drug development mistakes: Topics by WorldWideScience.org

Sample records for drug development mistakes

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...
Contractor’s mistakes during tendering

Science.gov (United States)

Kamil, A. I. M.; Othman, N.; Adnan, H.; Zaki, ZA M.

2018-02-01

The occurrence of overrun in cost and time in a project that is usually caused by contractors, will generally make peopleput the blameonthem. This happensas a result of the lack of knowledge possessed by the contractors in determining the solution to be undertakendue totheir mistakes, especially when it comes to tendering process as what had happened in the cases that were reported in Supreme Court of Canada. This paper aims to identify the types of mistakes, factors that contribute to the mistakes and the responsiveness to the mistakes so that the contractor will be able to manage and control the mistakes, as well as the solution, along with preventing them from happening, and in making decision whether or notthey may withdraw from the bidding when the fault has been discovered or whether they should request for leniency from the client for a second chance in re-submitting the bid after the discovered inaccuracy. This research has been done based on cases that were related to the contractor’s mistakes during tendering which were collected from the Supreme Courts of Canada. The data have been analysed and interpreted by legal methodology, in which the result shows that the ability level of the contractors to respond to the mistake is unsatisfactory,and the fault is continuouslybeingmade. The findings are expected to educate and provide awareness to the contractors relating to the matters discussed.
Mistake management in a foreign language classroom

OpenAIRE

Volkova, Ekaterina

2012-01-01

The aim of the thesis is to design general recomendations on mistake management in a foreign language classroom which would meet both teachers' and learners' requirements and methods of mistake management in a foreign language classroom which would contribute to development of learners' communicative competence. The following methods were used in the research: analysis of literature on pedagogy, psychology and methodology of foreign language teaching, interview, questionnaire and observation....
Libertarianism & Category-Mistake

OpenAIRE

Carlos G. Patarroyo G.

2009-01-01

This paper offers a defense against two accusations according to which libertarianism incurs in a category-mistake. The philosophy of Gilbert Ryle will be used to explain the reasons which ground these accusations. Further, it will be shown why, although certain sorts of libertarianism based on agent-causation or Cartesian dualism incur in these mistakes, there is at least one version of libertarianism to which this criticism does not necessarily apply: the version that seeks to find in physi...
The mistake of the causal relationship

Directory of Open Access Journals (Sweden)

О. Д. Комаров

2015-03-01

Full Text Available The article deals with issues of the mistake of the causal relationship. The modern criminal law science approaches to the content of the mistake of the causal relationship and its significance to the qualification of the crime are described. It is proved that in cases of dolus generalis different mental attitude of the guilty person to two separate acts of his conduct exist. Consequently, in mentioned above cases mistake of the causal relationship does not have place. The rules of qualification of the crimes commited with the mistake of causation and in cases of dolus generalis are proposed .
Quality prediction and mistake proofing: An LDRD final report

Energy Technology Data Exchange (ETDEWEB)

McDonald, M.J.

1998-03-01

Sandia National Laboratories is responsible for assuring that the US nuclear deterrent remains credible and that the one in a billion disaster of unintended nuclear detonation never occurs. Letting mistake-generated defects into the stockpile would undermine its mission. The current era of shrinking stockpiles is shrinking Sandia`s opportunities to discover and correct mistakes and fine tune processes over long production runs. In response, Sandia has chosen to develop and use a science-based, life cycle systems engineering practices that, in part, require understanding the design to manufacturing issues in enough detail to tune processes and eliminate mistakes before ever making a part. Defect prevention is a key area of concern that currently lacks sufficient theoretical understanding. This report is the result of a scoping study in the application of best-practice quality techniques that could address Sandia`s stockpile mission. The study provides detail on sources and control of mistakes, poka-yoke or mistake-proofing techniques, the Toyota Production system, and design theory in relation to manufacturing quality prediction. Scoping experiments are described and areas for future research are identified.
Libertarianism & Category-Mistake

Directory of Open Access Journals (Sweden)

Carlos G. Patarroyo G.

2009-12-01

Full Text Available This paper offers a defense against two accusations according to which libertarianism incurs in a category-mistake. The philosophy of Gilbert Ryle will be used to explain the reasons which ground these accusations. Further, it will be shown why, although certain sorts of libertarianism based on agent-causation or Cartesian dualism incur in these mistakes, there is at least one version of libertarianism to which this criticism does not necessarily apply: the version that seeks to find in physical indeterminism the grounding of human free will.
Disclosing medical mistakes: a communication management plan for physicians.

Science.gov (United States)

Petronio, Sandra; Torke, Alexia; Bosslet, Gabriel; Isenberg, Steven; Wocial, Lucia; Helft, Paul R

2013-01-01

There is a growing consensus that disclosure of medical mistakes is ethically and legally appropriate, but such disclosures are made difficult by medical traditions of concern about medical malpractice suits and by physicians' own emotional reactions. Because the physician may have compelling reasons both to keep the information private and to disclose it to the patient or family, these situations can be conceptualized as privacy dilemmas. These dilemmas may create barriers to effectively addressing the mistake and its consequences. Although a number of interventions exist to address privacy dilemmas that physicians face, current evidence suggests that physicians tend to be slow to adopt the practice of disclosing medical mistakes. This discussion proposes a theoretically based, streamlined, two-step plan that physicians can use as an initial guide for conversations with patients about medical mistakes. The mistake disclosure management plan uses the communication privacy management theory. The steps are 1) physician preparation, such as talking about the physician's emotions and seeking information about the mistake, and 2) use of mistake disclosure strategies that protect the physician-patient relationship. These include the optimal timing, context of disclosure delivery, content of mistake messages, sequencing, and apology. A case study highlighted the disclosure process. This Mistake Disclosure Management Plan may help physicians in the early stages after mistake discovery to prepare for the initial disclosure of a medical mistakes. The next step is testing implementation of the procedures suggested.
Preschoolers' Understanding of Lies and Innocent and Negligent Mistakes.

