High acceptability of a newly developed urological practical skills training program.

NARCIS (Netherlands)

Vries, A.H. de; Luijk, S.J. van; Scherpbier, A.J.J.A.; Hendrikx, A.J.M.; Koldewijn, E.L.; Wagner, C.; Schout, B.M.A.

2015-01-01

Background: Benefits of simulation training are widely recognized, but its structural implementation into urological curricula remains challenging. This study aims to gain insight into current and ideal urological practical skills training and presents the outline of a newly developed skills

High acceptability of a newly developed urological practical skills training program

NARCIS (Netherlands)

de Vries, A.H.; van Luijk, S.J.; Scherpbier, A.J.J.A.; Hendrikx, A.J.M.; Koldewijn, E.L.; Wagner, C.; Schout, B.M.A.

2015-01-01

Background: Benefits of simulation training are widely recognized, but its structural implementation into urological curricula remains challenging. This study aims to gain insight into current and ideal urological practical skills training and presents the outline of a newly developed skills

Diffusion of new medication across different income groups under a universal health insurance program: an example involving newly enlisted nonsteroidal anti-inflammatory drugs for elderly osteoarthritis patients.

Science.gov (United States)

Wang, Pen-Jen; Chou, Yiing-Jenq; Lee, Cheng-Hua; Pu, Christy

2010-10-01

The aim of this research was to determine whether socioeconomic status, as measured by income level, impacts on the diffusion to patients of newly reimbursed nonsteroidal anti-inflammatory drugs (NSAIDs) under the National Health Insurance program in Taiwan. We used income tax records to identify the income levels of 324 male and 551 female randomly sampled osteoarthritis patients aged over 60 years in 2000. The study period was 2 years (t (1) = April 2001-March 2002 and t (2) = April 2002-March 2003). Generalized estimating equation models were used to analyze the impact of income level on being prescribed one of the newly reimbursed NSAIDs. The impact of income level on being treated with the new drug was positive and significant for females (OR = 2.11, p < 0.01) but not for males. The interaction term between income groups and the time trend was insignificant. Other factors associated with being treated with the new drug include age, habit of health-care utilization, and residential characteristics. Diffusion of new drugs still depends on income level despite the presence of a universal national health insurance system in Taiwan.

Microemulsion Drug Delivery Systems for Radiopharmacy Studies

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Emre Ozgenc

2016-11-01

Full Text Available Microemulsions have been used increasingly for last year’s because of ideal properties like favorable drug delivery, ease of preparation and physical stability. They have been improved the solubility and efficacy of the drug and reduce the side effects. Use of radiolabeled microemulsions plays an alternative role in drug delivery systems by investigating the formation, stability and application of microemulsions in radiopharmacy. Gama scintigraphic method is well recognized for developing and detecting the biodistribution of newly developed drugs or formulation. This review will focus on how radionuclides are able to play role with characterization studies of microemulsion drug delivery systems.

Antimicrobial Drugs in Fighting against Antimicrobial Resistance

OpenAIRE

Cheng, Guyue; Dai, Menghong; Ahmed, Saeed; Hao, Haihong; Wang, Xu; Yuan, Zonghui

2016-01-01

The outbreak of antimicrobial resistance, together with the lack of newly developed antimicrobial drugs, represents an alarming signal for both human and animal healthcare worldwide. Selection of rational dosage regimens for traditional antimicrobial drugs based on pharmacokinetic/pharmacodynamic principles as well as development of novel antimicrobials targeting new bacterial targets or resistance mechanisms are key approaches in tackling AMR. In addition to the cellular level resistance (i....

Use of peri-operative anti-epileptic drugs in patients with newly diagnosed high grade malignant glioma: a single center experience.

Science.gov (United States)

Lwu, Shelly; Hamilton, Mark G; Forsyth, Peter A; Cairncross, J Gregory; Parney, Ian F

2010-02-01

An American Academy of Neurology practice parameter recommends that long-term prophylactic anti-epileptic drugs (AED) should not be routine in patients with newly diagnosed brain tumors. However, prospective multi-center North American data shows that most newly diagnosed glioma patients receive prophylactic AED. We examined our own peri-operative AED practice patterns in newly-diagnosed patients with malignant glioma to determine if we deviate from published guidelines. A retrospective chart review was performed in adult patients with newly diagnosed malignant gliomas undergoing surgery in southern Alberta between January 2003 and December 2005. Demographic information, AED use, seizure incidence, adverse effects, tumor size, and tumor location were recorded. Of 164 eligible patients, 54 (33%) presented with seizures and all received AED. Prophylactic AED were given to 44 patients (27%). Peri-operative seizures (within 1 week) occurred in two patients without (3%) and no patients with seizure prophylaxis. Adverse AED reactions and adverse effects attributable to seizures were both rare. Prophylactic AED were continued >1 week post-op in 30 patients (18%). Patients receiving prophylactic AED were more likely to have had tumors involving the temporal lobe than those who did not (50 vs. 20%; P < 0.01). Patients receiving peri-operative AED prophylaxis were common, had a trend to reduced peri-operative seizures, and had few adverse effects. However, most of these patients were maintained on prophylactic AED continued beyond the first peri-operative week, contradicting published guidelines. Increased awareness of practice guidelines may help modify AED prescription patterns in malignant glioma patients.

Quantitative decisions in drug development

CERN Document Server

Chuang-Stein, Christy

2017-01-01

This book offers a high-level treatise of evidence-based decisions in drug development. Because of the inseparable relationship between designs and decisions, a good portion of this book is devoted to the design of clinical trials. The book begins with an overview of product development and regulatory approval pathways. It then discusses how to incorporate prior knowledge into study design and decision making at different stages of drug development. The latter include selecting appropriate metrics to formulate decisions criteria, determining go/no-go decisions for progressing a drug candidate to the next stage and predicting the effectiveness of a product. Lastly, it points out common mistakes made by drug developers under the current drug-development paradigm. The book offers useful insights to statisticians, clinicians, regulatory affairs managers and decision-makers in the pharmaceutical industry who have a basic understanding of the drug-development process and the clinical trials conducted to support dru...

A newly developed lubricant, chitosan laurate, in the manufacture of acetaminophen tablets.

Science.gov (United States)

Bani-Jaber, Ahmad; Kobayashi, Asuka; Yamada, Kyohei; Haj-Ali, Dana; Uchimoto, Takeaki; Iwao, Yasunori; Noguchi, Shuji; Itai, Shigeru

2015-04-10

To study the usefulness of chitosan laurate (CS-LA), a newly developed chitosan salt, as a lubricant, lubrication properties such as the pressure transmission ratio and ejection force were determined at different concentrations of CS-LA in tableting. In addition, tablet properties such as the tensile strength, disintegration time, and dissolution behavior, were also determined. When CS-LA was mixed at concentrations of 0.1%-3.0%, the pressure transmission ratio was increased in a concentration-dependent manner, and the value at a CS-LA concentration of 3% was equal to that of magnesium stearate (Mg-St), a widely used lubricant. Additionally, a reduction in the ejection force was observed at a concentration from 1%, proving that CS-LA has good lubrication performance. A prolonged disintegration time and decreased tensile strength, which are known disadvantages of Mg-St, were not observed with CS-LA. Furthermore, with CS-LA, retardation of dissolution of the drug from the tablets was not observed. Conjugation of CS with LA was found to be quite important for both lubricant and tablet properties. In conclusion, CS-LA should be useful as an alternative lubricant to Mg-St. Copyright © 2015 Elsevier B.V. All rights reserved.

Preparation and Evaluation of Newly Developed Chitosan Salt Coating Dispersions for Colon Delivery without Requiring Overcoating.

Science.gov (United States)

Yamada, Kyohei; Iwao, Yasunori; Bani-Jaber, Ahmad; Noguchi, Shuji; Itai, Shigeru

2015-01-01

Although chitosan (CS) has been recognized as a good material for colon-specific drug delivery systems, an overcoating with an enteric coating polymer on the surface of CS is absolutely necessary because CS is soluble in acidic conditions before reaching the colon. In the present study, to improve its stability in the presence of acid, a newly developed CS-laurate (CS-LA) material was evaluated as a coating dispersion for the development of colon-specific drug delivery systems. Two types of CS with different molecular weights, CS250 and CS600, were used to prepare CS-LA films by the casting method. The CS250-LA films had smooth surfaces, whereas the surfaces of the CS600-LA films were rough, indicating that the CS250-LA dispersion could form a denser film than CS600-LA. Both of these CS-LA films maintained a constant shape over 22 h in a pH 1.2 HCl/NaCl buffer, where the corresponding CS films rapidly disintegrated. In addition, the CS250-LA film showed specific colon degradability in a pH 6.0 phosphate buffered solution containing 1.0% (w/v) β-glucosidase. As a result of tensile strength and elongation at the break, both CS-LA films were found to have flexible film properties. Finally, the release of acetaminophen from disks coated with CS250-LA dispersions was significantly suppressed in fluids at pH 1.2 and 6.8, whereas disks coated with CS solution rapidly released the drug in pH 1.2 fluids. Taken together, this study shows that LA modification could be a useful approach in preparing CS films with acid stability and colonic degradability properties without requiring overcoating.

Multi-target drugs: the trend of drug research and development.

Science.gov (United States)

Lu, Jin-Jian; Pan, Wei; Hu, Yuan-Jia; Wang, Yi-Tao

2012-01-01

Summarizing the status of drugs in the market and examining the trend of drug research and development is important in drug discovery. In this study, we compared the drug targets and the market sales of the new molecular entities approved by the U.S. Food and Drug Administration from January 2000 to December 2009. Two networks, namely, the target-target and drug-drug networks, have been set up using the network analysis tools. The multi-target drugs have much more potential, as shown by the network visualization and the market trends. We discussed the possible reasons and proposed the rational strategies for drug research and development in the future.

Metabonomics and drug development.

Science.gov (United States)

Ramana, Pranov; Adams, Erwin; Augustijns, Patrick; Van Schepdael, Ann

2015-01-01

Metabolites as an end product of metabolism possess a wealth of information about altered metabolic control and homeostasis that is dependent on numerous variables including age, sex, and environment. Studying significant changes in the metabolite patterns has been recognized as a tool to understand crucial aspects in drug development like drug efficacy and toxicity. The inclusion of metabonomics into the OMICS study platform brings us closer to define the phenotype and allows us to look at alternatives to improve the diagnosis of diseases. Advancements in the analytical strategies and statistical tools used to study metabonomics allow us to prevent drug failures at early stages of drug development and reduce financial losses during expensive phase II and III clinical trials. This chapter introduces metabonomics along with the instruments used in the study; in addition relevant examples of the usage of metabonomics in the drug development process are discussed along with an emphasis on future directions and the challenges it faces.

Drug Repurposing Is a New Opportunity for Developing Drugs against Neuropsychiatric Disorders

Directory of Open Access Journals (Sweden)

Hyeong-Min Lee

2016-01-01

Full Text Available Better the drugs you know than the drugs you do not know. Drug repurposing is a promising, fast, and cost effective method that can overcome traditional de novo drug discovery and development challenges of targeting neuropsychiatric and other disorders. Drug discovery and development targeting neuropsychiatric disorders are complicated because of the limitations in understanding pathophysiological phenomena. In addition, traditional de novo drug discovery and development are risky, expensive, and time-consuming processes. One alternative approach, drug repurposing, has emerged taking advantage of off-target effects of the existing drugs. In order to identify new opportunities for the existing drugs, it is essential for us to understand the mechanisms of action of drugs, both biologically and pharmacologically. By doing this, drug repurposing would be a more effective method to develop drugs against neuropsychiatric and other disorders. Here, we review the difficulties in drug discovery and development in neuropsychiatric disorders and the extent and perspectives of drug repurposing.

Drugs and development: the global impact of drug use and trafficking on social and economic development.

Science.gov (United States)

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.

[Development of antituberculous drugs: current status and future prospects].

Science.gov (United States)

Tomioka, Haruaki; Namba, Kenji

2006-12-01

national project in US started last year, Reverse Proteomics Research Institute Co., Ltd. (REPRORI) has developed the core technologies for chemical genomics. Here we describe the outline of chemical genomics study, especially that of REPRORI, and discuss about its possible application to the development of anti-tuberculosis drugs. 3. Anti-mycobacterial agents and drug delivery: Koichi IZUMIKAWA, Hideaki OHNO, Shigeru KOHNO (Second Department of Internal Medicine, Nagasaki University School of Medicine) Mycobacterium infection is a major clinical concern in whole world. Since the newly developed anti-mycobacterial agents are few and still unavailable in clinical settings, the applications of drug delivery system using conventional anti-mycobacterial agents are challenging to improve the compliance of treatment and better efficacy. The efficacy of anti-mycobacterial agents modified by liposome or polymer based technology have been investigated and reported using various animal models. Drug delivery system increased and prolonged the drug concentrations at the blood and targeted organs and the duration of sustained drug release, respectively. These effects lead to decrease in the frequency of drug administrations dramatically and better efficacy rates. The studies, however, were performed only in animal models, the further investigations and evaluations in human are required for practical use. 4. Adjunctive immunotherapy of mycobacterial infections: Toshiaki SHIMIZU, Katsumasa SATO, Haruaki TOMIOKA (Department of Microbiology and Immunology, Shimane University School of Medicine) There is an urgent need to develop new antimicrobials and protocols for the administration of drugs that are potently efficacious against intractable mycobacterial infections. Unfortunately, development of the new drugs for solving this problem is not progressing. (ABSTRACT TRUNCATED)

Drug development in neuropsychopharmacology.

Science.gov (United States)

Fritze, Jürgen

2008-03-01

Personalized medicine is still in its infancy concerning drug development in neuropsychopharmacology. Adequate biomarkers with clinical relevance to drug response and/or tolerability and safety largely remain to be identified. Possibly, this kind of personalized medicine will first gain clinical relevance in the dementias. The clinical relevance of the genotyping of drug-metabolizing enzymes as suggested by drug licensing authorities for the pharmacokinetic evaluation of medicinal products needs to be proven in sound clinical trials.

Pediatric Melanoma and Drug Development

Directory of Open Access Journals (Sweden)

Klaus Rose

2018-03-01

Full Text Available Importance—Pediatric melanoma occurs, albeit rarely. Should patients be treated by today’s medical standards, or be subjected to medically unnecessary clinical studies? Observations—We identified international, industry-sponsored pediatric melanoma studies triggered by regulatory demands in www.clinicaltrials.gov and further pediatric melanoma studies demanded by European Union pediatric investigation plans. We retrieved related regulatory documents from the internet. We analyzed these studies for rationale and medical beneficence on the basis of physiology, pediatric clinical pharmacology and rationale. Regulatory authorities define children by chronological age, not physiologically. Newborns’ organs are immature but they develop and mature rapidly. Separate proof of efficacy in underage patients is justified formally/regulatorily but lacks medical sense. Children—especially post-puberty—and adults vis-a-vis medications are physiologically very similar. Two adolescent melanoma studies were terminated in 2016 because of waning recruitment, while five studies in pediatric melanoma and other solid tumors, triggered by European Union pediatric investigation plans, continue recruiting worldwide. Conclusions and Relevance—Regulatory-demanded pediatric melanoma studies are medically superfluous. Melanoma patients of all ages should be treated with effective combination treatment. Babies need special attention. Children need dose-finding and pharmacokinetic studies but adolescents metabolize and respond to drugs similarly to adults. Institutional Review Boards/ethics committees should suspend ongoing questionable pediatric melanoma studies and reject newly submitted questionable studies.

New Zealand’s Drug Development Industry

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Christopher Carswell

2013-09-01

Full Text Available The pharmaceutical industry’s profitability depends on identifying and successfully developing new drug candidates while trying to contain the increasing costs of drug development. It is actively searching for new sources of innovative compounds and for mechanisms to reduce the enormous costs of developing new drug candidates. There is an opportunity for academia to further develop as a source of drug discovery. The rising levels of industry outsourcing also provide prospects for organisations that can reduce the costs of drug development. We explored the potential returns to New Zealand (NZ from its drug discovery expertise by assuming a drug development candidate is out-licensed without clinical data and has anticipated peak global sales of $350 million. We also estimated the revenue from NZ’s clinical research industry based on a standard per participant payment to study sites and the number of industry-sponsored clinical trials approved each year. Our analyses found that NZ’s clinical research industry has generated increasing foreign revenue and appropriate policy support could ensure that this continues to grow. In addition the probability-based revenue from the out-licensing of a drug development candidate could be important for NZ if provided with appropriate policy and financial support.

Assessing the comparative effectiveness of newly marketed medications: methodological challenges and implications for drug development.

Science.gov (United States)

Schneeweiss, S; Gagne, J J; Glynn, R J; Ruhl, M; Rassen, J A

2011-12-01

Comparative-effectiveness research (CER) aims to produce actionable evidence regarding the effectiveness and safety of medical products and interventions as they are used outside of controlled research settings. Although CER evidence regarding medications is particularly needed shortly after market approval, key methodological challenges include (i) potential bias due to channeling of patients to the newly marketed medication because of various patient-, physician-, and system-related factors; (ii) rapid changes in the characteristics of the user population during the early phase of marketing; and (iii) lack of timely data and the often small number of users in the first few months of marketing. We propose a mix of approaches to generate comparative-effectiveness data in the early marketing period, including sequential cohort monitoring with secondary health-care data and propensity score (PS) balancing, as well as extended follow-up of phase III and phase IV trials, indirect comparisons of placebo-controlled trials, and modeling and simulation of virtual trials.

Orphan drug: Development trends and strategies

Directory of Open Access Journals (Sweden)

Aarti Sharma

2010-01-01

Full Text Available The growth of pharma industries has slowed in recent years because of various reasons such as patent expiries, generic competition, drying pipelines, and increasingly stringent regulatory guidelines. Many blockbuster drugs will loose their exclusivity in next 5 years. Therefore, the current economic situation plus the huge generic competition shifted the focus of pharmaceutical companies from the essential medicines to the new business model - niche busters, also called orphan drugs. Orphan drugs may help pharma companies to reduce the impact of revenue loss caused by patent expiries of blockbuster drugs. The new business model of orphan drugs could offer an integrated healthcare solution that enables pharma companies to develop newer areas of therapeutics, diagnosis, treatment, monitoring, and patient support. Incentives for drug development provided by governments, as well as support from the FDA and EU Commission in special protocols, are a further boost for the companies developing orphan drugs. Although there may still be challenges ahead for the pharmaceutical industry, orphan drugs seem to offer the key to recovery and stability within the market. In our study, we have compared the policies and orphan drug incentives worldwide alongwith the challenges faced by the pharmaceutical companies. Recent developments are seen in orphan drug approval, the various drugs in orphan drug pipeline, and the future prospectives for orphan drugs and diseases.

Improving a newly developed patient-reported outcome for thyroid patients, using cognitive interviewing

DEFF Research Database (Denmark)

Watt, Torquil; Rasmussen, Ase Krogh; Groenvold, Mogens

2008-01-01

Objective To improve a newly developed patient-reported outcome measure for thyroid patients using cognitive interviewing. Methods Thirty-one interviews using immediate retrospective and expansive probing were conducted among patients with non-toxic goiter (n = 4), nodular toxic goiter (n = 5) Gr...

Newly Developed Ceramic Membranes for Dehydration and Separation of Organic Mixtures by Pervaporation

NARCIS (Netherlands)

Gemert, van R.W.; Cuperus, F.P.

1995-01-01

Polymeric pervaporation membranes sometimes show great variety in performance when they are alternately used for different solvent mixtures. In addition, membrane stability in time is a problem in case of some solvents. Therefore, newly developed ceramic silica membranes with a 'dense' top layer

Positron emission tomography in drug development

International Nuclear Information System (INIS)

Rubin, R. H.; Fischman, A. J.

1997-01-01

There are four kinds of measurements that can be carried out with positron emission tomography (PET) that can contribute significantly to the process of drug development: pharmacodynamic measurement of tissue metabolism influenced by a given drug; precise measurements of tissue blood flow; tissue pharmacokinetics of a given drug following administration of a particular dose; and the temporal course of ligand-receptor interaction. One or more of these measurements can greatly improve the decision making involved in determining the appropriate dose of a drug, the clinical situations in which a drug might be useful, and the linkage of pharmacokinetics with pharmacodynamics, which is at the heart of effective drug development. The greater the potential of a particular compound as a therapeutic agent, the greater the potential for PET to contribute to the drug development process

The Development Needs of Newly Appointed Senior School Leaders in the Western Cape South Africa: A Case Study

Directory of Open Access Journals (Sweden)

Nelius Jansen van Vuuren

2017-12-01

Full Text Available The essential role that senior school leaders play in school leadership teams to ensure effective strategic leadership in schools has been the subject of intense discussion for many years. Crucial to this debate is the establishment of professional learning and leadership approaches for newly appointed senior school leaders. Recommendations for policy and practice highlight the importance of appropriate, multifaceted, developmental support initiatives for newly appointed school leaders. In many countries, including South Africa, a teaching qualification and, in most cases, extensive teaching experience is the only requirement for being appointed as a senior school leader in a school. This tends to suggest that no further professional development is required for newly appointed school leaders, the problem addressed in this paper. This paper reports on the main findings of the perceived development needs of newly appointed senior school leaders in the Western Cape, South Africa, and suggests that school leaders occupy a unique and specialist role in education, which requires relevant and specific preparation to support effective leadership. The respondents of this study report a lack of contextualised training and support before and after their appointment in their new roles creating unique development needs. This paper, therefore, employs a mixed-method approach to gather data to understand the perceived needs of twenty newly appointed senior school leaders in the Western Cape, South Africa.

Development of a three-microneedle device for hypodermic drug delivery and clinical application.

Science.gov (United States)

Fukamizu, Hidekazu; Fujiwara, Masao; Kim, Taishi; Matsushita, Yuki; Tokura, Yoshiki

2012-08-01

There is a potential use for intradermic or hypodermic drug delivery in skin surgery or aesthetic surgery. Hypodermic delivery with the use of a noninvasive device can be a more useful, reliable, and effective administration route to obtain higher compliance. The authors developed a microneedle device composed of three fine needles (three-microneedle device). The tip of each needle was fabricated with a bevel angle to release a drug broadly into the tissue in a horizontal fashion. In this study, the authors investigated the usefulness of this newly developed three-microneedle device for hypodermic liquid injection, focusing on the optimum insertion depth and the diffusion of injected materials to the tissue. The authors also assessed the efficacy of and patient satisfaction with three-microneedle device injections of botulinum toxin type A for wrinkle reduction in patients with glabellar rhytides. The three-microneedle device yielded consistent results in hypodermal diffusion. On India ink diffusion test and ultrasonographic imaging, three-microneedle device injection showed a broad diffusion in horizontal extension, as compared with usual 31-gauge needle injection. The efficiency and satisfaction of the patients receiving botulinum toxin type A with the three-microneedle device were highly rated. Three-microneedle device delivery enables accurate and broad diffusion of injected substances, thus reducing the total dose and/or injection number of drugs. Therapeutic, IV.

Bibliometric study of radiation application on microdose useful for new drug development

International Nuclear Information System (INIS)

Komoda, Fumio; Suzuki, Akiko; Inoue, Tomio; Yanagisawa, Kazuaki

2009-01-01

In spite of the sharp increase in both private and government R and D fund, the number of newly approved medicines for market had decreased since the 1990s. This is attributed to a large extent to the bottleneck in the critical path arising from the great disparity between animal model in pre-clinical trial and human model in clinical trial. This bottleneck may be expected to be gotten rid of by change in paradigm of drug development based on microdosing, which is enabled by radiation-related imaging technology. However, this is impossible without being accompanied by interdisciplinary joint researches, in which clinical investigators belonging to medical schools or hospitals play the most decisive role. In this article, authors verify based on bibliometrics that Japan has not employed the opportunity for revitalizing drug research activities because Japanese researchers' attitude toward radiation technology may not be so positive in comparison with the United States (US), and because the role which clinical investigators play in the phase of preclinical trial is smaller in Japan than in the US. (author)

Lack of effect of intermittently administered sodium fusidate in patients with newly diagnosed type 1 diabetes mellitus: the FUSIDM trial

DEFF Research Database (Denmark)

Conget, I; Aguilera, E; Pellitero, S

2005-01-01

We evaluated in a double-blind study the effect of early treatment with the immunomodulatory drug fusidin in patients with newly diagnosed type 1 diabetes mellitus.......We evaluated in a double-blind study the effect of early treatment with the immunomodulatory drug fusidin in patients with newly diagnosed type 1 diabetes mellitus....

Success rates for product development strategies in new drug development.

Science.gov (United States)

Dahlin, E; Nelson, G M; Haynes, M; Sargeant, F

2016-04-01

While research has examined the likelihood that drugs progress across phases of clinical trials, no research to date has examined the types of product development strategies that are the most likely to be successful in clinical trials. This research seeks to identify the strategies that are most likely to reach the market-those generated using a novel product development strategy or strategies that combine a company's expertise with both drugs and indications, which we call combined experience strategies. We evaluate the success of product development strategies in the drug development process for a sample of 2562 clinical trials completed by 406 US pharmaceutical companies. To identify product development strategies, we coded each clinical trial according to whether it consisted of an indication or a drug that was new to the firm. Accordingly, a clinical trial that consists of both an indication and a drug that were both new to the firm represents a novel product development strategy; indication experience is a product development strategy that consists of an indication that a firm had tested previously in a clinical trial, but with a drug that was new to the firm; drug experience is a product development strategy that consists of a drug that the firm had prior experience testing in clinical trials, but with an indication that was new to the firm; combined experience consists of both a drug and an indication that the firm had experience testing in clinical trials. Success rates for product development strategies across clinical phases were calculated for the clinical trials in our sample. Combined experience strategies had the highest success rate. More than three and a half percent (0·036) of the trials that combined experience with drugs and indications eventually reached the market. The next most successful strategy is drug experience (0·025) with novel strategies trailing closely (0·024). Indication experience strategies are the least successful (0·008

Validating self-reported mobile phone use in adults using a newly developed smartphone application

NARCIS (Netherlands)

Goedhart, Geertje; Kromhout, Hans; Wiart, Joe; Vermeulen, Roel

2015-01-01

OBJECTIVE: Interpretation of epidemiological studies on health effects from mobile phone use is hindered by uncertainties in the exposure assessment. We used a newly developed smartphone application (app) to validate self-reported mobile phone use and behaviour among adults. METHODS: 107

Micro-computed tomography newly developed for in vivo small animal imaging

International Nuclear Information System (INIS)

Arai, Yoshinori; Ninomiya, Tadashi; Kato, Takafumi; Masuda, Yuji

2005-01-01

The aim of this paper is to report a newly developed micro-computed tomography system for in vivo use. The system was composed of a micro-focus X-ray tube and an image intensifier (I.I.), both of which rotated around the object stage. A guinea pig and a rat were examined. The anesthetized animal was set on the secure object stage. Images of the head of the guinea pig and the tibia knee joint of the rat were taken. In addition, an image of the rat's tail was taken. The reconstruction and the image viewing were carried out using I-View software. The voxel matrix was 512 x 512 x 384. The voxel sizes ranged from 10 x 10 x 10 μm to 100 x 100 x 100 μm. The exposure time was 17 s, and the reconstruction time was 150 s. The head of the guinea pig and the tibia/knee joint of the rat were observed clearly under 100-μm and 30μm voxels, respectively. The trabecular bone of the tail was also observed clearly under a 10 μm voxel. The newly developed micro-computed tomography system makes it possible to obtain images of anesthetized animals set on a secure object stage. Clear bone images of the small animals could be obtained within a short time. (author)

Assessing College Students' Perceptions of a Case Teacher's Pedagogical Content Knowledge Using a Newly Developed Instrument

Science.gov (United States)

Jang, Syh-Jong

2011-01-01

Ongoing professional development for college teachers has been much emphasized. However, previous research on learning environments has seldom addressed college students' perceptions of teachers' PCK. This study aimed to evaluate college students' perceptions of a physics teacher's PCK development using a newly developed instrument and workshop…

Towards a sustainable system of drug development

NARCIS (Netherlands)

Moors, Ellen H.M.; Cohen, Adam F.; Schellekens, Huub

2014-01-01

Drug development has become the exclusive activity of large pharmaceutical companies. However, the output of new drugs has been decreasing for the past decade and the prices of new drugs have risen steadily, leading to access problems for many patients. By analyzing the history of drug development

Applicability of newly developed 610MPa class heavy thickness high strength steel to boiler pressure vessel

Energy Technology Data Exchange (ETDEWEB)

Katayama, Norihiko; Kaihara, Shoichiro; Ishii, Jun [Ishikawajima-Harima Heavy Industries Corp., Yokohama (Japan); Kajigaya, Ichiro [Ishikawajima-Harima Heavy Industries Corp., Tokyo (Japan); Totsuka, Takehiro; Miyazaki, Takashi [Ishikawajima-Harima Heavy Industries Corp., Aioi (Japan)

1995-11-01

Construction of a 350 MW Class PFBC (Pressurized Fluidized Bed Combustion) boiler plant is under planning in Japan. Design temperature and pressure of the vessel are maximum 350 C and 1.69 MPa, respectively. As the plate thickness of the vessel exceeds over 100 mm, high strength steel plate of good weldability and less susceptible to reheat cracking was required and developed. The steel was aimed to satisfy the tensile strength over 610 MPa at 350 C after postweld heat treatment (PWHT), with good notch toughness. The authors investigated the welding performances of the newly developed steel by using 150 mm-thick plate welded by pulsed-MAG and SAW methods. It was confirmed that the newly developed steel and its welds possess sufficient strength and toughness after PWHT, and applicable to the actual pressure vessel.

Fundamental Characteristics of the Newly Developed ATA™ Membrane Dialyzer.

Science.gov (United States)

Sunohara, Takashi; Masuda, Toshiaki

2017-01-01

Dialysis membranes are often made from synthetic polymers, such as polysulfone. However, membranes made from cellulose triacetate have superior biocompatibility and have been used since the 1980s. On-line hemodiafiltration treatment accompanied by massive fluid replacement is increasingly being used in Europe and Japan, but cellulose triacetate is not suitable for this treatment. Our newly developed asymmetric triacetate membrane, the ATA™ membrane, substantially improved the filtration properties and blood compatibility because of the asymmetric structure and smooth surface of this cellulose acetate membrane. Key Message: The ATA membrane maintains its high permeability even after massive filtration and shows less temporal variation in its permeation performance, lower protein adsorption, and superior biocompatibility compared with conventional membranes. © 2017 S. Karger AG, Basel.

Emory University: MEDICI (Mining Essentiality Data to Identify Critical Interactions) for Cancer Drug Target Discovery and Development | Office of Cancer Genomics

Science.gov (United States)

The CTD2 Center at Emory University has developed a computational methodology to combine high-throughput knockdown data with known protein network topologies to infer the importance of protein-protein interactions (PPIs) for the survival of cancer cells.  Applying these data to the Achilles shRNA results, the CCLE cell line characterizations, and known and newly identified PPIs provides novel insights for potential new drug targets for cancer therapies and identifies important PPI hubs.

Fixed-dose combinations of drugs versus single-drug formulations for treating pulmonary tuberculosis

Science.gov (United States)

Gallardo, Carmen R; Rigau Comas, David; Valderrama Rodríguez, Angélica; Roqué i Figuls, Marta; Parker, Lucy Anne; Caylà, Joan; Bonfill Cosp, Xavier

2016-01-01

meta-analysis. We assessed the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Main results We included 13 randomized controlled trials (RCTs) in the review, which enrolled 5824 participants. Trials were published between 1987 and 2015 and included participants in treatment with newly diagnosed pulmonary TB in countries with high TB prevalence. Only two trials reported the HIV status of included participants. Overall there is little or no difference detected between FDCs and single-drug formulations for most outcomes reported. We did not detect a difference in treatment failure between FDCs compared with single-drug formulations (RR 1.28, 95% CI 0.82 to 2.00; 3606 participants, seven trials, moderate quality evidence). Relapse may be more frequent in people treated with FDCs compared to single-drug formulations, although the confidence interval (CI) includes no difference (RR 1.28, 95% CI 1.00 to 1.64; 3621 participants, 10 trials, low quality evidence). We did not detect any difference in death between fixed-dose and single-drug formulation groups (RR 0.96, 95% CI 0.67 to 1.39; 4800 participants, 11 trials, moderate quality evidence). When we compared FDCs with single-drug formulations we found little or no difference for sputum smear or culture conversion at the end of treatment (RR 0.99, 95% CI 0.96 to 1.02; 2319 participants, seven trials, high quality evidence), for serious adverse events (RR 1.45, 95% CI 0.90 to 2.33; 3388 participants, six trials, moderate quality evidence), and for adverse events that led to discontinuation of therapy (RR 0.96, 95% CI 0.56 to 1.66; 5530 participants, 13 trials, low quality evidence). We conducted a sensitivity analysis excluding studies at high risk of bias and this did not alter the review findings. Authors' conclusions Fixed-dose combinations and single-drug formulations probably have similar effects for treating people with newly diagnosed pulmonary TB. PLAIN

75 FR 32482 - Investigational New Drug Applications; Co-development of Investigational Drugs

Science.gov (United States)

2010-06-08

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2010-N-0247] Investigational New Drug Applications; Co-development of Investigational Drugs AGENCY: Food and Drug Administration, HHS. ACTION: Notice; establishment of docket; request for comments. SUMMARY: The Food and Drug...

Mechanistic models enable the rational use of in vitro drug-target binding kinetics for better drug effects in patients.

Science.gov (United States)

de Witte, Wilhelmus E A; Wong, Yin Cheong; Nederpelt, Indira; Heitman, Laura H; Danhof, Meindert; van der Graaf, Piet H; Gilissen, Ron A H J; de Lange, Elizabeth C M

2016-01-01

Drug-target binding kinetics are major determinants of the time course of drug action for several drugs, as clearly described for the irreversible binders omeprazole and aspirin. This supports the increasing interest to incorporate newly developed high-throughput assays for drug-target binding kinetics in drug discovery. A meaningful application of in vitro drug-target binding kinetics in drug discovery requires insight into the relation between in vivo drug effect and in vitro measured drug-target binding kinetics. In this review, the authors discuss both the relation between in vitro and in vivo measured binding kinetics and the relation between in vivo binding kinetics, target occupancy and effect profiles. More scientific evidence is required for the rational selection and development of drug-candidates on the basis of in vitro estimates of drug-target binding kinetics. To elucidate the value of in vitro binding kinetics measurements, it is necessary to obtain information on system-specific properties which influence the kinetics of target occupancy and drug effect. Mathematical integration of this information enables the identification of drug-specific properties which lead to optimal target occupancy and drug effect in patients.

Use of SPring-8 in drug development

International Nuclear Information System (INIS)

Nishijima, Kazumi

2006-01-01

Protein structure analysis consortium was established by 21 drug companies and has analyzed protein structures using the beam line BL32B2 of SPring-8 since September in 2002. Outline of the protein structure analysis consortium, contribution of SPring-8 to drug development, and the present status and future of use of SPring-8 are stated. For examples of structure analysis, the human nuclear enzyme (PARP-1) fragment complex crystal structure, human ISG20, human dipeptidine peptidase IV, human cMDH, chromatin binding human nuclear enzyme complex, change of structure of each step of tyrosine activation of bacteria tyrosine tRNA synthetase are described. Contribution of analysis of protein structure and functions to drug development, development process of new drug, drug screening using compounds database on the basis of the three dimensional structure of receptor active site, genome drug development, and the effects of a target drug on the market are explained. (S.Y.)

Pharmacogenomics to Revive Drug Development in Cardiovascular Disease.

Science.gov (United States)

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.

The discovery of drug-induced illness.

Science.gov (United States)

Jick, H

1977-03-03

The increased use of drugs (and the concurrent increased risks of drug-induced illness) require definition of relevant research areas and strategy. For established marketed drugs, research needs depend on the magnitudes of risk of an illness from a drug and the base-line risk. With the drug risk high and the base-line risk low, the problem surfaces in premarketing studies or through the epidemic that develops after marketing. If the drug adds slightly to a high base-line risk, the effect is undetectable. When both risks are low, adverse effects can be discovered by chance, but systematic case-referent studies can speed discovery. If both risks are high, clinical trials and nonexperimental studies may be used. With both risks intermediate, systematic evaluations, especially case-referent studies are needed. Newly marketed drugs should be routinely evaluated through compulsory registration and follow-up study of the earliest users.

Obesity and Pediatric Drug Development.

Science.gov (United States)

Vaughns, Janelle D; Conklin, Laurie S; Long, Ying; Zheng, Panli; Faruque, Fahim; Green, Dionna J; van den Anker, John N; Burckart, Gilbert J

2018-05-01

There is a lack of dosing guidelines for use in obese children. Moreover, the impact of obesity on drug safety and clinical outcomes is poorly defined. The paucity of information needed for the safe and effective use of drugs in obese patients remains a problem, even after drug approval. To assess the current incorporation of obesity as a covariate in pediatric drug development, the pediatric medical and clinical pharmacology reviews under the Food and Drug Administration (FDA) Amendments Act of 2007 and the FDA Safety and Innovation Act (FDASIA) of 2012 were reviewed for obesity studies. FDA labels were also reviewed for statements addressing obesity in pediatric patients. Forty-five drugs studied in pediatric patients under the FDA Amendments Act were found to have statements and key words in the medical and clinical pharmacology reviews and labels related to obesity. Forty-four products were identified similarly with pediatric studies under FDASIA. Of the 89 product labels identified, none provided dosing information related to obesity. The effect of body mass index on drug pharmacokinetics was mentioned in only 4 labels. We conclude that there is little information presently available to provide guidance related to dosing in obese pediatric patients. Moving forward, regulators, clinicians, and the pharmaceutical industry should consider situations in drug development in which the inclusion of obese patients in pediatric trials is necessary to facilitate the safe and effective use of new drug products in the obese pediatric population. © 2018, The American College of Clinical Pharmacology.

Imaging biomarkers as surrogate endpoints for drug development

International Nuclear Information System (INIS)

Richter, Wolf S.

2006-01-01

The employment of biomarkers (including imaging biomarkers, especially PET) in drug development has gained increasing attention during recent years. This has been partly stimulated by the hope that the integration of biomarkers into drug development programmes may be a means to increase the efficiency and effectiveness of the drug development process by early identification of promising drug candidates - thereby counteracting the rising costs of drug development. More importantly, however, the interest in biomarkers for drug development is the logical consequence of recent advances in biosciences and medicine which are leading to target-specific treatments in the framework of ''personalised medicine''. A considerable proportion of target-specific drugs will show effects in subgroups of patients only. Biomarkers are a means to identify potential responders, or patient subgroups at risk for specific side-effects. Biomarkers are used in early drug development in the context of translational medicine to gain information about the drug's potential in different patient groups and disease states. The information obtained at this stage is mainly important for designing subsequent clinical trials and to identify promising drug candidates. Biomarkers in later phases of clinical development may - if properly validated - serve as surrogate endpoints for clinical outcomes. Regulatory agencies in the EU and the USA have facilitated the use of biomarkers early in the development process. The validation of biomarkers as surrogate endpoints is part of FDA's ''critical path initiative''. (orig.)

PHL10/460: Cancerfacts.com - Vertical Portal with Newly Developed Health Profiler

OpenAIRE

Lenz, C; Brucksch, M

1999-01-01

Introduction Unlike general health portals such as WebMD and Drkoop.com that cover everything from the flu to heart disease, Silicon Valley-based cancerfacts.com is a so-called vertical portal. It covers only one small vertical niche of health care: cancer, and in particular, prostate cancer. As a value-added proprietary technology, the company offers its newly developed profile engine to health information retrievers. Methods Users are enabled to insert their specific medical information - r...

Drug discovery and developments in developing countries ...

African Journals Online (AJOL)

the major burden being in developing countries. Many of ... The driving force for drug discovery and development by pharmaceutical firms ... world and particularly in the third world countries ..... GFHR (2000) Global Forum for Health Research:.

The Prevalence of Transmitted Drug Resistance in Newly Diagnosed HIV-Infected Individuals in Croatia: The Role of Transmission Clusters of Men Who Have Sex with Men Carrying the T215S Surveillance Drug Resistance Mutation

Science.gov (United States)

Grgic, Ivana; Lunar, Maja M.; Poljak, Mario; Vince, Adriana; Vrakela, Ivana Baca; Planinic, Ana; Seme, Katja; Begovac, Josip

2013-01-01

Abstract The aim of this study was to determine the prevalence of transmitted drug resistance (TDR) in newly diagnosed and treatment-naive HIV-infected patients from Croatia and evaluate a possible contribution of transmission clusters to the spread of resistant virus. The study enrolled treatment-naive HIV-infected patients that entered clinical care at the Croatian Reference Center for HIV/AIDS between 2006 and 2008. The protease gene and a part of the reverse transcriptase gene of the HIV-1 genome were sequenced by using the Trugene HIV-1 Genotyping System. The prevalence of transmitted drug resistance was analyzed by using the surveillance drug resistance mutations (SDRM) list recommended by the WHO in 2009. We report findings for 118 of 180 eligible patients (65.6% coverage). SDRM were detected in 26 of 118 patients (22.0%) who were infected with subtype B and belonged mostly to the men having sex with men (MSM). The majority of patients with primary resistance carried SDRM associated with resistance to nucleoside analogues reverse transcriptase inhibitors (NRTIs, 23 of 118 patients, 19.5%). The most frequently found NRTI SDRM was T215S (17 of 118 patients, 14.4%). SDRM associated with resistance to nonnucleoside reverse transcriptase inhibitors were detected in three (2.5%) patients and primary resistance to protease inhibitors was not detected. Non-B subtypes were detected in 13/118 patients (11%). A total of 12 transmission pairs and eight distinct transmission clusters were identified with the largest cluster harboring sequences from 19 patients; among them all but two were carrying the T215S mutation. This study showed a high prevalence of TDR in newly diagnosed MSM from Croatia and is an important contribution concerning the relationship between local transmission clusters and the spread of resistant virus. PMID:22906365

Accelerating Precision Drug Development and Drug Repurposing by Leveraging Human Genetics.

Science.gov (United States)

Pulley, Jill M; 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

2017-04-01

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.

Pharmacometrics in early clinical drug development

NARCIS (Netherlands)

Keizer, R.J.

2010-01-01

Pharmacometrics, the science of quantitative clinical pharmacology, has been recognized as one of the main research fields able to improve efficiency in drug development, and to reduce attrition rates on the route from drug discovery to approval. This field of drug research, which builds heavily on

Newly developed semi-empirical formulas for (p, α) at 17.9 MeV and ...

Indian Academy of Sciences (India)

Home; Journals; Pramana – Journal of Physics; Volume 74; Issue 6. Newly developed semi-empirical formulas for (, ) at 17.9 MeV and (, ) at 22.3 MeV reaction cross-sections. Eyyup Tel Abdullah Aydin E Gamze Aydin Abdullah Kaplan Ömer Yavaş İskender A Reyhancan. Research Articles Volume 74 Issue 6 June ...

[New drug development by innovative drug administration--"change" in pharmaceutical field].

Science.gov (United States)

Nagai, T

1997-11-01

New drug development can be made by providing products of higher "selectivity for the drug" for medical treatment. There are two ways for the approach to get higher "selectivity of drug": 1) discovery of new compounds with high selectivity of drug; 2) innovation of new drug administration, that is new formulation and/or method with high selectivity of drug by integration and harmonization of various hard/soft technologies. An extensive increase of biological information and advancement of surrounding science and technology may modify the situation as the latter overcomes the former in the 21 century. As the science and technology in the 21 century is said to be formed on "3H", that is, 1. hybrid; 2. hi-quality; 3. husbandry, the new drug development by innovative drug administration is exactly based on the science and technology of 3H. Its characteristic points are interdisciplinary/interfusion, international, of philosophy/ethics, and systems of hard/hard/heart. From these points of view, not only the advance of unit technology but also a revolution in thinking way should be "must" subjects. To organize this type of research well, a total research activity such as ROR (research on research) might take an important and efficient role. Here the key words are the "Optimization technology" and "Change in Pharmaceutical Fields." As some examples of new drug innovation, our trials on several topical mucosal adhesive dosage forms and parenteral administration of peptide drugs such as insulin and erythropoietin will be described.

The newly developed Toyota plug-in hybrid system

Energy Technology Data Exchange (ETDEWEB)

Takaoka, Toshifumi; Ichinose, Hiroki [Toyota Motor Corporation (Japan)

2010-07-01

Toyota has been introducing several hybrid vehicles (HV) as a countermeasure to the automobile's concerns, like CO2 reduction, energy security, and emission reduction in urban areas. A next step towards an even more effective solution for these concerns is a plug-in hybrid vehicle (PHV). This vehicle combines the advantages of electric vehicles (EV), which use clean electric energy, and HV, with it's high environmental potential and user- friendliness comparable to conventional vehicles, such as a long cruising range. This paper describes a newly developed plug-in hybrid system and its vehicle performance. This system uses a Li-ion battery with high energy density and has an affordable EV range without sacrificing cabin space. The vehicle achieves a CO2 emission of 59g/km and meets the most stringent emission regulations in the world. The new PHV is a forerunner of the large-scale mass production PHV two years later. PHVs have the potential to become popular as a realistic solution towards sustainable mobility by renewable electricity usage in the future. (orig.)

Drug resistance in Mexico: results from the National Survey on Drug-Resistant Tuberculosis.

Science.gov (United States)

Bojorquez-Chapela, I; Bäcker, C E; Orejel, I; López, A; Díaz-Quiñonez, A; Hernández-Serrato, M I; Balandrano, S; Romero, M; Téllez-Rojo Solís, M M; Castellanos, M; Alpuche, C; Hernández-Ávila, M; López-Gatell, H

2013-04-01

To present estimations obtained from a population-level survey conducted in Mexico of prevalence rates of mono-, poly- and multidrug-resistant strains among newly diagnosed cases of pulmonary tuberculosis (TB), as well as the main factors associated with multidrug resistance (combined resistance to isoniazid and rifampicin). Study data came from the National Survey on TB Drug Resistance (ENTB-2008), a nationally representative survey conducted during 2008-2009 in nine states with a stratified cluster sampling design. Samples were obtained for all newly diagnosed cases of pulmonary TB in selected sites. Drug susceptibility testing (DST) was performed for anti-tuberculosis drugs. DST results were obtained for 75% of the cases. Of these, 82.2% (95%CI 79.5-84.7) were susceptible to all drugs. The prevalence of multidrug-resistant TB (MDR-TB) was estimated at 2.8% (95%CI 1.9-4.0). MDR-TB was associated with previous treatment (OR 3.3, 95%CI 1.1-9.4). The prevalence of drug resistance is relatively low in Mexico. ENTB-2008 can be used as a baseline for future follow-up of drug resistance.

[Chapter 2. Transitions in drug-discovery technology and drug-development in Japan (1980-2010)].

Science.gov (United States)

Sakakibara, Noriko; Yoshioka, Ryuzo; Matsumoto, Kazuo

2014-01-01

In 1970s, the material patent system was introduced in Japan. Since then, many Japanese pharmaceutical companies have endeavored to create original in-house products. From 1980s, many of the innovative products were small molecular drugs and were developed using powerful medicinal-chemical technologies. Among them were antibiotics and effective remedies for the digestive organs and circulatory organs. During this period, Japanese companies were able to launch some blockbuster drugs. At the same time, the pharmaceutical market, which had grown rapidly for two decades, was beginning to level off. From the late 1990s, drug development was slowing down due to the lack of expertise in biotechnology such as genetic engineering. In response to the circumstances, the research and development on biotechnology-based drugs such as antibody drugs have become more dynamic and popular at companies than small molecule drugs. In this paper, the writers reviewed in detail the transitions in drug discovery and development between 1980 and 2010.

How Schools Can Promote Healthy Development for Newly Arrived Immigrant and Refugee Adolescents: Research Priorities

Science.gov (United States)

McNeely, Clea A.; Morland, Lyn; Doty, S. Benjamin; Meschke, Laurie L.; Awad, Summer; Husain, Altaf; Nashwan, Ayat

2017-01-01

Background: The US education system must find creative and effective ways to foster the healthy development of the approximately 2 million newly arrived immigrant and refugee adolescents, many of whom contend with language barriers, limited prior education, trauma, and discrimination. We identify research priorities for promoting the school…

A computer literacy scale for newly enrolled nursing college students: development and validation.

Science.gov (United States)

Lin, Tung-Cheng

2011-12-01

Increasing application and use of information systems and mobile technologies in the healthcare industry require increasing nurse competency in computer use. Computer literacy is defined as basic computer skills, whereas computer competency is defined as the computer skills necessary to accomplish job tasks. Inadequate attention has been paid to computer literacy and computer competency scale validity. This study developed a computer literacy scale with good reliability and validity and investigated the current computer literacy of newly enrolled students to develop computer courses appropriate to students' skill levels and needs. This study referenced Hinkin's process to develop a computer literacy scale. Participants were newly enrolled first-year undergraduate students, with nursing or nursing-related backgrounds, currently attending a course entitled Information Literacy and Internet Applications. Researchers examined reliability and validity using confirmatory factor analysis. The final version of the developed computer literacy scale included six constructs (software, hardware, multimedia, networks, information ethics, and information security) and 22 measurement items. Confirmatory factor analysis showed that the scale possessed good content validity, reliability, convergent validity, and discriminant validity. This study also found that participants earned the highest scores for the network domain and the lowest score for the hardware domain. With increasing use of information technology applications, courses related to hardware topic should be increased to improve nurse problem-solving abilities. This study recommends that emphases on word processing and network-related topics may be reduced in favor of an increased emphasis on database, statistical software, hospital information systems, and information ethics.

Newly developed chitosan-silver hybrid nanoparticles: biosafety and apoptosis induction in HepG2 cells

International Nuclear Information System (INIS)

El-Sherbiny, Ibrahim M.; Salih, Ehab; Yassin, Abdelrahman M.; Hafez, Elsayed E.

