies-Study Design, Data Analysis, and Implications for Dosing and Labeling.
-
Goldberg, Kirsten B; Blumenthal, Gideon M; Pazdur, Richard
The Food and Drug Administration formally established the Oncology Center of Excellence (OCE) in January 2017, as authorized by the 21st Century Cures Act, to expedite the development and review of certain drugs, biologics, and devices for the treatment of cancer. In its first year, the OCE conducted the clinical reviews for several products, including the first 2 chimeric antigen receptor T-cell therapies approved for the treatment of advanced hematologic malignancies and an in vitro diagnostic next-generation sequencing panel, FoundationOne CDx. The OCE also worked with professional societies and patient advocates on efforts to modernize clinical trial eligibility criteria, resulting in recommendations regarding minimal age, brain metastases, organ dysfunction, and human immunodeficiency virus coinfection. Altogether in 2017, the Food and Drug Administration approved 16 new drug and biologic applications, 30 supplemental drug and biologic applications, and 2 biosimilar applications in oncology.
-
Li, Jianzong; Liu, Wei; Luo, Hao; Bao, Jinku
2016-09-01
Anaplastic lymphoma kinase (ALK) plays a crucial role in multiple malignant cancers. It is known as a well-established target for the treatment of ALK-dependent cancers. Even though substantial efforts have been made to develop ALK inhibitors, only crizotinib, ceritinib, and alectinib had been approved by the U.S. Food and Drug Administration for patients with ALK-positive non-small cell lung cancer (NSCLC). The secondary mutations with drug-resistance bring up difficulties to develop effective drugs for ALK-positive cancers. To give a comprehensive understanding of molecular mechanism underlying inhibitor response to ALK tyrosine kinase mutations, we established an accurate assessment for the extensive profile of drug against ALK mutations by means of computational approaches. The molecular mechanics-generalized Born surface area (MM-GBSA) method based on molecular dynamics (MD) simulation was carried out to calculate relative binding free energies for receptor-drug systems. In addition, the structure-based virtual screening was utilized to screen effective inhibitors targeting wild-type ALK and the gatekeeper mutation L1196M from 3180 approved drugs. Finally, the mechanism of drug resistance was discussed, several novel potential wild-type and L1196M mutant ALK inhibitors were successfully identified.
-
Weaver, Richard J; Betts, Catherine; Blomme, Eric A G; Gerets, Helga H J; Gjervig Jensen, Klaus; Hewitt, Philip G; Juhila, Satu; Labbe, Gilles; Liguori, Michael J; Mesens, Natalie; Ogese, Monday O; Persson, Mikael; Snoeys, Jan; Stevens, James L; Walker, Tracy; Park, B Kevin
2017-07-01
The liver is an important target for drug-induced toxicities. Early detection of hepatotoxic drugs requires use of well-characterized test systems, yet current knowledge, gaps and limitations of tests employed remains an important issue for drug development. Areas Covered: The current state of the science, understanding and application of test systems in use for the detection of drug-induced cytotoxicity, mitochondrial toxicity, cholestasis and inflammation is summarized. The test systems highlighted herein cover mostly in vitro and some in vivo models and endpoint measurements used in the assessment of small molecule toxic liabilities. Opportunities for research efforts in areas necessitating the development of specific tests and improved mechanistic understanding are highlighted. Expert Opinion: Use of in vitro test systems for safety optimization will remain a core activity in drug discovery. Substantial inroads have been made with a number of assays established for human Drug-induced Liver Injury. There nevertheless remain significant gaps with a need for improved in vitro tools and novel tests to address specific mechanisms of human Drug-Induced Liver Injury. Progress in these areas will necessitate not only models fit for application, but also mechanistic understanding of how chemical insult on the liver occurs in order to identify translational and quantifiable readouts for decision-making.
-
Total synthesis of teixobactin
NASA Astrophysics Data System (ADS)
Jin, Kang; Sam, Iek Hou; Po, Kathy Hiu Laam; Lin, Du'an; Ghazvini Zadeh, Ebrahim H.; Chen, Sheng; Yuan, Yu; Li, Xuechen
2016-08-01
To cope with the global bacterial multidrug resistance, scientific communities have devoted significant efforts to develop novel antibiotics, particularly those with new modes of actions. Teixobactin, recently isolated from uncultured bacteria, is considered as a promising first-in-class drug candidate for clinical development. Herein, we report its total synthesis by a highly convergent Ser ligation approach and this strategy allows us to prepare several analogues of the natural product.
-
ERIC Educational Resources Information Center
Wentland, Mark P.; Raza, Shaan; Yingtong Gao
2004-01-01
An appropriate assay to determine the inhibition potency of carboxypeptidase A (CPA) in 96-well format to illustrate how high throughput screening is used in modern drug discovery to identify bioactive molecules is developed. Efforts in developing a colorimetric 96-well plate assay for determination of the K(sub i) for inhibition of CPA by…
-
Zsila, Ferenc; Fitos, Ilona; Bencze, Gyula; Kéri, György; Orfi, László
2009-01-01
There are about 380 protein kinase inhibitors in drug development as of today and 15 drugs have been marketed already for the treatment of cancer. This time 139 validated kinase targets are in the focus of drug research of pharmaceutical companies and big efforts are made for the development of new, druglike kinase inhibitors. Plasma protein binding is an important factor of the ADME profiling of a drug compound. Human serum albumin (HSA) and alpha(1)-acid glycoprotein (AAG) are the most relevant drug carriers in blood plasma. Since previous literature data indicated that AAG is the principal plasma binding component of some kinase inhibitors the present work focuses on the comprehensive evaluation of AAG binding of a series of marketed and experimental kinase inhibitors by using circular dichroism (CD) spectroscopy approach. HSA binding was also evaluated by affinity chromatography. Protein binding interactions of twenty-six kinase inhibitors are characterized. The contribution of AAG and HSA binding data to the pharmacokinetic profiles of the investigated therapeutic agents is discussed. Structural, biological and drug binding properties of AAG as well as the applicability of the CD method in studying drug-protein binding interactions are also briefly reviewed.
-
ERIC Educational Resources Information Center
Chambliss, William; Scorza, Thomas
1989-01-01
Presents two opposing viewpoints concerning the legalization of drugs. States that control efforts are not cost effective and suggests that legalization with efforts at education is a better course of action (W. Chambliss). The opposing argument contends that the cost in human suffering negates any savings in dollars gained through legalization…
-
Tanner, Lloyd; Denti, Paolo; Wiesner, Lubbe; Warner, Digby F
2018-06-22
Anti-tuberculosis (TB) drugs possess diverse abilities to penetrate the different host tissues and cell types in which infecting Mycobacterium tuberculosis bacilli are located during active disease. This is important since there is increasing evidence that the respective "lesion-penetrating" properties of the front-line TB drugs appear to correlate well with their specific activity in standard combination therapy. In turn, these observations suggest that rational efforts to discover novel treatment-shortening drugs and drug combinations should incorporate knowledge about the comparative abilities of both existing and experimental anti-TB agents to access bacilli in defined physiological states at different sites of infection, as well as avoid elimination by efflux or inactivation by host or bacterial metabolism. However, while there is a fundamental requirement to understand the mode of action and pharmacological properties of any current or experimental anti-TB agent within the context of the obligate human host, this is complex and, until recently, has been severely limited by the available methodologies and models. Here, we discuss advances in analytical models and technologies which have enabled investigations of drug metabolism and pharmacokinetics (DMPK) for new TB drug development. In particular, we consider the potential to shift the focus of traditional pharmacokinetic-pharmacodynamic analyses away from plasma to a more specific "site of action" drug exposure as an essential criterion for drug development and the design of dosing strategies. Moreover, in summarising approaches to determine DMPK data for the "unit of infection" comprising host macrophage and intracellular bacillus, we evaluate the potential benefits of including these analyses at an early stage in the preclinical drug development algorithm. © 2018 IUBMB Life, 2018. © 2018 International Union of Biochemistry and Molecular Biology.
-
Strategies for the Optimization of Natural Leads to Anticancer Drugs or Drug Candidates
Xiao, Zhiyan; Morris-Natschke, Susan L.; Lee, Kuo-Hsiung
2015-01-01
Natural products have made significant contribution to cancer chemotherapy over the past decades and remain an indispensable source of molecular and mechanistic diversity for anticancer drug discovery. More often than not, natural products may serve as leads for further drug development rather than as effective anticancer drugs by themselves. Generally, optimization of natural leads into anticancer drugs or drug candidates should not only address drug efficacy, but also improve ADMET profiles and chemical accessibility associated with the natural leads. Optimization strategies involve direct chemical manipulation of functional groups, structure-activity relationship-directed optimization and pharmacophore-oriented molecular design based on the natural templates. Both fundamental medicinal chemistry principles (e.g., bio-isosterism) and state-of-the-art computer-aided drug design techniques (e.g., structure-based design) can be applied to facilitate optimization efforts. In this review, the strategies to optimize natural leads to anticancer drugs or drug candidates are illustrated with examples and described according to their purposes. Furthermore, successful case studies on lead optimization of bioactive compounds performed in the Natural Products Research Laboratories at UNC are highlighted. PMID:26359649
-
NATIONAL POLICIES TO MEET THE CHALLENGE OF SUBSTANCE ABUSE : PROGRAMMES AND IMPLEMENTATION
Malhotra, Anil; Mohan, Ashwin
2000-01-01
Drug abuse has become a growing issue of concern to humanity. India has a large consumer base of drug and alcohol abusers. This has serious repercussions in terms of morbidity & mortality. Hence the need for a national policy. In India, the Narcotic Drugs and Psychotropic Substances Act. 1985 (NDPS) provides the framework for drug abuse control in the country. A large number of measures have been undertaken as part of demand reduction activities. These include framing policies and programmes, setting up of centres, developing pilot projects, etc. However, the implementation still needs a lot to be desired. The efforts have not yet been streamlined and no revision of policies has taken place based on experience. This paper critically reviews the initiatives taken thus far to control drug abuse in our country. PMID:21407973
-
Gelpí-Acosta, Camila; Albizu-García, Carmen E.; González, Ángel; Des Jarlais, Don C.; Santiago-Negrón, Salvador
2014-01-01
High levels of HIV risk behaviors and prevalence have been reported among Puerto Rican people who inject drugs (PRPWID) since early in the HIV epidemic. Advances in HIV prevention and treatment have reduced HIV among people who inject drugs (PWID) in the United States. We examined HIV-related data for PRPWID in Puerto Rico and the US Northeast to assess whether disparities continue. Injection drug use as a risk for HIV is still overrepresented among Puerto Ricans. Lower availability of syringe exchanges, drug abuse treatment, and antiretroviral treatment for PWID in Puerto Rico contribute to higher HIV risk and incidence. These disparities should be addressed by the development of a federally supported Northeast–Puerto Rico collaboration to facilitate and coordinate efforts throughout both regions. PMID:25211722
-
Covell, David G
2015-01-01
Developing reliable biomarkers of tumor cell drug sensitivity and resistance can guide hypothesis-driven basic science research and influence pre-therapy clinical decisions. A popular strategy for developing biomarkers uses characterizations of human tumor samples against a range of cancer drug responses that correlate with genomic change; developed largely from the efforts of the Cancer Cell Line Encyclopedia (CCLE) and Sanger Cancer Genome Project (CGP). The purpose of this study is to provide an independent analysis of this data that aims to vet existing and add novel perspectives to biomarker discoveries and applications. Existing and alternative data mining and statistical methods will be used to a) evaluate drug responses of compounds with similar mechanism of action (MOA), b) examine measures of gene expression (GE), copy number (CN) and mutation status (MUT) biomarkers, combined with gene set enrichment analysis (GSEA), for hypothesizing biological processes important for drug response, c) conduct global comparisons of GE, CN and MUT as biomarkers across all drugs screened in the CGP dataset, and d) assess the positive predictive power of CGP-derived GE biomarkers as predictors of drug response in CCLE tumor cells. The perspectives derived from individual and global examinations of GEs, MUTs and CNs confirm existing and reveal unique and shared roles for these biomarkers in tumor cell drug sensitivity and resistance. Applications of CGP-derived genomic biomarkers to predict the drug response of CCLE tumor cells finds a highly significant ROC, with a positive predictive power of 0.78. The results of this study expand the available data mining and analysis methods for genomic biomarker development and provide additional support for using biomarkers to guide hypothesis-driven basic science research and pre-therapy clinical decisions.
-
Clinical trials for vaccine development in registry of Korea Food and Drug Administration.
Kang, Seog-Youn
2013-01-01
Based on the action plan "Ensuring a stable supply of National Immunization Program vaccines and sovereignty of biopharmaceutical products," Korea Food and Drug Administration (KFDA) has made efforts to develop vaccines in the context of self reliance and to protect public health. Along with the recognized infrastructures for clinical trials, clinical trials for vaccines have also gradually been conducted at multinational sites as well as at local sites. KFDA will support to expand six to eleven kinds of vaccines by 2017. In accordance with integrated regulatory system, KFDA has promoted clinical trials, established national lot release procedure, and strengthened good manufacturing practices inspection and post marketing surveillance. Against this backdrop, KFDA will support the vaccine development and promote excellent public health protection.
-
Leverson, Joel D.; Sampath, Deepak; Souers, Andrew J.; Rosenberg, Saul H.; Fairbrother, Wayne J.; Amiot, Martine; Konopleva, Marina; Letai, Anthony
2017-01-01
Since the discovery of apoptosis as a form of programmed cell death, targeting the apoptosis pathway to induce cancer cell death has been a high priority goal for cancer therapy. After decades of effort, drug discovery scientists have succeeded in generating small-molecule inhibitors of antiapoptotic BCL-2 family proteins. Innovative medicinal chemistry and structure-based drug design, coupled with a strong fundamental understanding of BCL-2 biology, were essential to the development of BH3 mimetics such as the BCL-2-selective inhibitor venetoclax. We review a number of preclinical studies that have deepened our understanding of BCL-2 biology and facilitated the clinical development of venetoclax. PMID:29146569
-
Wilson, Frederick J; Leiser, Steven C; Ivarsson, Magnus; Christensen, Søren R; Bastlund, Jesper F
2014-03-01
Pharmaco-electroencephalography has significant yet unrealised promise as a translatable intermediate biomarker of central pharmacodynamic activity that could help reduce Phase 2 attrition in the development of central nervous system drugs. In an effort to understand its true potential, a framework for decision-making was proposed and the utility of pharmaco-electroencephalography was assessed through several case studies. A key finding was that lack of standardisation reduces the value of data pooling and meta-analyses and renders assessment of translatability difficult, limiting utility in all but simple cases. Pre-competitive collaboration is essential both to improving understanding of translation and developing modern signal processing techniques. Copyright © 2013 Elsevier Ltd. All rights reserved.
-
Introduction to special section: Science and technology of over-the-horizon radar
NASA Astrophysics Data System (ADS)
Berkey, F. Tom
1998-07-01
The rationale for the development of over-the-horizon (OTH) radar systems operating at frequencies in the HF band arose out of a perceived need for an early-warning defense network. That need changed with the end of the Cold War; however, today OTH radars play a major role in the CounterDrug Program for the interdiction of drug-smuggling aircraft. This special section of Radio Science is devoted to a review of OTH radar technology, with emphasis on contemporary developments in this field. The collection of papers presented here has evolved largely from research and development efforts directed to improving the performance of OTH radar systems deployed both in the United States and in Australia.
-
Salamone, John D; Correa, Merce; Yohn, Samantha; Lopez Cruz, Laura; San Miguel, Noemi; Alatorre, Luisa
2016-06-01
This review paper is focused upon the involvement of mesolimbic dopamine (DA) and related brain systems in effort-based processes. Interference with DA transmission affects instrumental behavior in a manner that interacts with the response requirements of the task, such that rats with impaired DA transmission show a heightened sensitivity to ratio requirements. Impaired DA transmission also affects effort-related choice behavior, which is assessed by tasks that offer a choice between a preferred reinforcer that has a high work requirement vs. less preferred reinforcer that can be obtained with minimal effort. Rats and mice with impaired DA transmission reallocate instrumental behavior away from food-reinforced tasks with high response costs, and show increased selection of low reinforcement/low cost options. Tests of effort-related choice have been developed into models of pathological symptoms of motivation that are seen in disorders such as depression and schizophrenia. These models are being employed to explore the effects of conditions associated with various psychopathologies, and to assess drugs for their potential utility as treatments for effort-related symptoms. Studies of the pharmacology of effort-based choice may contribute to the development of treatments for symptoms such as psychomotor slowing, fatigue or anergia, which are seen in depression and other disorders. Copyright © 2016 Elsevier B.V. All rights reserved.
-
Moving forward in uveitis therapy: preclinical to phase II clinical trial drug development.
Salazar-Méndez, Raquel; Yilmaz, Taygan; Cordero-Coma, Miguel
2016-01-01
Several advances have been made in the diagnostic approach and therapeutic management of patients with immune-mediated uveitis over the last few decades, which have to lead to an improvement in the visual prognosis of patients. However, the use of available therapies, including steroids and immunosuppressive drugs, is still associated with limited efficacy and potentially serious side effects. Consequently, efforts have been made to develop novel therapeutic alternatives including new molecules and innovative therapeutic approaches. Herein, the authors provide an updated review of those drugs in the initial phases of evaluation for the treatment of immune-mediated uveitides as well as the latest evidence from basic research. Enhanced understanding of the pathogenic mechanisms leading to immune-mediated uveitis has led to the identification of new therapeutic targets and thus to the development of more specific drugs. In addition, considering that the eye is a semi-enclosed chamber and that local therapy has the benefit of sparing the rest of the body from potentially toxic exposure, several attempts of establishing direct ophthalmologic avenues for delivery of the established and emerging drugs have also been made. All these advances have been an unquestionable step forward in the challenging management of uveitis patients.
-
2015-08-01
exposure to aggression (e.g., drug / alcohol use, burnout , suicidal ideation). The proposed effort includes both individual level variables (e.g...aggression (e.g., drug / alcohol use, burnout , suicidal ideation). The proposed effort includes both individual level variables (e.g., differences in...anger / rage, bullying, harassment, intimate partner violence) and related physical health and mental health concerns (e.g., drug / alcohol use, burnout
-
ASTM and ASME-BPE Standards--Complying with the Needs of the Pharmaceutical Industry.
Huitt, William M
2011-01-01
Designing and building a pharmaceutical facility requires the owner, engineer of record, and constructor to be knowledgeable with regard to the industry codes and standards that apply to this effort. Up until 1997 there were no industry standards directed at the needs and requirements of the pharmaceutical industry. Prior to that time it was a patchwork effort at resourcing and adopting nonpharmaceutical-related codes and standards and then modifying them in order to meet the more stringent requirements of the Food and Drug Administration (FDA). In 1997 the American Society of Mechanical Engineers (ASME) published the first Bioprocessing Equipment (BPE) Standard. Through harmonization efforts this relatively new standard has brought together, scrutinized, and refined industry accepted methodologies together with FDA compliance requirements, and has established an American National Standard that provides a comprehensive set of standards that are integral to the pharmaceutical industry. This article describes various American National Standards, including those developed and published by the American Society for Testing and Materials (ASTM), and how they apply to the pharmaceutical industry. It goes on to discuss the harmonization effort that takes place between the various standards developers in an attempt to prevent conflicts and omissions between the many standards. Also included are examples of tables and figures taken from the ASME-BPE Standard. These examples provide the reader with insight to the relevant content of the ASME-BPE Standard. Designing and building a pharmaceutical facility requires the owner, engineer of record, and constructor to be knowledgeable with regard to the industry codes and standards that apply to this effort. Up until 1997 there were no industry standards directed at the needs and requirements of the pharmaceutical industry. Prior to that time it was a patchwork effort at resourcing and adopting nonpharmaceutical-related codes and standards and then modifying them in order to meet the more stringent requirements of the Food and Drug Administration (FDA). In 1997 the American Society of Mechanical Engineers (ASME) published the first Bioprocessing Equipment (BPE) Standard. In its initial development and ongoing maintenance it works with other American National Standards developers to harmonize the many standards associated with the design, engineering, and construction of bioprocessing facilities. This harmonization effort has established a comprehensive set of standards for the betterment of the pharmaceutical industry at large. This effort is, and will remain, very important as technology, along with new and improved product and processes, evolve into the future.
-
Recent Advances and Perspectives in Cancer Drug Design.
Magalhaes, Luma G; Ferreira, Leonardo L G; Andricopulo, Adriano D
2018-01-01
Cancer is one of the leading causes of death worldwide. With the increase in life expectancy, the number of cancer cases has reached unprecedented levels. In this scenario, the pharmaceutical industry has made significant investments in this therapeutic area. Despite these efforts, cancer drug research remains a remarkably challenging field, and therapeutic innovations have not yet achieved expected clinical results. However, the physiopathology of the disease is now better understood, and the discovery of novel molecular targets has refreshed the expectations of developing improved treatments. Several noteworthy advances have been made, among which the development of targeted therapies is the most significant. Monoclonal antibodies and antibody-small molecule conjugates have emerged as a worthwhile approach to improve drug selectivity and reduce adverse effects, which are the main challenges in cancer drug discovery. This review will examine the current panorama of drug research and development (R&D) with emphasis on some of the major advances brought to clinical trials and to the market in the past five years. Breakthrough discoveries will be highlighted along with the medicinal chemistry strategies used throughout the discovery process. In addition, this review will provide perspectives and updates on the discovery of novel molecular targets as well as drugs with innovative mechanisms of action.
-
Mendelian randomisation in cardiovascular research: an introduction for clinicians
Bennett, Derrick A; Holmes, Michael V
2017-01-01
Understanding the causal role of biomarkers in cardiovascular and other diseases is crucial in order to find effective approaches (including pharmacological therapies) for disease treatment and prevention. Classical observational studies provide naïve estimates of the likely role of biomarkers in disease development; however, such studies are prone to bias. This has direct relevance for drug development as if drug targets track to non-causal biomarkers, this can lead to expensive failure of these drugs in phase III randomised controlled trials. In an effort to provide a more reliable indication of the likely causal role of a biomarker in the development of disease, Mendelian randomisation studies are increasingly used, and this is facilitated by the availability of large-scale genetic data. We conducted a narrative review in order to provide a description of the utility of Mendelian randomisation for clinicians engaged in cardiovascular research. We describe the rationale and provide a basic description of the methods and potential limitations of Mendelian randomisation. We give examples from the literature where Mendelian randomisation has provided pivotal information for drug discovery including predicting efficacy, informing on target-mediated adverse effects and providing potential new evidence for drug repurposing. The variety of the examples presented illustrates the importance of Mendelian randomisation in order to prioritise drug targets for cardiovascular research. PMID:28596306
-
Contribution of hot-melt extrusion technology to advance drug delivery in the 21st century.
Tiwari, Roshan V; Patil, Hemlata; Repka, Michael A
2016-01-01
Hot-melt extrusion (HME) technology is applied successfully in the plastic, rubber and food industry. HME has also emerged as an important technology for drug delivery applications in pharmaceutical research and manufacturing because of its process automation and low-cost scale-up properties, which reduce labor costs and capital investment. There are a number of commercial FDA-approved HME-derived products, signifying the commercial feasibility of this novel technique in drug delivery applications. HME is a highly efficient, solvent-free continuous processing technique for the development of solid dispersions; thus, research efforts to develop sustained, modified and targeted drug delivery systems to improve the solubility and bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs) are of interest. This review focuses on both the innovations and applications of HME in the production of pharmaceutical formulations, and on the significant findings of the general principles regarding formulation and process development via HME as described in published articles. Challenges faced by pharmaceutical companies to produce efficient drug formulations may be partly overcome by HME's advantages - high drug-loading capacity, good content uniformity, cost-effectiveness, and ease of processing scale-up. Nevertheless, HME's high processing temperatures may be an obstacle if adequate knowledge about the product's formulation is lacking.
-
Castillo-Garit, Juan Alberto; Abad, Concepción; Rodríguez-Borges, J Enrique; Marrero-Ponce, Yovani; Torrens, Francisco
2012-01-01
The neglected tropical diseases (NTDs) affect more than one billion people (one-sixth of the world's population) and occur primarily in undeveloped countries in sub-Saharan Africa, Asia, and Latin America. Available drugs for these diseases are decades old and present an important number of limitations, especially high toxicity and, more recently, the emergence of drug resistance. In the last decade several Quantitative Structure-Activity Relationship (QSAR) studies have been developed in order to identify new organic compounds with activity against the parasites responsible for these diseases, which are reviewed in this paper. The topics summarized in this work are: 1) QSAR studies to identify new organic compounds actives against Chaga's disease; 2) Development of QSAR studies to discover new antileishmanial drusg; 3) Computational studies to identify new drug-like compounds against human African trypanosomiasis. Each topic include the general characteristics, epidemiology and chemotherapy of the disease as well as the main QSAR approaches to discovery/identification of new actives compounds for the corresponding neglected disease. The last section is devoted to a new approach know as multi-target QSAR models developed for antiparasitic drugs specifically those actives against trypanosomatid parasites. At present, as a result of these QSAR studies several promising compounds, active against these parasites, are been indentify. However, more efforts will be required in the future to develop more selective (specific) useful drugs.
-
Pharmacology and Clinical Drug Candidates in Redox Medicine
Casas, Ana I.; Maghzal, Ghassan J.; Seredenina, Tamara; Kaludercic, Nina; Robledinos-Anton, Natalia; Di Lisa, Fabio; Stocker, Roland; Ghezzi, Pietro; Jaquet, Vincent; Cuadrado, Antonio
2015-01-01
Abstract Significance: Oxidative stress is suggested to be a disease mechanism common to a wide range of disorders affecting human health. However, so far, the pharmacotherapeutic exploitation of this, for example, based on chemical scavenging of pro-oxidant molecules, has been unsuccessful. Recent Advances: An alternative emerging approach is to target the enzymatic sources of disease-relevant oxidative stress. Several such enzymes and isoforms have been identified and linked to different pathologies. For some targets, the respective pharmacology is quite advanced, that is, up to late-stage clinical development or even on the market; for others, drugs are already in clinical use, although not for indications based on oxidative stress, and repurposing seems to be a viable option. Critical Issues: For all other targets, reliable preclinical validation and drug ability are key factors for any translation into the clinic. In this study, specific pharmacological agents with optimal pharmacokinetic profiles are still lacking. Moreover, these enzymes also serve largely unknown physiological functions and their inhibition may lead to unwanted side effects. Future Directions: The current promising data based on new targets, drugs, and drug repurposing are mainly a result of academic efforts. With the availability of optimized compounds and coordinated efforts from academia and industry scientists, unambiguous validation and translation into proof-of-principle studies seem achievable in the very near future, possibly leading towards a new era of redox medicine. Antioxid. Redox Signal. 23, 1113–1129. PMID:26415051
-
Biomarkers as drug development tools: discovery, validation, qualification and use.
Kraus, Virginia B
2018-06-01
The 21st Century Cures Act, approved in the USA in December 2016, has encouraged the establishment of the national Precision Medicine Initiative and the augmentation of efforts to address disease prevention, diagnosis and treatment on the basis of a molecular understanding of disease. The Act adopts into law the formal process, developed by the FDA, of qualification of drug development tools, including biomarkers and clinical outcome assessments, to increase the efficiency of clinical trials and encourage an era of molecular medicine. The FDA and European Medicines Agency (EMA) have developed similar processes for the qualification of biomarkers intended for use as companion diagnostics or for development and regulatory approval of a drug or therapeutic. Biomarkers that are used exclusively for the diagnosis, monitoring or stratification of patients in clinical trials are not subject to regulatory approval, although their qualification can facilitate the conduct of a trial. In this Review, the salient features of biomarker discovery, analytical validation, clinical qualification and utilization are described in order to provide an understanding of the process of biomarker development and, through this understanding, convey an appreciation of their potential advantages and limitations.
-
The behavioral pharmacology and therapeutic potential of lorcaserin for substance use disorders.
Collins, Gregory T; Gerak, Lisa R; France, Charles P
2017-12-12
Substance abuse is serious public health problem for which there are few effective pharmacotherapies. Traditional strategies for drug development have focused on antagonists to block the abuse-related effects of a drug at its site of action, and agonists to replace/mimic the effects of the abused substance. However, recent efforts have targeted receptors, such as serotonin (5-HT) 2 receptors, that can indirectly modulate dopamine neurotransmission with the goal of developing a pharmacotherapy that might be effective at reducing the abuse-related effects of drugs more generally. Lorcaserin is a 5-HT 2C receptor-preferring agonist that is approved by the US Food and Drug Administration for the treatment of obesity. Mounting evidence from preclinical and clinical studies suggests that lorcaserin might also be effective at reducing the abuse-related effects of drugs with different pharmacological mechanisms (e.g., cocaine, heroin, ethanol, and nicotine). Lorcaserin represents a promising and important first step towards the development a new class of pharmacotherapies that have the potential to dramatically improve the treatment of substance abuse. This article will review the behavioral pharmacology of 5-HT 2C receptor-preferring agonists, with a focus on lorcaserin, and evaluate the preclinical evidence supporting the development of lorcaserin for treating substance abuse. Copyright © 2017 Elsevier Ltd. All rights reserved.
-
A Systematic Screen of FDA-Approved Drugs for Inhibitors of Biological Threat Agents
Madrid, Peter B.; Chopra, Sidharth; Manger, Ian D.; Gilfillan, Lynne; Keepers, Tiffany R.; Shurtleff, Amy C.; Green, Carol E.; Iyer, Lalitha V.; Dilks, Holli Hutcheson; Davey, Robert A.; Kolokoltsov, Andrey A.; Carrion, Ricardo; Patterson, Jean L.; Bavari, Sina; Panchal, Rekha G.; Warren, Travis K.; Wells, Jay B.; Moos, Walter H.; Burke, RaeLyn L.; Tanga, Mary J.
2013-01-01
Background The rapid development of effective medical countermeasures against potential biological threat agents is vital. Repurposing existing drugs that may have unanticipated activities as potential countermeasures is one way to meet this important goal, since currently approved drugs already have well-established safety and pharmacokinetic profiles in patients, as well as manufacturing and distribution networks. Therefore, approved drugs could rapidly be made available for a new indication in an emergency. Methodology/Principal Findings A large systematic effort to determine whether existing drugs can be used against high containment bacterial and viral pathogens is described. We assembled and screened 1012 FDA-approved drugs for off-label broad-spectrum efficacy against Bacillus anthracis; Francisella tularensis; Coxiella burnetii; and Ebola, Marburg, and Lassa fever viruses using in vitro cell culture assays. We found a variety of hits against two or more of these biological threat pathogens, which were validated in secondary assays. As expected, antibiotic compounds were highly active against bacterial agents, but we did not identify any non-antibiotic compounds with broad-spectrum antibacterial activity. Lomefloxacin and erythromycin were found to be the most potent compounds in vivo protecting mice against Bacillus anthracis challenge. While multiple virus-specific inhibitors were identified, the most noteworthy antiviral compound identified was chloroquine, which disrupted entry and replication of two or more viruses in vitro and protected mice against Ebola virus challenge in vivo. Conclusions/Significance The feasibility of repurposing existing drugs to face novel threats is demonstrated and this represents the first effort to apply this approach to high containment bacteria and viruses. PMID:23577127
-
Enhancing the incorporation of the patient's voice in drug development and evaluation.
Chalasani, Meghana; Vaidya, Pujita; Mullin, Theresa
2018-01-01
People living with a condition are uniquely positioned to inform the understanding of the therapeutic context for drug development and evaluation. In 2012, the U.S. Food and Drug Administration (FDA) established the Patient-Focused Drug Development (PFDD) initiative to more systematically obtain the patient perspective on specific diseases and their currently available treatments. PFDD meetings are unique among FDA public meetings, with a format designed to engage patients and elicit their perspectives on two topic areas: (1) the most significant symptoms of their condition and the impact of the condition on daily life; and, (2) their current approaches to treatment. FDA has conducted 24 disease-specific PFDD meetings to date. The lessons learned from PFDD meetings range from experiences common across rare diseases to more disease specific experiences that matter most to patients. FDA recognizes that FDA-led PFDD meetings alone cannot address the gaps in information on the patient perspective. Patient-focused drug development is an ongoing effort and FDA looks forward to the next steps in advancing the science and the utilization of patient input throughout drug development and evaluation. The U.S. Food and Drug Administration (FDA) has multiple mechanisms for its regulators and staff to interact with patients -- but none quite like its novel Patient-Focused Drug Development (PFDD) initiative. FDA established the PFDD initiative to more systematically obtain the patient perspective on specific diseases and their currently available treatments. Since the initiative's inception in 2012, FDA has held 24 PFDD meetings, covering a range of disease areas and hearing directly from thousands of patients and caregivers. FDA's PFDD meetings have also provided key stakeholders, including patient advocates, researchers, drug developers, healthcare providers, and other government officials, an opportunity to hear the patient's voice. The lessons learned include but are not limited to specific experiences that matter most to patients, patient perspectives on meaningful treatment benefits and how patients want to be engaged in the drug development process. FDA recognizes that FDA-led PFDD meetings alone cannot address the gaps in information on the patient perspective. Further enhancing the incorporation of the patient's voice in drug development and evaluation continues to be a priority for FDA.