Science.gov (United States)

Siegal, Michael; Peterson, Candida C.

1998-01-01

Examined preschoolers' ability to distinguish innocent and negligent mistakes from lies. Found that, when asked to identify a mistake or lie about a food's contact with contaminants and identify a bystander's reaction, children distinguished mistakes from lies; they could also discriminate between lies and both negligent mistakes that generate…
Learning from Mistakes in History--A Thematic Instructional Unit.

Science.gov (United States)

Richburg, Robert W.; Harward, Kathleen; Steinkamp, Kathy

2000-01-01

Describes a thematic unit for secondary education students that focuses on eight themes, with accompanying activities, on learning from mistakes, such as "mistakes are inevitable, and everyone makes them" and "making mistakes does not make you a faulty person." Provides a concluding activity on the Titanic. (CMK)
The Legal Duty to Incorporate Mistakes of the Victim

NARCIS (Netherlands)

L.T. Visscher (Louis)

2008-01-01

textabstractAbstract: In many jurisdictions, potential injurers are under a legal duty to incorporate possible mistakes of the potential victim. I distinguish three types of mistakes. First, victims might make mistakes because it is too costly to avoid them (e.g. little children in traffic). Second,
Perceptron Mistake Bounds

OpenAIRE

Mohri, Mehryar; Rostamizadeh, Afshin

2013-01-01

We present a brief survey of existing mistake bounds and introduce novel bounds for the Perceptron or the kernel Perceptron algorithm. Our novel bounds generalize beyond standard margin-loss type bounds, allow for any convex and Lipschitz loss function, and admit a very simple proof.
Difficulties and Mistakes in the Management of the Patient with Gout

Directory of Open Access Journals (Sweden)

S.A. Trypilka

2016-10-01

Full Text Available The issues of the most frequent mistakes and difficulties in the early gout diagnosis and further patient management are discussed in the article. It is known that the diagnosis of gout is made in the first year of the disease only in 1/4 cases, on the average 7–8 years pass until the disease is revealed. Only in one out of 4–5 cases gout is correctly verified in early stages. The reasons of the late diagnostics are the features of the course of gout with periods of absence of a symptom (intermittent gout, diagnostic errors at the first patient encounter, early conduction of X-ray examination without revealing the typical signs of the disease, the lack of joint puncture and verification of uric acid crystals in the synovial fluid. Another cause of diagnostic errors is the determination of the level of uric acid in the blood serum during acute attack. Late diagnosis of gout leads to a series of further diagnostic and tactical mistakes. First of all, this includes the prescription of non-steroidal anti-inflammatory drugs and glucocorticoids without the correct diagnosis. Current recommendations for the management of patients with gout emphasize that the use of glucocorticoids to treat gout is possible only for short courses, their long-term use is not allowed due to the high risk of side effects in this group of patients, who often have comorbidities. Another tactical error is the prescription of urate-lowering drugs in the period of acute arthritis without dose titration and without prescription of anti-inflammatory therapy. The paper presents a clinical case of the late diagnosis of gout involving inefficient treatment with the long-term use of glucocorticoids and absence of administration of urate-lowering drugs resulting in serious side effects — development of diabetes mellitus and hypertension. A detailed analysis of the clinical errors is conducted; recommendations on the rational tactics in this case are presented.
The Study of Synonymous Word "Mistake"

OpenAIRE

Suwardi, Albertus

2016-01-01

This article discusses the synonymous word "mistake*.The discussion will also cover the meaning of 'word' itself. Words can be considered as form whether spoken or written, or alternatively as composite expression, which combine and meaning. Synonymous are different phonological words which have the same or very similar meanings. The synonyms of mistake are error, fault, blunder, slip, slipup, gaffe and inaccuracy. The data is taken from a computer program. The procedure of data collection is...
Learning from Our Mistakes.

Science.gov (United States)

Perkinson, Henry J.

1979-01-01

Discusses the theories of leading educational theorists of the twentieth century, including John Dewey, Jean Piaget, B. F. Skinner, Maria Montessori, Carl Rogers, and A. S. Neill, to show that they have shared a common theory--that of "learning from our mistakes." (GT)
How to make mistakes

DEFF Research Database (Denmark)

Hallerstede, Stefan

2009-01-01

When teaching Event-B to beginners, we usually start with models that are already good enough, demonstrating occasionally some standard techniques like ``invariant strengthening''. We show that we got it essentially right but need to make improvements here and there. However, this is not how we......, invariant violation or non-termination. Mistakes that do not fall into one of these categories may slip through. In this article we present how a formal model is created by refinement and alteration. The approach employs mathematical methodology for problem solving and a software tool. Both aspects...... are important. Mathematical methodology provides ways to turn mistakes into improvements. The software tool is necessary to ease the impact of changes on a model and to obtain rapid feed back. We begin with a set of assumptions and requirements, the problem, and set out to solve it, giving a more vivid picture...
Evoked Feelings, Assigned Meanings and Constructed Knowledge Based on Mistakes

Directory of Open Access Journals (Sweden)

Luciane Guimarães Batistella Bianchini

2017-09-01

Full Text Available By means of Piaget's critical clinical method, the study investigated the meanings assigned to mistakes by four students in different activities and interactive situations. The research also analyzed the results of using self-regulatory situations in understanding mistakes initially committed by the students. Data collection instruments consisted of games, video recordings, diaries and interviews. Following intervention, the students were able to recognize their competence, establish positive interactions within the group, and avoid viewing mistakes as obstacles to learning. We concluded that the meanings assigned to mistakes depend on certain variables, among them feelings nurtured by the individuals about themselves, the other, and the object of knowledge.
Lexicography, or the Gentle Art of Making Mistakes