2016-01-01

The present study reports the biosafety assessment, the exact molecular effects, and apoptosis induction of newly developed chitosan-silver hybrid nanoparticles (Cs–Ag NPs) in HepG2 cells. The investigated hybrid NPs were green synthesized using Cs/grape leaves aqueous extract (Cs/GLE) or Cs/GLE NPs as reducing and stabilizing agents. The successful formation of Cs/GLE NPs and Cs–Ag hybrid NPs has been confirmed by UV–Vis spectrophotometry, FTIR spectroscopy, XRD, and HRTEM. From the TEM analysis, the prepared Cs/GLE NPs are uniform and spherical with an average size of 150 nm, and the AgNPs (5–10 nm) were formed mainly on their surface. The UV–Vis spectra of Cs–Ag NPs showed a surface plasmon resonance (SPR) peak at about 450 nm confirming their formation. The synthesized Cs–Ag NPs were found to be crystalline as shown by XRD patterns with fcc phase oriented along the (111), (200), (220), and (311) planes. The cytotoxicity patterns, the antiproliferative activities, and the possible mechanisms of anticancer activity at molecular level of the newly developed Cs–Ag hybrid NPs were investigated. Cytotoxicity patterns of all the preparations demonstrated that the nontoxic treatment concentrations are ranged from 0.39 to 50 %, and many of the newly prepared Cs–Ag hybrid NPs showed high anticancer activities against HpG2 cells, and induced cellular apoptosis by downregulating BCL2 gene and upregulating P53.Graphical Abstract

Newly developed chitosan-silver hybrid nanoparticles: biosafety and apoptosis induction in HepG2 cells

Energy Technology Data Exchange (ETDEWEB)

El-Sherbiny, Ibrahim M., E-mail: ielsherbiny@Zewailcity.edu.eg; Salih, Ehab [Zewail City of Science and Technology, Center for Materials Science (Egypt); Yassin, Abdelrahman M. [Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technology Applications, Biopharmaceutical Product Research Department (Egypt); Hafez, Elsayed E. [City of Scientific Research and Technology Applications, Plant Protection and Biomolecular Diagnosis Department (Egypt)

2016-07-15

The present study reports the biosafety assessment, the exact molecular effects, and apoptosis induction of newly developed chitosan-silver hybrid nanoparticles (Cs–Ag NPs) in HepG2 cells. The investigated hybrid NPs were green synthesized using Cs/grape leaves aqueous extract (Cs/GLE) or Cs/GLE NPs as reducing and stabilizing agents. The successful formation of Cs/GLE NPs and Cs–Ag hybrid NPs has been confirmed by UV–Vis spectrophotometry, FTIR spectroscopy, XRD, and HRTEM. From the TEM analysis, the prepared Cs/GLE NPs are uniform and spherical with an average size of 150 nm, and the AgNPs (5–10 nm) were formed mainly on their surface. The UV–Vis spectra of Cs–Ag NPs showed a surface plasmon resonance (SPR) peak at about 450 nm confirming their formation. The synthesized Cs–Ag NPs were found to be crystalline as shown by XRD patterns with fcc phase oriented along the (111), (200), (220), and (311) planes. The cytotoxicity patterns, the antiproliferative activities, and the possible mechanisms of anticancer activity at molecular level of the newly developed Cs–Ag hybrid NPs were investigated. Cytotoxicity patterns of all the preparations demonstrated that the nontoxic treatment concentrations are ranged from 0.39 to 50 %, and many of the newly prepared Cs–Ag hybrid NPs showed high anticancer activities against HpG2 cells, and induced cellular apoptosis by downregulating BCL2 gene and upregulating P53.Graphical Abstract.

Antimalarial Drug: From its Development to Deface.

Science.gov (United States)

Barik, Tapan Kumar

2015-01-01

Wiping out malaria is now the global concern as about three billion people are at risk of malaria infection globally. Despite of extensive research in the field of vaccine development for malaria, till now, no effective vaccine is available for use and hence only antimalarial drugs remain our best hope for both treatment and prevention of malaria. However, emergence and spread of drug resistance has been a major obstacle for the success of malaria elimination globally. This review will summarize the information related to antimalarial drugs, drug development strategies, drug delivery through nanoparticles, few current issues like adverse side effects of most antimalarial drugs, non availability of drugs in the market and use of fake/poor quality drugs that are hurdles to malaria control. As we don't have any other option in the present scenario, we have to take care of the existing tools and make them available to almost all malaria affected area.

Molecular science for drug development and biomedicine.

Science.gov (United States)

Zhong, Wei-Zhu; Zhou, Shu-Feng

2014-11-04

With the avalanche of biological sequences generated in the postgenomic age, molecular science is facing an unprecedented challenge, i.e., how to timely utilize the huge amount of data to benefit human beings. Stimulated by such a challenge, a rapid development has taken place in molecular science, particularly in the areas associated with drug development and biomedicine, both experimental and theoretical. The current thematic issue was launched with the focus on the topic of "Molecular Science for Drug Development and Biomedicine", in hopes to further stimulate more useful techniques and findings from various approaches of molecular science for drug development and biomedicine.[...].

Biomarker-guided repurposing of chemotherapeutic drugs for cancer therapy: a novel strategy in drug development

Directory of Open Access Journals (Sweden)

Jan eStenvang

2013-12-01

Full Text Available Cancer is a leading cause of mortality worldwide and matters are only set to worsen as its incidence continues to rise. Traditional approaches to combat cancer include improved prevention, early diagnosis, optimized surgery, development of novel drugs and honing regimens of existing anti-cancer drugs. Although discovery and development of novel and effective anti-cancer drugs is a major research area, it is well known that oncology drug development is a lengthy process, extremely costly and with high attrition rates. Furthermore, those drugs that do make it through the drug development mill are often quite expensive, laden with severe side-effects and, unfortunately, to date, have only demonstrated minimal increases in overall survival. Therefore, a strong interest has emerged to identify approved non-cancer drugs that possess anti-cancer activity, thus shortcutting the development process. This research strategy is commonly known as drug repurposing or drug repositioning and provides a faster path to the clinics. We have developed and implemented a modification of the standard drug repurposing strategy that we review here; rather than investigating target-promiscuous non-cancer drugs for possible anti-cancer activity, we focus on the discovery of novel cancer indications for already approved chemotherapeutic anti-cancer drugs. Clinical implementation of this strategy is normally commenced at clinical phase II trials and includes pre-treated patients. As the response rates to any non-standard chemotherapeutic drug will be relatively low in such a patient cohort it is a pre-requisite that such testing is based on predictive biomarkers. This review describes our strategy of biomarker-guided repurposing of chemotherapeutic drugs for cancer therapy, taking the repurposing of topoisomerase I inhibitors and topoisomerase I as a potential predictive biomarker as case in point.

Development and Optimization of controlled drug release ...

African Journals Online (AJOL)

The aim of this study is to develop and optimize an osmotically controlled drug delivery system of diclofenac sodium. Osmotically controlled oral drug delivery systems utilize osmotic pressure for controlled delivery of active drugs. Drug delivery from these systems, to a large extent, is independent of the physiological factors ...

Developing artemisinin based drug combinations for the treatment of drug resistant falciparum malaria: A review

Directory of Open Access Journals (Sweden)

Olliaro P

2004-01-01

Full Text Available The emergence and spread of drug resistant malaria represents a considerable challenge to controlling malaria. To date, malaria control has relied heavily on a comparatively small number of chemically related drugs, belonging to either the quinoline or the antifolate groups. Only recently have the artemisinin derivatives been used but mostly in south east Asia. Experience has shown that resistance eventually curtails the life-span of antimalarial drugs. Controlling resistance is key to ensuring that the investment put into developing new antimalarial drugs is not wasted. Current efforts focus on research into new compounds with novel mechanisms of action, and on measures to prevent or delay resistance when drugs are introduced. Drug discovery and development are long, risky and costly ventures. Antimalarial drug development has traditionally been slow but now various private and public institutions are at work to discover and develop new compounds. Today, the antimalarial development pipeline is looking reasonably healthy. Most development relies on the quinoline, antifolate and artemisinin compounds. There is a pressing need to have effective, easy to use, affordable drugs that will last a long time. Drug combinations that have independent modes of action are seen as a way of enhancing efficacy while ensuring mutual protection against resistance. Most research work has focused on the use of artesunate combined with currently used standard drugs, namely, mefloquine, amodiaquine, sulfadoxine/pyrimethamine, and chloroquine. There is clear evidence that combinations improve efficacy without increasing toxicity. However, the absolute cure rates that are achieved by combinations vary widely and depend on the level of resistance of the standard drug. From these studies, further work is underway to produce fixed dose combinations that will be packaged in blister packs. This review will summarise current antimalarial drug developments and outline recent

The worldwide trend of using botanical drugs and strategies for developing global drugs.

Science.gov (United States)

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].

A newly development RIA for thyroid hormone autoantibodies (THAAb)

International Nuclear Information System (INIS)

Li Fengying; Gu Liqiong; Chen Xiayin; Jin Yan; Chen Shuxian; Zhang Qun; Qiu Hongxia; Yang Jingren; Zhao Yongju; Chen Mingdao

2004-01-01

Objective: To report a newly developed RIA for THAAb from this laboratory. Methods: The tested serum samples were cultured with labelled thyroid hormone analogous ( 125 I T 3 , 125 I T 4 ) for 16 hours. Antigen-antibody complex was precipitated with anti-human IgG (immune precipitation method) and radio-activity determined. Results: The mean positive rate of THAAb in healthy euthyroid controls (n=186) was only 1.07%. The mean positive rate in patients with thyroid disorders was 14.4% (mean rate 13.5% in hyperthyroid subjects, n=118 and mean rate 15.2% in hypothyroid subjects, n=72). The serum THAAb titer could be markedly lowered after adding non-labelled thyroid hormones (P 3 and FT 4 would be significantly lowered (P 3 , FT 4 levels. In patients with positive THAAb (about 14.4% in patients with all thyroid disorders), the FT 3 , FT 4 levels were best determined after PEG precipitation. (authors)

Nuclear imaging drug development tools

International Nuclear Information System (INIS)

Buchanan, L.; Jurek, P.; Redshaw, R.

2007-01-01

This article describes the development of nuclear imaging as an enabling technology in the pharmaceutical industry. Molecular imaging is maturing into an important tool with expanding applications from validating that a drug reaches the intended target through to market launch of a new drug. Molecular imaging includes anatomical imaging of organs or tissues, computerized tomography (CT), magnetic resonance imaging (MRI) and ultrasound.

Muscle Attenuation Is Associated With Newly Developed Hypertension in Men of African Ancestry.

Science.gov (United States)

Zhao, Qian; Zmuda, Joseph M; Kuipers, Allison L; Bunker, Clareann H; Patrick, Alan L; Youk, Ada O; Miljkovic, Iva

2017-05-01

Increased ectopic adipose tissue infiltration in skeletal muscle is associated with insulin resistance and diabetes mellitus. We evaluated whether change in skeletal muscle adiposity predicts subsequent development of hypertension in men of African ancestry, a population sample understudied in previous studies. In the Tobago Health Study, a prospective longitudinal study among men of African ancestry (age range 40-91 years), calf intermuscular adipose tissue, and skeletal muscle attenuation were measured with computed tomography. Hypertension was defined as a systolic blood pressure ≥140 mm Hg, or a diastolic blood pressure ≥90 mm Hg, or receiving antihypertensive medications. Logistic regression was performed with adjustment for age, insulin resistance, baseline and 6-year change in body mass index, baseline and 6-year change in waist circumference, and other potential confounding factors. Among 746 normotensive men at baseline, 321 (43%) developed hypertension during the mean 6.2 years of follow-up. Decreased skeletal muscle attenuation was associated with newly developed hypertension after adjustment for baseline and 6-year change of body mass index (odds ratio [95% confidence interval] per SD, 1.3 [1.0-1.6]) or baseline and 6-year change of waist circumference (odds ratio [95% confidence interval] per SD, 1.3 [1.0-1.6]). No association was observed between increased intermuscular adipose tissue and hypertension. Our novel findings show that decreased muscle attenuation is associated with newly developed hypertension among men of African ancestry, independent of general and central adiposity and insulin resistance. Further studies are needed to adjust for inflammation, visceral and other ectopic adipose tissue depots, and to confirm our findings in other population samples. © 2017 American Heart Association, Inc.

Counterfeit drugs and medical devices in developing countries

Directory of Open Access Journals (Sweden)

Glass BD

2014-03-01

Full Text Available Beverley D GlassSchool of Pharmacy and Molecular Sciences, James Cook University, Townsville, QLD, AustraliaAbstract: The World Health Organization has reported that counterfeit medicines potentially make up more than 50% of the global drug market, with a significant proportion of these fake products being encountered in developing countries. This occurrence is attributed to a lack of effective regulation and a weak enforcement capacity existing in these countries, with an increase in this trade resulting from the growing size and sophistication of drug counterfeiters. In addition, due to both cost and lack of availability of medicines, consumers in developing countries are more likely to seek out these inexpensive options. The World Health Organization is mindful of the impact of counterfeit drugs on consumer confidence in health care systems, health professionals, the supply chain, and genuine suppliers of medicines and medical devices. Antibiotics, antituberculosis drugs, and antimalarial and antiretroviral drugs are frequently targeted, with reports of 60% of the anti-infective drugs in Asia and Africa containing active pharmaceutical ingredients outside their pharmacopoeial limits. This has obvious public health implications of increasing drug resistance and negating all the efforts that have already gone into the provision of medicines to treat these life threatening conditions in the developing world. This review, while focusing on counterfeit medicines and medical devices in developing countries, will present information on their impact and how these issues can be addressed by regulation and control of the supply chain using technology appropriate to the developing world. The complexity of the problem will also be highlighted in terms of the definition of counterfeit and substandard medicines, including gray pharmaceuticals. Although this issue presents as a global public health problem, outcomes in developing countries where counterfeit

Surrogacy in antiviral drug development

Science.gov (United States)

Shaunak, Sunil; Davies, Donald S

2002-01-01

The coming of age of molecular biology has resulted in an explosion in our understanding of the pathogenesis of virus related diseases. New pathogens have been identified and characterized as being responsible for old diseases. Empirical clinical evaluation of morbidity and mortality as outcome measures after a therapeutic intervention have started to give way to the use of an increasing number of surrogate markers. Using a combination of these markers, it is now possible to measure and monitor the pathogen as well as the host's response. Nowhere is this better exemplified in virology than in the field of AIDS. We have utilized the advances in pathogenesis and new antiretroviral drug development to: develop a new class of drugs which block the entry of HIV-1 into cells.develop a new approach for effectively delivering these drugs to those tissues in which most viral replication takes place. Over the last 10 years, our work has progressed from concept to clinical trial. Our laboratory based evaluation of the new molecules developed as well as our clinical evaluation of their safety and efficacy have had to respond and adapt to the rapid changes taking place in AIDS research. This paper discusses the problems encountered and the lessons learnt. PMID:12100230

Thymus function in drug-induced lupus.

Science.gov (United States)

Rubin, R L; Salomon, D R; Guerrero, R S

2001-01-01

Autoimmunity develops when a lupus-inducing drug is introduced into the thymus of normal mice, but the relevance of this model to the human disorder is unclear in part because it is widely assumed that the thymus is non-functional in the adult. We compared thymus function in 10 patients with symptomatic procainamide-induced lupus to that in 13 asymptomatic patients who only developed drug-induced autoantibodies. T cell output from the thymus was quantified using a competitive polymerase chain reaction that detects T cell receptor DNA excision circles in peripheral blood lymphocytes. Despite the advanced age of the patient population under study, newly generated T cells were detected in all subjects. Although there was no overall quantitative difference between the symptomatic and asymptomatic patients, we found a positive correlation between the level of T cell receptor excision circles in peripheral lymphocytes and serum IgG anti-chromatin antibody activity in patients with drug-induced lupus. The association between autoantibodies and nascent peripheral T cells supports the requirement for T cells in autoantibody production. Our observations are consistent with findings in mice in which autoreactive T cells derived from drug-induced abnormalities in T cell development in the thymus.

DEVELOPMENT AND REGISTRATION OF CHIRAL DRUGS

NARCIS (Netherlands)

WITTE, DT; ENSING, K; FRANKE, JP; DEZEEUW, RA

1993-01-01

In this review we describe the impact of chirality on drug development and registration in the United States, Japan and the European Community. Enantiomers may have differences in their pharmacological profiles, and, therefore, chiral drugs ask for special analytical and pharmacological attention

Development of cell-based quantitative evaluation method for cell cycle-arrest type cancer drugs for apoptosis by high precision surface plasmon resonance sensor

Science.gov (United States)

Ona, Toshihiro; Nishijima, Hiroshi; Kosaihira, Atsushi; Shibata, Junko

2008-04-01

In vitro rapid and quantitative cell-based assay is demanded to verify the efficacy prediction of cancer drugs since a cancer patient may have unconventional aspects of tumor development. Here, we show the rapid and non-label quantitative verifying method and instrumentation of apoptosis for cell cycle-arrest type cancer drugs (Roscovitine and D-allose) by reaction analysis of living liver cancer cells cultured on a sensor chip with a newly developed high precision (50 ndeg s -1 average fluctuation) surface plasmon resonance (SPR) sensor. The time-course cell reaction as the SPR angle change rate for 10 min from 30 min cell culture with a drug was significantly related to cell viability. By the simultaneous detection of differential SPR angle change and fluorescence by specific probes using the new instrument, the SPR angle was related to the nano-order potential decrease in inner mitochondrial membrane potential. The results obtained are universally valid for the cell cycle-arrest type cancer drugs, which mediate apoptosis through different cell-signaling pathways, by a liver cancer cell line of Hep G2 (P<0.001). This system towards the application to evaluate personal therapeutic potentials of drugs using cancer cells from patients in clinical use.

Isotope-labelled urea to test colon drug delivery devices in vivo : principles, calculations and interpretations

NARCIS (Netherlands)

Maurer, Marina; Schellekens, Reinout C. A.; Wutzke, Klaus D.; Stellaard, Frans

2013-01-01

This paper describes various methodological aspects that were encountered during the development of a system to monitor the in vivo behaviour of a newly developed colon delivery device that enables oral drug treatment of inflammatory bowel diseases. [C-13]urea was chosen as the marker substance.

When fragments link: a bibliometric perspective on the development of fragment-based drug discovery.

Science.gov (United States)

Romasanta, Angelo K S; van der Sijde, Peter; Hellsten, Iina; Hubbard, Roderick E; Keseru, Gyorgy M; van Muijlwijk-Koezen, Jacqueline; de Esch, Iwan J P

2018-05-05

Fragment-based drug discovery (FBDD) is a highly interdisciplinary field, rich in ideas integrated from pharmaceutical sciences, chemistry, biology, and physics, among others. To enrich our understanding of the development of the field, we used bibliometric techniques to analyze 3642 publications in FBDD, complementing accounts by key practitioners. Mapping its core papers, we found the transfer of knowledge from academia to industry. Co-authorship analysis showed that university-industry collaboration has grown over time. Moreover, we show how ideas from other scientific disciplines have been integrated into the FBDD paradigm. Keyword analysis showed that the field is organized into four interconnected practices: library design, fragment screening, computational methods, and optimization. This study highlights the importance of interactions among various individuals and institutions from diverse disciplines in newly emerging scientific fields. Copyright © 2018. Published by Elsevier Ltd.

Preclinical experimental models of drug metabolism and disposition in drug discovery and development

Directory of Open Access Journals (Sweden)

Donglu Zhang

2012-12-01

Full Text Available Drug discovery and development involve the utilization of in vitro and in vivo experimental models. Different models, ranging from test tube experiments to cell cultures, animals, healthy human subjects, and even small numbers of patients that are involved in clinical trials, are used at different stages of drug discovery and development for determination of efficacy and safety. The proper selection and applications of correct models, as well as appropriate data interpretation, are critically important in decision making and successful advancement of drug candidates. In this review, we discuss strategies in the applications of both in vitro and in vivo experimental models of drug metabolism and disposition.

Open source drug discovery--a new paradigm of collaborative research in tuberculosis drug development.

Science.gov (United States)

Bhardwaj, Anshu; Scaria, Vinod; Raghava, Gajendra Pal Singh; Lynn, Andrew Michael; Chandra, Nagasuma; Banerjee, Sulagna; Raghunandanan, Muthukurussi V; Pandey, Vikas; Taneja, Bhupesh; Yadav, Jyoti; Dash, Debasis; Bhattacharya, Jaijit; Misra, Amit; Kumar, Anil; Ramachandran, Srinivasan; Thomas, Zakir; Brahmachari, Samir K

2011-09-01

It is being realized that the traditional closed-door and market driven approaches for drug discovery may not be the best suited model for the diseases of the developing world such as tuberculosis and malaria, because most patients suffering from these diseases have poor paying capacity. To ensure that new drugs are created for patients suffering from these diseases, it is necessary to formulate an alternate paradigm of drug discovery process. The current model constrained by limitations for collaboration and for sharing of resources with confidentiality hampers the opportunities for bringing expertise from diverse fields. These limitations hinder the possibilities of lowering the cost of drug discovery. The Open Source Drug Discovery project initiated by Council of Scientific and Industrial Research, India has adopted an open source model to power wide participation across geographical borders. Open Source Drug Discovery emphasizes integrative science through collaboration, open-sharing, taking up multi-faceted approaches and accruing benefits from advances on different fronts of new drug discovery. Because the open source model is based on community participation, it has the potential to self-sustain continuous development by generating a storehouse of alternatives towards continued pursuit for new drug discovery. Since the inventions are community generated, the new chemical entities developed by Open Source Drug Discovery will be taken up for clinical trial in a non-exclusive manner by participation of multiple companies with majority funding from Open Source Drug Discovery. This will ensure availability of drugs through a lower cost community driven drug discovery process for diseases afflicting people with poor paying capacity. Hopefully what LINUX the World Wide Web have done for the information technology, Open Source Drug Discovery will do for drug discovery. Copyright © 2011 Elsevier Ltd. All rights reserved.

Prediction of resistance development against drug combinations by collateral responses to component drugs

DEFF Research Database (Denmark)

Munck, Christian; Gumpert, Heidi; Nilsson Wallin, Annika

2014-01-01

the genomes of all evolved E. coli lineages, we identified the mutational events that drive the differences in drug resistance levels and found that the degree of resistance development against drug combinations can be understood in terms of collateral sensitivity and resistance that occurred during...... adaptation to the component drugs. Then, using engineered E. coli strains, we confirmed that drug resistance mutations that imposed collateral sensitivity were suppressed in a drug pair growth environment. These results provide a framework for rationally selecting drug combinations that limit resistance......Resistance arises quickly during chemotherapeutic selection and is particularly problematic during long-term treatment regimens such as those for tuberculosis, HIV infections, or cancer. Although drug combination therapy reduces the evolution of drug resistance, drug pairs vary in their ability...

Drug development: from concept to marketing!

Science.gov (United States)

Tamimi, Nihad A M; Ellis, Peter

2009-01-01

Drug development is an expensive, long and high-risk business taking 10-15 years and is associated with a high attrition rate. It is driven by medical need, disease prevalence and the likelihood of success. Drug candidate selection is an iterative process between chemistry and biology, refining the molecular properties until a compound suitable for advancing to man is found. Typically, about one in a thousand synthesised compounds is ever selected for progression to the clinic. Prior to administration to humans, the pharmacology and biochemistry of the drug is established using an extensive range of in vitro and in vivo test procedures. It is also a regulatory requirement that the drug is administered to animals to assess its safety. Later-stage animal testing is also required to assess carcinogenicity and effects on the reproductive system. Clinical phases of drug development include phase I in healthy volunteers to assess primarily pharmacokinetics, safety and toleration, phase II in a cohort of patients with the target disease to establish efficacy and dose-response relationship and large-scale phase III studies to confirm safety and efficacy. Experience tells us that approximately only 1 in 10 drugs that start the clinical phase will make it to the market. Each drug must demonstrate safety and efficacy in the intended patient population and its benefits must outweigh its risks before it will be approved by the regulatory agencies. Strict regulatory standards govern the conduct of pre-clinical and clinical trials as well as the manufacturing of pharmaceutical products. The assessment of the new medicinal product's safety continues beyond the initial drug approval through post-marketing monitoring of adverse events. Copyright 2009 S. Karger AG, Basel.

Has molecular imaging delivered to drug development?

Science.gov (United States)

Murphy, Philip S.; Patel, Neel; McCarthy, Timothy J.

2017-10-01

Pharmaceutical research and development requires a systematic interrogation of a candidate molecule through clinical studies. To ensure resources are spent on only the most promising molecules, early clinical studies must understand fundamental attributes of the drug candidate, including exposure at the target site, target binding and pharmacological response in disease. Molecular imaging has the potential to quantitatively characterize these properties in small, efficient clinical studies. Specific benefits of molecular imaging in this setting (compared to blood and tissue sampling) include non-invasiveness and the ability to survey the whole body temporally. These methods have been adopted primarily for neuroscience drug development, catalysed by the inability to access the brain compartment by other means. If we believe molecular imaging is a technology platform able to underpin clinical drug development, why is it not adopted further to enable earlier decisions? This article considers current drug development needs, progress towards integration of molecular imaging into studies, current impediments and proposed models to broaden use and increase impact. This article is part of the themed issue 'Challenges for chemistry in molecular imaging'.

Multiscale Modeling in the Clinic: Drug Design and Development

Energy Technology Data Exchange (ETDEWEB)

Clancy, Colleen E.; An, Gary; Cannon, William R.; Liu, Yaling; May, Elebeoba E.; Ortoleva, Peter; Popel, Aleksander S.; Sluka, James P.; Su, Jing; Vicini, Paolo; Zhou, Xiaobo; Eckmann, David M.

2016-02-17

A wide range of length and time scales are relevant to pharmacology, especially in drug development, drug design and drug delivery. Therefore, multi-scale computational modeling and simulation methods and paradigms that advance the linkage of phenomena occurring at these multiple scales have become increasingly important. Multi-scale approaches present in silico opportunities to advance laboratory research to bedside clinical applications in pharmaceuticals research. This is achievable through the capability of modeling to reveal phenomena occurring across multiple spatial and temporal scales, which are not otherwise readily accessible to experimentation. The resultant models, when validated, are capable of making testable predictions to guide drug design and delivery. In this review we describe the goals, methods, and opportunities of multi-scale modeling in drug design and development. We demonstrate the impact of multiple scales of modeling in this field. We indicate the common mathematical techniques employed for multi-scale modeling approaches used in pharmacology and present several examples illustrating the current state-of-the-art regarding drug development for: Excitable Systems (Heart); Cancer (Metastasis and Differentiation); Cancer (Angiogenesis and Drug Targeting); Metabolic Disorders; and Inflammation and Sepsis. We conclude with a focus on barriers to successful clinical translation of drug development, drug design and drug delivery multi-scale models.

Pressure drop performance evaluation for test assemblies with the newly developed top and bottom nozzles

International Nuclear Information System (INIS)

Lee, S. K.; Park, N. K.; Su, J. M.; Kim, H. K.; Lee, J. N.; Kim, K. T.

2003-01-01

To perform the hydraulic test for the newly developed top and bottom nozzles, two kinds of test assemblies were manufactured i. e. one is the test assembly which has the newly developed top and bottom nozzles and the other is Guardian test assembly which is commercially in mass production now. The test results show that the test assembly with one top nozzle and two bottom nozzles has a greater pressure loss coefficient than Guardian test assembly by 60.9% and 90.4% at the bottom nozzle location. This cause is due to the debris filtering plate for bottom nozzle to improve a filtering efficiency aginst foreign material. In the region of mid grid and top nozzle, there is no difference in pressure loss coefficient between the test assemblies since the componet features in these regions are very similar or same each other. The loss coefficients are 14.2% and 21.9% for model A and B respectively in the scale of test assembly, and the value would be within the 10% in the scale of real fuel assembly. As a result of hydraulic performance evaluation, model A is superior to model B

Recent developments in oral lipid-based drug delivery

DEFF Research Database (Denmark)

Thomas, N.; Rades, T.; Müllertz, A.

2013-01-01

The increasing number of poorly water-soluble drugs in development in the pharmaceutical industry has sparked interest in novel drug delivery options such as lipid-based drug delivery systems (LbDDS). Several LbDDS have been marketed successfully and have shown superior and more reliable...... bioavailability compared to conventional formulations. However, some reluctance in the broader application of LbDDS still appears, despite the growing commercial interest in lipids as a drug delivery platform. This reluctance might at least in part be related to the complexity associated with the development...... and characterization of LbDDS. In particular, the lack of standardized test protocols can be identified as the major obstacles for the broader application of LbDDS. This review seeks to summarize recent approaches in the field of lipid-based drug delivery that try to elucidate some critical steps in their development...

How Schools Can Promote Healthy Development for Newly Arrived Immigrant and Refugee Adolescents: Research Priorities.

Science.gov (United States)

McNeely, Clea A; Morland, Lyn; Doty, S Benjamin; Meschke, Laurie L; Awad, Summer; Husain, Altaf; Nashwan, Ayat

2017-02-01

The US education system must find creative and effective ways to foster the healthy development of the approximately 2 million newly arrived immigrant and refugee adolescents, many of whom contend with language barriers, limited prior education, trauma, and discrimination. We identify research priorities for promoting the school success of these youth. The study used the 4-phase priority-setting method of the Child Health and Nutrition Research Initiative. In the final stage, 132 researchers, service providers, educators, and policymakers based in the United States were asked to rate the importance of 36 research options. The highest priority research options (range 1 to 5) were: evaluating newcomer programs (mean = 4.44, SD = 0.55), identifying how family and community stressors affect newly arrived immigrant and refugee adolescents' functioning in school (mean = 4.40, SD = 0.56), identifying teachers' major stressors in working with this population (mean = 4.36, SD = 0.72), and identifying how to engage immigrant and refugee families in their children's education (mean = 4.35, SD = 0.62). These research priorities emphasize the generation of practical knowledge that could translate to immediate, tangible benefits for schools. Funders, schools, and researchers can use these research priorities to guide research for the highest benefit of schools and the newly arrived immigrant and refugee adolescents they serve. © 2017, American School Health Association.

A multi-method approach to curriculum development for in-service training in China's newly established health emergency response offices.

Directory of Open Access Journals (Sweden)

Yadong Wang

Full Text Available To describe an innovative approach for developing and implementing an in-service curriculum in China for staff of the newly established health emergency response offices (HEROs, and that is generalisable to other settings.The multi-method training needs assessment included reviews of the competency domains needed to implement the International Health Regulations (2005 as well as China's policies and emergency regulations. The review, iterative interviews and workshops with experts in government, academia, the military, and with HERO staff were reviewed critically by an expert technical advisory panel.Over 1600 participants contributed to curriculum development. Of the 18 competency domains identified as essential for HERO staff, nine were developed into priority in-service training modules to be conducted over 2.5 weeks. Experts from academia and experienced practitioners prepared and delivered each module through lectures followed by interactive problem-solving exercises and desktop simulations to help trainees apply, experiment with, and consolidate newly acquired knowledge and skills.This study adds to the emerging literature on China's enduring efforts to strengthen its emergency response capabilities since the outbreak of SARS in 2003. The multi-method approach to curriculum development in partnership with senior policy-makers, researchers, and experienced practitioners can be applied in other settings to ensure training is responsive and customized to local needs, resources and priorities. Ongoing curriculum development should reflect international standards and be coupled with the development of appropriate performance support systems at the workplace for motivating staff to apply their newly acquired knowledge and skills effectively and creatively.

A multi-method approach to curriculum development for in-service training in China's newly established health emergency response offices.

Science.gov (United States)

Wang, Yadong; Li, Xiangrui; Yuan, Yiwen; Patel, Mahomed S

2014-01-01

To describe an innovative approach for developing and implementing an in-service curriculum in China for staff of the newly established health emergency response offices (HEROs), and that is generalisable to other settings. The multi-method training needs assessment included reviews of the competency domains needed to implement the International Health Regulations (2005) as well as China's policies and emergency regulations. The review, iterative interviews and workshops with experts in government, academia, the military, and with HERO staff were reviewed critically by an expert technical advisory panel. Over 1600 participants contributed to curriculum development. Of the 18 competency domains identified as essential for HERO staff, nine were developed into priority in-service training modules to be conducted over 2.5 weeks. Experts from academia and experienced practitioners prepared and delivered each module through lectures followed by interactive problem-solving exercises and desktop simulations to help trainees apply, experiment with, and consolidate newly acquired knowledge and skills. This study adds to the emerging literature on China's enduring efforts to strengthen its emergency response capabilities since the outbreak of SARS in 2003. The multi-method approach to curriculum development in partnership with senior policy-makers, researchers, and experienced practitioners can be applied in other settings to ensure training is responsive and customized to local needs, resources and priorities. Ongoing curriculum development should reflect international standards and be coupled with the development of appropriate performance support systems at the workplace for motivating staff to apply their newly acquired knowledge and skills effectively and creatively.

Inkjet Printing of Drug-Loaded Mesoporous Silica Nanoparticles—A Platform for Drug Development

Directory of Open Access Journals (Sweden)

Henrika Wickström

2017-11-01

Full Text Available Mesoporous silica nanoparticles (MSNs have shown great potential in improving drug delivery of poorly water soluble (BCS class II, IV and poorly permeable (BCS class III, IV drugs, as well as facilitating successful delivery of unstable compounds. The nanoparticle technology would allow improved treatment by reducing adverse reactions of currently approved drugs and possibly reintroducing previously discarded compounds from the drug development pipeline. This study aims to highlight important aspects in mesoporous silica nanoparticle (MSN ink formulation development for digital inkjet printing technology and to advice on choosing a method (2D/3D for nanoparticle print deposit characterization. The results show that both unfunctionalized and polyethyeleneimine (PEI surface functionalized MSNs, as well as drug-free and drug-loaded MSN–PEI suspensions, can be successfully inkjet-printed. Furthermore, the model BCS class IV drug remained incorporated in the MSNs and the suspension remained physically stable during the processing time and steps. This proof-of-concept study suggests that inkjet printing technology would be a flexible deposition method of pharmaceutical MSN suspensions to generate patterns according to predefined designs. The concept could be utilized as a versatile drug screening platform in the future due to the possibility of accurately depositing controlled volumes of MSN suspensions on various materials.

Inkjet Printing of Drug-Loaded Mesoporous Silica Nanoparticles-A Platform for Drug Development.

Science.gov (United States)

Wickström, Henrika; Hilgert, Ellen; Nyman, Johan O; Desai, Diti; Şen Karaman, Didem; de Beer, Thomas; Sandler, Niklas; Rosenholm, Jessica M

2017-11-21

Mesoporous silica nanoparticles (MSNs) have shown great potential in improving drug delivery of poorly water soluble (BCS class II, IV) and poorly permeable (BCS class III, IV) drugs, as well as facilitating successful delivery of unstable compounds. The nanoparticle technology would allow improved treatment by reducing adverse reactions of currently approved drugs and possibly reintroducing previously discarded compounds from the drug development pipeline. This study aims to highlight important aspects in mesoporous silica nanoparticle (MSN) ink formulation development for digital inkjet printing technology and to advice on choosing a method (2D/3D) for nanoparticle print deposit characterization. The results show that both unfunctionalized and polyethyeleneimine (PEI) surface functionalized MSNs, as well as drug-free and drug-loaded MSN-PEI suspensions, can be successfully inkjet-printed. Furthermore, the model BCS class IV drug remained incorporated in the MSNs and the suspension remained physically stable during the processing time and steps. This proof-of-concept study suggests that inkjet printing technology would be a flexible deposition method of pharmaceutical MSN suspensions to generate patterns according to predefined designs. The concept could be utilized as a versatile drug screening platform in the future due to the possibility of accurately depositing controlled volumes of MSN suspensions on various materials.

Development Considerations for Nanocrystal Drug Products.

Science.gov (United States)

Chen, Mei-Ling; John, Mathew; Lee, Sau L; Tyner, Katherine M

2017-05-01

Nanocrystal technology has emerged as a valuable tool for facilitating the delivery of poorly water-soluble active pharmaceutical ingredients (APIs) and enhancing API bioavailability. To date, the US Food and Drug Administration (FDA) has received over 80 applications for drug products containing nanocrystals. These products can be delivered by different routes of administration and are used in a variety of therapeutic areas. To aid in identifying key developmental considerations for these products, a retrospective analysis was performed on the submissions received by the FDA to date. Over 60% of the submissions were for the oral route of administration. Based on the Biopharmaceutics Classification System (BCS), most nanocrystal drugs submitted to the FDA are class II compounds that possess low aqueous solubility and high intestinal permeability. Impact of food on drug bioavailability was reduced for most nanocrystal formulations as compared with their micronized counterparts. For all routes of administration, dose proportionality was observed for some, but not all, nanocrystal products. Particular emphasis in the development of nanocrystal products was placed on the in-process tests and controls at critical manufacturing steps (such as milling process), mitigation and control of process-related impurities, and the stability of APIs or polymorphic form (s) during manufacturing and upon storage. This emphasis resulted in identifying challenges to the development of these products including accurate determination of particle size (distribution) of drug substance and/or nanocrystal colloidal dispersion, identification of polymorphic form (s), and establishment of drug substance/product specifications.

Development of anti-inflammatory drugs - the research and development process.

Science.gov (United States)

Knowles, Richard Graham

2014-01-01

The research and development process for novel drugs to treat inflammatory diseases is described, and several current issues and debates relevant to this are raised: the decline in productivity, attrition, challenges and trends in developing anti-inflammatory drugs, the poor clinical predictivity of experimental models of inflammatory diseases, heterogeneity within inflammatory diseases, 'improving on the Beatles' in treating inflammation, and the relationships between big pharma and biotechs. The pharmaceutical research and development community is responding to these challenges in multiple ways which it is hoped will lead to the discovery and development of a new generation of anti-inflammatory medicines. © 2013 Nordic Pharmacological Society. Published by John Wiley & Sons Ltd.

Development and economic trends in cancer therapeutic drugs: a 5-year update 2010-2014.

Science.gov (United States)

Savage, P; Mahmoud, S

2015-03-17

Over the past 20 years, the mechanisms of action, duration of benefits and economic costs of newly licenced cancer drugs have changed significantly; however, summary data on these characteristics are limited. In this study, using historical copies of the British National Formulary and relevant contemporary publications, we have documented for each new cancer drug the year of introduction, therapeutic classification, initial indication, median duration of treatment and the cost of treatment at introduction relative to the then current UK GDP per capita. Before 2000, there were 69 cancer treatment drugs available, of which 50 (72.5%) were classical cytotoxic drugs. In the subsequent 15 years, there have been 63 more new cancer treatment drugs added, including 20 kinase inhibitors and 11 monoclonal antibodies. The average median duration of treatment with a new drug has risen from 181 days in 1995-1999 to 263 days in 2010-2014. The average cost of treatment has also risen from £3036.91 (20.6% of UK per capita GDP) in 1995-1999 to £20 233 (89.0%) in 2005-2009 and now to £35 383 (141.7%) in 2010-2014. The last 5 years has seen 33 new cancer drugs. These drugs deliver significant benefits in patient outcomes and are taken for increasing lengths of time. Alongside these clinical benefits, the direct costs of new treatments have increased significantly over the past decade.

Low hanging fruit in infectious disease drug development.

Science.gov (United States)

Kraus, Carl N

2008-10-01

Cost estimates for developing new molecular entities (NME) are reaching non-sustainable levels and coupled with increasing regulatory requirements and oversight have led many pharmaceutical sponsors to divest their anti-microbial development portfolios [Projan SJ: Why is big Pharma getting out of anti-bacterial drug discovery?Curr Opin Microbiol 2003, 6:427-430] [Spellberg B, Powers JH, Brass EP, Miller LG, Edwards JE, Jr: Trends in antimicrobial drug development: implications for the future.Clin Infect Dis 2004, 38:1279-1286]. Operational issues such as study planning and execution are significant contributors to the overall cost of drug development that can benefit from the leveraging of pre-randomization data in an evidence-based approach to protocol development, site selection and patient recruitment. For non-NME products there is even greater benefit from available data resources since these data may permit smaller and shorter study programs. There are now many available open source intelligence (OSINT) resources that are being integrated into drug development programs, permitting an evidence-based or 'operational epidemiology' approach to study planning and execution.

Drug Resistance of Mycobacterium tuberculosis Complex among ...

African Journals Online (AJOL)

BACKGROUND: In Burkina Faso, there is no recent data about the level of drug resistance in Mycobacterium tuberculosis strains among newly diagnosed tuberculosis cases. OBJECTIVE: To provide an update of the primary drug resistance of mycobacterium tuberculosis among patients in Burkina faso. METHODS: ...

Association Between Manual Loading and Newly Developed Carpal Tunnel Syndrome in Subjects With Physical Disabilities: A Follow-Up Study.

Science.gov (United States)

Lin, Yen-Nung; Chiu, Chun-Chieh; Huang, Shih-Wei; Hsu, Wen-Yen; Liou, Tsan-Hon; Chen, Yi-Wen; Chang, Kwang-Hwa

2017-10-01

To identify the association between body composition and newly developed carpal tunnel syndrome (CTS) and to search for the best probabilistic cutoff value of associated factors to predict subjects with physical disabilities developing new CTS. Longitudinal. University-affiliated medical center. Subjects with physical disabilities (N=47; mean age ± SD, 42.1±7.7y). Not applicable. Median and ulnar sensory nerve conduction velocity (SNCV) were measured at the initial and follow-up tests (interval >2y). Total and regional body composition were measured with dual-energy x-ray absorptiometry at the initial test. Leg lean tissue percentage was calculated to delineate each participant's manual loading degree during locomotion. Leg lean tissue percentage is the lean tissue mass of both legs divided by body weight. Based on median SNCV changes, we divided all participants into 3 groups: subjects with bilateral CTS (median SNCV value normative ulnar SNCV value >37.8m/s) in the initial test (n=10), subjects with newly developed CTS in the follow-up test (n=8), and subjects without additional CTS in the follow-up test (n=27). Eight of 35 subjects not having bilateral CTS initially developed new CTS (8.8% per year; mean follow-up period, 2.6y). Leg lean tissue percentage was associated with the probability of newly developed CTS (adjusted odds ratio, .64; P12% were less likely to have developed new CTS at the follow-up test (sensitivity, .75; specificity, .85; area under the curve, .88; Pphysical disabilities. Therefore, a preventive program for those subjects at risk can start early. Copyright © 2017 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Delays in clinical development of neurological drugs in Japan.

Science.gov (United States)

Ikeda, Masayuki

2017-06-28

The delays in the approval and development of neurological drugs between Japan and other countries have been a major issue for patients with neurological diseases. The objective of this study was to analyze factors contributing to the delay in the launching of neurological drugs in Japan. We analyzed data from Japan and the US for the approval of 42 neurological drugs, all of which were approved earlier in the US than in Japan, and examined the potential factors that may cause the delay of their launch. Introductions of the 42 drugs in Japan occurred at a median of 87 months after introductions in the US. The mean review time of new drug applications for the 20 drugs introduced in Japan in January 2011 or later (15 months) was significantly shorter than that for the other 22 drugs introduced in Japan in December 2010 or earlier (24 months). The lag in the Japan's review time behind the US could not explain the approval delays. In the 31 of the 42 drugs, the application data package included overseas data. The mean review time of these 31 drugs (17 months) was significantly shorter than that of the other 11 drugs without overseas data (26 months). The mean approval lag behind the US of the 31 drugs (78 months) was also significantly shorter than that of the other 11 drugs (134 months). These results show that several important reforms in the Japanese drug development and approval system (e.g., inclusion of global clinical trial data) have reduced the delays in the clinical development of neurological drugs.

An In Vivo Platform for Rapid High-Throughput Antitubercular Drug Discovery

Directory of Open Access Journals (Sweden)

Kevin Takaki

2012-07-01

Full Text Available Treatment of tuberculosis, like other infectious diseases, is increasingly hindered by the emergence of drug resistance. Drug discovery efforts would be facilitated by facile screening tools that incorporate the complexities of human disease. Mycobacterium marinum-infected zebrafish larvae recapitulate key aspects of tuberculosis pathogenesis and drug treatment. Here, we develop a model for rapid in vivo drug screening using fluorescence-based methods for serial quantitative assessment of drug efficacy and toxicity. We provide proof-of-concept that both traditional bacterial-targeting antitubercular drugs and newly identified host-targeting drugs would be discovered through the use of this model. We demonstrate the model’s utility for the identification of synergistic combinations of antibacterial drugs and demonstrate synergy between bacterial- and host-targeting compounds. Thus, the platform can be used to identify new antibacterial agents and entirely new classes of drugs that thwart infection by targeting host pathways. The methods developed here should be widely applicable to small-molecule screens for other infectious and noninfectious diseases.

[Epidemiological characteristics of newly reported HIV infections in Chinese and Burmese residents, during 2012-2016 in Dehong Dai and Jingpo Autonomous Prefecture, Yunnan province].

Science.gov (United States)

Wang, J B; Chen, X C; Duan, X; Yang, J; Wang, Y K; Yang, T; Ye, R H; Yang, Y C; Yao, S T; Jiang, Y; Duan, S; He, N

2017-10-10

Objective: To understand the epidemiological characteristics of newly reported HIV infections in Chinese and Burmese residents during 2012-2016 in Dehong Dai and Jingpo Autonomous Prefecture of Yunnan province (Dehong) and to provide evidence for the development of related programs on prevention and control. Methods: All the HIV infections who were newly reported during 2012-2016 in Dehong, were recruited as the study subjects, with epidemiological characteristics of the cases analyzed by using the software SPSS 22.0. Results: A total of 5 692 HIV infections were newly reported between 2012 and 2016 (including 5 592 in this study), in which the Chinese patients accounted for 43.3 % (2 419) and the rest 56.7 % (3 173) were Burmese. Differences in age, gender and other social characteristics of these newly reported HIV infections were statistically significant between the Chinese and the Burmese (all p -values Chinese patients but through injecting drug use among the Burmese patients. Conclusions: Epidemiological characteristics of the newly reported HIV infections were different between the Chinese and the Burmese, between 2012 and 2016 in Dehong. Targeted prevention and control programs should be taken.

Recent trends for drug lag in clinical development of oncology drugs in Japan: does the oncology drug lag still exist in Japan?

Science.gov (United States)

Maeda, Hideki; Kurokawa, Tatsuo

2015-12-01

This study exhaustively and historically investigated the status of drug lag for oncology drugs approved in Japan. We comprehensively investigated oncology drugs approved in Japan between April 2001 and July 2014, using publicly available information. We also examined changes in the status of drug lag between Japan and the United States, as well as factors influencing drug lag. This study included 120 applications for approval of oncology drugs in Japan. The median difference over a 13-year period in the approval date between the United States and Japan was 875 days (29.2 months). This figure peaked in 2002, and showed a tendency to decline gradually each year thereafter. In 2014, the median approval lag was 281 days (9.4 months). Multiple regression analysis identified the following potential factors that reduce drug lag: "Japan's participation in global clinical trials"; "bridging strategies"; "designation of priority review in Japan"; and "molecularly targeted drugs". From 2001 to 2014, molecularly targeted drugs emerged as the predominant oncology drug, and the method of development has changed from full development in Japan or bridging strategy to global simultaneous development by Japan's taking part in global clinical trials. In line with these changes, the drug lag between the United States and Japan has significantly reduced to less than 1 year.

The development and impact of active learning strategies on self-confidence in a newly designed first-year self-care pharmacy course - outcomes and experiences.

Science.gov (United States)

Smith, Kathryn J; Grundmann, Oliver; Li, Robin Moorman

2018-04-01

The primary objective of this investigation was to determine the effectiveness of different active learning exercises in a newly-designed flipped-classroom self-care course in applying newly acquired knowledge of self-care and improving the confidence of first-year pharmacy students to recommend self-care treatments and counsel patients. The early development of these skills is essential for the subsequent Community Introductory Pharmacy Practice Experience (CIPPE). An unpaired anonymous survey was administered to students, pre- and post-course, to ascertain their opinions on the effectiveness of various teaching strategies and active learning exercises on learning and on their confidence in treatment-planning and patient counseling for self-care patients. Comparison between pre- and post-course Likert scores was conducted using a one-way ANOVA followed by a post-hoc Tukey's test with significance at p = 0.05. All other tests of significance were conducted using a student's t-test with significance at p = 0.05. Students' self-confidence in developing treatment plans and in counseling for non-prescription drugs and dietary supplements significantly improved from the beginning to the end of this self-care course. The response rate was high in both the pre- (N = 208, 88.1%) and post- (N = 198, 83.9%) course surveys. The positive change in confidence was not reflected in increased performance on the final exam represented by a lower average score than the midterm exam. Active learning sessions and the flipped classroom approach in this first-year pharmacy self-care course contributed to increased self-confidence in making recommendations and counseling patients on proper use of nonprescription medications and dietary supplements. Copyright © 2017 Elsevier Inc. All rights reserved.

Medicinal electronomics bricolage design of hypoxia-targeting antineoplastic drugs and invention of boron tracedrugs as innovative future-architectural drugs.

Science.gov (United States)

Hori, Hitoshi; Uto, Yoshihiro; Nakata, Eiji

2010-09-01

We describe herein for the first time our medicinal electronomics bricolage design of hypoxia-targeting antineoplastic drugs and boron tracedrugs as newly emerging drug classes. A new area of antineoplastic drugs and treatments has recently focused on neoplastic cells of the tumor environment/microenvironment involving accessory cells. This tumor hypoxic environment is now considered as a major factor that influences not only the response to antineoplastic therapies but also the potential for malignant progression and metastasis. We review our medicinal electronomics bricolage design of hypoxia-targeting drugs, antiangiogenic hypoxic cell radiosensitizers, sugar-hybrid hypoxic cell radiosensitizers, and hypoxia-targeting 10B delivery agents, in which we design drug candidates based on their electronic structures obtained by molecular orbital calculations, not based solely on pharmacophore development. These drugs include an antiangiogenic hypoxic cell radiosensitizer TX-2036, a sugar-hybrid hypoxic cell radiosensitizer TX-2244, new hypoxia-targeting indoleamine 2,3-dioxygenase (IDO) inhibitors, and a hypoxia-targeting BNCT agent, BSH (sodium borocaptate-10B)-hypoxic cytotoxin tirapazamine (TPZ) hybrid drug TX-2100. We then discuss the concept of boron tracedrugs as a new drug class having broad potential in many areas.