-
In Vitro Screening of an FDA-Approved Library Against ESKAPE Pathogens
Younis, Waleed; AbdelKhalek, Ahmed; Mayhoub, Abdelrahman S.; Seleem, Mohamed N.
2017-01-01
Bacterial resistance to conventional antibiotics is an increasingly serious threat to public health worldwide that requires immediate exploration and the development of novel antimicrobial compounds. Drug repurposing is an inexpensive and untapped source of new antimicrobial leads, and it holds many attractive features warranting further attention for antimicrobial drug discovery. In an effort to repurpose drugs and explore new leads in the field of antimicrobial drug discovery, we performed a whole-cell screening assay of 1,600 Food and Drug Administration (FDA) approved drugs against Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter cloacae (ESKAPE) pathogens. The in vitro screening identified 49 non-antimicrobial drugs that were active against at least one species of ESKAPE pathogen. Although some of these drugs were known to have antibacterial activity, many have never been reported before. In particular, sulfonamide-containing structures represent a novel drug scaffold that should be investigated further. The characteristics of these drugs as antimicrobial agents may offer a safe, effective, and quick supplement to current approaches to treating bacterial infections. PMID:28190396
-
2008-07-15
The Food and Drug Administration (FDA) is amending the current good manufacturing practice (CGMP) regulations for human drugs, including biological products, to exempt most phase 1 investigational drugs from complying with the regulatory CGMP requirements. FDA will continue to exercise oversight of the manufacture of these drugs under FDA's general statutory CGMP authority and through review of the investigational new drug applications (IND). In addition, elsewhere in this issue of the Federal Register, FDA is announcing the availability of a guidance document entitled "Guidance for Industry: CGMP for Phase 1 Investigational Drugs" dated November 2007 (the companion guidance). This guidance document sets forth recommendations on approaches to compliance with statutory CGMP for the exempted phase 1 investigational drugs. FDA is taking this action to focus a manufacturer's effort on applying CGMP that is appropriate and meaningful for the manufacture of the earliest stage investigational drug products intended for use in phase 1 clinical trials while ensuring safety and quality. This action will also streamline and promote the drug development process.
-
Prevention and treatment of college student drug use: A review of the literature.
Dennhardt, Ashley A; Murphy, James G
2013-10-01
Drug use during the college years is a significant public health concern. The primary goal of this paper is to provide a comprehensive review of prevention and treatment studies of college student drug use in order to guide college prevention efforts and to inform and stimulate new research in this area. First, established risk factors for drug use were reviewed. High levels of personality traits including, impulsivity, sensation-seeking, negative emotionality, emotional dysregulation, and personality disorder symptoms increase risk for drug use. Drug use has also been linked to overestimating normative levels of drug use and experiencing negative life events, and specific motives for drug use are linked to more problematic patterns. There have been very few studies examining prevention and treatment, but parent-based and in-person brief motivational interventions appear to be promising. Longitudinal studies of the development and course of drug use among college students, as well as clinical trials to evaluate novel theoretically-based intervention and prevention programs that take into account established risk factors for drug abuse are needed. Copyright © 2013 Elsevier Ltd. All rights reserved.
-
Indermun, Sunaina; Choonara, Yahya E; Kumar, Pradeep; Du Toit, Lisa C; Modi, Girish; Luttge, Regina; Pillay, Viness
2014-02-01
Chronic pain poses a major concern to modern medicine and is frequently undertreated, causing suffering and disability. Patient-controlled analgesia, although successful, does have limitations. Transdermal delivery is the pivot to which analgesic research in drug delivery has centralized, especially with the confines of needle phobias and associated pain related to traditional injections, and the existing limitations associated with oral drug delivery. Highlighted within is the possibility of further developing transdermal drug delivery for chronic pain treatment using iontophoresis-based microneedle array patches. A concerted effort was made to review critically all available therapies designed for the treatment of chronic pain. The drug delivery systems developed for this purpose and nondrug routes are elaborated on, in a systematic manner. Recent developments and future goals in transdermal delivery as a means to overcome the individual limitations of the aforementioned delivery routes are represented as well. The approval of patch-like devices that contain both the microelectronic-processing mechanism and the active medicament in a small portable device is still awaited by the pharmaceutical industry. This anticipated platform may provide transdermal electro-activated and electro-modulated drug delivery systems a feasible attempt in chronic pain treatment. Iontophoresis has been proven an effective mode used to administer ionized drugs in physiotherapeutic, diagnostic, and dermatological applications and may be an encouraging probability for the development of devices and aids in the treatment of chronic pain. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.
-
On the use of fractional order PK-PD models
NASA Astrophysics Data System (ADS)
Ionescu, Clara; Copot, Dana
2017-01-01
Quantifying and controlling depth of anesthesia is a challenging process due to lack of measurement technology for direct effects of drug supply into the body. Efforts are being made to develop new sensor techniques and new horizons are explored for modeling this intricate process. This paper introduces emerging tools available on the ‘engineering market’ imported from the area of fractional calculus. A novel interpretation of the classical drug-effect curve is given, enabling linear control. This enables broadening the horizon of signal processing and control techniques and suggests future research lines.
-
2012-01-01
The Village/Commune Safety Policy was launched by the Ministry of Interior of the Kingdom of Cambodia in 2010 and, due to a priority focus on “cleaning the streets”, has created difficulties for HIV prevention programs attempting to implement programs that work with key affected populations including female sex workers and people who inject drugs. The implementation of the policy has forced HIV program implementers, the UN and various government counterparts to explore and develop collaborative ways of delivering HIV prevention services within this difficult environment. The following case study explores some of these efforts and highlights the promising development of a Police Community Partnership Initiative that it is hoped will find a meaningful balance between the Village/Commune Safety Policy and HIV prevention efforts with key affected populations in Cambodia. PMID:22770267
-
Leveraging consumer's behaviour to promote generic drugs in Italy.
Zerbini, Cristina; Luceri, Beatrice; Vergura, Donata Tania
2017-04-01
The aim of this study was to fill the lack of knowledge regarding a more grounded exploration of the consumer's decision-making process in the context of generic drugs. In this perspective, a model, within the theoretical framework of the Theory of Planned Behaviour (TPB), for studying the consumers' purchase intention of generic drugs was developed. An online survey on 2,222 Italian people who bought drugs in the past was conducted. The proposed model was tested through structural equation modelling (SEM). Almost all the constructs considered in the model, except the perceived behavioural control, contribute to explain the consumer's purchase intention of generic drugs, after controlling for demographic variables (age, income, education). Specifically, attitude, subjective norm, past behaviour, self-identity and trust in the pharmacist have a positive influence on the intention to buy generic drugs. On the contrary, perceived risk towards products and brand sensitivity act negatively. The results of the present study could be useful to public policy makers in developing effective policies and educational campaigns aimed at promoting generic drugs. Specifically, marketing efforts should be directed to inform consumers about the generic drugs' characteristics to mitigate the perceived risk towards these products and to raise awareness during their decision-making process. Copyright © 2017 Elsevier B.V. All rights reserved.
-
Setting priorities for a research agenda to combat drug-resistant tuberculosis in children.
Velayutham, B; Nair, D; Ramalingam, S; Perez-Velez, C M; Becerra, M C; Swaminathan, S
2015-12-21
Numerous knowledge gaps hamper the prevention and treatment of childhood drug-resistant tuberculosis (TB). Identifying research priorities is vital to inform and develop strategies to address this neglected problem. To systematically identify and rank research priorities in childhood drug-resistant TB. Adapting the Child Health and Nutrition Research Initiative (CHNRI) methodology, we compiled 53 research questions in four research areas, then classified the questions into three research types. We invited experts in childhood drug-resistant TB to score these questions through an online survey. A total of 81 respondents participated in the survey. The top-ranked research question was to identify the best combination of existing diagnostic tools for early diagnosis. Highly ranked treatment-related questions centred on the reasons for and interventions to improve treatment outcomes, adverse effects of drugs and optimal treatment duration. The prevalence of drug-resistant TB was the highest-ranked question in the epidemiology area. The development type questions that ranked highest focused on interventions for optimal diagnosis, treatment and modalities for treatment delivery. This is the first effort to identify and rank research priorities for childhood drug-resistant TB. The result is a resource to guide research to improve prevention and treatment of drug-resistant TB in children.
-
McCormick, Frank
2015-04-15
KRAS proteins play a major role in human cancer, but have not yielded to therapeutic attack. New technologies in drug discovery and insights into signaling pathways that KRAS controls have promoted renewed efforts to develop therapies through direct targeting of KRAS itself, new ways of blocking KRAS processing, or by identifying targets that KRAS cancers depend on for survival. Although drugs that block the well-established downstream pathways, RAF-MAPK and PI3K, are being tested in the clinic, new efforts are under way to exploit previously unrecognized vulnerabilities, such as altered metabolic networks, or novel pathways identified through synthetic lethal screens. Furthermore, new ways of suppressing KRAS gene expression and of harnessing the immune system offer further hope that new ways of treating KRAS are finally coming into view. These issues are discussed in this edition of CCR Focus. ©2015 American Association for Cancer Research.
-
Good, Andrew C; Hermsmeier, Mark A
2007-01-01
Research into the advancement of computer-aided molecular design (CAMD) has a tendency to focus on the discipline of algorithm development. Such efforts are often wrought to the detriment of the data set selection and analysis used in said algorithm validation. Here we highlight the potential problems this can cause in the context of druglikeness classification. More rigorous efforts are applied to the selection of decoy (nondruglike) molecules from the ACD. Comparisons are made between model performance using the standard technique of random test set creation with test sets derived from explicit ontological separation by drug class. The dangers of viewing druglike space as sufficiently coherent to permit simple classification are highlighted. In addition the issues inherent in applying unfiltered data and random test set selection to (Q)SAR models utilizing large and supposedly heterogeneous databases are discussed.
-
Singh, Juswinder; Deng, Zhan; Narale, Gaurav; Chuaqui, Claudio
2006-01-01
The combination of advances in structure-based drug design efforts in the pharmaceutical industry in parallel with structural genomics initiatives in the public domain has led to an explosion in the number of structures of protein-small molecule complexes structures. This information has critical importance to both the understanding of the structural basis for molecular recognition in biological systems and the design of better drugs. A significant challenge exists in managing this vast amount of data and fully leveraging it. Here, we review our work to develop a simple, fast way to store, organize, mine, and analyze large numbers of protein-small molecule complexes. We illustrate the utility of the approach to the management of inhibitor complexes from the protein kinase family. Finally, we describe our recent efforts in applying this method to the design of target-focused chemical libraries.
-
Garces, Andrea P; Watowich, Stanley J
2013-10-01
West Nile virus (WNV) is a mosquito-borne flavivirus with a rapidly expanding global distribution. Infection can cause severe neurological disease and fatality in humans. Efforts are ongoing to develop antiviral drugs that inhibit the WNV protease, a viral enzyme required for polyprotein processing. Unfortunately, little is known about the solution structure of recombinant WNV protease (NS2B-NS3pro) used for antiviral drug discovery and development, although X-ray crystal structures and nuclear magnetic resonance (NMR) studies have provided valuable insights into the interactions between NS2B-NS3pro and peptide-based inhibitors. We completed small-angle X-ray scattering and Fourier transform infrared spectroscopy experiments to determine the solution structure and dynamics of WNV NS2B-NS3pro in the absence of a bound substrate or inhibitor. Importantly, these solution studies suggested that all or most of the NS2B cofactor was highly flexible and formed an ensemble of structures, in contrast to the NS2B tertiary structures observed in crystallographic and NMR studies. The secondary structure of NS2B-NS3pro in solution had high β-content, similar to the secondary structure observed in crystallographic studies. This work provided evidence of the intrinsic flexibility and conformational heterogeneity of the NS2B chain of the WNV protease in the absence of substratelike ligands, which should be considered during antiviral drug discovery and development efforts.
-
Kant Jha, Chandra; M Donovan, Dennis
2013-01-01
Drug use has numerous consequences on health, the economy, culture and the peace and security of families and communities. Drug users often engage in various criminal activities, including drug dealing, to sustain their drug use. Under Nepalese law, consumption, possession and sale of drugs are illegal, which increases the risk of incarceration for drug users. Using a phenomenological/qualitative approach, the paper explores how various activities can lead to the arrest of drug users, how they cope without taking drugs in custody and prison and how they plan abstinence after release. Participants engaged in various categories of criminal activity, including stealing, looting, etc. Most of the drug users were in custody and prison at least once. Drug use relapses led the participants to re-engage in criminal activities including drug dealing. Parents were often overburdened by their sons and daughter's drug use and were worried about their repeated relapses. Finally, some parents negotiated with their sons and daughters to keep them in prison where they would be able to stay without taking drugs and their involvement in crimes and conflicts would decrease. Keeping substance abusers in prison does not appear to be an effective strategy, as many participants relapse after release from prison. However, a prison-based educational and health promotion strategy would be beneficial for drug users to develop knowledge and skills on staying drug-free. However, to date, no effort has been made to provide such services to drug users and develop their coping strategy after release.
-
USDA-ARS?s Scientific Manuscript database
Increases in the prevalence of antibiotic resistant strains of Staphylococcus (S.) aureus have elicited efforts to develop novel antimicrobials to treat these drug-resistant pathogens. One potential treatment repurposes the lytic enzymes produced by bacteriophages as antimicrobials. The phage Twor...
-
USDA-ARS?s Scientific Manuscript database
Chitosan is a natural compound with proven antimicrobial activity having GRAS status (generally recognized as safe) as determined by the United States Food and Drug Administration (Smith et al., 2014). Efforts are underway to develop and improve the use of chitosan based films as packaging material...
-
A Community in Crisis: The Opioid Epidemic on Staten Island
ERIC Educational Resources Information Center
Tooker, Patricia A.
2017-01-01
There is no "magic potion" or vaccine to prevent youth from using alcohol or other drugs. Adolescent substance abuse prevention programs have been largely ineffective because the messaging is taken for granted. Efforts based on theories of growth and development patterns, and are inclusive of strategies beyond the classroom and home,…
-
ERIC Educational Resources Information Center
Schreier, Hans; And Others
1990-01-01
The University of Florida's efforts to include aspects of genetically engineered drugs into undergraduate teaching and develop a graduate program focusing on the pharmaceutical aspects of technology are outlined, including constituent contributions, attendance, and evaluation. The program's current status and plans for a lab course are discussed.…
-
Eternal Hope: America’s International Narcotics Efforts,
1985-02-01
85 10 02 110 -. ’%6 X:V§: kv7 V * The Rand Paper Series Papers are issued by The Rand Corporation as a service to its profes- sional staff. Their...drug entrepreneurs. Second, new export-import channels developed very rapidly too. Prior to 1970, there seems to have been a trivial amount of Mexican
-
Stahel, R; Bogaerts, J; Ciardiello, F; de Ruysscher, D; Dubsky, P; Ducreux, M; Finn, S; Laurent-Puig, P; Peters, S; Piccart, M; Smit, E; Sotiriou, C; Tejpar, S; Van Cutsem, E; Tabernero, J
2015-02-01
Despite intense efforts, the socioeconomic burden of cancer remains unacceptably high and treatment advances for many common cancers have been limited, suggesting a need for a new approach to drug development. One issue central to this lack of progress is the heterogeneity and genetic complexity of many tumours. This results in considerable variability in therapeutic response and requires knowledge of the molecular profile of the tumour to guide appropriate treatment selection for individual patients. While recent advances in the molecular characterisation of different cancer types have the potential to transform cancer treatment through precision medicine, such an approach presents a major economic challenge for drug development, since novel targeted agents may only be suitable for a small cohort of patients. Identifying the patients who would benefit from individual therapies and recruiting sufficient numbers of patients with particular cancer subtypes into clinical trials is challenging, and will require collaborative efforts from research groups and industry in order to accelerate progress. A number of molecular screening platforms have already been initiated across Europe, and it is hoped that these networks, along with future collaborations, will benefit not only patients but also society through cost reductions as a result of more efficient use of resources. This review discusses how current developments in translational oncology may be applied in clinical practice in the future, assesses current programmes for the molecular characterisation of cancer and describes possible collaborative approaches designed to maximise the benefits of translational science for patients with cancer. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.
-
Collaborative Effort for a Centralized Worldwide Tuberculosis Relational Sequencing Data Platform.
Starks, Angela M; Avilés, Enrique; Cirillo, Daniela M; Denkinger, Claudia M; Dolinger, David L; Emerson, Claudia; Gallarda, Jim; Hanna, Debra; Kim, Peter S; Liwski, Richard; Miotto, Paolo; Schito, Marco; Zignol, Matteo
2015-10-15
Continued progress in addressing challenges associated with detection and management of tuberculosis requires new diagnostic tools. These tools must be able to provide rapid and accurate information for detecting resistance to guide selection of the treatment regimen for each patient. To achieve this goal, globally representative genotypic, phenotypic, and clinical data are needed in a standardized and curated data platform. A global partnership of academic institutions, public health agencies, and nongovernmental organizations has been established to develop a tuberculosis relational sequencing data platform (ReSeqTB) that seeks to increase understanding of the genetic basis of resistance by correlating molecular data with results from drug susceptibility testing and, optimally, associated patient outcomes. These data will inform development of new diagnostics, facilitate clinical decision making, and improve surveillance for drug resistance. ReSeqTB offers an opportunity for collaboration to achieve improved patient outcomes and to advance efforts to prevent and control this devastating disease. Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.
-
Relating Human Genetic Variation to Variation in Drug Responses
Madian, Ashraf G.; Wheeler, Heather E.; Jones, Richard Baker; Dolan, M. Eileen
2012-01-01
Although sequencing a single human genome was a monumental effort a decade ago, more than one thousand genomes have now been sequenced. The task ahead lies in transforming this information into personalized treatment strategies that are tailored to the unique genetics of each individual. One important aspect of personalized medicine is patient-to-patient variation in drug response. Pharmacogenomics addresses this issue by seeking to identify genetic contributors to human variation in drug efficacy and toxicity. Here, we present a summary of the current status of this field, which has evolved from studies of single candidate genes to comprehensive genome-wide analyses. Additionally, we discuss the major challenges in translating this knowledge into a systems-level understanding of drug physiology with the ultimate goal of developing more effective personalized clinical treatment strategies. PMID:22840197
-
Differentiating drugs by harm potential: the rational versus the feasible.
Kalant, H
1999-01-01
In an ideal harm reduction model, drugs would be ranked according to their potential to cause harm, with varying implications for control policies and interventions. In such a public health oriented approach, the maximum protection of the public from harm would be balanced with the least possible restriction of freedom. In reality, however, the accuracy and completeness of the necessary information for such a ranking is highly limited. Many other factors not readily incorporated in a rational model, such as values, beliefs, and traditions, also affect drug policy decisions. Thus, rather than relying on acquisition of the necessary knowledge, it may be preferable to focus efforts on developing effective nonlegal measures to reduce drug use and harm. [Translations are provided in the International Abstracts Section of this issue.
-
Ticehurst, Martyn David; Marziano, Ivan
2015-06-01
This review seeks to offer a broad perspective that encompasses an understanding of the drug product attributes affected by active pharmaceutical ingredient (API) physical properties, their link to solid form selection and the role of particle engineering. While the crucial role of active pharmaceutical ingredient (API) solid form selection is universally acknowledged in the pharmaceutical industry, the value of increasing effort to understanding the link between solid form, API physical properties and drug product formulation and manufacture is now also being recognised. A truly holistic strategy for drug product development should focus on connecting solid form selection, particle engineering and formulation design to both exploit opportunities to access simpler manufacturing operations and prevent failures. Modelling and predictive tools that assist in establishing these links early in product development are discussed. In addition, the potential for differences between the ingoing API physical properties and those in the final product caused by drug product processing is considered. The focus of this review is on oral solid dosage forms and dry powder inhaler products for lung delivery. © 2015 Royal Pharmaceutical Society.
-
Goldring, Christopher; Antoine, Daniel J; Bonner, Frank; Crozier, Jonathan; Denning, Chris; Fontana, Robert J; Hanley, Neil A; Hay, David C; Ingelman-Sundberg, Magnus; Juhila, Satu; Kitteringham, Neil; Silva-Lima, Beatriz; Norris, Alan; Pridgeon, Chris; Ross, James A; Young, Rowena Sison; Tagle, Danilo; Tornesi, Belen; van de Water, Bob; Weaver, Richard J; Zhang, Fang; Park, B Kevin
2017-02-01
Current preclinical drug testing does not predict some forms of adverse drug reactions in humans. Efforts at improving predictability of drug-induced tissue injury in humans include using stem cell technology to generate human cells for screening for adverse effects of drugs in humans. The advent of induced pluripotent stem cells means that it may ultimately be possible to develop personalized toxicology to determine interindividual susceptibility to adverse drug reactions. However, the complexity of idiosyncratic drug-induced liver injury means that no current single-cell model, whether of primary liver tissue origin, from liver cell lines, or derived from stem cells, adequately emulates what is believed to occur during human drug-induced liver injury. Nevertheless, a single-cell model of a human hepatocyte which emulates key features of a hepatocyte is likely to be valuable in assessing potential chemical risk; furthermore, understanding how to generate a relevant hepatocyte will also be critical to efforts to build complex multicellular models of the liver. Currently, hepatocyte-like cells differentiated from stem cells still fall short of recapitulating the full mature hepatocellular phenotype. Therefore, we convened a number of experts from the areas of preclinical and clinical hepatotoxicity and safety assessment, from industry, academia, and regulatory bodies, to specifically explore the application of stem cells in hepatotoxicity safety assessment and to make recommendations for the way forward. In this short review, we particularly discuss the importance of benchmarking stem cell-derived hepatocyte-like cells to their terminally differentiated human counterparts using defined phenotyping, to make sure the cells are relevant and comparable between labs, and outline why this process is essential before the cells are introduced into chemical safety assessment. (Hepatology 2017;65:710-721). © 2016 by the American Association for the Study of Liver Diseases.
-
Drug-resistant tuberculosis clinical trials: proposed core research definitions in adults.
Furin, J; Alirol, E; Allen, E; Fielding, K; Merle, C; Abubakar, I; Andersen, J; Davies, G; Dheda, K; Diacon, A; Dooley, K E; Dravnice, G; Eisenach, K; Everitt, D; Ferstenberg, D; Goolam-Mahomed, A; Grobusch, M P; Gupta, R; Harausz, E; Harrington, M; Horsburgh, C R; Lienhardt, C; McNeeley, D; Mitnick, C D; Nachman, S; Nahid, P; Nunn, A J; Phillips, P; Rodriguez, C; Shah, S; Wells, C; Thomas-Nyang'wa, B; du Cros, P
2016-03-01
Drug-resistant tuberculosis (DR-TB) is a growing public health problem, and for the first time in decades, new drugs for the treatment of this disease have been developed. These new drugs have prompted strengthened efforts in DR-TB clinical trials research, and there are now multiple ongoing and planned DR-TB clinical trials. To facilitate comparability and maximise policy impact, a common set of core research definitions is needed, and this paper presents a core set of efficacy and safety definitions as well as other important considerations in DR-TB clinical trials work. To elaborate these definitions, a search of clinical trials registries, published manuscripts and conference proceedings was undertaken to identify groups conducting trials of new regimens for the treatment of DR-TB. Individuals from these groups developed the core set of definitions presented here. Further work is needed to validate and assess the utility of these definitions but they represent an important first step to ensure there is comparability in clinical trials on multidrug-resistant TB.
-
Anti-mitotic agents: Are they emerging molecules for cancer treatment?
Penna, Larissa Siqueira; Henriques, João Antonio Pêgas; Bonatto, Diego
2017-05-01
Mutations in cancer cells frequently result in cell cycle alterations that lead to unrestricted growth compared to normal cells. Considering this phenomenon, many drugs have been developed to inhibit different cell-cycle phases. Mitotic phase targeting disturbs mitosis in tumor cells, triggers the spindle assembly checkpoint and frequently results in cell death. The first anti-mitotics to enter clinical trials aimed to target tubulin. Although these drugs improved the treatment of certain cancers, and many anti-microtubule compounds are already approved for clinical use, severe adverse events such as neuropathies were observed. Since then, efforts have been focused on the development of drugs that also target kinases, motor proteins and multi-protein complexes involved in mitosis. In this review, we summarize the major proteins involved in the mitotic phase that can also be targeted for cancer treatment. Finally, we address the activity of anti-mitotic drugs tested in clinical trials in recent years. Copyright © 2017 Elsevier Inc. All rights reserved.
-
Developing strategies for AIDS prevention research with black and Hispanic drug users.
Schilling, R F; Schinke, S P; Nichols, S E; Zayas, L H; Miller, S O; Orlandi, M A; Botvin, G J
1989-01-01
More than 8 of 10 intravenous drug users infected with the human immunodeficiency virus (HIV) are black or Hispanic. Recognizing that sociocultural factors affect HIV transmission, public health officials have called for interventions designed for ethnic-racial minority groups. Considered in this paper are the nature and extent of AIDS among ethnic-racial minorities and the cultural aspects of drug use and sexual behavior related to HIV transmission. That drug users and their associates are practicing safer needle use is evident; that they are changing their sexual behavior is less so. Calling for rapid advances in knowledge and expanded efforts in intervention, Federal agencies have instituted numerous programs to support innovative research and demonstration projects in ethnic-racial minority communities. Needed are studies that (a) describe the phenomena of drug use and sexual behavior among ethnic-racial minority populations, (b) establish the efficacy of culturally specific AIDS prevention strategies in drug treatment and community settings, and (c) demonstrate new ways of recruiting, treating, and reducing relapse among drug users. PMID:2493660
-
APPLICATIONS OF HOT-MELT EXTRUSION FOR DRUG DELIVERY
Repka, Michael A.; Majumdar, Soumyajit; Battu, Sunil Kumar; Srirangam, Ramesh; Upadhye, Sampada B.
2018-01-01
In today’s pharmaceutical arena, it is estimated that more than 40% of new chemical entities produced during drug discovery efforts exhibit poor solubility characteristics. However, over the last decade hot-melt extrusion (HME) has emerged as a powerful processing technology for drug delivery and has opened the door to a host of such molecules previously considered unviable as drugs. HME is considered to be an efficient technique in developing solid molecular dispersions and has been demonstrated to provide sustained, modified and targeted drug delivery resulting in improved bioavailability. This article reviews the myriad of HME applications for pharmaceutical dosage forms such as tablets, capsules, films and implants for drug delivery through oral, transdermal, transmucosal, transungual, as well as other routes of administration. Interest in HME as a pharmaceutical process continues to grow and the potential of automation and reduction of capital investment and labor costs have made this technique worthy of consideration as a drug delivery solution. PMID:19040397
-
KCa 3.1-a microglial target ready for drug repurposing?
Dale, Elena; Staal, Roland G W; Eder, Claudia; Möller, Thomas
2016-10-01
Over the past decade, glial cells have attracted attention for harboring unexploited targets for drug discovery. Several glial targets have attracted de novo drug discovery programs, as highlighted in this GLIA Special Issue. Drug repurposing, which has the objective of utilizing existing drugs as well as abandoned, failed, or not yet pursued clinical development candidates for new indications, might provide a faster opportunity to bring drugs for glial targets to patients with unmet needs. Here, we review the potential of the intermediate-conductance calcium-activated potassium channels KCa 3.1 as the target for such a repurposing effort. We discuss the data on KCa 3.1 expression on microglia in vitro and in vivo and review the relevant literature on the two KCa 3.1 inhibitors TRAM-34 and Senicapoc. Finally, we provide an outlook of what it might take to harness the potential of KCa 3.1 as a bona fide microglial drug target. GLIA 2016;64:1733-1741. © 2016 Wiley Periodicals, Inc.
-
Current trends in the use of liposomes for tumor targeting
Deshpande, Pranali P; Biswas, Swati; Torchilin, Vladimir P
2013-01-01
The use of liposomes for drug delivery began early in the history of pharmaceutical nanocarriers. These nanosized, lipid bilayered vesicles have become popular as drug delivery systems owing to their efficiency, biocompatibility, nonimmunogenicity, enhanced solubility of chemotherapeutic agents and their ability to encapsulate a wide array of drugs. Passive and ligand-mediated active targeting promote tumor specificity with diminished adverse off-target effects. The current field of liposomes focuses on both clinical and diagnostic applications. Recent efforts have concentrated on the development of multifunctional liposomes that target cells and cellular organelles with a single delivery system. This review discusses the recent advances in liposome research in tumor targeting. PMID:23914966
-
Sources for Leads: Natural Products and Libraries.
van Herwerden, Eric F; Süssmuth, Roderich D
2016-01-01
Natural products have traditionally been a major source of leads in the drug discovery process. However, the development of high-throughput screening led to an increased interest in synthetic methods that enabled the rapid construction of large libraries of molecules. This resulted in the termination or downscaling of many natural product research programs, but the chemical libraries did not necessarily produce a larger amount of drug leads. On one hand, this chapter explores the current state of natural product research within the drug discovery process. On the other hand it evaluates the efforts made to increase the amount of leads generated from chemical libraries and considers what role natural products could play here.
-
Remotely Triggered Cisplatin Release from Carbon Nanocapsules by Radiofrequency Fields
Raoof, Mustafa; Cisneros, Brandon T.; Guven, Adem; Corr, Stuart J.; Wilson, Lon J.; Curley, Steven A.
2013-01-01
The efficacy of nanoparticle-mediated drug delivery is limited by its peri-vascular sequestration, thus necessitating a strategy to trigger drug release from such intra-tumoral nanocarrier-drug depots. In our efforts to explore remotely-activated nanocarriers, we have developed carbon nanocapsules comprised of an ultrashort carbon nanotube shell (US-tubes) loaded with cisplatin (CDDP@US-tubes) and covered with a Pluronic surfactant wrapping to minimize passive release. We demonstrate here that non-invasive radiofrequency (RF) field activation of the CDDP@US-tubes produces heat that causes Pluronic disruption which triggers cisplatin release in an RF-dependent manner. Furthermore, release-dependent cytotoxicity is demonstrated in human hepatocellular carcinoma cell lines. PMID:23228421
-
Antimalarial compounds in Phase II clinical development.
Held, Jana; Jeyaraj, Sankarganesh; Kreidenweiss, Andrea
2015-03-01
Malaria is a major health problem in endemic countries and chemotherapy remains the most important tool in combating it. Treatment options are limited and essentially rely on a single drug class - the artemisinins. Efforts are ongoing to restrict the evolving threat of artemisinin resistance but declining sensitivity has been reported. Fueled by the ambitious aim of malaria eradication, novel antimalarial compounds, with improved properties, are now in the progressive phase of drug development. Herein, the authors describe antimalarial compounds currently in Phase II clinical development and present the results of these investigations. Thanks to recent efforts, a number of promising antimalarial compounds are now in the pipeline. First safety data have been generated for all of these candidates, although their efficacy as antimalarials is still unclear for most of them. Of particular note are KAE609, KAF156 and DSM265, which are of chemical scaffolds new to malaria chemotherapy and would truly diversify antimalarial options. Apart from SAR97276, which also has a novel chemical scaffold that has had its development stopped, all other compounds in the pipeline belong to already known substance classes, which have been chemically modified. At this moment in time, there is not one standout compound that will revolutionize malaria treatment but several compounds that will add to its control in the future.