Directory of Open Access Journals (Sweden)

Giovanni Iamartino

2017-04-01

Full Text Available The man in the street’s attitude of mind towards dictionaries is that they are the true repositories of all the words in a language, and that they are both authoritative and objective – in short, dictionaries are perfect. By mainly referring to the early history of English mono- and bilingual lexicography, this essay explodes the myth of the perfect dictionary and shows that mistakes in dictionaries may profitably be discussed under two headings: lexicographical mistakes, i.e. vague or circular definitions and the so-called ghost words in monolingual dictionaries, and non-insertable equivalents in bilingual dictionaries; and socio-cultural mistakes, which are related to the often elusive impact of ideology on dictionary-making.
Billions on the Sidewalk: Improving Savings by Reducing Investment Mistakes

OpenAIRE

Ugo Panizza

2015-01-01

This paper contributes the on-going debate on income inequality in advanced economies with a proposal aimed at reducing costly investment mistakes that are prevalent among middle-class households. The paper starts by describing how households should invest, compares it with what we know about how households do invest, and highlights discrepancies between the two (investment mistakes). After evaluating the costs of investment mistakes, the paper suggests that they could be reduced by accommoda...
Inner Mongolia must ''leapfrog'' the energy mistakes of the western developed nations

International Nuclear Information System (INIS)

Clark, Woodrow W. II.; Isherwood, William

2010-01-01

The purpose of the Asian Development Bank Report was to investigate and study the energy infrastructure development of western industrialized nations along with their impact on the environment. Then there could be an analysis of how IMAR could ''leapfrog'' or jump over the mistakes of the west and create an energy infrastructure for itself and China. The report reflects and summarizes this historical energy infrastructure development over the 20th Century. The five countries were the UK, Germany, S. Africa, USA and Australia. The foreign energy advisors felt that there were two additional elements that needed to be included. First was the fact that the USA as a whole was different than its regions or states, particularly California. So the nation-state of California was added. Secondly, the western nations of Germany and S. Africa in particular, had carefully considered some advanced coal technologies that were ''cleaner'' than the traditional and conventional approaches to mining. Both nations developed these ''clean coal'' technologies that are now being used more and more today in other developed nations like the USA. If IMAR was to retain much of its coal production and reduce it over time, then it had to install these technologies now to reduce global warming and reverse the climate change caused by current coal mining. (author)

48 CFR 750.7106-3 - Mistakes.

Science.gov (United States)

2010-10-01

... policy interests of the United States by expediting the procurement program and by giving contractors... MANAGEMENT EXTRAORDINARY CONTRACTUAL ACTIONS Extraordinary Contractual Actions To Protect Foreign Policy Interests of the United States 750.7106-3 Mistakes. A contract may be amended or modified to corrrect or...
Ajax Mistakes

Directory of Open Access Journals (Sweden)

2007-01-01

Full Text Available Ajax, shorthand for Asynchronous JavaScript and XML, is a web development technique for creating interactive web applications. The intent is to make web pages feel more responsive by exchanging small amounts of data with the server behind the scenes, so that the entire web page does not have to be reloaded each time the user requests a change. This is meant to increase the web page's interactivity, speed, and usability. However, there are several common mistakes using it, like: using Axaj just for the sake of Ajax, moreover the back button of the browser become unuseful, there might be a delay displaying enhanced GUI widgets, offline content is not supported, concurrent page loading is dramatically slowed down, sensitive information might be sent encrypted, cross-browser implementation is not one of developers primary concerns, concurrent access is not well supported, running the entire application on the client side makes it slower, there is no support for user without a JavaScript enable browser, GUI might change unexpectedly, there are no URLs which may be referred and indexed by users and search engines, pop-up blockers might kill opening windows, there are a lot of asynchronous operations happening in the background which might be difficult to be controlled, inventing new controls which are less intuitive than the classic ones, style and internationalization issues due to partial page rendering, the lack of data posted back from the user, Web traffic cannot be reported for each section of a given site.
Payoff non-linearity sways the effect of mistakes on the evolution of reciprocity.

Science.gov (United States)

Kurokawa, Shun

2016-09-01

The existence of cooperation is considered to require explanation, and reciprocity is a potential explanatory mechanism. Animals sometimes fail to cooperate even when they attempt to do so, and a reciprocator has an Achilles' heel: it is vulnerable to error (the interaction between two reciprocators can lead to an endless vendetta.). However, the strategy favored by natural selection is determined also by its interaction with other strategies. The relationship between two reciprocators leading to a collapse of cooperation through error does not straightforwardly imply that mistakes make the conditions under which reciprocity evolves stringent. Hence, mistakes may facilitate the evolution of reciprocity. However, it has been shown through the analysis of the interaction between reciprocators and unconditional defectors that the existence of mistakes makes the conditions for reciprocators stable against invasion by an unconditional defector more stringent, which indicates that mistakes discourage the evolution of reciprocity. However, this result is based on the assumption that the effects of cooperation are additive (payoff is linear), while the game played by real animals does not always display this feature. In such cases, the result may be swayed. In this paper, we remove this assumption, reexamining whether mistakes disturb the evolution of reciprocity. Using the analysis of an evolutionarily stable strategy (ESS), we show that when extra fitness costs are present in cases where mutual cooperation is established, mistakes can facilitate the evolution of reciprocity; whereas, when the effect of cooperation is additive, mistakes always disturb the evolution of reciprocity, as has been shown previously. Copyright © 2016. Published by Elsevier Inc.
The commonest mistakes in the treatment of adult patients with congenital heart disease

Directory of Open Access Journals (Sweden)

Jure Dolenc

2012-04-01

Full Text Available Background: General practitioners and medical specialists are seeing adults with congenital heart disease in their everyday practice more frequently than ever. The lack of experience and knowledge in this field of cardiology often leads to mistakes in the treatment of these patients. The purpose of this article is to point out the commonest problems and mistakes in dealing with this group of patients. Conclusions: In the following article we pointed out the commonest problems and mistakes in dealing with adults with congenital heart disease, such as differing various types of atrial septal defects and differing atrial septal defect from patent foramen ovale. We also pointed out the commonest mistakes in dealing with patients with cyanotic heart disease, especially those with Eisenmenger syndrome.
Mistake and non-disclosure of facts: models for English contract law

NARCIS (Netherlands)

Beale, H.