Hydroxypropyl-β-cyclodextrin–graphene oxide conjugates: Carriers for anti-cancer drugs

Energy Technology Data Exchange (ETDEWEB)

Tan, Jingting; Meng, Na; Fan, Yunting; Su, Yutian; Zhang, Ming [Jiangsu Collaborative Innovation Center for Biological Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023 (China); National and Local Joint Engineering Research Center of Biomedical Functional Materials, Nanjing 210023 (China); Jiangsu Key Laboratory of Biofunctional Materials, Jiangsu Engineering Research Center for Biomedical Function Materials, Nanjing 210023 (China); Xiao, Yinghong, E-mail: yhxiao@njnu.edu.cn [Jiangsu Collaborative Innovation Center for Biological Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023 (China); National and Local Joint Engineering Research Center of Biomedical Functional Materials, Nanjing 210023 (China); Jiangsu Key Laboratory of Biofunctional Materials, Jiangsu Engineering Research Center for Biomedical Function Materials, Nanjing 210023 (China); Zhou, Ninglin, E-mail: zhouninglin@njnu.edu.cn [Jiangsu Collaborative Innovation Center for Biological Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023 (China); National and Local Joint Engineering Research Center of Biomedical Functional Materials, Nanjing 210023 (China); Jiangsu Key Laboratory of Biofunctional Materials, Jiangsu Engineering Research Center for Biomedical Function Materials, Nanjing 210023 (China); Nanjing Zhou Ninglin Advanced Materials Technology Company Limited, Nanjing 211505 (China)

2016-04-01

A novel drug carrier based on hydroxypropyl-β-cyclodextrin (HP-β-CD) modified carboxylated graphene oxide (GO-COOH) was designed to incorporate anti-cancer drug paclitaxel (PTX). The formulated nanomedicines were characterized by Fourier transform infrared spectroscopy (FTIR) and atomic force microscopy (AFM). Results showed that PTX can be incorporated into GO-COO-HP-β-CD nanospheres successfully, with an average diameter of about 100 nm. The solubility and stability of PTX-loaded GO-COO-HP-β-CD nanospheres in aqueous media were greatly enhanced compared with the untreated PTX. The results of hemolysis test demonstrated that the drug-loaded nanospheres were qualified with good blood compatibility for intravenous use. In vitro anti-tumor activity was measured and results demonstrated that the incorporation of PTX into the newly developed GO-COO-HP-β-CD carrier could confer significantly improved cytotoxicity to the nanosystem against tumor cells than single application of PTX. GO-COO-HP-β-CD nanospheres may represent a promising formulation platform for a broad range of therapeutic agent, especially those with poor solubility. - Highlights: • Hydroxypropyl-β-cyclodextrin (HP-β-CD) modified carboxylated graphene oxide (GO-COOH) was designed as a drug carrier. • The prepared PTX-loaded nanospheres can be dispersed in aqueous medium stably. • The GO-COO-HP-β-CD nanospheres are safe for blood-contact applications. • This newly developed PTX-delivery system could confer significantly improved cytotoxicity against tumor cells.

Organotypic cultures as tools for testing neuroactive drugs - link between in-vitro and in-vivo experiments.

Science.gov (United States)

Drexler, B; Hentschke, H; Antkowiak, B; Grasshoff, C

2010-01-01

The development of neuroactive drugs is a time consuming procedure. Candidate drugs must be run through a battery of tests, including receptor studies and behavioural tests on animals. As a rule, numerous substances with promising properties as assessed in receptor studies must be eliminated from the development pipeline in advanced test phases because of unforeseen problems like intolerable side-effects or unsatisfactory performance in the whole organism. Clearly, test systems of intermediate complexity would alleviate this inefficiency. In this review, we propose cultured organotypic brain slices as model systems that could bridge the 'interpolation gap' between receptors and the brain, with a focus on the development of new general anaesthetics with lesser side effects. General anaesthesia is based on the modulation of neurotransmitter receptors and other conductances located on neurons in diverse brain regions, including cerebral cortex and spinal cord. It is well known that different components of general anaesthesia, e.g. hypnosis and immobility, are produced by the depression of neuronal activity in distinct brain regions. The ventral horn of the spinal cord is an important structure for the induction of immobility. Thus, the potentially immobilizing effects of a newly designed drug can be estimated from its depressant effect on neuronal network activity in cultured spinal slices. A drug's sedative and hypnotic potential can be examined in cortical cultures. Combined with genetically engineered mice, this approach can point to receptor subtypes most relevant to the drug's intended net effect and in return can help in the design of more selective drugs. In conclusion, the use of organotypic cultures permits predictions of neuroactive properties of newly designed drugs on an intermediate level, and should therefore open up avenues for a more creative and economic drug development process.

Impact of biomarker development on drug safety assessment

International Nuclear Information System (INIS)

Marrer, Estelle; Dieterle, Frank

2010-01-01

Drug safety has always been a key aspect of drug development. Recently, the Vioxx case and several cases of serious adverse events being linked to high-profile products have increased the importance of drug safety, especially in the eyes of drug development companies and global regulatory agencies. Safety biomarkers are increasingly being seen as helping to provide the clarity, predictability, and certainty needed to gain confidence in decision making: early-stage projects can be stopped quicker, late-stage projects become less risky. Public and private organizations are investing heavily in terms of time, money and manpower on safety biomarker development. An illustrative and 'door opening' safety biomarker success story is the recent recognition of kidney safety biomarkers for pre-clinical and limited translational contexts by FDA and EMEA. This milestone achieved for kidney biomarkers and the 'know how' acquired is being transferred to other organ toxicities, namely liver, heart, vascular system. New technologies and molecular-based approaches, i.e., molecular pathology as a complement to the classical toolbox, allow promising discoveries in the safety biomarker field. This review will focus on the utility and use of safety biomarkers all along drug development, highlighting the present gaps and opportunities identified in organ toxicity monitoring. A last part will be dedicated to safety biomarker development in general, from identification to diagnostic tests, using the kidney safety biomarkers success as an illustrative example.

Accessing external innovation in drug discovery and development.

Science.gov (United States)

Tufféry, Pierre

2015-06-01

A decline in the productivity of the pharmaceutical industry research and development (R&D) pipeline has highlighted the need to reconsider the classical strategies of drug discovery and development, which are based on internal resources, and to identify new means to improve the drug discovery process. Accepting that the combination of internal and external ideas can improve innovation, ways to access external innovation, that is, opening projects to external contributions, have recently been sought. In this review, the authors look at a number of external innovation opportunities. These include increased interactions with academia via academic centers of excellence/innovation centers, better communication on projects using crowdsourcing or social media and new models centered on external providers such as built-to-buy startups or virtual pharmaceutical companies. The buzz for accessing external innovation relies on the pharmaceutical industry's major challenge to improve R&D productivity, a conjuncture favorable to increase interactions with academia and new business models supporting access to external innovation. So far, access to external innovation has mostly been considered during early stages of drug development, and there is room for enhancement. First outcomes suggest that external innovation should become part of drug development in the long term. However, the balance between internal and external developments in drug discovery can vary largely depending on the company strategies.

Impact of Dendrimers on Solubility of Hydrophobic Drug Molecules

Directory of Open Access Journals (Sweden)

Sonam Choudhary

2017-05-01

Full Text Available Adequate aqueous solubility has been one of the desired properties while selecting drug molecules and other bio-actives for product development. Often solubility of a drug determines its pharmaceutical and therapeutic performance. Majority of newly synthesized drug molecules fail or are rejected during the early phases of drug discovery and development due to their limited solubility. Sufficient permeability, aqueous solubility and physicochemical stability of the drug are important for achieving adequate bioavailability and therapeutic outcome. A number of different approaches including co-solvency, micellar solubilization, micronization, pH adjustment, chemical modification, and solid dispersion have been explored toward improving the solubility of various poorly aqueous-soluble drugs. Dendrimers, a new class of polymers, possess great potential for drug solubility improvement, by virtue of their unique properties. These hyper-branched, mono-dispersed molecules have the distinct ability to bind the drug molecules on periphery as well as to encapsulate these molecules within the dendritic structure. There are numerous reported studies which have successfully used dendrimers to enhance the solubilization of poorly soluble drugs. These promising outcomes have encouraged the researchers to design, synthesize, and evaluate various dendritic polymers for their use in drug delivery and product development. This review will discuss the aspects and role of dendrimers in the solubility enhancement of poorly soluble drugs. The review will also highlight the important and relevant properties of dendrimers which contribute toward drug solubilization. Finally, hydrophobic drugs which have been explored for dendrimer assisted solubilization, and the current marketing status of dendrimers will be discussed.

Fragment-based drug discovery as alternative strategy to the drug development for neglected diseases.

Science.gov (United States)

Mello, Juliana da Fonseca Rezende E; Gomes, Renan Augusto; Vital-Fujii, Drielli Gomes; Ferreira, Glaucio Monteiro; Trossini, Gustavo Henrique Goulart

2017-12-01

Neglected diseases (NDs) affect large populations and almost whole continents, representing 12% of the global health burden. In contrast, the treatment available today is limited and sometimes ineffective. Under this scenery, the Fragment-Based Drug Discovery emerged as one of the most promising alternatives to the traditional methods of drug development. This method allows achieving new lead compounds with smaller size of fragment libraries. Even with the wide Fragment-Based Drug Discovery success resulting in new effective therapeutic agents against different diseases, until this moment few studies have been applied this approach for NDs area. In this article, we discuss the basic Fragment-Based Drug Discovery process, brief successful ideas of general applications and show a landscape of its use in NDs, encouraging the implementation of this strategy as an interesting way to optimize the development of new drugs to NDs. © 2017 John Wiley & Sons A/S.

Molecular epidemiological analysis of env and pol sequences in newly diagnosed HIV type 1-infected, untreated patients in Hungary.

Science.gov (United States)

Mezei, Mária; Ay, Eva; Koroknai, Anita; Tóth, Renáta; Balázs, Andrea; Bakos, Agnes; Gyori, Zoltán; Bánáti, Ferenc; Marschalkó, Márta; Kárpáti, Sarolta; Minárovits, János

2011-11-01

The aim of our study was to monitor the diversity of HIV-1 strains circulating in Hungary and investigate the prevalence of resistance-associated mutations to reverse transcriptase (RT) and protease (PR) inhibitors in newly diagnosed, drug-naive patients. A total of 30 HIV-1-infected patients without prior antiretroviral treatment diagnosed during the period 2008-2010 were included into this study. Viral subtypes and the presence of RT, PR resistance-associated mutations were established by sequencing. Classification of HIV-1 strains showed that 29 (96.6%) patients were infected with subtype B viruses and one patient (3.3%) with subtype A virus. The prevalence of HIV-1 strains with transmitted drug resistance mutations in newly diagnosed individuals was 16.6% (5/30). This study showed that HIV-1 subtype B is still highly predominant in Hungary and documented a relatively high transmission rate of drug resistance in our country.

Mind the gap : predicting cardiovascular risk during drug development

NARCIS (Netherlands)

Chain, Anne S. Y.

2012-01-01

Cardiovascular safety issues, specifically drug-induced QT/QTc-interval prolongation, remain a major cause of drug attrition during clinical development and is one of the main causes for post-market drug withdrawals accounting for 15-34% of all drug discontinuation. Given the potentially fatal

Improving clinical drug development regulatory procedures for anticonvulsants

Directory of Open Access Journals (Sweden)

Janković Slobodan

2015-01-01

Full Text Available Background: Clinical development of antiepileptic drugs is demanding due to complex character of the disorder and to diversity of its forms and etiologies. Objective: The aim of this review was to suggest improvements in regulatory procedures for clinical development of antiepileptic drugs. Methods: The following databases of scientific articles were searched: MEDLINE, SCOPUS and SCINDEKS. In total 558 publications were retrieved. The types of articles selected were reviews, reports on clinical trials and letters to the Editor. Results: There are several changes of regulatory documents necessary for improving process of clinical development of antiepileptic drugs: preference of parallel groups design for add-on trials should be explicit; the noninferiority design for monotherapy clinical trials should be acceptable; restrictive formulations when trials of antiepileptic drugs in children are in question should be avoided; requirements in regard to the efficacy measures should be harmonized among the regulatory bodies; proactive attitude towards discovery of adverse events; and precise requirements for clinical trials specifically designed to prove anti-epileptogenic effects should be made clear. Conclusion: Current regulatory documents are incomplete in many aspects; an international effort to improve and harmonize guidelines for clinical development of antiepileptic drugs is necessary for improvement of this process.

Antibody-drug conjugates for cancer therapy: The technological and regulatory challenges of developing drug-biologic hybrids.

Science.gov (United States)

Hamilton, Gregory S

2015-09-01

Antibody-drug conjugates (ADCs) are a new class of therapeutic agents that combine the targeting ability of monoclonal antibodies (mAbs) with small molecule drugs. The combination of a mAb targeting a cancer-specific antigen with a cytotoxin has tremendous promise as a new type of targeted cancer therapy. Two ADCs have been approved and many more are in clinical development, suggesting that this new class of drugs is coming to the forefront. Because of their unique nature as biologic-small drug hybrids, ADCs are challenging to develop, from both the scientific and regulatory perspectives. This review discusses both these aspects in current practice, and surveys the current state of the art of ADC drug development. Copyright © 2015 The International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

TRPV1: A Target for Rational Drug Design

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Vincenzo Carnevale

2016-08-01

Full Text Available Transient Receptor Potential Vanilloid 1 (TRPV1 is a non-selective, Ca2+ permeable cation channel activated by noxious heat, and chemical ligands, such as capsaicin and resiniferatoxin (RTX. Many compounds have been developed that either activate or inhibit TRPV1, but none of them are in routine clinical practice. This review will discuss the rationale for antagonists and agonists of TRPV1 for pain relief and other conditions, and strategies to develop new, better drugs to target this ion channel, using the newly available high-resolution structures.

The intersection of stress, drug abuse and development.

Science.gov (United States)

Thadani, Pushpa V

2002-01-01

Use or abuse of licit and illicit substances is often associated with environmental stress. Current clinical evidence clearly demonstrates neurobehavioral, somatic growth and developmental deficits in children born to drug-using mothers. However, the effects of environmental stress and its interaction with prenatal drug exposure on a child's development is unknown. Studies in pregnant animals under controlled conditions show drug-induced long-term alterations in brain structures and functions of the offspring. These cytoarchitecture alterations in the brain are often associated with perturbations in neurotransmitter systems that are intimately involved in the regulation of the stress responses. Similar abnormalities have been observed in the brains of animals exposed to other adverse exogenous (e.g., environmental stress) and/or endogenous (e.g., glucocorticoids) experiences during early life. The goal of this article is to: (1) provide evidence and a perspective that common neural systems are influenced during development both by perinatal drug exposure and early stress exposure; and (2) identify gaps and encourage new research examining the effects of early stress and perinatal drug exposure, in animal models, that would elucidate how stress- and drug-induced perturbations in neural systems influence later vulnerability to abused drugs in adult offspring.

Challenges in developing drugs for primary headaches

DEFF Research Database (Denmark)

Schytz, Henrik Winther; Hargreaves, Richard; Ashina, Messoud

2017-01-01

This review considers the history of drug development in primary headaches and discusses challenges to the discovery of innovative headache therapeutics. Advances in headache genetics have yet to translate to new classes of therapeutics and there are currently no clear predictive human biomarkers...... for any of the primary headaches that can guide preventative drug discovery and development. Primary headache disorder subtypes despite common phenotypic presentation are undoubtedly heterogeneous in their pathophysiology as judged by the variability of response to headache medicines. Sub......, despite having promising effects in basic pain models, have not delivered efficacy in the clinic. Future efforts may triage novel physiological mediators using human experimental models of headache pain to support drug discovery strategies that target active pathways pharmacologically....

[Development of new drugs: opportunities and benefits for Peru].

Science.gov (United States)

Bayona, Andrés; Fajardo, Natalia

2012-01-01

The development of innovative drugs allows coming up with new medicines to prevent and better treat illnesses. This improves people's quality of life and makes it more productive. Therefore, the mission of pharmaceutical research is to develop safe and effective drugs. Clinical trials allow the evaluation of the safety and efficacy profiles of new medicines, medical devices and diagnostic tests. Research and development (R&D) of new drugs is a long and costly process, where out of every 5000 to 10000 new components that enter preclinical testing, only one is approved. Compared to 2011, drug development has increased by 7.6%. According to ClinicalTrials.gov, 5% of the trials take place in Latin America, and Peru is in the fifth position. On the other hand, according to the Global Competitiveness Report issued by the World Economic Forum, Peru ranks 61st, its biggest challenges being the functioning of its public institutions, investment in R&D and technological capacity. The complexity of drug R&D results in a search for competitive places to develop clinical trials. Clinical Research is a humanized industry due to its ethical platform, stated in the guidelines of good clinical practices. This industry demands our country to develop a differentiating value that contributes to the development of knowledge and its competitiveness.

The risk of newly developed visual impairment in treated normal-tension glaucoma: 10-year follow-up.

Science.gov (United States)

Choi, Yun Jeong; Kim, Martha; Park, Ki Ho; Kim, Dong Myung; Kim, Seok Hwan

2014-12-01

To investigate the risk and risk factors for newly developed visual impairment in treated patients with normal-tension glaucoma (NTG) followed up on for 10 years. Patients with NTG, who did not have visual impairment at the initial diagnosis and had undergone intraocular pressure (IOP)-lowering treatment for more than 7 years, were included on the basis of a retrospective chart review. Visual impairment was defined as either low vision (0.05 [20/400] ≤ visual acuity (VA) visual field (VF) visual impairment, Kaplan-Meier survival analysis and generalized linear mixed effects models were utilized. During the 10.8 years mean follow-up period, 20 eyes of 16 patients were diagnosed as visual impairment (12 eyes as low vision, 8 as blindness) among 623 eyes of 411 patients. The cumulative risk of visual impairment in at least one eye was 2.8% at 10 years and 8.7% at 15 years. The risk factors for visual impairment from treated NTG were worse VF mean deviation (MD) at diagnosis and longer follow-up period. The risk of newly developed visual impairment in the treated patients with NTG was relatively low. Worse VF MD at diagnosis and longer follow-up period were associated with development of visual impairment. © 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Ethnically diverse pluripotent stem cells for drug development.

Science.gov (United States)

Fakunle, Eyitayo S; Loring, Jeanne F

2012-12-01

Genetic variation is an identified factor underlying drug efficacy and toxicity, and adverse drug reactions, such as liver toxicity, are the primary reasons for post-marketing drug failure. Genetic predisposition to toxicity might be detected early in the drug development pipeline by introducing cell-based assays that reflect the genetic and ethnic variation of the expected treatment population. One challenge for this approach is obtaining a collection of suitable cell lines derived from ethnically diverse populations. Induced pluripotent stem cells (iPSCs) seem ideal for this purpose. They can be obtained from any individual, can be differentiated into multiple relevant cell types, and their self-renewal capability makes it possible to generate large quantities of quality-controlled cell types. Here, we discuss the benefits and challenges of using iPSCs to introduce genetic diversity into the drug development process. Copyright © 2012 Elsevier Ltd. All rights reserved.

Underground trials on a newly developed EDW 150-2 L unit

Energy Technology Data Exchange (ETDEWEB)

Wille, G.; Klimek, K.H.

1982-01-01

Coal-getting from medium thick coalbeds (> 1.7 m) requires high-performance shearer-loaders. Machine length and adjustability have to be such as to permit smooth cutting through geological faults. Furthermore they should be suitable to cut out niches for the AFC drives so that gateroads can be driven along with the face line. The newly developed EDW 150-2 L shearer-loader meets these expectations after various mechanical and electrical improvements. The unit proved its usefulness from the beginning and in the most difficult geological conditions where other shearer-loaders normally available for the range of coalbed thickness would mostly have failed. The multiple requirements and disturbances have led to a number of separate improvements and disturbances have led to a number of separate improvements which together contribute to a basic improvement of the machine concept as far as applications, operational flexibility and safety are concerned.

5-FU Metabolism in Cancer and Orally-Administrable 5-FU Drugs

Directory of Open Access Journals (Sweden)

Iwao Sasaki

2010-09-01

Full Text Available 5-Fluorouracil (5-FU is a key anticancer drug that for its broad antitumor activity, as well as for its synergism with other anticancer drugs, has been used to treat various types of malignancies. In chemotherapeutic regimens, 5-FU has been combined with oxaliplatin, irinotecan and other drugs as a continuous intravenous infusion. Recent clinical chemotherapy studies have shown that several of the regimens with oral 5-FU drugs are not inferior compared to those involving continuous 5-FU infusion chemotherapy, and it is probable that in some regimens continuous 5-FU infusion can be replaced by oral 5-FU drugs. Historically, both the pharmaceutical industry and academia in Japan have been involved in the development of oral 5-FU drugs, and this review will focus on the current knowledge of 5-FU anabolism and catabolism, and the available information about the various orally-administrable 5-FU drugs, including UFT, S-1 and capecitabine. Clinical studies comparing the efficacy and adverse events of S-1 and capecitabine have been reported, and the accumulated results should be utilized to optimize the treatment of cancer patients. On the other hand, it is essential to elucidate the pharmacokinetic mechanism of each of the newly-developed drugs, to correctly select the drugs for each patient in the clinical setting, and to further develop optimized drug derivatives.

The role of globalization in drug development and access to orphan drugs: orphan drug legislation in the US/EU and in Latin America.

Science.gov (United States)

Arnold, Renée J G; Bighash, Lida; Bryón Nieto, Alejandro; Tannus Branco de Araújo, Gabriela; Gay-Molina, Juan Gabriel; Augustovski, Federico

2015-01-01

Compared to a decade ago, nearly three times as many drugs for rare diseases are slated for development. This article addresses the market access issues associated with orphan drug status in Europe and the United States in contrast to the legislation in five Latin American (LA) countries that have made strides in this regard--Mexico, Brazil, Colombia, Chile and Argentina. Based on the success of orphan drug legislation in the EU and US, LA countries should strive to adopt similar strategies with regard to rare diseases and drug development. With the implementation of new targeted regulations, reimbursement strategies, and drug approvals, accessibility to treatment will be improved for people afflicted with rare diseases in these developing countries.

Phase II clinical development of new drugs

CERN Document Server

Ting, Naitee; Ho, Shuyen; Cappelleri, Joseph C

2017-01-01

This book focuses on how to appropriately plan and develop a Phase II program, and how to design Phase II clinical trials and analyze their data. It provides a comprehensive overview of the entire drug development process and highlights key questions that need to be addressed for the successful execution of Phase II, so as to increase its success in Phase III and for drug approval. Lastly it warns project team members of the common potential pitfalls and offers tips on how to avoid them.

Liposomal Drug Product Development and Quality: Current US Experience and Perspective.

Science.gov (United States)

Kapoor, Mamta; Lee, Sau L; Tyner, Katherine M

2017-05-01

Research in the area of liposomes has grown substantially in the past few decades. Liposomes are lipid bilayer structures that can incorporate drug substances to modify the drug's pharmacokinetic profile thereby improving drug delivery. The agency has received over 400 liposomal drug product submissions (excluding combination therapies), and there are currently eight approved liposomal drug products on the US market. In order to identify the pain points in development and manufacturing of liposomal drug products, a retrospective analysis was performed from a quality perspective on submissions for new and generic liposomal drug products. General analysis on liposomal drug product submissions was also performed. Results indicated that 96% of the submissions were Investigational New Drug (IND) applications, 3% were New Drug Applications (NDAs), and the remaining 1% was Abbreviated New Drug Applications (ANDAs). Doxorubicin hydrochloride was the most commonly used drug substance incorporated into the liposomes (31%). The majority of the liposomal products were administered via intravenous route (84%) with cancer (various types) being the most common indication (63%). From a quality perspective, major challenges during the development of liposomal drug products included identification and (appropriate) characterization of critical quality attributes of liposomal drug products and suitable control strategies during product development. By focusing on these areas, a faster and more efficient development of liposomal drug products may be achieved. Additionally, in this way, the drug review process for such products can be streamlined.

Fatal adverse drug reactions of anticancer drugs detected by all-case post-marketing surveillance in Japan.

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Mori, Jinichi; Tanimoto, Tetsuya; Miura, Yuji; Kami, Masahiro

2015-06-01

All-case post-marketing surveillance of newly approved anticancer drugs is usually conducted on all patients in Japan. The present study investigates whether all-case post-marketing surveillance identifies fatal adverse drug reactions undetected before market entry. We examined fatal adverse drug reactions identified via all-case post-marketing surveillance by reviewing the disclosed post-marketing surveillance results, and determined the time points in which the fatal adverse drug reactions were initially reported by reviewing drug labels. We additionally scanned emergency alerts on the Japanese regulatory authority website to assess the relationship between all-case post-marketing surveillance and regulatory action. Twenty-five all-case post-marketing surveillances were performed between January 1999 and December 2009. Eight all-case post-marketing surveillances with final results included information on all fatal cases. Of these, the median number of patients was 1287 (range: 106-4998), the median number of fatal adverse drug reactions was 14.5 (range: 4-23). Of the 111 fatal adverse drug reactions detected in the eight post-marketing surveillances, only 28 (25.0%) and 22 (19.6%) were described on the initial global and the initial Japanese drug label, respectively, and 58 (52.3%) fatal adverse drug reactions were first described in the all-case post-marketing surveillance reports. Despite this, the regulatory authority issued only four warning letters, and two of these were prompted by case reports from the all-case post-marketing surveillance. All-case post-marketing surveillance of newly approved anticancer drugs in Japan was useful for the rigorous compilation of non-specific adverse drug reactions, but it rarely detected clinically significant fatal adverse drug reactions. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Development of a brazilian nanoencapsulated drug for schistosomiasis treatment

Directory of Open Access Journals (Sweden)

Laís Bastos da Fonseca

2013-11-01

Full Text Available Schistosomiasis is a parasitic disease that, according to the World Health Organization, constitutes a major public health problem associated with severe morbidity, mostly children in preschool age. The administration of drugs in children always constitutes a difficult task, especially when formulations are not developed specifically for pediatric use, when high doses of drug are required and the drug has a bitter taste, as in the case of praziquantel. Polymer nanoparticles are promising systems for development of encapsulated drugs with low water solubility and bitter taste, due to the good physical and chemical stability, adequate biocompatibility and simple manufacturing processes. Moreover, they can enhance the bioavailabili-ty and reduce variability of treatment among patients. Poly (methyl methacrylate doped with praziquantel was produced through a miniemulsion polymerization pro-cess to compose a pediatric pharmaceutical suspension. Nanoparticles were cha-racterized in terms of physico-chemical properties, toxicological properties and biological activity in mice, being concluded that obtained results were satisfactory. The results were encapsulation rate around 90%, absence of chemical interaction drug - polymer and the presence of biological activity. A collaborative approach was used for this development, involving national partnerships and independent funding mechanisms, a powerful pathway for development of drugs for neglected diseases.

Drug development against tuberculosis: Impact of alkaloids.

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Mishra, Shardendu K; Tripathi, Garima; Kishore, Navneet; Singh, Rakesh K; Singh, Archana; Tiwari, Vinod K

2017-09-08

Despite of the advances made in the treatment and management, tuberculosis (TB) still remains one of main public health problem. The contrary effects of first and second-line anti-tuberculosis drugs have generated extended research interest in natural products in the hope of devising new antitubercular leads. Interestingly, plethoras of natural products have been discovered to exhibit activity towards various resistant strains of M. tuberculosis. Extensive applications of alkaloids in the field of therapeutics is well-established and nowday's researches being pursued to develop new potent drugs from natural sources for tuberculosis. Alkaloids are categorized in quite a few groups according to their structures and isolation from both terrestrial and marine sources. These new drugs might be a watershed in the battle against tuberculosis. This review summarizes alkaloids, which were found active against Mycobacteria since last ten years with special attention on the study of structure-activity relationship (SAR) and mode of action with their impact in drug discovery and development against tuberculosis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Drug development for airway diseases: looking forward

NARCIS (Netherlands)

Holgate, Stephen; Agusti, Alvar; Strieter, Robert M.; Anderson, Gary P.; Fogel, Robert; Bel, Elisabeth; Martin, Thomas R.; Reiss, Theodore F.

2015-01-01

Advancing drug development for airway diseases beyond the established mechanisms and symptomatic therapies requires redefining the classifications of airway diseases, considering systemic manifestations, developing new tools and encouraging collaborations

Cost-effectiveness analysis of microdose clinical trials in drug development.

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Yamane, Naoe; Igarashi, Ataru; Kusama, Makiko; Maeda, Kazuya; Ikeda, Toshihiko; Sugiyama, Yuichi

2013-01-01

Microdose (MD) clinical trials have been introduced to obtain human pharmacokinetic data early in drug development. Here we assessed the cost-effectiveness of microdose integrated drug development in a hypothetical model, as there was no such quantitative research that weighed the additional effectiveness against the additional time and/or cost. First, we calculated the cost and effectiveness (i.e., success rate) of 3 types of MD integrated drug development strategies: liquid chromatography-tandem mass spectrometry, accelerator mass spectrometry, and positron emission tomography. Then, we analyzed the cost-effectiveness of 9 hypothetical scenarios where 100 drug candidates entering into a non-clinical toxicity study were selected by different methods as the conventional scenario without MD. In the base-case, where 70 drug candidates were selected without MD and 30 selected evenly by one of the three MD methods, incremental cost-effectiveness ratio per one additional drug approved was JPY 12.7 billion (US$ 0.159 billion), whereas the average cost-effectiveness ratio of the conventional strategy was JPY 24.4 billion, which we set as a threshold. Integrating MD in the conventional drug development was cost-effective in this model. This quantitative analytical model which allows various modifications according to each company's conditions, would be helpful for guiding decisions early in clinical development.

Otic drug delivery systems: formulation principles and recent developments.

Science.gov (United States)

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.

Open source biotechnology : A drug for developing countries' health problems?

NARCIS (Netherlands)

Schellekens, M.H.M.

2008-01-01

In developing countries, many people suffer from diseases for which there are no drugs or for which drugs exist that they cannot afford because they are too expensive. The advent of genomics has sparked the idea that new drugs can be more easily developed and that genomics thus could lessen the

Challenges in orphan drug development and regulatory policy in China.

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Cheng, Alice; Xie, Zhi

2017-01-18

While regulatory policy is well defined for orphan drug development in the United States and Europe, rare disease policy in China is still evolving. Many Chinese patients currently pay out of pocket for international treatments that are not yet approved in China. The lack of a clear definition and therefore regulatory approval process for rare diseases has, until now, de-incentivized pharmaceutical companies to pursue rare disease drug development in China. In turn, many grassroots movements have begun to support rare disease patients and facilitate drug discovery through research. Recently, the Chinese FDA set new regulatory guidelines for drugs being developed in China, including an expedited review process for life-saving treatments. In this review, we discuss the effects of these new policy changes on and suggest potential solutions to innovate orphan drug development in China.

[Alternatives to the drug research and development model].

Science.gov (United States)

Velásquez, Germán

2015-03-01

One-third of the global population lacks access to medications; the situation is worse in poor countries, where up to 50% of the population lacks access. The failure of current incentive systems based in intellectual property to offer the necessary pharmaceutical products, especially in the global south, is a call to action. Problems related to drug access cannot be solved solely through improvements or modifications in the existing incentive models. The intellectual property system model does not offer sufficient innovation for developing countries; new mechanisms that effectively promote innovation and drug access simultaneously are needed. A binding international agreement on research and development, negotiated under the auspices of the World Health Organization, could provide an adequate framework for guaranteeing priority-setting, coordination, and sustainable financing of drugs at reasonable prices for developing countries.

Challenges in the clinical development of new antiepileptic drugs.

Science.gov (United States)

Franco, Valentina; French, Jacqueline A; Perucca, Emilio

2016-01-01

Despite the current availability in the market of over two dozen antiepileptic drugs (AEDs), about one third of people with epilepsy fail to achieve complete freedom from seizures with existing medications. Moreover, currently available AEDs have significant limitations in terms of safety, tolerability and propensity to cause or be a target for clinically important adverse drug interactions. A review of the evidence shows that there are many misperceptions about the viability of investing into new therapies for epilepsy. In fact, there are clear incentives to develop newer and more efficacious medications. Developing truly innovative drugs requires a shift in the paradigms for drug discovery, which is already taking place by building on greatly expanded knowledge about the mechanisms involved in epileptogenesis, seizure generation, seizure spread and development of co-morbidities. AED development can also benefit by a review of the methodology currently applied in clinical AED development, in order to address a number of ethical and scientific concerns. As discussed in this article, many processes of clinical drug development, from proof-of-concept-studies to ambitious programs aimed at demonstrating antiepileptogenesis and disease-modification, can be facilitated by a greater integration of preclinical and clinical science, and by application of knowledge acquired during decades of controlled epilepsy trials. Copyright © 2015 Elsevier Ltd. All rights reserved.

Evaluation of transporters in drug development: Current status and contemporary issues.

Science.gov (United States)

Lee, Sue-Chih; Arya, Vikram; Yang, Xinning; Volpe, Donna A; Zhang, Lei

2017-07-01

Transporters govern the access of molecules to cells or their exit from cells, thereby controlling the overall distribution of drugs to their intracellular site of action. Clinically relevant drug-drug interactions mediated by transporters are of increasing interest in drug development. Drug transporters, acting alone or in concert with drug metabolizing enzymes, can play an important role in modulating drug absorption, distribution, metabolism and excretion, thus affecting the pharmacokinetics and/or pharmacodynamics of a drug. The drug interaction guidance documents from regulatory agencies include various decision criteria that may be used to predict the need for in vivo assessment of transporter-mediated drug-drug interactions. Regulatory science research continues to assess the prediction performances of various criteria as well as to examine the strength and limitations of each prediction criterion to foster discussions related to harmonized decision criteria that may be used to facilitate global drug development. This review discusses the role of transporters in drug development with a focus on methodologies in assessing transporter-mediated drug-drug interactions, challenges in both in vitro and in vivo assessments of transporters, and emerging transporter research areas including biomarkers, assessment of tissue concentrations, and effect of diseases on transporters. Published by Elsevier B.V.

A Newly Developed Nested PCR Assay for the Detection of Helicobacter pylori in the Oral Cavity.

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Ismail, Hawazen; Morgan, Claire; Griffiths, Paul; Williams, John; Jenkins, Gareth

2016-01-01

To develop a new nested polymerase chain reaction (PCR) assay for identifying Helicobacter pylori DNA from dental plaque. H. pylori is one of the most common chronic bacterial pathogens in humans. The accurate detection of this organism is essential for proper patient management and for the eradication of the bacteria following treatment. Forty-nine patients (24 males and 25 females; mean age: 51; range, 19 to 94 y) were investigated for the presence of H. pylori in dental plaque by single-step PCR and nested PCR and in the stomach by single-step PCR, nested PCR, and histologic examination. The newly developed nested PCR assay identified H. pylori DNA in gastric biopsies of 18 patients who were histologically classified as H. pylori-positive and 2 additional biopsies of patients who were H. pylori-negative by histologic examination (20/49; 40.8%). Dental plaque samples collected before and after endoscopy from the 49 patients revealed that single-step PCR did not detect H. pylori but nested PCR was able to detect H. pylori DNA in 40.8% (20/49) patients. Nested PCR gave a higher detection rate (40.8%, 20/49) than that of histology (36.7%, 18/49) and single-step PCR. When nested PCR results were compared with histology results there was no significant difference between the 2 methods. Our newly developed nested PCR assay is at least as sensitive as histology and may be useful for H. pylori detection in patients unfit for endoscopic examination.

Characteristics of bread prepared from wheat flours blended with various kinds of newly developed rice flours.

Science.gov (United States)

Nakamura, S; Suzuki, K; Ohtsubo, K

2009-04-01

Characteristics of the bread prepared from wheat flour blended with the flour of various kinds of newly developed rice cultivars were investigated. Qualities of the bread made from wheat flour blended with rice flour have been reported to be inferior to those from 100% wheat flour bread. To improve its qualities, we searched for the new-characteristic rice flours among the various kinds of newly developed rice cultivars to blend with the wheat flour for the bread preparation. The most suitable new characteristic rices are combination of purple waxy rice, high-amylose rice, and sugary rice. Specific volume of the bread from the combination of wheat and these 3 kinds of rice flours showed higher specific volume (3.93) compared with the traditional wheat/rice bread (3.58). We adopted the novel method, continuous progressive compression test, to measure the physical properties of the dough and the bread in addition to the sensory evaluation. As a result of the selection of the most suitable rice cultivars and blending ratio with the wheat flour, we could develop the novel wheat/rice bread, of which loaf volume, physical properties, and tastes are acceptable and resistant to firming on even 4 d after the bread preparation. To increase the ratio of rice to wheat, we tried to add a part of rice as cooked rice grains. The specific volume and qualities of the bread were maintained well although the rice content of total flour increased from 30% to 40%.

Impact of Drug Metabolism/Pharmacokinetics and Their Relevance upon Taxus-based Drug Development.

Science.gov (United States)

Hao, Da-Cheng; Ge, Guang-Bo; Wang, Ping; Yang, Ling

2018-05-22

Drug metabolism and pharmacokinetic (DMPK) studies of Taxus natural products, their semi-synthetic derivatives and analogs are indispensable in the optimization of lead compounds and clinical therapy. These studies can lead to development of new drug entities with improved absorption, distribution, metabolism, excretion and toxicity (ADME/T) profiles. To date, there have been no comprehensive reviews of the DMPK features of Taxus derived medicinal compounds.Natural and semi-synthetic taxanes may cause and could be affected by drug-drug interaction (DDI). Hence ADME/T studies of various taxane-containing formulations are important; to date these studies indicate that the role of cytochrome p450s and drug transporters is more prominent than phase II drug metabolizing enzymes. Mechanisms of taxane DMPK mediated by nuclear receptors, microRNAs, and single nucleotide polymorphisms are being revealed. Herein we review the latest knowledge on these topics, as well as the gaps in knowledge of the DMPK issues of Taxus compounds. DDIs significantly impact the PK/pharmacodynamics performance of taxanes and co-administered chemicals, which may inspire researchers to develop novel formula. While the ADME/T profiles of some taxanes are well defined, DMPK studies should be extended to more Taxus compounds, species, and Taxus -involved formulations, which would be streamlined by versatile omics platforms and computational analyses. Further biopharmaceutical investigations will be beneficial tothe translation of bench findings to the clinical applications. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A Comparison of Individual-Level and Community-Level Predictors of Marijuana and Cocaine Use among a Sample of Newly Arrested Juvenile Offenders

Science.gov (United States)

Childs, Kristina; Dembo, Richard; Belenko, Steven; Wareham, Jennifer; Schmeidler, James

2011-01-01

Variations in drug use have been found across individual-level factors and community characteristics, and by type of drug used. Relatively little research, however, has examined this variation among juvenile offenders. Based on a sample of 924 newly arrested juvenile offenders, two multilevel logistic regression models predicting marijuana test…

Perestroika in pharma: evolution or revolution in drug development?

Science.gov (United States)

FitzGerald, Garret A

2010-01-01

New-drug approvals have remained roughly constant since 1950, while the cost of drug development has soared. It seems likely that a more modular approach to drug discovery and development will evolve, deriving some features from the not-for-profit sector. For this to occur, we must address the deficit in human capital with expertise in both translational medicine and therapeutics and also in regulatory science; utilize regulatory reform to incentivize innovation and the expansion of the precompetitive space; and develop an informatics infrastructure that permits the global, secure, and compliant sharing of heterogeneous data across academic and industry sectors. These developments, likely prompted by the perception of crisis rather than opportunity, will require linked initiatives among academia, the pharmaceutical industry, the US National Institutes of Health, and the US Food and Drug Administration, along with a more adventurous role for venture capital. A failure to respond threatens the United States' lead in biomedical science and in the development and regulation of novel therapeutics. 2010 Mount Sinai School of Medicine.

Establishment probability in newly founded populations

Directory of Open Access Journals (Sweden)

Gusset Markus

2012-06-01

Full Text Available Abstract Background Establishment success in newly founded populations relies on reaching the established phase, which is defined by characteristic fluctuations of the population’s state variables. Stochastic population models can be used to quantify the establishment probability of newly founded populations; however, so far no simple but robust method for doing so existed. To determine a critical initial number of individuals that need to be released to reach the established phase, we used a novel application of the “Wissel plot”, where –ln(1 – P0(t is plotted against time t. This plot is based on the equation P0t=1–c1e–ω1t, which relates the probability of extinction by time t, P0(t, to two constants: c1 describes the probability of a newly founded population to reach the established phase, whereas ω1 describes the population’s probability of extinction per short time interval once established. Results For illustration, we applied the method to a previously developed stochastic population model of the endangered African wild dog (Lycaon pictus. A newly founded population reaches the established phase if the intercept of the (extrapolated linear parts of the “Wissel plot” with the y-axis, which is –ln(c1, is negative. For wild dogs in our model, this is the case if a critical initial number of four packs, consisting of eight individuals each, are released. Conclusions The method we present to quantify the establishment probability of newly founded populations is generic and inferences thus are transferable to other systems across the field of conservation biology. In contrast to other methods, our approach disaggregates the components of a population’s viability by distinguishing establishment from persistence.

Mathematical modeling of efficacy and safety for anticancer drugs clinical development.

Science.gov (United States)

Lavezzi, Silvia Maria; Borella, Elisa; Carrara, Letizia; De Nicolao, Giuseppe; Magni, Paolo; Poggesi, Italo

2018-01-01

Drug attrition in oncology clinical development is higher than in other therapeutic areas. In this context, pharmacometric modeling represents a useful tool to explore drug efficacy in earlier phases of clinical development, anticipating overall survival using quantitative model-based metrics. Furthermore, modeling approaches can be used to characterize earlier the safety and tolerability profile of drug candidates, and, thus, the risk-benefit ratio and the therapeutic index, supporting the design of optimal treatment regimens and accelerating the whole process of clinical drug development. Areas covered: Herein, the most relevant mathematical models used in clinical anticancer drug development during the last decade are described. Less recent models were considered in the review if they represent a standard for the analysis of certain types of efficacy or safety measures. Expert opinion: Several mathematical models have been proposed to predict overall survival from earlier endpoints and validate their surrogacy in demonstrating drug efficacy in place of overall survival. An increasing number of mathematical models have also been developed to describe the safety findings. Modeling has been extensively used in anticancer drug development to individualize dosing strategies based on patient characteristics, and design optimal dosing regimens balancing efficacy and safety.

The basics of preclinical drug development for neurodegenerative disease indications.

Science.gov (United States)

Steinmetz, Karen L; Spack, Edward G

2009-06-12

Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA) Good Laboratory Practices and international guidelines, including the International Conference on Harmonization. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s). Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot Program provide funding and

Rethinking the Food and Drug Administration's 2013 guidance on developing drugs for early-stage Alzheimer's disease.

Science.gov (United States)

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.

Long-term outcome of patients with newly diagnosed chronic myeloid leukemia: a randomized comparison of stem cell transplantation with drug treatment.

Science.gov (United States)

Gratwohl, A; Pfirrmann, M; Zander, A; Kröger, N; Beelen, D; Novotny, J; Nerl, C; Scheid, C; Spiekermann, K; Mayer, J; Sayer, H G; Falge, C; Bunjes, D; Döhner, H; Ganser, A; Schmidt-Wolf, I; Schwerdtfeger, R; Baurmann, H; Kuse, R; Schmitz, N; Wehmeier, A; Fischer, J Th; Ho, A D; Wilhelm, M; Goebeler, M-E; Lindemann, H W; Bormann, M; Hertenstein, B; Schlimok, G; Baerlocher, G M; Aul, C; Pfreundschuh, M; Fabian, M; Staib, P; Edinger, M; Schatz, M; Fauser, A; Arnold, R; Kindler, T; Wulf, G; Rosselet, A; Hellmann, A; Schäfer, E; Prümmer, O; Schenk, M; Hasford, J; Heimpel, H; Hossfeld, D K; Kolb, H-J; Büsche, G; Haferlach, C; Schnittger, S; Müller, M C; Reiter, A; Berger, U; Saußele, S; Hochhaus, A; Hehlmann, R

2016-03-01

Tyrosine kinase inhibitors represent today's treatment of choice in chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as salvage therapy. This prospective randomized CML-study IIIA recruited 669 patients with newly diagnosed CML between July 1997 and January 2004 from 143 centers. Of these, 427 patients were considered eligible for HSCT and were randomized by availability of a matched family donor between primary HSCT (group A; N=166 patients) and best available drug treatment (group B; N=261). Primary end point was long-term survival. Survival probabilities were not different between groups A and B (10-year survival: 0.76 (95% confidence interval (CI): 0.69-0.82) vs 0.69 (95% CI: 0.61-0.76)), but influenced by disease and transplant risk. Patients with a low transplant risk showed superior survival compared with patients with high- (Ptreatment (56% vs 6%; P<0.001). Differences in symptoms and Karnofsky score were not significant. In the era of tyrosine kinase inhibitors, HSCT remains a valid option when both disease and transplant risk are considered.

Drugs' development in acute heart failure: what went wrong?

Science.gov (United States)

Teneggi, Vincenzo; Sivakumar, Nithy; Chen, Deborah; Matter, Alex

2018-05-08

Acute heart failure (AHF) is a major burden disease, with a complex physiopathology, unsatisfactory diagnosis, treatment and a very poor prognosis. In the last two decades, a number of drugs have progressed from preclinical to early and late clinical development, but only a few of them have been approved and added to a stagnant pharmacological armamentarium. We have reviewed the data published on drugs developed for AHF since early 2000s, trying to recognise factors that have worked for a successful approval or for the stoppage of the program, in an attempt to delineate future trajectories for AHF drug development. Our review has identified limitations at both preclinical and clinical levels. At the preclinical level, the major shortcoming is represented by animal models looking at short-term endpoints which do not recapitulate the complexity of the human disease. At the clinical level, the main weakness is given by the disconnect between short-term endpoints assessed in the early stage of drug development, and medium-long-term endpoints requested in Phase 3 for regulatory approval. This is further amplified by the lack of validation and standardisation of short- and long-term endpoints; absence of predictive biomarkers; conduct of studies on heterogeneous populations; and use of different eligibility criteria, time of assessments, drug schedules and background therapies. Key goals remain a better understanding of AHF and the construction of a successful drug development program. A reasonable way to move forward resides in a strong collaboration between main stakeholders of therapeutic innovation: scientific community, industry and regulatory agencies.

An active role for machine learning in drug development

Science.gov (United States)

Murphy, Robert F.

2014-01-01

Due to the complexity of biological systems, cutting-edge machine-learning methods will be critical for future drug development. In particular, machine-vision methods to extract detailed information from imaging assays and active-learning methods to guide experimentation will be required to overcome the dimensionality problem in drug development. PMID:21587249

A two-pronged approach in leishmaniasis drug development in ...

African Journals Online (AJOL)

Nancy Kamau

Trouiller P; Olliaro P; Torreele E;. Orbinski J; Laing R and Ford N. Drug development for neglected diseases: a deficient market and a public-health policy failure. Lancet. 2002; 359: 2188–94. 9. Nwaka S and Ridley RG. Virtual drug discovery and development for neglected diseases through public-private partnerships.

A New Drug Release Method in Early Development of Transdermal Drug Delivery Systems

Directory of Open Access Journals (Sweden)

Bing Cai

2012-01-01

Full Text Available In vitro drug release tests are a widely used tool to measure the variance between transdermal product performances and required by many authorities. However, the result cannot provide a good estimation of the in vivo drug release. In the present work, a new method for measuring drug release from patches has been explored and compared with the conventional USP apparatus 2 and 5 methods. Durogesic patches, here used as a model patch, were placed on synthetic skin simulator and three moisture levels (29, 57, 198 μL cm−2 were evaluated. The synthetic skin simulators were collected after 1, 2, 3, 4, 6, and 24 hours and extracted with pH 1.0 hydrochloric acid solution. The drug concentrations in the extractions were measured by isocratic reverse phase high-pressure liquid chromatography. The results showed that, with the increasing moisture level on the synthetic skin simulator, the drug release rate increased. In comparison with the conventional USP method, the drug release results performed by the new method were in more correlation to the release rate claimed in the product label. This new method could help to differentiate the drug release rates among assorted formulations of transdermal drug delivery systems in the early stage of development.

Prodrug Strategy in Drug Development

Directory of Open Access Journals (Sweden)

Hajnal Kelemen

2016-09-01

Full Text Available Prodrugs are chemically modified derivatives introduced in therapy due to their advantageous physico-chemical properties (greater stability, improved solubility, increased permeability, used in inactive form. Biological effect is exerted by the active derivatives formed in organism through chemical transformation (biotransformation. Currently, 10% of pharmaceutical products are used as prodrugs, nearly half of them being converted to active form by hydrolysis, mainly by ester hydrolysis. The use of prodrugs aims to improve the bioavailability of compounds in order to resolve some unfavorable characteristics and to reduce first-pass metabolism. Other objectives are to increase drug absorption, to extend duration of action or to achieve a better tissue/organ selective transport in case of non-oral drug delivery forms. Prodrugs can be characterized by chemical structure, activation mechanism or through the presence of certain functional groups suitable for their preparation. Currently we distinguish in therapy traditional prodrugs prepared by chemical derivatisation, bioprecursors and targeted delivery systems. The present article is a review regarding the introduction and applications of prodrug design in various areas of drug development.

Novel investigational drugs for constipation-predominant irritable bowel syndrome: a review.

Science.gov (United States)

Mosińska, Paula; Salaga, Maciej; Fichna, Jakub

2016-01-01

Constipation-predominant irritable bowel syndrome (IBS-C) is a functional gastrointestinal (GI) disorder with an unknown etiology. A number of the drugs tested for IBS-C have also been applied to chronic constipation and chronic idiopathic constipation. Unfortunately, due to severe adverse effects, many drugs envisioned for IBS-C had been withdrawn from the market. Nevertheless, a number of potential new agents for this indication are now under development. The following review describes the most recently developed agents in preclinical as well as Phase 1 and Phase 2 clinical studies. Information was obtained from published literature, abstracts and the latest results found in Clinicaltrial.gov database. The authors put a special interest on glucagon-like peptide 1 analogue, bile acid modulators, serotonergic agents, guanylate cyclase C and cannabinoid antagonists. To enter the market, a newly-developed drug has to meet several criteria, such as good bioavailability or the absence of drug-related adverse events. Taking into account constipation and abdominal pain as the main symptoms in IBS-C, a novel successful drug is usually able to improve both at the same time. Four out of fifteen investigational drugs described in this paper belong to the serotonergic family and have a good prognosis to reach the market; still, more long-term clinical studies are warranted.

The effectiveness of newly developed written asthma action plan in improvement of asthma outcome in children.

Science.gov (United States)

Lakupoch, Kingthong; Manuyakorn, Wiparat; Preutthipan, Aroonwan; Kamalaporn, Harutai

2017-09-17

Providing asthma education about controller medication use and appropriate management of asthma exacerbation are the keys to improving the disease outcome. Many asthma guidelines recommend that physicians provide written asthma action plan (WAAP) to all of their asthmatic patients. However, the benefit of WAAP is unclear. Thus, we have created a new WAAP which is simplified in Thai and more user friendly. To determine the effectiveness of the newly developed asthma action plan in management of children with asthma. Asthmatic children who meet inclusion criteria all received the WAAP and they were followed up for 6 months with measurement of outcome variables, such as asthma exacerbation that required emergency room visit, unscheduled OPD visit, admission and school absence in order to compare with the past 6 months before receiving the WAAP. The analyzed outcomes of forty-nine children show significantly reduced emergency room visit (P-value 0.005), unscheduled OPD visit (P-value 0.046), admission days (P-value 0.026) and school absence days (P-value 0.022). Well controlled group and mild severity group were not the factors that contribute to decreased emergency room visit but step up therapy may be the co-factor to decreased ER visit. The results of this study suggest that the provision of newly developed WAAP is useful for improving self-care of asthma patients and reducing asthma exacerbation.