-
Structure and Ligand Based Drug Design Strategies in the Development of Novel 5-LOX Inhibitors
Aparoy, Polamarasetty; Kumar Reddy, Kakularam; Reddanna, Pallu
2012-01-01
Lipoxygenases (LOXs) are non-heme iron containing dioxygenases involved in the oxygenation of polyunsaturated fatty acids (PUFAs) such as arachidonic acid (AA). Depending on the position of insertion of oxygen, LOXs are classified into 5-, 8-, 9-, 12- and 15-LOX. Among these, 5-LOX is the most predominant isoform associated with the formation of 5-hydroperoxyeicosatetraenoic acid (5-HpETE), the precursor of non-peptido (LTB4) and peptido (LTC4, LTD4, and LTE4) leukotrienes. LTs are involved in inflammatory and allergic diseases like asthma, ulcerative colitis, rhinitis and also in cancer. Consequently 5-LOX has become target for the development of therapeutic molecules for treatment of various inflammatory disorders. Zileuton is one such inhibitor of 5-LOX approved for the treatment of asthma. In the recent times, computer aided drug design (CADD) strategies have been applied successfully in drug development processes. A comprehensive review on structure based drug design strategies in the development of novel 5-LOX inhibitors is presented in this article. Since the crystal structure of 5-LOX has been recently solved, efforts to develop 5-LOX inhibitors have mostly relied on ligand based rational approaches. The present review provides a comprehensive survey on these strategies in the development of 5-LOX inhibitors. PMID:22680930
-
Experimental therapies for yellow fever
Julander, Justin G.
2013-01-01
A number of viruses in the family Flaviviridae are the focus of efforts to develop effective antiviral therapies. Success has been achieved with inhibitors for the treatment of hepatitis C, and there is interest in clinical trials of drugs against dengue fever. Antiviral therapies have also been evaluated in patients with Japanese encephalitis and West Nile encephalitis. However, no treatment has been developed against the prototype flavivirus, yellow fever virus (YFV). Despite the availability of the live, attenuated 17D vaccine, thousands of cases of YF continue to occur each year in Africa and South America, with a significant mortality rate. In addition, a small number of vaccinees develop severe systemic infections with the 17D virus. This paper reviews current efforts to develop antiviral therapies, either directly targeting the virus or blocking detrimental host responses to infection. PMID:23237991
-
Transepithelial transport and toxicity of PAMAM dendrimers: implications for oral drug delivery.
Sadekar, S; Ghandehari, H
2012-05-01
This article summarizes efforts to evaluate poly(amido amine) (PAMAM) dendrimers as carriers for oral drug delivery. Specifically, the effect of PAMAM generation, surface charge and surface modification on toxicity, cellular uptake and transepithelial transport is discussed. Studies on Caco-2 monolayers, as models of intestinal epithelial barrier, show that by engineering surface chemistry of PAMAM dendrimers, it is possible to minimize toxicity while maximizing transepithelial transport. It has been demonstrated that PAMAM dendrimers are transported by a combination of paracellular and transcellular routes. Depending on surface chemistry, PAMAM dendrimers can open the tight junctions of epithelial barriers. This tight junction opening is in part mediated by internalization of the dendrimers. Transcellular transport of PAMAM dendrimers is mediated by a variety of endocytic mechanisms. Attachment or complexation of cytotoxic agents to PAMAM dendrimers enhances the transport of such drugs across epithelial barriers. A remaining challenge is the design and development of linker chemistries that are stable in the gastrointestinal tract (GIT) and the blood stream, but amenable to cleavage at the target site of action. Recent efforts have focused on the use of PAMAM dendrimers as penetration enhancers. Detailed in vivo oral bioavailability of PAMAM dendrimer-drug conjugates, as a function of physicochemical properties will further need to be assessed. Copyright © 2011 Elsevier B.V. All rights reserved.
-
Paradigms of public policies for licit and illicit drugs in Brazil.
Gigliotti, Analice; Ribeiro, Marcelo; Tapia Aguilera, Amarílis; Rezende, Elton; Ogata Perrenoud, Luciane
2014-01-01
Brazil is a country of continental dimensions that, over the last 3 decades, has been making increased efforts to develop effective public policies for controlling the use of both licit and illicit psychoactive substances. In the case of licit drugs, Brazil was a pioneer in following the guidance of the World Health Organization for tobacco control and has witnessed surprising results relating to reduction of smoking prevalence and correlated morbidity and mortality. Today, Brazil has a national structure for organizing, applying, and monitoring laws relating to tobacco. However, in the field of illicit drugs, with crack consumption as a paradigm, the situation is the opposite: its use has been increasing year by year and is being consumed at increasingly young ages and by all social classes. Thus, it is becoming an enormous challenge for public policies relating to prevention and treatment. In this context, the aim of this article is to present a review of the epidemiological data relating to tobacco and crack use in Brazil, with an analysis on the impact of public policies for controlling consumption over recent years. Despite the efforts made over the last 3 decades, Brazil still has a long way to go in order to construct a consistent and effective national drugs policy.
-
TRANSEPITHELIAL TRANSPORT AND TOXICITY OF PAMAM DENDRIMERS: IMPLICATIONS FOR ORAL DRUG DELIVERY
Sadekar, S.; Ghandehari, H.
2011-01-01
This article summarizes efforts to evaluate poly(amido amine) (PAMAM) dendrimers as carriers for oral drug delivery. Specifically, the effect of PAMAM generation, surface charge and surface modification on toxicity, cellular uptake and transepithelial transport is discussed. Studies on Caco-2 monolayers, as models of intestinal epithelial barrier, show that by engineering surface chemistry of PAMAM dendrimers, it is possible to minimize toxicity while maximizing transepithelial transport. It has been demonstrated that PAMAM dendrimers are transported by a combination of paracellular and transcellular routes. Depending on surface chemistry, PAMAM dendrimers can open the tight junctions of epithelial barriers. This tight junction opening is in part mediated by internalization of the dendrimers. Transcellular transport of PAMAM dendrimers is mediated by a variety of endocytic mechanisms. Attachment or complexation of cytotoxic agents to PAMAM dendrimers enhances the transport of such drugs across epithelial barriers. A remaining challenge is the design and development of linker chemistries that are stable in the gastrointestinal tract (GIT) and the blood stream, but amenable to cleavage at the target site of action. Recent efforts have focused on the use of PAMAM dendrimers as penetration enhancers. Detailed in vivo oral bioavailability of PAMAM dendrimer – drug conjugates, as a function of physicochemical properties will further need to be assessed. PMID:21983078
-
Fetal Abuse and the Criminalization of Behavior during Pregnancy.
ERIC Educational Resources Information Center
Farr, Kathryn Ann
1995-01-01
Discusses efforts to criminalize fetal abuse, harm caused from a pregnant woman's use of illegal drugs. Such efforts have typically failed to withstand judicial scrutiny. Suggests that criminal prosecution for fetal abuse relies on questionable procedures, is unevenly applied, and may keep women from seeking drug treatment or prenatal care. (LKS)
-
[Drug supplies in primary care units at the Ministry of Health in Mexico].
Gómez-Dantés, O; Garrido-Latorre, F; Tirado-Gómez, L L; Ramírez, D; Macías, C
2001-01-01
To identify the availability of some essential drugs (ED) at primary health care units of the Mexican Ministry of Health (SSA), using data from a research work conducted in 1996 and 1997. A random sample of the 18 sanitary jurisdictions of states participating in the Extension of Coverage Program (ECP) was drawn. All primary care units from selected jurisdictions were evaluated through an inspection visit, using a checklist that included 36 ED. In phase I of the analysis, the absolute number and proportion of units without a single item of any of the 36 drugs were calculated. In the units with available drugs, the median of the distribution was also calculated. In phase II, the medians according to the type of health unit and state was obtained. The statistic utilized for the comparison of the medians was the Scheffé test with one way variance analysis. In addition, the drugs were classified according to their therapeutic indication and the medians and proportion of available drugs were calculated. The differences in proportion were evaluated with the statistic chi 2. During the visits, on average, 18 of the 36 drugs included in the list of the study were found in the health units. The availability of antibiotics, antituberculosis drugs, and antimalarial drugs was particularly poor. In contrast, oral rehydration salts, family planning methods and vaccines were usually available. In general, the PAC3 states presented the best availability figures. The Ministry of Health of México will have to develop an enormous effort to overcome the obstacles related to the supply of essential drugs in primary health care units. Otherwise, all other efforts directed to meet the needs of the non-insured population will end up being useless, and enormous amounts of the already scarce resources of the health sector will be wasted since drugs are a vital component of the long chain of health care.
-
Contreras-Mora, Hector; Rowland, Margaret A; Yohn, Samantha E; Correa, Merce; Salamone, John D
2018-03-01
People with depression and Parkinsonism frequently show effort-related motivational symptoms, such as anergia, psychomotor retardation, and fatigue. Tasks that assess effort-related choice are being used as animal models of these motivational symptoms. The present studies characterized the ability of monoamine oxidase (MAO) inhibitors with varying selectivity profiles to reverse the low effort bias induced by the monoamine storage inhibitor tetrabenazine. Tetrabenazine produces depressive symptoms in humans, and because of its selective inhibition of VMAT-2, it preferentially depletes DA at low doses. Effort-based decision making is studied with tasks offering choices between high effort options leading to highly valued reinforcers vs. low effort/low reward options. Tetrabenazine shifted choice behavior, reducing selection of fixed ratio 5 lever pressing, but increasing intake of the concurrently available but less preferred lab chow. These effects of 0.75mg/kg tetrabenazine were attenuated by co-administration of the MAO-B inhibitor deprenyl (selegiline). The ability of deprenyl to reverse the effects of tetrabenazine was marked by an inverted-U shaped dose response curve, with the middle dose (2.5mg/kg) being effective. In contrast, neither the MAO-A selective antagonist moclobemide nor the nonselective drug pargyline reversed the effects of tetrabenazine, and moclobemide decreased lever pressing when administered alone. Deprenyl was originally developed as an antiparkinsonian drug, but it also has been shown to have antidepressant effects in humans and induce antidepressant-like effects in classical rodent models of depression. These studies have implications for the potential use of MAO-B inhibitors as treatments for the motivational symptoms of depression and Parkinsonism. Copyright © 2017. Published by Elsevier Inc.
-
Penazzato, Martina; Lewis, Linda; Watkins, Melynda; Prabhu, Vineet; Pascual, Fernando; Auton, Martin; Kreft, Wesley; Morin, Sébastien; Vicari, Marissa; Lee, Janice; Jamieson, David; Siberry, George K
2018-02-01
Despite the coordinated efforts by several stakeholders to speed up access to HIV treatment for children, development of optimal paediatric formulations still lags 8 to 10 years behind that of adults, due mainly to lack of market incentives and technical complexities in manufacturing. The small and fragmented paediatric market also hinders launch and uptake of new formulations. Moreover, the problems affecting HIV similarly affect other disease areas where development and introduction of optimal paediatric formulations is even slower. Therefore, accelerating processes for developing and commercializing optimal paediatric drug formulations for HIV and other disease areas is urgently needed. The Global Accelerator for Paediatric Formulations (GAP-f) is an innovative collaborative model that will accelerate availability of optimized treatment options for infectious diseases, such as HIV, tuberculosis and viral hepatitis, affecting children in low- and middle-income countries (LMICs). It builds on the HIV experience and existing efforts in paediatric drug development, formalizing collaboration between normative bodies, research networks, regulatory agencies, industry, supply and procurement organizations and funding bodies. Upstream, the GAP-f will coordinate technical support to companies to design and study optimal paediatric formulations, harmonize efforts with regulators and incentivize manufacturers to conduct formulation development. Downstream, the GAP-f will reinforce coordinated procurement and communication with suppliers. The GAP-f will be implemented in a three-stage process: (1) development of a strategic framework and promotion of key regulatory efficiencies; (2) testing of feasibility and results, building on the work of existing platforms such as the Paediatric HIV Treatment Initiative (PHTI) including innovative approaches to incentivize generic development and (3) launch as a fully functioning structure. GAP-f is a key partnership example enhancing North-South and international cooperation on and access to science and technology and capacity building, responding to Sustainable Development Goal (SDG) 17.6 (technology) and 17.9. (capacity-building). By promoting access to the most needed paediatric formulations for HIV and high-burden infectious diseases in low-and middle-income countries, GAP-f will support achievement of SDG 3.2 (infant mortality), 3.3 (end of AIDS and combat other communicable diseases) and 3.8 (access to essential medicines), and be an essential component of meeting the global Start Free, Stay Free, AIDS Free super-fast-track targets. © 2018 World Health Organization; licensee IAS.
-
Surveillance of emerging drugs of abuse in Hong Kong: validation of an analytical tool.
Tang, Magdalene H Y; Ching, C K; Tse, M L; Ng, Carol; Lee, Caroline; Chong, Y K; Wong, Watson; Mak, Tony W L
2015-04-01
To validate a locally developed chromatography-based method to monitor emerging drugs of abuse whilst performing regular drug testing in abusers. Cross-sectional study. Eleven regional hospitals, seven social service units, and a tertiary level clinical toxicology laboratory in Hong Kong. A total of 972 drug abusers and high-risk individuals were recruited from acute, rehabilitation, and high-risk settings between 1 November 2011 and 31 July 2013. A subset of the participants was of South Asian ethnicity. In total, 2000 urine or hair specimens were collected. Proof of concept that surveillance of emerging drugs of abuse can be performed whilst conducting routine drug of abuse testing in patients. The method was successfully applied to 2000 samples with three emerging drugs of abuse detected in five samples: PMMA (paramethoxymethamphetamine), TFMPP [1-(3-trifluoromethylphenyl)piperazine], and methcathinone. The method also detected conventional drugs of abuse, with codeine, methadone, heroin, methamphetamine, and ketamine being the most frequently detected drugs. Other findings included the observation that South Asians had significantly higher rates of using opiates such as heroin, methadone, and codeine; and that ketamine and cocaine had significantly higher detection rates in acute subjects compared with the rehabilitation population. This locally developed analytical method is a valid tool for simultaneous surveillance of emerging drugs of abuse and routine drug monitoring of patients at minimal additional cost and effort. Continued, proactive surveillance and early identification of emerging drugs will facilitate prompt clinical, social, and legislative management.
-
Prakash, Chandra; Sharma, Raman; Gleave, Michelle; Nedderman, Angus
2008-11-01
Drug induced toxicity remains one of the major reasons for failures of new pharmaceuticals, and for the withdrawal of approved drugs from the market. Efforts are being made to reduce attrition of drug candidates, and to minimize their bioactivation potential in the early stages of drug discovery in order to bring safer compounds to the market. Therefore, in addition to potency and selectivity; drug candidates are now selected on the basis of acceptable metabolism/toxicology profiles in preclinical species. To support this, new approaches have been developed, which include extensive in vitro methods using human and animal hepatic cellular and subcellular systems, recombinant human drug metabolizing enzymes, increased automation for higher-throughput screens, sensitive analytical technologies and in silico computational models to assess the metabolism aspects of the new chemical entities. By using these approaches many compounds that might have serious adverse reactions associated with them are effectively eliminated before reaching clinical trials, however some toxicities such as those caused by idiosyncratic responses, are not detected until a drug is in late stages of clinical trials or has become available to the market. One of the proposed mechanisms for the development of idiosyncratic drug toxicity is the bioactivation of drugs to form reactive metabolites by drug metabolizing enzymes. This review discusses the different approaches to, and benefits of using existing in vitro techniques, for the detection of reactive intermediates in order to minimize bioactivation potential in drug discovery.
-
Advances in MRSA drug discovery: where are we and where do we need to be?
Kurosu, Michio; Siricilla, Shajila; Mitachi, Katsuhiko
2013-01-01
Introduction Methicillin-resistant Staphylococcus aureus (MRSA) have been on the increase during the past decade, due to the steady growth of the elderly and immunocompromised patients, and the emergence of multi-drug-resistant (MDR) bacterial strains. Although, only a limited number of anti-MRSA drugs are available, a number of different combination antimicrobial drug regimens have been used to treat serious MRSA infections. Thus, addition of several new antistaphylococcal drugs into clinical practice should broaden therapeutic options. Because MRSA is one of the most common and problematic bacteria associated with increasing antimicrobial resistance, continuous efforts on discovery of lead compounds as well as development of alternative therapies and faster diagnostics to ensure effective antistaphylococcal therapy are required. Areas covered This article summarizes the FDA approved drugs to treat MRSA infections, the drugs in clinical trials, and the drug leads for MRSA and related Gram-positive bacterial infections. In addition, the mode of action of antistaphylococcal molecules and resistant mechanisms of some molecules are briefly discussed. Expert opinion The number of pipeline drugs presently undergoing clinical trials is not particularly encouraging. There are limited and rather expensive therapeutic options for the infections by MRSA in the critically ill. This review article provides an update on antistaphylococcal drugs in clinical trials and antibacterial molecules effective against Gram-positive bacteria including MRSA. The structural and biological information of antibacterials summarized here are very useful for designing drug leads to develop into new anti-MRSA drugs. PMID:23829425
-
New dialogue for the way forward in maternal health: addressing market inefficiencies.
McCarthy, Katharine; Ramarao, Saumya; Taboada, Hannah
2015-06-01
Despite notable progress in Millennium Development Goal (MDG) five, to reduce maternal deaths three-quarters by 2015, deaths due to treatable conditions during pregnancy and childbirth continue to concentrate in the developing world. Expanding access to three effective and low-cost maternal health drugs can reduce preventable maternal deaths, if available to all women. However, current failures in markets for maternal health drugs limit access to lifesaving medicines among those most in need. In effort to stimulate renewed action planning in the post-MDG era, we present three case examples from other global health initiatives to illustrate how market shaping strategies can scale-up access to essential maternal health drugs. Such strategies include: sharing intelligence among suppliers and users to better approximate and address unmet need for maternal health drugs, introducing innovative financial strategies to catalyze otherwise unattractive markets for drug manufacturers, and employing market segmentation to create a viable and sustainable market. By building on lessons learned from other market shaping interventions and capitalizing on opportunities for renewed action planning and partnership, the maternal health field can utilize market dynamics to better ensure sustainable and equitable distribution of essential maternal health drugs to all women, including the most marginalized.
-
Bialer, Meir; Johannessen, Svein I; Levy, René H; Perucca, Emilio; Tomson, Torbjörn; White, H Steve
2017-02-01
The Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII) took place in Madrid, Spain, on June 26-29, 2016, and was attended by >200 delegates from 31 countries. The present Progress Report provides an update on experimental and clinical results for drugs presented at the Conference. Compounds for which summary data are presented include an AED approved in 2016 (brivaracetam), 12 drugs in phase I-III clinical development (adenosine, allopregnanolone, bumetanide, cannabidiol, cannabidivarin, 2-deoxy-d-glucose, everolimus, fenfluramine, huperzine A, minocycline, SAGE-217, and valnoctamide) and 6 compounds or classes of compounds for which only preclinical data are available (bumetanide derivatives, sec-butylpropylacetamide, FV-082, 1OP-2198, NAX 810-2, and SAGE-689). Overall, the results presented at the Conference show that considerable efforts are ongoing into discovery and development of AEDs with potentially improved therapeutic profiles compared with existing agents. Many of the drugs discussed in this report show innovative mechanisms of action and many have shown promising results in patients with pharmacoresistant epilepsies, including previously neglected rare and severe epilepsy syndromes. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.
-
TCMSP: a database of systems pharmacology for drug discovery from herbal medicines.
Ru, Jinlong; Li, Peng; Wang, Jinan; Zhou, Wei; Li, Bohui; Huang, Chao; Li, Pidong; Guo, Zihu; Tao, Weiyang; Yang, Yinfeng; Xu, Xue; Li, Yan; Wang, Yonghua; Yang, Ling
2014-01-01
Modern medicine often clashes with traditional medicine such as Chinese herbal medicine because of the little understanding of the underlying mechanisms of action of the herbs. In an effort to promote integration of both sides and to accelerate the drug discovery from herbal medicines, an efficient systems pharmacology platform that represents ideal information convergence of pharmacochemistry, ADME properties, drug-likeness, drug targets, associated diseases and interaction networks, are urgently needed. The traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) was built based on the framework of systems pharmacology for herbal medicines. It consists of all the 499 Chinese herbs registered in the Chinese pharmacopoeia with 29,384 ingredients, 3,311 targets and 837 associated diseases. Twelve important ADME-related properties like human oral bioavailability, half-life, drug-likeness, Caco-2 permeability, blood-brain barrier and Lipinski's rule of five are provided for drug screening and evaluation. TCMSP also provides drug targets and diseases of each active compound, which can automatically establish the compound-target and target-disease networks that let users view and analyze the drug action mechanisms. It is designed to fuel the development of herbal medicines and to promote integration of modern medicine and traditional medicine for drug discovery and development. The particular strengths of TCMSP are the composition of the large number of herbal entries, and the ability to identify drug-target networks and drug-disease networks, which will help revealing the mechanisms of action of Chinese herbs, uncovering the nature of TCM theory and developing new herb-oriented drugs. TCMSP is freely available at http://sm.nwsuaf.edu.cn/lsp/tcmsp.php.
-
Substandard drugs: a potential crisis for public health
Johnston, Atholl; Holt, David W
2014-01-01
Poor-quality medicines present a serious public health problem, particularly in emerging economies and developing countries, and may have a significant impact on the national clinical and economic burden. Attention has largely focused on the increasing availability of deliberately falsified drugs, but substandard medicines are also reaching patients because of poor manufacturing and quality-control practices in the production of genuine drugs (either branded or generic). Substandard medicines are widespread and represent a threat to health because they can inadvertently lead to healthcare failures, such as antibiotic resistance and the spread of disease within a community, as well as death or additional illness in individuals. This article reviews the different aspects of substandard drug formulation that can occur (for example, pharmacological variability between drug batches or between generic and originator drugs, incorrect drug quantity and presence of impurities). The possible means of addressing substandard manufacturing practices are also discussed. A concerted effort is required on the part of governments, drug manufacturers, charities and healthcare providers to ensure that only drugs of acceptable quality reach the patient. PMID:24286459
-
Advances towards the design and development of personalized non-small-cell lung cancer drug therapy.
Vari, Sabrina; Pilotto, Sara; Maugeri-Saccà, Marcello; Ciuffreda, Ludovica; Cesta Incani, Ursula; Falcone, Italia; Del Curatolo, Anais; Ceribelli, Anna; Gelibter, Alain; De Maria, Ruggero; Tortora, Giampaolo; Cognetti, Francesco; Bria, Emilio; Milella, Michele
2013-11-01
Non-small-cell lung cancer (NSCLC) subtypes are driven by specific genetic aberrations. For reasons such as this, there is a call for treatment personalization. The ability to instigate NSCLC fragmentation poses new methodological problems, and new 'driver' molecular aberrations are being discovered at an unprecedented pace. This article describes the clinical development of epidermal growth factor-tyrosine kinase inhibitors (EGFR-TKIs) and crizotinib for EGFR-mutant and anaplastic lymphoma kinase (ALK)-rearranged NSCLC. Further, the authors briefly describe the emerging molecular targets in NSCLC, in terms of both rationale for therapeutic targeting and strategies, for clinical development. Target identification and validation in NSCLC still requires considerable effort, as not all of the molecular alterations are clear 'drivers' nor can they be efficiently targeted with available drugs. However, 50% of the NSCLC cases are without clear-defined molecular aberrations. Clinical trial methodology will need to develop novel paradigms for targeted drug development, aiming at the validation of an ideal 'biology-to-trial' approach. Despite significant challenges, a truly 'personalized' approach to NSCLC therapy appears to be within our reach.
-
Personality, Drug Preference, Drug Use, and Drug Availability
ERIC Educational Resources Information Center
Feldman, Marc; Boyer, Bret; Kumar, V. K.; Prout, Maurice
2011-01-01
This study examined the relationship between drug preference, drug use, drug availability, and personality among individuals (n = 100) in treatment for substance abuse in an effort to replicate the results of an earlier study (Feldman, Kumar, Angelini, Pekala, & Porter, 2007) designed to test prediction derived from Eysenck's (1957, 1967)…
-
Metastatic melanoma - a review of current and future drugs.
Velho, Tiago Rodrigues
2012-11-19
Melanoma is one of the most aggressive cancers, and it is estimated that 76,250 men and women will be diagnosed with melanoma of the skin in the USA in 2012. Over the last few decades many drugs have been developed but only in 2011 have new drugs demonstrated an impact on survival in metastatic melanoma. A systematic search of literature was conducted, and studies providing data on the effectiveness of current and/or future drugs used in the treatment of metastatic melanoma were selected for review. This review discusses the advantages and limitations of these agents, evaluating past, current and future clinical trials designed to overcome such limitations. To date, there are four drugs approved by the Food and Drug Administration for melanoma (dacarbazine, interleukin-2, ipilimumab and vemurafenib). Despite efforts to develop new drugs, few of them have demonstrated any clinical benefits. Approved in 1975, dacarbazine remains the gold standard in chemotherapy, although ipilimumab and vemurafenib have raised many hopes in the last few years. Combining dacarbazine or other chemotherapy agents with new pharmacological agents may be a new way to achieve better clinical responses in patients with metastatic melanoma. Advances in the molecular knowledge of melanoma have led to major improvements in the treatment of patients with metastatic melanoma, providing new targets and insights. However, heterogeneity amongst study populations, different approaches to treatment and the different melanoma types and localisations included in the trials makes their comparison difficult. New studies focusing on drugs developed in recent decades are warranted.
-
Antenatal drug consumption: the burden of self-medication in a developing world setting.
Adanikin, Abiodun Idowu; Awoleke, Jacob Olumuyiwa
2017-07-01
This institutional-based cross-sectional study examines the burden of self-medication during pregnancy in a middle-income country setting and the impact on fetal wellbeing. Using a blend of open-ended and indication-oriented questionnaires, 346 pregnant women at term were interviewed about their pregnancy complaints and drug intake. Inferential statistical data analysis was employed with level of significance (α) set at 0.05. Excluding routine supplements and vaccinations, 251 (72.5%) women used medicines, of whom 79 (31.5%) had self-medicated. Consuming drugs without prescription was associated with increased US Food & Drug Administration (FDA) risk category (χ 2 = 8.375; P = 0.015). There is therefore a need to scale up efforts towards educating women about the dangers of self-medication, while also introducing effective restrictive policies on over-the-counter drug sales.
-
Principles of nanoparticle design for overcoming biological barriers to drug delivery
Blanco, Elvin; Shen, Haifa; Ferrari, Mauro
2016-01-01
Biological barriers to drug transport prevent successful accumulation of nanotherapeutics specifically at diseased sites, limiting efficacious responses in disease processes ranging from cancer to inflammation. Although substantial research efforts have aimed to incorporate multiple functionalities and moieties within the overall nanoparticle design, many of these strategies fail to adequately address these barriers. Obstacles, such as nonspecific distribution and inadequate accumulation of therapeutics, remain formidable challenges to drug developers. A reimagining of conventional nanoparticles is needed to successfully negotiate these impediments to drug delivery. Site-specific delivery of therapeutics will remain a distant reality unless nanocarrier design takes into account the majority, if not all, of the biological barriers that a particle encounters upon intravenous administration. By successively addressing each of these barriers, innovative design features can be rationally incorporated that will create a new generation of nanotherapeutics, realizing a paradigmatic shift in nanoparticle-based drug delivery. PMID:26348965
-
Evaluation of the resistance of a geopolymer-based drug delivery system to tampering.
Cai, Bing; Engqvist, Håkan; Bredenberg, Susanne
2014-04-25
Tamper-resistance is an important property of controlled-release formulations of opioid drugs. Tamper-resistant formulations aim to increase the degree of effort required to override the controlled release of the drug molecules from extended-release formulations for the purpose of non-medical use. In this study, the resistance of a geopolymer-based formulation to tampering was evaluated by comparing it with a commercial controlled-release tablet using several methods commonly used by drug abusers. Because of its high compressive strength and resistance to heat, much more effort and time was required to extract the drug from the geopolymer-based formulation. Moreover, in the drug-release test, the geopolymer-based formulation maintained its controlled-release characteristics after milling, while the drug was released immediately from the milled commercial tablets, potentially resulting in dose dumping. Although the tampering methods used in this study does not cover all methods that abuser could access, the results obtained by the described methods showed that the geopolymer matrix increased the degree of effort required to override the controlled release of the drug, suggesting that the formulation has improved resistance to some common drug-abuse tampering methods. The geopolymer matrix has the potential to make the opioid product less accessible and attractive to non-medical users. Copyright © 2014 Elsevier B.V. All rights reserved.
-
Inhibition of Ras for cancer treatment: the search continues
Baines, Antonio T.; Xu, Dapeng; Der, Channing J.
2012-01-01
Background The RAS oncogenes (HRAS, NRAS and KRAS) comprise the most frequently mutated class of oncogenes in human cancers (33%), stimulating intensive effort in developing anti-Ras inhibitors for cancer treatment. Discussion Despite intensive effort, to date no effective anti-Ras strategies have successfully made it to the clinic. We present an overview of past and ongoing strategies to inhibit oncogenic Ras in cancer. Conclusions Since approaches to directly target mutant Ras have not been successful, most efforts have focused on indirect approaches to block Ras membrane association or downstream effector signaling. While inhibitors of effector signaling are currently under clinical evaluation, genome-wide unbiased genetic screens have identified novel directions for future anti-Ras drug discovery. PMID:22004085
-
Accrediting retail drug shops to strengthen Tanzania's public health system: an ADDO case study.
Rutta, Edmund; Liana, Jafary; Embrey, Martha; Johnson, Keith; Kimatta, Suleiman; Valimba, Richard; Lieber, Rachel; Shekalaghe, Elizabeth; Sillo, Hiiti
2015-01-01
Retail drug sellers are a major source of health care and medicines in many countries. In Tanzania, drug shops are widely used, particularly in rural and underserved areas. Previously, the shops were allowed to sell only over-the-counter medicines, but sellers who were untrained and unqualified often illegally sold prescription drugs of questionable quality. In 2003, we worked with Tanzania's Ministry of Health and Social Welfare to develop a public-private partnership based on a holistic approach that builds the capacity of owners, dispensers, and institutions that regulate, own, or work in retail drug shops. For shop owners and dispensers, this was achieved by combining training, business incentives, supervision, and regulatory enforcement with efforts to increase client demand for and expectations of quality products and services. The accredited drug dispensing outlet (ADDO) program's goal is to improve access to affordable, quality medicines and pharmaceutical services in retail drug outlets in rural or peri-urban areas with few or no registered pharmacies. The case study characterizes how the ADDO program achieved that goal based on the World Health Organization's health system strengthening building blocks: 1) service delivery, 2) health workforce, 3) health information systems, 4) access to essential medicines, 5) financing, and 6) leadership and governance. The ADDO program has proven to be scalable, sustainable, and transferable: Tanzania has rolled out the program nationwide; the ADDO program has been institutionalized as part of the country's health system; shops are profitable and meeting consumer demands; and the ADDO model has been adapted and implemented in Uganda and Liberia. The critical element that was essential to the ADDO program's success is stakeholder engagement-the successful buy-in and sustained commitment came directly from the effort, time, and resources spent to fully connect with vital stakeholders at all levels. Beyond improving the quality of medicines and dispensing services, availability of essential medicines, and the regulatory system, the impact of a nationwide accredited drug seller approach on the pharmaceutical sector promises to provide a model framework for private-sector pharmaceutical delivery in the developing world that is sustainable without ongoing donor support.
-
Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?
Cox, Adrienne D.; Der, Channing J.; Philips, Mark R.