2012-01-01

This book examines the case for reforming the law on mistake and non-disclosure of fact to bring English law closer to the law in much of continental Europe. There, and in common law countries like the US, a party may avoid a contract for mistake of fact on a more liberal basis, and a party who
Case Study: Learner Attitudes Towards the Correction of Mistakes

Directory of Open Access Journals (Sweden)

Galina Kavaliauskienė

2012-07-01

Full Text Available The objective of the research is to explore learner attitudes to correction of mistakes or feedback as a language learning tool in oral, electronically- and paper-written work as well as peer correction of mistakes.Feedback is a method used in the teaching of languages to improve performance by sharing observations, concerns and suggestions with regard to written work or oral presentation. It includes not only correcting learners, but also assessing them. Both correction and assessment depend on mistakes being made, reasons for mistakes, and class activities. Recently the value of feedback in language studies has been a matter of debate among language teaching practitioners. The research into the effects of feedback is far from conclusive. Teachers’ and students’ expectations toward feedback are found to be opposing, and the most frequent reason given is its negative impact on students’ confidence and motivation. However, at the university level the issue of feedback has been examined in passing and there is insufficient research into learner attitudes to feedback in English for Specific Purposes.The hypothesis for the present study is to find out whether criticism has a negative impact on student confidence and whether perceptions of feedback depend on professional specialization.The research methods. A survey of students’ perceptions of teachers’ feedback in various class activities was administered to various groups of undergraduate students of psychology and penitentiary law. Statistical treatment of students’ responses using Statistical Package for the Social Sciences software (SPSS was carried out in order to establish the level of significance for the two small samples of participants.The respondents in this research participated students of two different specializations, penitentiary law and psychology, who study English for Specific Purposes at the Faculty of Social Policy, Mykolas Romeris University in Vilnius, Lithuania
Case Study: Learner Attitudes Towards the Correction of Mistakes

Directory of Open Access Journals (Sweden)

Galina Kavaliauskienė

2013-01-01

Full Text Available The objective of the research is to explore learner attitudes to correction of mistakes or feedback as a language learning tool in oral, electronically- and paper-written work as well as peer correction of mistakes. Feedback is a method used in the teaching of languages to improve performance by sharing observations, concerns and suggestions with regard to written work or oral presentation. It includes not only correcting learners, but also assessing them. Both correction and assessment depend on mistakes being made, reasons for mistakes, and class activities. Recently the value of feedback in language studies has been a matter of debate among language teaching practitioners. The research into the effects of feedback is far from conclusive. Teachers’ and students’ expectations toward feedback are found to be opposing, and the most frequent reason given is its negative impact on students’ confidence and motivation. However, at the university level the issue of feedback has been examined in passing and there is insufficient research into learner attitudes to feedback in English for Specific Purposes. The hypothesis for the present study is to find out whether criticism has a negative impact on student confidence and whether perceptions of feedback depend on professional specialization. The research methods. A survey of students’ perceptions of teachers’ feedback in various class activities was administered to various groups of undergraduate students of psychology and penitentiary law. Statistical treatment of students’ responses using Statistical Package for the Social Sciences software (SPSS was carried out in order to establish the level of significance for the two small samples of participants. The respondents in this research participated students of two different specializations, penitentiary law and psychology, who study English for Specific Purposes at the Faculty of Social Policy, Mykolas Romeris University in Vilnius
Instructional design in mathematics for undergraduate students based on learning by mistakes approach utilizing scilab assistance

Science.gov (United States)

Kartika, H.

2018-03-01

The issue related to making mistake while learning such as negative emotion is found while students learn mathematics with the aid of a computer. When the computer output showed a mistake message, the students considered it as a computer software malfunction. Based on this issue, the writer designs an instructional model based on learning by mistake approach and which is Scilab assisted. The method used in this research is research design involving undergraduate students in matrix algebra courses. The data collected throught survey with questionnaire to gain feedback about the approach implemented. The data analyzed using quantitative descriptive. The instructional design proposed is the student act as a mistake corrector while the teacher acts as a mistake maker. Teacher deliberately makes mistakes with the help of Scilab software. On the other hand, students correct, analyze and explain errors resulting from Scilab software. The result of this research is an ICT based instructional design which is expected to be applicable as an alternative learning in directing students to think positively about mistakes in learning. Furthermore, students are also expected to improve their ability in understanding and thinking critically while solving problems and improving themselves in learning mathematics.
[Learning from mistakes].