Developing drugs for the developing world: an economic, legal, moral, and political dilemma.

Science.gov (United States)

Resnik, D B

2001-05-01

This paper discusses the economic, legal, moral, and political difficulties in developing drugs for the developing world. It argues that large, global pharmaceutical companies have social responsibilities to the developing world, and that they may exercise these responsibilities by investing in research and development related to diseases that affect developing nations, offering discounts on drug prices, and initiating drug giveaways. However, these social responsibilities are not absolute requirements and may be balanced against other obligations and commitments in light of economic, social, legal, political, and other conditions. How a company decides to exercise its social responsibilities to the developing world depends on (1) the prospects for a reasonable profit and (2) the prospects for a productive business environment. Developing nations can either help or hinder the pharmaceutical industry's efforts to exercise social responsibility through various policies and practices. To insure that companies can make a reasonable profit, developing nations should honor pharmaceutical product patents and adhere to international intellectual property treaties, such as the Trade-Related Aspects of Intellectual Property Rights (TRIPS) agreement. To insure the companies have a good business environment, developing nations should try to promote the rule of law, ethical business practices, stable currencies, reliable banking systems, free and open markets, democracy, and other conditions conducive to business. Overall, this paper advocates for reciprocity and cooperation between pharmaceutical companies and developing nations to address the problem of developing drugs for the developing world. In pursuing this cooperative approach, developing nations may use a variety of other techniques to encourage pharmaceutical companies to act responsibly, such as subsidizing pharmaceutical research, helping to design and implement research protocols, providing a guaranteed market, and

Measuring clinical trial transparency: an empirical analysis of newly approved drugs and large pharmaceutical companies.

Science.gov (United States)

Miller, Jennifer E; Wilenzick, Marc; Ritcey, Nolan; Ross, Joseph S; Mello, Michelle M

2017-12-05

To define a series of clinical trial transparency measures and apply them to large pharmaceutical and biotechnology companies and their 2014 FDA-approved drugs. Cross-sectional descriptive analysis of all clinical trials supporting 2014 Food and Drugs Administration (FDA)-approved new drug applications (NDAs) for novel drugs sponsored by large companies. Data from over 45 sources, including Drugs@FDA.gov, ClinicalTrials.gov, corporate and international registries; PubMed, Google Scholar, EMBASE, corporate press releases, Securities and Exchange Commission (SEC) filings and personal communications with drug manufacturers. Trial registration, results reporting, clinical study report (CSR) synopsis sharing, biomedical journal publication, and FDA Amendments Acts (FDAAA) compliance, analysed on the drug level. The FDA approved 19 novel new drugs, sponsored by 11 large companies, involving 553 trials, in 2014. We analysed 505 relevant trials. Per drug, a median of 100% (IQR 86%-100%) of trials in patients were registered, 71% (IQR 57%-100%) reported results or shared a CSR synopsis, 80% (70%-100%) were published and 96% (80%-100%) were publicly available in some form by 13 months after FDA approval. Disclosure rates were lower at FDA approval (65%) and improved significantly by 6 months post FDA approval. Per drug, a median of 100% (IQR 75%-100%) of FDAAA-applicable trials were compliant. Half of reviewed drugs had publicly disclosed results for all trials in patients in our sample. One trial was uniquely registered in a corporate registry, and not ClinicalTrials.gov; 0 trials were uniquely registered in international registries. Among large pharmaceutical companies and new drugs, clinical trial transparency is high based on several standards, although opportunities for improvement remain. Transparency is markedly higher for trials in patients than among all trials supporting drug approval, including trials in healthy volunteers. Ongoing efforts to publicly track

The drug-minded protein interaction database (DrumPID) for efficient target analysis and drug development.

Science.gov (United States)

Kunz, Meik; Liang, Chunguang; Nilla, Santosh; Cecil, Alexander; Dandekar, Thomas

2016-01-01

The drug-minded protein interaction database (DrumPID) has been designed to provide fast, tailored information on drugs and their protein networks including indications, protein targets and side-targets. Starting queries include compound, target and protein interactions and organism-specific protein families. Furthermore, drug name, chemical structures and their SMILES notation, affected proteins (potential drug targets), organisms as well as diseases can be queried including various combinations and refinement of searches. Drugs and protein interactions are analyzed in detail with reference to protein structures and catalytic domains, related compound structures as well as potential targets in other organisms. DrumPID considers drug functionality, compound similarity, target structure, interactome analysis and organismic range for a compound, useful for drug development, predicting drug side-effects and structure-activity relationships.Database URL:http://drumpid.bioapps.biozentrum.uni-wuerzburg.de. © The Author(s) 2016. Published by Oxford University Press.

Drug development for neurodevelopmental disorders

DEFF Research Database (Denmark)

Berry-Kravis, Elizabeth M; Lindemann, Lothar; Jønch, Aia E

2018-01-01

Neurodevelopmental disorders such as fragile X syndrome (FXS) result in lifelong cognitive and behavioural deficits and represent a major public health burden. FXS is the most frequent monogenic form of intellectual disability and autism, and the underlying pathophysiology linked to its causal ge......, FMR1, has been the focus of intense research. Key alterations in synaptic function thought to underlie this neurodevelopmental disorder have been characterized and rescued in animal models of FXS using genetic and pharmacological approaches. These robust preclinical findings have led...... to the implementation of the most comprehensive drug development programme undertaken thus far for a genetically defined neurodevelopmental disorder, including phase IIb trials of metabotropic glutamate receptor 5 (mGluR5) antagonists and a phase III trial of a GABAB receptor agonist. However, none of the trials has...... been able to unambiguously demonstrate efficacy, and they have also highlighted the extent of the knowledge gaps in drug development for FXS and other neurodevelopmental disorders. In this Review, we examine potential issues in the previous studies and future directions for preclinical and clinical...

Age-Dependent Cellular and Behavioral Deficits Induced by Molecularly Targeted Drugs Are Reversible.

Science.gov (United States)

Scafidi, Joseph; Ritter, Jonathan; Talbot, Brooke M; Edwards, Jorge; Chew, Li-Jin; Gallo, Vittorio

2018-04-15

Newly developed targeted anticancer drugs inhibit signaling pathways commonly altered in adult and pediatric cancers. However, as these pathways are also essential for normal brain development, concerns have emerged of neurologic sequelae resulting specifically from their application in pediatric cancers. The neural substrates and age dependency of these drug-induced effects in vivo are unknown, and their long-term behavioral consequences have not been characterized. This study defines the age-dependent cellular and behavioral effects of these drugs on normally developing brains and determines their reversibility with post-drug intervention. Mice at different postnatal ages received short courses of molecularly targeted drugs in regimens analagous to clinical treatment. Analysis of rapidly developing brain structures important for sensorimotor and cognitive function showed that, while adult administration was without effect, earlier neonatal administration of targeted therapies attenuated white matter oligodendroglia and hippocampal neuronal development more profoundly than later administration, leading to long-lasting behavioral deficits. This functional impairment was reversed by rehabilitation with physical and cognitive enrichment. Our findings demonstrate age-dependent, reversible effects of these drugs on brain development, which are important considerations as treatment options expand for pediatric cancers. Significance: Targeted therapeutics elicit age-dependent long-term consequences on the developing brain that can be ameliorated with environmental enrichment. Cancer Res; 78(8); 2081-95. ©2018 AACR . ©2018 American Association for Cancer Research.

Adolescent Brain Development and Drugs

Science.gov (United States)

Winters, Ken C.; Arria, Amelia

2011-01-01

Research now suggests that the human brain is still maturing during adolescence. The developing brain may help explain why adolescents sometimes make decisions that are risky and can lead to safety or health concerns, including unique vulnerabilities to drug abuse. This article explores how this new science may be put to use in our prevention and…

A Development of Hybrid Drug Information System Using Image Recognition

Directory of Open Access Journals (Sweden)

HwaMin Lee

2015-04-01

Full Text Available In order to prevent drug abuse or misuse cases and avoid over-prescriptions, it is necessary for medicine taker to be provided with detailed information about the medicine. In this paper, we propose a drug information system and develop an application to provide information through drug image recognition using a smartphone. We designed a contents-based drug image search algorithm using the color, shape and imprint of drug. Our convenient application can provide users with detailed information about drugs and prevent drug misuse.

The basics of preclinical drug development for neurodegenerative disease indications

Directory of Open Access Journals (Sweden)

Spack Edward G

2009-06-01

Full Text Available Abstract Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA Good Laboratory Practices and international guidelines, including the International Conference on Harmonisation. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s. Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot

Application of PBPK modelling in drug discovery and development at Pfizer.

Science.gov (United States)

Jones, Hannah M; Dickins, Maurice; Youdim, Kuresh; Gosset, James R; Attkins, Neil J; Hay, Tanya L; Gurrell, Ian K; Logan, Y Raj; Bungay, Peter J; Jones, Barry C; Gardner, Iain B

2012-01-01

Early prediction of human pharmacokinetics (PK) and drug-drug interactions (DDI) in drug discovery and development allows for more informed decision making. Physiologically based pharmacokinetic (PBPK) modelling can be used to answer a number of questions throughout the process of drug discovery and development and is thus becoming a very popular tool. PBPK models provide the opportunity to integrate key input parameters from different sources to not only estimate PK parameters and plasma concentration-time profiles, but also to gain mechanistic insight into compound properties. Using examples from the literature and our own company, we have shown how PBPK techniques can be utilized through the stages of drug discovery and development to increase efficiency, reduce the need for animal studies, replace clinical trials and to increase PK understanding. Given the mechanistic nature of these models, the future use of PBPK modelling in drug discovery and development is promising, however, some limitations need to be addressed to realize its application and utility more broadly.

Design and Development of a Proniosomal Transdermal Drug ...

African Journals Online (AJOL)

Purpose: The aim of the study was to develop a proniosomal carrier system for captopril for the treatment of hypertension that is capable of efficiently delivering entrapped drug over an extended period of time. Method: The potential of proniosomes as a transdermal drug delivery system for captopril was investigated by ...

Visual System Involvement in Patients with Newly Diagnosed Parkinson Disease.

Science.gov (United States)

Arrigo, Alessandro; Calamuneri, Alessandro; Milardi, Demetrio; Mormina, Enricomaria; Rania, Laura; Postorino, Elisa; Marino, Silvia; Di Lorenzo, Giuseppe; Anastasi, Giuseppe Pio; Ghilardi, Maria Felice; Aragona, Pasquale; Quartarone, Angelo; Gaeta, Michele

2017-12-01

Purpose To assess intracranial visual system changes of newly diagnosed Parkinson disease in drug-naïve patients. Materials and Methods Twenty patients with newly diagnosed Parkinson disease and 20 age-matched control subjects were recruited. Magnetic resonance (MR) imaging (T1-weighted and diffusion-weighted imaging) was performed with a 3-T MR imager. White matter changes were assessed by exploring a white matter diffusion profile by means of diffusion-tensor imaging-based parameters and constrained spherical deconvolution-based connectivity analysis and by means of white matter voxel-based morphometry (VBM). Alterations in occipital gray matter were investigated by means of gray matter VBM. Morphologic analysis of the optic chiasm was based on manual measurement of regions of interest. Statistical testing included analysis of variance, t tests, and permutation tests. Results In the patients with Parkinson disease, significant alterations were found in optic radiation connectivity distribution, with decreased lateral geniculate nucleus V2 density (F, -8.28; P Parkinson disease and that the entire intracranial visual system can be involved. © RSNA, 2017 Online supplemental material is available for this article.

Use of biomarkers in ALS drug development and clinical trials.

Science.gov (United States)

Bakkar, Nadine; Boehringer, Ashley; Bowser, Robert

2015-05-14

The past decade has seen a dramatic increase in the discovery of candidate biomarkers for ALS. These biomarkers typically can either differentiate ALS from control subjects or predict disease course (slow versus fast progression). At the same time, late-stage clinical trials for ALS have failed to generate improved drug treatments for ALS patients. Incorporation of biomarkers into the ALS drug development pipeline and the use of biologic and/or imaging biomarkers in early- and late-stage ALS clinical trials have been absent and only recently pursued in early-phase clinical trials. Further clinical research studies are needed to validate biomarkers for disease progression and develop biomarkers that can help determine that a drug has reached its target within the central nervous system. In this review we summarize recent progress in biomarkers across ALS model systems and patient population, and highlight continued research directions for biomarkers that stratify the patient population to enrich for patients that may best respond to a drug candidate, monitor disease progression and track drug responses in clinical trials. It is crucial that we further develop and validate ALS biomarkers and incorporate these biomarkers into the ALS drug development process. This article is part of a Special Issue entitled ALS complex pathogenesis. Copyright © 2014 Elsevier B.V. All rights reserved.

[Significance of re-evaluation and development of Chinese herbal drugs].

Science.gov (United States)

Gao, Yue; Ma, Zengchun; Zhang, Boli

2012-01-01

The research of new herbal drugs involves in new herbal drugs development and renew the old drugs. It is necessary to research new herbal drugs based on the theory of traditional Chinese medicine (TCM). The current development of famous TCM focuses on the manufacture process, quality control standards, material basis and clinical research. But system management of security evaluation is deficient, the relevant system for the safety assessment TCM has not been established. The causes of security problems, security risks, target organ of toxicity, weak link of safety evaluation, and ideas of safety evaluation are discussed in this paper. The toxicology research of chinese herbal drugs is necessary based on standard of good laboratory practices (GLP), the characteristic of Chinese herbal drugs is necessary to be fully integrated into safety evaluation. The safety of new drug research is necessary to be integrated throughout the entire process. Famous Chinese medicine safety research must be paid more attention in the future.

Reflection of successful anticancer drug development processes in the literature.

Science.gov (United States)

Heinemann, Fabian; Huber, Torsten; Meisel, Christian; Bundschus, Markus; Leser, Ulf

2016-11-01

The development of cancer drugs is time-consuming and expensive. In particular, failures in late-stage clinical trials are a major cost driver for pharmaceutical companies. This puts a high demand on methods that provide insights into the success chances of new potential medicines. In this study, we systematically analyze publication patterns emerging along the drug discovery process of targeted cancer therapies, starting from basic research to drug approval - or failure. We find clear differences in the patterns of approved drugs compared with those that failed in Phase II/III. Feeding these features into a machine learning classifier allows us to predict the approval or failure of a targeted cancer drug significantly better than educated guessing. We believe that these findings could lead to novel measures for supporting decision making in drug development. Copyright © 2016 Elsevier Ltd. All rights reserved.

Conventional and improved cytotoxicity test methods of newly developed biodegradable magnesium alloys

Science.gov (United States)

Han, Hyung-Seop; Kim, Hee-Kyoung; Kim, Yu-Chan; Seok, Hyun-Kwang; Kim, Young-Yul

2015-11-01

Unique biodegradable property of magnesium has spawned countless studies to develop ideal biodegradable orthopedic implant materials in the last decade. However, due to the rapid pH change and extensive amount of hydrogen gas generated during biocorrosion, it is extremely difficult to determine the accurate cytotoxicity of newly developed magnesium alloys using the existing methods. Herein, we report a new method to accurately determine the cytotoxicity of magnesium alloys with varying corrosion rate while taking in-vivo condition into the consideration. For conventional method, extract quantities of each metal ion were determined using ICP-MS and the result showed that the cytotoxicity due to pH change caused by corrosion affected the cell viability rather than the intrinsic cytotoxicity of magnesium alloy. In physiological environment, pH is regulated and adjusted within normal pH (˜7.4) range by homeostasis. Two new methods using pH buffered extracts were proposed and performed to show that environmental buffering effect of pH, dilution of the extract, and the regulation of eluate surface area must be taken into consideration for accurate cytotoxicity measurement of biodegradable magnesium alloys.

[Does the public sector have an independent research role in the development of drugs?].

Science.gov (United States)

Poulsen, Henrik Enghusen; Grønlykke, Thor Buch

2003-04-14

Exclusively private companies do drug development. The State contributes with education of academics and basic research constituting the basis of half of the drugs developed by the private companies. The Danish private drug research amounts to six billion DKK per year, corresponding to the estimated price of the development of one new drug. The development shows a negative tendency. There are doubts about the scientific credibility, the number of new drugs is declining, drug development costs are rising, and the competitiveness in Europe is declining compared with the one of The United States. Continued improvement of Danish drug development can be achieved by stimulation of the public research related to drug development.

Pharmacogenomics and its potential impact on drug and formulation development.

Science.gov (United States)

Regnstrom, Karin; Burgess, Diane J

2005-01-01

Recent advances in genomic research have provided the basis for new insights into the importance of genetic and genomic markers during the different stages of drug development. A new field of research, pharmacogenomics, which studies the relationship between drug effects and the genome, has emerged. Structural pharmacogenomics maps the complete DNA sequences of whole genomes (genotypes) including individual variations, and functional pharmacogenomics assesses the expression levels of thousands of genes in one single experiment. Together, these two areas of pharmacogenomics have generated massive databases, which have become a challenge for the research field of informatics and have fostered a new branch of research, bioinformatics. If skillfully used, the databases generated by pharmacogenomics together with data mining on the Web promise to improve the drug development process in a variety of areas: identification of drug targets, evaluation of toxicity, classification of diseases, evaluation of formulations, assessment of drug response and treatment, post-marketing applications, and development of personalized medicines.

The Development Impact of the Illegality of Drug Trade

OpenAIRE

Keefer, Philip; Loayza, Norman V.; Soares, Rodrigo R.

2008-01-01

This paper reviews the unintended consequences of the war on drugs, particularly for developing countries, and weighs them against the evidence regarding the efficacy of prohibition to curb drug use and trade. It reviews the available evidence and presents new results that indicate that prohibition has limited effects on drug prevalence and prices, most likely indicating a combination of i...

Do national drug policies influence antiretroviral drug prices? Evidence from the Southern African Development community.

Science.gov (United States)

Liu, Yao; Galárraga, Omar

2017-03-01

The efficacy of low- and middle-income countries’ (LMIC) national drug policies in managing antiretroviral (ARV) pharmaceutical prices is not well understood. Though ARV drug prices have been declining in LMIC over the past decade, little research has been done on the role of their national drug policies. This study aims to (i) analyse global ARV prices from 2004 to 2013 and (ii) examine the relationship of national drug policies to ARV prices. Analysis of ARV drug prices utilized data from the Global Price Reporting Mechanism from the World Health Organization (WHO). Ten of the most common ARV drugs (first-line and second-line) were selected. National drug policies were also assessed for 12 countries in the South African Development Community (SADC), which self-reported their policies through WHO surveys. The best predictor of ARV drug price was generic status—the generic versions of 8 out of 10 ARV drugs were priced lower than branded versions. However, other factors such as transaction volume, HIV prevalence, national drug policies and PEPFAR/CHAI involvement were either not associated with ARV drug price or were not consistent predictors of price across different ARV drugs. In the context of emerging international trade agreements, which aim to strengthen patent protections internationally and potentially delay the sale of generic drugs in LMIC, this study shines a spotlight on the importance of generic drugs in controlling ARV prices. Further research is needed to understand the impact of national drug policies on ARV prices.

Evaluation of Shielding Performance for Newly Developed Composite Materials

Science.gov (United States)

Evans, Beren Richard

This work details an investigation into the contributing factors behind the success of newly developed composite neutron shield materials. Monte Carlo simulation methods were utilized to assess the neutron shielding capabilities and secondary radiation production characteristics of aluminum boron carbide, tungsten boron carbide, bismuth borosilicate glass, and Metathene within various neutron energy spectra. Shielding performance and secondary radiation data suggested that tungsten boron carbide was the most effective composite material. An analysis of the macroscopic cross-section contributions from constituent materials and interaction mechanisms was then performed in an attempt to determine the reasons for tungsten boron carbide's success over the other investigated materials. This analysis determined that there was a positive correlation between a non-elastic interaction contribution towards a material's total cross-section and shielding performance within the thermal and epi-thermal energy regimes. This finding was assumed to be a result of the boron-10 absorption reaction. The analysis also determined that within the faster energy regions, materials featuring higher non-elastic interaction contributions were comparable to those exhibiting primarily elastic scattering via low Z elements. This allowed for the conclusion that composite shield success within higher energy neutron spectra does not necessitate the use elastic scattering via low Z elements. These findings suggest that the inclusion of materials featuring high thermal absorption properties is more critical to composite neutron shield performance than the presence of constituent materials more inclined to maximize elastic scattering energy loss.

The role of radiolabelled compounds in preclinical drug development

International Nuclear Information System (INIS)

Hawkins, D.R.

1988-01-01

The role of radiolabelled compounds in the development of new drugs is discussed, with particular reference to their use in toxicological, metabolic and pharmacokinetic studies for the pre-clinical safety evaluation of new drugs. (U.K.)

A Trojan horse in drug development

DEFF Research Database (Denmark)

Christensen, Søren Brøgger; Skytte, Dorthe Mondrup; Denmeade, Samuel R

2009-01-01

Available chemotherapeutics take advantage of the fast proliferation of cancer cells. Consequently slow growth makes androgen refractory prostate cancer resistant towards available drugs. No treatment is available at the present, when the cancer has developed metastases outside the prostate (T4 s...

Novel 3D Culture Systems for Studies of Human Liver Function and Assessments of the Hepatotoxicity of Drugs and Drug Candidates.

Science.gov (United States)

Lauschke, Volker M; Hendriks, Delilah F G; Bell, Catherine C; Andersson, Tommy B; Ingelman-Sundberg, Magnus

2016-12-19

The liver is an organ with critical importance for drug treatment as the disposition and response to a given drug is often determined by its hepatic metabolism. Patient-specific factors can entail increased susceptibility to drug-induced liver injury, which constitutes a major risk for drug development programs causing attrition of promising drug candidates or costly withdrawals in postmarketing stages. Hitherto, mainly animal studies and 2D hepatocyte systems have been used for the examination of human drug metabolism and toxicity. Yet, these models are far from satisfactory due to extensive species differences and because hepatocytes in 2D cultures rapidly dedifferentiate resulting in the loss of their hepatic phenotype and functionality. With the increasing comprehension that 3D cell culture systems more accurately reflect in vivo physiology, in the recent decade more and more research has focused on the development and optimization of various 3D culture strategies in an attempt to preserve liver properties in vitro. In this contribution, we critically review these developments, which have resulted in an arsenal of different static and perfused 3D models. These systems include sandwich-cultured hepatocytes, spheroid culture platforms, and various microfluidic liver or multiorgan biochips. Importantly, in many of these models hepatocytes maintain their phenotype for prolonged times, which allows probing the potential of newly developed chemical entities to cause chronic hepatotoxicity. Moreover, some platforms permit the investigation of drug action in specific genetic backgrounds or diseased hepatocytes, thereby significantly expanding the repertoire of tools to detect drug-induced liver injuries. It is concluded that the development of 3D liver models has hitherto been fruitful and that systems are now at hand whose sensitivity and specificity in detecting hepatotoxicity are superior to those of classical 2D culture systems. For the future, we highlight the

78 FR 68459 - Medical Device Development Tools; Draft Guidance for Industry, Tool Developers, and Food and Drug...

Science.gov (United States)

2013-11-14

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2013-D-1279] Medical Device Development Tools; Draft Guidance for Industry, Tool Developers, and Food and Drug Administration Staff; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food...

Developing drug formularies for the "National Medical Holding" JSC.

Science.gov (United States)

Akhmadyar, N S; Khairulin, B E; Amangeldy-Kyzy, S; Ospanov, M A

2015-01-01

One of the main problems of drug provision of multidisciplinary hospitals is the necessity to improve the efficiency of budget spending. Despite the efforts undertaken in Kazakhstan for improving the mechanism of drug distribution (creation of the Kazakhstan National Formulary, Unified National Health System, the handbook of medicines (drugs) costs in the electronic register of inpatients (ERI), having a single distributor), the number of unresolved issues still remain."National Medical Holding" JSC (NMH) was established in 2008 and unites 6 innovational healthcare facilities with up to 1431 beds (700 children and 731 adults), located in the medical cluster - which are "National Research Center for Maternal and Child Health" JSC (NRCMC), "Republic Children's Rehabilitation Center" JSC (RCRC), "Republican Diagnostic Center" JSC (RDC), "National Centre for Neurosurgery" JSC (NCN), "National Research Center for Oncology and Transplantation" JSC (NRCOT) and "National Research Cardiac Surgery Center" JSC (NRCSC). The main purpose of NMH is to create an internationally competitive "Hospital of the Future", which will provide the citizens of Kazakhstan and others with a wide range of medical services based on advanced medical technology, modern hospital management, international quality and safety standards. These services include emergency care, outpatient diagnostic services, obstetrics and gynecology, neonatal care, internal medicine, neurosurgery, cardiac surgery, transplantation, cancer care for children and adults, as well as rehabilitation treatment. To create a program of development of a drug formulary of NMH and its subsidiaries. In order to create drug formularies of NMH, analytical, software and statistical methods were used.AII subsidiary organizations of NMH (5 out of 6) except for the NRCOT have been accredited by Joint Commission International (JCI) standards, which ensure the safety of patients and clinical staff, by improving the technological

Drug Development for Metastasis Prevention.

Science.gov (United States)

Fontebasso, Yari; Dubinett, Steven M

2015-01-01

Metastatic disease is responsible for 90% of death from solid tumors. However, only a minority of metastasis-specific targets has been exploited therapeutically, and effective prevention and suppression of metastatic disease is still an elusive goal. In this review, we will first summarize the current state of knowledge about the molecular features of the disease, with particular focus on steps and targets potentially amenable to therapeutic intervention. We will then discuss the reasons underlying the paucity of metastatic drugs in the current oncological arsenal and potential ways to overcome this therapeutic gap. We reason that the discovery of novel promising targets, an increased understanding of the molecular features of the disease, the effect of disruptive technologies, and a shift in the current preclinical and clinical settings have the potential to create more successful drug development endeavors.

DEVELOPMENT OF DOMESTIC INFUSION DRUGS BASED ON PARACETAMOL

Directory of Open Access Journals (Sweden)

Almakaeva L.G.

2016-06-01

Full Text Available The intravenous form of paracetamol compared with oral more reliably supports effective drug concentration in blood plasma that promotes a higher therapeutic effect. Recent studies have confirmed that the use of the intravenous form of paracetamol to deal with postoperative pain multimodal analgesia modes results in reducing the frequency and quantity of opioids administered , and, as a consequence, its associated side effects. The drug Paracetamol , infusion solution 10 mg / ml to 100 ml glass bottles is a drug - generic . His qualitative and quantitative composition is developed from the study of literature data about the drug - similar to " Perfalhan , 10 mg / ml solution for infusion in 100 mL " company Bristol - Myers Squibb, France and experimental work. The aim of our study is development and support of the national composition of the infusion of the drug on the basis of paracetamol, selection of excipients that provide stability of the active substances. Materials and methods. The object of the study was the substance of paracetamol manufactured by Zhejiang Kangle Pharmaceutical Co. , Ltd, China. During the work conducted qualitative and quantitative monitoring sample preparation for indicators of stability: pH content of the active ingredient , transparency, color, impurities , contamination by the methods described in the SFU [and nor- ral documentation to the drug . One potential factor of instability is the effect of paracetamol oxygen, due to the presence in the molecule of paracetamol and -NH possibility of oxidation. Results and Discussion. Paracetamol is derived atsetamina . Substance acetylation are p - aminophenol with acetic anhydride . Saturated aqueous solution has a pH of paracetamol - ment about 6 . Paracetamol is a crystalline white powder , sparingly soluble in water, soluble in 96% alcohol, very slightly soluble in metilenhloride . . Active substance enters in comparison drug in the concentration of 10 mg/ml. Stable

Melatonergic drugs in development

Directory of Open Access Journals (Sweden)

Carocci A

2014-09-01

Full Text Available Alessia Carocci,1 Alessia Catalano,1 Maria Stefania Sinicropi2 1Department of Pharmacy–Drug Sciences, University of Bari Aldo Moro, Bari, 2Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Cosenza, Italy Abstract: Melatonin (N-acetyl-5-methoxytryptamine is widely known as "the darkness hormone". It is a major chronobiological regulator involved in circadian phasing and sleep-wake cycle in humans. Numerous other functions, including cyto/neuroprotection, immune modulation, and energy metabolism have been ascribed to melatonin. A variety of studies have revealed a role for melatonin and its receptors in different pathophysiological conditions. However, the suitability of melatonin as a drug is limited because of its short half-life, poor oral bioavailability, and ubiquitous action. Due to the therapeutic potential of melatonin in a wide variety of clinical conditions, the development of new agents able to interact selectively with melatonin receptors has become an area of great interest during the last decade. Therefore, the field of melatonergic receptor agonists comprises a great number of structurally different chemical entities, which range from indolic to nonindolic compounds. Melatonergic agonists are suitable for sleep disturbances, neuropsychiatric disorders related to circadian dysphasing, and metabolic diseases associated with insulin resistance. The results of preclinical studies on animal models show that melatonin receptor agonists can be considered promising agents for the treatment of central nervous system-related pathologies. An overview of recent advances in the field of investigational melatonergic drugs will be presented in this review. Keywords: MT1/MT2 ligands, circadian rhythms, melatonin 

Heterocyclic Scaffolds: Centrality in Anticancer Drug Development.

Science.gov (United States)

Ali, Imran; Lone, Mohammad Nadeem; Al-Othman, Zeid A; Al-Warthan, Abdulrahman; Sanagi, Mohd Marsin

2015-01-01

Cancer has been cursed for human beings for long time. Millions people lost their lives due to cancer. Despite of the several anticancer drugs available, cancer cannot be cured; especially at the late stages without showing any side effect. Heterocyclic compounds exhibit exciting medicinal properties including anticancer. Some market selling heterocyclic anticancer drugs include 5-flourouracil, methortrexate, doxorubicin, daunorubicin, etc. Besides, some natural products such as vinblastine and vincristine are also used as anticancer drugs. Overall, heterocyclic moeities have always been core parts in the expansion of anticancer drugs. This article describes the importance of heterocyclic nuclei in the development of anticancer drugs. Besides, the attempts have been made to discuss both naturally occurring and synthetic heterocyclic compounds as anticancer agents. In addition, some market selling anticancer heterocyclic compounds have been described. Moreover, the efforts have been made to discuss the mechanisms of actions and recent advances in heterocyclic compounds as anticancer agents. The current challenges and future prospectives of heterocyclic compounds have also been discussed. Finally, the suggestions for syntheses of effective, selective, fast and human friendly anticancer agents are discussed into the different sections.

Combustion, performance and emissions characteristics of a newly ...

Indian Academy of Sciences (India)

of a newly developed CRDI single cylinder diesel engine. AVINASH ... In case of unit injector and unit pump systems, fuel injection pressure depends on ... nozzle hole diameters were effective in reducing smoke and PM emissions. However ...

Anti-influenza drugs: the development of sialidase inhibitors.

Science.gov (United States)

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.

Large-scale structural and textual similarity-based mining of knowledge graph to predict drug-drug interactions

KAUST Repository

Abdelaziz, Ibrahim; Fokoue, Achille; Hassanzadeh, Oktie; Zhang, Ping; Sadoghi, Mohammad

2017-01-01

Drug-Drug Interactions (DDIs) are a major cause of preventable Adverse Drug Reactions (ADRs), causing a significant burden on the patients’ health and the healthcare system. It is widely known that clinical studies cannot sufficiently and accurately identify DDIs for new drugs before they are made available on the market. In addition, existing public and proprietary sources of DDI information are known to be incomplete and/or inaccurate and so not reliable. As a result, there is an emerging body of research on in-silico prediction of drug-drug interactions. In this paper, we present Tiresias, a large-scale similarity-based framework that predicts DDIs through link prediction. Tiresias takes in various sources of drug-related data and knowledge as inputs, and provides DDI predictions as outputs. The process starts with semantic integration of the input data that results in a knowledge graph describing drug attributes and relationships with various related entities such as enzymes, chemical structures, and pathways. The knowledge graph is then used to compute several similarity measures between all the drugs in a scalable and distributed framework. In particular, Tiresias utilizes two classes of features in a knowledge graph: local and global features. Local features are derived from the information directly associated to each drug (i.e., one hop away) while global features are learnt by minimizing a global loss function that considers the complete structure of the knowledge graph. The resulting similarity metrics are used to build features for a large-scale logistic regression model to predict potential DDIs. We highlight the novelty of our proposed Tiresias and perform thorough evaluation of the quality of the predictions. The results show the effectiveness of Tiresias in both predicting new interactions among existing drugs as well as newly developed drugs.

Large-scale structural and textual similarity-based mining of knowledge graph to predict drug-drug interactions

KAUST Repository

Abdelaziz, Ibrahim

2017-06-12

Drug-Drug Interactions (DDIs) are a major cause of preventable Adverse Drug Reactions (ADRs), causing a significant burden on the patients’ health and the healthcare system. It is widely known that clinical studies cannot sufficiently and accurately identify DDIs for new drugs before they are made available on the market. In addition, existing public and proprietary sources of DDI information are known to be incomplete and/or inaccurate and so not reliable. As a result, there is an emerging body of research on in-silico prediction of drug-drug interactions. In this paper, we present Tiresias, a large-scale similarity-based framework that predicts DDIs through link prediction. Tiresias takes in various sources of drug-related data and knowledge as inputs, and provides DDI predictions as outputs. The process starts with semantic integration of the input data that results in a knowledge graph describing drug attributes and relationships with various related entities such as enzymes, chemical structures, and pathways. The knowledge graph is then used to compute several similarity measures between all the drugs in a scalable and distributed framework. In particular, Tiresias utilizes two classes of features in a knowledge graph: local and global features. Local features are derived from the information directly associated to each drug (i.e., one hop away) while global features are learnt by minimizing a global loss function that considers the complete structure of the knowledge graph. The resulting similarity metrics are used to build features for a large-scale logistic regression model to predict potential DDIs. We highlight the novelty of our proposed Tiresias and perform thorough evaluation of the quality of the predictions. The results show the effectiveness of Tiresias in both predicting new interactions among existing drugs as well as newly developed drugs.

Actors of Columbian drug trade : development and transformation

Directory of Open Access Journals (Sweden)

Soňa Smolíková

2011-06-01

Full Text Available The aim of this article is to portray the main shifts which have been taking place in Colombian drug scene since the 70’s up to the present especially in relation to actors of this business and form of their activity. At first the development of Colombian drug trade till the 80’s when two big cartels centered in Medellín and Cali arose will be briefly outlined. These cartels were able to control a great part of domestic drug trade and due to their enormous power represented serious threat to Colombian state. Thus the cartels declared open warfare with the state in the 80’s. After the cartels’ elimination in the middle of 90’s new actors represented by small drug organizations arose in Colombian drug scene. These small groups were dependent upon cooperation with foreign partners, especially with Mexican cartels. Ever more important role in drug business is played by Colombian left-wing guerilla groups which will be described in the next part of the article. The problem of right-wing paramilitary groups and their participation in Colombian drug trade will be mentioned as well.

The use of newly developed real-time PCR for the rapid identification of bacteria in culture-negative osteomyelitis.

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Kobayashi, Naomi; Bauer, Thomas W; Sakai, Hiroshige; Togawa, Daisuke; Lieberman, Isador H; Fujishiro, Takaaki; Procop, Gary W

2006-12-01

We report a case of a culture-negative osteomyelitis in which our newly developed real-time polymerase chain reaction (PCR) could differentiate Staphylococcus aureus from Staphylococcus epidermidis. This is the first report that described the application of this novel assay to an orthopedics clinical sample. This assay may be useful for other clinical culture-negative cases in a combination with a broad-spectrum assay as a rapid microorganism identification method.

Drug-diagnostics co-development in oncology

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Richard eSimon

2013-12-01

Full Text Available Developments in genomics are providing a biological basis for the heterogeneity of clinical course and response to treatment that have long been apparent to clinicians The ability to molecularly characterize of human diseases presents new opportunities to develop more effective treatments and new challenges for the design and analysis of clinical trials.In oncology, treatment of broad populations with regimens that benefit a minority of patients is less economically sustainable with expensive molecularly targeted therapeutics. The established molecular heterogeneity of human diseases requires the development of new paradigms for the design and analysis of randomized clinical trials as a reliable basis for predictive medicine. We review prospective designs for the development of new therapeutics and predictive biomarkers to inform their use. We cover designs for a wide range of settings. At one extreme is the development of a new drug with a single candidate biomarker and strong biological evidence that marker negative patients are unlikely to benefit from the new drug. At the other extreme are phase III clinical trials involving both genome-wide discovery of a predictive classifier and internal validation of that classifier. We have outlined a prediction based approach to the analysis of randomized clinical trials that both preserves the type I error and provides a reliable internally validated basis for predicting which patients are most likely or unlikely to benefit from a new regimen.

Laboratory monitoring of patients treated with antihypertensive drugs and newly exposed to non steroidal anti-inflammatory drugs: a cohort study.

Directory of Open Access Journals (Sweden)

Jean-Pascal Fournier

Full Text Available BACKGROUND: Drug-Drug Interactions between Non Steroidal Anti-Inflammatory Drugs (NSAIDs and Angiotensin Converting Enzyme Inhibitors (ACEIs, Angiotensin Receptor Blocker (ARBs or diuretics can lead to renal failure and hyperkalemia. Thus, monitoring of serum creatinine and potassium is recommended when a first dispensing of NSAID occur in patients treated with these drugs. METHODS: We conducted a pharmacoepidemiological retrospective cohort study using data from the French Health Insurance Reimbursement Database to evaluate the proportion of serum creatinine and potassium laboratory monitoring in patients treated with ACEI, ARB or diuretic and receiving a first dispensing of NSAID. We described the first dispensing of NSAID among 3,500 patients of a 4-year cohort (6,633 patients treated with antihypertensive drugs and analyzed serum creatinine and potassium laboratory monitoring within the 3 weeks after the first NSAID dispensing. RESULTS: General Practitioners were the most frequent prescribers of NSAIDs (85.5%, 95% CI: 84.3-86.6. The more commonly prescribed NSAIDs were ibuprofen (20%, ketoprofen (15%, diclofenac (15% and piroxicam (12%. Serum creatinine and potassium monitoring was 10.7% (95% CI: 9.5-11.8 in patients treated by ACEIs, ARBs or diuretics. Overall, monitoring was more frequently performed to women aged over 60, treated with digoxin or glucose lowering drugs, but not to patients treated with ACEIs, ARBs or diuretics. Monitoring was more frequent when NSAIDs' prescribers were cardiologists or anesthesiologists. CONCLUSION: Monitoring of serum creatinine and potassium of patients treated with ACEIs, ARBs or diuretics and receiving a first NSAID dispensing is insufficiently performed and needs to be reinforced through specific interventions.

Cutaneous drug hypersensitivity : Immunological and genetic perspective

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Kisalay Ghosh

2011-01-01

Full Text Available Drug hypersensitivity is an unpredictable, immunologically mediated adverse reaction, clustered in a genetically predisposed individual. The role of "hapten concept" in immune sensitization has recently been contested by the "pharmacological interaction" hypothesis. After completion of the "human genome project" and with the availability of high-resolution genotyping, genetic susceptibility to hypersensitivity for certain drugs has been proved beyond doubt though the trend is ethnicity and phenotype dependent. Application of this newly acquired knowledge may reduce or abolish the morbidity and mortality associated with cutaneous drug hypersensitivity.

Perceptions of the clinical competence of newly registered nurses in the North West province

Directory of Open Access Journals (Sweden)

M.R. Moeti

2004-09-01

Full Text Available The clinical competence of newly registered nurses relating to the care of individual Clients, depends on their ability to correlate theoretical knowledge learned in the classroom with practice and the development of clinical skills. Its foundation lies in the ability to identify and solve problems that emanate from critical thinking, analytical reasoning and reflective practice. It is clear that the quality of clinical exposure plays a leading role in the development of nursing professionals. Nursing skills alone cannot ensure quality care of clients without the application of theory. Facilitation of this theory to practice therefore remains an essential component of nursing education. This study was aimed at identifying areas of incompetence of newly registered nurses (1998- 2001 in the clinical area by determining the newly registered nurses1 and professional nurses1 perceptions of the competence of the newly registered nurses. A quantitative, non-experimental, descriptive survey was used to collect the data regarding the clinical competence of newly registered nurses (1998-2001.

Ethical challenges in developing drugs for psychiatric disorders.

Science.gov (United States)

Carrier, Felix; Banayan, David; Boley, Randy; Karnik, Niranjan

2017-05-01

As the classification of mental disorders advances towards a disease model as promoted by the National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC), there is hope that a more thorough neurobiological understanding of mental illness may allow clinicians and researchers to determine treatment efficacy with less diagnostic variability. This paradigm shift has presented a variety of ethical issues to be considered in the development of psychiatric drugs. These challenges are not limited to informed consent practices, industry funding, and placebo use. The consideration for alternative research models and quality of research design also present ethical challenges in the development of psychiatric drugs. The imperatives to create valid and sound research that justify the human time, cost, risk and use of limited resources must also be considered. Clinical innovation, and consideration for special populations are also important aspects to take into account. Based on the breadth of these ethical concerns, it is particularly important that scientific questions regarding the development of psychiatric drugs be answered collaboratively by a variety of stakeholders. As the field expands, new ethical considerations will be raised with increased focus on genetic markers, personalized medicine, patient-centered outcomes research, and tension over funding. We suggest that innovation in trial design is necessary to better reflect practices in clinical settings and that there must be an emphasized focus on expanding the transparency of consent processes, regard for suicidality, and care in working with special populations to support the goal of developing sound psychiatric drug therapies. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Improvement of Pediatric Drug Development: Regulatory and Practical Frameworks.

Science.gov (United States)

Tsukamoto, Katusra; Carroll, Kelly A; Onishi, Taku; Matsumaru, Naoki; Brasseur, Daniel; Nakamura, Hidefumi

2016-03-01

A dearth in pediatric drug development often leaves pediatricians with no alternative but to prescribe unlicensed or off-label drugs with a resultant increased risk of adverse events. We present the current status of pediatric drug development and, based on our data analysis, clarify the problems in this area. Further action is proposed to improve the drug development that has pediatric therapeutic orphan status. We analyzed all Phase II/III and Phase III trials in ClinicalTrials.gov that only included pediatric participants (Performance index, an indicator of pediatric drug development, was calculated by dividing the annual number of pediatric clinical trials by million pediatric populations acquired from Census.gov. Effects of the 2 Japanese premiums introduced in 2010, for the enhancement of pediatric drug development, were analyzed by comparing mean performance index prepremiums (2006-2009) and postpremiums (2010-2014) among Japan, the European Union, and the United States. The European Union Clinical Trials Register and published reports from the European Medicines Agency were also surveyed to investigate the Paediatric Committee effect on pediatric clinical trials in the European Union. Mean difference of the performance index in prepremiums and postpremiums between Japan and the European Union were 0.296 (P 15% after 2008. Recruitment and ethical obstacles make conducting pediatric clinical trials challenging. An improved operational framework for conducting clinical trials should mirror the ever-improving regulatory framework that incentivizes investment in pediatric clinical trials. Technological approaches, enhancements in electronic medical record systems, and community approaches that actively incorporate input from physicians, researchers, and patients could offer a sustainable solution to recruitment of pediatric study participants. The key therefore is to improve pediatric pharmacotherapy collaboration among industry, government, academia, and

Comorbidities and risk factors associated with newly diagnosed epilepsy in the U.S. pediatric population.

Science.gov (United States)

Oh, Ahyuda; Thurman, David J; Kim, Hyunmi

2017-10-01

Neurobehavioral comorbidities can be related to underlying etiology of epilepsy, epilepsy itself, and adverse effects of antiepileptic drugs. We examined the relationship between neurobehavioral comorbidities and putative risk factors for epilepsy in children with newly diagnosed epilepsy. We conducted a retrospective analysis of children aged ≤18years in 50 states and the District of Columbia, using the Truven Health MarketScan® commercial claims and encounters database from January 1, 2009 to December 31, 2013. The eligible study cohort was continuously enrolled throughout 2013 as well as enrolled for any days during a baseline period of at least the prior 2years. Newly diagnosed cases of epilepsy were defined by International Classification of Diseases, Ninth Revision, Clinical Modification-coded diagnoses of epilepsy or recurrent seizures and evidence of prescribed antiepileptic drugs during 2013, when neither seizure codes nor seizure medication claims were recorded during baseline periods. Twelve neurobehavioral comorbidities and eleven putative risk factors for epilepsy were measured. More than 6 million children were analyzed (male, 51%; mean age, 8.8years). A total of 7654 children were identified as having newly diagnosed epilepsy (125 per 100,000, 99% CI=122-129). Neurobehavioral comorbidities were more prevalent in children with epilepsy than children without epilepsy (60%, 99% CI=58.1-61.0 vs. 23%, CI=23.1-23.2). Children with epilepsy were far more likely to have multiple comorbidities (36%, 99% CI=34.3-37.1) than those without epilepsy (8%, 99% CI=7.45-7.51, Pepilepsy were detected in 28% (99% CI=26.9-29.6) of children with epilepsy. After controlling for demographics, neurobehavioral comorbidities, family history of epilepsy, and other risk factors than primary interest, neonatal seizures had the strongest independent association with the development of epilepsy (OR=29.8, 99% CI=23.7-37.3, Pepilepsy, those with both epilepsy and risk factors were

Measurement equivalence of the newly developed Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55).

Science.gov (United States)

Ferro, Mark A; Goodwin, Shane W; Sabaz, Mark; Speechley, Kathy N

2016-03-01

The aim of this study was to examine measurement equivalence of the newly developed Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55) across age, sex, and time in a representative sample of children with newly diagnosed epilepsy. Data come from 373 children enrolled in the Health-related Quality of Life in Children with Epilepsy Study (HERQULES), a multisite prospective cohort study. Measurement equivalence was examined using a multiple-group confirmatory factor analysis framework, whereby increasingly stringent parameter constraints are imposed on the model. Comparison groups were stratified based on age (4-7 years vs. 8-12 years), sex (male vs. female), and time (measurement of health-related quality of life at diagnosis vs. 24 months later). The QOLCE-55 demonstrated measurement equivalence at the level of strict invariance for each model tested--age: χ(2) (3,123) = 4,097.3, p QOLCE-55 are perceived similarly among groups stratified by age, sex, and time and provide further evidence supporting the validity of the scale in children with epilepsy. Health professionals and researchers should be confident that group comparisons made using the QOLCE-55 are unbiased and that any group differences detected are meaningful; that is, not related to differences in the interpretation of items by informants. Future research replicating these findings is encouraged. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

Practicing on Newly Dead

Directory of Open Access Journals (Sweden)

Jewel Abraham

2015-07-01

Full Text Available A newly dead cadaver simulation is practiced on the physical remains of the dead before the onset of rigor mortis. This technique has potential benefits for providing real-life in-situ experience for novice providers in health care practices. Evolving ethical views in health care brings into question some of the ethical aspects associated with newly dead cadaver simulation in terms of justification for practice, autonomy, consent, and the need of disclosure. A clear statement of policies and procedures on newly dead cadaver simulation has yet to be implemented. Although there are benefits and disadvantages to an in-situ cadaver simulation, such practices should not be carried out in secrecy as there is no compelling evidence that suggests such training as imperative. Secrecy in these practices is a violation of honor code of nursing ethics. As health care providers, practitioners are obliged to be ethically honest and trustworthy to their patients. The author explores the ethical aspects of using newly dead cadaver simulation in training novice nursing providers to gain competency in various lifesaving skills, which otherwise cannot be practiced on a living individual. The author explores multiple views on cadaver simulation in relation to ethical theories and practices such as consent and disclosure to family.

Newly qualified teachers´ possibilities to get foothold in a lifelong career course

DEFF Research Database (Denmark)

Krøjgaard, Frede; Frederiksen, Lisbeth Angela Lunde

Keyword: Induction program, newly qualified teachers, NQT, retention, professional development In Contrary to many other countries in Europe Denmark does not have any kind of national program regarding teacher induction program (TIP) or support in general to newly qualified teachers what so ever...

The practical skills of newly qualified nurses.

Science.gov (United States)

Danbjørg, Dorthe Boe; Birkelund, Regner

2011-02-01

This paper reports the findings from a study of newly qualified nurses and which subjects the nurses regarded as the most important in order to be able to live up to the requirements of clinical practice, and how they experience their potential for developing practical and moral skills, after the decrease in practical training. A qualitative approach guided the research process and the analysis of the data. The data was collected by participant observation and qualitative interviews with four nurses as informants. The conclusions made in this study are based on the statements and the observations of the newly qualified nurses. Our findings are discussed in relation to the Aristotelian concept and other relevant literature. The main message is that the newly qualified nurses did not feel equipped when they finished their training. This could be interpreted as a direct consequence of the decrease in practical training. Our study also underlines that the way nursing theory is perceived and taught is problematic. The interviews revealed that the nurses think that nursing theories should be applied directly in practice. This misunderstanding is probably also applicable to the teachers of the theories. Copyright © 2010 Elsevier Ltd. All rights reserved.

Comparison of newly developed anti-bone morphogenetic protein 4 llama-derived antibodies with commercially available BMP4 inhibitors.

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Calpe, Silvia; Correia, Ana C P; Sancho-Serra, Maria Del Carmen; Krishnadath, Kausilia K

2016-01-01

Due to improved understanding of the role of bone morphogenetic protein 4 (BMP4) in an increasing number of diseases, the development of selective inhibitors of BMP4 is an attractive therapeutic option. The currently available BMP4 inhibitors are not suitable as therapeutics because of their low specificity and low effectiveness. Here, we compared newly generated anti-BMP4 llama-derived antibodies (VHHs) with 3 different types of commercially available BMP4 inhibitors, natural antagonists, small molecule BMPR inhibitors and conventional anti-BMP4 monoclonal antibodies. We found that the anti-BMP4 VHHs were as effective as the natural antagonist or small molecule inhibitors, but had higher specificity. We also showed that commercial anti-BMP4 antibodies were inferior in terms of both specificity and effectiveness. These findings might result from the fact that the VHHs C4C4 and C8C8 target a small region within the BMPR1 epitope of BMP4, whereas the commercial antibodies target other areas of the BMP4 molecule. Our results show that the newly developed anti-BMP4 VHHs are promising antibodies with better specificity and effectivity for inhibition of BMP4, making them an attractive tool for research and for therapeutic applications.