2015-01-01
RAS proteins require membrane association for their biological activity, making this association a logical target for anti-RAS therapeutics. Lipid modification of RAS proteins by a farnesyl isoprenoid is an obligate step in that association, and is an enzymatic process. Accordingly, farnesyltransferase inhibitors (FTIs) were developed as potential anti-RAS drugs. The lack of efficacy of FTIs as anti-cancer drugs was widely seen as indicating that blocking RAS membrane association was a flawed approach to cancer treatment. However, a deeper understanding of RAS modification and trafficking has revealed that this was an erroneous conclusion. In the presence of FTIs, KRAS and NRAS, which are the RAS isoforms most frequently mutated in cancer, become substrates for alternative modification, can still associate with membranes, and can still function. Thus, FTIs failed not because blocking RAS membrane association is an ineffective approach, but because FTIs failed to accomplish that task. Recent findings regarding RAS isoform trafficking and the regulation of RAS subcellular localization have rekindled interest in efforts to target these processes. In particular, improved understanding of the palmitoylation/depalmitoylation cycle that regulates RAS interaction with the plasma membrane, endomembranes and cytosol, and of the potential importance of RAS chaperones, have led to new approaches. Efforts to validate and target other enzymatically regulated post-translational modifications are also ongoing. In this review, we revisit lessons learned, describe the current state of the art, and highlight challenging but promising directions to achieve the goal of disrupting RAS membrane association and subcellular localization for anti-RAS drug development. PMID:25878363
-
Victor, Grant A; Walker, Robert; Cole, Jennifer; Logan, T K
2017-08-01
In an effort to mitigate Kentucky's prescription drug misuse, legislative intervention efforts were introduced in 2012 and 2013 to better regulate pain clinics, prescribed use of opioid analgesics, and to expand the monitoring of opioid prescriptions. The focus of this paper is primarily on opioid analgesics and heroin and the relationship of use/misuse patterns of these drugs to state drug policy initiatives. A secondary data analysis of drug treatment clients (N=52,360) was conducted to project illicit drug use trends in Kentucky. This study describes temporal and geographic trends of self-reported illicit drug use among individuals in state-funded treatment in Kentucky between fiscal year 2010 and fiscal year 2013. Significant reductions in the prevalence of illicit opioid use, declined from fiscal year 2010 to fiscal year 2013 (p<.01, CI=-.298 to -.215). However, heroin use rates significantly increased over the years studied, suggesting there may be a transition from prescription opioids to heroin (p<.01, CI=.143 to .178). The analysis suggests these trends may continue. Findings suggest Kentucky's legislative efforts were effective in reducing illicit prescription opioid use, but heroin use has increased. One possible explanation for this relationship is that as prescription opioids became more difficult to obtain, users turned to heroin as a substitute. The finding of rising heroin use suggests a need for further policy initiatives to reduce heroin use, but the potential effectiveness of this policy remains unclear. Understanding trends may help to guide future policy efforts and pain management treatment strategies to where they might have their greatest impact. Copyright © 2017 Elsevier B.V. All rights reserved.
-
Stang, Paul E; Ryan, Patrick B; Racoosin, Judith A; Overhage, J Marc; Hartzema, Abraham G; Reich, Christian; Welebob, Emily; Scarnecchia, Thomas; Woodcock, Janet
2010-11-02
The U.S. Food and Drug Administration (FDA) Amendments Act of 2007 mandated that the FDA develop a system for using automated health care data to identify risks of marketed drugs and other medical products. The Observational Medical Outcomes Partnership is a public-private partnership among the FDA, academia, data owners, and the pharmaceutical industry that is responding to the need to advance the science of active medical product safety surveillance by using existing observational databases. The Observational Medical Outcomes Partnership's transparent, open innovation approach is designed to systematically and empirically study critical governance, data resource, and methodological issues and their interrelationships in establishing a viable national program of active drug safety surveillance by using observational data. This article describes the governance structure, data-access model, methods-testing approach, and technology development of this effort, as well as the work that has been initiated.
-
Clinical trials for vaccine development in registry of Korea Food and Drug Administration
2013-01-01
Based on the action plan "Ensuring a stable supply of National Immunization Program vaccines and sovereignty of biopharmaceutical products," Korea Food and Drug Administration (KFDA) has made efforts to develop vaccines in the context of self reliance and to protect public health. Along with the recognized infrastructures for clinical trials, clinical trials for vaccines have also gradually been conducted at multinational sites as well as at local sites. KFDA will support to expand six to eleven kinds of vaccines by 2017. In accordance with integrated regulatory system, KFDA has promoted clinical trials, established national lot release procedure, and strengthened good manufacturing practices inspection and post marketing surveillance. Against this backdrop, KFDA will support the vaccine development and promote excellent public health protection. PMID:23596594
-
Long-acting injectable hormonal dosage forms for contraception.
Wu, Linfeng; Janagam, Dileep R; Mandrell, Timothy D; Johnson, James R; Lowe, Tao L
2015-07-01
Although great efforts have been made to develop long-acting injectable hormonal contraceptives for more than four decades, few long-acting injectable contraceptives have reached the pharmaceutical market or even entered clinical trials. On the other hand, in clinical practice there is an urgent need for injectable long-acting reversible contraceptives which can provide contraceptive protection for more than 3 months after one single injection. Availability of such products will offer great flexibility to women and resolve certain continuation issues currently occurring in clinics. Herein, we reviewed the strategies exploited in the past to develop injectable hormonal contraceptive dosages including drug microcrystal suspensions, drug-loaded microsphere suspensions and in situ forming depot systems for long-term contraception and discussed the potential solutions for remaining issues met in the previous development.
-
Manoharan, Prabu; Chennoju, Kiranmai; Ghoshal, Nanda
2015-07-01
BACE1 is an attractive target in Alzheimer's disease (AD) treatment. A rational drug design effort for the inhibition of BACE1 is actively pursued by researchers in both academic and pharmaceutical industries. This continued effort led to the steady accumulation of BACE1 crystal structures, co-complexed with different classes of inhibitors. This wealth of information is used in this study to develop target specific proteochemometric models and these models are exploited for predicting the prospective BACE1 inhibitors. The models developed in this study have performed excellently in predicting the computationally generated poses, separately obtained from single and ensemble docking approaches. The simple protein-ligand contact (SPLC) model outperforms other sophisticated high end models, in virtual screening performance, developed during this study. In an attempt to account for BACE1 protein active site flexibility information in predictive models, we included the change in the area of solvent accessible surface and the change in the volume of solvent accessible surface in our models. The ensemble and single receptor docking results obtained from this study indicate that the structural water mediated interactions improve the virtual screening results. Also, these waters are essential for recapitulating bioactive conformation during docking study. The proteochemometric models developed in this study can be used for the prediction of BACE1 inhibitors, during the early stage of AD drug discovery.
-
The evolving landscape of therapeutic drug development for hepatocellular carcinoma.
Chong, Dawn Qingqing; Tan, Iain Beehuat; Choo, Su-Pin; Toh, Han Chong
2013-11-01
Currently, only one drug, sorafenib, is FDA approved for the treatment of advanced hepatocellular carcinoma (HCC), achieving modest objective response rates while still conferring an overall survival benefit. Unlike other solid tumors, no oncogenic addiction loops have been validated as clinically actionable targets in HCC. Outcomes of HCC could potentially be improved if critical molecular subclasses with distinct therapeutic vulnerabilities can be identified, biomarkers that predict recurrence or progression early can be determined and key epigenetic, genetic or microenvironment drivers that determine best response to a specific targeting treatment can be uncovered. Our group and others have examined the molecular heterogeneity of hepatocellular carcinoma. We have developed a panel of patient derived xenograft models to enable focused pre-clinical drug development of rationally designed therapies in specific molecular subgroups. We observed unique patterns, including synergies, of drug activity across our molecularly diverse HCC xenografts, pointing to specific therapeutic vulnerabilities for individual tumors. These efforts inform clinical trial designs and catalyze therapeutic development. It also argues for efficient strategic allocation of patients into appropriate enriched clinical trials. Here, we will discuss some of the recent important therapeutic studies in advanced HCC and also some of the potential strategies to optimize clinical therapeutic development moving forward. Copyright © 2013 Elsevier Inc. All rights reserved.
-
Accelerating drug development and approval.
Cole, Patrick
2010-01-01
Regulatory agencies are the gateway between the pharma/biotech industry and patients and can serve as stimulators of new drug development. This article highlights several means of doing so implemented thus far, many with already impressive histories, such as orphan drug legislation, and others of a more experimental nature, such as the FDA's priority review voucher program. These initiatives represent different approaches to finding treatments for rare and widespread but neglected diseases, as well as speeding the development process for pharmaceutical and biological agents more generally. Commercial incentives, streamlined regulatory processing, exploratory trial designs, research assistance and cash infusions are all means of promoting drug development being explored in the United States, Europe and beyond. In some cases, such as fast track designation and priority review vouchers, regulatory agencies have turned their own processes into incentives, offering advantageous alternative routes to product approval, like a faster lane on the highway for vehicles carrying multiple passengers. In 2009, regulatory agencies and the governments they represent also had to confront two tremendous challenges: the global recession and the H1N1 influenza virus pandemic. These tests have been met with increased funding in the former case and coordinated efforts to develop, approve and stockpile H1N1 vaccines in the latter.
-
2013-06-13
Security 2009, 4). Additionally, CBP is the component within the DHS that serves as America’s first line of defense to detect and prevent terrorist and...especially smugglers of humans and drugs. The USBP’s concentration of efforts and resources shifted to preventing terrorists and their weapons from
-
Using the Community Readiness Model in Native Communities.
ERIC Educational Resources Information Center
Jumper-Thurman, Pamela; Plested, Barbara A.; Edwards, Ruth W.; Helm, Heather M.; Oetting, Eugene R.
The effects of alcohol and other drug abuse are recognized as a serious problem in U.S. communities. Policy efforts and increased law enforcement have only a minimal impact if prevention strategies are not consistent with the community's level of readiness, are not culturally relevant, and are not community-specific. A model has been developed for…
-
Creating Community Change to Improve Youth Development: The Communities That Care System
ERIC Educational Resources Information Center
Brooke-Weiss, Blaire; Haggerty, Kevin P.; Fagan, Abigail A.; Hawkins, J. David; Cady, Rick
2008-01-01
Advances in prevention science in the past 25 years provide important direction for neighborhood and community efforts to improve the lives of youth. Prevention scientists have applied a public health approach to youth problems such as drug use and delinquency, and have shown that these problems can be prevented. The identification of risk and…
-
Development of a Drug Rehabilitation Center or Mistakes We Have Made.
ERIC Educational Resources Information Center
Fox, Twilah A.; And Others
The authors discuss their first efforts at providing a contact point where young people could come for information crisis intervention and talk. Major mistakes, such as too exclusive reliance on ex-users, are elaborated. Clients' demographic and psychiatric data receive brief mention, as does the initial screening procedure. The bulk of the paper…
-
Global control of tuberculosis: from extensively drug-resistant to untreatable tuberculosis
Dheda, Keertan; Gumbo, Tawanda; Gandhi, Neel R; Murray, Megan; Theron, Grant; Udwadia, Zarir; Migliori, G B; Warren, Robin
2017-01-01
Extensively drug-resistant tuberculosis is a burgeoning global health crisis mainly affecting economically active young adults, and has high mortality irrespective of HIV status. In some countries such as South Africa, drug-resistant tuberculosis represents less than 3% of all cases but consumes more than a third of the total national budget for tuberculosis, which is unsustainable and threatens to destabilise national tuberculosis programmes. However, concern about drug-resistant tuberculosis has been eclipsed by that of totally and extremely drug-resistant tuberculosis—ie, resistance to all or nearly all conventional first-line and second-line antituberculosis drugs. In this Review, we discuss the epidemiology, pathogenesis, diagnosis, management, implications for health-care workers, and ethical and medicolegal aspects of extensively drug-resistant tuberculosis and other resistant strains. Finally, we discuss the emerging problem of functionally untreatable tuberculosis, and the issues and challenges that it poses to public health and clinical practice. The emergence and growth of highly resistant strains of tuberculosis make the development of new drugs and rapid diagnostics for tuberculosis—and increased funding to strengthen global control efforts, research, and advocacy—even more pressing. PMID:24717628
-
Multiphase flow microfluidics for the production of single or multiple emulsions for drug delivery.
Zhao, Chun-Xia
2013-11-01
Considerable effort has been directed towards developing novel drug delivery systems. Microfluidics, capable of generating monodisperse single and multiple emulsion droplets, executing precise control and operations on these droplets, is a powerful tool for fabricating complex systems (microparticles, microcapsules, microgels) with uniform size, narrow size distribution and desired properties, which have great potential in drug delivery applications. This review presents an overview of the state-of-the-art multiphase flow microfluidics for the production of single emulsions or multiple emulsions for drug delivery. The review starts with a brief introduction of the approaches for making single and multiple emulsions, followed by presentation of some potential drug delivery systems (microparticles, microcapsules and microgels) fabricated in microfluidic devices using single or multiple emulsions as templates. The design principles, manufacturing processes and properties of these drug delivery systems are also discussed and compared. Furthermore, drug encapsulation and drug release (including passive and active controlled release) are provided and compared highlighting some key findings and insights. Finally, site-targeting delivery using multiphase flow microfluidics is also briefly introduced. Copyright © 2013 Elsevier B.V. All rights reserved.
-
A Novel Application of Synthetic Biology and Directed Evolution to Engineer Phage-based Antibiotics
DOE Office of Scientific and Technical Information (OSTI.GOV)
Wu, Meiye
The emergence of multiple drug resistant bacteria poses threats to human health, agriculture and food safety. Annually over 100,000 deaths and up to $20 billion loss to the U.S. economy are attributed to multiple drug resistant bacteria. With only four new chemical antibiotics in the drug development pipeline, we are in dire need of new solutions to address the emerging threat of multiple drug resistance. We propose a paradigm-changing approach to address the multi-drug resistant bacteria problem by utilizing Synthetic Biology (SynBio) methodologies to create and evolve “designer” bacteriophages or phages – viruses that specifically infect bacteria – to infectmore » and kill newly emerging pathogenic bacterial strains WITHOUT the need for chemical antibiotics. A major advantage of using phage to combat pathogenic bacteria is that phages can co-evolve with their bacterial host, and Sandia can be the first in the world to establish an industrial scale Synthetic Biology pipeline for phage directed evolution for safe, targeted, customizable solution to bacterial drug resistance. Since there is no existing phage directed evolution effort within or outside of Sandia, this proposal is suitable as a high-risk LDRD effort to create the first pipeline for such an endeavor. The high potential reward nature of this proposal will be the immediate impact in decontamination and restoration of surfaces and infrastructure, with longer term impact in human or animal therapeutics. The synthetic biology and screening approaches will lead to fundamental knowledge of phage/bacteria co-evolution, making Sandia a world leader in directed evolution of bacteriophages.« less
-
Polysaccharide-based micro/nanocarriers for oral colon-targeted drug delivery.
Zhang, Lin; Sang, Yuan; Feng, Jing; Li, Zhaoming; Zhao, Aili
2016-08-01
Oral colon-targeted drug delivery has attracted many researchers because of its distinct advantages of increasing the bioavailability of the drug at the target site and reducing the side effects. Polysaccharides that are precisely activated by the physiological environment of the colon hold greater promise for colon targeting. Considerable research efforts have been directed towards developing polysaccharide-based micro/nanocarriers. Types of polysaccharides for colon targeting and in vitro/in vivo assessments of polysaccharide-based carriers for oral colon-targeted drug delivery are summarised. Polysaccharide-based microspheres have gained increased importance not just for the delivery of the drugs for the treatment of local diseases associated with the colon (colon cancer, inflammatory bowel disease (IBD), amoebiasis and irritable bowel syndrome (IBS)), but also for it's potential for the delivery of anti-rheumatoid arthritis and anti-chronic stable angina drugs. Besides, Polysaccharide-based micro/nanocarriers such as microbeads, microcapsules, microparticles, nanoparticles, nanogels and nanospheres are also introduced in this review.
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Wang, Kejian, E-mail: kejian.wang.bio@gmail.com; Weng, Zuquan; Sun, Liya
Adverse drug reaction (ADR) is of great importance to both regulatory agencies and the pharmaceutical industry. Various techniques, such as quantitative structure–activity relationship (QSAR) and animal toxicology, are widely used to identify potential risks during the preclinical stage of drug development. Despite these efforts, drugs with safety liabilities can still pass through safety checkpoints and enter the market. This situation raises the concern that conventional chemical structure analysis and phenotypic screening are not sufficient to avoid all clinical adverse events. Genomic expression data following in vitro drug treatments characterize drug actions and thus have become widely used in drug repositioning. Inmore » the present study, we explored prediction of ADRs based on the drug-induced gene-expression profiles from cultured human cells in the Connectivity Map (CMap) database. The results showed that drugs inducing comparable ADRs generally lead to similar CMap expression profiles. Based on such ADR-gene expression association, we established prediction models for various ADRs, including severe myocardial and infectious events. Drugs with FDA boxed warnings of safety liability were effectively identified. We therefore suggest that drug-induced gene expression change, in combination with effective computational methods, may provide a new dimension of information to facilitate systematic drug safety evaluation. - Highlights: • Drugs causing common toxicity lead to similar in vitro gene expression changes. • We built a model to predict drug toxicity with drug-specific expression profiles. • Drugs with FDA black box warnings were effectively identified by our model. • In vitro assay can detect severe toxicity in the early stage of drug development.« less
-
Laboratory-Induced Cue Reactivity among Individuals with Prescription Opioid Dependence
Back, Sudie E.; Gros, Daniel F.; McCauley, Jenna; Flanagan, Julianne; Cox, Elizabeth; Barth, Kelly; Brady, Kathleen T.
2014-01-01
Prescription opioid (PO) dependence is a critical health problem. Although examination of drug cue reactivity paradigms has advanced the understanding of risk factors for relapse for a variety of substances (e.g., cocaine, alcohol, nicotine), no PO specific drug cue paradigm has been developed. The current study addressed this gap in the literature and evaluated the ability of a newly developed PO drug cue paradigm to elicit subjective, physiological, and neuroendocrine changes among PO-dependent participants (n = 20) as compared to controls (n = 17). The drug cue paradigm included an induction script, viewing and handling paraphernalia (e.g., bottle of oxycontin pills, pill crusher) and watching a video depicting people using POs as well as places related to POs (e.g., pharmacies). Consistent with hypotheses, the PO group demonstrated significant pre- to post-cue increases on subjective ratings of craving, difficulty resisting POs, stress, and anger. The control group did not demonstrate significant changes on any of the subjective measures. Both the PO group and the control group evidenced significant pre- to post-cue increases in physiological responses (e.g., blood pressure, skin conductance), as expected given the arousing nature of the drug cue stimuli. The PO group, but not the control group, evidenced a significant pre- to post-cue increase in heart rate and salivary cortisol levels. The development and validation of a drug cue paradigm for POs may help inform future research and treatment development efforts for patients with PO dependence. PMID:24813546
-
Medicinal chemistry inspired fragment-based drug discovery.
Lanter, James; Zhang, Xuqing; Sui, Zhihua
2011-01-01
Lead generation can be a very challenging phase of the drug discovery process. The two principal methods for this stage of research are blind screening and rational design. Among the rational or semirational design approaches, fragment-based drug discovery (FBDD) has emerged as a useful tool for the generation of lead structures. It is particularly powerful as a complement to high-throughput screening approaches when the latter failed to yield viable hits for further development. Engagement of medicinal chemists early in the process can accelerate the progression of FBDD efforts by incorporating drug-friendly properties in the earliest stages of the design process. Medium-chain acyl-CoA synthetase 2b and ketohexokinase are chosen as examples to illustrate the importance of close collaboration of medicinal chemists, crystallography, and modeling. Copyright © 2011 Elsevier Inc. All rights reserved.
-
Drug resistance in eukaryotic microorganisms
Fairlamb, Alan H.; Gow, Neil A. R.; Matthews, Keith R.; Waters, Andrew P.
2016-01-01
Eukaryotic microbial pathogens are major contributors to illness and death globally. Although much of their impact can be controlled by drug therapy as with prokaryotic microorganisms, the emergence of drug resistance has threatened these treatment efforts. Here, we discuss the challenges posed by eukaryotic microbial pathogens and how these are similar to, or differ from, the challenges of prokaryotic antibiotic resistance. The therapies used for several major eukaryotic microorganisms are then detailed, and the mechanisms that they have evolved to overcome these therapies are described. The rapid emergence of resistance and the restricted pipeline of new drug therapies pose considerable risks to global health and are particularly acute in the developing world. Nonetheless, we detail how the integration of new technology, biological understanding, epidemiology and evolutionary analysis can help sustain existing therapies, anticipate the emergence of resistance or optimize the deployment of new therapies. PMID:27572976
-
[Clinical drug trials in Germany--an assessment of current status from the viewpoint of industry].
Baumbauer, E
1996-01-01
Drug development today is a highly professional and costly affair, whereby quality and speed are decisive competitive factors in a global setting. Germany is in the process of losing its attractiveness for clinical drug research as evidenced by a significant decrease in funding of clinical drug research which at the moment amounts to about 1.5 billion DM/year. This decrease is due to an adverse environment created by a certain anxiety in public opinion regarding technological advances, an overburden of regulations, lack of an infrastructure in hospitals to work according to GCP and a regulatory agency which has to compete with momentarily more effective agencies in Europe (UK, France). A joint effort between industry and the medical profession is called for to change this situation for the better.
-
ERIC Educational Resources Information Center
Frederick, Charles L.; Guldbrandsen, Frank
1976-01-01
Most concern for drug abuse among drug educators focuses on illicit, youth oriented chemicals such as marijuana and halluninogens. An effort needs to be made in drug education aimed at physicians, working toward dealing with the problem of abuse of over the counter, licit drugs. (Author)
-
McKenary, Joanne; Hayes, Brian; Patel, Champa; Smith, Janet; Bridges, Angela; Fosberry, Andrew; Bhardwaja, Anshu; Mouzon, Bernadette; Chung, Chun-Wa; Barrett, Nathalie; Richmond, Nicola; Modha, Sundip; Solari, Roberto
2012-01-01
SIRT6 is involved in inflammation, aging and metabolism potentially by modulating the functions of both NFκB and HIF1α. Since it is possible to make small molecule activators and inhibitors of Sirtuins we wished to establish biochemical and cellular assays both to assist in drug discovery efforts and to validate whether SIRT6 represents a valid drug target for these indications. We confirmed in cellular assays that SIRT6 can deacetylate acetylated-histone H3 lysine 9 (H3K9Ac), however this deacetylase activity is unusually low in biochemical assays. In an effort to develop alternative assay formats we observed that SIRT6 overexpression had no influence on TNFα induced nuclear translocation of NFκB, nor did it have an effect on nuclear mobility of RelA/p65. In an effort to identify a gene expression profile that could be used to identify a SIRT6 readout we conducted genome-wide expression studies. We observed that overexpression of SIRT6 had little influence on NFκB-dependent genes, but overexpression of the catalytically inactive mutant affected gene expression in developmental pathways. PMID:22792191
-
Giacoia, George P; Taylor-Zapata, Perdita; Zajicek, Anne
2012-11-01
The Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH) organized a workshop held in November 2011 to address knowledge gaps that limit the availability of adequate pediatric formulations. This workshop was used as a means to identify the types of research innovations needed and to stimulate research efforts designed to improve the availability of pediatric formulations and the technologies required to make these formulations. Information for this article was gathered from the proceedings of the Second US PFI Workshop sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development in Bethesda, Maryland, on November 1 and 2, 2011, as well as from post-workshop discussions. The workshop preparation began with formation of 4 working groups: Biopharmaceutics, Biopharmaceutics Classification System (BCS), New Technology and Drug Delivery Systems, and Taste and Flavor. The recommendations of the 4 working groups will form the basis for the development of a blueprint to guide future research efforts. The pediatric-specific problems identified include the heterogeneity of the population, the small size of the pediatric drug market, the limited number of new formulations for the large number of off-patent and unlabeled drugs, and the lack of universal agreement on how to define appropriate formulations for different ages and stages of development. There was consensus on the need to develop a universal technology platform for flexible pediatric dosage forms, transforming an empirical process into a science-based platform. A number of problems affect the availability of drugs in the developing world. Age-appropriate solid oral pediatric medicines for common diseases can have a global impact. Success on a global scale depends on the commitment of policy makers, regulators, scientists, pharmaceutical companies, sponsors, government, and research foundations to address gaps in knowledge and solve public health issues related to the availability of formulations in the developing world. Solutions to the worldwide lack of appropriate pediatric formulations will require the development of a road map and the commitment of policy makers, regulators, scientists, pharmaceutical sponsors, academic institutions, governments, and research foundations. The development of a universal, cost-effective platform using existing or developing innovative technology that produces flexible pediatric dosage forms remains an important but elusive goal. Published by EM Inc USA.
-
Anthelmintic Resistance in Haemonchus contortus: History, Mechanisms and Diagnosis.
Kotze, A C; Prichard, R K
2016-01-01
Haemonchus contortus has shown a great ability to develop resistance to anthelmintic drugs. In many instances, resistance has appeared less than 10years after the introduction of a new drug class. Field populations of this species now show resistance to all major anthelmintic drug classes, including benzimidazoles (BZs), imidazothiazoles and macrocyclic lactones. In addition, resistance to the recently introduced amino-acetonitrile derivative class (monepantel) has already been reported. The existence of field populations showing resistance to all three major drug classes, and the early appearance of resistance to monepantel, threatens the sustainability of sheep and goat production systems worldwide. This chapter reviews the history of the development of resistance to the various anthelmintics in H. contortus and examines the mechanisms utilized by this species to resist the effects of these drugs. Some of these mechanisms are well understood, particularly for BZ drugs, while our knowledge and understanding of others are increasing. Finally, we summarize methods available for the diagnosis of resistance. While such diagnosis currently relies largely on the faecal egg count reduction test, which suffers from issues of expense and sensitivity, we describe past and current efforts to utilize cheaper and less laborious phenotypic assays with free-living life stages, and then describe progress on the development of molecular assays to provide sensitive resistance-detection tests. Copyright © 2016 Elsevier Ltd. All rights reserved.
-
Using X-Ray Crystallography to Simplify and Accelerate Biologics Drug Development.
Brader, Mark L; Baker, Edward N; Dunn, Michael F; Laue, Thomas M; Carpenter, John F
2017-02-01
Every major biopharmaceutical company incorporates a protein crystallography unit that is central to its structure-based drug discovery efforts. Yet these capabilities are rarely leveraged toward the formal higher order structural characterization that is so challenging but integral to large-scale biologics manufacturing. Although the biotech industry laments the shortcomings of its favored biophysical techniques, x-ray crystallography is not even considered for drug development. Why not? We suggest that this is due, at least in part, to outdated thinking (for a recent industry-wide survey, see Gabrielson JP, Weiss IV WF. Technical decision-making with higher order structure data: starting a new dialogue. J Pharm Sci. 2015;104(4):1240-1245). We examine some myths surrounding protein crystallography and highlight the inherent properties of protein crystals (molecular identity, biochemical purity, conformational uniformity, and macromolecular crowding) as having practicable commonalities with today's patient-focused liquid drug products. In the new millennium, protein crystallography has become essentially a routine analytical test. Its application may aid the identification of better candidate molecules that are more amenable to high-concentration processing, formulation, and analysis thereby helping to make biologics drug development quicker, simpler, and cheaper. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.
-
2012-01-01
Background Drugs safety issues are now recognized as being factors generating the most reasons for drug withdrawals at various levels of development and at the post-approval stage. Among them cardiotoxicity remains the main reason, despite the substantial effort put into in vitro and in vivo testing, with the main focus put on hERG channel inhibition as the hypothesized surrogate of drug proarrhythmic potency. The large interest in the IKr current has resulted in the development of predictive tools and informative databases describing a drug's susceptibility to interactions with the hERG channel, although there are no similar, publicly available sets of data describing other ionic currents driven by the human cardiomyocyte ionic channels, which are recognized as an overlooked drug safety target. Discussion The aim of this database development and publication was to provide a scientifically useful, easily usable and clearly verifiable set of information describing not only IKr (hERG), but also other human cardiomyocyte specific ionic channels inhibition data (IKs, INa, ICa). Summary The broad range of data (chemical space and in vitro settings) and the easy to use user interface makes tox-database.net a useful tool for interested scientists. Database URL http://tox-database.net. PMID:22947121
-
The role of human drug self-administration procedures in the development of medications
Comer, SD; Ashworth, JB; Foltin, RW; Johanson, CE; Zacny, JP; Walsh, SL
2008-01-01
The purpose of this review is to illustrate the utility and value of employing human self-administration procedures in medication development, including abuse liability assessments of novel medications and evaluation of potential pharmacotherapies for substance use disorders. Traditionally, human abuse liability testing has relied primarily on subjective reports describing drug action by use of questionnaires; similarly, drug interactions between putative treatment agents and the drugs of abuse have relied on these measures. Subjective reports are highly valued because they provide qualitative and quantitative information about the characteristics of central and peripheral pharmacodynamic effects as well as safety and tolerability. However, self-administration procedures directly examine the behavior of interest – that is, drug taking. The present paper 1) reviews the most commonly used human self-administration procedures, 2) discusses the concordance of subjective reports and self-administration within the context of medications development for substance use disorders, focusing primarily on illustrative examples from development efforts with opioid and cocaine dependence, and 3) explores the utility of applying self-administration procedures to assess the abuse liability of novel compounds, including “abuse deterrent” formulations (ADFs). The review will focus on opioid and cocaine dependence because a rich database from both clinical laboratory and clinical trial research exists for these two drug classes. The data reviewed suggest that drug-induced changes in self-administration and subjective effects are not always concordant. Therefore, assessment of self-administration in combination with subjective effects provides a more comprehensive picture that may have improved predictive validity for translating to the clinical setting. PMID:18436394
-
Pharmacotherapy of amphetamine-type stimulant dependence: an update.
Brensilver, Matthew; Heinzerling, Keith G; Shoptaw, Steven
2013-09-01
Methamphetamine- or amphetamine-type stimulants are the second most frequently used illicit drug worldwide, second only to cannabis. Behavioural treatments are efficacious, but their impact is limited underscoring the need for other treatment options, notably, pharmacotherapy. A review of randomised controlled trials of pharmacotherapies for methamphetamine- or amphetamine-type stimulants was performed using PubMed and Google Scholar databases. Evidence for efficacy of medications is reported. Clinical trials have yielded no broadly effective pharmacotherapy. Promising signals have been observed for methylphenidate, naltrexone, bupropion and mirtazapine in subgroups of patients in reducing stimulant use (e.g. patients with less severe dependence at baseline and men who have sex with men), though none has produced an unambiguous, replicable signal of efficacy. Problems in Phase II trials, including high dropout rates, missing data and a lack of agreement on outcomes, complicate efforts to find a broadly effective pharmacotherapy for amphetamine-type stimulant disorders. Efforts to address these problems include calls for better validation of pharmacological target exposure, receptor binding and functional modulation. As well, there is a need for agreement in using findings from preclinical and early phases of the medication development process for selecting better pharmacotherapy candidates. After over 20 years of efforts worldwide to develop a broadly effective medication for dependence on methamphetamine- or amphetamine-type stimulants, no candidate has emerged. This highlights the need for new compounds, consistent and stringent research methods, better integration between preclinical and clinical stages of medication development, and improved collaboration between government, industry and researchers. © 2013 Australasian Professional Society on Alcohol and other Drugs.
-
Levecke, Bruno; Brooker, Simon J; Knopp, Stefanie; Steinmann, Peter; Sousa-Figueiredo, Jose Carlos; Stothard, J Russell; Utzinger, Jürg; Vercruysse, Jozef
2014-12-01
It is generally recommended to perform multiple stool examinations in order to improve the diagnostic accuracy when assessing the impact of mass drug administration programmes to control human intestinal worm infections and determining efficacy of the drugs administered. However, the collection and diagnostic work-up of multiple stool samples increases costs and workload. It has been hypothesized that these increased efforts provide more accurate results when infection and drug efficacy are summarized by prevalence (proportion of subjects infected) and cure rate (CR, proportion of infected subjects that become egg-negative after drug administration), respectively, but not when these indicators are expressed in terms of infection intensity and egg reduction rate (ERR). We performed a meta-analysis of six drug efficacy trials and one epidemiological survey. We compared prevalence and intensity of infection, CR and ERR based on collection of one or two stool samples that were processed with single or duplicate Kato-Katz thick smears. We found that the accuracy of prevalence estimates and CR was lowest with the minimal sampling effort, but that this was not the case for estimating infection intensity and ERR. Hence, a single Kato-Katz thick smear is sufficient for reporting infection intensity and ERR following drug treatment.
-
The antiretrovirals in pregnancy registry: a fifteenth anniversary celebration.