Science.gov (United States)

Arndt, M

1996-03-01

Learning from mistakes. Moral aspects in nursing Medication errors are experiences which may serve to demonstrate variables of moral action in nursing. Qualitative research in nursing is asking philosophical questions by exploring the meaning of experiences. Still, philosophical answers cannot be expected from the use of research tools that have been developed by the social sciences. The usefulness of such research is found foremost in the thorough understanding of the problems relating to a certain topic and in making complex realities more transparent by analysing concrete data. Recent feminist philosophy emphasises thinking in the context of empathy and concrete relationships. Ethics, taking recourse to these basic elements will be contextual. In this paper I offer some results of discourse analysis as a qualitative research approach to the understanding of the experiences of nurses who have been involved with medication errors. The interpretation of narrative texts allows a close look at everyday nursing experiences. Herewith, a contribution is made to a contextual ethics that is of value to nursing. I show how different modalities of identification are likewise compatible with a teleological and a deontological approach to ethics. Even though an ethic of care may well dominate human relationships, such an ethic does not have to dispense with rules and policies.
Mistake of Criminal Law and Its Influence on the Classification of Crime

Science.gov (United States)

Veresha, Roman V.

2016-01-01

The paper examines the characteristics of a mistake of the commitment of crime as an optional feature of the mental state of the crime. The analysis conducted offers an opportunity to state that in international criminal law, a mistake of law, although taken into account, does not generally affect the classification of crime. We uncovered and…
Mistakes and inconsistencies regarding adsorption of contaminants from aqueous solutions: A critical review.

Science.gov (United States)

Tran, Hai Nguyen; You, Sheng-Jie; Hosseini-Bandegharaei, Ahmad; Chao, Huan-Ping

2017-09-01

In recent years, adsorption science and technology for water and wastewater treatment has attracted substantial attention from the scientific community. However, the number of publications containing inconsistent concepts is increasing. Many publications either reiterate previously discussed mistakes or create new mistakes. The inconsistencies are reflected by the increasing publication of certain types of article in this field, including "short communications", "discussions", "critical reviews", "comments", "letters to the editor", and "correspondence (comment/rebuttal)". This article aims to discuss (1) the inaccurate use of technical terms, (2) the problem associated with quantities for measuring adsorption performance, (3) the important roles of the adsorbate and adsorbent pK a , (4) mistakes related to the study of adsorption kinetics, isotherms, and thermodynamics, (5) several problems related to adsorption mechanisms, (6) inconsistent data points in experimental data and model fitting, (7) mistakes in measuring the specific surface area of an adsorbent, and (8) other mistakes found in the literature. Furthermore, correct expressions and original citations of the relevant models (i.e., adsorption kinetics and isotherms) are provided. The authors hope that this work will be helpful for readers, researchers, reviewers, and editors who are interested in the field of adsorption studies. Copyright © 2017 Elsevier Ltd. All rights reserved.
Common mistakes at First Certificate… and how to avoid them

CERN Document Server

Tayfoor, Susanne

2004-01-01

This useful little book highlights typical mistakes that learners make at First Certificate level and shows how to avoid them. This useful little book highlights typical mistakes that learners make at First Certificate level and shows how to avoid them. Based on the analysis of thousands of actual exam scripts in the Cambridge Learner Corpus, each unit focuses on a key problem area. Clear explanations and varied FCE-style exercises help learners to use the language accurately. Regular tests offer learners a further opportunity to check and consolidate what they have learnt.
Medical management of radiological accidents in non-specialized clinics: mistakes and lessons

International Nuclear Information System (INIS)

Jikia, D.

2009-01-01

In 1996-2002 three radiological accidents were developed in Georgia. There were some people injured in those accidents. During medical management of the injured some mistakes and errors were revealed both in diagnostics and scheme of the treatment. The goal of this article is to summarize medical management of the mentioned radiological accidents, to estimate reasons of mistakes and errors, to present the lessons drawn in result of Georgia radiological accidents. There was no clinic with specialized profile and experience. Accordingly due to having no relevant experience late diagnosis can be considered as the main error. It had direct influence on the patients' health and results of treatment. Lessons to be drawn after analyzing Georgian radiological accidents: 1. informing medical staff about radiological injuries (pathogenesis, types, symptoms, clinical course, principles of treatment and etc.); 2. organization of training and meetings in non-specialized clinics or medical institutions for medical staff; 3. preparation of informational booklets and guidelines.(author)
Litigation-proof patents: avoiding the most common patent mistakes

National Research Council Canada - National Science Library

Goldstein, Larry M

2014-01-01

"Litigation-Proof Patents: Avoiding the Most Common Patent Mistakes explains the principles of excellent patents, presents the ten most common errors in patents, and details a step-by-step method for avoiding these common errors...
English exposed common mistakes made by Chinese speakers

CERN Document Server

Hart, Steve

2017-01-01

Having analysed the most common English errors made in over 600 academic papers written by Chinese undergraduates, postgraduates, and researchers, Steve Hart has written an essential, practical guide specifically for the native Chinese speaker on how to write good academic English. English Exposed: Common Mistakes Made by Chinese Speakers is divided into three main sections. The first section examines errors made with verbs, nouns, prepositions, and other grammatical classes of words. The second section focuses on problems of word choice. In addition to helping the reader find the right word, it provides instruction for selecting the right style too. The third section covers a variety of other areas essential for the academic writer, such as using punctuation, adding appropriate references, referring to tables and figures, and selecting among various English date and time phrases. Using English Exposed will allow a writer to produce material where content and ideas-not language mistakes-speak the loudest.
Integrated system for error prevention in process of drugs used in oncology

International Nuclear Information System (INIS)

Soriano Garcia, Jorge L; Lima Perez, Mayte; Gonzalez Gonzalez, Joaquin; Batista Albuerne, Noyde; Rodriguez Lopez, Roberto; Garcia Dieguez, Robin; Gonzalez Duennas, Marta; Ugando, Elizabeth

2007-01-01

Medication mistakes in case of chemotherapy or adjuvant treatment used in any stage of drug application process: prescription, transcription, preparation, dispense or administration, are a frequent cause of side effects of antineoplastic drugs. (Author)
A Mistake Based Approach Probing Students' Understanding of PV ...