Mixed WTO ruling on generic drug development.

Science.gov (United States)

Elliott, R

2000-01-01

On 17 March 2000, the World Trade Organization upheld the provision in Canada's patent laws that allows generic drug manufacturers to develop (but not sell) their cheaper versions of patented medicines before the 20-year patients expire. The decision prevents pharmaceutical companies from enjoying market monopolies beyond their patent terms, avoiding what would otherwise be even lengthier delays in the sale of cheaper, generic drugs in Canada. This decision is of significance not only to Canada, but also to other WTO member countries and to all individuals who use pharmaceutical products. However, the decision is not all positive: the WTO also ruled that Canada is violating international agreements by letting generic manufacturers stockpile their versions of patented drugs before patents expire. This article explains the issues, the arguments, and the decision.

A new roadmap for biopharmaceutical drug product development: Integrating development, validation, and quality by design.

Science.gov (United States)

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.

Integration of Antibody Array Technology into Drug Discovery and Development.

Science.gov (United States)

Huang, Wei; Whittaker, Kelly; Zhang, Huihua; Wu, Jian; Zhu, Si-Wei; Huang, Ruo-Pan

Antibody arrays represent a high-throughput technique that enables the parallel detection of multiple proteins with minimal sample volume requirements. In recent years, antibody arrays have been widely used to identify new biomarkers for disease diagnosis or prognosis. Moreover, many academic research laboratories and commercial biotechnology companies are starting to apply antibody arrays in the field of drug discovery. In this review, some technical aspects of antibody array development and the various platforms currently available will be addressed; however, the main focus will be on the discussion of antibody array technologies and their applications in drug discovery. Aspects of the drug discovery process, including target identification, mechanisms of drug resistance, molecular mechanisms of drug action, drug side effects, and the application in clinical trials and in managing patient care, which have been investigated using antibody arrays in recent literature will be examined and the relevance of this technology in progressing this process will be discussed. Protein profiling with antibody array technology, in addition to other applications, has emerged as a successful, novel approach for drug discovery because of the well-known importance of proteins in cell events and disease development.

Modeling the development of drug addiction in male and female animals.

Science.gov (United States)

Lynch, Wendy J

2018-01-01

An increasing emphasis has been placed on the development and use of animal models of addiction that capture defining features of human drug addiction, including escalation/binge drug use, enhanced motivation for the drug, preference for the drug over other reward options, use despite negative consequences, and enhanced drug-seeking/relapse vulnerability. The need to examine behavior in both males and females has also become apparent given evidence demonstrating that the addiction process occurs differently in males and females. This review discusses the procedures that are used to model features of addiction in animals, as well as factors that influence their development. Individual differences are also discussed, with a particular focus on sex differences. While no one procedure consistently produces all characteristics, different models have been developed to focus on certain characteristics. A history of escalating/binge patterns of use appears to be critical for producing other features characteristic of addiction, including an enhanced motivation for the drug, enhanced drug seeking, and use despite negative consequences. These characteristics tend to emerge over abstinence, and appear to increase rather than decrease in magnitude over time. In females, these characteristics develop sooner during abstinence and/or following less drug exposure as compared to males, and for psychostimulant addiction, may require estradiol. Although preference for the drug over other reward options has been demonstrated in non-human primates, it has been more difficult to establish in rats. Future research is needed to define the parameters that optimally induce each of these features of addiction in the majority of animals. Such models are essential for advancing our understanding of human drug addiction and its treatment in men and women. Copyright © 2017 Elsevier Inc. All rights reserved.

A primer of drug safety surveillance: an industry perspective. Part I: Information flow, new drug development, and federal regulations.

Science.gov (United States)

Allan, M C

1992-01-01

To place the fundamentals of clinical drug safety surveillance in a conceptual framework that will facilitate understanding and application of adverse drug event data to protect the health of the public and support a market for pharmaceutical manufacturers' products. Part I of this series provides a background for the discussion of drug safety by defining the basic terms and showing the flow of safety information through a pharmaceutical company. The customers for adverse drug event data are identified to provide a basis for providing quality service. The development of a drug product is briefly reviewed to show the evolution of safety data. Drug development and safety are defined by federal regulations. These regulations are developed by the FDA with information from pharmaceutical manufacturers. The intent of the regulations and the accompanying guidelines is described. An illustration from the news media is cited to show an alternative, positive approach to handling an adverse event report. This review uses primary sources from the federal laws (regulations), commentaries, and summaries. Very complex topics are briefly summarized in the text and additional readings are presented in an appendix. Secondary sources, ranging from newspaper articles to judicial summaries, illustrate the interpretation of adverse drug events and opportunities for drug safety surveillance intervention. The reference materials used were articles theoretically or practically applicable in the day-to-day practice of drug safety surveillance. The role of clinical drug safety surveillance in product monitoring and drug development is described. The process of drug safety surveillance is defined by the Food and Drug Administration regulations, product labeling, product knowledge, and database management. Database management is subdivided into the functions of receipt, retention, retrieval, and review of adverse event reports. Emphasis is placed on the dynamic interaction ;of the components

Development of a framework for identification of political environmental issues faced by multinational hotel chains in newly industrialized countries in Asia

OpenAIRE

Kim, Chol Yong

1992-01-01

The primary/objective of this study was to develop a framework for identification of political environmental issues faced by multinational hotel chains in newly industrialized countries in Asia. To accomplish the objective, key factors having an impact upon these hotel chains were identified using the Delphi Technique.

Development of a gastroretentive pulsatile drug delivery platform.

Science.gov (United States)

Thitinan, Sumalee; McConville, Jason T

2012-04-01

To develop a novel gastroretentive pulsatile drug delivery platform by combining the advantages of floating dosage forms for the stomach and pulsatile drug delivery systems. A gastric fluid impermeable capsule body was used as a vessel to contain one or more drug layer(s) as well as one or more lag-time controlling layer(s). A controlled amount of air was sealed in the innermost portion of the capsule body to reduce the overall density of the drug delivery platform, enabling gastric floatation. An optimal mass fill inside the gastric fluid impermeable capsule body enabled buoyancy in a vertical orientation to provide a constant surface area for controlled erosion of the lag-time controlling layer. The lag-time controlling layer consisted of a swellable polymer, which rapidly formed a gel to seal the mouth of capsule body and act as a barrier to gastric fluid ingress. By varying the composition of the lag-time controlling layer, it was possible to selectively program the onset of the pulsatile delivery of a drug. This new delivery platform offers a new method of delivery for a variety of suitable drugs targeted in chronopharmaceutical therapy. This strategy could ultimately improve drug efficacy and patient compliance, and reduce harmful side effects by scaling back doses of drug administered. © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.

Nano-formulations of drugs: Recent developments, impact and challenges.

Science.gov (United States)

Jeevanandam, Jaison; Chan, Yen San; Danquah, Michael K

2016-01-01

Nano-formulations of medicinal drugs have attracted the interest of many researchers for drug delivery applications. These nano-formulations enhance the properties of conventional drugs and are specific to the targeted delivery site. Dendrimers, polymeric nanoparticles, liposomes, nano-emulsions and micelles are some of the nano-formulations that are gaining prominence in pharmaceutical industry for enhanced drug formulation. Wide varieties of synthesis methods are available for the preparation of nano-formulations to deliver drugs in biological system. The choice of synthesis methods depend on the size and shape of particulate formulation, biochemical properties of drug, and the targeted site. This article discusses recent developments in nano-formulation and the progressive impact on pharmaceutical research and industries. Additionally, process challenges relating to consistent generation of nano-formulations for drug delivery are discussed. Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

[The trend of developing new disease-modifying drugs in Alzheimer's disease].

Science.gov (United States)

Arai, Hiroyuki; Furukawa, Katsutoshi; Tomita, Naoki; Ishiki, Aiko; Okamura, Nobuyuki; Kudo, Yukitsuka

2016-03-01

Development of symptomatic treatment of Alzheimer s disease by cholinesterase inhibitors like donepezil was successful. However, it is a disappointment that development of disease-modifying drugs such as anti-amyloid drug based on amyloid-cascade theory has been interrupted or unsuccessful. Therefore, we have to be more cautious regarding inclusion criteria for clinical trials of new drugs. We agree that potentially curative drugs should be started before symptoms begin as a preemptive therapy or prevention trial. The concept of personalized medicine also is important when ApoE4-related amyloid reducing therapy is considered. Unfortunately, Japanese-ADNI has suffered a setback since 2014. However, Ministry of Health, Labour and Welfare gave a final remark that there was nothing wrong in the data managing process in the J-ADNI data center. We should pay more attention to worldwide challenges of speeding up new drug development.

Newly Identified CYP2C93 Is a Functional Enzyme in Rhesus Monkey, but Not in Cynomolgus Monkey

OpenAIRE

Uno, Yasuhiro; Uehara, Shotaro; Kohara, Sakae; Iwasaki, Kazuhide; Nagata, Ryoichi; Fukuzaki, Koichiro; Utoh, Masahiro; Murayama, Norie; Yamazaki, Hiroshi

2011-01-01

Cynomolgus monkey and rhesus monkey are used in drug metabolism studies due to their evolutionary closeness and physiological resemblance to human. In cynomolgus monkey, we previously identified cytochrome P450 (P450 or CYP) 2C76 that does not have a human ortholog and is partly responsible for species differences in drug metabolism between cynomolgus monkey and human. In this study, we report characterization of CYP2C93 cDNA newly identified in cynomolgus monkey and rhesus monkey. The CYP2C9...

Development, implementation and management of a drug testing program in the workplace

Energy Technology Data Exchange (ETDEWEB)

Burtis, C.A.

1990-01-01

To combat the rising use of drugs in the workplace many American companies have implemented drug testing programs and are testing employees and job applicants for use of illegal drugs. In addition, on September 15, 1986, Executive Order No.12564 was issued by President Reagan, which requires all federal agencies to develop programs and policies, one of the goals of which is to achieve a drug-free federal workplace. Included in this Executive Order is the requirement that federal agencies implement drug testing has become a prevalent practice as a means to detect and deter drug use in the workplace. Before a drug testing program is implemented, it is imperative that policies and procedures are developed that (1) ensure the accuracy of test results, (2) protect the validity and integrity of the specimen, (3) guarantee due process, and (4) maintain confidentiality. To make certain that these prerequisites were met in the government drug testing programs, the US Department of Health and Human Services (HHS) was directed to develop technical and scientific guidelines for conducting such programs. 15 refs., 1 fig., 2 tabs.

Investigational drugs in early development for treating dengue infection.

Science.gov (United States)

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.

Preparative Scale Resolution of Enantiomers Enables Accelerated Drug Discovery and Development

Directory of Open Access Journals (Sweden)

Hanna Leek

2017-01-01

Full Text Available The provision of pure enantiomers is of increasing importance not only for the pharmaceutical industry but also for agro-chemistry and biotechnology. In drug discovery and development, the enantiomers of a chiral drug depict unique chemical and pharmacological behaviors in a chiral environment, such as the human body, in which the stereochemistry of the chiral drugs determines their pharmacokinetic, pharmacodynamic and toxicological properties. We present a number of challenging case studies of up-to-kilogram separations of racemic or enriched isomer mixtures using preparative liquid chromatography and super critical fluid chromatography to generate individual enantiomers that have enabled the development of new candidate drugs within AstraZeneca. The combination of chromatography and racemization as well as strategies on when to apply preparative chiral chromatography of enantiomers in a multi-step synthesis of a drug compound can further facilitate accelerated drug discovery and the early clinical evaluation of the drug candidates.

Potential drug development candidates for human soil-transmitted helminthiases.

Directory of Open Access Journals (Sweden)

Piero Olliaro

2011-06-01

Full Text Available Few drugs are available for soil-transmitted helminthiasis (STH; the benzimidazoles albendazole and mebendazole are the only drugs being used for preventive chemotherapy as they can be given in one single dose with no weight adjustment. While generally safe and effective in reducing intensity of infection, they are contra-indicated in first-trimester pregnancy and have suboptimal efficacy against Trichuris trichiura. In addition, drug resistance is a threat. It is therefore important to find alternatives.We searched the literature and the animal health marketed products and pipeline for potential drug development candidates. Recently registered veterinary products offer advantages in that they have undergone extensive and rigorous animal testing, thus reducing the risk, cost and time to approval for human trials. For selected compounds, we retrieved and summarised publicly available information (through US Freedom of Information (FoI statements, European Public Assessment Reports (EPAR and published literature. Concomitantly, we developed a target product profile (TPP against which the products were compared.The paper summarizes the general findings including various classes of compounds, and more specific information on two veterinary anthelmintics (monepantel, emodepside and nitazoxanide, an antiprotozoal drug, compiled from the EMA EPAR and FDA registration files.Few of the compounds already approved for use in human or animal medicine qualify for development track decision. Fast-tracking to approval for human studies may be possible for veterinary compounds like emodepside and monepantel, but additional information remains to be acquired before an informed decision can be made.

Utilization of the Bridging Strategy for the Development of New Drugs in Oncology to Avoid Drug Lag.

Science.gov (United States)

Kogure, Seiji; Koyama, Nobuyuki; Hidaka, Shinji

2017-11-01

Global trial (GT) strategy and bridging (BG) strategy are currently the main clinical development strategies of oncology drugs in Japan, but the relationship between development style and drug lag and how the bridging strategy has contributed to the solution of drug lag have not been clear. We investigated the potential factors that influenced submission lag (SL), and also compared the differences in SL among early-initiation BG strategy, late-initiation BG strategy, and GT strategy. A stepwise linear regression analysis identified the potential factors that shorten SL: development start lag and development style. Comparison of the differences in SL among the strategies also indicated that the SL in the GT strategy and that in the early-initiation BG strategy were significantly shorter than that in the late-initiation BG strategy. The findings in our study suggest that the late-initiation BG strategy may not contribute to shortening drug lag. Because the number of late-initiation BG studies has not decreased, we propose first that pharmaceutical companies should initiate clinical development as early as possible in Japan so that they can choose the GT strategy as a first option at the next step, and second when they cannot choose the GT strategy after investigating differences in exposure between Japanese and non-Japanese in a phase 1 study, they should select the early BG strategy to avoid future drug lag. It is also important for the regulatory authorities to provide reasonable guidance to have a positive impact on strategic decisions, even for foreign-capital companies. © 2017, The American College of Clinical Pharmacology.

Diabetes mellitus: Exploring the challenges in the drug development process

Directory of Open Access Journals (Sweden)

Julius A Vaz

2012-01-01

Full Text Available Diabetes mellitus has reached epidemic proportions and continues to be a major burden on society globally. The International Diabetes Federation (IDF estimated the global burden of diabetes to be 366 million in 2011 and predicted that by 2030 this will have risen to 552 million. In spite of newer and effective treatment options, newer delivery and diagnostic devices, stricter glycaemic targets, better treatment guidelines and increased awareness of the disease, baseline glycosylated hemoglobin remains relatively high in subjects diagnosed and treated with type 2 diabetes. The search continues for an ideal anti diabetic drug that will not only normalize blood glucose but also provide beta cell rest and possibly restoration of beta cell function. The development of anti diabetic drugs is riddled with fundamental challenges. The concept of beta cell rest and restoration is yet to be completely understood and proven on a long term. The ideal therapeutic approach to treating type 2 diabetes is not yet determined. Our understanding of drug safety in early clinical development is primarily limited to "Type A" reactions. Until marketing authorization most drugs are approved based on the principle of confirming non-inferiority with an existing gold standard or determining superiority to a placebo. The need to obtain robust pharmaco-economic data prior to marketing authorization in order to determine appropriate pricing of a new drug remains a major challenge. The present review outlines some of the challenges in drug development of anti-diabetic drugs citing examples of pulmonary insulin, insulin analogues, thiazolidinediones and the GLP1 analogues.

Diabetes mellitus: Exploring the challenges in the drug development process.

Science.gov (United States)

Vaz, Julius A; Patnaik, Ashis

2012-07-01

Diabetes mellitus has reached epidemic proportions and continues to be a major burden on society globally. The International Diabetes Federation (IDF) estimated the global burden of diabetes to be 366 million in 2011 and predicted that by 2030 this will have risen to 552 million. In spite of newer and effective treatment options, newer delivery and diagnostic devices, stricter glycaemic targets, better treatment guidelines and increased awareness of the disease, baseline glycosylated hemoglobin remains relatively high in subjects diagnosed and treated with type 2 diabetes. The search continues for an ideal anti diabetic drug that will not only normalize blood glucose but also provide beta cell rest and possibly restoration of beta cell function. The development of anti diabetic drugs is riddled with fundamental challenges. The concept of beta cell rest and restoration is yet to be completely understood and proven on a long term. The ideal therapeutic approach to treating type 2 diabetes is not yet determined. Our understanding of drug safety in early clinical development is primarily limited to "Type A" reactions. Until marketing authorization most drugs are approved based on the principle of confirming non-inferiority with an existing gold standard or determining superiority to a placebo. The need to obtain robust pharmaco-economic data prior to marketing authorization in order to determine appropriate pricing of a new drug remains a major challenge. The present review outlines some of the challenges in drug development of anti-diabetic drugs citing examples of pulmonary insulin, insulin analogues, thiazolidinediones and the GLP1 analogues.

Development of novel small molecules for imaging and drug release

Science.gov (United States)

Cao, Yanting

Small organic molecules, including small molecule based fluorescent probes, small molecule based drugs or prodrugs, and smart multifunctional fluorescent drug delivery systems play important roles in biological research, drug discovery, and clinical practices. Despite the significant progress made in these fields, the development of novel and diverse small molecules is needed to meet various demands for research and clinical applications. My Ph.D study focuses on the development of novel functional molecules for recognition, imaging and drug release. In the first part, a turn-on fluorescent probe is developed for the detection of intracellular adenosine-5'-triphosphate (ATP) levels based on multiplexing recognitions. Considering the unique and complicated structure of ATP molecules, a fluorescent probe has been implemented with improved sensitivity and selectivity due to two synergistic binding recognitions by incorporating of 2, 2'-dipicolylamine (Dpa)-Zn(II) for targeting of phospho anions and phenylboronic acid group for cis-diol moiety. The novel probe is able to detect intracellular ATP levels in SH-SY5Y cells. Meanwhile, the advantages of multiplexing recognition design concept have been demonstrated using two control molecules. In the second part, a prodrug system is developed to deliver multiple drugs within one small molecule entity. The prodrug is designed by using 1-(2-nitrophenyl)ethyl (NPE) as phototrigger, and biphenol biquaternary ammonium as the prodrug. With controlled photo activation, both DNA cross-linking agents mechlorethamine and o-quinone methide are delivered and released at the preferred site, leading to efficient DNA cross-links formation and cell death. The prodrug shows negligible cytotoxicity towards normal skin cells (Hekn cells) with and without UV activation, but displays potent activity towards cancer cells (HeLa cells) upon UV activation. The multiple drug release system may hold a great potential for practical application. In the

The Use of Social Media in Orphan Drug Development.

Science.gov (United States)

Milne, Christopher-Paul; Ni, Wendi

2017-11-01

Social media has transformed how people interact with one another through the Internet, and it has the potential to do the same for orphan drug development. Currently, social media influences the orphan drug development process in the following three ways: assisting the study of orphan diseases, increasing the awareness of orphan disease, and playing a vital role in clinical trials. However, there are some caveats to the utilization of social media, such as the need to protect patient privacy by adequately de-identifying personal health information, assuring consistent quality and representativeness of the data, and preventing the unblinding of patient group assignments. Social media has both potential for improving orphan drug development and pitfalls, but with proper oversight on the part of companies, support and participation of patients and their advocacy groups, and timely guidance from regulatory authorities, the positives outweigh the negatives for this powerful and patient-centric tool. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

The microculture-kinetic (MiCK) assay: the role of a drug-induced apoptosis assay in drug development and clinical care.

Science.gov (United States)

Bosserman, Linda; Prendergast, Franklyn; Herbst, Roy; Fleisher, Martin; Salom, Emery; Strickland, Steven; Raptis, Anastasios; Hallquist, Allan; Perree, Mathieu; Rajurkar, Swapnil; Karimi, Misagh; Rogers, Karl; Davidson, Dirk; Willis, Carl; Penalver, Manuel; Homesley, Howard; Burrell, Matthew; Garrett, Audrey; Rutledge, James; Chernick, Michael; Presant, Cary A

2012-08-15

A drug-induced apoptosis assay, termed the microculture-kinetic (MiCK) assay, has been developed. Blinded clinical trials have shown higher response rates and longer survival in groups of patients with acute myelocytic leukemia and epithelial ovarian cancer who have been treated with drugs that show high apoptosis in the MiCK assay. Unblinded clinical trials in multiple tumor types have shown that the assay will be used frequently by clinicians to determine treatment, and when used, results in higher response rates, longer times to relapse, and longer survivals. Model economic analyses suggest possible cost savings in clinical use based on increased generic drug use and single-agent substitution for combination therapies. Two initial studies with drugs in development are promising. The assay may help reduce costs and speed time to drug approval. Correlative studies with molecular biomarkers are planned. This assay may have a role both in personalized clinical therapy and in more efficient drug development. ©2012 AACR.

Improving Predictive Modeling in Pediatric Drug Development: Pharmacokinetics, Pharmacodynamics, and Mechanistic Modeling

Energy Technology Data Exchange (ETDEWEB)

Slikker, William; Young, John F.; Corley, Rick A.; Dorman, David C.; Conolly, Rory B.; Knudsen, Thomas; Erstad, Brian L.; Luecke, Richard H.; Faustman, Elaine M.; Timchalk, Chuck; Mattison, Donald R.

2005-07-26

A workshop was conducted on November 18?19, 2004, to address the issue of improving predictive models for drug delivery to developing humans. Although considerable progress has been made for adult humans, large gaps remain for predicting pharmacokinetic/pharmacodynamic (PK/PD) outcome in children because most adult models have not been tested during development. The goals of the meeting included a description of when, during development, infants/children become adultlike in handling drugs. The issue of incorporating the most recent advances into the predictive models was also addressed: both the use of imaging approaches and genomic information were considered. Disease state, as exemplified by obesity, was addressed as a modifier of drug pharmacokinetics and pharmacodynamics during development. Issues addressed in this workshop should be considered in the development of new predictive and mechanistic models of drug kinetics and dynamics in the developing human.

Newly graduated nurses' use of knowledge sources

DEFF Research Database (Denmark)

Voldbjerg, Siri Lygum; Grønkjaer, Mette; Sørensen, Erik Elgaard

2016-01-01

AIM: To advance evidence on newly graduated nurses' use of knowledge sources. BACKGROUND: Clinical decisions need to be evidence-based and understanding the knowledge sources that newly graduated nurses use will inform both education and practice. Qualitative studies on newly graduated nurses' use...... underscoring progression in knowledge use and perception of competence and confidence among newly graduated nurses. CONCLUSION: The transition phase, feeling of confidence and ability to use critical thinking and reflection, has a great impact on knowledge sources incorporated in clinical decisions....... The synthesis accentuates that for use of newly graduated nurses' qualifications and skills in evidence-based practice, clinical practice needs to provide a supportive environment which nurtures critical thinking and questions and articulates use of multiple knowledge sources....

Development and Evaluation of Chronotherapeutic Drug Delivery ...

African Journals Online (AJOL)

Conclusion: The developed system is capable of releasing the drug after a 4-h lag period. However ... concentration would be at its maximum level, ... spheronizer (Caleva MBS, UK)operating at .... capsules show that the color intensity of the.

Being a team leader: newly registered nurses relate their experiences.

Science.gov (United States)

Ekström, Louise; Idvall, Ewa

2015-01-01

This paper presents a study that explores how newly qualified registered nurses experience their leadership role in the ward-based nursing care team. A nurse's clinical leadership affects the quality of care provided. Newly qualified nurses experience difficulties during the transition period from student to qualified professional and find it challenging to lead nursing care. Twelve nurses were interviewed and the transcribed texts analysed using qualitative content analysis to assess both manifest and latent content. Five themes were identified: feeling stranded; forming well-functioning teams; learning to lead; having the courage, strength, and desire to lead; and ensuring appropriate care. The findings indicate that many factors limit nurses' leadership but some circumstances are supportive. The leadership prerequisites for newly registered nurses need to improve, emphasizing different ways to create a supportive atmosphere that promotes professional development and job satisfaction. To increase nurse retention and promote quality of care, nurse managers need to clarify expectations and guide and support newly qualified nurses in a planned way. © 2013 John Wiley & Sons Ltd.

Melatonergic drugs in development.

Science.gov (United States)

Carocci, Alessia; Catalano, Alessia; Sinicropi, Maria Stefania

2014-01-01

Melatonin (N-acetyl-5-methoxytryptamine) is widely known as "the darkness hormone". It is a major chronobiological regulator involved in circadian phasing and sleep-wake cycle in humans. Numerous other functions, including cyto/neuroprotection, immune modulation, and energy metabolism have been ascribed to melatonin. A variety of studies have revealed a role for melatonin and its receptors in different pathophysiological conditions. However, the suitability of melatonin as a drug is limited because of its short half-life, poor oral bioavailability, and ubiquitous action. Due to the therapeutic potential of melatonin in a wide variety of clinical conditions, the development of new agents able to interact selectively with melatonin receptors has become an area of great interest during the last decade. Therefore, the field of melatonergic receptor agonists comprises a great number of structurally different chemical entities, which range from indolic to nonindolic compounds. Melatonergic agonists are suitable for sleep disturbances, neuropsychiatric disorders related to circadian dysphasing, and metabolic diseases associated with insulin resistance. The results of preclinical studies on animal models show that melatonin receptor agonists can be considered promising agents for the treatment of central nervous system-related pathologies. An overview of recent advances in the field of investigational melatonergic drugs will be presented in this review.

Mathematical modeling for novel cancer drug discovery and development.

Science.gov (United States)

Zhang, Ping; Brusic, Vladimir

2014-10-01

Mathematical modeling enables: the in silico classification of cancers, the prediction of disease outcomes, optimization of therapy, identification of promising drug targets and prediction of resistance to anticancer drugs. In silico pre-screened drug targets can be validated by a small number of carefully selected experiments. This review discusses the basics of mathematical modeling in cancer drug discovery and development. The topics include in silico discovery of novel molecular drug targets, optimization of immunotherapies, personalized medicine and guiding preclinical and clinical trials. Breast cancer has been used to demonstrate the applications of mathematical modeling in cancer diagnostics, the identification of high-risk population, cancer screening strategies, prediction of tumor growth and guiding cancer treatment. Mathematical models are the key components of the toolkit used in the fight against cancer. The combinatorial complexity of new drugs discovery is enormous, making systematic drug discovery, by experimentation, alone difficult if not impossible. The biggest challenges include seamless integration of growing data, information and knowledge, and making them available for a multiplicity of analyses. Mathematical models are essential for bringing cancer drug discovery into the era of Omics, Big Data and personalized medicine.

Big Data: transforming drug development and health policy decision making.

Science.gov (United States)

Alemayehu, Demissie; Berger, Marc L

The explosion of data sources, accompanied by the evolution of technology and analytical techniques, has created considerable challenges and opportunities for drug development and healthcare resource utilization. We present a systematic overview these phenomena, and suggest measures to be taken for effective integration of the new developments in the traditional medical research paradigm and health policy decision making. Special attention is paid to pertinent issues in emerging areas, including rare disease drug development, personalized medicine, Comparative Effectiveness Research, and privacy and confidentiality concerns.

Accelerating drug development for neuroblastoma - New Drug Development Strategy: an Innovative Therapies for Children with Cancer, European Network for Cancer Research in Children and Adolescents and International Society of Paediatric Oncology Europe Neuroblastoma project.

Science.gov (United States)

Moreno, Lucas; Caron, Hubert; Geoerger, Birgit; Eggert, Angelika; Schleiermacher, Gudrun; Brock, Penelope; Valteau-Couanet, Dominique; Chesler, Louis; Schulte, Johannes H; De Preter, Katleen; Molenaar, Jan; Schramm, Alexander; Eilers, Martin; Van Maerken, Tom; Johnsen, John Inge; Garrett, Michelle; George, Sally L; Tweddle, Deborah A; Kogner, Per; Berthold, Frank; Koster, Jan; Barone, Giuseppe; Tucker, Elizabeth R; Marshall, Lynley; Herold, Ralf; Sterba, Jaroslav; Norga, Koen; Vassal, Gilles; Pearson, Andrew Dj

2017-08-01

Neuroblastoma, the commonest paediatric extra-cranial tumour, remains a leading cause of death from cancer in children. There is an urgent need to develop new drugs to improve cure rates and reduce long-term toxicity and to incorporate molecularly targeted therapies into treatment. Many potential drugs are becoming available, but have to be prioritised for clinical trials due to the relatively small numbers of patients. Areas covered: The current drug development model has been slow, associated with significant attrition, and few new drugs have been developed for neuroblastoma. The Neuroblastoma New Drug Development Strategy (NDDS) has: 1) established a group with expertise in drug development; 2) prioritised targets and drugs according to tumour biology (target expression, dependency, pre-clinical data; potential combinations; biomarkers), identifying as priority targets ALK, MEK, CDK4/6, MDM2, MYCN (druggable by BET bromodomain, aurora kinase, mTORC1/2) BIRC5 and checkpoint kinase 1; 3) promoted clinical trials with target-prioritised drugs. Drugs showing activity can be rapidly transitioned via parallel randomised trials into front-line studies. Expert opinion: The Neuroblastoma NDDS is based on the premise that optimal drug development is reliant on knowledge of tumour biology and prioritisation. This approach will accelerate neuroblastoma drug development and other poor prognosis childhood malignancies.

Development of a novel cell-based assay system EPISSAY for screening epigenetic drugs and liposome formulated decitabine

International Nuclear Information System (INIS)

Lim, Sue Ping; Callen, David F; Kumar, Raman; Akkamsetty, Yamini; Wang, Wen; Ho, Kristen; Neilsen, Paul M; Walther, Diego J; Suetani, Rachel J; Prestidge, Clive

2013-01-01

Despite the potential of improving the delivery of epigenetic drugs, the subsequent assessment of changes in their epigenetic activity is largely dependent on the availability of a suitable and rapid screening bioassay. Here, we describe a cell-based assay system for screening gene reactivation. A cell-based assay system (EPISSAY) was designed based on a silenced triple-mutated bacterial nitroreductase TMnfsB fused with Red-Fluorescent Protein (RFP) expressed in the non-malignant human breast cell line MCF10A. EPISSAY was validated using the target gene TXNIP, which has previously been shown to respond to epigenetic drugs. The potency of a epigenetic drug model, decitabine, formulated with PEGylated liposomes was also validated using this assay system. Following treatment with DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors such as decitabine and vorinostat, increases in RFP expression were observed, indicating expression of RFP-TMnfsB. The EPISSAY system was then used to test the potency of decitabine, before and after PEGylated liposomal encapsulation. We observed a 50% higher potency of decitabine when encapsulated in PEGylated liposomes, which is likely to be due to its protection from rapid degradation. The EPISSAY bioassay system provides a novel and rapid system to compare the efficiencies of existing and newly formulated drugs that reactivate gene expression

Privileged Electrophile Sensors: A Resource for Covalent Drug Development.

Science.gov (United States)

Long, Marcus John Curtis; Aye, Yimon

2017-07-20

This Perspective delineates how redox signaling affects the activity of specific enzyme isoforms and how this property may be harnessed for rational drug design. Covalent drugs have resurged in recent years and several reports have extolled the general virtues of developing irreversible inhibitors. Indeed, many modern pharmaceuticals contain electrophilic appendages. Several invoke a warhead that hijacks active-site nucleophiles whereas others take advantage of spectator nucleophilic side chains that do not participate in enzymatic chemistry, but are poised to bind/react with electrophiles. The latest data suggest that innate electrophile sensing-which enables rapid reaction with an endogenous signaling electrophile-is a quintessential resource for the development of covalent drugs. For instance, based on recent work documenting isoform-specific electrophile sensing, isozyme non-specific drugs may be converted to isozyme-specific analogs by hijacking privileged first-responder electrophile-sensing cysteines. Because this approach targets functionally relevant cysteines, we can simultaneously harness previously untapped moonlighting roles of enzymes linked to redox sensing. Copyright © 2017 Elsevier Ltd. All rights reserved.

The current status of orphan drug development in Europe and the US

OpenAIRE

Hall, Anthony K; Carlson, Marilyn R

2014-01-01

Orphan drug legislation has been introduced in a number of countries in order to stimulate the development of treatments for rare diseases by introducing commercial incentives for companies wishing to undertake that development. In order to navigate the maze of regulatory regulations and procedures so that companies can make proper use of the orphan drug incentives, specialist knowledge is required. This article will review the current status of orphan drug development in the EU and the US, e...

Development of ODL in a Newly Industrialized Country according to Face-to-Face Contact, ICT, and E-Readiness

Directory of Open Access Journals (Sweden)

J. Marinda van Zyl

2013-03-01

Full Text Available A large number of unqualified and under-qualified in-service teachers are holding back socio-economical development in South Africa, a newly industrialized country. Open and distance learning (ODL provides an innovative strategy and praxis for developing and newly industrialized countries to reach their educational and socio-economical objectives through professional development and training. In order to examine factors which affect the success of ODL offered by the North-West University in South Africa, a qualitative and quantitative research approach is used. Factors examined include face-to-face classroom contact, the implementation and use of ICTs, and e-readiness. The relationships between these factors are also discussed. A questionnaire was administered to 87 teacher-students in four Advanced Certificate in Education (ACE programs to collect quantitative data regarding aspects of their classes and the e-readiness of students. This data was qualitatively elaborated upon by three semi-structured, open-ended focus-group interviews. Besides descriptive statistics, Spearman’s rank-order correlations (r were determined between variables pertaining to negative feelings towards face-to-face classroom contact, ODL as students’ choice of delivery mode, and students’ positive attitude towards information and communication technology (ICT. Combined quantitative and qualitative findings were used to evaluate the effectiveness of contact classes as well as the e-readiness of students towards the attainment of ODL development Phase D. This phase refers to UNESCO’s description of ICT implementation, integration, and use. Relationships (Spearman’s rank-order correlations between ODL, as teacher-students’ choice of educational delivery mode, and aspects of their e-readiness suggest that the e-readiness of teacher-students is implicit to their choice of ODL as educational delivery mode for professional development.

Altered modulation of prefrontal and subcortical brain activity in newly diagnosed schizophrenia and schizophreniform disorder. A regional cerebral blood flow study

DEFF Research Database (Denmark)

Rubin, P; Holm, S; Friberg, L

1991-01-01

To measure prefrontal and subcortical activity during a cognitive task, we examined 19 newly diagnosed schizophrenics and patients with schizophreniform psychosis. Seven healthy volunteers served as controls. The patients were drug naive or had received neuroleptics for a few days only. Cerebral ...

Erosion of newly developed CFCs and Be under disruption heat loads

Science.gov (United States)

Nakamura, K.; Akiba, M.; Araki, M.; Dairaku, M.; Sato, K.; Suzuki, S.; Yokoyama, K.; Linke, J.; Duwe, R.; Bolt, H.; Roedig, M.

1996-10-01

An evaluation of the erosion under disruption heat loads is very important to the lifetime prediction of divertor armour tiles of next fusion devices such as ITER. In particular, erosion data on CFCs (carbon fiber reinforced composites) and beryllium (Be) as the armour materials is urgently required in the ITER design. For CFCs, high heat flux experiments on the newly developed CFCs with high thermal conductivity have been performed under the heat flux of around 800-2000 MW/m 2 and the pulse length of 2-5 ms in JAERI electron beam irradiation systems (JEBIS). As a result, the weight losses of B 4C doped CFCs after heating were almost same to those of the non doped CFC up to 5 wt% boron content. For Be, we have carried out our first disruption experiments on S65/C grade Be specimens in the Juelich divertor test facility in hot cells (JUDITH) facility as a frame work of the J—EU collaboration. The heating conditions were heat loads of 1250-5000 MW/m 2 for 2-8 ms, and the heated area was 3 × 3 mm 2. As a result, the protuberances of the heated area of Be were observed under the lower heat flux.

Erosion of newly developed CFCs and Be under disruption heat loads

International Nuclear Information System (INIS)

Nakamura, K.; Duwe, R.; Bolt, H.; Roedig, M.

1996-01-01

An evaluation of the erosion under disruption heat loads is very important to the lifetime prediction of divertor armour tiles of next fusion devices such as ITER. In particular, erosion data on CFCs (carbon fiber reinforced composites) and beryllium (Be) as the armour materials is urgently required in the ITER design. For CFCs, high heat flux experiments on the newly developed CFCs with high thermal conductivity have been performed under the heat flux of around 800-2000 MW/m 2 and the pulse length of 2-5 ms in JAERI electron beam irradiation systems (JEBIS). As a result, the weight losses of B 4 C doped CFCs after heating were almost same to those of the non doped CFC up to 5 wt% boron content. For Be, we have carried out our first disruption experiments on S65/C grade Be specimens in the Juelich divertor test facility in hot cells (JUDITH) facility as a frame work of the J-EU collaboration. The heating conditions were heat loads of 1250-5000 MW/m 2 for 2-8 ms, and the heated area was 3 x 3 mm 2 . As a result, the protuberances of the heated area of Be were observed under the lower heat flux. (orig.)

Weldability aspects of a newly developed duplex stainless steel LDX 2101

Energy Technology Data Exchange (ETDEWEB)

Westin, E.M. [Avesta Research Centre, Avesta (Sweden). Outokumpu Stainless; Brolund, B. [SSAB Tunnplat, Borlaenge (Sweden); Hertzman, S. [Outokumpu Stainless Research Foundation, Stockholm (Sweden)

2008-06-15

Duplex grades have, due to balanced chemical compositions of both filler and base metals, a weldability that allows for successful welding using a majority of the technically relevant techniques of today. In order to fulfil the performance requirements several aspects must be considered. In the heat affected zone (HAZ) the austenite reformation must be reasonably high and in the weld metal the microstructure must be stable so that e.g. high productivity welding and multi-pass welding are possible, without precipitation of detrimental phases in previous passes. This paper addresses the effect of alloying elements and thermal cycles on phase balance in the high temperature HAZ (HTHAZ) of the newly developed lean duplex grade LDX 2101 (EN 1.4162, UNS S32101). Bead-on-plate welds and simulated weld structures have been produced and investigated using metallography, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The results are analysed using the thermodynamic database Thermo-Calc and a model for phase transformation based on a paraequilibrium assumption for ferrite-austenite transformation. In the temperature region outside the paraequilibrium domain, growth controlled by diffusion of substitutional elements was considered. The analysis follows a model by Cahn regarding grain boundary nucleated growth and the Hillert-Engberg model on kinetics of spherical and planar growth. (orig.)

NUMERICAL MODELLING OF THE SOIL BEHAVIOUR BY USING NEWLY DEVELOPED ADVANCED MATERIAL MODEL

Directory of Open Access Journals (Sweden)

Jan Veselý

2017-02-01

Full Text Available This paper describes a theoretical background, implementation and validation of the newly developed Jardine plastic hardening-softening model (JPHS model, which can be used for numerical modelling of the soils behaviour. Although the JPHS model is based on the elasto-plastic theory, like the Mohr-Coulomb model that is widely used in geotechnics, it contains some improvements, which removes the main disadvantages of the MC model. The presented model is coupled with an isotopically hardening and softening law, non-linear elastic stress-strain law, non-associated elasto-plastic material description and a cap yield surface. The validation of the model is done by comparing the numerical results with real measured data from the laboratory tests and by testing of the model on the real project of the tunnel excavation. The 3D numerical analysis is performed and the comparison between the JPHS, Mohr-Coulomb, Modified Cam-Clay, Hardening small strain model and monitoring in-situ data is done.

The paradigm shift to an “open” model in drug development

Directory of Open Access Journals (Sweden)

Regina Au

2014-12-01

Full Text Available The rising cost of healthcare, the rising cost for drug development, the patent cliff for Big pharma, shorter patent protection, decrease reimbursement, and the recession have made it more difficult for the pharmaceutical and biotechnology industry to develop drugs. Due to the unsustainable amount of time and money in developing a drug that will have a significant return on investment (ROI it has become hard to sustain a robust pipeline. The industry is transforming its business model to meet these challenges. In essence a paradigm shift is occurring; the old “closed” model is giving way to a new “open” business model.

Parsing multiple processes of high temperature impacts on corn/soybean yield using a newly developed CLM-APSIM modeling framework

Science.gov (United States)

Peng, B.; Guan, K.; Chen, M.

2016-12-01

Future agricultural production faces a grand challenge of higher temperature under climate change. There are multiple physiological or metabolic processes of how high temperature affects crop yield. Specifically, we consider the following major processes: (1) direct temperature effects on photosynthesis and respiration; (2) speed-up growth rate and the shortening of growing season; (3) heat stress during reproductive stage (flowering and grain-filling); (4) high-temperature induced increase of atmospheric water demands. In this work, we use a newly developed modeling framework (CLM-APSIM) to simulate the corn and soybean growth and explicitly parse the above four processes. By combining the strength of CLM in modeling surface biophysical (e.g., hydrology and energy balance) and biogeochemical (e.g., photosynthesis and carbon-nitrogen interactions), as well as that of APSIM in modeling crop phenology and reproductive stress, the newly developed CLM-APSIM modeling framework enables us to diagnose the impacts of high temperature stress through different processes at various crop phenology stages. Ground measurements from the advanced SoyFACE facility at University of Illinois is used here to calibrate, validate, and improve the CLM-APSIM modeling framework at the site level. We finally use the CLM-APSIM modeling framework to project crop yield for the whole US Corn Belt under different climate scenarios.

Imaging mass spectrometry in drug development and toxicology.

Science.gov (United States)

Karlsson, Oskar; Hanrieder, Jörg

2017-06-01

During the last decades, imaging mass spectrometry has gained significant relevance in biomedical research. Recent advances in imaging mass spectrometry have paved the way for in situ studies on drug development, metabolism and toxicology. In contrast to whole-body autoradiography that images the localization of radiolabeled compounds, imaging mass spectrometry provides the possibility to simultaneously determine the discrete tissue distribution of the parent compound and its metabolites. In addition, imaging mass spectrometry features high molecular specificity and allows comprehensive, multiplexed detection and localization of hundreds of proteins, peptides and lipids directly in tissues. Toxicologists traditionally screen for adverse findings by histopathological examination. However, studies of the molecular and cellular processes underpinning toxicological and pathologic findings induced by candidate drugs or toxins are important to reach a mechanistic understanding and an effective risk assessment strategy. One of IMS strengths is the ability to directly overlay the molecular information from the mass spectrometric analysis with the tissue section and allow correlative comparisons of molecular and histologic information. Imaging mass spectrometry could therefore be a powerful tool for omics profiling of pharmacological/toxicological effects of drug candidates and toxicants in discrete tissue regions. The aim of the present review is to provide an overview of imaging mass spectrometry, with particular focus on MALDI imaging mass spectrometry, and its use in drug development and toxicology in general.

Use of newly developed standardized form for interpretation of high-resolution CT in screening for pneumoconiosis

International Nuclear Information System (INIS)

Julien, P.J.; Sider, L.; Silverman, J.M.; Dahlgren, J.; Harber, P.; Bunn, W.

1991-01-01

This paper reports that although the International Labour Office (ILO) standard for interpretation of the posteroanterior chest radiograph has been available for 10 years, there has been no attempt to standardize the high-resolution CT (HRTC) readings for screening of pneumoconiosis. An integrated respirator surveillance program for 87 workers exposed to inorganic dust was conducted. This program consisted of a detailed occupational exposure history, physical symptoms and signs, spirometry, chest radiography, and HRCT. Two groups of workers with known exposure were studied with HRCT. Group 1 had normal spirometry results and chest radiographs, and group 2 had abnormalities at spirometry or on chest radiographs. The HRCT scans were read independently of the clinical findings and chest radiographs. The HRCT scans were interpreted by using an ILO-based standard form developed by the authors for this project. With the newly developed HRCT form, individual descriptive abnormality localized severity, and overall rating systems have been developed and compared for inter- and intraobserver consistency

Old and new therapeutics for Rheumatoid Arthritis: in vivo models and drug development

DEFF Research Database (Denmark)

Sardar, Samra; Andersson, Åsa

2016-01-01

Development of novel drugs for treatment of chronic inflammatory diseases is to a large extent dependent on the availability of good experimental in vivo models in order to perform preclinical tests of new drugs and for the identification of novel drug targets. Here, we review a number of existing...... of in vivo models during development of anti-rheumatic drugs; from Methotrexate to various antibody treatments, to novel drugs that are, or have recently been, in clinical trials. For novel drugs, we have explored websites for clinical trials. Although one Rheumatoid Arthritis in vivo model cannot mirror...

Mechanistic systems modeling to guide drug discovery and development.

Science.gov (United States)

Schmidt, Brian J; Papin, Jason A; Musante, Cynthia J

2013-02-01

A crucial question that must be addressed in the drug development process is whether the proposed therapeutic target will yield the desired effect in the clinical population. Pharmaceutical and biotechnology companies place a large investment on research and development, long before confirmatory data are available from human trials. Basic science has greatly expanded the computable knowledge of disease processes, both through the generation of large omics data sets and a compendium of studies assessing cellular and systemic responses to physiologic and pathophysiologic stimuli. Given inherent uncertainties in drug development, mechanistic systems models can better inform target selection and the decision process for advancing compounds through preclinical and clinical research. Copyright © 2012 Elsevier Ltd. All rights reserved.

MPD3: a useful medicinal plants database for drug designing.

Science.gov (United States)

Mumtaz, Arooj; Ashfaq, Usman Ali; Ul Qamar, Muhammad Tahir; Anwar, Farooq; Gulzar, Faisal; Ali, Muhammad Amjad; Saari, Nazamid; Pervez, Muhammad Tariq

2017-06-01

Medicinal plants are the main natural pools for the discovery and development of new drugs. In the modern era of computer-aided drug designing (CADD), there is need of prompt efforts to design and construct useful database management system that allows proper data storage, retrieval and management with user-friendly interface. An inclusive database having information about classification, activity and ready-to-dock library of medicinal plant's phytochemicals is therefore required to assist the researchers in the field of CADD. The present work was designed to merge activities of phytochemicals from medicinal plants, their targets and literature references into a single comprehensive database named as Medicinal Plants Database for Drug Designing (MPD3). The newly designed online and downloadable MPD3 contains information about more than 5000 phytochemicals from around 1000 medicinal plants with 80 different activities, more than 900 literature references and 200 plus targets. The designed database is deemed to be very useful for the researchers who are engaged in medicinal plants research, CADD and drug discovery/development with ease of operation and increased efficiency. The designed MPD3 is a comprehensive database which provides most of the information related to the medicinal plants at a single platform. MPD3 is freely available at: http://bioinform.info .

Animal Migraine Models for Drug Development

DEFF Research Database (Denmark)

Jansen-Olesen, Inger; Tfelt-Hansen, Peer; Olesen, Jes

2013-01-01

Migraine is number seven in WHO's list of all diseases causing disability and the third most costly neurological disorder in Europe. Acute attacks are treatable by highly selective drugs such as the triptans but there is still a huge unmet therapeutic need. Unfortunately, drug development...... for headache has almost come to a standstill partly because of a lack of valid animal models. Here we review previous models with emphasis on optimal characteristics of a future model. In addition to selection of animal species, the method of induction of migraine-like changes and the method of recording...... responses elicited by such measures are crucial. The most naturalistic way of inducing attacks is by infusion of endogenous signaling molecules that are known to cause migraine in patients. The most valid response is recording of neural activity in the trigeminal system. The most useful headache related...

ROLE OF NATURAL POLYMERS IN SUSTAINED RELEASE DRUG DELIVERY SYSTEM: APPLICATIONS AND RECENT APPROACHES

OpenAIRE

Prakash Pawan; Porwal Mayur; Saxena Ashwin

2011-01-01

In recent years there have been important developments in different dosage forms for existing and newly designed drugs and natural products, and semi-synthetic as well as synthetic excipients often need to be used for a variety of purposes. Gums and mucilages are widely used natural materials for conventional and novel dosage forms. These natural materials have advantages over synthetic ones since they are chemically inert, nontoxic, less expensive, biodegradable and widely available. They c...

Ion channels and transporters in the development of drug resistance in cancer cells

DEFF Research Database (Denmark)

Hoffmann, Else Kay; Lambert, Ian Henry

2014-01-01

Multi-drug resistance (MDR) to chemotherapy is the major challenge in the treatment of cancer. MDR can develop by numerous mechanisms including decreased drug uptake, increased drug efflux and the failure to undergo drug-induced apoptosis. Evasion of drug-induced apoptosis through modulation of i...

The current status of orphan drug development in Europe and the US.

Science.gov (United States)

Hall, Anthony K; Carlson, Marilyn R

2014-02-01

Orphan drug legislation has been introduced in a number of countries in order to stimulate the development of treatments for rare diseases by introducing commercial incentives for companies wishing to undertake that development. In order to navigate the maze of regulatory regulations and procedures so that companies can make proper use of the orphan drug incentives, specialist knowledge is required. This article will review the current status of orphan drug development in the EU and the US, explain the incentives and procedures, and touch on the role of patient organisations in the process.