Tilson, Hugh H; Doi, Peggy A; Covington, Deborah L; Parker, Artist; Shields, Kristine; White, Alice
2007-02-01
The year 2007 marks the fifteenth anniversary year of the founding of a landmark effort in drug safety risk management, the formation of the first monitoring effort of an antiretroviral (ARV) drug in pregnancy which has become the Antiretrovirals in Pregnancy Registry, the APR. This multicompany, multi-national voluntary collaborative registry monitors pregnancy exposure to a class of highly important drugs for any indication of an increase in the postexposure incidence of birth defects in the offspring of these pregnancies. To recognize the anniversary, the Steering Committee of the APR has commissioned this review of the contributions and lessons learned over the past decade and a half and, in the spirit of continuous process improvement, has committed to apply these lessons for the next fifteen years. This retrospective examines the antecedents to this registry and the context in which the APR was formed; the early efforts to establish technical and organizational procedures and policies; the evolving experiences with enrollment and follow-up, patient and participant protections, information management and oversight; public and regulatory dissemination; and of course, the accomplishments and lessons learned. Obstetricians & Gynecologists, Family Physicians. After completion of this article, the reader should be able to explain the value of a drug registry in determining safety risk management; summarize that the Antiretroviral (ARV) drugs in Pregnancy Registry (APR) is a very successful multinational, multicompany collaborative effort that has been in place for 15 years; and state that it has been an ideal public interest effort dealing with the devastating pandemic of human immunodeficiency viral disease.
-
Prodrugs of phosphonates and phosphates: crossing the membrane barrier
Wiemer, Andrew J.; Wiemer, David F.
2016-01-01
A substantial portion of metabolism involves transformation of phosphate esters, including pathways leading to nucleotides and oligonucleotides, carbohydrates, isoprenoids and steroids, and phosphorylated proteins. Because the natural substrates bear one or more negative charges, drugs that target these enzymes generally must be charged as well but small charged molecules can have difficulty traversing the cell membrane other than by endocytosis. The resulting dichotomy has stimulated abundant effort to develop effective prodrugs, compounds that carry little or no charge to enable them to transit biological membranes but then able to release the parent drug once inside the target cell. This chapter will present recent studies on advances in prodrug forms, along with representative examples of their application to marketed and developmental drugs. PMID:25391982
-
In Vitro Screening of an FDA-Approved Library Against ESKAPE Pathogens.
Younis, Waleed; AbdelKhalek, Ahmed; Mayhoub, Abdelrahman S; Seleem, Mohamed N
2017-01-01
Bacterial resistance to conventional antibiotics is an increasingly serious threat to public health worldwide that requires immediate exploration and the development of novel antimicrobial compounds. Drug repurposing is an inexpensive and untapped source of new antimicrobial leads, and it holds many attractive features warranting further attention for antimicrobial drug discovery. In an effort to repurpose drugs and explore new leads in the field of antimicrobial drug discovery, we performed a whole-cell screening assay of 1,600 Food and Drug Administration (FDA) approved drugs against Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter cloacae (ESKAPE) pathogens. The in vitro screening identified 49 non-antimicrobial drugs that were active against at least one species of ESKAPE pathogen. Although some of these drugs were known to have antibacterial activity, many have never been reported before. In particular, sulfonamide-containing structures represent a novel drug scaffold that should be investigated further. The characteristics of these drugs as antimicrobial agents may offer a safe, effective, and quick supplement to current approaches to treating bacterial infections. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
-
Strategies of bringing drug product marketing applications to meet current regulatory standards.
Wu, Yan; Freed, Anita; Lavrich, David; Raghavachari, Ramesh; Huynh-Ba, Kim; Shah, Ketan; Alasandro, Mark
2015-08-01
In the past decade, many guidance documents have been issued through collaboration of global organizations and regulatory authorities. Most of these are applicable to new products, but there is a risk that currently marketed products will not meet the new compliance standards during audits and inspections while companies continue to make changes through the product life cycle for continuous improvement or market demands. This discussion presents different strategies to bringing drug product marketing applications to meet current and emerging standards. It also discusses stability and method designs to meet process validation and global development efforts.
-
Schleifer, Rebecca; Pol, Luciana
2017-06-01
Discrimination and inequality shape women's experiences of drug use and in the drug trade and the impact of drug control efforts on them, with disproportionate burdens faced by poor and otherwise marginalized women. In recent years, UN member states and UN drug control and human rights entities have recognized this issue and made commitments to integrate a 'gender perspective' into drug control policies, with 'gender' limited to those conventionally deemed women. But the concept of gender in international law is broader, rooted in socially constructed and culturally determined norms and expectations around gender roles, sex, and sexuality. Also, drug control policies often fail to meaningfully address the specific needs and circumstances of women (inclusively defined), leaving them at risk of recurrent violations of their rights in the context of drugs. This article explores what it means to 'mainstream' this narrower version of gender into drug control efforts, using as examples various women's experiences as people who use drugs, in the drug trade, and in the criminal justice system. It points to international guidelines on human rights and drug control as an important tool to ensure attention to women's rights in drug control policy design and implementation.
-
Zhang, Rui Xue; Li, Jason; Zhang, Tian; Amini, Mohammad A; He, Chunsheng; Lu, Brian; Ahmed, Taksim; Lip, HoYin; Rauth, Andrew M; Wu, Xiao Yu
2018-05-01
Nanotechnology has been applied extensively in drug delivery to improve the therapeutic outcomes of various diseases. Tremendous efforts have been focused on the development of novel nanoparticles and delineation of the physicochemical properties of nanoparticles in relation to their biological fate and functions. However, in the design and evaluation of these nanotechnology-based drug delivery systems, the pharmacology of delivered drugs and the (patho-)physiology of the host have received less attention. In this review, we discuss important pharmacological mechanisms, physiological characteristics, and pathological factors that have been integrated into the design of nanotechnology-enabled drug delivery systems and therapies. Firsthand examples are presented to illustrate the principles and advantages of such integrative design strategies for cancer treatment by exploiting 1) intracellular synergistic interactions of drug-drug and drug-nanomaterial combinations to overcome multidrug-resistant cancer, 2) the blood flow direction of the circulatory system to maximize drug delivery to the tumor neovasculature and cells overexpressing integrin receptors for lung metastases, 3) endogenous lipoproteins to decorate nanocarriers and transport them across the blood-brain barrier for brain metastases, and 4) distinct pathological factors in the tumor microenvironment to develop pH- and oxidative stress-responsive hybrid manganese dioxide nanoparticles for enhanced radiotherapy. Regarding the application in diabetes management, a nanotechnology-enabled closed-loop insulin delivery system was devised to provide dynamic insulin release at a physiologically relevant time scale and glucose levels. These examples, together with other research results, suggest that utilization of the interplay of pharmacology, (patho-)physiology and nanotechnology is a facile approach to develop innovative drug delivery systems and therapies with high efficiency and translational potential.
-
Drug Abuse, U.S.A.: How Serious? How Soluble?
ERIC Educational Resources Information Center
Pollin, William
1987-01-01
Discusses the findings of the 1986 National Institute on Drug Abuse household survey. Points out the limitations of the survey and identifies trends associated with drug use. Reviews current efforts in dealing with the drug problem and recommends specific policy changes. (ML)
-
Recent developments in nitric oxide donor drugs
Miller, M R; Megson, I L
2007-01-01
During the 1980s, the free radical, nitric oxide (NO), was discovered to be a crucial signalling molecule, with wide-ranging functions in the cardiovascular, nervous and immune systems. Aside from providing a credible explanation for the actions of organic nitrates and sodium nitroprusside that have long been used in the treatment of angina and hypertensive crises respectively, the discovery generated great hopes for new NO-based treatments for a wide variety of ailments. Decades later, however, we are still awaiting novel licensed agents in this arena, despite an enormous research effort to this end. This review explores some of the most promising recent advances in NO donor drug development and addresses the challenges associated with NO as a therapeutic agent. PMID:17401442
-
Zhu, Lei; Zhou, Zhiyang; Mao, Hui; Yang, Lily
2017-01-01
Recent advances in the development of magnetic nanoparticles (MNPs) have shown promise in the development of new personalized therapeutic approaches for clinical management of cancer patients. The unique physicochemical properties of MNPs endow them with novel multifunctional capabilities for imaging, drug delivery and therapy, which are referred to as theranostics. To facilitate the translation of those theranostic MNPs into clinical applications, extensive efforts have been made on designing and improving biocompatibility, stability, safety, drug-loading ability, targeted delivery, imaging signal and thermal- or photodynamic response. In this review, we provide an overview of the physicochemical properties, toxicity and theranostic applications of MNPs with a focus on magnetic iron oxide nanoparticles. PMID:27876448
-
Impedance-based cellular assay technologies: recent advances, future promise.
McGuinness, Ryan
2007-10-01
Cell-based assays are continuing to grow in importance in the drug discovery workflow. Their early introduction holds the promise of limiting attrition in the later, more costly phases of the process. This article reviews recent advances in the development of impedance technologies for label-free cell-based assays. These systems are capable of monitoring endogenous receptor activation, and thus generate more physiologically relevant measures of pharmacological endpoints. Primary cells can be investigated as well, thus producing disease relevant information. Label-free assays significantly decrease assay development efforts and avoid many complications inherent in recombinant readout systems. Impedance-based systems have great potential to advance the utility of cell-based assays as they are applied to drug discovery and pharmacology.
-
Perspectives on Preventing Student Drug Abuse.
ERIC Educational Resources Information Center
Pedone, Ronald, Ed.; Gwaltney, Margaret K., Ed.
This set of papers is one part of the United States Department of Education's effort to establish a research agenda for drug use. It consists of a foreword and 10 papers that examine issues of drug abuse, students, and schools. It presents different views on the drug abuse problem in order to affect research on schools, drugs, and drug education.…
-
Bridging Adult Experience to Pediatrics in Oncology Drug Development.
Leong, Ruby; Zhao, Hong; Reaman, Gregory; Liu, Qi; Wang, Yaning; Stewart, Clinton F; Burckart, Gilbert
2017-10-01
Pediatric drug development in the United States has grown under the current regulations made permanent by the Food and Drug Administration Safety and Innovation Act of 2012. Over 1200 pediatric studies have now been submitted to the US FDA, but there is still a high rate of failure to obtain pediatric labeling for the indication pursued. Pediatric oncology represents special problems in that the disease is most often dissimilar to any cancer found in the adult population. Therefore, the development of drug dosing in pediatric oncology patients represents a special challenge. Potential approaches to pediatric dosing in oncology patients include extrapolation of efficacy from adult studies in those few cases where the disease is similar, inclusion of adolescent patients in adult trials when possible, and bridging the adult dose to the pediatric dose. An analysis of the recommended phase 2 dose for 40 molecularly targeted agents in pediatric patients provides some insight into current practices. Increased knowledge of tumor biology and efforts to identify and validate molecular targets and genetic abnormalities that drive childhood cancers can lead to increased opportunities for precision medicine in the treatment of pediatric cancers. © 2017, The American College of Clinical Pharmacology.
-
Clinical pharmacology of novel anti-Alzheimer disease modifying medications.
Caraci, Filippo; Bosco, Paolo; Leggio, Gian Marco; Malaguarnera, Michele; Drago, Filippo; Bucolo, Claudio; Salomone, Salvatore
2013-01-01
In recent years, efforts have been directed to develop "disease-modifying" medications to treat Alzheimer's disease (AD), able to halt or slow the pathological process. Because the earlier the treatment starts, the greater is the possibility of efficacy, it is important to set up biomarkers for early diagnosis of functional brain abnormalities, before the clinical manifestation of the overt disease. Up to now, strategies to develop disease-modifying drugs have mainly targeted β amyloid (Aβ, accumulation, aggregation, clearance) and/or tau protein (phosphorylation and aggregation). Active and passive immunotherapy is the main strategy aimed at increasing Aβ clearance. Unfortunately several candidate diseasemodifying drugs have failed in phase III clinical trials conducted in mild to moderate AD. More recently, in phase III studies, bapineuzumab has been discontinued because it did not prove clinically effective (despite its significant effect on biomarkers), while solaneuzumab has been found effective in slowing AD progression. Several methological problems have been recently pointed out to explain the lack of clinical efficacy of novel disease-modifying drug-treatments; moreover, new insights in pathophysiology of AD give the premise to develop novel drug targeting. Clinical trials recently completed and/or still ongoing are discussed in the present review.
-
Awad, A George; Voruganti, Lakshmi L N P
2015-06-01
Persons with schizophrenia are at a high risk, almost 4.6 times more likely, of having drug abuse problems than persons without psychiatric illness. Among the influential proposals to explain such a high comorbidity rate, the 'self-medication hypothesis' proposed that persons with schizophrenia take to drugs in an effort to cope with the illness and medication side effects. In support of the self-medication hypothesis, data from our earlier clinical study confirmed the strong association between neuroleptic dysphoria and negative subjective responses and comorbid drug abuse. Though dopamine has been consistently suspected as one of the major culprits for the development of neuroleptic dysphoria, it is only recently our neuroimaging studies correlated the emergence of neuroleptic dysphoria to the low level of striatal dopamine functioning. Similarly, more evidence has recently emerged linking low striatal dopamine with the development of vulnerability for drug addictive states in schizophrenia. The convergence of evidence from both the dysphoria and comorbidity research, implicating the role of low striatal dopamine in both conditions, has led us to propose that the person with schizophrenia who develops dysphoria and comorbid addictive disorder is likely to be one and the same.
-
Multi-step high-throughput conjugation platform for the development of antibody-drug conjugates.
Andris, Sebastian; Wendeler, Michaela; Wang, Xiangyang; Hubbuch, Jürgen
2018-07-20
Antibody-drug conjugates (ADCs) form a rapidly growing class of biopharmaceuticals which attracts a lot of attention throughout the industry due to its high potential for cancer therapy. They combine the specificity of a monoclonal antibody (mAb) and the cell-killing capacity of highly cytotoxic small molecule drugs. Site-specific conjugation approaches involve a multi-step process for covalent linkage of antibody and drug via a linker. Despite the range of parameters that have to be investigated, high-throughput methods are scarcely used so far in ADC development. In this work an automated high-throughput platform for a site-specific multi-step conjugation process on a liquid-handling station is presented by use of a model conjugation system. A high-throughput solid-phase buffer exchange was successfully incorporated for reagent removal by utilization of a batch cation exchange step. To ensure accurate screening of conjugation parameters, an intermediate UV/Vis-based concentration determination was established including feedback to the process. For conjugate characterization, a high-throughput compatible reversed-phase chromatography method with a runtime of 7 min and no sample preparation was developed. Two case studies illustrate the efficient use for mapping the operating space of a conjugation process. Due to the degree of automation and parallelization, the platform is capable of significantly reducing process development efforts and material demands and shorten development timelines for antibody-drug conjugates. Copyright © 2018 Elsevier B.V. All rights reserved.
-
Phytochemicals - A Novel and Prominent Source of Anti-cancer Drugs Against Colorectal Cancer.
Mahadevappa, Ravikiran; Kwok, Hang Fai
2017-01-01
Colorectal cancer (CRC) is a malignant disease whose incidence and mortality rates are greatly influenced by environmental factors. Under-treatment of CRC such as a poor diagnostic evaluation, less aggressive surgery, less intensive chemotherapy results in metastasizing of the primary tumor cells and recurrence of cancer. Prolonged chemotherapy treatment against cancer is hazardous to the patients, which also limits its use in cancer therapy. Current research in developing a novel anti-cancer agent, direct towards finding a better antimetastatic and an anti-invasive drug with reduced side effects. In this direction, plant derived chemical compounds or phytochemical act as a prominent source of new compounds for drug development. Phytochemicals have a multi-action and a multi-target capacity, and has gained attention among the research communities from last two decades. Epidemiological study shows a direct relationship between a diet and CRC development. A diet rich in plant based products such as vegetables, fruits and cereals is known to prevent CRC development. This review is an effort to explore more about the potential phytochemicals in CRC prevention and also in CRC treatment. Here, we have discussed few phytochemicals actively used in CRC research and are in clinical trials against CRC. We have explored more on some of these phytochemicals which can act as a source for new drug or can act as a lead compound for further modifications during the drug development against cancer. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
-
Penazzato, Martina; Watkins, Melynda; Morin, Sébastien; Lewis, Linda; Pascual, Fernando; Vicari, Marissa; Lee, Janice; Hargreaves, Sally; Doherty, Meg; Siberry, George K
2018-05-01
Progress in the development and introduction of paediatric formulations for key infectious diseases is poor in low-income and middle-income countries (LMICs). Although major steps have been made in the scale-up of antiretroviral medicines in LMICs, the development and deployment of formulations for infants and children is suboptimal. Of the children living with HIV globally (most in Africa), only 43% are receiving antiretroviral therapy (ART), many with suboptimal formulations. These shortfalls pose a series of challenges to meeting global treatment targets of 1·6 million children (aged 0-14 years) on ART by the end of 2018 (95% coverage) and to ensuring that 95% of those on ART are virologically suppressed. The Global Accelerator for Paediatric Formulations (GAP-f) has been developed to accelerate research, development, regulatory filing, introduction, and uptake of prioritised paediatric antiretrovirals in age-appropriate formulations by 2020, with innovative, strategic, and sustainable financing. The GAP-f will build on existing efforts to maximise coordination and alignment of policy makers, research networks, regulatory agencies, funding organisations, and manufacturers in paediatric HIV and other paediatric diseases, including tuberculosis, viral hepatitis, and other infectious diseases. Paediatric drug development and scale-up will require special efforts to bring greater visibility and new solutions to ensure that children in LMICs have access to effective and appropriate treatment options. Copyright © 2018 World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved. Published by Elsevier Ltd.. All rights reserved.
-
International Guidelines on Human Rights and Drug Control
Pol, Luciana
2017-01-01
Abstract Discrimination and inequality shape women’s experiences of drug use and in the drug trade and the impact of drug control efforts on them, with disproportionate burdens faced by poor and otherwise marginalized women. In recent years, UN member states and UN drug control and human rights entities have recognized this issue and made commitments to integrate a ‘gender perspective’ into drug control policies, with ‘gender’ limited to those conventionally deemed women. But the concept of gender in international law is broader, rooted in socially constructed and culturally determined norms and expectations around gender roles, sex, and sexuality. Also, drug control policies often fail to meaningfully address the specific needs and circumstances of women (inclusively defined), leaving them at risk of recurrent violations of their rights in the context of drugs. This article explores what it means to ‘mainstream’ this narrower version of gender into drug control efforts, using as examples various women’s experiences as people who use drugs, in the drug trade, and in the criminal justice system. It points to international guidelines on human rights and drug control as an important tool to ensure attention to women’s rights in drug control policy design and implementation. PMID:28630557
-
[New drugs, new obstacles in the fight against HIV].
Fonseca, M S
1996-01-01
Treatment with protease inhibitors, drugs that inhibit HIV protease, an essential enzyme for the survival of the HIV virus, decreases HIV to undetectable levels and has generated great optimism. Although far from finding a cure, these findings are steps toward understanding HIV. In December 1995, the Food and Drug Administration (FDA) approved saquinavir, followed by Norvir and Crixivan, all of which are protease inhibitors. Although the availability of these drugs varies, efforts are being made to provide the drugs to everyone. President Bill Clinton has asked Congress to approve $52 million, a 50 percent increase for AIDS research, to assist people who need these drugs throughout the country. In Latin America, efforts have been made to approve these drugs. According to Miklos Salgo, director of virology at Hoffmann-La Roche, Brazil has been the first country in Central and South America to approve saquinavir. Other scientists are optimistic that these new drugs will arrive in Latin America within a year.
-
DockingApp: a user friendly interface for facilitated docking simulations with AutoDock Vina.
Di Muzio, Elena; Toti, Daniele; Polticelli, Fabio
2017-02-01
Molecular docking is a powerful technique that helps uncover the structural and energetic bases of the interaction between macromolecules and substrates, endogenous and exogenous ligands, and inhibitors. Moreover, this technique plays a pivotal role in accelerating the screening of large libraries of compounds for drug development purposes. The need to promote community-driven drug development efforts, especially as far as neglected diseases are concerned, calls for user-friendly tools to allow non-expert users to exploit the full potential of molecular docking. Along this path, here is described the implementation of DockingApp, a freely available, extremely user-friendly, platform-independent application for performing docking simulations and virtual screening tasks using AutoDock Vina. DockingApp sports an intuitive graphical user interface which greatly facilitates both the input phase and the analysis of the results, which can be visualized in graphical form using the embedded JMol applet. The application comes with the DrugBank set of more than 1400 ready-to-dock, FDA-approved drugs, to facilitate virtual screening and drug repurposing initiatives. Furthermore, other databases of compounds such as ZINC, available also in AutoDock format, can be readily and easily plugged in.
-
Interest Groups' Influence over Drug Pricing Policy Reform in South Korea
Chung, Woojin
2005-01-01
In 1999, the Korean government made a drug pricing policy reform to improve the efficiency and transparency of the drug distribution system. Yet, its policy formation process was far from being rational. Facing harsh resistance from various interest groups, the government changed its details into something different from what was initially investigated and planned. So far, little evidence supports any improvement in Korea's drug distribution system. Instead, the new drug pricing policy has deteriorated Korea's national health insurance budget, indicating a heavier economic burden for the general public. From Korea's experience, we may draw some lessons for the future development of a better health care system. As a society becomes more pluralistic, the government should come out of authoritarianism and thoroughly prepare in advance for resistance to reform, by making greater efforts to persuade strong interest groups while informing the general public of potential benefits of the reform. Additionally, facing developing civic groups, the government should listen but not rely too much on them at the final stage of the policy formation. Many of the civic groups lack expertise to evaluate the details of policy and tend to act in a somewhat emotional way. PMID:15988802
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Chen, Qi; Cheng, Xiaolin; Univ. of Tennessee, Knoxville, TN
Although Elvitegravir (EVG) is a newly developed antiretrovirals drug to treat the acquired immunodeficiency syndrome (AIDS), drug resistance has already been found in clinic, such as E92Q/N155H and Q148H/G140S. Several structural investigations have already been reported to reveal the molecular mechanism of the drug resistance. As full length crystal structure for HIV-1 integrase is still unsolved, we use in this paper the crystal structure of the full length prototype foamy virus (PFV) in complex with virus DNA and inhibitor Elvitegravir as a template to construct the wild type and E92Q/N155H mutant system of HIV-1 integrase. Molecular dynamic simulations was usedmore » to revel the binding mode and the drug resistance of the EVG ligand in E92Q/N155H. Several important interactions were discovered between the mutated residues and the residues in the active site of the E92Q/N155H double mutant pattern, and cross correlation and clustering methods were used for detailed analysis. The results from the MD simulation studies will be used to guide the experimental efforts of developing novel inhibitors against drug-resistant HIV integrase mutants.« less
-
DockingApp: a user friendly interface for facilitated docking simulations with AutoDock Vina
NASA Astrophysics Data System (ADS)
Di Muzio, Elena; Toti, Daniele; Polticelli, Fabio
2017-02-01
Molecular docking is a powerful technique that helps uncover the structural and energetic bases of the interaction between macromolecules and substrates, endogenous and exogenous ligands, and inhibitors. Moreover, this technique plays a pivotal role in accelerating the screening of large libraries of compounds for drug development purposes. The need to promote community-driven drug development efforts, especially as far as neglected diseases are concerned, calls for user-friendly tools to allow non-expert users to exploit the full potential of molecular docking. Along this path, here is described the implementation of DockingApp, a freely available, extremely user-friendly, platform-independent application for performing docking simulations and virtual screening tasks using AutoDock Vina. DockingApp sports an intuitive graphical user interface which greatly facilitates both the input phase and the analysis of the results, which can be visualized in graphical form using the embedded JMol applet. The application comes with the DrugBank set of more than 1400 ready-to-dock, FDA-approved drugs, to facilitate virtual screening and drug repurposing initiatives. Furthermore, other databases of compounds such as ZINC, available also in AutoDock format, can be readily and easily plugged in.
-
Perspectives on Advances in Tuberculosis Diagnostics, Drugs, and Vaccines.
Schito, Marco; Migliori, Giovanni Battista; Fletcher, Helen A; McNerney, Ruth; Centis, Rosella; D'Ambrosio, Lia; Bates, Matthew; Kibiki, Gibson; Kapata, Nathan; Corrah, Tumena; Bomanji, Jamshed; Vilaplana, Cris; Johnson, Daniel; Mwaba, Peter; Maeurer, Markus; Zumla, Alimuddin
2015-10-15
Despite concerted efforts over the past 2 decades at developing new diagnostics, drugs, and vaccines with expanding pipelines, tuberculosis remains a global emergency. Several novel diagnostic technologies show promise of better point-of-care rapid tests for tuberculosis including nucleic acid-based amplification tests, imaging, and breath analysis of volatile organic compounds. Advances in new and repurposed drugs for use in multidrug-resistant (MDR) or extensively drug-resistant (XDR) tuberculosis have focused on development of several new drug regimens and their evaluation in clinical trials and now influence World Health Organization guidelines. Since the failure of the MVA85A vaccine 2 years ago, there have been no new tuberculosis vaccine candidates entering clinical testing. The current status quo of the lengthy treatment duration and poor treatment outcomes associated with MDR/XDR tuberculosis and with comorbidity of tuberculosis with human immunodeficiency virus and noncommunicable diseases is unacceptable. New innovations and political and funder commitment for early rapid diagnosis, shortening duration of therapy, improving treatment outcomes, and prevention are urgently required. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
-
Interest groups' influence over drug pricing policy reform in South Korea.
Chung, Woo Jin; Kim, Han Joong
2005-06-30
In 1999, the Korean government made a drug pricing policy reform to improve the efficiency and transparency of the drug distribution system. Yet, its policy formation process was far from being rational. Facing harsh resistance from various interest groups, the government changed its details into something different from what was initially investigated and planned. So far, little evidence supports any improvement in Korea's drug distribution system. Instead, the new drug pricing policy has deteriorated Korea's national health insurance budget, indicating a heavier economic burden for the general public. From Korea's experience, we may draw some lessons for the future development of a better health care system. As a society becomes more pluralistic, the government should come out of authoritarianism and thoroughly prepare in advance for resistance to reform, by making greater efforts to persuade strong interest groups while informing the general public of potential benefits of the reform. Additionally, facing developing civic groups, the government should listen but not rely too much on them at the final stage of the policy formation. Many of the civic groups lack expertise to evaluate the details of policy and tend to act in a somewhat emotional way.
-
Cheung, Connie; Gonzalez, Frank J
2008-01-01
Cytochrome P450s (P450s) are important enzymes involved in the metabolism of xenobiotics, particularly clinically used drugs, and are also responsible for metabolic activation of chemical carcinogens and toxins. Many xenobiotics can activate nuclear receptors that in turn induce the expression of genes encoding xenobiotic metabolizing enzymes and drug transporters. Marked species differences in the expression and regulation of cytochromes P450 and xenobiotic nuclear receptors exist. Thus obtaining reliable rodent models to accurately reflect human drug and carcinogen metabolism is severely limited. Humanized transgenic mice were developed in an effort to create more reliable in vivo systems to study and predict human responses to xenobiotics. Human P450s or human xenobiotic-activated nuclear receptors were introduced directly or replaced the corresponding mouse gene, thus creating “humanized” transgenic mice. Mice expressing human CYP1A1/CYP1A2, CYP2E1, CYP2D6, CYP3A4, CY3A7, PXR, PPARα were generated and characterized. These humanized mouse models offers a broad utility in the evaluation and prediction of toxicological risk that may aid in the development of safer drugs. PMID:18682571
-
Novel drug discovery approaches for treating arenavirus infections.
Pasquato, Antonella; Kunz, Stefan
2016-01-01
Arenaviruses are enveloped negative stranded viruses endemic in Africa, Europe and the Americas. Several arenaviruses cause severe viral hemorrhagic fever with high mortality in humans and pose serious public health threats. So far, there are no FDA-approved vaccines and therapeutic options are restricted to the off-label use of ribavirin. The major human pathogenic arenaviruses are classified as Category A agents and require biosafety level (BSL)-4 containment. Herein, the authors cover the recent progress in the development of BSL2 surrogate systems that recapitulate the entire or specific steps of the arenavirus life cycle and are serving as powerful platforms for drug discovery. Furthermore, they highlight the identification of selected novel drugs that target individual steps of arenavirus multiplication describing their discovery, their targets, and mode of action. The lack of effective drugs against arenaviruses is an unmatched challenge in current medical virology. Novel technologies have provided important insights into the basic biology of arenaviruses and the mechanisms underlying virus-host cell interaction. Significant progress of our understanding of how the virus invades the host cell paved the way to develop powerful novel screening platforms. Recent efforts have provided a range of promising drug candidates currently under evaluation for therapeutic intervention in vivo.
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Young, Shamar, E-mail: youn1862@umn.edu; D’Souza, Donna; Flanagan, Siobhan
2017-04-15
Colorectal cancer is a common malignancy that most commonly metastasizes to the liver. There has been considerable effort in developing new treatment options for these patients. One method that has been developed for the treatment of colorectal metastases to the liver is irinotecan-loaded drug-eluting bead (DEBIRI) embolization. This article reviews the current literature on DEBIRI and discusses the state of current knowledge and possible areas of future investigation.
-
Free energy landscape for the binding process of Huperzine A to acetylcholinesterase
Bai, Fang; Xu, Yechun; Chen, Jing; Liu, Qiufeng; Gu, Junfeng; Wang, Xicheng; Ma, Jianpeng; Li, Honglin; Onuchic, José N.; Jiang, Hualiang
2013-01-01
Drug-target residence time (t = 1/koff, where koff is the dissociation rate constant) has become an important index in discovering better- or best-in-class drugs. However, little effort has been dedicated to developing computational methods that can accurately predict this kinetic parameter or related parameters, koff and activation free energy of dissociation (). In this paper, energy landscape theory that has been developed to understand protein folding and function is extended to develop a generally applicable computational framework that is able to construct a complete ligand-target binding free energy landscape. This enables both the binding affinity and the binding kinetics to be accurately estimated. We applied this method to simulate the binding event of the anti-Alzheimer’s disease drug (−)−Huperzine A to its target acetylcholinesterase (AChE). The computational results are in excellent agreement with our concurrent experimental measurements. All of the predicted values of binding free energy and activation free energies of association and dissociation deviate from the experimental data only by less than 1 kcal/mol. The method also provides atomic resolution information for the (−)−Huperzine A binding pathway, which may be useful in designing more potent AChE inhibitors. We expect this methodology to be widely applicable to drug discovery and development. PMID:23440190
-
Free energy landscape for the binding process of Huperzine A to acetylcholinesterase.
Bai, Fang; Xu, Yechun; Chen, Jing; Liu, Qiufeng; Gu, Junfeng; Wang, Xicheng; Ma, Jianpeng; Li, Honglin; Onuchic, José N; Jiang, Hualiang
2013-03-12
Drug-target residence time (t = 1/k(off), where k(off) is the dissociation rate constant) has become an important index in discovering better- or best-in-class drugs. However, little effort has been dedicated to developing computational methods that can accurately predict this kinetic parameter or related parameters, k(off) and activation free energy of dissociation (ΔG(off)≠). In this paper, energy landscape theory that has been developed to understand protein folding and function is extended to develop a generally applicable computational framework that is able to construct a complete ligand-target binding free energy landscape. This enables both the binding affinity and the binding kinetics to be accurately estimated. We applied this method to simulate the binding event of the anti-Alzheimer's disease drug (-)-Huperzine A to its target acetylcholinesterase (AChE). The computational results are in excellent agreement with our concurrent experimental measurements. All of the predicted values of binding free energy and activation free energies of association and dissociation deviate from the experimental data only by less than 1 kcal/mol. The method also provides atomic resolution information for the (-)-Huperzine A binding pathway, which may be useful in designing more potent AChE inhibitors. We expect this methodology to be widely applicable to drug discovery and development.
-
Velasco, Veronica; Griffin, Kenneth W; Antichi, Mariella; Celata, Corrado
2015-10-01
Across developed countries, experimentation with alcohol, tobacco, and other drugs often begins in the early adolescent years. Several evidence-based programs have been developed to prevent adolescent substance use. Many of the most rigorously tested and empirically supported prevention programs were initially developed and tested in the United States. Increasingly, these interventions are being adopted for use in Europe and throughout the world. This paper reports on a large-scale comprehensive initiative designed to select, adapt, implement, and sustain an evidence-based drug abuse prevention program in Italy. As part of a large-scale regionally funded collaboration in the Lombardy region of Italy, we report on processes through which a team of stakeholders selected, translated and culturally adapted, planned, implemented and evaluated the Life Skills Training (LST) school-based drug abuse prevention program, an evidence-based intervention developed in the United States. We discuss several challenges and lessons learned and implications for prevention practitioners and researchers attempting to undertake similar international dissemination projects. We review several published conceptual models designed to promote the replication and widespread dissemination of effective programs, and discuss their strengths and limitations in the context of planning and implementing a complex, large-scale real-world dissemination effort. Copyright © 2015 Elsevier Ltd. All rights reserved.