Indian Academy of Sciences (India)

There are several concepts in molecular thermodynamics whicheasily befuddle students. PV-type work done, presents onesuch example. Classifying the systematic mistakes made bystudents in response to a concept-based question on workdone in thermodynamics, and sharing them across a publicforum results in a ...
Net Survey: "Top Ten Mistakes" in Academic Web Design.

Science.gov (United States)

Petrik, Paula

2000-01-01

Highlights the top ten mistakes in academic Web design: (1) bloated graphics; (2) scaling images; (3) dense text; (4) lack of contrast; (5) font size; (6) looping animations; (7) courseware authoring software; (8) scrolling/long pages; (9) excessive download; and (10) the nothing site. Includes resources. (CMK)
Cicero’s mistake and denied conjunctions: did Stoic logic include six indemonstrables?

Directory of Open Access Journals (Sweden)

Miguel López-Astorga

2017-07-01

Full Text Available Cicero attributes an inference schema that is not logically valid to Stoic logic. This fact has been deemed as a Cicero’s mistake. However, in this paper, I assume the thesis that Cicero was not actually wrong and that, by means of his schema, he could be showing us interesting aspects of Stoicism that are not clear in the ancient sources. In this way, I use the mental models theory as a methodological tool and argue that the case of Cicero’s mistake allows us to suppose that there were six indemonstrables in Stoic logic, and not five.
Category mistakes: A barrier to effective environmental management.

Science.gov (United States)

Wallace, Ken J; Jago, Mark

2017-09-01

How entities, the things that exist, are defined and categorised affects all aspects of environmental management including technical descriptions, quantitative analyses, participatory processes, planning, and decisions. Consequently, ambiguous definitions and wrongly assigning entities to categories, referred to as category mistakes, are barriers to effective management. Confusion caused by treating the term 'biodiversity' variously as the property of an area, the biota of an area, and a preferred end state (a value) - quite different categories of entities - is one example. To overcome such difficulties, we develop and define four entity categories - elements, processes, properties, and values - and two derived categories - states and systems. We argue that adoption of these categories and definitions will significantly improve environmental communication and analysis, and thus strengthen planning and decision-making. Copyright © 2017 Elsevier Ltd. All rights reserved.

A Category Mistake: Why Contemporary Australian Religious Education in Catholic Schools May Be Doomed to Failure

Science.gov (United States)

Hyde, Brendan

2013-01-01

Assuming religious education to be the same as other subject areas of a Catholic school's curriculum by, for example, applying the outcomes based philosophy and language of other subject areas to religious education renders a category mistake. A prominent notion in the work of metaphysical philosopher Gilbert Ryle, a category mistake arises when…
Trouble Spots in Online Direct-to-Consumer Prescription Drug Promotion: Teaching Drug Marketers How to Inform Better or Spin Better?

Science.gov (United States)

Doran, Evan

2016-01-01

Hyosun Kim’s report "Trouble Spots in Online Direct to Consumer Prescription Drug Promotion: A content Analysis of FDA Warning Letters" aims to teach marketers how to avoid breaching current Food and Drug Administration (FDA) guidelines in their online drug promotion. While Kim hopes to minimise the potential for online promotion to misinform consumers and the study is carefully conducted, teaching drug marketers how to avoid the common mistakes in online drug promotion is more likely to make marketers more adept at spinning information than appropriately balancing it PMID:27239884
The Most Common Mistakes of Teacher Trainees' Former Teachers

Science.gov (United States)

Özer, Bayram; Gelen, Ismail; Alkan, Sinem Hizli; Çinar, Gonca; Duran, Volkan

2016-01-01

The fundamental parts of the educational processes are teachers and students. The study aims to determine the common mistakes done by teachers in the classrooms. The research was conducted to 278 third year students in the departments of English Language Teaching, Turkish Language Teaching, and Fine Arts Teaching in 2012-2013 academic year. The…
Third Party Fraud inducing Material Mistake Slip Knot Investments ...

African Journals Online (AJOL)

The decision is commendable for bringing a measure of certainty to the law of mistake on this point and indicating that the reliance theory (as opposed to the iustus error doctrine) is the appropriate means to resolving such cases. Nevertheless, it is suggested that although the general rule implied by the court's approach is ...
Seven Common Mistakes Solar Installers Make | Solar Research | NREL

Science.gov (United States)

stay in touch with customer Ted is that your past solar customers are arguably your best marketing , big data project led by NREL to understand why some customers go solar and why so many more don't have identified the seven most common mistakes that may be keeping customers away. 1. Not following up
Twenty Common Testing Mistakes for EFL Teachers to Avoid

Science.gov (United States)

Henning, Grant

2012-01-01

To some extent, good testing procedure, like good language use, can be achieved through avoidance of errors. Almost any language-instruction program requires the preparation and administration of tests, and it is only to the extent that certain common testing mistakes have been avoided that such tests can be said to be worthwhile selection,…
Learning by Identification of Mistakes in Workings in Engineering Modules

Science.gov (United States)

Chian, S. C.

2018-01-01

Conventional graded assignments are commonly structured in a format where students attempt a prescribed question and are graded based on the completeness of their workings rather than the understanding of concepts. An alternative assignment format was proposed which requires students to identify and explain mistakes in a given set of workings…
Trouble Spots in Online Direct-to-Consumer Prescription Drug Promotion: Teaching Drug Marketers How to Inform Better or Spin Better? Comment on "Trouble Spots in Online Direct-to-Consumer Prescription Drug Promotion: A Content Analysis of FDA Warning Letters".