Verification of gamma knife based fractionated radiosurgery with newly developed head-thorax phantom

International Nuclear Information System (INIS)

Bisht, Raj Kishor; Kale, Shashank Sharad; Natanasabapathi, Gopishankar; Singh, Manmohan Jit; Agarwal, Deepak; Garg, Ajay; Rath, Goura Kishore; Julka, Pramod Kumar; Kumar, Pratik; Thulkar, Sanjay; Sharma, Bhawani Shankar

2016-01-01

Objective: Purpose of the study is to verify the Gamma Knife Extend™ system (ES) based fractionated stereotactic radiosurgery with newly developed head-thorax phantom. Methods: Phantoms are extensively used to measure radiation dose and verify treatment plan in radiotherapy. A human upper body shaped phantom with thorax was designed to simulate fractionated stereotactic radiosurgery using Extend™ system of Gamma Knife. The central component of the phantom aids in performing radiological precision test, dosimetric evaluation and treatment verification. A hollow right circular cylindrical space of diameter 7.0 cm was created at the centre of this component to place various dosimetric devices using suitable adaptors. The phantom is made of poly methyl methacrylate (PMMA), a transparent thermoplastic material. Two sets of disk assemblies were designed to place dosimetric films in (1) horizontal (xy) and (2) vertical (xz) planes. Specific cylindrical adaptors were designed to place thimble ionization chamber inside phantom for point dose recording along xz axis. EBT3 Gafchromic films were used to analyze and map radiation field. The focal precision test was performed using 4 mm collimator shot in phantom to check radiological accuracy of treatment. The phantom head position within the Extend™ frame was estimated using encoded aperture measurement of repositioning check tool (RCT). For treatment verification, the phantom with inserts for film and ion chamber was scanned in reference treatment position using X-ray computed tomography (CT) machine and acquired stereotactic images were transferred into Leksell Gammaplan (LGP). A patient treatment plan with hypo-fractionated regimen was delivered and identical fractions were compared using EBT3 films and in-house MATLAB codes. Results: RCT measurement showed an overall positional accuracy of 0.265 mm (range 0.223 mm–0.343 mm). Gamma index analysis across fractions exhibited close agreement between LGP and film

Effects of Psychostimulant Drugs on Developing Brain

Directory of Open Access Journals (Sweden)

Ibrahim Durukan

2013-08-01

Full Text Available Although psychostimulants have been used for the treatment of attention deficit hyperactivity disorder for approximately 70 years, little is known about the long term effects of these drugs on developing brain. The observable effects of psychostimulants are influenced by the timing of exposure, the age of examination after drug exposure and sex. Preclinical studies point out that chronic psychostimulant exposure before adolescence cause reverse sensitization or tolerance and this leads to reduction in stimulant effectiveness in adolesecence and adulthood. Preclinical studies show the potential long term effects of psychostimulants. But it is necessary to investigate the relationship between preclinical effects and clinical practice. A developmental approach is needed to understand the impact of pediatric medications on the brain that includes assessment at multiple ages to completely characterize the long term effects of these medications. The aim of this paper is to review the effects of psychostimulants on developing brain.

Newly developed controlled release subcutaneous formulation for tramadol hydrochloride

Directory of Open Access Journals (Sweden)

Mostafa Mabrouk

2018-05-01

Full Text Available This study presents a drug delivery system of poly (Ɛ-caprolactone (PCL ribbons to optimize the pharmaceutical action of tramadol for the first time according to our knowledge. PCL ribbons were fabricated and loaded with tramadol HCl. Ribbons were prepared by slip casting technique and coated with dipping technique with β-cyclodextrin. The chemical integrity and surface morphology of the ribbons were confirmed using FTIR and SEM coupled with EDX. In addition, thermodynamic behavior of the fabricated ribbons was investigated using DSC/TGA. Tramadol loading into PCL ribbons, biodegradation of ribbons and tramadol release kinetics were studied in PBS.The results revealed that the formulated composition did not affect the chemical integrity of the drug. Furthermore, SEM/EDX confirmed the inclusion of tramadol into the PCL matrix in homogenous distribution pattern without any observation of porous structure. The particle size of loaded tramadol was found to be in the range of (2–4 nm. The formulated composition did not affect the chemical integrity of the drug and should be further investigated for bioavailability. Tramadol exhibited controlled release behavior from PCL ribbons up to 45 days governed mainly by diffusion mechanism. The fabricated ribbons have a great potentiality to be implemented in the long term subcutaneous delivery of tramadol. Keywords: Tramadol, Polycaprolcatone, Subcutaneous membrane, Ribbons, β-Cyclodextrin, Controlled release

Data-intensive drug development in the information age: applications of Systems Biology/Pharmacology/Toxicology.

Science.gov (United States)

Kiyosawa, Naoki; Manabe, Sunao

2016-01-01

Pharmaceutical companies continuously face challenges to deliver new drugs with true medical value. R&D productivity of drug development projects depends on 1) the value of the drug concept and 2) data and in-depth knowledge that are used rationally to evaluate the drug concept's validity. A model-based data-intensive drug development approach is a key competitive factor used by innovative pharmaceutical companies to reduce information bias and rationally demonstrate the value of drug concepts. Owing to the accumulation of publicly available biomedical information, our understanding of the pathophysiological mechanisms of diseases has developed considerably; it is the basis for identifying the right drug target and creating a drug concept with true medical value. Our understanding of the pathophysiological mechanisms of disease animal models can also be improved; it can thus support rational extrapolation of animal experiment results to clinical settings. The Systems Biology approach, which leverages publicly available transcriptome data, is useful for these purposes. Furthermore, applying Systems Pharmacology enables dynamic simulation of drug responses, from which key research questions to be addressed in the subsequent studies can be adequately informed. Application of Systems Biology/Pharmacology to toxicology research, namely Systems Toxicology, should considerably improve the predictability of drug-induced toxicities in clinical situations that are difficult to predict from conventional preclinical toxicology studies. Systems Biology/Pharmacology/Toxicology models can be continuously improved using iterative learn-confirm processes throughout preclinical and clinical drug discovery and development processes. Successful implementation of data-intensive drug development approaches requires cultivation of an adequate R&D culture to appreciate this approach.

Incentives for orphan drug research and development in the United States.

Science.gov (United States)

Seoane-Vazquez, Enrique; Rodriguez-Monguio, Rosa; Szeinbach, Sheryl L; Visaria, Jay

2008-12-16

The Orphan Drug Act (1983) established several incentives to encourage the development of orphan drugs (ODs) to treat rare diseases and conditions. This study analyzed the characteristics of OD designations, approvals, sponsors, and evaluated the effective patent and market exclusivity life of orphan new molecular entities (NMEs) approved in the US between 1983 and 2007. Primary data sources were the FDA Orange Book, the FDA Office of Orphan Drugs Development, and the US Patent and Trademark Office. Data included all orphan designations and approvals listed by the FDA and all NMEs approved by the FDA during the study period. The FDA listed 1,793 orphan designations and 322 approvals between 1983 and 2007. Cancer was the main group of diseases targeted for orphan approvals. Eighty-three companies concentrated 67.7% of the total orphan NMEs approvals. The average time from orphan designation to FDA approval was 4.0 +/- 3.3 years (mean +/- standard deviation). The average maximum effective patent and market exclusivity life was 11.7 +/- 5.0 years for orphan NME. OD market exclusivity increased the average maximum effective patent and market exclusivity life of ODs by 0.8 years. Public programs, federal regulations, and policies support orphan drugs R&D. Grants, research design support, FDA fee waivers, tax incentives, and orphan drug market exclusivity are the main incentives for orphan drug R&D. Although the 7-year orphan drug market exclusivity provision had a positive yet relatively modest overall effect on effective patent and market exclusivity life, economic incentives and public support mechanisms provide a platform for continued orphan drug development for a highly specialized market.

Safe procedure development to manage hazardous drugs in the workplace.

Science.gov (United States)

Gaspar Carreño, Marisa; Achau Muñoz, Rubén; Torrico Martín, Fátima; Agún Gonzalez, Juan José; Sanchez Santos, Jose Cristobal; Cercos Lletí, Ana Cristina; Ramos Orozco, Pedro

2017-03-01

To develop a safety working procedure for the employees in the Intermutual Hospital de Levante (HIL) in those areas of activity that deal with the handling of hazardous drugs (MP). The procedure was developed in six phases: 1) hazard definition; 2) definition and identification of processes and development of general correct work practices about hazardous drugs' selection and special handling; 3) detection, selection and set of specific recommendations to handle with hazardous drugs during the processes of preparation and administration included in the hospital GFT; 4) categorization of risk during the preparation/administration and development of an identification system; 5) information and training of professionals; 6) implementation of the identification measures and prevention guidelines. Six processes were detected handling HD. During those processes, thirty HD were identified included in the hospital GFT and a safer alternative was found for 6 of them. The HD were classified into 4 risk categories based on those measures to be taken during the preparation and administration of each of them. The development and implementation of specific safety-work processes dealing with medication handling, allows hospital managers to accomplish effectively with their legal obligations about the area of prevention and provides healthcare professional staff with the adequate techniques and safety equipment to avoid possible dangers and risks of some drugs. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Phenotypic Screening Approaches to Develop Aurora Kinase Inhibitors: Drug Discovery Perspectives.

Science.gov (United States)

Marugán, Carlos; Torres, Raquel; Lallena, María José

2015-01-01

Targeting mitotic regulators as a strategy to fight cancer implies the development of drugs against key proteins, such as Aurora-A and -B. Current drugs, which target mitosis through a general mechanism of action (stabilization/destabilization of microtubules), have several side effects (neutropenia, alopecia, and emesis). Pharmaceutical companies aim at avoiding these unwanted effects by generating improved and selective drugs that increase the quality of life of the patients. However, the development of these drugs is an ambitious task that involves testing thousands of compounds through biochemical and cell-based assays. In addition, molecules usually target complex biological processes, involving several proteins and different molecular pathways, further emphasizing the need for high-throughput screening techniques and multiplexing technologies in order to identify drugs with the desired phenotype. We will briefly describe two multiplexing technologies [high-content imaging (HCI) and flow cytometry] and two key processes for drug discovery research (assay development and validation) following our own published industry quality standards. We will further focus on HCI as a useful tool for phenotypic screening and will provide a concrete example of HCI assay to detect Aurora-A or -B selective inhibitors discriminating the off-target effects related to the inhibition of other cell cycle or non-cell cycle key regulators. Finally, we will describe other assays that can help to characterize the in vitro pharmacology of the inhibitors.

Emerging drugs which target the renin-angiotensin-aldosterone system.

Science.gov (United States)

Steckelings, Ulrike Muscha; Paulis, Ludovit; Unger, Thomas; Bader, Michael

2011-12-01

The renin-angiotensin-aldosterone system (RAAS) is already the most important target for drugs in the cardiovascular system. However, still new developments are underway to interfere with the system on different levels. The novel strategies to interfere with RAAS aim to reduce the synthesis of the two major RAAS effector hormones, angiotensin (Ang) II and aldosterone, or interfere with their receptors, AT1 and mineralocorticoid receptor, respectively. Moreover, novel targets have been identified in RAAS, such as the (pro)renin receptor, and molecules, which counteract the classical actions of Ang II and are therefore beneficial in cardiovascular diseases. These include the AT2 receptor and the ACE2/Ang-(1-7)/Mas axis. The search for drugs activating these tissue-protective arms of RAAS is therefore the most innovative field in RAAS pharmacology. Most of the novel pharmacological strategies to inhibit the classical RAAS need to prove their superiority above the existing treatment in clinical trials and then have to compete against these now quite cheap drugs in a competitive market. The newly discovered targets have functions beyond the cardiovascular system opening up novel therapeutic areas for drugs interfering with RAAS components.

The economics of pediatric formulation development for off-patent drugs.

Science.gov (United States)

Milne, Christopher-Paul; Bruss, Jon B

2008-11-01

Many drugs currently used in children have never been adequately studied in rigorous scientific trials. Although these medications can still be prescribed in the pediatric setting, they are considered "off-label" because they are not specifically approved for use in children. The role of the Economics Working Group (EWG) within the Pediatric Formulation Initiative (PFI) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) is to identify economic barriers and to propose possible mechanisms to create cost-effective and appropriately formulated products for off-patent pediatric drugs and to ensure their distribution and availability. The purpose of this article was to briefly outline the EWG's considerations and recommendations on these topics. Information for this article was gathered from the proceedings of a PFI workshop sponsored by the NICHD, held December 6 and 7, 2005, in Bethesda, Maryland. Other information was based on: the authors' unpublished and published research as well as personal communication with members of the EWG; a comprehensive search of Web sites, publications, and publicly accessible databases of the European Medicines Agency, the US Food and Drug Administration, the Agency for Healthcare Research and Quality, and the NICHD; and the databases and publications available from the Louis Lasagna Library of the Tufts Center for the Study of Drug Development (Boston, Massachusetts). The US Congress has attempted to remedy the lack of incentives to develop pediatric drugs by passing 2 key pieces of legislation. After >10 years, this US pediatric initiative has stimulated a great deal of pediatric drug research, and similar initiatives have been emulated in Europe and proposed in Japan. Although the initiative is generally considered successful in the United States, an incentive gap exists that still hinders pediatric drug development. It results from a series of factors, including: (1) a relatively small

PCTFPeval: a web tool for benchmarking newly developed algorithms for predicting cooperative transcription factor pairs in yeast.

Science.gov (United States)

Lai, Fu-Jou; Chang, Hong-Tsun; Wu, Wei-Sheng

2015-01-01

Computational identification of cooperative transcription factor (TF) pairs helps understand the combinatorial regulation of gene expression in eukaryotic cells. Many advanced algorithms have been proposed to predict cooperative TF pairs in yeast. However, it is still difficult to conduct a comprehensive and objective performance comparison of different algorithms because of lacking sufficient performance indices and adequate overall performance scores. To solve this problem, in our previous study (published in BMC Systems Biology 2014), we adopted/proposed eight performance indices and designed two overall performance scores to compare the performance of 14 existing algorithms for predicting cooperative TF pairs in yeast. Most importantly, our performance comparison framework can be applied to comprehensively and objectively evaluate the performance of a newly developed algorithm. However, to use our framework, researchers have to put a lot of effort to construct it first. To save researchers time and effort, here we develop a web tool to implement our performance comparison framework, featuring fast data processing, a comprehensive performance comparison and an easy-to-use web interface. The developed tool is called PCTFPeval (Predicted Cooperative TF Pair evaluator), written in PHP and Python programming languages. The friendly web interface allows users to input a list of predicted cooperative TF pairs from their algorithm and select (i) the compared algorithms among the 15 existing algorithms, (ii) the performance indices among the eight existing indices, and (iii) the overall performance scores from two possible choices. The comprehensive performance comparison results are then generated in tens of seconds and shown as both bar charts and tables. The original comparison results of each compared algorithm and each selected performance index can be downloaded as text files for further analyses. Allowing users to select eight existing performance indices and 15

Mass spectrometry-driven drug discovery for development of herbal medicine.

Science.gov (United States)

Zhang, Aihua; Sun, Hui; Wang, Xijun

2018-05-01

Herbal medicine (HM) has made a major contribution to the drug discovery process with regard to identifying products compounds. Currently, more attention has been focused on drug discovery from natural compounds of HM. Despite the rapid advancement of modern analytical techniques, drug discovery is still a difficult and lengthy process. Fortunately, mass spectrometry (MS) can provide us with useful structural information for drug discovery, has been recognized as a sensitive, rapid, and high-throughput technology for advancing drug discovery from HM in the post-genomic era. It is essential to develop an efficient, high-quality, high-throughput screening method integrated with an MS platform for early screening of candidate drug molecules from natural products. We have developed a new chinmedomics strategy reliant on MS that is capable of capturing the candidate molecules, facilitating their identification of novel chemical structures in the early phase; chinmedomics-guided natural product discovery based on MS may provide an effective tool that addresses challenges in early screening of effective constituents of herbs against disease. This critical review covers the use of MS with related techniques and methodologies for natural product discovery, biomarker identification, and determination of mechanisms of action. It also highlights high-throughput chinmedomics screening methods suitable for lead compound discovery illustrated by recent successes. © 2016 Wiley Periodicals, Inc.

AMS in drug development at GSK

International Nuclear Information System (INIS)

Young, G.C.; Ellis, W.J.

2007-01-01

A history of the use of AMS in GSK studies spanning the last 8 years (1998-2005) is presented, including use in pilot studies through to clinical, animal and in vitro studies. A brief summary of the status of GSK's in-house AMS capability is outlined and views on the future of AMS in GSK are presented, including potential impact on drug development and potential advances in AMS technology

Flagellation of Pseudomonas aeruginosa in newly divided cells

Science.gov (United States)

Zhao, Kun; Lee, Calvin; Anda, Jaime; Wong, Gerard

2015-03-01

For monotrichous bacteria, Pseudomonas aeruginosa, after cell division, one daughter cell inherits the old flagellum from its mother cell, and the other grows a new flagellum during or after cell division. It had been shown that the new flagellum grows at the distal pole of the dividing cell when the two daughter cells haven't completely separated. However, for those daughter cells who grow new flagella after division, it still remains unknown at which pole the new flagellum will grow. Here, by combining our newly developed bacteria family tree tracking techniques with genetic manipulation method, we showed that for the daughter cell who did not inherit the old flagellum, a new flagellum has about 90% chances to grow at the newly formed pole. We proposed a model for flagellation of P. aeruginosa.

Quantitative PET Imaging in Drug Development: Estimation of Target Occupancy.

Science.gov (United States)

Naganawa, Mika; Gallezot, Jean-Dominique; Rossano, Samantha; Carson, Richard E

2017-12-11

Positron emission tomography, an imaging tool using radiolabeled tracers in humans and preclinical species, has been widely used in recent years in drug development, particularly in the central nervous system. One important goal of PET in drug development is assessing the occupancy of various molecular targets (e.g., receptors, transporters, enzymes) by exogenous drugs. The current linear mathematical approaches used to determine occupancy using PET imaging experiments are presented. These algorithms use results from multiple regions with different target content in two scans, a baseline (pre-drug) scan and a post-drug scan. New mathematical estimation approaches to determine target occupancy, using maximum likelihood, are presented. A major challenge in these methods is the proper definition of the covariance matrix of the regional binding measures, accounting for different variance of the individual regional measures and their nonzero covariance, factors that have been ignored by conventional methods. The novel methods are compared to standard methods using simulation and real human occupancy data. The simulation data showed the expected reduction in variance and bias using the proper maximum likelihood methods, when the assumptions of the estimation method matched those in simulation. Between-method differences for data from human occupancy studies were less obvious, in part due to small dataset sizes. These maximum likelihood methods form the basis for development of improved PET covariance models, in order to minimize bias and variance in PET occupancy studies.

Surface ultrastuctures of the human laryngeal mucosa - observation by an newly developed technique of SEM cinematography

International Nuclear Information System (INIS)

Ohyama, M.; Ohno, I.; Fujita, T.; Adachi, K.

1981-01-01

With the newly-developed techniques of SEM cinematography, surface ultrastructures of the human normal and pathological laryngeal mucosa were demonstrated. The high specialization of the laryngeal mucosa with its marked regional differences stresses the fact that even the squamous epithelium and nonciliated epithelium may play a role of utmost importance. All specimens were obtained after laryngectomy from 10 patients affected by laryngeal cancer which had been treated with or without preoperative irradiation of Lineac in total doses of 3,500-4,500 rad. Special attention was paid to the occurrence of microvilli and microplicae in the normal and pathological mucosa of the larynx, and their morphological and physiological significances were discussed briefly. (Auth.)

Recent advances in (therapeutic protein drug development [version 1; referees: 2 approved

Directory of Open Access Journals (Sweden)

H.A. Daniel Lagassé

2017-02-01

Full Text Available Therapeutic protein drugs are an important class of medicines serving patients most in need of novel therapies. Recently approved recombinant protein therapeutics have been developed to treat a wide variety of clinical indications, including cancers, autoimmunity/inflammation, exposure to infectious agents, and genetic disorders. The latest advances in protein-engineering technologies have allowed drug developers and manufacturers to fine-tune and exploit desirable functional characteristics of proteins of interest while maintaining (and in some cases enhancing product safety or efficacy or both. In this review, we highlight the emerging trends and approaches in protein drug development by using examples of therapeutic proteins approved by the U.S. Food and Drug Administration over the previous five years (2011–2016, namely January 1, 2011, through August 31, 2016.

Undocumented Immigration, Drug Problems, and Driving Under the Influence in the United States, 1990-2014.

Science.gov (United States)

Light, Michael T; Miller, Ty; Kelly, Brian C

2017-09-01

To examine the influence of undocumented immigration in the United States on 4 different metrics of drug and alcohol problems: drug arrests, drug overdose fatalities, driving under the influence (DUI) arrests, and DUI deaths. We combined newly developed state-level estimates of the undocumented population between 1990 and 2014 from the Center for Migration Studies with arrest data from the Federal Bureau of Investigation Uniform Crime Reports and fatality information from the Fatality Analysis Reporting System and the Centers for Disease Control and Prevention Underlying Cause of Death database. We used fixed-effects regression models to examine the longitudinal association between increased undocumented immigration and drug problems and drunk driving. Increased undocumented immigration was significantly associated with reductions in drug arrests, drug overdose deaths, and DUI arrests, net of other factors. There was no significant relationship between increased undocumented immigration and DUI deaths. This study provides evidence that undocumented immigration has not increased the prevalence of drug or alcohol problems, but may be associated with reductions in these public health concerns.

Microdosing and drug development: past, present and future

Science.gov (United States)

Lappin, Graham; Noveck, Robert; Burt, Tal

2015-01-01

Introduction Microdosing is an approach to early drug development where exploratory pharmacokinetic data are acquired in humans using inherently safe sub-pharmacologic doses of drug. The first publication of microdose data was 10 years ago and this review comprehensively explores the microdose concept from conception, over the past decade, up until the current date. Areas covered The authors define and distinguish the concept of microdosing from similar approaches. The authors review the ability of microdosing to provide exploratory pharmacokinetics (concentration-time data) but exclude microdosing using positron emission tomography. The article provides a comprehensive review of data within the peer-reviewed literature as well as the latest applications and a look into the future, towards where microdosing may be headed. Expert opinion Evidence so far suggests that microdosing may be a better predictive tool of human pharmacokinetics than alternative methods and combination with physiologically based modelling may lead to much more reliable predictions in the future. The concept has also been applied to drug-drug interactions, polymorphism and assessing drug concentrations over time at its site of action. Microdosing may yet have more to offer in unanticipated directions and provide benefits that have not been fully realised to date. PMID:23550938

78 FR 63223 - Fibromyalgia Public Meeting on Patient-Focused Drug Development; Correction

Science.gov (United States)

2013-10-23

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-N-2013-1041] Fibromyalgia Public Meeting on Patient-Focused Drug Development; Correction AGENCY: Food and Drug... 23, 2013 (78 FR 58313). The document announced a public meeting entitled ``Fibromyalgia Public...

Recent developments of 2-aminothiazoles in medicinal chemistry.

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Das, Debasis; Sikdar, Papiya; Bairagi, Moumita

2016-02-15

The 2-aminothiazole (2-AT) core is an active pharmacophore and used in medicinal chemistry and drug discovery research. A number of drugs with 2-AT core are in the market, e.g. Famotidine, Cefdinir, Meloxcam etc. Recently, 2-AT core has been explored for many more important therapeutic areas and identified new 2-aminothiazoles with anticancer, antitumor, antidiebatic and anticonvulsant activity. In this review, we discuss the newly identified and developed 2-aminothiazoles in recent years and their use in medicinal chemistry and pharmacology. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Transferability of Newly Developed Pear SSR Markers to Other Rosaceae Species.

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Fan, L; Zhang, M-Y; Liu, Q-Z; Li, L-T; Song, Y; Wang, L-F; Zhang, S-L; Wu, J

2013-01-01

A set of 120 simple sequence repeats (SSRs) was developed from the newly assembled pear sequence and evaluated for polymorphisms in seven genotypes of pear from different genetic backgrounds. Of these, 67 (55.8 %) primer pairs produced polymorphic amplifications. Together, the 67 SSRs detected 277 alleles with an average of 4.13 per locus. Sequencing of the amplification products from randomly picked loci NAUPy31a and NAUpy53a verified the presence of the SSR loci. When the 67 primer pairs were tested on 96 individual members of eight species in the Rosaceae family, 61.2 % (41/67) of the tested SSRs successfully amplified a PCR product in at least one of the Rosaceae genera. The transferability from pear to different species varied from 58.2 % (apple) to 11.9 % (cherry). The ratio of transferability also reflected the closer relationships within Maloideae over Prunoideae. Two pear SSR markers, NAUpy43c and NAUpy55k, could distinguish the 20 different apple genotypes thoroughly, and UPGMA cluster analysis grouped them into three groups at the similarity level of 0.56. The high level of polymorphism and good transferability of pear SSRs to Rosaceae species indicate their promise for application to future molecular screening, map construction, and comparative genomic studies among pears and other Rosaceae species.

Drug development in Parkinson's disease: from emerging molecules to innovative drug delivery systems.

Science.gov (United States)

Garbayo, E; Ansorena, E; Blanco-Prieto, M J

2013-11-01

Current treatments for Parkinson's disease (PD) are aimed at addressing motor symptoms but there is no therapy focused on modifying the course of the disease. Successful treatment strategies have been so far limited and brain drug delivery remains a major challenge that restricts its treatment. This review provides an overview of the most promising emerging agents in the field of PD drug discovery, discussing improvements that have been made in brain drug delivery for PD. It will be shown that new approaches able to extend the length of the treatment, to release the drug in a continuous manner or to cross the blood-brain barrier and target a specific region are still needed. Overall, the results reviewed here show that there is an urgent need to develop both symptomatic and disease-modifying treatments, giving priority to neuroprotective treatments. Promising perspectives are being provided in this field by rasagiline and by neurotrophic factors like glial cell line-derived neurotrophic factor. The identification of disease-relevant genes has also encouraged the search for disease-modifying therapies that function by identifying molecularly targeted drugs. The advent of new molecular and cellular targets like α-synuclein, leucine-rich repeat serine/threonine protein kinase 2 or parkin, among others, will require innovative delivery therapies. In this regard, drug delivery systems (DDS) have shown great potential for improving the efficacy of conventional and new PD therapy and reducing its side effects. The new DDS discussed here, which include microparticles, nanoparticles and hydrogels among others, will probably open up possibilities that extend beyond symptomatic relief. However, further work needs to be done before DDS become a therapeutic option for PD patients. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Cross-Linking Mast Cell Specific Gangliosides Stimulates the Release of Newly Formed Lipid Mediators and Newly Synthesized Cytokines

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Edismauro Garcia Freitas Filho

2016-01-01

Full Text Available Mast cells are immunoregulatory cells that participate in inflammatory processes. Cross-linking mast cell specific GD1b derived gangliosides by mAbAA4 results in partial activation of mast cells without the release of preformed mediators. The present study examines the release of newly formed and newly synthesized mediators following ganglioside cross-linking. Cross-linking the gangliosides with mAbAA4 released the newly formed lipid mediators, prostaglandins D2 and E2, without release of leukotrienes B4 and C4. The effect of cross-linking these gangliosides on the activation of enzymes in the arachidonate cascade was then investigated. Ganglioside cross-linking resulted in phosphorylation of cytosolic phospholipase A2 and increased expression of cyclooxygenase-2. Translocation of 5-lipoxygenase from the cytosol to the nucleus was not induced by ganglioside cross-linking. Cross-linking of GD1b derived gangliosides also resulted in the release of the newly synthesized mediators, interleukin-4, interleukin-6, and TNF-α. The effect of cross-linking the gangliosides on the MAP kinase pathway was then investigated. Cross-linking the gangliosides induced the phosphorylation of ERK1/2, JNK1/2, and p38 as well as activating both NFκB and NFAT in a Syk-dependent manner. Therefore, cross-linking the mast cell specific GD1b derived gangliosides results in the activation of signaling pathways that culminate with the release of newly formed and newly synthesized mediators.

Development of novel drug delivery systems using phage display technology for clinical application of protein drugs.

Science.gov (United States)

Nagano, Kazuya; Tsutsumi, Yasuo

2016-01-01

Attempts are being made to develop therapeutic proteins for cancer, hepatitis, and autoimmune conditions, but their clinical applications are limited, except in the cases of drugs based on erythropoietin, granulocyte colony-stimulating factor, interferon-alpha, and antibodies, owing to problems with fundamental technologies for protein drug discovery. It is difficult to identify proteins useful as therapeutic seeds or targets. Another problem in using bioactive proteins is pleiotropic actions through receptors, making it hard to elicit desired effects without side effects. Additionally, bioactive proteins have poor therapeutic effects owing to degradation by proteases and rapid excretion from the circulatory system. Therefore, it is essential to establish a series of novel drug delivery systems (DDS) to overcome these problems. Here, we review original technologies in DDS. First, we introduce antibody proteomics technology for effective selection of proteins useful as therapeutic seeds or targets and identification of various kinds of proteins, such as cancer-specific proteins, cancer metastasis-related proteins, and a cisplatin resistance-related protein. Especially Ephrin receptor A10 is expressed in breast tumor tissues but not in normal tissues and is a promising drug target potentially useful for breast cancer treatment. Moreover, we have developed a system for rapidly creating functional mutant proteins to optimize the seeds for therapeutic applications and used this system to generate various kinds of functional cytokine muteins. Among them, R1antTNF is a TNFR1-selective antagonistic mutant of TNF and is the first mutein converted from agonist to antagonist. We also review a novel polymer-conjugation system to improve the in vivo stability of bioactive proteins. Site-specific PEGylated R1antTNF is uniform at the molecular level, and its bioactivity is similar to that of unmodified R1antTNF. In the future, we hope that many innovative protein drugs will be

Development and testing of a mobile application to support diabetes self-management for people with newly diagnosed type 2 diabetes: a design thinking case study.

Science.gov (United States)

Petersen, Mira; Hempler, Nana F

2017-06-26

Numerous mobile applications have been developed to support diabetes-self-management. However, the majority of these applications lack a theoretical foundation and the involvement of people with diabetes during development. The aim of this study was to develop and test a mobile application (app) supporting diabetes self-management among people with newly diagnosed type 2 diabetes using design thinking. The app was developed and tested in 2015 using a design-based research approach involving target users (individuals newly diagnosed with type 2 diabetes), research scientists, healthcare professionals, designers, and app developers. The research approach comprised three major phases: inspiration, ideation, and implementation. The first phase included observations of diabetes education and 12 in-depth interviews with users regarding challenges and needs related to living with diabetes. The ideation phrase consisted of four interactive workshops with users focusing on app needs, in which ideas were developed and prioritized. Finally, 14 users tested the app over 4 weeks; they were interviewed about usability and perceptions about the app as a support tool. A multifunctional app was useful for people with newly diagnosed type 2 diabetes. The final app comprised five major functions: overview of diabetes activities after diagnosis, recording of health data, reflection games and goal setting, knowledge games and recording of psychological data such as sleep, fatigue, and well-being. Users found the app to be a valuable tool for support, particularly for raising their awareness about their psychological health and for informing and guiding them through the healthcare system after diagnosis. The design thinking processes used in the development and implementation of the mobile health app were crucial to creating value for users. More attention should be paid to the training of professionals who introduce health apps. Danish Data Protection Agency: 2012-58-0004. Registered 6

Annual banned-substance review: analytical approaches in human sports drug testing.

Science.gov (United States)

Thevis, Mario; Kuuranne, Tiia; Geyer, Hans; Schänzer, Wilhelm

2017-01-01

There has been an immense amount of visibility of doping issues on the international stage over the past 12 months with the complexity of doping controls reiterated on various occasions. Hence, analytical test methods continuously being updated, expanded, and improved to provide specific, sensitive, and comprehensive test results in line with the World Anti-Doping Agency's (WADA) 2016 Prohibited List represent one of several critical cornerstones of doping controls. This enterprise necessitates expediting the (combined) exploitation of newly generated information on novel and/or superior target analytes for sports drug testing assays, drug elimination profiles, alternative test matrices, and recent advances in instrumental developments. This paper is a continuation of the series of annual banned-substance reviews appraising the literature published between October 2015 and September 2016 concerning human sports drug testing in the context of WADA's 2016 Prohibited List. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Pharmacogenetics in diverse ethnic populations--implications for drug discovery and development.

Science.gov (United States)

McCarthy, Linda C; Davies, Kirstie J; Campbell, David A

2002-07-01

It is widely acknowledged that the vast quantities of data now publicly available as a result of the human genome initiative have the potential to revolutionize the pharmaceutical industry. More tangibly to the drug development business, the dawn of the pharmacogenetics era has the potential to impact not only the discovery of new medicines but also the safety and efficacy of pharmaceutical agents. Coincident with these scientific advances is the emergence of new markets for pharmaceutical agents. Japan, which represents the world's second biggest market, is a good example. With the ICH E5 agreement in 1998 and a rapid change in the drug registration process in Japan, there are increasing opportunities to improve access to more medicines in all parts of the world. However, it is increasingly clear that significant genetic variation still exists between populations, with a host of data on interethnic variation in drug metabolizing enzyme and drug transporter activity. Evidence suggesting that this genetic variation may play an important role in defining some of the interethnic variation in drug response to currently marketed compounds is reviewed here, and future possibilities of using such information to better streamline the drug development process are discussed.

Newly Homeless Youth Typically Return Home

OpenAIRE

Milburn, Norweeta G.; Rosenthal, Doreen; Rotheram-Borus, Mary Jane; Mallett, Shelley; Batterham, Philip; Rice, Eric; Solorio, Rosa

2007-01-01

165 newly homeless adolescents from Melbourne, Australia and 261 from Los Angeles, United States were surveyed and followed for two years. Most newly homeless adolescents returned home (70% U.S., 47% Australia) for significant amounts of time (39% U.S., 17% Australia more than 12 months) within two years of becoming homeless.

HIV and AIDS among adolescents who use drugs: opportunities for drug policy reform within the sustainable development agenda.

Science.gov (United States)

Tinasti, Khalid

2018-02-01

The international community's commitment to halve by 2015 the HIV transmission among people who inject drugs has not only been largely missed, instead new HIV infections have increased by 30%. Moreover, drug injection remains one of the drivers of new HIV infections due to punitive responses and lack of harm reduction resourcing. In the midst of this situation, adolescents are a forgotten component of the global response to illegal drugs and their link with HIV infection. The Sustainable Development Goals (SDGs) present an opportunity to achieve the global objective of ending AIDS among adolescents who use drugs, by addressing the structural vulnerabilities they face be they economic, social, criminal, health-related or environmental. The implementation of the SDGs presents an opportunity to address the horizontal nature of drug policy and to efficiently address the drugs-adolescents-HIV risk nexus. Adolescent-focused drug policies are linked to goals 1, 3, 4, 10, 16 and 17. Goals 3 and 16 are the most relevant; the targets of the latter link to the criminalization of drug use and punitive policy environments and their impact on adolescents' health and HIV transmission risks. Moreover, it presents an opportunity to include adolescent needs that are missing in the three drug control conventions (1961, 1971 and 1988), and link them with the provisions of the Convention on the Rights of the Child (1989). Finally, the six principles to deliver on sustainable development are also an opportunity to divert adolescents who use drugs away from criminalization and punitive environments in which their vulnerability to HIV is greater. Addressing HIV among adolescents who use drugs is an extremely complex policy issue depending on different sets of binding and non-binding commitments, interventions and stakeholders. The complexity requires a horizontal response provided by the SDGs framework, starting with the collection of disaggregated data on this specific subgroup. Ending

Technetium-99m carboxymethylcellulose: A newly developed fibre marker for gastric emptying studies

International Nuclear Information System (INIS)

Schade, J.H.; Hoving, J.; Brouweres, J.R.B.J.; Riedstra-van Gent, H.G.; Zijlstra, J.; Dijkstra, J.P.H.

1991-01-01

We report a study of technetium-99m-labelled carboxymethyl-cellulose ( 99m Tc-CMC) as a newly developed non-digestible marker of the solid phase of gastric contents. The radiosynthesis is simple and shows a high labelling efficiency. In vitro and in vivo experiments demonstrated stability of the marker in the gastrointestinal tract during the process of gastric emptying. The gastric half-emptying time in ten healthy volunteers of both sexes was 105±17 min (mean±SD). This rate of gastric emptying is similar to that of non-digestible solid-phase markers such as in vivo labelled 99m Tc-chicken liver or radio-iodinated cellulose. In comparison with digestible solid-phase markers such as 99m Tc-labelled pancake or 99m Tc-cooked egg, gastric emptying of 99m Tc-CMC occurred more slowly, confirming the expected behaviour of a non-digestible solid-phase marker. We conclude that 99m Tc-CMC has the advantage of a simple and rapid labelling procedure and may be useful for clinical studies of gastric emptying. (orig.)

Phenotypic screening approaches to develop Aurora kinase inhibitors: Drug Discovery perspectives

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Carlos eMarugán

2016-01-01

Full Text Available Targeting mitotic regulators as a strategy to fight cancer implies the development of drugs against key proteins such as Aurora A and B. Current drugs which target mitosis through a general mechanism of action (stabilization/destabilization of microtubules, have several side effects (neutropenia, alopecia, emesis. Pharmaceutical companies aim at avoiding these unwanted effects by generating improved and selective drugs that increase the quality of life of the patients. However, the development of these drugs is an ambitious task that involves testing thousands of compounds through biochemical and cell-based assays. In addition, molecules usually target complex biological processes, involving several proteins and different molecular pathways, further emphasizing the need for high-throughput screening techniques and multiplexing technologies in order to identify drugs with the desired phenotype.We will briefly describe two multiplexing technologies (high-content imaging, microarrays and flow cytometry and two key processes for drug discovery research (assay development and validation following our own published industry quality standards. We will further focus on high-content imaging as a useful tool for phenotypic screening and will provide a concrete example of high-content imaging assay to detect Aurora A or B selective inhibitors discriminating the off-target effects related to inhibition of other cell cycle or non-cell cycle key regulators. Finally, we will describe other assays that can help to characterize the in vitro pharmacology of the inhibitors.

Cancer Drug Development: New Targets for Cancer Treatment.

Science.gov (United States)

Curt

1996-01-01

cancer drug screening and cancer drug development. At the NCI, for example, the old in vivo mouse screen using mouse lymphomas has been shelved; it discovered compounds with some activity in lymphomas, but not the common solid tumors of adulthood. It has been replaced with an initial in vitro screen of some sixty cell lines, representing the common solid tumors-ovary, G.I., lung, breast, CNS, melanoma and others. The idea was to not only discover new drugs with specific anti-tumor activity but also to use the small volumes required for in vitro screening as a medium to screen for new natural product compounds, one of the richest sources of effective chemotherapy. The cell line project had an unexpected dividend. The pattern of sensitivity in the panel predicted the mechanism of action of unknown compounds. An antifolate suppressed cell growth of the different lines like other antifolates, anti-tubulin compounds suppressed like other anti-tubulins, and so on. It now became possible, at a very early stage of cancer drug screening, to select for drugs with unknown-and potentially novel-mechanisms of action. The idea was taken to the next logical step, and that was to characterize the entire panel for important molecular properties of human malignancy: mutations in the tumor suppressor gene p53, expression of important oncogenes like ras or myc, the gp170 gene which confers multiple drug resistance, protein-specific kinases, and others. It now became possible to use the cell line panel as a tool to detect new drugs which targeted a specific genetic property of the tumor cell. Researchers can now ask whether a given drug is likely to inhibit multiple drug resistance or kill cells which over-express specific oncogenes at the earliest phase of drug discovery. In this issue of The Oncologist, Tom Connors celebrates the fiftieth anniversary of cancer chemotherapy. His focus is on the importance of international collaboration in clinical trials and the negative impact of

78 FR 32669 - New Approaches to Antibacterial Drug Development; Request for Comments

Science.gov (United States)

2013-05-31

... Management (HFA- 305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. FOR... concern, we are seeking to explore new clinical development paradigms for antibacterial drugs. Areas of ongoing need are numerous and include new drugs for treatment of hospital-acquired bacterial pneumonia...

Core competencies for pharmaceutical physicians and drug development scientists

Science.gov (United States)

Silva, Honorio; Stonier, Peter; Buhler, Fritz; Deslypere, Jean-Paul; Criscuolo, Domenico; Nell, Gerfried; Massud, Joao; Geary, Stewart; Schenk, Johanna; Kerpel-Fronius, Sandor; Koski, Greg; Clemens, Norbert; Klingmann, Ingrid; Kesselring, Gustavo; van Olden, Rudolf; Dubois, Dominique

2013-01-01

Professional groups, such as IFAPP (International Federation of Pharmaceutical Physicians and Pharmaceutical Medicine), are expected to produce the defined core competencies to orient the discipline and the academic programs for the development of future competent professionals and to advance the profession. On the other hand, PharmaTrain, an Innovative Medicines Initiative project, has become the largest public-private partnership in biomedicine in the European Continent and aims to provide postgraduate courses that are designed to meet the needs of professionals working in medicines development. A working group was formed within IFAPP including representatives from PharmaTrain, academic institutions and national member associations, with special interest and experience on Quality Improvement through education. The objectives were: to define a set of core competencies for pharmaceutical physicians and drug development scientists, to be summarized in a Statement of Competence and to benchmark and align these identified core competencies with the Learning Outcomes (LO) of the PharmaTrain Base Course. The objectives were successfully achieved. Seven domains and 60 core competencies were identified and aligned accordingly. The effective implementation of training programs using the competencies or the PharmaTrain LO anywhere in the world may transform the drug development process to an efficient and integrated process for better and safer medicines. The PharmaTrain Base Course might provide the cognitive framework to achieve the desired Statement of Competence for Pharmaceutical Physicians and Drug Development Scientists worldwide. PMID:23986704

Core Competencies for Pharmaceutical Physicians and Drug Development Scientists

Directory of Open Access Journals (Sweden)

Honorio eSilva

2013-08-01

Full Text Available Professional groups, such as IFAPP (International Federation of Pharmaceutical Physicians and Pharmaceutical Medicine, are expected to produce the defined core competencies to orient the discipline and the academic programs for the development of future competent professionals and to advance the profession. On the other hand, PharmaTrain, an Innovative Medicines Initiative project, has become the largest public-private partnership in biomedicine in the European Continent and aims to provide postgraduate courses that are designed to meet the needs of professionals working in medicines development. A working group was formed within IFAPP including representatives from PharmaTrain, academic institutions and national member associations, with special interest and experience on Quality Improvement through education. The objectives were: to define a set of core competencies for pharmaceutical physicians and drug development scientists, to be summarized in a Statement of Competence and to benchmark and align these identified core competencies with the Learning Outcomes of the PharmaTrain Base Course. The objectives were successfully achieved. Seven domains and 60 core competencies were identified and aligned accordingly. The effective implementation of training programs using the competencies or the PharmaTrain Learning Outcomes anywhere in the world may transform the drug development process to an efficient and integrated process for better and safer medicines. The PharmaTrain Base Course might provide the cognitive framework to achieve the desired Statement of Competence for Pharmaceutical Physicians and Drug Development Scientists worldwide.

Development of gellan gum containing formulations for transdermal drug delivery: Component evaluation and controlled drug release using temperature responsive nanogels.

Science.gov (United States)

Carmona-Moran, Carlos A; Zavgorodnya, Oleksandra; Penman, Andrew D; Kharlampieva, Eugenia; Bridges, S Louis; Hergenrother, Robert W; Singh, Jasvinder A; Wick, Timothy M

2016-07-25

Enhancing skin permeation is important for development of new transdermal drug delivery formulations. This is particularly relevant for non-steroidal anti-inflammatory drugs (NSAIDs). To address this, semisolid gel and solid hydrogel film formulations containing gellan gum as a gelling agent were developed and the effects of penetration enhancers (dimethyl sulfoxide, isopropyl alcohol and propylene glycol) on transport of the NSAID diclofenac sodium was quantified. A transwell diffusion system was used to accelerate formulation development. After 4h, diclofenac flux from a superior formulation of the semisolid gel or the solid hydrogel film was 130±11μg/cm(2)h and 108±7μg/cm(2)h, respectively, and significantly greater than that measured for a currently available diclofenac sodium topical gel (30±4μg/cm(2)h, ptransdermal drug formulations with adjustable drug transport kinetics. Copyright © 2016 Elsevier B.V. All rights reserved.

The Nicotinic Acetylcholine Receptor as a Target for Antidepressant Drug Development

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Noah S. Philip

2012-01-01

Full Text Available An important new area of antidepressant drug development involves targeting the nicotinic acetylcholine receptor (nAChR. This receptor, which is distributed widely in regions of the brain associated with depression, is also implicated in other important processes that are relevant to depression, such as stress and inflammation. The two classes of drugs that target nAChRs can be broadly divided into mecamylamine- and cytisine-based compounds. These drugs probably exert their effects via antagonism at α4β2 nAChRs, and strong preclinical data support the antidepressant efficacy of both classes when used in conjunction with other primary antidepressants (e.g., monoamine reuptake inhibitors. Although clinical data remain limited, preliminary results in this area constitute a compelling argument for further evaluation of the nAChR as a target for future antidepressant drug development.

Projecting ADME Behavior and Drug-Drug Interactions in Early Discovery and Development: Application of the Extended Clearance Classification System.

Science.gov (United States)

El-Kattan, Ayman F; Varma, Manthena V; Steyn, Stefan J; Scott, Dennis O; Maurer, Tristan S; Bergman, Arthur

2016-12-01

To assess the utility of Extended Clearance Classification System (ECCS) in understanding absorption, distribution, metabolism, and elimination (ADME) attributes and enabling victim drug-drug interaction (DDI) predictions. A database of 368 drugs with relevant ADME parameters, main metabolizing enzymes, uptake transporters, efflux transporters, and highest change in exposure (%AUC) in presence of inhibitors was developed using published literature. Drugs were characterized according to ECCS using ionization, molecular weight and estimated permeability. Analyses suggested that ECCS class 1A drugs are well absorbed and systemic clearance is determined by metabolism mediated by CYP2C, esterases, and UGTs. For class 1B drugs, oral absorption is high and the predominant clearance mechanism is hepatic uptake mediated by OATP transporters. High permeability neutral/basic drugs (class 2) showed high oral absorption, with metabolism mediated generally by CYP3A, CYP2D6 and UGTs as the predominant clearance mechanism. Class 3A/4 drugs showed moderate absorption with dominant renal clearance involving OAT/OCT2 transporters. Class 3B drugs showed low to moderate absorption with hepatic uptake (OATPs) and/or renal clearance as primary clearance mechanisms. The highest DDI risk is typically seen with class 2/1B/3B compounds manifested by inhibition of either CYP metabolism or active hepatic uptake. Class 2 showed a wider range in AUC change likely due to a variety of enzymes involved. DDI risk for class 3A/4 is small and associated with inhibition of renal transporters. ECCS provides a framework to project ADME profiles and further enables prediction of victim DDI liabilities in drug discovery and development.

Development of drugs and technology for radiation theragnosis

Energy Technology Data Exchange (ETDEWEB)

Jeong, Hwan Jeong [Dept. of Nuclear Medicine, Biomedical Research Institute, Chonbuk National University Medical School and Hospital, Jeonju (Korea, Republic of); Lee, Byung Chul [Dept. of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Sungnam (Korea, Republic of); Ahn, Byeong Cheol [Dept. of Nuclear Medicine, Kyungpook National University School of Medicine and Hospital, Daegu (Korea, Republic of); Kang, Keon Wook [Dept. of Nuclear Medicine and Cancer Research Institute, Seoul National University, Seoul (Korea, Republic of)

2016-06-15

Personalized medicine is tailored medical treatment that targets the individual characteristics of each patient. Theragnosis, combining diagnosis and therapy, plays an important role in selecting appropriate patients. Noninvasive in vivo imaging can trace small molecules, antibodies, peptides, nanoparticles, and cells in the body. Recently, imaging methods have been able to reveal molecular events in cells and tissues. Molecular imaging is useful not only for clinical studies but also for developing new drugs and new treatment modalities. Preclinical and early clinical molecular imaging shows biodistribution, pharmacokinetics, mechanisms of action, and efficacy. When therapeutic materials are labeled using radioisotopes, nuclear imaging with positron emission tomography or gamma camera can be used to treat diseases and monitor therapy simultaneously. Such nuclear medicine technology is defined as radiation theragnosis. We review the current development of drugs and technology for radiation theragnosis using peptides, albumin, nanoparticles, and cells.

Recent developments in drug eluting devices with tailored interfacial properties.

Science.gov (United States)

Sanchez-Rexach, Eva; Meaurio, Emilio; Sarasua, Jose-Ramon

2017-11-01

Drug eluting devices have greatly evolved during past years to become fundamental products of great marketing importance in the biomedical field. There is currently a large diversity of highly specialized devices for specific applications, making the development of these devices an exciting field of research. The replacement of the former bare metal devices by devices loaded with drugs allowed the sustained and controlled release of drugs, to achieve the desired local therapeutic concentration of drug. The newer devices have been "engineered" with surfaces containing micro- and nanoscale features in a well-controlled manner, that have shown to significantly affect cellular and subcellular function of various biological systems. For example, the topography can be structured to form an antifouling surface mimicking the defense mechanisms found in nature, like the skin of the shark. In the case of bone implants, well-controlled nanostructured interfaces can promote osteoblast differentiation and matrix production, and enhance short-term and long-term osteointegration. In any case, the goal of current research is to design implants that induce controlled, guided, and rapid healing. This article reviews recent trends in the development of drug eluting devices, as well as recent developments on the micro/nanotechnology scales, and their future challenges. For this purpose medical devices have been divided according to the different systems of the body they are focused to: orthopedic devices, breathing stents, gastrointestinal and urinary systems, devices for cardiovascular diseases, neuronal implants, and wound dressings. Copyright © 2017 Elsevier B.V. All rights reserved.

Drug Development Process

Science.gov (United States)

... Preclinical Research Preclinical Research Drugs undergo laboratory and animal testing to answer basic questions about safety. More Information ... Medical Devices Radiation-Emitting Products Vaccines, Blood & Biologics Animal & Veterinary Cosmetics Tobacco Products

THE NEXUS BETWEEN ENERGY CONSUMPTION AND FINANCIAL DEVELOPMENT WITH ASYMMETRIC CAUSALITY TEST: NEW EVIDENCE FROM NEWLY INDUSTRIALIZED COUNTRIES

Directory of Open Access Journals (Sweden)

Feyyaz Zeren

2014-01-01

Full Text Available In this study, the relationship between energy consumption and financial development is investigated via Hatemi-J asymmetric causality test (2012 which is able to separate positive and negative shocks in analysis. In order to determine different dimensions of financial system, deposit money bank assets to GDP (dbagdp, financial system deposits to GDP (fdgdp and private credit to GDP (pcrdbgdp were used as three different indicators. As a result of this study on Newly Industrialized 7 Countries spanning the period 1971 till 2010, both positive and negative shocks existed for Malaysia and Mexico, causality from energy consumption to financial developments emerged for Philippines in only negative shocks. While two-way causality occurred for India, Turkey and Thailand, there was not for South Africa.