-
Murakami, Madoka; Suzuki, Yuka; Tominaga, Toshiyoshi
2018-02-23
Delays in the introduction to the Japanese market of drug-eluting stents (DES) developed overseas (i.e., "device lag") decreased sharply between 2004 and 2012. The reduction accompanied a shift in clinical development from a succession pattern (initial product development and approval overseas followed by eventual entrance into the Japanese market) to parallel development (employing multiregional clinical trials (MRCTs)). Although resource-intensive in the short-term, MRCTs are proving to be an effective tool in simultaneous global product development. Creative study designs and the absence of significant ethnic differences in Japanese subjects regarding DES safety and efficacy and the pharmacokinetic behavior of their coating drugs propel this process. More general factors such as medical need and industry incentivization also encourage this shift. Physicians' preference for DES over other percutaneous coronary interventions, the expanding global DES market, and streamlined development and approval prospects each motivate industry to continue investing in DES product development. The efforts of various stakeholders were also integral to overcoming practical obstacles, and contributions by 'Harmonization by Doing' and a premarket collaboration initiative between the USA and Japan were particularly effective. Today, USA/Japan regulatory cooperation is routine, and Japan is now integrated into global medical device development. MRCTs including Japanese subjects, sites, and investigators are now commonplace.
-
Optimising research to speed up availability of paediatric antiretroviral drugs and formulations
Penazzato, M; Gnanashanmugam, D; Rojo, P; Lallemant, M; Lewis, L; Rocchi, F; Saint Raymond, A; Ford, N; Hazra, R; Giaquinto, C; Gibb, D; Abrams, Elaine J
2018-01-01
Globally 1.8 million children are estimated to be living with HIV, yet only 51% of those eligible actually start treatment. The completion of research and development (R&D) for paediatric antiretrovirals (ARVs) is a lengthy process and licensing of new paediatric ARVs continues to lag considerably behind adults. Providing safe, effective, and well-tolerated drugs for children remains critical to ensuring scale-up of paediatric treatment globally. In this manuscript we review current approaches to R&D for paediatric ARVs and suggest innovations to enable simplified, faster, and more comprehensive strategies to develop optimal formulations. Several approaches could be adopted, including enrolment of multiple age-cohorts concurrently and the early introduction of dosing approaches for both single and fixed-dose combination (FDC) drug formulations (preferably scored and dispersible) that match WHO weight-bands. Efforts to speed up development of optimal drugs and formulations for children should focus on a limited number of prioritised formulations. This work should build upon existing partnerships and collaborations to ensure that paediatric investigation plans are developed early in the drug development process but can be modified in a streamlined manner as more information becomes available. In addition, simplified and more efficient mechanisms to undertake R&D need to be put in place, and financing mechanisms must be made more efficient and sustainable. Registration, implementation, and strategic use of drugs should not be seen as a sequential process, with research designed to address multiple questions simultaneously to respond to the needs of HIV-infected children where they live. It is imperative that lessons learned from HIV should be shared to support progress in developing paediatric formulations for other diseases with similar treatment challenges, including tuberculosis and viral hepatitis. PMID:29190337
-
Identifying Cytochrome P450 Functional Networks and Their Allosteric Regulatory Elements
2013-12-03
drug alters the metabolism of another drug, potentially altering the pharmacological properties of either drug and leading to adverse toxic effects ...Despite extensive efforts in past decades to understand the mechanism behind these effects , drug metabolism and drug-drug interactions remain...important isoforms that is responsible for >50% of all drug metabolism, exhibits atypical kinetics due to allosteric effects [6]. Recently, Woods et al
-
ERIC Educational Resources Information Center
Volk, Robert J.; Lewis, Robert A.
Causal models of adolescent substance abuse from a family systems perspective are developed using data from a large-scale family therapy efficacy grant. It is argued that the literature on families of adolescent substance abusers is scattered in its theoretical and empirical efforts, tends to not account for individual and family developmental…
-
ERIC Educational Resources Information Center
Hawkins, Elizabeth H.; Cummins, Lillian H.; Marlatt, G. Alan
2004-01-01
Substance abuse has had profoundly devastating effects on the health and well-being of American Indians and Alaska Natives. A wide variety of intervention methods has been used to prevent or stem the development of alcohol and drug problems in Indian youth, but there is little empirical research evaluating these efforts. This article is an…
-
As part of an effort to develop a rapid in vivo screen for EPA’s prioritization of toxic chemicals, we have begun to characterize the locomotor activity of zebrafish (Danio rerio) larvae. We are assessing the acute effects of prototypic drugs that are known to act on the central ...
-
Martins, João Pedro; Torrieri, Giulia; Santos, Hélder A
2018-05-01
Nanoparticles are anticipated to overcome persistent challenges in efficient drug delivery, but the limitations associated with conventional methods of preparation are resulting in slow translation from research to clinical applications. Due to their enormous potential, microfluidic technologies have emerged as an advanced approach for the development of drug delivery systems with well-defined physicochemical characteristics and in a reproducible manner. Areas covered: This review provides an overview of microfluidic devices and materials used for their manufacturing, together with the flow patterns and regimes commonly used for nanoparticle preparation. Additionally, the different geometries used in droplet microfluidics are reviewed, with particular attention to the co-flow geometry used for the production of nanoparticles. Finally, this review summarizes the main and most recent nanoparticulate systems prepared using microfluidics, including drug nanosuspensions, polymeric, lipid, structured, and theranostic nanoparticles. Expert opinion: The production of nanoparticles at industrial scale is still a challenge, but the microfluidic technologies bring exciting opportunities to develop drug delivery systems that can be engineered in an easy, cost-effective and reproducible manner. As a highly interdisciplinary research field, more efforts and general acceptance are needed to allow for the translation of nanoparticulate drug delivery systems from academic research to the clinical practice.
-
Falling Short of the Rights to Health and Scientific Progress
Henry, Ian; Lessem, Erica
2016-01-01
Abstract The incorporation of human rights-based approaches into TB programs is gaining traction, but little work has explored the application of human rights norms and principles to TB research (a domain traditionally left to bioethics). TB research is gravely underfunded, and the scarcity of resources for TB drug development has contributed to the stubborn persistence of the TB epidemic and helped to create the conditions under which drug-resistant TB has developed and spread. This article shows how human rights—particularly human rights standards, norms, and principles related to the rights to health and benefits of scientific progress—can provide insight into understanding how underfunding TB drug research undermines efforts to secure access to safe, effective, and optimized treatment for all people with TB. By analyzing TB research in relation to the rights to health and scientific progress, we aim to clarify the legal obligations of governments to improve the TB drug research system, fund TB research, and make medical advances that result from research available to all people with TB. PMID:27780996
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Lountos, George T.; Tropea, Joseph E.; Waugh, David S.
2013-06-05
Chagas’ disease, a neglected tropical affliction transmitted by the flagellated protozoan Trypanosoma cruzi, is prevalent in Latin America and affects nearly 18 million people worldwide, yet few approved drugs are available to treat the disease. Moreover, the currently available drugs exhibit severe toxicity or are poorly effective in the chronic phase of the disease. This limitation, along with the large population at risk, underscores the urgent need to discover new molecular targets and novel therapeutic agents. Recently, the T. cruzi protein tyrosine phosphatase TcPTP1 has been implicated in the cellular differentiation and infectivity of the parasite and is therefore amore » promising target for the design of novel anti-parasitic drugs. Here, we report the X-ray crystal structure of TcPTP1 refined to a resolution of 2.18 Å, which provides structural insights into the active site environment that can be used to initiate structure-based drug design efforts to develop specific TcPTP1 inhibitors. Potential strategies to develop such inhibitors are also discussed.« less
-
Gandhi, Shivani V; Rodriguez, William; Khan, Mansoor; Polli, James E
2014-06-01
It has been advocated that biopharmaceutic risk assessment should be conducted early in pediatric product development and synchronized with the adult product development program. However, we are unaware of efforts to classify drugs into a Biopharmaceutics Classification System (BCS) framework for pediatric patients. The objective was to classify five drugs into a potential BCS. These five drugs were selected since both oral and intravenous pharmacokinetic data were available for each drug, and covered the four BCS classes in adults. Literature searches for each drug were conducted using Medline and applied to classify drugs with respect to solubility and permeability in pediatric subpopulations. Four pediatric subpopulations were considered: neonates, infants, children, and adolescents. Regarding solubility, dose numbers were calculated using a volume for each subpopulation based on body surface area (BSA) relative to 250 ml for a 1.73 m(2) adult. Dose numbers spanned a range of values, depending upon the pediatric dose formula and subpopulation. Regarding permeability, pharmacokinetic literature data required assumptions and decisions about data collection. Using a devised pediatric BCS framework, there was agreement in adult and pediatric BCS class for two drugs, azithromycin (class 3) and ciprofloxacin (class 4). There was discordance for the three drugs that have high adult permeability since all pediatric permeabilities were low: dolasetron (class 3 in pediatric), ketoprofen (class 4 in pediatric), and voriconazole (class 4 in pediatric). A main contribution of this work is the identification of critical factors required for a pediatric BCS.
-
[Obesity: a review of currently used antiobesity drugs and new compounds in clinical development].
Zieba, Remigiusz
2007-10-19
This review summarizes data on currently used antiobesity drugs and new compounds under clinical development. Three antiobesity drugs are currently accepted for long-term use. Sibutramine is a noradrenaline and serotonin reuptake inhibitor which reduces body weight by about 4-5 kg but increases heart rate and arterial blood pressure. Orlistat is a gastrointestinal lipase inhibitor which results in mean weight loss by about 3 kg and reduces the incidence of type 2 diabetes in patients with impaired glucose tolerance; however, adverse gastrointestinal effects have been observed. Rimonabant is an endocannabinoid CB1 receptor antagonist which induces a 4-5 kg mean weight loss and improves glycemic and lipid profiles, but it induces anxiety and depressive disorders. Unfortunately, there are no data on the chronic administration of these drugs. Other drugs can induce weight loss, e.g. some antidepressants, antiseizure agents, and antidiabetic drugs. The moderate efficacy of currently used antiobesity drugs has led to an intense effort to identify new, safe antiobesity drugs with better therapeutic profiles. The new antiobesity drugs under clinical development include: 1) agents that affect neurotransmitters in the central nervous system, including noradrenaline and dopamine reuptake inhibitors (bupropion, radafaxine), selective 5HT2C receptor agonists (lorcaserin), and selective 5HT6 receptor antagonists, 2) agents that modulate the activity of neuropeptides influencing food intake, including leptin analogues, human ciliary neurotrophic factor (Axokine), neuropeptide Y antagonists, and melanine-concentrating hormone antagonists, 3) agents that affect the peripheral satiety signals and brain-gut axis, e.g. selective cholecystokinin receptor A agonists, PYY3-36, agents decreasing ghrelin activity, 4) thermogenic agents, e.g. selective beta3 receptor agonists and selective thyroid hormone receptor beta agonists, and 5) others, e.g. human growth hormone fragment (AOD9604) and gastrointestinal lipase inhibitor (cetilistat).
-
A Kernel for Open Source Drug Discovery in Tropical Diseases
Ortí, Leticia; Carbajo, Rodrigo J.; Pieper, Ursula; Eswar, Narayanan; Maurer, Stephen M.; Rai, Arti K.; Taylor, Ginger; Todd, Matthew H.; Pineda-Lucena, Antonio; Sali, Andrej; Marti-Renom, Marc A.
2009-01-01
Background Conventional patent-based drug development incentives work badly for the developing world, where commercial markets are usually small to non-existent. For this reason, the past decade has seen extensive experimentation with alternative R&D institutions ranging from private–public partnerships to development prizes. Despite extensive discussion, however, one of the most promising avenues—open source drug discovery—has remained elusive. We argue that the stumbling block has been the absence of a critical mass of preexisting work that volunteers can improve through a series of granular contributions. Historically, open source software collaborations have almost never succeeded without such “kernels”. Methodology/Principal Findings Here, we use a computational pipeline for: (i) comparative structure modeling of target proteins, (ii) predicting the localization of ligand binding sites on their surfaces, and (iii) assessing the similarity of the predicted ligands to known drugs. Our kernel currently contains 143 and 297 protein targets from ten pathogen genomes that are predicted to bind a known drug or a molecule similar to a known drug, respectively. The kernel provides a source of potential drug targets and drug candidates around which an online open source community can nucleate. Using NMR spectroscopy, we have experimentally tested our predictions for two of these targets, confirming one and invalidating the other. Conclusions/Significance The TDI kernel, which is being offered under the Creative Commons attribution share-alike license for free and unrestricted use, can be accessed on the World Wide Web at http://www.tropicaldisease.org. We hope that the kernel will facilitate collaborative efforts towards the discovery of new drugs against parasites that cause tropical diseases. PMID:19381286
-
Suppression of Emergence of Resistance in Pathogenic Bacteria: Keeping Our Powder Dry, Part 1
Louie, Arnold; MacGowan, Alasdair; Hope, William
2015-01-01
We are in a crisis of bacterial resistance. For economic reasons, most pharmaceutical companies are abandoning antimicrobial discovery efforts, while, in health care itself, infection control and antibiotic stewardship programs have generally failed to prevent the spread of drug-resistant bacteria. At this point, what can be done? The first step has been taken. Governments and international bodies have declared there is a worldwide crisis in antibiotic drug resistance. As discovery efforts begin anew, what more can be done to protect newly developing agents and improve the use of new drugs to suppress resistance emergence? A neglected path has been the use of recent knowledge regarding antibiotic dosing as single agents and in combination to minimize resistance emergence, while also providing sufficient early bacterial kill. In this review, we look at the data for resistance suppression. Approaches include increasing the intensity of therapy to suppress resistant subpopulations; developing concepts of clinical breakpoints to include issues surrounding suppression of resistance; and paying attention to the duration of therapy, which is another important issue for resistance suppression. New understanding of optimizing combination therapy is of interest for difficult-to-treat pathogens like Pseudomonas aeruginosa, Acinetobacter spp., and multidrug-resistant (MDR) Enterobacteriaceae. These lessons need to be applied to our old drugs to preserve them as well and need to be put into national and international antibiotic resistance strategies. As importantly, from a regulatory perspective, new chemical entities should have a corresponding resistance suppression plan at the time of regulatory review. In this way, we can make the best of our current situation and improve future prospects. PMID:26711759
-
The Elusive Anti-Candida Vaccine: Lessons From the Past and Opportunities for the Future
Tso, Gloria Hoi Wan; Reales-Calderon, Jose Antonio; Pavelka, Norman
2018-01-01
Candidemia is a bloodstream fungal infection caused by Candida species and is most commonly observed in hospitalized patients. Even with proper antifungal drug treatment, mortality rates remain high at 40–50%. Therefore, prophylactic or preemptive antifungal medications are currently recommended in order to prevent infections in high-risk patients. Moreover, the majority of women experience at least one episode of vulvovaginal candidiasis (VVC) throughout their lifetime and many of them suffer from recurrent VVC (RVVC) with frequent relapses for the rest of their lives. While there currently exists no definitive cure, the only available treatment for RVVC is again represented by antifungal drug therapy. However, due to the limited number of existing antifungal drugs, their associated side effects and the increasing occurrence of drug resistance, other approaches are greatly needed. An obvious prevention measure for candidemia or RVVC relapse would be to immunize at-risk patients with a vaccine effective against Candida infections. In spite of the advanced and proven techniques successfully applied to the development of antibacterial or antiviral vaccines, however, no antifungal vaccine is still available on the market. In this review, we first summarize various efforts to date in the development of anti-Candida vaccines, highlighting advantages and disadvantages of each strategy. We next unfold and discuss general hurdles encountered along these efforts, such as the existence of large genomic variation and phenotypic plasticity across Candida strains and species, and the difficulty in mounting protective immune responses in immunocompromised or immunosuppressed patients. Lastly, we review the concept of “trained immunity” and discuss how induction of this rapid and nonspecific immune response may potentially open new and alternative preventive strategies against opportunistic infections by Candida species and potentially other pathogens. PMID:29755472
-
Initial lessons from public-private partnerships in drug and vaccine development.
Wheeler, C.; Berkley, S.
2001-01-01
In recent years, venture capital approaches have delivered impressive results in identifying and funding promising health discoveries and bringing them to market. This success has inspired public sector experiments with "social venture capital" approaches to address the dearth of affordable treatment and prevention for diseases of the developing world. Employing the same focus on well-defined and measurable objectives, and the same type of connections to pool and deploy resources as their for-profit counterparts, social venture capitalists seek to use the tools and incentives of capitalism to solve one of its biggest failures: the lack of drugs and vaccines for diseases endemic to low-income populations. As part of a larger trend of partnerships emerging in health product donation and distribution, public-private partnerships for pharmaceutical development have led research and development (R&D) efforts to generate more accessible and efficacious products for diseases such as malaria, tuberculosis, and AIDS. In this article, three R&D-focused partnerships are explored: the International AIDS Vaccine Initiative; the Medicines for Malaria Venture; and the newly formed Global Alliance for TB Drug Development. The article highlights key elements essential to the success of these ventures. PMID:11545329
-
DOT National Transportation Integrated Search
1980-05-01
This report presents findings of a study to describe (1) present knowledge about the relationship between drug use by drivers and highway safety, and (2) efforts to detect and prevent drug-impaired driving. Past, ongoing, and planned activities at fe...
-
Zelnick, Jennifer R; Gibbs, Andrew; Loveday, Marian; Padayatchi, Nesri; O'Donnell, Max R
2013-08-01
Drug-resistant tuberculosis (TB) is an occupational hazard for health-care workers (HCWs) in South Africa. We undertook this qualitative study to contextualize epidemiological findings suggesting that HCWs' elevated risk of drug-resistant TB is related to workplace exposure. A total of 55 HCWs and 7 hospital managers participated in focus groups and interviews about infection control (IC). Participants discussed caring for patients with drug-resistant TB, IC measures, occupational health programs, also stigma and support in the workplace. Key themes included: (i) lack of resources that hinders IC, (ii) distrust of IC efforts among HCWs, and (iii) disproportionate focus on individual-level personal protections, particularly N95 masks. IC programs should be evaluated, and the impact of new policies to rapidly diagnose drug-resistant TB and decentralize treatment should be assessed as part of the effort to control drug-resistant TB and create a safe workplace.
-
Titanium-based, fenestrated, in-plane microneedles for passive ocular drug delivery.
Khandan, Omid; Famili, Amin; Kahook, Malik Y; Rao, Masaru P
2012-01-01
Drug delivery to the eye remains a key challenge, due to limitations inherent to prevailing delivery techniques. For example, while topical delivery offers simplicity and safety, its efficacy is often limited by poor bioavailability, due to natural transport barriers and clearance mechanisms. Similarly, while intravitreal injections performed across the ocular tunic provide means for circumventing such limitations, non-negligible potential for retinal detachment and other complications adversely affects safety. Herein, we discuss our initial efforts to address these limitations through development of titanium-based microneedles (MNs) which seek to provide a safer, simpler, and more efficacious means of ocular drug delivery. Devices with in-plane geometry and through-thickness fenestrations that serve as drug reservoirs for passive delivery via diffusive transport from fast-dissolving coatings are demonstrated. Details regarding device design, fabrication, and mechanical testing are presented, as are results from preliminary coating characterization and insertion testing in ex vivo rabbit cornea.
-
Drugs, consumption, and supply in Asia: the case of cocaine in colonial India, c. 1900 - c. 1930.
Mills, James H
2007-05-01
This article examines the market for cocaine in India during the early twentieth century and the efforts of the colonial state to control it. The British authorities issued regulations to prohibit the drug's use as early as 1900, and yet by the start of World War I, cocaine's appeal had become socially diverse and geographically wide. This account of a significant market for a powerful new drug suggests that Indian society was able to rapidly develop a demand for such products even when the colonial state had no part in their introduction. Indians used these new products in complex ways- as medicines, as tonics, and as intoxicants, albeit through the localized medium of the everyday paan leaf. The study points to a reconsideration of a number of debates about the history of drugs and modern medicines in Asia.
-
Machine-Learning Techniques Applied to Antibacterial Drug Discovery
Durrant, Jacob D.; Amaro, Rommie E.
2014-01-01
The emergence of drug-resistant bacteria threatens to catapult humanity back to the pre-antibiotic era. Even now, multi-drug-resistant bacterial infections annually result in millions of hospital days, billions in healthcare costs, and, most importantly, tens of thousands of lives lost. As many pharmaceutical companies have abandoned antibiotic development in search of more lucrative therapeutics, academic researchers are uniquely positioned to fill the resulting vacuum. Traditional high-throughput screens and lead-optimization efforts are expensive and labor intensive. Computer-aided drug discovery techniques, which are cheaper and faster, can accelerate the identification of novel antibiotics in an academic setting, leading to improved hit rates and faster transitions to pre-clinical and clinical testing. The current review describes two machine-learning techniques, neural networks and decision trees, that have been used to identify experimentally validated antibiotics. We conclude by describing the future directions of this exciting field. PMID:25521642
-
Zylberberg, Claudia; Matosevic, Sandro
2016-11-01
Liposomes were the first nanoscale drug to be approved for clinical use in 1995. Since then, the technology has grown considerably, and pioneering recent work in liposome-based delivery systems has brought about remarkable developments with significant clinical implications. This includes long-circulating liposomes, stimuli-responsive liposomes, nebulized liposomes, elastic liposomes for topical, oral and transdermal delivery and covalent lipid-drug complexes for improved drug plasma membrane crossing and targeting to specific organelles. While the regulatory bodies' opinion on liposomes is well-documented, current guidance that address new delivery systems are not. This review describes, in depth, the current state-of-the-art of these new liposomal delivery systems and provides a critical overview of the current regulatory landscape surrounding commercialization efforts of higher-level complexity systems, the expected requirements and the hurdles faced by companies seeking to bring novel liposome-based systems for clinical use to market.
-
Nanotechnology for the delivery of phytochemicals in cancer therapy.
Xie, Jing; Yang, Zhaogang; Zhou, Chenguang; Zhu, Jing; Lee, Robert J; Teng, Lesheng
2016-01-01
The aim of this review is to summarize advances that have been made in the delivery of phytochemicals for cancer therapy by the use of nanotechnology. Over recent decades, much research effort has been invested in developing phytochemicals as cancer therapeutic agents. However, several impediments to their wide spread use as drugs still have to be overcome. Among these are low solubility, poor penetration into cells, high hepatic disposition, and narrow therapeutic index. Rapid clearance or uptake by normal tissues and wide tissue distribution result in low drug accumulation in the target tumor sites can result in undesired drug exposure in normal tissues. Association with or encapsulation in nanoscale drug carriers is a potential strategy to address these problems. This review discussed lessons learned on the use of nanotechnology for delivery of phytochemicals that been tested in clinical trials or are moving towards the clinic. Copyright © 2016 Elsevier Inc. All rights reserved.
-
Personalized Nanoparticles for Cancer Therapy: A Call for Greater Precision.
Sahakyan, Nare; Haddad, Amir; Richardson, Shye; Forcha-Etieundem, Valery; Christopher, Lee; Alharbi, Hanan; Campbell, Robert
2017-01-01
Nanotechnology has brought about the advent of personalized medicine in the era of targeted therapeutic strategies for cancer therapy. The ability to exploit tumor features for therapeutic gain has made it possible to manufacture more effective nanomedicines for cancer treatment. However, known obstacles, including the inability to overcome pathophysiological barriers of tumors, have impeded disease management. In spite of this, recent efforts have been made to develop more functionalized nanosystems that utilize the active-targeting approach. This article reviews the FDA-approved cancer drug delivery systems in the general framework of personalized nanomedicine. We discuss the latest efforts in the development of functionalized nano-systems, and summarize relevant ongoing preclinical and clinical trials. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
-
Health risk from veterinary antimicrobial use in China's food animal production and its reduction.
Hu, Yuanan; Cheng, Hefa
2016-12-01
The overuse and misuse of veterinary drugs, particularly antimicrobials, in food animal production in China cause environmental pollution and wide food safety concerns, and pose public health risk with the selection of antimicrobial resistance (AMR) that can spread from animal populations to humans. Elevated abundance and diversity of antimicrobial resistance genes (ARGs) and resistant bacteria (including multi-drug resistant strains) in food-producing animals, food products of animal origin, microbiota of human gut, and environmental media impacted by intensive animal farming have been reported. To rein in drug use in food animal production and protect public health, the government made a total of 227 veterinary drugs, including 150 antimicrobial products, available only by prescription from licensed veterinarians for curing, controlling, and preventing animal diseases in March 2014. So far the regulatory ban on non-therapeutic use has failed to bring major changes to the long-standing practice of drug overuse and misuse in animal husbandry and aquaculture, and significant improvement in its implementation and enforcement is necessary. A range of measures, including improving access to veterinary services, strengthening supervision on veterinary drug production and distribution, increasing research and development efforts, and enhancing animal health management, are recommended to facilitate transition toward rational use of veterinary drugs, particularly antimicrobials, and to reduce the public health risk arising from AMR development in animal agriculture. Copyright © 2016 Elsevier Ltd. All rights reserved.
-
Scaling up interventions to achieve global tuberculosis control: progress and new developments.
Raviglione, Mario; Marais, Ben; Floyd, Katherine; Lönnroth, Knut; Getahun, Haileyesus; Migliori, Giovanni B; Harries, Anthony D; Nunn, Paul; Lienhardt, Christian; Graham, Steve; Chakaya, Jeremiah; Weyer, Karin; Cole, Stewart; Kaufmann, Stefan H E; Zumla, Alimuddin
2012-05-19
Tuberculosis is still one of the most important causes of death worldwide. The 2010 Lancet tuberculosis series provided a comprehensive overview of global control efforts and challenges. In this update we review recent progress. With improved control efforts, the world and most regions are on track to achieve the Millennium Development Goal of decreasing tuberculosis incidence by 2015, and the Stop TB Partnership target of halving 1990 mortality rates by 2015; the exception is Africa. Despite these advances, full scale-up of tuberculosis and HIV collaborative activities remains challenging and emerging drug-resistant tuberculosis is a major threat. Recognition of the effect that non-communicable diseases--such as smoking-related lung disease, diet-related diabetes mellitus, and alcohol and drug misuse--have on individual vulnerability, as well as the contribution of poor living conditions to community vulnerability, shows the need for multidisciplinary approaches. Several new diagnostic tests are being introduced in endemic countries and for the first time in 40 years a coordinated portfolio of promising new tuberculosis drugs exists. However, none of these advances offer easy solutions. Achievement of international tuberculosis control targets and maintenance of these gains needs optimum national health policies and services, with ongoing investment into new approaches and strategies. Despite growing funding in recent years, a serious shortfall persists. International and national financial uncertainty places gains at serious risk. Perseverance and renewed commitment are needed to achieve global control of tuberculosis, and ultimately, its elimination. Copyright © 2012 Elsevier Ltd. All rights reserved.
-
Cell Cycle Inhibition To Treat Sleeping Sickness.
Epting, Conrad L; Emmer, Brian T; Du, Nga Y; Taylor, Joann M; Makanji, Ming Y; Olson, Cheryl L; Engman, David M
2017-09-19
African trypanosomiasis is caused by infection with the protozoan parasite Trypanosoma brucei During infection, this pathogen divides rapidly to high density in the bloodstream of its mammalian host in a manner similar to that of leukemia. Like all eukaryotes, T. brucei has a cell cycle involving the de novo synthesis of DNA regulated by ribonucleotide reductase (RNR), which catalyzes the conversion of ribonucleotides into their deoxy form. As an essential enzyme for the cell cycle, RNR is a common target for cancer chemotherapy. We hypothesized that inhibition of RNR by genetic or pharmacological means would impair parasite growth in vitro and prolong the survival of infected animals. Our results demonstrate that RNR inhibition is highly effective in suppressing parasite growth both in vitro and in vivo These results support drug discovery efforts targeting the cell cycle, not only for African trypanosomiasis but possibly also for other infections by eukaryotic pathogens. IMPORTANCE The development of drugs to treat infections with eukaryotic pathogens is challenging because many key virulence factors have closely related homologues in humans. Drug toxicity greatly limits these development efforts. For pathogens that replicate at a high rate, especially in the blood, an alternative approach is to target the cell cycle directly, much as is done to treat some hematologic malignancies. The results presented here indicate that targeting the cell cycle via inhibition of ribonucleotide reductase is effective at killing trypanosomes and prolonging the survival of infected animals. Copyright © 2017 Epting et al.
-
Mining hidden knowledge for drug safety assessment: topic modeling of LiverTox as a case study
2014-01-01
Background Given the significant impact on public health and drug development, drug safety has been a focal point and research emphasis across multiple disciplines in addition to scientific investigation, including consumer advocates, drug developers and regulators. Such a concern and effort has led numerous databases with drug safety information available in the public domain and the majority of them contain substantial textual data. Text mining offers an opportunity to leverage the hidden knowledge within these textual data for the enhanced understanding of drug safety and thus improving public health. Methods In this proof-of-concept study, topic modeling, an unsupervised text mining approach, was performed on the LiverTox database developed by National Institutes of Health (NIH). The LiverTox structured one document per drug that contains multiple sections summarizing clinical information on drug-induced liver injury (DILI). We hypothesized that these documents might contain specific textual patterns that could be used to address key DILI issues. We placed the study on drug-induced acute liver failure (ALF) which was a severe form of DILI with limited treatment options. Results After topic modeling of the "Hepatotoxicity" sections of the LiverTox across 478 drug documents, we identified a hidden topic relevant to Hy's law that was a widely-accepted rule incriminating drugs with high risk of causing ALF in humans. Using this topic, a total of 127 drugs were further implicated, 77 of which had clear ALF relevant terms in the "Outcome and management" sections of the LiverTox. For the rest of 50 drugs, evidence supporting risk of ALF was found for 42 drugs from other public databases. Conclusion In this case study, the knowledge buried in the textual data was extracted for identification of drugs with potential of causing ALF by applying topic modeling to the LiverTox database. The knowledge further guided identification of drugs with the similar potential and most of them could be verified and confirmed. This study highlights the utility of topic modeling to leverage information within textual drug safety databases, which provides new opportunities in the big data era to assess drug safety. PMID:25559675
-
Mining hidden knowledge for drug safety assessment: topic modeling of LiverTox as a case study.
Yu, Ke; Zhang, Jie; Chen, Minjun; Xu, Xiaowei; Suzuki, Ayako; Ilic, Katarina; Tong, Weida
2014-01-01
Given the significant impact on public health and drug development, drug safety has been a focal point and research emphasis across multiple disciplines in addition to scientific investigation, including consumer advocates, drug developers and regulators. Such a concern and effort has led numerous databases with drug safety information available in the public domain and the majority of them contain substantial textual data. Text mining offers an opportunity to leverage the hidden knowledge within these textual data for the enhanced understanding of drug safety and thus improving public health. In this proof-of-concept study, topic modeling, an unsupervised text mining approach, was performed on the LiverTox database developed by National Institutes of Health (NIH). The LiverTox structured one document per drug that contains multiple sections summarizing clinical information on drug-induced liver injury (DILI). We hypothesized that these documents might contain specific textual patterns that could be used to address key DILI issues. We placed the study on drug-induced acute liver failure (ALF) which was a severe form of DILI with limited treatment options. After topic modeling of the "Hepatotoxicity" sections of the LiverTox across 478 drug documents, we identified a hidden topic relevant to Hy's law that was a widely-accepted rule incriminating drugs with high risk of causing ALF in humans. Using this topic, a total of 127 drugs were further implicated, 77 of which had clear ALF relevant terms in the "Outcome and management" sections of the LiverTox. For the rest of 50 drugs, evidence supporting risk of ALF was found for 42 drugs from other public databases. In this case study, the knowledge buried in the textual data was extracted for identification of drugs with potential of causing ALF by applying topic modeling to the LiverTox database. The knowledge further guided identification of drugs with the similar potential and most of them could be verified and confirmed. This study highlights the utility of topic modeling to leverage information within textual drug safety databases, which provides new opportunities in the big data era to assess drug safety.