Science.gov (United States)

Doran, Evan

2016-02-21

Hyosun Kim's report "Trouble Spots in Online Direct to Consumer Prescription Drug Promotion: A content Analysis of FDA Warning Letters" aims to teach marketers how to avoid breaching current Food and Drug Administration (FDA) guidelines in their online drug promotion. While Kim hopes to minimise the potential for online promotion to misinform consumers and the study is carefully conducted, teaching drug marketers how to avoid the common mistakes in online drug promotion is more likely to make marketers more adept at spinning information than appropriately balancing it. © 2016 by Kerman University of Medical Sciences.
Orphan drugs: trends and issues in drug development.

Science.gov (United States)

Rana, Proteesh; Chawla, Shalini

2018-04-12

Research in rare diseases has contributed substantially toward the current understanding in the pathophysiology of the common diseases. However, medical needs of patients with rare diseases have always been neglected by the society and pharmaceutical industries based on their small numbers and unprofitability. The Orphan Drug Act (1983) was the first serious attempt to address the unmet medical needs for patients with rare diseases and to provide impetus for the pharmaceutical industry to promote orphan drug development. The process of drug development for rare diseases is no different from common diseases but involves significant cost and infrastructure. Further, certain aspect of drug research may not be feasible for the rare diseases. The drug-approving authority must exercise their scientific judgment and ensure due flexibility while evaluating data at various stages of orphan drug development. The emergence of patent cliff combined with the government incentives led the pharmaceutical industry to realize the good commercial prospects in developing an orphan drug despite the small market size. Indeed, many drugs that were given orphan designation ended up being blockbusters. The orphan drug market is projected to reach $178 billion by 2020, and the prospects of research and development in rare diseases appears to be quite promising and rewarding.
DYSPNEA ASSOCIATED WITH ANXIETY: MISTAKES AND DIFFICULTIES IN THE DIAGNOSIS

Directory of Open Access Journals (Sweden)

L. I. Tyukalova

2013-01-01

Full Text Available Two clinical cases that demonstrate the difficulties diagnosing the causes of shortness of breath, coupled with anxiety, are analyzed. From the standpoint of modern neurophysiology it explains the relationship of these conditions. There were revealed typical diagnostic mistakes: «the effect of precocious focusing", "the negative effect of the narrow specialization
Trouble Spots in Online Direct-to-Consumer Prescription Drug Promotion: Teaching Drug Marketers How to Inform Better or Spin Better?; Comment on “Trouble Spots in Online Direct-to-Consumer Prescription Drug Promotion: A Content Analysis of FDA Warning Letters”

Directory of Open Access Journals (Sweden)

Evan Doran

2016-05-01

Full Text Available Hyosun Kim’s report “Trouble Spots in Online Direct to Consumer Prescription Drug Promotion: A content Analysis of FDA Warning Letters”aims to teach marketers how to avoid breaching current Food and Drug Administration (FDA guidelines in their online drug promotion. While Kim hopes to minimise the potential for online promotion to misinform consumers and the study is carefully conducted, teaching drug marketers how to avoid the common mistakes in online drug promotion is more likely to make marketers more adept at spinning information than appropriately balancing it.
New graduate occupational therapists' perceptions of near-misses and mistakes in the workplace.

Science.gov (United States)

Clark, Michele; Gray, Marion; Mooney, Jane

2013-01-01

The purpose of this paper is to explore the perceptions of near-misses and mistakes among new graduate occupational therapists from Australia and Aotearoa/New Zealand (NZ), and their knowledge of current incident reporting systems. New graduate occupational therapists in Australia and Aotearoa/NZ in their first year of practice (n = 228) participated in an online electronic survey that examined five areas of work preparedness. Near-misses and mistakes was one focus area. The occurrence and disclosure of practice errors among new graduate occupational therapists are similar between Australian and Aotearoa/NZ participants. Rural location, structured supervision and registration status significantly influenced the perceptions and reporting of practice errors. Structured supervision significantly impacted on reporting procedure knowledge. Current registration status was strongly correlated with perceptions that the workplace encouraged event reporting. Areas for further investigation include investigating the perceptions and knowledge of practice errors within a broader profession and the need to explore definitional aspects and contextual factors of adverse events that occur in allied health settings. Selection bias may be a factor in this study. Findings have implications for university and workplace structures, such as clinical management, supervision, training about practice errors and reporting mechanisms in allied health. Findings may enable the development of better strategies for detecting, managing and preventing practice errors in the allied health professions.
Analyses of Common Grammar Mistakes in High-school English

Institute of Scientific and Technical Information of China (English)

Yang Liou

2017-01-01

English has an important position in the basic education stage as a language subject. English teaching requires students to have the abilities of listening, speaking, reading and writing in high school. If students want to learn these skills well, they should not only memorize vocabularies, but also master grammar knowledge. This paper illustrates the importance of English grammar for learning English and lists the common grammar mistakes. It also introduces some skills of learning English grammar.
Mistakes To Avoid In Attacking The Moral/Conventional Distinction

Directory of Open Access Journals (Sweden)

Alejandro Rosas

2012-11-01

Full Text Available In an experimental critique of the moral/conventional (M/C distinction, Kelly et al. (2007 present new experimental data about responses to transgressions involving harm, where the novelty is that transgressors are grown-ups, rather than children. Their data do not support the moral/conventional distinction. The contrast between grown-up and schoolyard transgressions does not seem, however, to explain their results: they also use two schoolyard transgressions with similar negative results for the M/C distinction.I here attempt to explain away their results by calling attention to two mistakes in their experimental design. One refers to the use of questionnaire-items of the type that Turiel and collaborators have called mixed-domain situations, which extend over both a moral and a conventional domain. Participants respond to these cases differently than to prototypical moral situations, because some allow the authority rule to override the moral rule. The second mistake emerges in the grown-up transgressions labeled as Whipping/temporal, Whipping/Authority, Spanking/Authority, Prisoner abuse/Authority. These are not the typical transgressions unambiguously “involving a victim who has been harmed, whose rights have been violated, or who has been subject to an injustice”. The victims are also transgressors and harm is inflicted on them as punishment. Plausibly, rules about corporal punishment depend on authority in a way that rules about harming the innocent do not.
Popper's Epistemology as a Pedagogic and Didactic Principle, or: Let Them Make More "Mistakes."