Stem cells: a model for screening, discovery and development of drugs

Directory of Open Access Journals (Sweden)

Kitambi SS

2011-09-01

Full Text Available Satish Srinivas Kitambi1, Gayathri Chandrasekar21Department of Medical Biochemistry and Biophysics; 2Department of Biosciences, Karolinska Institutet, Stockholm, SwedenAbstract: The identification of normal and cancerous stem cells and the recent advances made in isolation and culture of stem cells have rapidly gained attention in the field of drug discovery and regenerative medicine. The prospect of performing screens aimed at proliferation, directed differentiation, and toxicity and efficacy studies using stem cells offers a reliable platform for the drug discovery process. Advances made in the generation of induced pluripotent stem cells from normal or diseased tissue serves as a platform to perform drug screens aimed at developing cell-based therapies against conditions like Parkinson's disease and diabetes. This review discusses the application of stem cells and cancer stem cells in drug screening and their role in complementing, reducing, and replacing animal testing. In addition to this, target identification and major advances in the field of personalized medicine using induced pluripotent cells are also discussed.Keywords: therapeutics, stem cells, cancer stem cells, screening models, drug development, high throughput screening

Controlling type I error rate for fast track drug development programmes.

Science.gov (United States)

Shih, Weichung J; Ouyang, Peter; Quan, Hui; Lin, Yong; Michiels, Bart; Bijnens, Luc

2003-03-15

The U.S. Food and Drug Administration (FDA) Modernization Act of 1997 has a Section (No. 112) entitled 'Expediting Study and Approval of Fast Track Drugs' (the Act). In 1998, the FDA issued a 'Guidance for Industry: the Fast Track Drug Development Programs' (the FTDD programmes) to meet the requirement of the Act. The purpose of FTDD programmes is to 'facilitate the development and expedite the review of new drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs'. Since then many health products have reached patients who suffered from AIDS, cancer, osteoporosis, and many other diseases, sooner by utilizing the Fast Track Act and the FTDD programmes. In the meantime several scientific issues have also surfaced when following the FTDD programmes. In this paper we will discuss the concept of two kinds of type I errors, namely, the 'conditional approval' and the 'final approval' type I errors, and propose statistical methods for controlling them in a new drug submission process. Copyright 2003 John Wiley & Sons, Ltd.

Regulatory perspective on remaining challenges for utilization of pharmacogenomics-guided drug developments.

Science.gov (United States)

Otsubo, Yasuto; Ishiguro, Akihiro; Uyama, Yoshiaki

2013-01-01

Pharmacogenomics-guided drug development has been implemented in practice in the last decade, resulting in increased labeling of drugs with pharmacogenomic information. However, there are still many challenges remaining in utilizing this process. Here, we describe such remaining challenges from the regulatory perspective, specifically focusing on sample collection, biomarker qualification, ethnic factors, codevelopment of companion diagnostics and means to provide drugs for off-target patients. To improve the situation, it is important to strengthen international harmonization and collaboration among academia, industries and regulatory agencies, followed by the establishment of an international guideline on this topic. Communication with a regulatory agency from an early stage of drug development is also a key to success.

77 FR 11133 - Draft Guidance for Industry on Complicated Urinary Tract Infections: Developing Drugs for...

Science.gov (United States)

2012-02-24

...] Draft Guidance for Industry on Complicated Urinary Tract Infections: Developing Drugs for Treatment... Urinary Tract Infections: Developing Drugs for Treatment.'' The purpose of this guidance is to assist sponsors in the clinical development of drugs for the treatment of complicated urinary tract infections (c...

Formulary Drug Review: Betrixaban.

Science.gov (United States)

Baker, Danial E

2018-02-01

Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are available online to subscribers. Monographs can be customized to meet the needs of a facility. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service , contact Wolters Kluwer customer service at 866-397-3433.

Formulary Drug Review: Ocrelizumab.

Science.gov (United States)

Ali, Zaynah K; Baker, Danial E

2017-10-01

Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are available online to subscribers. Monographs can be customized to meet the needs of a facility. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service , contact Wolters Kluwer customer service at 866-397-3433.

Formulary Drug Review: Edaravone.

Science.gov (United States)

Ali, Zaynah K; Baker, Danial E

2017-12-01

Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are available online to subscribers. Monographs can be customized to meet the needs of a facility. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service , contact Wolters Kluwer customer service at 866-397-3433.

Molecular Genetics of Drug-resistance in Epilepsies

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Kurupath Radhakrishnan

2015-06-01

Full Text Available Nearly one-third of newly diagnosed patients with epilepsy remain unresponsive to antiepileptic drugs (AEDs, etiopathogenesis of which is poorly understood. The genes encoding the proteins that regulate the pharmacokinetics such as P-glycoprotein [ABCBI], major vault protein [MVP gene] and drug metabolizing enzymes [ABCB1, ABCG2, MVP, CYP2C9, CYP2C19, CYP3A4, CYP3A5, EPHX1, UGT1A1, UGT2B7], and pharmacodynamics such as sodium channels [SCN1A, SCN2A] and GABA receptors [GABRA1, GABRA6, GABRB2, GABRG2] of AEDs are under intense investigation to unravel the mysteries of AED-resistance. However, till today, a consistent and reliable result that could help the clinician either to predict drug resistance or to overcome it has not been forthcoming. The discrepant results may be related to variations in the definition of drug-resistance, heterogeneous patient populations, ethnic variations in the frequency distribution of single nucleotide polymorphisms (SNPs and the selection of SNPs. Understanding of these limitations of existing studies, hopefully, will help in designing better studies. Nearly one-third of newly diagnosed patients with epilepsy remain unresponsive toantiepileptic drugs (AEDs, etiopathogenesis of which is poorly understood. The genesencoding the proteins that regulate the pharmacokinetics such as P-glycoprotein[ABCBI], major vault protein [MVP gene] and drug metabolizing enzymes [ABCB1,ABCG2, MVP, CYP2C9, CYP2C19, CYP3A4, CYP3A5, EPHX1, UGT1A1, UGT2B7],and pharmacodynamics such as sodium channels [SCN1A, SCN2A] and GABAreceptors [GABRA1, GABRA6, GABRB2, GABRG2] of AEDs are under intenseinvestigation to unravel the mysteries of AED-resistance. However, till today, aconsistent and reliable result that could help the clinician either to predict drugresistanceor to overcome it has not been forthcoming. The discrepant results may berelated to variations in the definition of drug-resistance, heterogeneous patientpopulations, ethnic

Personalized Medicine: Pharmacogenomics and Drug Development

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Somayeh Mirsadeghi

2017-03-01

Full Text Available Personalized medicine aims is to supply the proper drug to the proper patient within the right dose. Pharmacogenomics (PGx is to recognize genetic variants that may influence drug efficacy and toxicity. All things considered, the fields cover a wide area, including basic drug discovery researches, the genetic origin of pharmacokinetics and pharmacodynamics, novel drug improvement, patient genetic assessment and clinical patient administration. At last, the objective of Pharmacogenomics is to anticipate a patient’s genetic response to a particular drug as a way of presenting the best possible medical treatment. By predicting the drug response of an individual, it will be possible to increase the success of therapies and decrease the incidence of adverse side effect.

Primary drug-resistant tuberculosis in Hanoi, Viet Nam: present status and risk factors.

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Nguyen Thi Le Hang

Full Text Available INTRODUCTION: Resistance of Mycobacterium tuberculosis (MTB to anti-tuberculosis (TB drugs presents a serious challenge to TB control worldwide. We investigated the status of drug resistance, including multidrug-resistant (MDR TB, and possible risk factors among newly diagnosed TB patients in Hanoi, the capital of Viet Nam. METHODS: Clinical and epidemiological information was collected from 506 newly diagnosed patients with sputum smear- and culture-positive TB, and 489 (96.6% MTB isolates were subjected to conventional drug susceptibility testing, spoligotyping, and 15-locus variable numbers of tandem repeats typing. Adjusted odds ratios (aORs were calculated to analyze the risk factors for primary drug resistance. RESULTS: Of 489 isolates, 298 (60.9% were sensitive to all drugs tested. Resistance to isoniazid, rifampicin, streptomycin, ethambutol, and MDR accounted for 28.2%, 4.9%, 28.2%, 2.9%, and 4.5%, respectively. Of 24 isolates with rifampicin resistance, 22 (91.7% were MDR and also resistant to streptomycin, except one case. Factors associated with isoniazid resistance included living in old urban areas, presence of the Beijing genotype, and clustered strains [aOR = 2.23, 95% confidence interval (CI 1.15-4.35; 1.91, 1.18-3.10; and 1.69, 1.06-2.69, respectively. The Beijing genotype was also associated with streptomycin resistance (aOR = 2.10, 95% CI 1.29-3.40. Human immunodeficiency virus (HIV coinfection was associated with rifampicin resistance and MDR (aOR = 5.42, 95% CI 2.07-14.14; 6.23, 2.34-16.58, respectively. CONCLUSION: Isoniazid and streptomycin resistance was observed in more than a quarter of TB patients without treatment history in Hanoi. Transmission of isoniazid-resistant TB among younger people should be carefully monitored in urban areas, where Beijing strains and HIV coinfection are prevalent. Choosing an optimal treatment regimen on the basis of the results of drug susceptibility tests and monitoring of treatment

Design of an X-band accelerating structure using a newly developed structural optimization procedure

Energy Technology Data Exchange (ETDEWEB)

Huang, Xiaoxia [Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800 (China); University of Chinese Academy of Sciences, Beijing 100049 (China); Fang, Wencheng; Gu, Qiang [Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800 (China); Zhao, Zhentang, E-mail: zhaozhentang@sinap.ac.cn [Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800 (China); University of Chinese Academy of Sciences, Beijing 100049 (China)

2017-05-11

An X-band high gradient accelerating structure is a challenging technology for implementation in advanced electron linear accelerator facilities. The present work discusses the design of an X-band accelerating structure for dedicated application to a compact hard X-ray free electron laser facility at the Shanghai Institute of Applied Physics, and numerous design optimizations are conducted with consideration for radio frequency (RF) breakdown, RF efficiency, short-range wakefields, and dipole/quadrupole field modes, to ensure good beam quality and a high accelerating gradient. The designed X-band accelerating structure is a constant gradient structure with a 4π/5 operating mode and input and output dual-feed couplers in a racetrack shape. The design process employs a newly developed effective optimization procedure for optimization of the X-band accelerating structure. In addition, the specific design of couplers providing high beam quality by eliminating dipole field components and reducing quadrupole field components is discussed in detail.

Duplex ultrasound: Indications and findings in a newly created ...

African Journals Online (AJOL)

Duplex ultrasound: Indications and findings in a newly created facility at the University of Calabar Teaching Hospital, Calabar. ... It is recommended that timely referrals be made, and mobile Doppler units be acquired to save more lives and limbs in the developing world. Keywords: Calabar, deep venous thrombosis, duplex ...

Competence of newly qualified registered nurses from a nursing college

Directory of Open Access Journals (Sweden)

BG Morolong

2005-09-01

Full Text Available The South African education and training system, through its policy of outcomesbased education and training, has made competency a national priority. In compliance to this national requirement of producing competent learners, the South African Nursing Council ( 1999 B require that the beginner professional nurse practitioners and midwives have the necessary knowledge, skills, attitudes and values which will enable them to render efficient professional service. The health care system also demands competent nurse practitioners to ensure quality in health care. In the light of competency being a national priority and a statutory demand, the research question that emerges is, how competent are the newly qualified registered nurses from a specific nursing college in clinical nursing education? A quantitative, non-experimental contextual design was used to evaluate the competence of newly qualified registered nurses from a specific nursing college. The study was conducted in two phases. The first phase dealt with the development of an instrument together with its manual through the conceptualisation process. The second phase focused on the evaluation of the competency of newly qualified nurses using the instrument based on the steps of the nursing process. A pilot study was conducted to test the feasibility of the items of the instrument. During the evaluation phase, a sample of twenty-six newly qualified nurses was selected by simple random sampling from a target population of thirty-six newly qualified registered nurses. However, six participants withdrew from the study. Data was collected in two general hospitals where the newly qualified registered nurses were working. Observation and questioning were used as data collection techniques in accordance with the developed instrument. Measures were taken to ensure internal validity and reliability of the results. To protect the rights of the participants, the researcher adhered to DENOSA’S (1998

A newly developed grab sampling system for collecting stratospheric air over Antarctica

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Hideyuki Honda

1996-07-01

Full Text Available In order to measure the concentrations of various minor constituents and their isotopic ratios in the stratosphere over Antarctica, a simple grab sampling system was newly developed. The sampling system was designed to be launched by a small number of personnel using a rubber balloon under severe experimental conditions. Special attention was paid to minimize the contamination of sample air, as well as to allow easy handling of the system. The sampler consisted mainly of a 15l sample container with electromagnetic and manual valves, control electronics for executing the air sampling procedures and sending the position and status information of the sampler to the ground station, batteries and a transmitter. All these parts were assembled in an aluminum frame gondola with a shock absorbing system for landing. The sampler was equipped with a turn-over mechanism of the gondola to minimize contamination from the gondola, as well as with a GPS receiver and a rawinsonde for its tracking. Total weight of the sampler was about 11kg. To receive, display and store the position and status data of the sampling system at the ground station, a simple data acquisition system with a portable receiver and a microcomputer was also developed. A new gas handling system was prepared to simplify the injection of He gas into the balloon. For air sampling experiments, three sampling systems were launched at Syowa Station (69°00′S, 39°35′E, Antarctica and then recovered on sea ice near the station on January 22 and 25,1996.

Evaluation of newly developed veterinary portable blood glucose meter with hematocrit correction in dogs and cats.

Science.gov (United States)

Mori, Akihiro; Oda, Hitomi; Onozawa, Eri; Shono, Saori; Sako, Toshinori

2017-10-07

This study evaluated the accuracy of a newly developed veterinary portable blood glucose meter (PBGM) with hematocrit correction in dogs and cats. Sixty-one dogs and 31 cats were used for the current study. Blood samples were obtained from each dog and cat one to six times. Acceptable results were obtained in error grid analysis between PBGM and reference method values (glucose oxidation methods) in both dogs and cats. Bland-Altman plot analysis revealed a mean difference between the PBGM value and reference method value of -1.975 mg/dl (bias) in dogs and 1.339 mg/dl (bias) in cats. Hematocrit values did not affect the results of the veterinary PBGM. Therefore, this veterinary PBGM is clinically useful in dogs and cats.

Newly-graduated midwives transcending barriers: a grounded theory study.

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Barry, Michele J; Hauck, Yvonne L; O'Donoghue, Thomas; Clarke, Simon

2013-12-01

Midwifery has developed its own philosophy to formalise its unique identity as a profession. Newly-graduated midwives are taught, and ideally embrace, this philosophy during their education. However, embarking in their career within a predominantly institutionalised and the medically focused health-care model may challenge this application. The research question guiding this study was as follows: 'How do newly graduated midwives deal with applying the philosophy of midwifery in their first six months of practice?' The aim was to generate a grounded theory around this social process. This Western Australian grounded theory study is conceptualised within the social theory of symbolic interactionism. Data were collected by means of in-depth, semi-structured interviews with 11 recent midwifery graduates. Participant and interviewer's journals provided supplementary data. The 'constant comparison' approach was used for data analysis. The substantive theory of transcending barriers was generated. Three stages in transcending barriers were identified: Addressing personal attributes, Understanding the 'bigger picture', and finally, 'Evaluating, planning and acting' to provide woman-centred care. An overview of these three stages provides the focus of this article. The theory of transcending barriers provides a new perspective on how newly-graduated midwives deal with applying the philosophy of midwifery in their first six months of practice. A number of implications for pre and post registration midwifery education and policy development are suggested, as well as recommendations for future research. Copyright © 2013 Elsevier Ltd. All rights reserved.

Site-specific antibody-drug conjugates: the nexus of bioorthogonal chemistry, protein engineering, and drug development.

Science.gov (United States)

Agarwal, Paresh; Bertozzi, Carolyn R

2015-02-18

Antibody-drug conjugates (ADCs) combine the specificity of antibodies with the potency of small molecules to create targeted drugs. Despite the simplicity of this concept, generation of clinically successful ADCs has been very difficult. Over the past several decades, scientists have learned a great deal about the constraints on antibodies, linkers, and drugs as they relate to successful construction of ADCs. Once these components are in hand, most ADCs are prepared by nonspecific modification of antibody lysine or cysteine residues with drug-linker reagents, which results in heterogeneous product mixtures that cannot be further purified. With advances in the fields of bioorthogonal chemistry and protein engineering, there is growing interest in producing ADCs by site-specific conjugation to the antibody, yielding more homogeneous products that have demonstrated benefits over their heterogeneous counterparts in vivo. Here, we chronicle the development of a multitude of site-specific conjugation strategies for assembly of ADCs and provide a comprehensive account of key advances and their roots in the fields of bioorthogonal chemistry and protein engineering.

Experimental methods and transport models for drug delivery across the blood-brain barrier.

Science.gov (United States)

Fu, Bingmei M

2012-06-01

The blood-brain barrier (BBB) is a dynamic barrier essential for maintaining the micro-environment of the brain. Although the special anatomical features of the BBB determine its protective role for the central nervous system (CNS) from blood-born neurotoxins, however, the BBB extremely limits the therapeutic efficacy of drugs into the CNS, which greatly hinders the treatment of major brain diseases. This review summarized the unique structures of the BBB, described a variety of in vivo and in vitro experimental methods for determining the transport properties of the BBB, e.g., the permeability of the BBB to water, ions, and solutes including nutrients, therapeutic agents and drug carriers, and presented newly developed mathematical models which quantitatively correlate the anatomical structures of the BBB with its barrier functions. Finally, on the basis of the experimental observations and the quantitative models, several strategies for drug delivery through the BBB were proposed.

Newly Synthesized Doxorubicin Complexes with Selected Metals—Synthesis, Structure and Anti-Breast Cancer Activity

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Agata Jabłońska-Trypuć

2017-07-01

Full Text Available Doxorubicin (DOX is very effective chemotherapeutic agent, however it has several major drawbacks. Therefore the motivation for developing novel drug complexes as anticancer agents with different mechanism of action has arisen. The aim of the present study was to evaluate the influence of newly synthesized DOX complexes with selected metals (Mg, Mn, Co, Ni, Fe, Cu, Zn on apoptosis, cell cycle, viability, proliferation and cytotoxicity in the breast cancer cell line MCF-7. Complexation of DOX with metals has likewise been the subject of our research. The current work showed that the tested bivalent metals at a given pH condition formed metal:DOX complexes in a ratio of 2:1, while iron complexes with DOX in a ratio of 3:1. The studies also showed that selected metal-DOX complexes (Mg-DOX, Mn-DOX, Ni-DOX at 0.5 µM concentration significantly decreased cell viability and proliferation, however they increased caspase 7 activity. Results also indicated that studied metal-DOX complexes showed high cytotoxicity in MCF-7 cells. Therefore they were chosen for cell cycle check-points and apoptosis/necrosis analysis studied by flow cytometry. Obtained results suggest that doxorubicin complexed by specified metals can be considered as a potential anti-breast cancer agent, which is characterized by a higher efficacy than a parent drug.

Thirty Years of Orphan Drug Legislation and the Development of Drugs to Treat Rare Seizure Conditions: A Cross Sectional Analysis.

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Döring, Jan Henje; Lampert, Anette; Hoffmann, Georg F; Ries, Markus

2016-01-01

Epilepsy is a serious chronic health condition with a high morbidity impairing the life of patients and afflicted families. Many epileptic conditions, especially those affecting children, are rare disorders generating an urgent medical need for more efficacious therapy options. Therefore, we assessed the output of the US and European orphan drug legislations. Quantitative analysis of the FDA and EMA databases for orphan drug designations according to STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) criteria. Within the US Orphan Drug Act 40 designations were granted delivering nine approvals, i.e. clobazam, diazepam viscous solution for rectal administration, felbamate, fosphenytoin, lamotrigine, repository corticotropin, rufinamide, topiramate, and vigabatrin. Since 2000 the EMA granted six orphan drug designations whereof two compounds were approved, i.e. rufinamide and stiripentol. In the US, two orphan drug designations were withdrawn. Orphan drugs were approved for conditions including Lennox-Gastaut syndrome, infantile spasms, Dravet syndrome, and status epilepticus. Comparing time to approval for rufinamide, which was approved in the US and the EU to treat rare seizure conditions, the process seems faster in the EU (2.2 years) than in the US (4.3 years). Orphan drug development in the US and in the EU delivered only few molecular entities to treat rare seizure disorders. The development programs focused on already approved antiepileptic drugs or alternative pharmaceutical formulations. Most orphan drugs approved in the US are not approved in the EU to treat rare seizures although some were introduced after 2000 when the EU adopted the Orphan Drug Regulation.

Development of Drugs and Technology for Radiation Theragnosis

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Hwan-Jeong Jeong

2016-06-01

Full Text Available Personalized medicine is tailored medical treatment that targets the individual characteristics of each patient. Theragnosis, combining diagnosis and therapy, plays an important role in selecting appropriate patients. Noninvasive in vivo imaging can trace small molecules, antibodies, peptides, nanoparticles, and cells in the body. Recently, imaging methods have been able to reveal molecular events in cells and tissues. Molecular imaging is useful not only for clinical studies but also for developing new drugs and new treatment modalities. Preclinical and early clinical molecular imaging shows biodistribution, pharmacokinetics, mechanisms of action, and efficacy. When therapeutic materials are labeled using radioisotopes, nuclear imaging with positron emission tomography or gamma camera can be used to treat diseases and monitor therapy simultaneously. Such nuclear medicine technology is defined as radiation theragnosis. We review the current development of drugs and technology for radiation theragnosis using peptides, albumin, nanoparticles, and cells.

Non-profit Drug Research and Development at a Crossroads.

Science.gov (United States)

Jarosławski, Szymon; Toumi, Mondher; Auquier, Pascal; Dussart, Claude

2018-02-07

In wealthy nations, non-profit drug R&D has been proposed to reduce the prices of medicines. We sought to review the ethical and economic issues concerning non-profit drug R&D companies, and the possible impact that their pricing strategy may have on the innovation efforts from for-profit companies targeting the same segment of the pharmaceutical market. There are two possible approaches to pricing drugs developed by non-profit R&D programs: pricing that maximises profits and "affordable" pricing that reflects the cost of manufacturing and distribution, plus a margin that ensures sustainability of the drug supply. Overall, the non-profits face ethical challenges - due to the lack of resources, they are unable to independently commercialize their products on a large scale; however, the antitrust law does not permit them to impose prices on potential licensees. Also, reduced prices for the innovative products may result in drying the for-profit R&D in the area.

Immunoparesis in newly diagnosed Multiple Myeloma patients

DEFF Research Database (Denmark)

Sorrig, Rasmus; Klausen, Tobias W.; Salomo, Morten

2017-01-01

Immunoparesis (hypogammaglobulinemia) is associated to an unfavorable prognosis in newly diagnosed Multiple myeloma (MM) patients. However, this finding has not been validated in an unselected population-based cohort. We analyzed 2558 newly diagnosed MM patients in the Danish Multiple Myeloma...

Applicability of bioanalysis of multiple analytes in drug discovery and development: review of select case studies including assay development considerations.

Science.gov (United States)

Srinivas, Nuggehally R

2006-05-01

The development of sound bioanalytical method(s) is of paramount importance during the process of drug discovery and development culminating in a marketing approval. Although the bioanalytical procedure(s) originally developed during the discovery stage may not necessarily be fit to support the drug development scenario, they may be suitably modified and validated, as deemed necessary. Several reviews have appeared over the years describing analytical approaches including various techniques, detection systems, automation tools that are available for an effective separation, enhanced selectivity and sensitivity for quantitation of many analytes. The intention of this review is to cover various key areas where analytical method development becomes necessary during different stages of drug discovery research and development process. The key areas covered in this article with relevant case studies include: (a) simultaneous assay for parent compound and metabolites that are purported to display pharmacological activity; (b) bioanalytical procedures for determination of multiple drugs in combating a disease; (c) analytical measurement of chirality aspects in the pharmacokinetics, metabolism and biotransformation investigations; (d) drug monitoring for therapeutic benefits and/or occupational hazard; (e) analysis of drugs from complex and/or less frequently used matrices; (f) analytical determination during in vitro experiments (metabolism and permeability related) and in situ intestinal perfusion experiments; (g) determination of a major metabolite as a surrogate for the parent molecule; (h) analytical approaches for universal determination of CYP450 probe substrates and metabolites; (i) analytical applicability to prodrug evaluations-simultaneous determination of prodrug, parent and metabolites; (j) quantitative determination of parent compound and/or phase II metabolite(s) via direct or indirect approaches; (k) applicability in analysis of multiple compounds in select

Considerations for a business model for the effective integration of novel biomarkers into drug development.

Science.gov (United States)

Frueh, Felix W

2008-11-01

It is 10 years since the introduction of trastuzumab into the US market, and we are still waiting for a validation of the business case for biomarker-driven drug development. While many reasons for the lack of duplication of this model may exist, the need for accelerated innovation in drug development paired with the opportunity of integrating biomarker-driven research into drug development programs may lead to new and creative ways of fostering the cooperation between drug developers and test manufacturers. The rapid increase in knowledge about biomarkers and our understanding of disease and disease mechanisms open unprecedented prospects to make not only better, more informed decisions regarding patient care, but also strategic decisions during drug development. This requires that a biomarker strategy becomes an integral part of (early) drug development and that new, innovative paths are tried towards a model that combines the scientific approach with an economically feasible implementation strategy. Collaborative research, the use of new communication tools, the exploration of alternative ways to position a product in the market, and other considerations are part of such a strategy. This perspective article illustrates the current landscape and takes a look at some of these new ways for more effectively integrating biomarkers into drug development.

Polymeric drugs: Advances in the development of pharmacologically active polymers

Science.gov (United States)

Li, Jing; Yu, Fei; Chen, Yi; Oupický, David

2015-01-01

Synthetic polymers play a critical role in pharmaceutical discovery and development. Current research and applications of pharmaceutical polymers are mainly focused on their functions as excipients and inert carriers of other pharmacologically active agents. This review article surveys recent advances in alternative pharmaceutical use of polymers as pharmacologically active agents known as polymeric drugs. Emphasis is placed on the benefits of polymeric drugs that are associated with their macromolecular character and their ability to explore biologically relevant multivalency processes. We discuss the main therapeutic uses of polymeric drugs as sequestrants, antimicrobials, antivirals, and anticancer and anti-inflammatory agents. PMID:26410809

The impact of South Korea's new drug-pricing policy on market competition among off-patent drugs.

Science.gov (United States)

Kwon, Hye-Young; Kim, Hyungmin; Godman, Brian; Reich, Michael R

2015-01-01

A new pricing policy was introduced in Korea in April 2012 with the aim of strengthening competition among off-patent drugs by eliminating price gaps between originators and generics. Examine the effect of newly implemented pricing policy. Retrospectively examining the effects through extracting from the National Health Insurance claims data a 30-month panel dataset (January 2011-June 2013) containing consumption data in four major therapeutic classes (antihypertensives, lipid-lowering drugs, antiulcerants and antidepressants). Proxies for market competition were examined before and after the policy. The new pricing policy did not enhance competition among off-patent drugs. In fact, price dispersion significantly decreased as opposed to the expected change. Originator-to-generic utilization increased 6.12 times (p = 0.000) after the new policy. The new pricing policy made no impact on competition among off-patent drugs. Competition in the off-patent market cannot be enhanced unless both supply and demand side measures are coordinated.

Ecological Assessment of Substance-abuse Experiences (EASE): findings from a new instrument development pilot study.

Science.gov (United States)

Matto, Holly C; Miller, Keith; Spera, Christopher

2005-08-01

A newly developed instrument that assesses a client's orientation to addiction or recovery communities using social context referents was pilot tested with a sample of 103 adults seeking treatment for substance abuse at outpatient and residential treatment facilities on the East Coast. Preliminary findings show promising subscale reliabilities, and suggest that drug- and recovery-related social identities are related to drug-use severity and drug-use concern; and drug-related attitudinal congruence between the treatment-seeker and family and treatment-seeker and other significant persons are related to intention to make behavioral changes in reducing substance abuse.

Development of immunotoxicity testing strategies for immunomodulatory drugs.

Science.gov (United States)

Kawabata, Thomas T; Evans, Ellen W

2012-01-01

The ICH S8 immunotoxicity testing guideline for human pharmaceuticals was published in 2006 and was intended to provide guidance for assessing the immunotoxicity potential of low-molecular-weight drugs that are not intended to alter the immune system. For drugs intended to modulate the immune system, immunotoxicity testing strategies are generally developed on a case-by-case approach since the targets, intended patient population, and mechanisms of action of the test compound will determine the type of testing needed. Some of the general principles of ICH S8, however, may be applied to immunotoxicity testing strategies for immunomodulatory drugs. A weight-of-evidence approach using factors discussed in ICH S8 in concert with an assessment of the potential value of additional immunotoxicity testing should be considered. For most situations, immunotoxicity studies with immunomodulatory compounds evaluate off-target effects on the immune system and exaggerated pharmacology. The potential use of data from these studies and considerations such as translatability to humans are discussed.

Recent Advances in Drug Development and Regulatory Science in China.

Science.gov (United States)

Chen, Jie; Zhao, Naiqing

2018-01-01

As the second largest pharmaceutical market with a great potential for future growth, China has drawn much attention from the global pharmaceutical community. With an increasing government investment in biomedical research, the domestic biopharmaceutical (biotechnological) companies in China are turning their attention to the development of innovative medicines and targeting the global market. To introduce innovative products to Chinese patients sooner, to improve the efficiency of its review and approval processes, and to harmonize its regulatory science with international standards, the China Food and Drug Administration (CFDA) has initiated a series of major changes to its policies and regulations. This paper presents a snapshot of China's pharmaceutical market, and research and development status, and introduces technical guidelines pertaining to clinical trials and new drug applications. The recent wave of ground-breaking reforms in CFDA's regulatory science is discussed. Examples of clinical trials and new drug applications are provided throughout the discussion.

Titration calorimetry of surfactant–drug interactions: Micelle formation and saturation studies

International Nuclear Information System (INIS)

Waters, Laura J.; Hussain, Talib; Parkes, Gareth M.B.

2012-01-01

Highlights: ► Isothermal titration calorimetry can be used to monitor the saturation of micelles with pharmaceutical compounds. ► The number of drug molecules per micelle varies depending on the drug used and the temperature of the calorimeter. ► The change in enthalpy for the saturation of micelles with drugs can be endothermic or exothermic. ► The critical micellar concentration of an anionic surfactant (SDS) does not appear to vary in the presence of drugs. - Abstract: Isothermal titration calorimetry (ITC) was employed to monitor the addition of five model drugs to anionic surfactant based micelles, composed of sodium dodecyl sulfate (SDS), through to the point at which they were saturated with drug. Analysis of the resultant data using this newly developed method has confirmed the suitability of the technique to acquire such data with saturation limits established in all cases. Values for the point at which saturation occurred ranged from 17 molecules of theophylline per micelle at T = 298 K up to 63 molecules of caffeine per micelle at 310 K. Micellar systems can be disrupted by the presence of additional chemicals, such as the drugs used in this study, therefore a separate investigation was undertaken to determine the critical micellar concentration (CMC) for SDS in the presence of each drug at T = 298 K and 310 K using ITC. In the majority of cases, there was no appreciable alteration to the CMC of SDS with drug present.

Fatigue associated with newly approved vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: an up-to-date meta-analysis.

Science.gov (United States)

Li, Jing; Gu, Jian

2017-10-01

The fatigue associated with five newly approved vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) (regorafenib, vandetanib, cabozantinib, lenvatinib, axitinib) is poorly understood. We conducted this systematic review to fully investigate the fatigue associated with these VEGFR-TKIs in cancer patients. Relevant studies of randomized controlled trials in cancer patients treated with the five VEGFR-TKIs were retrieved and a systematic evaluation was conducted. EMBASE, MEDLINE, and PubMed were searched for articles published until March 2017. Thirteen randomized controlled trials and 4395 patients were included. The current analysis suggested that the use of five newly approved VEGFR-TKIs increased the risk of all-grade fatigue (1.43; 95% CI 1.23-1.66; p fatigue (1.97; 95% CI1.44-2.70; p fatigue varied significantly within drug type, but high-grade fatigue did not. The RR of all-grade and high-grade fatigue did not vary significantly according to cancer type, treatment line, and treatment duration. The risk of high-grade fatigue may vary with treatment duration, whereas all-grade fatigue may not. The available data suggest that the use of the five newly approved VEGFR-TKIs is associated with a significantly increased risk of fatigue in cancer patients. Physicians should be aware of this adverse effect and should monitor cancer patients receiving these drugs.

In vivo real-time monitoring system of electroporation mediated control of transdermal and topical drug delivery.

Science.gov (United States)

Blagus, Tanja; Markelc, Bostjan; Cemazar, Maja; Kosjek, Tina; Preat, Veronique; Miklavcic, Damijan; Sersa, Gregor

2013-12-28

Electroporation (EP) is a physical method for the delivery of molecules into cells and tissues, including the skin. In this study, in order to control the degree of transdermal and topical drug delivery, EP at different amplitudes of electric pulses was evaluated. A new in vivo real-time monitoring system based on fluorescently labeled molecules was developed, for the quantification of transdermal and topical drug delivery. EP of the mouse skin was performed with new non-invasive multi-array electrodes, delivering different amplitudes of electric pulses ranging from 70 to 570 V, between the electrode pin pairs. Patches, soaked with 4 kDa fluorescein-isothiocyanate labeled dextran (FD), doxorubicin (DOX) or fentanyl (FEN), were applied to the skin before and after EP. The new monitoring system was developed based on the delivery of FD to and through the skin. FD relative quantity was determined with fluorescence microscopy imaging, in the treated region of the skin for topical delivery and in a segment of the mouse tail for transdermal delivery. The application of electric pulses for FD delivery resulted in enhanced transdermal delivery. Depending on the amplitude of electric pulses, it increased up to the amplitude of 360 V, and decreased at higher amplitudes (460 and 570 V). Topical delivery steadily enhanced with increasing the amplitude of the delivered electric pulses, being even higher than after tape stripping used as a positive control. The non-invasive monitoring of the delivery of DOX, a fluorescent chemotherapeutic drug, qualitatively and quantitatively confirmed the effects of EP at 360 and 570 V pulse amplitudes on topical and transdermal drug delivery. Delivery of FEN at 360 and 570 V pulse amplitudes verified the observed effects as obtained with FD and DOX, by the measured physiological responses of the mice as well as FEN plasma concentration. This study demonstrates that with the newly developed non-invasive multi-array electrodes and with the

Patents and access to drugs in developing countries: an ethical analysis.

Science.gov (United States)

Sterckx, Sigrid

2004-05-01

More than a third of the world's population has no access to essential drugs. More than half of this group of people live in the poorest regions of Africa and Asia. Several factors determine the accessibility of drugs in developing countries. Hardly any medicines for tropical diseases are being developed, but even existing drugs are often not available to the patients who need them. One of the important determinants of access to drugs is the working of the patent system. This paper first maps out some facts about the global patent regime that has emerged as a consequence of the conclusion of the WTO-TRIPs Agreement in 1994. Attempts to construct a moral justification of the patent system have been based on three grounds: natural rights, distributive justice, and utilitarian arguments. This paper examines to what extent and on which grounds drug patents can be justified. The final section looks at the so-called 'Doha Declaration on the TRIPs Agreement and Public Health', which was adopted by the WTO Ministerial Conference two years ago, recognising the primacy of public health over the interests of patent proprietors.

Safe procedure development to manage hazardous drugs in the workplace

Directory of Open Access Journals (Sweden)

Marisa Gaspar Carreño

2017-03-01

Full Text Available Objective: To develop a safety working procedure for the employees in the Intermutual Hospital de Levante (HIL in those areas of activity that deal with the handling of hazardous drugs (MP. Methods: The procedure was developed in six phases: 1 hazard definition; 2 definition and identification of processes and development of general correct work practices about hazardous drugs’ selection and special handling; 3 detection, selection and set of specific recommendations to handle with hazardous drugs during the processes of preparation and administration included in the hospital GFT; 4 categorization of risk during the preparation/administration and development of an identification system; 5 information and training of professionals; 6 implementation of the identification measures and prevention guidelines. Results: Six processes were detected handling HD. During those processes, thirty HD were identified included in the hospital GFT and a safer alternative was found for 6 of them. The HD were classified into 4 risk categories based on those measures to be taken during the preparation and administration of each of them. Conclusions: The development and implementation of specific safety-work processes dealing with medication handling, allows hospital managers to accomplish effectively with their legal obligations about the area of prevention and provides healthcare professional staff with the adequate techniques and safety equipment to avoid possible dangers and risks of some drugs.

The impact of the written request process on drug development in childhood cancer.

Science.gov (United States)

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.

The role of radio pharmacological imaging in streamlining the drug development process

International Nuclear Information System (INIS)

Campbell, D. B.

1997-01-01

Radio imaging techniques have found a place in clinical diagnosis, but there has been a hesitancy to use this approach in drug development. This reluctance may have been due to the availability of ligands, the time and cost of synthesis and the number of centres and for many the benefits are not evident. The use in drug development is potentially large since tomography can measure drug levels, specific binding, blood flow and activity within the human body. In drug discovery, the synthesis of candidate drugs with specific binding properties are dependent on understanding the disease and using appropriate in vitro or animal models. Using small animal tomographs, these can be validated using radio imaging. Pharmacokinetics and metabolic problems, such as the distribution of inhaled gases, drug targeting into tumours of the brain or specific gastrointestinal absorption sites can be investigated within the human rather than relying on animals. The high specific activity allows low doses to be administered to man with limited safety studies permitting kinetic and metabolic studies to be undertaken early in development. Safety studies and ensuing toxicological endpoints in animals rely on histopathology for gross degenerative in physiological function. Where concern exists, radio imaging could detect early in situ changes in humans, for example hepatic toxicity, before they become hazardous. In clinical studies, the action of drugs can be measured directly at the effector site prior to undertaking longer studies, which is important for many diseases, but particularly for those such as Alzheimer's disease, where improvements may be slow or subtle

A Newly Developed Method for Computing Reliability Measures in a Water Supply Network

Directory of Open Access Journals (Sweden)

Jacek Malinowski

2016-01-01

Full Text Available A reliability model of a water supply network has beens examined. Its main features are: a topology that can be decomposed by the so-called state factorization into a (relativelysmall number of derivative networks, each having a series-parallel structure (1, binary-state components (either operative or failed with given flow capacities (2, a multi-state character of the whole network and its sub-networks - a network state is defined as the maximal flow between a source (sources and a sink (sinks (3, all capacities (component, network, and sub-network have integer values (4. As the network operates, its state changes due to component failures, repairs, and replacements. A newly developed method of computing the inter-state transition intensities has been presented. It is based on the so-called state factorization and series-parallel aggregation. The analysis of these intensities shows that the failure-repair process of the considered system is an asymptotically homogenous Markov process. It is also demonstrated how certain reliability parameters useful for the network maintenance planning can be determined on the basis of the asymptotic intensities. For better understanding of the presented method, an illustrative example is given. (original abstract

Nonimaging detectors in drug development and approval.

Science.gov (United States)

Wagner, H N

2001-07-01

Regulatory applications for imaging biomarkers will expand in proportion to the validation of specific parameters as they apply to individual questions in the management of disease. This validation is likely to be applicable only to a particular class of drug or a single mechanism of action. Awareness among the world's regulatory authorities of the potential for these emerging technologies is high, but so is the cost to the sponsor (including the logistics of including images in a dossier), and therefore the pharmaceutical industry must evaluate carefully the potential benefit of each technology for its drug development programs, just as the authorities must consider carefully the extent to which the method is valid for the use to which the applicant has put it. For well-characterized tracer systems, it may be possible to design inexpensive cameras that make rapid assessments.

Generational differences among newly licensed registered nurses.

Science.gov (United States)

Keepnews, David M; Brewer, Carol S; Kovner, Christine T; Shin, Juh Hyun

2010-01-01

Responses of 2369 newly licensed registered nurses from 3 generational cohorts-Baby Boomers, Generation X, and Generation Y-were studied to identify differences in their characteristics, work-related experiences, and attitudes. These responses revealed significant differences among generations in: job satisfaction, organizational commitment, work motivation, work-to-family conflict, family-to-work conflict, distributive justice, promotional opportunities, supervisory support, mentor support, procedural justice, and perceptions of local job opportunities. Health organizations and their leaders need to anticipate intergenerational differences among newly licensed nurses and should provide for supportive working environments that recognize those differences. Orientation and residency programs for newly licensed nurses should be tailored to the varying needs of different generations. Future research should focus on evaluating the effectiveness of orientation and residency programs with regard to different generations so that these programs can be tailored to meet the varying needs of newly licensed nurses at the start of their careers. Copyright 2010 Mosby, Inc. All rights reserved.

Biomarkers in early phase development of central nervous system drugs : a conceptual framework

NARCIS (Netherlands)

Post, Jeroen-Paul van der

2006-01-01

The main objective of this thesis is to provide a conceptual framework for the use of Central Nervous System (CNS) biomarkers in early phase clinical drug development. In the Introduction the current use of biomarkers in early CNS drug development is discussed. A conceptual framework for the

Drug development for breast, colorectal, and non-small cell lung cancers from 1979 to 2014.

Science.gov (United States)

Nixon, Nancy A; Khan, Omar F; Imam, Hasiba; Tang, Patricia A; Monzon, Jose; Li, Haocheng; Sun, Gavin; Ezeife, Doreen; Parimi, Sunil; Dowden, Scot; Tam, Vincent C

2017-12-01

Understanding the drug development pathway is critical for streamlining the development of effective cancer treatments. The objective of the current study was to delineate the drug development timeline and attrition rate of different drug classes for common cancer disease sites. Drugs entering clinical trials for breast, colorectal, and non-small cell lung cancer were identified using a pharmaceutical business intelligence database. Data regarding drug characteristics, clinical trials, and approval dates were obtained from the database, clinical trial registries, PubMed, and regulatory Web sites. A total of 411 drugs met the inclusion criteria for breast cancer, 246 drugs met the inclusion criteria for colorectal cancer, and 315 drugs met the inclusion criteria for non-small cell lung cancer. Attrition rates were 83.9% for breast cancer, 87.0% for colorectal cancer, and 92.0% for non-small cell lung cancer drugs. In the case of non-small cell lung cancer, there was a trend toward higher attrition rates for targeted monoclonal antibodies compared with other agents. No tumor site-specific differences were noted with regard to cytotoxic chemotherapy, immunomodulatory, or small molecule kinase inhibitor drugs. Drugs classified as "others" in breast cancer had lower attrition rates, primarily due to the higher success of hormonal medications. Mean drug development times were 8.9 years for breast cancer, 6.7 years for colorectal cancer, and 6.6 years for non-small cell lung cancer. Overall oncologic drug attrition rates remain high, and drugs are more likely to fail in later-stage clinical trials. The refinement of early-phase trial design may permit the selection of drugs that are more likely to succeed in the phase 3 setting. Cancer 2017;123:4672-4679. © 2017 American Cancer Society. © 2017 American Cancer Society.

Public and private sector contributions to the discovery and development of "impact" drugs.

Science.gov (United States)

Reichert, Janice M; Milne, Christopher-Paul

2002-01-01

Recently, well-publicized reports by Public Citizen and the Joint Economic Committee (JEC) of the US Congress questioned the role of the drug industry in the discovery and development of therapeutically important drugs. To gain a better understanding of the relative roles of the public and private sectors in pharmaceutic innovation, the Tufts Center for the Study of Drug Development evaluated the underlying National Institutes of Health (NIH) and academic research cited in the Public Citizen and JEC reports and performed its own assessment of the relationship between the private and public sectors in drug discovery and development of 21 "impact" drugs. We found that, ultimately, any attempt to measure the relative contribution of the public and private sectors to the research and development (R&D) of therapeutically important drugs by output alone, such as counting publications or even product approvals, is flawed. Several key factors (eg, degree of uncertainty, expected market value, potential social benefit) affect investment decisions and determine whether public or private sector funds, or both, are most appropriate. Because of the competitiveness and complexity of today's R&D environment, both sectors are increasingly challenged to show returns on their investment and the traditional boundaries separating the roles of the private and public research spheres have become increasingly blurred. What remains clear, however, is that the process still starts with good science and ends with good medicine.

Bridging Adult Experience to Pediatrics in Oncology Drug Development.

Science.gov (United States)

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.

[Present status and future of hypnotic drug treatment for insomnia].

Science.gov (United States)

Uchiyama, Makoto; Konno, Michiko

2012-07-01

Pharmacological treatments of insomnia have become safer since the first benzodiazepine receptor agonist (BzRA) hypnotic was introduced in the 1960's. Though BzRAs could hardly cause a fatal condition even in cases of overdosing, they had inherited the arguments on addiction and withdrawal from the prior studies of barbiturate hypnotics that indicated they are strongly addictive. In the 2000s, it was repeatedly demonstrated that insomnia as well as sleep deprivation underlie the development and deterioration of comorbid diseases such as hypertension, cardiovascular diseases, diabetes and depression, and that the proper use of hypnotic drugs is unlikely to cause tolerance, addiction nor rebound phenomena, but likely to be associated with improvement of QOL. Thus, the 2005's consensus report on chronic insomnia by NIH has recommended general physicians to facilitate insomnia treatment to prevent the development of physical and/or mental disorders. The author reviewed in this article the efficacy and side effects of BzRA hypnotics, a hypnotic drug therapy combined with cognitive and behavioral interventions, uses of melatonin receptor agonist in general and sleep medicine practices, and future utilization of newly-developed orexin antagonists for insomnia treatment.

Drug Development Pipeline

Science.gov (United States)

... molecule that contains genetic instructions to make proteins. Delivery of CFTR-encoded mRNA would allow the lung cells to create normally functioning CFTR protein, regardless of an individual’s specific CFTR gene mutation. This drug is delivered via inhalation. Editas This program is ...

Mentorship for newly appointed physicians: a strategy for enhancing patient safety?

Science.gov (United States)

Harrison, Reema; McClean, Serwaa; Lawton, Rebecca; Wright, John; Kay, Clive

2014-09-01

Mentorship is an increasingly popular innovation from business and industry that is being applied in health-care contexts. This paper explores the concept of mentorship for newly appointed physicians in their first substantive senior post, and specifically its utilization to enhance patient safety. Semi-structured face to face and telephone interviews with Medical Directors (n = 5), Deputy Medical Directors (n = 4), and Clinical Directors (n = 6) from 9 acute NHS Trusts in the Yorkshire and Humber region in the north of England. A focused thematic analysis was used. A number of beneficial outcomes were associated with mentorship for newly appointed physicians including greater personal and professional support, organizational commitment, and general well-being. Providing newly appointed senior physicians with support through mentorship was considered to enhance the safety of patient care. Mentorship may prevent or reduce active failures, be used to identify threats in the local working environment, and in the longer term, address latent threats to safety within the organization by encouraging a healthier safety culture. Offering mentorship to all newly appointed physicians in their first substantive post in health care may be a useful strategy to support the development of their clinical, professional, and personal skills in this transitional period that may also enhance the safety of patient care.

Developments in platinum anticancer drugs

Science.gov (United States)

Tylkowski, Bartosz; Jastrząb, Renata; Odani, Akira

2018-01-01

Platinum compounds represent one of the great success stories of metals in medicine. Following the unexpected discovery of the anticancer activity of cisplatin (Fig. 1) in 1965 by Prof. Rosenberg [1], a large number of its variants have been prepared and tested for their ability to kill cancer cells and inhibit tumor growth. Although cisplatin has been in use for over four decades, new and more effective platinum-based therapeutics are finally on the horizon. A wide introduction to anticancer studies is given by the authors of the previous chapter. This chapter aims at providing the readers with a comprehensive and in-depth understanding of recent developments of platinum anticancer drugs and to review the state of the art. The chapter is divided into two parts. In the first part we present a historical aspect of platinum and its complexes, while in the second part we give an overview of developments in the field of platinum anticancer agents.

Antiviral Information Management System (AIMS): a prototype for operational innovation in drug development.

Science.gov (United States)

Jadhav, Pravin R; Neal, Lauren; Florian, Jeff; Chen, Ying; Naeger, Lisa; Robertson, Sarah; Soon, Guoxing; Birnkrant, Debra

2010-09-01

This article presents a prototype for an operational innovation in knowledge management (KM). These operational innovations are geared toward managing knowledge efficiently and accessing all available information by embracing advances in bioinformatics and allied fields. The specific components of the proposed KM system are (1) a database to archive hepatitis C virus (HCV) treatment data in a structured format and retrieve information in a query-capable manner and (2) an automated analysis tool to inform trial design elements for HCV drug development. The proposed framework is intended to benefit drug development by increasing efficiency of dose selection and improving the consistency of advice from US Food and Drug Administration (FDA). It is also hoped that the framework will encourage collaboration among FDA, industry, and academic scientists to guide the HCV drug development process using model-based quantitative analysis techniques.

Enhancing the Pediatric Drug Development Framework to Deliver Better Pediatric Therapies Tomorrow.

Science.gov (United States)

Bucci-Rechtweg, Christina

2017-10-01

Health care professionals involved in the clinical management of children have long appreciated the limited number of therapies suitably evaluated for their optimal use in the pediatric population. In the past century, advances in regulatory policy significantly evolved adult drug evaluation. The scarcity of available patient populations, practical complexities of drug development research, and minimal financial returns have hampered pharmaceutical investment in the study of therapies for children. More recently, pediatric policy and legislation in the United States and Europe have instituted a system of obligations and incentives to stimulate investment in pediatric drug development. These initiatives, in conjunction with a more sophisticated process of drug discovery and development, have led to significant advancements in the labeling of drugs for pediatric use. Facilitated by the emergence of new targets, precision medicine, and innovations in regulatory science, there is now a subtle shift in focus toward drug development research for children rather than simply in children. Although there has been an increase in pediatric studies of investigational agents and labeling of pediatric information for use, there have been unintended consequences of existing policies. As a result, limited progress has been made in certain therapeutic areas and for off-patent therapies. Future policy reform to enhance the availability and accessibility of pediatric medicines should not only reflect an understanding not only of the successes of existing policy and legislative initiatives but also constructively address failures and unintended consequences. Taken together, policy reform, global cooperation, and innovation in regulatory science will more ably deliver better pediatric therapies tomorrow. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

Novel approaches in anti-arenaviral drug development

International Nuclear Information System (INIS)

Lee, Andrew M.; Pasquato, Antonella; Kunz, Stefan

2011-01-01

Hemorrhagic fevers caused by arenaviruses are among the most devastating emerging human diseases. Considering the number of individuals affected, the current lack of a licensed vaccine, and the limited therapeutic options, arenaviruses are arguably among the most neglected tropical pathogens and the development of efficacious anti-arenaviral drugs is of high priority. Over the past years significant efforts have been undertaken to identify novel potent inhibitors of arenavirus infection. High throughput screening of small molecule libraries employing pseudotype platforms led to the discovery of several potent and broadly active inhibitors of arenavirus cell entry that are effective against the major hemorrhagic arenaviruses. Mechanistic studies revealed that these novel entry inhibitors block arenavirus membrane fusion and provided novel insights into the unusual mechanism of this process. The success of these approaches highlights the power of small molecule screens in antiviral drug discovery and establishes arenavirus membrane fusion as a robust drug target. These broad screenings have been complemented by strategies targeting cellular factors involved in productive arenavirus infection. Approaches targeting the cellular protease implicated in maturation of the fusion-active viral envelope glycoprotein identified the proteolytic processing of the arenavirus glycoprotein precursor as a novel and promising target for anti-arenaviral strategies.