-
Cell-specific prediction and application of drug-induced gene expression profiles.
Hodos, Rachel; Zhang, Ping; Lee, Hao-Chih; Duan, Qiaonan; Wang, Zichen; Clark, Neil R; Ma'ayan, Avi; Wang, Fei; Kidd, Brian; Hu, Jianying; Sontag, David; Dudley, Joel
2018-01-01
Gene expression profiling of in vitro drug perturbations is useful for many biomedical discovery applications including drug repurposing and elucidation of drug mechanisms. However, limited data availability across cell types has hindered our capacity to leverage or explore the cell-specificity of these perturbations. While recent efforts have generated a large number of drug perturbation profiles across a variety of human cell types, many gaps remain in this combinatorial drug-cell space. Hence, we asked whether it is possible to fill these gaps by predicting cell-specific drug perturbation profiles using available expression data from related conditions--i.e. from other drugs and cell types. We developed a computational framework that first arranges existing profiles into a three-dimensional array (or tensor) indexed by drugs, genes, and cell types, and then uses either local (nearest-neighbors) or global (tensor completion) information to predict unmeasured profiles. We evaluate prediction accuracy using a variety of metrics, and find that the two methods have complementary performance, each superior in different regions in the drug-cell space. Predictions achieve correlations of 0.68 with true values, and maintain accurate differentially expressed genes (AUC 0.81). Finally, we demonstrate that the predicted profiles add value for making downstream associations with drug targets and therapeutic classes.
-
Cell-specific prediction and application of drug-induced gene expression profiles
Hodos, Rachel; Zhang, Ping; Lee, Hao-Chih; Duan, Qiaonan; Wang, Zichen; Clark, Neil R.; Ma'ayan, Avi; Wang, Fei; Kidd, Brian; Hu, Jianying; Sontag, David
2017-01-01
Gene expression profiling of in vitro drug perturbations is useful for many biomedical discovery applications including drug repurposing and elucidation of drug mechanisms. However, limited data availability across cell types has hindered our capacity to leverage or explore the cell-specificity of these perturbations. While recent efforts have generated a large number of drug perturbation profiles across a variety of human cell types, many gaps remain in this combinatorial drug-cell space. Hence, we asked whether it is possible to fill these gaps by predicting cell-specific drug perturbation profiles using available expression data from related conditions--i.e. from other drugs and cell types. We developed a computational framework that first arranges existing profiles into a three-dimensional array (or tensor) indexed by drugs, genes, and cell types, and then uses either local (nearest-neighbors) or global (tensor completion) information to predict unmeasured profiles. We evaluate prediction accuracy using a variety of metrics, and find that the two methods have complementary performance, each superior in different regions in the drug-cell space. Predictions achieve correlations of 0.68 with true values, and maintain accurate differentially expressed genes (AUC 0.81). Finally, we demonstrate that the predicted profiles add value for making downstream associations with drug targets and therapeutic classes. PMID:29218867
-
Patterns of Drug Use Among College Students. A Preliminary Report.
ERIC Educational Resources Information Center
Mizner, George L.; And Others
Initial data from a survey of drug usage among college students was presented. A large-scale effort was made to produce reliable figures on: (1) drug use patterns; (2) attitudes toward drug use; and (3) incidence of drug use among college students. Questionnaires were answered by 26,000 college students from the Denver-Boulder area, who were…
-
Preventing Alcohol and Other Drug Problems through Drug Education. Policy Bulletin No. 3.
ERIC Educational Resources Information Center
Bailey, William J.
Public schools have a responsibility to educate students about drug abuse, and states have a responsibility to assist schools in their efforts. Properly designed and implemented drug education programs are the most cost-effective means of preventing alcohol and other drug problems. Poorly designed and implemented programs, on the other hand, can…
-
Breaking the Cycle of Drug Abuse. 1993 Interim National Drug Control Strategy.
ERIC Educational Resources Information Center
Office of National Drug Control Policy, Washington, DC.
This Interim Drug Strategy is intended to give a new sense of direction and to reinvigorate the nation's efforts against drug trafficking and abuse. The preface to the report lists eight new strategies that the Administration will implement: (1) make drug policy a cornerstone of domestic and social policy; (2) target pregnant women, children, and…
-
Curricula, Competition and Conventional Bonds: The Educational Role in Drug Control.
ERIC Educational Resources Information Center
Norland, Stephen; And Others
1996-01-01
Evaluations of school curricular drug control efforts show they are only modestly successful because they are based on an inaccurate theory of drug taking. Social control theory is suggested as a better model of drug taking and drug resistance. Asserts strong bonds to school decrease the likelihood of interaction with delinquent peers and thereby…
-
Factors affecting the uptake of new medicines: a systematic literature review.
Lublóy, Ágnes
2014-10-20
The successful diffusion of new drugs is crucial for both pharmaceutical companies and patients-and of wider stakeholder concern, including for the funding of healthcare provision. Micro-level characteristics (the socio-demographic and professional characteristics of medical professionals), meso-level characteristics (the prescribing characteristics of doctors, the marketing efforts of pharmaceutical companies, interpersonal communication among doctors, drug attributes, and the characteristics of patients), and macro-level characteristics (government policies) all influence the diffusion of new drugs. This systematic literature review examines the micro- and meso-level characteristics of early prescribers of newly introduced drugs. Understanding the characteristics of early adopters may help to speed up the diffusion process, promote cost-efficient prescribing habits, forecast utilisation, and develop targeted intervention strategies. The PubMed and Scopus electronic databases were chosen for their extensive coverage of the pertinent literature and used to identify 205 potentially relevant studies by means of a four-layered search string. The 35 studies deemed eligible were then synthetized carefully and critically, to extract variables relevant to this review. Early adoption of new drugs is not a personal trait, independent of drug type, but early adopters share both micro- and meso-level characteristics. At prescriber level, doctors' interest in particular therapeutic areas, participation in clinical trials, and volume of prescribing-either in total or within the therapeutic class of the new drug-increase the likelihood of early adoption. The marketing efforts of pharmaceutical companies and doctors' professional and social interactions leading to prescribing contagion are very powerful predictors of new drug uptake. At patient level, doctors with younger patients, patients with higher socioeconomic statuses and/or patients with poorer health statuses are more inclined to prescribe new drugs early. In contrast, the socio-demographic characteristics of prescribers and many practice-related factors play little role in the adoption process. The most powerful predictors of new drug uptake include the doctors' strong scientific commitment, high prescribing volume in total or in within the therapeutic class of the new drug, high exposure to marketing, and intense communication with colleagues.
-
ERIC Educational Resources Information Center
Scorzelli, James F.
This report examines the incidence of drug abuse and the methods of treatment and prevention of drug abuse used in Southeast Asia. Countries studied include Malaysia, Singapore, Thailand, Indonesia, and the Philippines. Because of Malaysia's intensive effort to eliminate its drug abuse problem, emphasis is placed on this country's treatment and…
-
Treatment for Drug Abusing Offenders during Correctional Supervision: A Nationwide Overview.
ERIC Educational Resources Information Center
Lipton, Douglas S.
1998-01-01
Discusses problems associated with the increasing number of drug offenders in U.S. correctional institutions. Explores the relationship between drugs and crime, the history of treating drug-using offenders, and efforts afoot in the Federal Correctional Options Program and the Bureau of Prisons to rehabilitate these prisoners. (MKA)
-
21 CFR 601.5 - Revocation of license.
Code of Federal Regulations, 2010 CFR
2010-04-01
... 21 Food and Drugs 7 2010-04-01 2010-04-01 false Revocation of license. 601.5 Section 601.5 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) BIOLOGICS... any of the following: (i) Authorized Food and Drug Administration employees after reasonable efforts...
-
ERIC Educational Resources Information Center
Levesque, Cynthia
With increases in consumer focused advertising for prescription drugs, the Federal Drug Administration has renewed efforts to protect the public from false advertising. In 1982, it charged that the press kits Eli Lilly and Company distributed to reporters on its new antiarthritis drug, Oraflex, misrepresented the product. It recommended that Lilly…
-
Covalent nano delivery systems for selective imaging and treatment of brain tumors.
Ljubimova, Julia Y; Sun, Tao; Mashouf, Leila; Ljubimov, Alexander V; Israel, Liron L; Ljubimov, Vladimir A; Falahatian, Vida; Holler, Eggehard
2017-04-01
Nanomedicine is a rapidly evolving form of therapy that holds a great promise for superior drug delivery efficiency and therapeutic efficacy than conventional cancer treatment. In this review, we attempt to cover the benefits and the limitations of current nanomedicines with special attention to covalent nano conjugates for imaging and drug delivery in the brain. The improvement in brain tumor treatment remains dismal despite decades of efforts in drug development and patient care. One of the major obstacles in brain cancer treatment is the poor drug delivery efficiency owing to the unique blood-brain barrier (BBB) in the CNS. Although various anti-cancer agents are available to treat tumors outside of the CNS, the majority fails to cross the BBB. In this regard, nanomedicines have increasingly drawn attention due to their multi-functionality and versatility. Nano drugs can penetrate BBB and other biological barriers, and selectively accumulate in tumor cells, while concurrently decreasing systemic toxicity. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.
-
Ilardi, Elizabeth A; Vitaku, Edon; Njardarson, Jon T
2014-04-10
Among carbon, hydrogen, oxygen, and nitrogen, sulfur and fluorine are both leading constituents of the pharmaceuticals that comprise our medicinal history. In efforts to stimulate the minds of both the general public and expert scientist, statistics were collected from the trends associated with therapeutics spanning 12 disease categories (a total of 1969 drugs) from our new graphical montage compilation: disease focused pharmaceuticals posters. Each poster is a vibrant display of a collection of pharmaceuticals (including structural image, Food and Drug Administration (FDA) approval date, international nonproprietary name (INN), initial market name, and a color-coded subclass of function) organized chronologically and classified according to an association with a particular clinical indication. Specifically, the evolution and structural diversity of sulfur and the popular integration of fluorine into drugs introduced over the past 50 years are evaluated. The presented qualitative conclusions in this article aim to promote innovative insights into drug development.
-
Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy.
Montero, Joan; Sarosiek, Kristopher A; DeAngelo, Joseph D; Maertens, Ophélia; Ryan, Jeremy; Ercan, Dalia; Piao, Huiying; Horowitz, Neil S; Berkowitz, Ross S; Matulonis, Ursula; Jänne, Pasi A; Amrein, Philip C; Cichowski, Karen; Drapkin, Ronny; Letai, Anthony
2015-02-26
There is a lack of effective predictive biomarkers to precisely assign optimal therapy to cancer patients. While most efforts are directed at inferring drug response phenotype based on genotype, there is very focused and useful phenotypic information to be gained from directly perturbing the patient's living cancer cell with the drug(s) in question. To satisfy this unmet need, we developed the Dynamic BH3 Profiling technique to measure early changes in net pro-apoptotic signaling at the mitochondrion ("priming") induced by chemotherapeutic agents in cancer cells, not requiring prolonged ex vivo culture. We find in cell line and clinical experiments that early drug-induced death signaling measured by Dynamic BH3 Profiling predicts chemotherapy response across many cancer types and many agents, including combinations of chemotherapies. We propose that Dynamic BH3 Profiling can be used as a broadly applicable predictive biomarker to predict cytotoxic response of cancers to chemotherapeutics in vivo. Copyright © 2015 Elsevier Inc. All rights reserved.
-
Kim, Seong-Hoon; Ryu, Hye Guk; Lee, Juhyun; Shin, Joon; Harikishore, Amaravadhi; Jung, Hoe-Yune; Jung, Hoe-Youn; Kim, Ye Seul; Lyu, Ha-Na; Oh, Eunji; Baek, Nam-In; Choi, Kwan-Yong; Yoon, Ho Sup; Kim, Kyong-Tai
2015-09-28
Many mitotic kinases have been targeted for the development of anti-cancer drugs, and inhibitors of these kinases have been expected to perform well for cancer therapy. Efforts focused on selecting good targets and finding specific drugs to target are especially needed, largely due to the increased frequency of anti-cancer drugs used in the treatment of lung cancer. Vaccinia-related kinase 1 (VRK1) is a master regulator in lung adenocarcinoma and is considered a key molecule in the adaptive pathway, which mainly controls cell survival. We found that ursolic acid (UA) inhibits the catalytic activity of VRK1 via direct binding to the catalytic domain of VRK1. UA weakens surveillance mechanisms by blocking 53BP1 foci formation induced by VRK1 in lung cancer cells, and possesses synergistic anti-cancer effects with DNA damaging drugs. Taken together, UA can be a good anti-cancer agent for targeted therapy or combination therapy with DNA damaging drugs for lung cancer patients.
-
Huang, Ruili; Southall, Noel; Wang, Yuhong; Yasgar, Adam; Shinn, Paul; Jadhav, Ajit; Nguyen, Dac-Trung; Austin, Christopher P.
2011-01-01
Small-molecule compounds approved for use as drugs may be “repurposed” for new indications and studied to determine the mechanisms of their beneficial and adverse effects. A comprehensive collection of all small-molecule drugs approved for human use would be invaluable for systematic repurposing across human diseases, particularly for rare and neglected diseases, for which the cost and time required for development of a new chemical entity are often prohibitive. Previous efforts to build such a comprehensive collection have been limited by the complexities, redundancies, and semantic inconsistencies of drug naming within and among regulatory agencies worldwide; a lack of clear conceptualization of what constitutes a drug; and a lack of access to physical samples. We report here the creation of a definitive, complete, and nonredundant list of all approved molecular entities as a freely available electronic resource and a physical collection of small molecules amenable to high-throughput screening. PMID:21525397
-
Patel, Puja; Spears, David; Eriksen, Betina Østergaard; Lollike, Karsten; Sacco, Michael
2018-03-01
Global health care manufacturer Novo Nordisk commissioned research regarding awareness of drug safety department activities and potential to increase patient feedback. Objectives were to examine patients' knowledge of pharmaceutical manufacturers' responsibilities and efforts regarding drug safety, their perceptions and experiences related to these efforts, and how these factors influence their thoughts and behaviors. Data were collected before and after respondents read a description of a drug safety department and its practices. We conducted quantitative survey research across 608 health care consumers receiving treatment for diabetes in the United States, Germany, United Kingdom, and Italy. This research validated initial, exploratory qualitative research (across 40 comparable consumers from the same countries) which served to guide design of the larger study. Before reading a drug safety department description, 55% of respondents were unaware these departments collect safety information on products and patients. After reading the description, 34% reported the department does more than they expected to ensure drug safety, and 56% reported "more confidence" in the industry as a whole. Further, 66% reported themselves more likely to report an adverse event or product complaint, and 60% reported that they were more likely to contact a drug safety department with questions. The most preferred communication methods were websites/online forums (39%), email (27%), and telephone (25%). Learning about drug safety departments elevates consumers' confidence in manufacturers' safety efforts and establishes potential for patients to engage in increased self-monitoring and reporting. Study results reveal potentially actionable insights for the industry across patient and physician programs and communications.
-
Herrera, Sabina; Husain, Shahid
2018-05-21
The diagnosis of invasive aspergillosis remains challenging in solid organ transplants in general, and in lung transplant recipients, in particular, because of colonization. Lung transplant recipients may be over treated with antifungal drugs because of the lack of appropriate diagnostic tools. A review of the new developments of diagnostic tools and whether this help distinguishing colonization from invasive disease is presented. Efforts are being made to develop new tools that will allow us to identify which patients will develop IPA, and those who will be able to control the disease.
-
Baron, D A; Foley, T
2009-10-01
Regardless of one's stance on the topic, drugs are an important issue in sports. Sports pages in newspapers around the globe routinely report on athletes at every level ofcompetition using performance enhancing substances to gain an unfair advantage over their competitors. The level of sophistication in beating drug testing, and developing "next-generation" agents continues to raise. The relative paucity of well designed research has been an additional factor impeding attempts to adequately address the problem. Very limited funds are currently available to conduct the necessary research. Without credible data, athletes are more vulnerable to the claims made by those benefiting from the sales of these compounds. Many younger fans and those dreaming of a similar future admire highly successful professional athletes. A strong, consistent statement admonishing drug use is needed. Actions speak louder than words. Every time a successful athlete is caught using PE drugs, every effort to diminish drug use is negatively impacted. The "win at all cost" and "second place is the first loser" mentality needs to be continually challenged by words and actions in youth sports at every level of competition. Finally, the war on drugs in sports needs to be a coordinated, well organized international undertaking as sports play an important role in virtually every culture. If we are to maintain the integrity of competition and protect the health of the athletes, we must dramatically increase our efforts to eliminate performance enhancing drugs as an acceptable option for any athlete. Sports science professionals and sports psychiatrists need to work with coaches, trainers, athletes, and national governing bodies to educating athletes on the effects of performance enhancing drug use. To achieve this important goal everyone involved in sports needs to be knowledgeable on the negative impact this has on all aspects of organized sports. It is a difficult challenge, but one that must be addressed.
-
Botulinum neurotoxin vaccines: Past history and recent developments.
Rusnak, Janice M; Smith, Leonard A
2009-12-01
Botulinum toxin may cause a neuroparalytic illness that may result in respiratory failure and require prolonged mechanical ventilation. As medical resources needed for supportive care of botulism in a bioterrorist event may quickly overwhelm the local healthcare systems, biodefense research efforts have been directed towards the development of a vaccine to prevent botulism. While human botulism has been caused only by toxin serotypes A, B, and E (rarely serotype F), all seven known immunologically distinct toxin serotypes (A - G) may potentially cause intoxication in humans from a bioterrorist event. A pentavalent (ABCDE) botulinum toxoid (PBT) has been administered as an investigation new drug (IND) to at-risk individuals for nearly 50 years. Due to declining immunogenicity of the PBT, research efforts have been directed at development of both improved (less local reactogenicity) botulinum toxoids and recombinant vaccines as potential vaccine candidates to replace the PBT.
-
Synergizing Engineering and Biology to Treat and Model Skeletal Muscle Injury and Disease
Bursac, Nenad; Juhas, Mark; Rando, Thomas A.
2016-01-01
Although skeletal muscle is one of the most regenerative organs in our body, various genetic defects, alterations in extrinsic signaling, or substantial tissue damage can impair muscle function and the capacity for self-repair. The diversity and complexity of muscle disorders have attracted much interest from both cell biologists and, more recently, bioengineers, leading to concentrated efforts to better understand muscle pathology and develop more efficient therapies. This review describes the biological underpinnings of muscle development, repair, and disease, and discusses recent bioengineering efforts to design and control myomimetic environments, both to study muscle biology and function and to aid in the development of new drug, cell, and gene therapies for muscle disorders. The synergy between engineering-aided biological discovery and biology-inspired engineering solutions will be the path forward for translating laboratory results into clinical practice. PMID:26643021
-
Decolonising drugs in Asia: the case of cocaine in colonial India
2018-01-01
Abstract This article examines a drugs trade in Asia that has been largely forgotten by historians and policy-makers, that in cocaine. It will briefly trace some of the contours of this commerce and the efforts to control it. It will also assess how successful these efforts were. The article is designed to contribute fresh perspectives on recent controversies in the historiography of drugs in Asia to argue that the agendas and agency of consumers are central to understanding why markets have formed there for psychoactive substances in the modern period. PMID:29503986
-
Lazarević, Tatjana; Rilak, Ana; Bugarčić, Živadin D
2017-12-15
Metallodrugs offer potential for unique mechanism of drug action based on the choice of the metal, its oxidation state, the types and number of coordinated ligands and the coordination geometry. This review illustrates notable recent progress in the field of medicinal bioinorganic chemistry as many new approaches to the design of innovative metal-based anticancer drugs are emerging. Current research addressing the problems associated with platinum drugs has focused on other metal-based therapeutics that have different modes of action and on prodrug and targeting strategies in an effort to diminish the side-effects of cisplatin chemotherapy. Examples of metal compounds and chelating agents currently in clinical use, clinical trials or preclinical development are highlighted. Copyright © 2017 Elsevier Masson SAS. All rights reserved.
-
Chandler, Redonna K; Kahana, Shoshana Y; Fletcher, Bennett; Jones, Dionne; Finger, Matthew S; Aklin, Will M; Hamill, Kathleen; Webb, Candace
2015-12-01
Large-scale, multisite data sets offer the potential for exploring the public health benefits of biomedical interventions. Data harmonization is an emerging strategy to increase the comparability of research data collected across independent studies, enabling research questions to be addressed beyond the capacity of any individual study. The National Institute on Drug Abuse recently implemented this novel strategy to prospectively collect and harmonize data across 22 independent research studies developing and empirically testing interventions to effectively deliver an HIV continuum of care to diverse drug-abusing populations. We describe this data collection and harmonization effort, collectively known as the Seek, Test, Treat, and Retain Data Collection and Harmonization Initiative, which can serve as a model applicable to other research endeavors.
-
Mitragotri, S
2013-01-01
Transdermal drug delivery continues to provide an advantageous route of drug administration over injections. While the number of drugs delivered by passive transdermal patches has increased over the years, no macromolecule is currently delivered by the transdermal route. Substantial research efforts have been dedicated by a large number of researchers representing varied disciplines including biology, chemistry, pharmaceutics and engineering to understand, model and overcome the skin's barrier properties. This article focuses on engineering contributions to the field of transdermal drug delivery. The article pays tribute to Prof. Robert Langer, who pioneered the engineering approach towards transdermal drug delivery. Over a period spanning nearly 25 years since his first publication in the field of transdermal drug delivery, Bob Langer has deeply impacted the field by quantitative analysis and innovative engineering. At the same time, he has inspired several generations of engineers by collaborations and mentorship. His scientific insights, innovative technologies, translational efforts and dedicated mentorship have transformed the field. © 2013 S. Karger AG, Basel.
-
Romero, Klaus; Clay, Robert; Hanna, Debra
2015-08-15
The first nonclinical drug development tool (DDT) advanced by the Critical Path to TB Drug Regimens (CPTR) Initiative through a regulatory review process has been endorsed by leading global regulatory authorities. DDTs with demonstrated predictive accuracy for clinical and microbiological outcomes are needed to support decision making. Regulatory endorsement of these DDTs is critical for drug developers, as it promotes confidence in their use in Investigational New Drug and New Drug Application filings. The in vitro hollow fiber system model of tuberculosis (HFS-TB) is able to recapitulate concentration-time profiles (exposure) observed in patients for single drugs and combinations, by evaluating exposure measures for the ability to kill tuberculosis in different physiologic conditions. Monte Carlo simulations make this quantitative output useful to inform susceptibility breakpoints, dosage, and optimal combination regimens in patients, and to design nonclinical experiments in animal models. The Pre-Clinical and Clinical Sciences Working Group within CPTR executed an evidence-based evaluation of the HFS-TB for predictive accuracy. This extensive effort was enabled through the collaboration of subject matter experts representing the pharmaceutical industry, academia, product development partnerships, and regulatory authorities including the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). A comprehensive analysis plan following the regulatory guidance documents for DDT qualification was developed, followed by individual discussions with the FDA and the EMA. The results from the quantitative analyses were submitted to both agencies, pursuing regulatory DDT endorsement. The EMA Qualification Opinion for the HFS-TB DDT was published 26 January 2015 (available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000319.jsp). © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
-
Thomas, Craig E; Will, Yvonne
2012-02-01
Attrition in the drug industry due to safety findings remains high and requires a shift in the current safety testing paradigm. Many companies are now positioning safety assessment at each stage of the drug development process, including discovery, where an early perspective on potential safety issues is sought, often at chemical scaffold level, using a variety of emerging technologies. Given the lengthy development time frames of drugs in the pharmaceutical industry, the authors believe that the impact of new technologies on attrition is best measured as a function of the quality and timeliness of candidate compounds entering development. The authors provide an overview of in silico and in vitro models, as well as more complex approaches such as 'omics,' and where they are best positioned within the drug discovery process. It is important to take away that not all technologies should be applied to all projects. Technologies vary widely in their validation state, throughput and cost. A thoughtful combination of validated and emerging technologies is crucial in identifying the most promising candidates to move to proof-of-concept testing in humans. In spite of the challenges inherent in applying new technologies to drug discovery, the successes and recognition that we cannot continue to rely on safety assessment practices used for decades have led to rather dramatic strategy shifts and fostered partnerships across government agencies and industry. We are optimistic that these efforts will ultimately benefit patients by delivering effective and safe medications in a timely fashion.
-
[Treatment of gamma-hydroxybutyrate withdrawal].
Strand, Niels August Willer; Petersen, Tonny Studsgaard; Nielsen, Lars Martin; Boegevig, Soren
2017-12-11
Gamma-hydroxybutyrate (GHB) is a drug of abuse, for which physical addiction develops quickly. GHB withdrawal can develop into a life-threatening condition and has previously been treated mainly with benzodiazepines. These have not always proven effective, leading to long hospitalizations in intensive care units. Based on successful Dutch treatment results for using GHB to treat GHB withdrawal symptoms, we propose to implement a similar method in Denmark. The method requires an interdisciplinary effort for which The Danish Poison Information Centre should be consulted for expertise.
-
Huh, Ae Jung; Kwon, Young Jik
2011-12-10
Despite the fact that we live in an era of advanced and innovative technologies for elucidating underlying mechanisms of diseases and molecularly designing new drugs, infectious diseases continue to be one of the greatest health challenges worldwide. The main drawbacks for conventional antimicrobial agents are the development of multiple drug resistance and adverse side effects. Drug resistance enforces high dose administration of antibiotics, often generating intolerable toxicity, development of new antibiotics, and requests for significant economic, labor, and time investments. Recently, nontraditional antibiotic agents have been of tremendous interest in overcoming resistance that is developed by several pathogenic microorganisms against most of the commonly used antibiotics. Especially, several classes of antimicrobial nanoparticles (NPs) and nanosized carriers for antibiotics delivery have proven their effectiveness for treating infectious diseases, including antibiotics resistant ones, in vitro as well as in animal models. This review summarizes emerging efforts in combating against infectious diseases, particularly using antimicrobial NPs and antibiotics delivery systems as new tools to tackle the current challenges in treating infectious diseases. Copyright © 2011 Elsevier B.V. All rights reserved.
-
NASA Astrophysics Data System (ADS)
Hosseini, Yaser; Mollica, Adriano; Mirzaie, Sako
2016-12-01
The human immunodeficiency virus (HIV) which is strictly related to the development of AIDS, is treated by a cocktail of drugs, but due its high propensity gain drug resistance, the rational development of new medicine is highly desired. Among the different mechanism of action we selected the reverse transcriptase (RT) inhibition, for our studies. With the aim to identify new chemical entities to be used for further rational drug design, a set of 3000 molecules from the Zinc Database have been screened by docking experiments using AutoDock Vina software. The best ranked compounds with respect of the crystallographic inhibitor MK-4965 resulted to be five compounds, and the best among them was further tested by molecular dynamics (MD) simulation. Our results indicate that comp1 has a stronger interaction with the subsite p66 of RT than MK-4965 and that both are able to stabilize specific conformational changes of the RT 3D structure, which may explain their activity as inhibitors. Therefore comp1 could be a good candidate for biological tests and further development.
-
Exploring the Role of Receptor Flexibility in Structure-Based Drug Discovery
Feixas, Ferran; Lindert, Steffen; Sinko, William; McCammon, J. Andrew
2015-01-01
The proper understanding of biomolecular recognition mechanisms that take place in a drug target is of paramount importance to improve the efficiency of drug discovery and development. The intrinsic dynamic character of proteins has a strong influence on biomolecular recognition mechanisms and models such as conformational selection have been widely used to account for this dynamic association process. However, conformational changes occurring in the receptor prior and upon association with other molecules are diverse and not obvious to predict when only a few structures of the receptor are available. In view of the prominent role of protein flexibility in ligand binding and its implications for drug discovery, it is of great interest to identify receptor conformations that play a major role in biomolecular recognition before starting rational drug design efforts. In this review, we discuss a number of recent advances in computer-aided drug discovery techniques that have been proposed to incorporate receptor flexibility into structure-based drug design. The allowance for receptor flexibility provided by computational techniques such as molecular dynamics simulations or enhanced sampling techniques helps to improve the accuracy of methods used to estimate binding affinities and, thus, such methods can contribute to the discovery of novel drug leads. PMID:24332165
-
Towards soft robotic devices for site-specific drug delivery.
Alici, Gursel
2015-01-01
Considerable research efforts have recently been dedicated to the establishment of various drug delivery systems (DDS) that are mechanical/physical, chemical and biological/molecular DDS. In this paper, we report on the recent advances in site-specific drug delivery (site-specific, controlled, targeted or smart drug delivery are terms used interchangeably in the literature, to mean to transport a drug or a therapeutic agent to a desired location within the body and release it as desired with negligibly small toxicity and side effect compared to classical drug administration means such as peroral, parenteral, transmucosal, topical and inhalation) based on mechanical/physical systems consisting of implantable and robotic drug delivery systems. While we specifically focus on the robotic or autonomous DDS, which can be reprogrammable and provide multiple doses of a drug at a required time and rate, we briefly cover the implanted DDS, which are well-developed relative to the robotic DDS, to highlight the design and performance requirements, and investigate issues associated with the robotic DDS. Critical research issues associated with both DDSs are presented to describe the research challenges ahead of us in order to establish soft robotic devices for clinical and biomedical applications.
-
Bai, Jane P F
2016-10-01
There are emergent needs for cost-effective treatment worldwide, for which repurposing to develop a drug with existing marketing approval of disease(s) for new disease(s) is a valid option. Although strategic mining of electronic health records has produced real-world evidences to inform drug repurposing, using omics data (drug and disease), knowledge base of protein interactions, and database of transcription factors have been explored. Structured integration of all the existing data under the framework of drug repurposing will facilitate decision making. The ability to foresee the need to integrate new data types produced by emergent technologies and to enable data connectivity in the context of human biology and targeted diseases, as well as to use the existing crucial quality data of all approved drugs will catapult the number of drugs being successfully repurposed. However, translational pharmacodynamics databases for modeling information across human biology in the context of host factors are lacking and are critically needed for drug repurposing to improve global public health, especially for the efforts to combat neglected tropic diseases as well as emergent infectious diseases such as Zika or Ebola virus. Published by Elsevier Inc.
-
Recruiting drug-using men who have sex with men into behavioral interventions: a two-stage approach.
Kanouse, David E; Bluthenthal, Ricky N; Bogart, Laura; Iguchi, Martin Y; Perry, Suzanne; Sand, Kelly; Shoptaw, Steven
2005-03-01
Drug-using men who have sex with men (MSM) are at high risk of acquiring or transmitting HIV infection. Efforts to change behaviors in this population have been hampered by difficulties in recruiting drug-using MSM into behavioral interventions. This study sought to develop an effective strategy for recruiting drug-using MSM into behavioral interventions that consist of motivational interviewing alone or motivational interviewing plus contingency management. MSM were recruited through advertising and community outreach into groups to discuss party drugs, party burnout, and sexual behavior, with the intervention subsequently described and enrollment offered in the group setting. Many more eligible MSM responded to advertisements for the discussion groups than advertisements for the interventions, and 58% of those who participated in the discussion groups volunteered for counseling. Men who entered counseling reported high levels of drug use and sexual activity and were racially and ethnically diverse; only 35% were willing to accept drug treatment. Results demonstrate that a two-stage strategy in which drug-using MSM are first recruited into discussion groups before they are offered a behavioral intervention can be an effective way to induce voluntary acceptance of an intervention employing a behavioral risk-reduction approach.
-
Maluf, Fernando V.; McElroy, Stuart; James, Daniel; Frearson, Julie; Gray, David; Hunter, William N.
2012-01-01
The bifunctional enzyme methylenetetrahydrofolate dehydrogenase – cyclohydrolase (FolD) is identified as a potential drug target in Gram-negative bacteria, in particular the troublesome Pseudomonas aeruginosa. In order to provide a comprehensive and realistic assessment of the potential of this target for drug discovery we generated a highly efficient recombinant protein production system and purification protocol, characterized the enzyme, carried out screening of two commercial compound libraries by differential scanning fluorimetry, developed a high-throughput enzyme assay and prosecuted a screening campaign against almost 80,000 compounds. The crystal structure of P. aeruginosa FolD was determined at 2.2 Å resolution and provided a template for an assessment of druggability and for modelling of ligand complexes as well as for comparisons with the human enzyme. New FolD inhibitors were identified and characterized but the weak levels of enzyme inhibition suggest that these compounds are not optimal starting points for future development. Furthermore, the close similarity of the bacterial and human enzyme structures suggest that selective inhibition might be difficult to attain. In conclusion, although the preliminary biological data indicates that FolD represents a valuable target for the development of new antibacterial drugs, indeed spurred us to investigate it, our screening results and structural data suggest that this would be a difficult enzyme to target with respect to developing the appropriate lead molecules required to underpin a serious drug discovery effort. PMID:22558288
-
Mehta, Heer H.; Prater, Amy G.; Shamoo, Yousif
2017-01-01
With multi-drug and pan-drug resistant bacteria becoming increasingly common in hospitals, antibiotic resistance has threatened to return us to a pre-antibiotic era that would completely undermine modern medicine. There is an urgent need to develop new antibiotics and strategies to combat resistance that are substantially different from earlier drug discovery efforts. One such strategy that would complement current and future antibiotics would be a class of co-drugs that target the evolution of resistance and thereby extend the efficacy of specific classes of antibiotics. A critical step in the development of such strategies lies in understanding the critical evolutionary trajectories responsible for resistance and which proteins or biochemical pathways within those trajectories would be good candidates for co-drug discovery. We identify the most important steps in the evolution of resistance for a specific pathogen and antibiotic combination by evolving highly polymorphic populations of pathogens to resistance in a novel bioreactor that favors biofilm development. As the populations evolve to increasing drug concentrations, we use deep sequencing to elucidate the network of genetic changes responsible for resistance and subsequent in vitro biochemistry and often structure determination to determine how the adaptive mutations produce resistance. Importantly, the identification of the molecular steps, their frequency within the populations and their chronology within the evolutionary trajectory toward resistance is critical to assessing their relative importance. In this work, we discuss findings from the evolution of the ESKAPE pathogen, Pseudomonas aeruginosa to the drug of last resort, colistin to illustrate the power of this approach. PMID:28928474
-
Targeting RSV with Vaccines and Small Molecule Drugs
Costello, Heather M.; Ray, William C.; Chaiwatpongsakorn, Supranee; Peeples, Mark E.
2012-01-01
Respiratory syncytial virus (RSV) is the most significant cause of pediatric respiratory infections. Palivizumab (Synagis®), a humanized monoclonal antibody, has been used successfully for a number of years to prevent severe RSV disease in at-risk infants. However, despite intense efforts, there is no approved vaccine or small molecule drug for RSV. As an enveloped virus, RSV must fuse its envelope with the host cell membrane, which is accomplished through the actions of the fusion (F) glycoprotein, with attachment help from the G glycoprotein. Because of their integral role in initiation of infection and their accessibility outside the lipid bilayer, these proteins have been popular targets in the discovery and development of antiviral compounds and vaccines against RSV. This review examines advances in the development of antiviral compounds and vaccine candidates. PMID:22335496
-
Schweppe, K W; Probst, C
1982-03-15
The essay deals with the development of medical research in Vienna - especially the development of therapeutic drugs. This progress is related to the philosophical, historical, and political background of the enlightened absolutism and the reformatory efforts of van Swieten during the regency of Maria Theresia in Austria. Anton Störck's research on hemlock (Conium maculatum) is used as an example. The method of Störck's research-work is described. Furthermore it is demonstrated to what extent Störck's data, deduced from empirical examinations, are integrated in the official medical system, i.e. Boerhaave's iatromechanic system. Finally the attempt is made to correlate these processes of medical history with the scientific-historical model of Thomas Kuhn.
-
NATURAL PRODUCTS: A CONTINUING SOURCE OF NOVEL DRUG LEADS
Cragg, Gordon M.; Newman, David J.
2013-01-01
1. Background Nature has been a source of medicinal products for millennia, with many useful drugs developed from plant sources. Following discovery of the penicillins, drug discovery from microbial sources occurred and diving techniques in the 1970s opened the seas. Combinatorial chemistry (late 1980s), shifted the focus of drug discovery efforts from Nature to the laboratory bench. 2. Scope of Review This review traces natural products drug discovery, outlining important drugs from natural sources that revolutionized treatment of serious diseases. It is clear Nature will continue to be a major source of new structural leads, and effective drug development depends on multidisciplinary collaborations. 3. Major Conclusions The explosion of genetic information led not only to novel screens, but the genetic techniques permitted the implementation of combinatorial biosynthetic technology and genome mining. The knowledge gained has allowed unknown molecules to be identified. These novel bioactive structures can be optimized by using combinatorial chemistry generating new drug candidates for many diseases. 4 General Significance: The advent of genetic techniques that permitted the isolation / expression of biosynthetic cassettes from microbes may well be the new frontier for natural products lead discovery. It is now apparent that biodiversity may be much greater in those organisms. The numbers of potential species involved in the microbial world are many orders of magnitude greater than those of plants and multi-celled animals. Coupling these numbers to the number of currently unexpressed biosynthetic clusters now identified (>10 per species) the potential of microbial diversity remains essentially untapped. PMID:23428572
-
Generic Drug Cost Containment in Medicaid: Lessons from Five State MAC Programs
Abramson, Richard G.; Harrington, Catherine A.; Missmar, Raad; Li, Susan P.; Mendelson, Daniel N.
2004-01-01
In Medicaid, generic drug cost containment revolves around two programs: the Federal upper limit (FUL) program and State maximum allowable cost (MAC) programs. This article analyzes MAC programs in five States and finds considerable variation between these programs and the FUL program in both size and pricing aggressiveness. We conclude that expansion of existing MAC programs and creation of new ones could contribute to cost containment efforts nationwide. Options for States seeking to optimize their efforts include focusing on pricing for drugs with high sales volumes, ensuring that MAC lists include prices for all forms and dosages of listed drug entities, and collaborating with other States or the Federal Government on MAC list operations. PMID:15229994
-
Cancer nanomedicines: so many papers and so few drugs!
Venditto, Vincent J; Szoka, Francis C
2013-01-01
This review identifies a timeline to nanomedicine anticancer drug approval using the business model of inventors, innovators and imitators. By evaluating the publication record of nanomedicine cancer therapeutics we identified a trend of very few publications prior to FDA approval. We first enumerated the publications related to cancer involving polymers, liposomes or monoclonal antibodies and determined the number of citations per publication as well as the number of published clinical trials among the publications. Combining these data with the development of specific nanomedicines, we are able to identify an invention phase consisting of seminal papers in basic science necessary for the development of a specific nanomedicine. The innovation phase includes the first report, the development and the clinical trials involving that nanomedicine. Finally, the imitation phase begins after approval when others ride the wave of success by using the same formulation for new drugs or using the same drug to validate other nanomedicines. We then focused our analysis on nanomedicines containing camptothecin derivatives, which are not yet approved including two polymers considered innovations and one liposomal formulation in the imitation phase. The conclusion that may be drawn from the analysis of the camptothecins is that approved drugs reformulated in polymeric and liposomal cancer nanomedicines have a more difficult time navigating through the approval process than the parent molecule. This is probably due to the fact that for most currently approved drugs, reformulating them in a nanocarrier provides a small increase in performance that large pharmaceutical companies do not consider being worth the time, effort and expense of development. It also appears that drug carriers have a more difficult path through the clinic than monoclonal antibodies. The added complexity of nanocarriers also deters their use to deliver new molecular entities. Thus, the new drug candidates that might be most improved by drug delivery in nanocarriers are not formulated in this fashion. Copyright © 2012 Elsevier B.V. All rights reserved.
-
Natural product and natural product derived drugs in clinical trials.
Butler, Mark S; Robertson, Avril A B; Cooper, Matthew A
2014-11-01
There are a significant number of natural product (NP) drugs in development. We review the 100 NP and NP-derived compounds and 33 Antibody Drug Conjugates (ADCs) with a NP-derived cytotoxic component being evaluated in clinical trials or in registration at the end of 2013. 38 of these compounds and 33 ADCs are being investigated as potential oncology treatments, 26 as anti-infectives, 19 for the treatment of cardiovascular and metabolic diseases, 11 for inflammatory and related diseases and 6 for neurology. There was a spread of the NP and NP-derived compounds through the different development phases (17 in phase I, 52 in phase II, 23 in phase III and 8 NDA and/or MAA filed), while there were 23 ADCs in phase I and 10 in phase II. 50 of these 100 compounds were either NPs or semi-synthetic (SS) NPs, which indicated the original NP still plays an important role. NP and NP-derived compounds for which clinical trials have been halted or discontinued since 2008 are listed in the Supplementary Information. The 25 NP and NP-derived drugs launched since 2008 are also reviewed, and late stage development candidates and new NP drug pharmacophores analysed. The short term prospect for new NP and NP-derived drug approvals is bright, with 31 compounds in phase III or in registration, which should ensure a steady stream of approvals for at least the next five years. However, there could be future issues for new drug types as only five new drug pharmacophores discovered in the last 15 years are currently being evaluated in clinical trials. The next few years will be critical for NP-driven lead discovery, and a concerted effort is required to identify new biologically active pharmacophores and to progress these and existing compounds through pre-clinical drug development into clinical trials.
-
Antiprotozoal activity of proton-pump inhibitors.
Pérez-Villanueva, Jaime; Romo-Mancillas, Antonio; Hernández-Campos, Alicia; Yépez-Mulia, Lilián; Hernández-Luis, Francisco; Castillo, Rafael
2011-12-15
Parasitic diseases are still a major health problem in developing countries. In our effort to find new antiparasitic agents, in this Letter we report the in vitro antiprotozoal activity of omeprazole, lansoprazole, rabeprazole and pantoprazole against Trichomonas vaginalis, Giardia intestinalis and Entamoeba histolytica. Molecular modeling studies were an important tool to highlight the potential antiprotozoal activity of these drugs. Experimental evaluations revealed a strong activity for all compounds tested. Rabeprazole and pantoprazole were the most active compounds, having IC(50) values in the nanomolar range, which were even better than metronidazole, the drug of choice for these parasites. Copyright © 2011 Elsevier Ltd. All rights reserved.
-
Practices of excellent companies in the drug industry.
Pringle, F; Kleiner, B H
1997-01-01
Examines excellence in three major pharmaceutical companies: Merck, Lilly, and Glaxo. Provides an overview of recent trends in the health care industry. Shows that although all three companies are facing tough competition and strict cost-containment pressures, they continue to develop innovative strategies for increasing the quality of their product offering. Analyses Merck's recent acquisition of Medco and its implications; also highlights Merck's "Vital Interests" programme. Discusses Lilly's recent purchase of PCS from McKesson Drug and Lilly's recent efforts to concentrate on its core business. Introduces Helix, Glaxo's new computer network for pharmacists and explains the benefits of this unique service, both to its users and the sponsor.
-
Bisphosphonate-Based Strategies for Bone Tissue Engineering and Orthopedic Implants
Cattalini, Juan Pablo; Boccaccini, Aldo R.; Lucangioli, Silvia
2012-01-01
Bisphosphonates (BPs) are a group of well-established drugs that are applied in the development of metabolic bone disorder-related therapies. There is increasing interest also in the application of BPs in the context of bone tissue engineering, which is the topic of this review, in which an extensive overview of published studies on the development and applications of BPs-based strategies for bone regeneration is provided with special focus on the rationale for the use of different BPs in three-dimensional (3D) bone tissue scaffolds. The different alternatives that are investigated to address the delivery and sustained release of these therapeutic drugs in the nearby tissues are comprehensively discussed, and the most significant published approaches on bisphosphonate-conjugated drugs in multifunctional 3D scaffolds as well as the role of BPs within coatings for the improved fixation of orthopedic implants are presented and critically evaluated. Finally, the authors' views regarding the remaining challenges in the fields and directions for future research efforts are highlighted. PMID:22440082
-
Pharming Pharmacopoeia: Living Apothecaries from the Sea
NASA Astrophysics Data System (ADS)
Baden, D. G.
2012-12-01
The quest for, and development of, new drugs to treat extant and emerging diseases is an interdisciplinary effort, often requiring isolation of pro-drugs from new organisms, environments, and species followed by activity measurement. Exploitation of cultivated microalgae from marine sources has produced some of the most potent natural biological agents known, with specific receptor-mediated activities in pulmonary medicine, toxicology, cancer chemotherapy, the cardiovascular system, central and peripheral nervous system, and in dermatology. Our recent discovery that one class of marine-derived molecule promotes trans-membrane transport, a second that enhances mucus secretion, and a third which is an inhibitor of inflammation--- all isolated from the same organism, highlights the increasingly broad potential for innovative exploitation of natural products that occur in marine microalgae. Approaches that include interdisciplinary teams, permanent innovation, and disruptive technologies all will be described in the context of discoveries made in the treatment of cystic fibrosis, in the improvement of drug efficacy, and in the development of multiple for translational sciences in the ocean and health arenas.
-
Miniaturized pre-clinical cancer models as research and diagnostic tools
Håkanson, Maria; Cukierman, Edna; Charnley, Mirren
2014-01-01
Cancer is one of the most common causes of death worldwide. Consequently, important resources are directed towards bettering treatments and outcomes. Cancer is difficult to treat due to its heterogeneity, plasticity and frequent drug resistance. New treatment strategies should strive for personalized approaches. These should target neoplastic and/or activated microenvironmental heterogeneity and plasticity without triggering resistance and spare host cells. In this review, the putative use of increasingly physiologically relevant microfabricated cell-culturing systems intended for drug development is discussed. There are two main reasons for the use of miniaturized systems. First, scaling down model size allows for high control of microenvironmental cues enabling more predictive outcomes. Second, miniaturization reduces reagent consumption, thus facilitating combinatorial approaches with little effort and enables the application of scarce materials, such as patient-derived samples. This review aims to give an overview of the state-of-the-art of such systems while predicting their application in cancer drug development. PMID:24295904
-
Bateman, Randall J.; Benzinger, Tammie L.; Berry, Scott; Clifford, David B.; Duggan, Cynthia; Fagan, Anne M.; Fanning, Kathleen; Farlow, Martin R.; Hassenstab, Jason; McDade, Eric M.; Mills, Susan; Paumier, Katrina; Quintana, Melanie; Salloway, Stephen P.; Santacruz, Anna; Schneider, Lon S.; Wang, Guoqiao; Xiong, Chengjie
2016-01-01
INTRODUCTION The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) trial is an adaptive platform trial testing multiple drugs to slow or prevent the progression of Alzheimer’s disease in autosomal dominant Alzheimer’s disease (ADAD) families. With completion of enrollment of the first two drug arms, the DIAN-TU now plans to add new drugs to the platform, designated as the Next Generation Prevention Trial (NexGen). METHODS In collaboration with ADAD families, philanthropic organizations, academic leaders, the DIAN-TU Pharma Consortium, the NIH, and regulatory colleagues, the DIAN-TU developed innovative clinical study designs for the DIAN-TU NexGen trial. RESULTS Our expanded trials toolbox consists of a Disease Progression Model for ADAD, primary endpoint DIAN-TU cognitive performance composite, biomarker development, self-administered cognitive assessments, adaptive dose adjustments, and blinded data collection through the last participant completion. CONCLUSION These steps represent elements to improve efficacy of the adaptive platform trial and a continued effort to optimize prevention and treatment trials in ADAD. PMID:27583651
-
Safeguarding against substandard/counterfeit drugs: mitigating a macroeconomic pandemic.
Wertheimer, Albert I; Norris, Jeremiah
2009-03-01
Counterfeiting and the sale of substandard pharmaceutical products can no longer be ignored. At 10% of global trade, counterfeiting is affecting many countries, causing serious downstream expenses and resource shortages. To describe the nature and impact of drug product counterfeiting and substandard product sale and to present strategies that may have value in ameliorating these phenomena. A literature review was conducted, supplemented by interviews of key leaders/experts in the field and the search of relevant web sites. All of the data were combined, integrated, and coordinated to present the complete picture of this problem. In addition to known corruption in some of the least developed countries, the trail through developed countries was detected. This report identifies means to detect faulty products and describes efforts toward resisting and ending these corrupt practices. Counterfeit drugs, if not stopped, can be responsible for a macroeconomic pandemic where major portions of some populations may be too ill to work and where the health sector resources are completely overwhelmed, as with the case of HIV/AIDS.
-
Saneja, Ankit; Dubey, Ravindra Dhar; Alam, Noor; Khare, Vaibhav; Gupta, Prem N
2014-01-01
Scientific community is striving to understand the role of P-glycoprotein (P-gp) in drug discovery programs due to its impact on pharmacokinetic and multi-drug resistance (MDR) of anticancer drugs. A number of efforts to resolve the crystal structure and understanding the mechanism of P-gp mediated efflux have been made. Several generations of Pgp inhibitors have been developed to tackle this multi-specific efflux protein. Unfortunately, these inhibitors lack selectivity, exhibit poor solubility and severe pharmacokinetic interactions restricting their clinical use. The nanocarrier drug delivery systems (NDDS) are receiving increasing attention for P-gp modulating activity of pharmaceutical excipients which are used in their fabrication. In addition, NDDS can enhance the solubility and exhibited ability to bypass P-gp mediated efflux. The co-formulation of P-gp inhibitors and substrate anticancer drugs in single drug delivery system offers the advantage of bypassing P-gp mediated drug efflux as well as inhibiting the P-gp. Moreover, severe pharmacokinetic interactions between P-gp inhibitor and substrate anticancer drugs could be avoided by using this strategy. In this article we describe the co-formulation strategies using nanocarriers for modulation of pharmacokinetics as well as multi-drug resistance of anticancer drugs along with the challenges in this area.
-
Assessment of U.S. Government and Coalition Efforts to Develop the Afghan Local Police
2012-07-09
Forces Fund (ASFF) transferred to the MoI for payment of the ALP. Furthermore, ALP payroll processes utilized by Coalition partners to provide...Afghan Local Police Equipment 53 Observation 11. Afghan Local Police Payroll —Fund Accountability..................................... 57...prints, along with biometric data, administering a urinalysis for drug screening, administering medical exams, and completing PRO documents
-
ERIC Educational Resources Information Center
Duryea, Elias J.; And Others
An alcohol and drug use education program was developed by teachers and administrators in Mora, a small, isolated Hispanic community in northern New Mexico, in cooperation with the town's public health nurses and a University of New Mexico research team. Pre- and posttests were given to 150 students in grades 7-9 in the Mora Public Schools to…
-
Introduction to biological complexity as a missing link in drug discovery.
Gintant, Gary A; George, Christopher H
2018-06-06
Despite a burgeoning knowledge of the intricacies and mechanisms responsible for human disease, technological advances in medicinal chemistry, and more efficient assays used for drug screening, it remains difficult to discover novel and effective pharmacologic therapies. Areas covered: By reference to the primary literature and concepts emerging from academic and industrial drug screening landscapes, the authors propose that this disconnect arises from the inability to scale and integrate responses from simpler model systems to outcomes from more complex and human-based biological systems. Expert opinion: Further collaborative efforts combining target-based and phenotypic-based screening along with systems-based pharmacology and informatics will be necessary to harness the technological breakthroughs of today to derive the novel drug candidates of tomorrow. New questions must be asked of enabling technologies-while recognizing inherent limitations-in a way that moves drug development forward. Attempts to integrate mechanistic and observational information acquired across multiple scales frequently expose the gap between our knowledge and our understanding as the level of complexity increases. We hope that the thoughts and actionable items highlighted will help to inform the directed evolution of the drug discovery process.
-
Hepatocellular carcinoma: Will novel targeted drugs really impact the next future?
Montella, Liliana; Palmieri, Giovannella; Addeo, Raffaele; Del Prete, Salvatore
2016-07-21
Cancer treatment has been revolutionized by the advent of new molecular targeted and immunotherapeutic agents. Identification of the role of tumor angiogenesis changed the understanding of many tumors. After the unsuccessful results with chemotherapy, sorafenib, by interfering with angiogenic pathways, has become pivotal in the treatment of hepatocellular carcinoma. Sorafenib is the only systemic treatment to show a modest but statistically significant survival benefit. All novel drugs and strategies for treatment of advanced hepatocellular carcinoma must be compared with the results obtained with sorafenib, but no new drug or drug combination has yet achieved better results. In our opinion, the efforts to impact the natural history of the disease will be directed not only to drug development but also to understanding the underlying liver disease (usually hepatitis B virus- or hepatitis C virus-related) and to interrupting the progression of cirrhosis. It will be important to define the role and amount of mutations in the complex pathogenesis of hepatocellular carcinoma and to better integrate locoregional and systemic therapies. It will be important also to optimize the therapeutic strategies with existing chemotherapeutic drugs and new targeted agents.
-
Pharmacokinetics and disposition of various drug loaded liposomes.
Qian, Shuai; Li, Chenrui; Zuo, Zhong
2012-05-01
Due to great efforts in past 45 years, several liposomal products including two liposomal vaccine products have been commercialized and many more potential products are now under clinical trial stage. Although liposome has significantly reduced the toxicity of the drugs with improved or maintained the efficacy, its further development has been limited by its instabilities during preparation and storage, incompatibility with certain drugs, relative high cost of production and quality control as well as unspecified drug release time and sites in vivo. In vivo behaviors of liposomal drugs highly depend on their physiochemical properties including lipid composition, particle size, surface charge, surface modifications and the administrated dose as well as the route of administration. Based on the literature reports from the past two decades, the current review provided an updated summary of the key factors in liposomal preparations for clinical usage and its impact on the alternation of pharmacokinetic and disposition behaviors of drugs encapsulated in the liposome formulations. Clinical applications of liposomal preparation in anti-tumor agents, anti-infective agents as well as the macromolecules have been highlighted.
-
de Béthune, Marie-Pierre
2010-01-01
It is almost 20 years since NNRTIs were identified as a new class of antiretroviral drugs for the treatment of HIV-1 infection. Although they belong to different and diverse chemical families, they share a common and unique mechanism of action: their interaction with HIV-1 reverse transcriptase induces conformational changes that inhibit the catalytic activities of the enzyme. They are characterized by their specificity for HIV-1, which makes them very selective inhibitors of the virus. First generation NNRTIs nevirapine and efavirenz, in combination with other antiretroviral drugs, have become a cornerstone for the treatment of HIV-1 infection, in patients initiating antiretroviral therapy. Further research has led to the discovery and development of next generation NNRTIs with an increased genetic barrier to the development of resistance. Etravirine is the first NNRTI to show sustained virologic efficacy in patients with NNRTI resistant HIV-1. This review covers the NNRTI class of anti-HIV-1 drugs, from the initial discovery of the class in 1990 to the current compounds in clinical development, i.e. around 20 years of research and development efforts. It describes the characteristics of the NNRTIs, their mechanisms of action, HIV-1 resistance to the inhibitors, and the drugs that have been approved for the treatment of HIV-1 infection, or are currently in clinical development. The role of NNRTIs in prevention of HIV transmission is also addressed. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, vol. 85, issue 1, 2010. Copyright 2009 Elsevier B.V. All rights reserved.
-
Macleod, Stuart M; Finch, Janet K; Macharia, William M; Anabwani, Gabriel M
2013-08-01
A commentary is presented on the urgent need for a comprehensive effort to improve the practice of pediatric therapeutics in Africa. A call for action is addressed to a variety of practitioners internationally, many of whom possess skills that could be fruitfully applied to the improvement of health outcomes for African children. Successful engagement with the many challenges requires the complementary effort of researchers in basic and clinical pharmacology and toxicology, nurses, pharmacists, physicians, clinical pharmacologists, clinical pharmacists, and political leaders and civil servants. While a comprehensive or systematic review of the relevant literature has not been attempted, the authors have highlighted promising initiatives driven by international agencies and academic networks. Two African perspectives are presented to reinforce the prospect of child health gains that can be achieved through consistent pursuit of optimal therapy for conditions such as respiratory infection, diarrhea, malaria, and HIV/AIDS. There is an imperative for development of north-south and south-south partnerships that will amplify current research efforts and mobilize existing knowledge concerning pediatric drugs. The overall goal is a multidisciplinary commitment to making essential medicines available at the right time, the right place, and in the right formulation for African children from infancy to adolescence.
-
The Molecular Basis of Drug Resistance against Hepatitis C Virus NS3/4A Protease Inhibitors
Romano, Keith P.; Ali, Akbar; Aydin, Cihan; Soumana, Djade; Özen, Ayşegül; Deveau, Laura M.; Silver, Casey; Cao, Hong; Newton, Alicia; Petropoulos, Christos J.; Huang, Wei; Schiffer, Celia A.
2012-01-01
Hepatitis C virus (HCV) infects over 170 million people worldwide and is the leading cause of chronic liver diseases, including cirrhosis, liver failure, and liver cancer. Available antiviral therapies cause severe side effects and are effective only for a subset of patients, though treatment outcomes have recently been improved by the combination therapy now including boceprevir and telaprevir, which inhibit the viral NS3/4A protease. Despite extensive efforts to develop more potent next-generation protease inhibitors, however, the long-term efficacy of this drug class is challenged by the rapid emergence of resistance. Single-site mutations at protease residues R155, A156 and D168 confer resistance to nearly all inhibitors in clinical development. Thus, developing the next-generation of drugs that retain activity against a broader spectrum of resistant viral variants requires a comprehensive understanding of the molecular basis of drug resistance. In this study, 16 high-resolution crystal structures of four representative protease inhibitors – telaprevir, danoprevir, vaniprevir and MK-5172 – in complex with the wild-type protease and three major drug-resistant variants R155K, A156T and D168A, reveal unique molecular underpinnings of resistance to each drug. The drugs exhibit differential susceptibilities to these protease variants in both enzymatic and antiviral assays. Telaprevir, danoprevir and vaniprevir interact directly with sites that confer resistance upon mutation, while MK-5172 interacts in a unique conformation with the catalytic triad. This novel mode of MK-5172 binding explains its retained potency against two multi-drug-resistant variants, R155K and D168A. These findings define the molecular basis of HCV N3/4A protease inhibitor resistance and provide potential strategies for designing robust therapies against this rapidly evolving virus. PMID:22910833
-
Wang, Wei
2015-01-01
It is well recognized that protein product development is far more challenging than that for small-molecule drugs. The major challenges include inherent sensitivity to different types of stresses during the drug product manufacturing process, high rate of physical and chemical degradation during long-term storage, and enhanced aggregation and/or viscosity at high protein concentrations. In the past decade, many novel formulation concepts and technologies have been or are being developed to address these product development challenges for proteins. These concepts and technologies include use of uncommon/combination of formulation stabilizers, conjugation or fusion with potential stabilizers, site-specific mutagenesis, and preparation of nontraditional types of dosage forms—semiaqueous solutions, nonfreeze-dried solid formulations, suspensions, and other emerging concepts. No one technology appears to be mature, ideal, and/or adequate to address all the challenges. These gaps will likely remain in the foreseeable future and need significant efforts for ultimate resolution. PMID:25858529
-
Hatakeyama, Hiroto
2018-01-01
Nucleic acid therapy is expected to be a next generation medicine. We recently developed a multifunctional envelope-type nano device (MEND) for use as a novel delivery system. The modification of polyethylene glycol (PEG), i.e., PEGylation, is useful for achieving the delivery of MENDs to tumors via an enhanced permeability and retention (EPR) effect. However, PEGylation strongly inhibits the cellular uptake and endosomal escape of MEND, which results in significant loss of action, and therefore lost effectiveness, of the cargo therapeutic. For successful nucleic acid delivery in cancer treatment, the crucial problem associated with the use of PEG, known as the "PEG dilemma", must be solved. In this review, we describe the development and application of MEND in overcoming the PEG dilemma based on manipulating both the pharmacokinetics and intracellular trafficking of cellular uptake and endosomal release using a cleavable PEG lipid, a pH-sensitive fusogenic peptide, and a pH-sensitive cationic lipid. We also developed dual-ligand liposomes with a controlled diameter of around 300 nm, then modified these with a specific ligand and a cell penetrating peptide designed to target the neovasculature of tumors. Dual-ligand liposomes could induce an anti-tumor effect in drug resistant tumors by delivering drugs to tumor blood vessels, rather than to the cancer cells themselves. Here, we review our recent efforts to develop a novel liposomal drug delivery system (DDS) by manipulating pharmacokinetics and intracellular trafficking for drug therapy and nucleic acid medicine.
-
Lead Phytochemicals for Anticancer Drug Development
Singh, Sukhdev; Sharma, Bhupender; Kanwar, Shamsher S.; Kumar, Ashok
2016-01-01
Cancer is a serious concern at present. A large number of patients die each year due to cancer illnesses in spite of several interventions available. Development of an effective and side effects lacking anticancer therapy is the trending research direction in healthcare pharmacy. Chemical entities present in plants proved to be very potential in this regard. Bioactive phytochemicals are preferential as they pretend differentially on cancer cells only, without altering normal cells. Carcinogenesis is a complex process and includes multiple signaling events. Phytochemicals are pleiotropic in their function and target these events in multiple manners; hence they are most suitable candidate for anticancer drug development. Efforts are in progress to develop lead candidates from phytochemicals those can block or retard the growth of cancer without any side effect. Several phytochemicals manifest anticancer function in vitro and in vivo. This article deals with these lead phytomolecules with their action mechanisms on nuclear and cellular factors involved in carcinogenesis. Additionally, druggability parameters and clinical development of anticancer phytomolecules have also been discussed. PMID:27877185
-
The Implications and Future Perspectives of Nanomedicine for Cancer Stem Cell Targeted Therapies
Singh, Vimal K.; Saini, Abhishek; Chandra, Ramesh
2017-01-01
Cancer stem cells (CSCs) are believed to exhibit distinctive self-renewal, proliferation, and differentiation capabilities, and thus play a significant role in various aspects of cancer. CSCs have significant impacts on the progression of tumors, drug resistance, recurrence and metastasis in different types of malignancies. Due to their primary role, most researchers have focused on developing anti-CSC therapeutic strategies, and tremendous efforts have been put to explore methods for selective eradication of these therapeutically resistant CSCs. In recent years, many reports have shown the use of CSCs-specific approaches such as ATP-binding cassette (ABC) transporters, blockade of self-renewal and survival of CSCs, CSCs surface markers targeted drugs delivery and eradication of the tumor microenvironment. Also, various therapeutic agents such as small molecule drugs, nucleic acids, and antibodies are said to destroy CSCs selectively. Targeted drug delivery holds the key to the success of most of the anti-CSCs based drugs/therapies. The convention CSCs-specific therapeutic agents, suffer from various problems. For instance, limited water solubility, small circulation time and inconsistent stability of conventional therapeutic agents have significantly limited their efficacy. Recent advancement in the drug delivery technology has demonstrated that specially designed nanocarrier-based drug delivery approaches (nanomedicine) can be useful in delivering sufficient amount of drug molecules even in the most interiors of CSCs niches and thus can overcome the limitations associated with the conventional free drug delivery methods. The nanomedicine has also been promising in designing effective therapeutic regime against pump-mediated drug resistance (ATP-driven) and reduces detrimental effects on normal stem cells. Here we focus on the biological processes regulating CSCs' drug resistance and various strategies developed so far to deal with them. We also review the various nanomedicine approaches developed so far to overcome these CSCs related issues and their future perspectives. PMID:28785557
-
West Nile Virus Drug Discovery
Lim, Siew Pheng; Shi, Pei-Yong
2013-01-01
The outbreak of West Nile virus (WNV) in 1999 in the USA, and its continued spread throughout the Americas, parts of Europe, the Middle East and Africa, underscored the need for WNV antiviral development. Here, we review the current status of WNV drug discovery. A number of approaches have been used to search for inhibitors of WNV, including viral infection-based screening, enzyme-based screening, structure-based virtual screening, structure-based rationale design, and antibody-based therapy. These efforts have yielded inhibitors of viral or cellular factors that are critical for viral replication. For small molecule inhibitors, no promising preclinical candidate has been developed; most of the inhibitors could not even be advanced to the stage of hit-to-lead optimization due to their poor drug-like properties. However, several inhibitors developed for related members of the family Flaviviridae, such as dengue virus and hepatitis C virus, exhibited cross-inhibition of WNV, suggesting the possibility to re-purpose these antivirals for WNV treatment. Most promisingly, therapeutic antibodies have shown excellent efficacy in mouse model; one of such antibodies has been advanced into clinical trial. The knowledge accumulated during the past fifteen years has provided better rationale for the ongoing WNV and other flavivirus antiviral development. PMID:24300672