The principle of safety evaluation in medicinal drug - how can toxicology contribute to drug discovery and development as a multidisciplinary science?

Science.gov (United States)

Horii, Ikuo

2016-01-01

Pharmaceutical (drug) safety assessment covers a diverse science-field in the drug discovery and development including the post-approval and post-marketing phases in order to evaluate safety and risk management. The principle in toxicological science is to be placed on both of pure and applied sciences that are derived from past/present scientific knowledge and coming new science and technology. In general, adverse drug reactions are presented as "biological responses to foreign substances." This is the basic concept of thinking about the manifestation of adverse drug reactions. Whether or not toxic expressions are extensions of the pharmacological effect, adverse drug reactions as seen from molecular targets are captured in the category of "on-target" or "off-target", and are normally expressed as a biological defense reaction. Accordingly, reactions induced by pharmaceuticals can be broadly said to be defensive reactions. Recent molecular biological conception is in line with the new, remarkable scientific and technological developments in the medical and pharmaceutical areas, and the viewpoints in the field of toxicology have shown that they are approaching toward the same direction as well. This paper refers to the basic concept of pharmaceutical toxicology, the differences for safety assessment in each stage of drug discovery and development, regulatory submission, and the concept of scientific considerations for risk assessment and management from the viewpoint of "how can multidisciplinary toxicology contribute to innovative drug discovery and development?" And also realistic translational research from preclinical to clinical application is required to have a significant risk management in post market by utilizing whole scientific data derived from basic and applied scientific research works. In addition, the significance for employing the systems toxicology based on AOP (Adverse Outcome Pathway) analysis is introduced, and coming challenges on precision

Metabotropic glutamate receptor 5 - a promising target in drug development and neuroimaging

Energy Technology Data Exchange (ETDEWEB)

Pillai, Rajapillai L.I.; Tipre, Dnyanesh N. [Stony Brook University Health Science Center, Department of Psychiatry, Stony Brook, NY (United States)

2016-06-15

This review summarizes the contributions by various teams of scientists in assessing the metabotropic glutamate receptor 5 (mGluR5) as a biomarker in neuropsychiatric disorders and diseases. Development of positive and negative allosteric modulators of mGluR5 is reviewed, as is the development of PET radioligands that have the potential to measure mGluR5 receptor density in neurological disorders and during therapeutic interventions. PET imaging provides an effective tool to assess the specificity of new drugs, select dose regimens in clinical trials, and study drug mechanisms of action. We summarize and deliver comparative analyses of mGluR5-specific PET radiotracers and their applications in understanding the pathophysiology of mGluR5-related nervous system disorders and to speed up drug development. (orig.)

Metabotropic glutamate receptor 5 - a promising target in drug development and neuroimaging

International Nuclear Information System (INIS)

Pillai, Rajapillai L.I.; Tipre, Dnyanesh N.

2016-01-01

This review summarizes the contributions by various teams of scientists in assessing the metabotropic glutamate receptor 5 (mGluR5) as a biomarker in neuropsychiatric disorders and diseases. Development of positive and negative allosteric modulators of mGluR5 is reviewed, as is the development of PET radioligands that have the potential to measure mGluR5 receptor density in neurological disorders and during therapeutic interventions. PET imaging provides an effective tool to assess the specificity of new drugs, select dose regimens in clinical trials, and study drug mechanisms of action. We summarize and deliver comparative analyses of mGluR5-specific PET radiotracers and their applications in understanding the pathophysiology of mGluR5-related nervous system disorders and to speed up drug development. (orig.)

[An Introduction to A Newly-developed "Acupuncture Needle Manipulation Training-evaluation System" Based on Optical Motion Capture Technique].

Science.gov (United States)

Zhang, Ao; Yan, Xing-Ke; Liu, An-Guo

2016-12-25

In the present paper, the authors introduce a newly-developed "Acupuncture Needle Manipulation Training-evaluation System" based on optical motion capture technique. It is composed of two parts, sensor and software, and overcomes some shortages of mechanical motion capture technique. This device is able to analyze the data of operations of the pressing-hand and needle-insertion hand during acupuncture performance and its software contains personal computer (PC) version, Android version, and Internetwork Operating System (IOS) Apple version. It is competent in recording and analyzing information of any ope-rator's needling manipulations, and is quite helpful for teachers in teaching, training and examining students in clinical practice.

75 FR 65495 - Draft Guidance for Industry on Qualification Process for Drug Development Tools; Availability

Science.gov (United States)

2010-10-25

...] Draft Guidance for Industry on Qualification Process for Drug Development Tools; Availability AGENCY... Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, rm... Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 21, rm...

Drugs in development for Parkinson's disease: an update.

Science.gov (United States)

Johnston, Tom H; Brotchie, Jonathan M

2006-01-01

The current development of emerging pharmacological treatments for Parkinson's disease (PD), front preclinical to launch, is summarized. Advances over the past year are highlighted, including the significant progress of several drugs through various stages of development. Several agents have been discontinued from development, either because of adverse effects or lack of clinical efficacy. The methyl-esterified form of L-DOPA (melevodopa) and the monoamine oxidase type B inhibitor rasagiline have both been launched. With regard to the monoamine re-uptake inhibitors, many changes have been witnessed, with new agents reaching preclinical development and pre-existing ones being discontinued or having no development reported. Of the dopamine agonists, many continue to progress successfully through clinical trials. Others have struggled to demonstrate a significant advantage over currently available treatments and have been discontinued. The field of non-dopaminergic treatments remains dynamic. The alpha2 adrenergic receptor antagonists and the adenosine A2A receptor antagonists remain in clinical trials. Trials of the neuronal' synchronization modulator levetiracetam are at an advanced stage, and there has also been a new addition to the class (ie, seletracetam). There has been a change in the landscape of neuroprotective agents that modulate disease progression. Candidates from the classes of growth factors and glyceraldehyde-3-phosphate dehydrogenase inhibitors have been discontinued, or no development has been reported, and the mixed lineage kinase inhibitor CEP-1347 has been discontinued for PD treatment. Other drugs in this field, such as neuroimmunophilins, estrogens and alpha-synuclein oligomerization inhibitors, remain in development.

Newly approved antibiotics and antibiotics reserved for resistant infections: Implications for emergency medicine.

Science.gov (United States)

Mazer-Amirshahi, Maryann; Pourmand, Ali; May, Larissa

2017-01-01

Millions of patients are evaluated every year in the emergency department (ED) for bacterial infections. Emergency physicians often diagnose and prescribe initial antibiotic therapy for a variety of bacterial infections, ranging from simple urinary tract infections to severe sepsis. In life-threatening infections, inappropriate choice of initial antibiotic has been shown to increase morbidity and mortality. As such, initiation of appropriate antibiotic therapy on the part of the emergency physician is critical. Increasing rates of antibiotic resistance, drug allergies, and antibiotic shortages further complicates the choice of antibiotics. Patients may have a history of prior resistant infections or culture data indicating that common first-line antibiotics used in the ED may be ineffective. In recent years, there have been several new antibiotic approvals as well as renewed interest in second and third line antibiotics because of the aforementioned concerns. In addition, several newly approved antibiotics have the advantage of being administered once weekly or even as a single infusion, which has the potential to decrease hospitalizations and healthcare costs. This article reviews newly approved antibiotics and antibiotics used to treat resistant infections with a focus on implications for emergency medicine. Copyright © 2016 Elsevier Inc. All rights reserved.

The effect of strain distribution on microstructural developments during forging in a newly developed nickel base superalloy

Energy Technology Data Exchange (ETDEWEB)

Buckingham, R.C. [Institute of Structural Materials, Swansea University, Bay Campus, Fabian Way, Swansea SA1 8EN (United Kingdom); Argyrakis, C.; Hardy, M.C. [Rolls-Royce plc, PO Box 31, Derby DE24 8BJ (United Kingdom); Birosca, S., E-mail: 522042@swansea.ac.uk [Institute of Structural Materials, Swansea University, Bay Campus, Fabian Way, Swansea SA1 8EN (United Kingdom)

2016-01-27

In the current study, the effect of strain distribution in a simple forging geometry on the propensity for recrystallization, and its impact on mechanical properties has been investigated in a newly developed experimental nickel-based superalloy. The new alloy was produced via a Powder Metallurgy (PM) route and was subsequently Hot Isostatic Processed (HIP), isothermally forged, and heat treated to produce a coarse grain microstructure with average grain size of 23–32 μm. The alloy was examined by means of Electron Back-Scatter Diffraction (EBSD) to characterise the microstructural features such as grain orientation and morphology, grain boundary characteristics and the identification of potential Prior Particle Boundaries (PPBs) throughout each stage of the processing route. Results at the central region of the cross-section plane parallel to the loading direction showed significant microstructural differences across the forging depth. This microstructural variation was found to be highly dependent on the value of local strain imparted during forging such that areas of low effective strain showed partial recrystallisation and a necklace grain structure was observed following heat treatment. Meanwhile, a fully recrystallised microstructure with no PPBs was observed in the areas of high strain values, in the central region of the forging.

OSIRIS, an entirely in-house developed drug discovery informatics system.

Science.gov (United States)

Sander, Thomas; Freyss, Joel; von Korff, Modest; Reich, Jacqueline Renée; Rufener, Christian

2009-02-01

We present OSIRIS, an entirely in-house developed drug discovery informatics system. Its components cover all information handling aspects from compound synthesis via biological testing to preclinical development. Its design principles are platform and vendor independence, a consistent look and feel, and complete coverage of the drug discovery process by custom tailored applications. These include electronic laboratory notebook applications for biology and chemistry, tools for high-throughput and secondary screening evaluation, chemistry-aware data visualization, physicochemical property prediction, 3D-pharmacophore comparisons, interactive modeling, computing grid based ligand-protein docking, and more. Most applications are developed in Java and are built on top of a Java library layer that provides reusable cheminformatics functionality and GUI components such as chemical editors, structure canonicalization, substructure search, combinatorial enumeration, enhanced stereo perception, force field minimization, and conformation generation.

Formulary Drug Reviews: Glecaprevir/Pibrentasvir.

Science.gov (United States)

Levien, Terri L; Baker, Danial E

2018-04-01

Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are available online to subscribers. Monographs can be customized to meet the needs of a facility. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service , contact Wolters Kluwer customer service at 866-397-3433.

Guidelines for developing certification programs for newly generated TRU waste

International Nuclear Information System (INIS)

Whitty, W.J.; Ostenak, C.A.; Pillay, K.K.S.; Geoffrion, R.R.

1983-05-01

These guidelines were prepared with direction from the US Department of Energy (DOE) Transuranic (TRU) Waste Management Program in support of the DOE effort to certify that newly generated TRU wastes meet the Waste Isolation Pilot Plant (WIPP) Waste Acceptance Criteria. The guidelines provide instructions for generic Certification Program preparation for TRU-waste generators preparing site-specific Certification Programs in response to WIPP requirements. The guidelines address all major aspects of a Certification Program that are necessary to satisfy the WIPP Waste Acceptance Criteria and their associated Compliance Requirements and Certification Quality Assurance Requirements. The details of the major element of a Certification Program, namely, the Certification Plan, are described. The Certification Plan relies on supporting data and control documentation to provide a traceable, auditable account of certification activities. Examples of specific parts of the Certification Plan illustrate the recommended degree of detail. Also, a brief description of generic waste processes related to certification activities is included

Newly democratic Mongolia offering exploration contracts

International Nuclear Information System (INIS)

Penttila, W.C.

1992-01-01

This paper reports that Mongolia, formerly the Mongolian People's Republic, is working to open its exploration prospects to international operators as it emerges as the world's 15th largest independent nation. The country, about the same size as Alaska with a population of 2 million, held its first free election in July 1990. The newly elected government drafted a constitution that took effect Feb. 12, 1992. The document modifies the previous government's structures to eliminate bureaucracy and allows for political pluralism. At the same time, the government is formulating energy policies, state oil company structure, and resource development philosophy

Drug repurposing based on drug-drug interaction.

Science.gov (United States)

Zhou, Bin; Wang, Rong; Wu, Ping; Kong, De-Xin

2015-02-01

Given the high risk and lengthy procedure of traditional drug development, drug repurposing is gaining more and more attention. Although many types of drug information have been used to repurpose drugs, drug-drug interaction data, which imply possible physiological effects or targets of drugs, remain unexploited. In this work, similarity of drug interaction was employed to infer similarity of the physiological effects or targets for the drugs. We collected 10,835 drug-drug interactions concerning 1074 drugs, and for 700 of them, drug similarity scores based on drug interaction profiles were computed and rendered using a drug association network with 589 nodes (drugs) and 2375 edges (drug similarity scores). The 589 drugs were clustered into 98 groups with Markov Clustering Algorithm, most of which were significantly correlated with certain drug functions. This indicates that the network can be used to infer the physiological effects of drugs. Furthermore, we evaluated the ability of this drug association network to predict drug targets. The results show that the method is effective for 317 of 561 drugs that have known targets. Comparison of this method with the structure-based approach shows that they are complementary. In summary, this study demonstrates the feasibility of drug repurposing based on drug-drug interaction data. © 2014 John Wiley & Sons A/S.

Evaluating the administration costs of biologic drugs: development of a cost algorithm.

Science.gov (United States)

Tetteh, Ebenezer K; Morris, Stephen

2014-12-01

Biologic drugs, as with all other medical technologies, are subject to a number of regulatory, marketing, reimbursement (financing) and other demand-restricting hurdles applied by healthcare payers. One example is the routine use of cost-effectiveness analyses or health technology assessments to determine which medical technologies offer value-for-money. The manner in which these assessments are conducted suggests that, holding all else equal, the economic value of biologic drugs may be determined by how much is spent on administering these drugs or trade-offs between drug acquisition and administration costs. Yet, on the supply-side, it seems very little attention is given to how manufacturing and formulation choices affect healthcare delivery costs. This paper evaluates variations in the administration costs of biologic drugs, taking care to ensure consistent inclusion of all relevant cost resources. From this, it develops a regression-based algorithm with which manufacturers could possibly predict, during process development, how their manufacturing and formulation choices may impact on the healthcare delivery costs of their products.

In silico machine learning methods in drug development.

Science.gov (United States)

Dobchev, Dimitar A; Pillai, Girinath G; Karelson, Mati

2014-01-01

Machine learning (ML) computational methods for predicting compounds with pharmacological activity, specific pharmacodynamic and ADMET (absorption, distribution, metabolism, excretion and toxicity) properties are being increasingly applied in drug discovery and evaluation. Recently, machine learning techniques such as artificial neural networks, support vector machines and genetic programming have been explored for predicting inhibitors, antagonists, blockers, agonists, activators and substrates of proteins related to specific therapeutic targets. These methods are particularly useful for screening compound libraries of diverse chemical structures, "noisy" and high-dimensional data to complement QSAR methods, and in cases of unavailable receptor 3D structure to complement structure-based methods. A variety of studies have demonstrated the potential of machine-learning methods for predicting compounds as potential drug candidates. The present review is intended to give an overview of the strategies and current progress in using machine learning methods for drug design and the potential of the respective model development tools. We also regard a number of applications of the machine learning algorithms based on common classes of diseases.

NMR spectroscopy and drug development

International Nuclear Information System (INIS)

Craik, D.; Munro, S.

1990-01-01

The use of nuclear magnetic resonance (NMR) spectroscopy for structural and conformational studies on drug molecules, the three-dimensional investigation of proteins structure and their interactions with ligands are discussed. In-vivo NMR studies of the effects of drugs on metabolism in perfused organs and whole animals are also briefly presented. 5 refs., ills

Comparison of a newly developed binary typing with ribotyping and multilocus sequence typing methods for Clostridium difficile.

Science.gov (United States)

Li, Zhirong; Liu, Xiaolei; Zhao, Jianhong; Xu, Kaiyue; Tian, Tiantian; Yang, Jing; Qiang, Cuixin; Shi, Dongyan; Wei, Honglian; Sun, Suju; Cui, Qingqing; Li, Ruxin; Niu, Yanan; Huang, Bixing

2018-04-01

Clostridium difficile is the causative pathogen for antibiotic-related nosocomial diarrhea. For epidemiological study and identification of virulent clones, a new binary typing method was developed for C. difficile in this study. The usefulness of this newly developed optimized 10-loci binary typing method was compared with two widely used methods ribotyping and multilocus sequence typing (MLST) in 189 C. difficile samples. The binary typing, ribotyping and MLST typed the samples into 53 binary types (BTs), 26 ribotypes (RTs), and 33 MLST sequence types (STs), respectively. The typing ability of the binary method was better than that of either ribotyping or MLST expressed in Simpson Index (SI) at 0.937, 0.892 and 0.859, respectively. The ease of testing, portability and cost-effectiveness of the new binary typing would make it a useful typing alternative for outbreak investigations within healthcare facilities and epidemiological research. Copyright © 2018 Elsevier B.V. All rights reserved.

Who Is Doing Well? A Typology of Newly Homeless Adolescents

Science.gov (United States)

Milburn, Norweeta; Liang, Li-Jung; Lee, Sung-Jae; Rotheram-Borus, Mary Jane; Rosenthal, Doreen; Mallett, Shelley; Lightfoot, Marguerita; Lester, Patricia

2009-01-01

There is growing evidence to support developing new typologies for homeless adolescents. Current typologies focus on the risks associated with being homeless, with less consideration of the positive attributes of homeless adolescents. The authors examined both risk and protective factors in a sample of newly homeless adolescents. Using cluster…

The Precipitation Behavior of Poorly Water-Soluble Drugs with an Emphasis on the Digestion of Lipid Based Formulations.

Science.gov (United States)

Khan, Jamal; Rades, Thomas; Boyd, Ben

2016-03-01

An increasing number of newly discovered drugs are poorly water-soluble and the use of natural and synthetic lipids to improve the oral bioavailability of these drugs by utilizing the digestion pathway in-vivo has proved an effective formulation strategy. The mechanisms responsible for lipid digestion and drug solubilisation during gastrointestinal transit have been explored in detail, but the implications of drug precipitation beyond the potential adverse effect on bioavailability have received attention only in recent years. Specifically, these implications are that different solid forms of drug on precipitation may affect the total amount of drug absorbed in-vivo through their different physico-chemical properties, and the possibility that the dynamic environment of the small intestine may afford re-dissolution of precipitated drug if present in a high-energy form. This review describes the events that lead to drug precipitation during the dispersion and digestion of lipid based formulations, common methods used to inhibit precipitation, as well as conventional and newly emerging characterization techniques for studying the solid state form of the precipitated drug. Moreover, selected case studies are discussed where drug precipitation has ensued from the digestion of lipid based formulations, as well as the apparent link between drug ionisability and altered solid forms on precipitation, culminating in a discussion about the importance of the solid form on precipitation with relevance to the total drug absorbed.

Status of drug development for the prevention and treatment of osteoporosis

DEFF Research Database (Denmark)

Schwarz, Peter; Jørgensen, Niklas Rye; Abrahamsen, Bo

2014-01-01

supplementation. Several new medications for the treatment of postmenopausal osteoporosis are in the pipeline. AREAS COVERED: The authors present the most recent studies on new and current antiresorptive as well as anabolic drugs. Specifically, the authors present the current knowledge on drugs directed against...... cathepsin K and sclerostin as well as the new pathways of interest from preclinical studies. EXPERT OPINION: New scientific results have identified novel signaling pathways as potential targets for future development of anti-osteoporotic drugs. The treatments close to marketing at the moment are odanacatib...

Newly graduated nurses' empowerment regarding professional competence and other work-related factors.

Science.gov (United States)

Kuokkanen, Liisa; Leino-Kilpi, Helena; Numminen, Olivia; Isoaho, Hannu; Flinkman, Mervi; Meretoja, Riitta

2016-01-01

Although both nurse empowerment and competence are fundamental concepts of describing newly graduated nurses' professional development and job satisfaction, only few studies exist on the relationship between these concepts. Therefore, the purpose of this study was to determine how newly graduated nurses assess their empowerment and to clarify professional competence compared to other work-related factors. A descriptive, cross-sectional and correlational design was applied. The sample comprised newly graduated nurses (n = 318) in Finland. Empowerment was measured using the 19-item Qualities of an Empowered Nurse scale and the Nurse Competence Scale measured nurses' self-assessed generic competence. In addition to demographic data, the background data included employment sector (public/private), job satisfaction, intent to change/leave job, work schedule (shifts/business hours) and assessments of the quality of care in the workplace. The data were analysed statistically by using Spearman's correlation coefficient as well as the One-Way and Multivariate Analysis of Variance. Cronbach's alpha coefficient was used to estimate the internal consistency. Newly graduated nurses perceived their level of empowerment and competence fairly high. The association between nurse empowerment and professional competence was statistically significant. Other variables correlating positively to empowerment included employment sector, age, job satisfaction, intent to change job, work schedule, and satisfaction with the quality of care in the work unit. The study indicates competence had the strongest effect on newly graduated nurses' empowerment. New graduates need support and career opportunities. In the future, nurses' further education and nurse managers' resources for supporting and empowering nurses should respond to the newly graduated nurses' requisites for attractive and meaningful work.

Use of a newly developed active thermal neutron detector for in-phantom measurements in a medical LINAC

Energy Technology Data Exchange (ETDEWEB)

Bodogni, R.; Sanchez-Doblado, F.; Pola, A.; Gentile, A.; Esposito, A.; Gomez-ros, J. M.; Pressello, M. C.; Lagares, J. I.; Terron, J. A.; Gomez, F.

2013-07-01

In this work a newly developed active thermal neutron detector, based on a solid state analog device, was used to determine the thermal neutron fluence in selected positions of a simplified human phantom undergoing radiotherapy with a 15 MV LINAC. The results are compared with TLD, the predictions from a Monte Carlo simulation and with measurements indirectly performed with a digital device, located far from the phantom, inside the treatment room. In this work only TLD comparison is presented. Since active neutron instruments are usually affected by systematic deviations when used in a pulsed field with large photon background, the new detector offered in this work may represent an innovative and useful tool for neutron evaluations in accelerator-based radiotherapy. (Author)

Adapted to change: The rapid development of symbiosis in newly settled, fast-maturing chemosymbiotic mussels in the deep sea.

Science.gov (United States)

Laming, Sven R; Duperron, Sébastien; Gaudron, Sylvie M; Hilário, Ana; Cunha, Marina R

2015-12-01

Symbioses between microbiota and marine metazoa occur globally at chemosynthetic habitats facing imminent threat from anthropogenic disturbance, yet little is known concerning the role of symbiosis during early development in chemosymbiotic metazoans: a critical period in any benthic species' lifecycle. The emerging symbiosis of Idas (sensu lato) simpsoni mussels undergoing development is assessed over a post-larval-to-adult size spectrum using histology and fluorescence in situ hybridisation (FISH). Post-larval development shows similarities to that of both heterotrophic and chemosymbiotic mussels. Data from newly settled specimens confirm aposymbiotic, planktotrophic larval development. Sulphur-oxidising (SOX) symbionts subsequently colonise multiple exposed, non-ciliated epithelia shortly after metamorphosis, but only become abundant on gills as these expand with greater host size. This wide-spread bathymodiolin recorded from sulphidic wood, bone and cold-seep habitats, displays a suite of adaptive traits that could buffer against anthropogenic disturbance. Copyright © 2015 Elsevier Ltd. All rights reserved.

Provisional in-silico biopharmaceutics classification (BCS) to guide oral drug product development.

Science.gov (United States)

Wolk, Omri; Agbaria, Riad; Dahan, Arik

2014-01-01

The main objective of this work was to investigate in-silico predictions of physicochemical properties, in order to guide oral drug development by provisional biopharmaceutics classification system (BCS). Four in-silico methods were used to estimate LogP: group contribution (CLogP) using two different software programs, atom contribution (ALogP), and element contribution (KLogP). The correlations (r(2)) of CLogP, ALogP and KLogP versus measured LogP data were 0.97, 0.82, and 0.71, respectively. The classification of drugs with reported intestinal permeability in humans was correct for 64.3%-72.4% of the 29 drugs on the dataset, and for 81.82%-90.91% of the 22 drugs that are passively absorbed using the different in-silico algorithms. Similar permeability classification was obtained with the various in-silico methods. The in-silico calculations, along with experimental melting points, were then incorporated into a thermodynamic equation for solubility estimations that largely matched the reference solubility values. It was revealed that the effect of melting point on the solubility is minor compared to the partition coefficient, and an average melting point (162.7 °C) could replace the experimental values, with similar results. The in-silico methods classified 20.76% (± 3.07%) as Class 1, 41.51% (± 3.32%) as Class 2, 30.49% (± 4.47%) as Class 3, and 6.27% (± 4.39%) as Class 4. In conclusion, in-silico methods can be used for BCS classification of drugs in early development, from merely their molecular formula and without foreknowledge of their chemical structure, which will allow for the improved selection, engineering, and developability of candidates. These in-silico methods could enhance success rates, reduce costs, and accelerate oral drug products development.

Physicochemical properties of newly developed bioactive glass cement and its effects on various cells.

Science.gov (United States)

Washio, Ayako; Nakagawa, Aika; Nishihara, Tatsuji; Maeda, Hidefumi; Kitamura, Chiaki

2015-02-01

Biomaterials used in dental treatments are expected to have favorable properties such as biocompatibility and an ability to induce tissue formation in dental pulp and periapical tissue, as well as sealing to block external stimuli. Bioactive glasses have been applied in bone engineering, but rarely applied in the field of dentistry. In the present study, bioactive glass cement for dental treatment was developed, and then its physicochemical properties and effects on cell responses were analyzed. To clarify the physicochemical attributes of the cement, field emission scanning electron microscopy, X-ray diffraction, and pH measurement were carried out. Cell attachment, morphology, and viability to the cement were also examined to clarify the effects of the cement on odontoblast-like cells (KN-3 cells), osteoblastic cells (MC3T3-E1 cells), human periodontal ligament stem/progenitor cells and neuro-differentiative cells (PC-12 cells). Hydroxyapatite-like precipitation was formed on the surface of the hardened cement and the pH level changed from pH10 to pH9, then stabilized in simulate body fluid. The cement had no cytotxic effects on these cells, and particulary induced process elongation of PC-12 cells. Our results suggest that the newly developed bioactive glass cement have capability of the application in dental procedures as bioactive cement. © 2014 Wiley Periodicals, Inc.

Newly developed low-temperature scanning tunneling microscope and its application to the study of superconducting materials

International Nuclear Information System (INIS)

Gao, F.; Dai, C.; Chen, Z.; Huang, G.; Bai, C.; Tao, H.; Yin, B.; Yang, Q.; Zhao, Z.

1994-01-01

A newly developed scanning tunneling microscope (STM) capable of operating at room temperature, 77 K, and 4.2 K is presented. This compact STM has a highly symmetric and rigid tunneling unit designed as an integral frame except the coarse and fine adjustment parts. The tunneling unit is incorporated into a small vacuum chamber that is usually pumped down to 2x10 -4 Pa to avoid water contamination. The fine mechanic adjustment makes the tip approach the sample in 5 nm steps. The coarse adjustment not only changes the distance between the tip and the sample, but also adjusts the tip to be normal to the surface of the sample. With this low-temperature STM atomic resolution images of Bi-2212 single-crystal and large-scale topographies of a YBa 2 Cu 3 O 7 thin film are observed at 77 K

Enrichment Strategies in Pediatric Drug Development: An Analysis of Trials Submitted to the US Food and Drug Administration.

Science.gov (United States)

Green, Dionna J; Liu, Xiaomei I; Hua, Tianyi; Burnham, Janelle M; Schuck, Robert; Pacanowski, Michael; Yao, Lynne; McCune, Susan K; Burckart, Gilbert J; Zineh, Issam

2017-12-08

Clinical trial enrichment involves prospectively incorporating trial design elements that increase the probability of detecting a treatment effect. The use of enrichment strategies in pediatric drug development has not been systematically assessed. We analyzed the use of enrichment strategies in pediatric trials submitted to the US Food and Drug Administration from 2012-2016. In all, 112 efficacy studies associated with 76 drug development programs were assessed and their overall success rates were 78% and 75%, respectively. Eighty-eight trials (76.8%) employed at least one enrichment strategy; of these, 66.3% employed multiple enrichment strategies. The highest trial success rates were achieved when all three enrichment strategies (practical, predictive, and prognostic) were used together within a single trial (87.5%), while the lowest success rate was observed when no enrichment strategy was used (65.4%). The use of enrichment strategies in pediatric trials was found to be associated with trial and program success in our analysis. © 2017 American Society for Clinical Pharmacology and Therapeutics.

How modeling and simulation have enhanced decision making in new drug development.

Science.gov (United States)

Miller, Raymond; Ewy, Wayne; Corrigan, Brian W; Ouellet, Daniele; Hermann, David; Kowalski, Kenneth G; Lockwood, Peter; Koup, Jeffrey R; Donevan, Sean; El-Kattan, Ayman; Li, Cheryl S W; Werth, John L; Feltner, Douglas E; Lalonde, Richard L

2005-04-01

The idea of model-based drug development championed by Lewis Sheiner, in which pharmacostatistical models of drug efficacy and safety are developed from preclinical and available clinical data, offers a quantitative approach to improving drug development and development decision-making. Examples are presented that support this paradigm. The first example describes a preclinical model of behavioral activity to predict potency and time-course of response in humans and assess the potential for differentiation between compounds. This example illustrates how modeling procedures expounded by Lewis Sheiner provided the means to differentiate potency and the lag time between drug exposure and response and allow for rapid decision making and dose selection. The second example involves planning a Phase 2a dose-ranging and proof of concept trial in Alzheimer's disease (AD). The issue was how to proceed with the study and what criteria to use for a go/no go decision. The combined knowledge of AD disease progression, and preclinical and clinical information about the drug were used to simulate various clinical trial scenarios to identify an efficient and effective Phase 2 study. A design was selected and carried out resulting in a number of important learning experiences as well as extensive financial savings. The motivation for this case in point was the "Learn-Confirm" paradigm described by Lewis Sheiner. The final example describes the use of Pharmacokinetic and Pharmacodynamic (PK/PD) modeling and simulation to confirm efficacy across doses. In the New Drug Application for gabapentin, data from two adequate and well-controlled clinical trials was submitted to the Food and Drug Administration (FDA) in support of the approval of the indication for the treatment of post-herpetic neuralgia. The clinical trial data was not replicated for each of the sought dose levels in the drug application presenting a regulatory dilemma. Exposure response analysis submitted in the New Drug

The Expected Net Present Value of Developing Weight Management Drugs in the Context of Drug Safety Litigation.

Science.gov (United States)

Chawla, Anita; Carls, Ginger; Deng, Edmund; Tuttle, Edward

2015-07-01

Following withdrawals, failures, and significant litigation settlements, drug product launches in the anti-obesity category slowed despite a large and growing unmet need. Litigation concerns, a more risk-averse regulatory policy, and the difficulty of developing a product with a compelling risk-benefit profile in this category may have limited innovators' expected return on investment and restricted investment in this therapeutic area. The objective of the study was to estimate perceived manufacturer risk associated with product safety litigation and increased development costs vs. revenue expectations on anticipated return on investment and to determine which scenarios might change a manufacturer's investment decision. Expected net present value of a weight-management drug entering pre-clinical trials was calculated for a range of scenarios representing evolving expectations of development costs, revenue, and litigation risk over the past 25 years. These three factors were based on published estimates, historical data, and analogs from other therapeutic areas. The main driver in expected net present value calculations is expected revenue, particularly if one assumes that litigation risk and demand are positively correlated. Changes in development costs associated with increased regulatory concern with potential safety issues for the past 25 years likely did not impact investment decisions. Regulatory policy and litigation risk both played a role in anti-obesity drug development; however, product revenue-reflecting efficacy at acceptable levels of safety-was by far the most important factor. To date, relatively modest sales associated with recent product introductions suggest that developing a product that is sufficiently efficacious with an acceptable level of safety continues to be the primary challenge in this market.

Frequency and structure of stimulant designer drug consumption among suspected drug users in Budapest and South-East Hungary in 2012-2013.

Science.gov (United States)

Institóris, László; Árok, Zsófia; Seprenyi, Katalin; Varga, Tibor; Sára-Klausz, Gabriella; Keller, Éva; Tóth, Réka A; Sala, Leonardo; Kereszty, Éva; Róna, Kálmán

2015-03-01

Identification of abuse and frequency patterns of stimulant designer drugs (SDDs) provides important information for their risk assessment and legislative control. In the present study urine and/or blood samples of suspected drug users in criminal cases were analysed by GC-MS for 38 SDDs, and for the most frequent illicit and psychoactive licit drugs in Hungary. Between July 2012 and June 2013, 2744 suspected drug users were sampled in Budapest and during 2012 and 2013, 774 persons were sampled in South-East Hungary (Csongrád County - neighbour the Romanian and Serbian borders). In Budapest 71.4% of cases, and in South-East Hungary 61% of cases were positive for at least one substance. Pentedrone was the most frequent SDD in both regions; however, the frequency distribution of the remaining drugs was highly diverse. SDDs were frequently present in combination with other drugs - generally with amphetamine or other stimulants, cannabis and/or benzodiazepines. The quarterly distribution of positive samples indicated remarkable seasonal changes in the frequency and pattern of consumption. Substances placed on the list of illicit drugs (mephedrone, 4-fluoro-amphetamine, MDPV, methylone, 4-MEC) showed a subsequent drop in frequency and were replaced by other SDDs (pentedrone, 3-MMC, methiopropamine, etc.). Newly identified compounds from seized materials were added to the list of new psychoactive substances ("Schedule C"). While the risk assessment of substances listed in Schedule C has to be performed within 2 years after scheduling, continuous monitoring of their presence and frequency among drug users is essential. In summary, our results suggest which substances should be dropped from the list of SDDs measured in biological samples; while the appearance of new substances from seized materials indicate the need for developing adequate standard analytical methods. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Progress and promise for the MDMA drug development program.

Science.gov (United States)

Feduccia, Allison A; Holland, Julie; Mithoefer, Michael C

2018-02-01

Pharmacotherapy is often used to target symptoms of posttraumatic stress disorder (PTSD), but does not provide definitive treatment, and side effects of daily medication are often problematic. Trauma-focused psychotherapies are more likely than drug treatment to achieve PTSD remission, but have high dropout rates and ineffective for a large percentage of patients. Therefore, research into drugs that might increase the effectiveness of psychotherapy is a logical avenue of investigation. The most promising drug studied as a catalyst to psychotherapy for PTSD thus far is 3,4-methylenedioxymethamphetamine (MDMA), commonly known as the recreational drug "Ecstasy." MDMA stimulates the release of hormones and neurochemicals that affect key brain areas for emotion and memory processing. A series of recently completed phase 2 clinical trials of MDMA-assisted psychotherapy for treatment of PTSD show favorable safety outcomes and large effect sizes that warrant expansion into multi-site phase 3 trials, set to commence in 2018. The nonprofit sponsor of the MDMA drug development program, the Multidisciplinary Association for Psychedelic Studies (MAPS), is supporting these trials to explore whether MDMA, administered on only a few occasions, can increase the effectiveness of psychotherapy. Brain imaging techniques and animal models of fear extinction are elucidating neural mechanisms underlying the robust effects of MDMA on psychological processing; however, much remains to be learned about the complexities of MDMA effects as well as the complexities of PTSD itself.

Formulary Drug Review: Naldemedine.

Science.gov (United States)

Baker, Danial E

2017-07-01

Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are available online to subscribers. Monographs can be customized to meet the needs of a facility. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, contact Wolters Kluwer customer service at 866-397-3433. The September 2017 monograph topics are brigatinib, durvalumab, edaravone, midostaurin, and sarilumab. The MUE is on sarilumab.

Ethnobotany and ethnopharmacy--their role for anti-cancer drug development.

Science.gov (United States)

Heinrich, Michael; Bremner, Paul

2006-03-01

Local and traditional knowledge has been the starting point for many successful drug development projects over the last decades. Here we discuss some examples of anti-cancer drugs which have had enormous impact as anti-cancer agents (camptothecan, taxol and derivatives) and a few examples of drugs currently under various stages of preclinical development. Ethnobotanists investigate the relationship between humans and plants in all its complexity, and such research is generally based on a detailed observation and study of the use a society makes of plants. The requirements of modern research on natural products as, for example, outlined in the Convention on Biological Diversity (Rio Convention) and the overall approach in ethnobotanical research are also discussed. Selected phytochemical-pharmacological studies based on traditional plant use are used to highlight the potential of ethnobotany driven anti-cancer research. The link between traditionally used plants and targets of the NF-kappaB pathway is discussed using on an EU-funded, multidisciplinary project as an example. Lastly the potential of chemopreventive agents derived from traditional food plants is briefly addressed.

78 FR 29755 - Human Immunodeficiency Virus Patient-Focused Drug Development and Human Immunodeficiency Virus...

Science.gov (United States)

2013-05-21

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2013-N-0473] Human Immunodeficiency Virus Patient-Focused Drug Development and Human Immunodeficiency Virus Cure... an opportunity for public comment on human immunodeficiency virus (HIV) Patient-Focused Drug...

Advancing tuberculosis drug regimen development through innovative quantitative translational pharmacology methods and approaches.

Science.gov (United States)

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.

Feasibility and preliminary effects of an intervention targeting schema development for caregivers of newly admitted hospice patients.

Science.gov (United States)

Lindstrom, Kathryn B; Mazurek Melnyk, Bernadette

2013-06-01

The transition to hospice care is a stressful experience for caregivers, who report high anxiety, unpreparedness, and lack of confidence. These sequelae are likely explained by the lack of an accurate cognitive schema, not knowing what to expect or how to help their loved one. Few interventions exist for this population and most do not measure preparedness, confidence, and anxiety using a schema building a conceptual framework for a new experience. The purpose of this study was to test the feasibility and preliminary effects of an intervention program, Education and Skill building Intervention for Caregivers of Hospice patients (ESI-CH), using an innovative conceptual design that targets cognitive schema development and basic skill building for caregivers of loved ones newly admitted to hospice services. A pre-experimental one-group pre- and post-test study design was used. Eighteen caregivers caring for loved ones in their homes were recruited and twelve completed the pilot study. Depression, anxiety, activity restriction, preparedness, and beliefs/confidence were measured. Caregivers reported increased preparedness, more helpful beliefs, and more confidence about their ability to care for their loved one. Preliminary trends suggested decreased anxiety levels for the intervention group. Caregivers who completed the intervention program rated the program very good or excellent, thought the information was helpful and timely, and would recommend it to friends. Results show promise that the ESI-CH program may assist as an evidence-based program to support caregivers in their role as a caregiver to a newly admitted hospice patient.

The road to commercialization in Africa: lessons from developing the sickle-cell drug Niprisan.

Science.gov (United States)

Perampaladas, Kumar; Masum, Hassan; Kapoor, Andrew; Shah, Ronak; Daar, Abdallah S; Singer, Peter A

2010-12-13

Developing novel drugs from traditional medicinal knowledge can serve as a means to improve public health. Yet countries in sub-Saharan Africa face barriers in translating traditional medicinal knowledge into commercially viable health products. Barriers in moving along the road towards making a new drug available include insufficient manufacturing capacity; knowledge sharing between scientists and medical healers; regulatory hurdles; quality control issues; pricing and distribution; and lack of financing. The case study method was used to illustrate efforts to overcome these barriers during the development in Nigeria of Niprisan - a novel drug for the treatment of sickle cell anemia, a chronic blood disorder with few effective therapies. Building on the knowledge of a traditional medicine practitioner, Nigeria's National Institute for Pharmaceutical Research and Development (NIPRD) developed the traditional herbal medicine Niprisan. The commercialization of Niprisan reached a number of commercial milestones, including regulatory approval in Nigeria; securing US-based commercial partner XeChem; demonstrating clinical efficacy and safety; being awarded orphan drug status by the US Food and Drug Administration; and striking important relationships with domestic and international groups. Despite these successes, however, XeChem did not achieve mainstream success for Niprisan in Nigeria or in the United States. A number of reasons, including inconsistent funding and manufacturing and management challenges, have been put forth to explain Niprisan's commercial demise. As of this writing, NIPRD is considering options for another commercial partner to take the drug forward. Evidence from the Niprisan experience suggests that establishing benefit-sharing agreements, fostering partnerships with established research institutions, improving standardization and quality control, ensuring financial and managerial due diligence, and recruiting entrepreneurial leaders capable of

The road to commercialization in Africa: lessons from developing the sickle-cell drug Niprisan

Directory of Open Access Journals (Sweden)

Daar Abdallah S

2010-12-01

Full Text Available Abstract Background Developing novel drugs from traditional medicinal knowledge can serve as a means to improve public health. Yet countries in sub-Saharan Africa face barriers in translating traditional medicinal knowledge into commercially viable health products. Barriers in moving along the road towards making a new drug available include insufficient manufacturing capacity; knowledge sharing between scientists and medical healers; regulatory hurdles; quality control issues; pricing and distribution; and lack of financing. The case study method was used to illustrate efforts to overcome these barriers during the development in Nigeria of Niprisan – a novel drug for the treatment of sickle cell anemia, a chronic blood disorder with few effective therapies. Discussion Building on the knowledge of a traditional medicine practitioner, Nigeria’s National Institute for Pharmaceutical Research and Development (NIPRD developed the traditional herbal medicine Niprisan. The commercialization of Niprisan reached a number of commercial milestones, including regulatory approval in Nigeria; securing US-based commercial partner XeChem; demonstrating clinical efficacy and safety; being awarded orphan drug status by the US Food and Drug Administration; and striking important relationships with domestic and international groups. Despite these successes, however, XeChem did not achieve mainstream success for Niprisan in Nigeria or in the United States. A number of reasons, including inconsistent funding and manufacturing and management challenges, have been put forth to explain Niprisan’s commercial demise. As of this writing, NIPRD is considering options for another commercial partner to take the drug forward. Summary Evidence from the Niprisan experience suggests that establishing benefit-sharing agreements, fostering partnerships with established research institutions, improving standardization and quality control, ensuring financial and managerial due

76 FR 58398 - Revised Guidance on Marketed Unapproved Drugs; Compliance Policy Guide Sec. 440.100; Marketed New...

Science.gov (United States)

2011-09-21

... guidance the manufacture and marketing of newly introduced unapproved drugs. This guidance represents the... United States that do not have required FDA approval for marketing. CPG 440.100 has been revised to state..., 2011. All unapproved new drugs introduced onto the market after that date are subject to immediate...

Drug Design, Development, and Delivery: An Interdisciplinary Course on Pharmaceuticals

Science.gov (United States)

Prausnitz, Mark R.; Bommarius, Andreas S.

2011-01-01

We developed a new interdisciplinary course on pharmaceuticals to address needs of undergraduate and graduate students in chemical engineering and other departments. This course introduces drug design, development, and delivery in an integrated fashion that provides scientific depth in context with broader impacts in business, policy, and ethics.…

78 FR 46969 - Human Immunodeficiency Virus Patient-Focused Drug Development and Human Immunodeficiency Virus...

Science.gov (United States)

2013-08-02

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2013-N-0473] Human Immunodeficiency Virus Patient-Focused Drug Development and Human Immunodeficiency Virus Cure... for the notice of public meeting entitled ``Human Immunodeficiency Virus (HIV) Patient-Focused Drug...

Fluorescent and radiolabelling of pepsin-digested human glomerular basement membrane with a newly developed hydroxy-coumarin derivative (CASE)

International Nuclear Information System (INIS)

Rand-Weaver, M.; Abuknesha, R.A.; Price, R.G.

1985-01-01

The labelling of pepsin-digested human glomerular basement membrane (pHGBM) with a newly developed fluorescent iodine acceptor 7-hydroxy-coumarin-3-acetic acid N-hydroxysucciniimydyl ester (CASE) is described. The binding of a monoclonal antibody to pHGBM was assessed by radiobinding assays, and when directly iodinated pHGBM was used there was no apparent binding. When CASE was conjugated to pHGBM prior to iodination 11% binding was achieved. CASE acting as an iodine acceptor may be useful for proteins containing few or inaccessible tyrosine residues or which are destroyed by introduction of 125 I. Since CASE is fluorescent, small amounts of material can be detected during isolation prior to iodination. (orig.)

Cerebral glucose metabolism and cognition in newly diagnosed Parkinson's disease: ICICLE-PD study.

Science.gov (United States)

Firbank, M J; Yarnall, A J; Lawson, R A; Duncan, G W; Khoo, T K; Petrides, G S; O'Brien, J T; Barker, R A; Maxwell, R J; Brooks, D J; Burn, D J

2017-04-01

To assess reductions of cerebral glucose metabolism in Parkinson's disease (PD) with 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET), and their associations with cognitive decline. FDG-PET was performed on a cohort of 79 patients with newly diagnosed PD (mean disease duration 8 months) and 20 unrelated controls. PD participants were scanned while on their usual dopaminergic medication. Cognitive testing was performed at baseline, and after 18 months using the Cognitive Drug Research (CDR) and Cambridge Neuropsychological Test Automated Battery (CANTAB) computerised batteries, the Mini-Mental State Examination (MMSE), and the Montreal Cognitive Assessment (MoCA). We used statistical parametric mapping (SPM V.12) software to compare groups and investigate voxelwise correlations between FDG metabolism and cognitive score at baseline. Linear regression was used to evaluate how levels of cortical FDG metabolism were predictive of subsequent cognitive decline rated with the MMSE and MoCA. PD participants showed reduced glucose metabolism in the occipital and inferior parietal lobes relative to controls. Low performance on memory-based tasks was associated with reduced FDG metabolism in posterior parietal and temporal regions, while attentional performance was associated with more frontal deficits. Baseline parietal to cerebellum FDG metabolism ratios predicted MMSE (β=0.38, p=0.001) and MoCA (β=0.3, p=0.002) at 18 months controlling for baseline score. Reductions in cortical FDG metabolism were present in newly diagnosed PD, and correlated with performance on neuropsychological tests. A reduced baseline parietal metabolism is associated with risk of cognitive decline and may represent a potential biomarker for this state and the development of PD dementia. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Process Pharmacology: A Pharmacological Data Science Approach to Drug Development and Therapy.

Science.gov (United States)

Lötsch, Jörn; Ultsch, Alfred

2016-04-01

A novel functional-genomics based concept of pharmacology that uses artificial intelligence techniques for mining and knowledge discovery in "big data" providing comprehensive information about the drugs' targets and their functional genomics is proposed. In "process pharmacology", drugs are associated with biological processes. This puts the disease, regarded as alterations in the activity in one or several cellular processes, in the focus of drug therapy. In this setting, the molecular drug targets are merely intermediates. The identification of drugs for therapeutic or repurposing is based on similarities in the high-dimensional space of the biological processes that a drug influences. Applying this principle to data associated with lymphoblastic leukemia identified a short list of candidate drugs, including one that was recently proposed as novel rescue medication for lymphocytic leukemia. The pharmacological data science approach provides successful selections of drug candidates within development and repurposing tasks. © 2016 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

The Impact of Breakthrough Therapy Designation on Development Strategies and Timelines for Nononcology Drugs and Vaccines.

Science.gov (United States)

Poirier, A F; Murphy, W R

2016-12-01

The US Food and Drug Administration (FDA) Safety and Innovation Act (FDASIA, 2012) introduced the Breakthrough Therapy Designation (BTD), a new tool to expedite development of medicines to treat serious or life-threatening diseases. The majority of BTDs have gone to oncology drugs, and a recent publication by Shea et al. 1 reviewed the impact of BTD on oncology drug development. This article reviews the impact of BTD on development strategies and timelines for nononcology drugs. © 2016 American Society for Clinical Pharmacology and Therapeutics.

Development of Bilayer Tablets with Modified Release of Selected Incompatible Drugs.

Science.gov (United States)

Dhiman, Neha; Awasthi, Rajendra; Jindal, Shammy; Khatri, Smriti; Dua, Kamal

2016-01-01

The oral route is considered to be the most convenient and commonly-employed route for drug delivery. When two incompatible drugs need to be administered at the same time and in a single formulation, bilayer tablets are the most appropriate dosage form to administer such incompatible drugs in a single dose. The aim of the present investigation was to develop bilayered tablets of two incompatible drugs; telmisartan and simvastatin. The bilayer tablets were prepared containing telmisartan in a conventional release layer using croscarmellose sodium as a super disintegrant and simvastatin in a slow-release layer using HPMC K15M, Carbopol 934P and PVP K 30 as matrix forming polymers. The tablets were evaluated for various physical properties, drug-excipient interactions using FTIR spectroscopy and in vitro drug release using 0.1M HCl (pH 1.2) for the first hour and phosphate buffer (pH 6.8) for the remaining period of time. The release kinetics of simvastatin from the slow release layer were evaluated using the zero order, first order, Higuchi equation and Peppas equation. All the physical parameters (such as hardness, thickness, disintegration, friability and layer separation tests) were found to be satisfactory. The FTIR studies indicated the absence of interactions between the components within the individual layers, suggesting drug-excipient compatibility in all the formulations. No drug release from the slow-release layer was observed during the first hour of the dissolution study in 0.1M HCl. The release-controlling polymers had a significant effect on the release of simvastatin from the slow-release layer. Thus, the formulated bilayer tablets avoided incompatibility issues and proved the conventional release of telmisartan (85% in 45 min) and slow release of simvastatin (80% in 8 h). Stable and compatible bilayer tablets containing telmisartan and simvastatin were developed with better patient compliance as an alternative to existing conventional dosage forms.

In vitro cellular drug resistance adds prognostic information to other known risk-factors in childhood acute lymphoblastic leukemia

DEFF Research Database (Denmark)

Lönnerholm, Gudmar; Thörn, Ingrid; Sundström, Christer

2011-01-01

Leukemic cells from 230 children with newly diagnosed B-cell precursor ALL were tested for in vitro drug resistance to a panel of anti-cancer drugs. Minimal residual disease (MRD) was measured by RQ-PCR. During follow-up, 24 relapses occurred in the 159 children with MRD...