Science.gov (United States)

Derkse, W.

1981-01-01

Describes the relationship of Popper's theory of knowledge to chemistry instruction. Suggests that students be allowed to learn from their mistakes and presents five experiments with an implicit falsification purpose. (JN)
[Mistakes and omissions in judicial reports prepared in emergency services].

Science.gov (United States)

Turla, Ahmet; Aydin, Berna; Sataloğlu, Neva

2009-03-01

We aimed in this study to determine any mistakes or omissions made while preparing judicial reports, which contribute to the judicial process. In this study, we evaluated as samples 351 judicial reports of victims who applied to the Emergency Service of Ondokuz Mayis University between January 1, 2005 and December 31, 2005 with respect to the judicial facts, and we recorded any mistakes or omissions of data in these reports. We determined that there was no record of age in 6% of the judicial reports, of examination time in 71.8%, of traumatic lesion or not in 30.5%, of the state of consciousness in 58.7%, and of the presence or not of life-threatening risks in 2.6%. The name of the physician who prepared the report was not provided in 8.0% of the reports. The most important omission is that none of the reports had the name, surname or signature of the person who had taken the prepared report. We concluded that, after graduation, it is necessary for physicians, who are responsible for both treating the patients and writing judicial reports, to attend in-service training programs. They must also be properly advised regarding their responsibilities in judicial cases.
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.
Seven common mistakes in population genetics and how to avoid them.

Science.gov (United States)

Meirmans, Patrick G

2015-07-01

As the data resulting from modern genotyping tools are astoundingly complex, genotyping studies require great care in the sampling design, genotyping, data analysis and interpretation. Such care is necessary because, with data sets containing thousands of loci, small biases can easily become strongly significant patterns. Such biases may already be present in routine tasks that are present in almost every genotyping study. Here, I discuss seven common mistakes that can be frequently encountered in the genotyping literature: (i) giving more attention to genotyping than to sampling, (ii) failing to perform or report experimental randomization in the laboratory, (iii) equating geopolitical borders with biological borders, (iv) testing significance of clustering output, (v) misinterpreting Mantel's r statistic, (vi) only interpreting a single value of k and (vii) forgetting that only a small portion of the genome will be associated with climate. For every of those issues, I give some suggestions how to avoid the mistake. Overall, I argue that genotyping studies would benefit from establishing a more rigorous experimental design, involving proper sampling design, randomization and better distinction of a priori hypotheses and exploratory analyses. © 2015 John Wiley & Sons Ltd.

A Proposal of Operational Risk Management Method Using FMEA for Drug Manufacturing Computerized System

Science.gov (United States)

Takahashi, Masakazu; Nanba, Reiji; Fukue, Yoshinori

This paper proposes operational Risk Management (RM) method using Failure Mode and Effects Analysis (FMEA) for drug manufacturing computerlized system (DMCS). The quality of drug must not be influenced by failures and operational mistakes of DMCS. To avoid such situation, DMCS has to be conducted enough risk assessment and taken precautions. We propose operational RM method using FMEA for DMCS. To propose the method, we gathered and compared the FMEA results of DMCS, and develop a list that contains failure modes, failures and countermeasures. To apply this list, we can conduct RM in design phase, find failures, and conduct countermeasures efficiently. Additionally, we can find some failures that have not been found yet.
Oops – that was a mistake! How toddler brains react to feedback

NARCIS (Netherlands)

Meyer, M.; Vijayakumar, S.; Bekkering, H.; Janssen, D.J.C.; Bruijn, E.R.A. de; Hunnius, S.

2015-01-01

Oops, I just clicked on the wrong button on my computer (mistake) and it made this error sound that you might know. This is an example of feedback. Feedback is useful information to indicate if something was correct or wrong and we can use feedback to improve something. For example, I do not want to
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.
Mistakes in the usage of anatomical terminology in clinical practice.

Science.gov (United States)

Kachlik, David; Bozdechova, Ivana; Cech, Pavel; Musil, Vladimir; Baca, Vaclav

2009-06-01

Anatomical terminology serves as a basic communication tool in all the medical fields. Therefore Latin anatomical nomenclature has been repetitively issued and revised from 1895 (Basiliensia Nomina Anatomica) until 1998, when the last version was approved and published as the Terminologia Anatomica (International Anatomical Terminology) by the Federative Committee on Anatomical Terminology. A brief history of the terminology and nomenclature development is mentioned, along with the concept and contributions of the Terminologia Anatomica including the employed abbreviations. Examples of obsolete anatomical terms and their current synonyms are listed. Clinicians entered the process of the nomenclature revision and this aspect is demonstrated with several examples of terms used in clinical fields only, some already incorporated in the Terminologia Anatomica and a few obsolete terms still alive in non-theoretical communication. Frequent mistakes in grammar and orthography are stated as well. Authors of the article strongly recommend the use of the recent revision of the Latin anatomical nomenclature both in theoretical and clinical medicine.
Análise de erros ortográficos em diferentes problemas de aprendizagem Analyzing typical orthographic mistakes related to different learning problems

Directory of Open Access Journals (Sweden)

Jaime Luiz Zorzi

2009-09-01

learning problems, check if the types of produced mistakes are those found in the learning that is considered normal and analyze if orthographic or phonological nature problems prevail in each disorder. METHODS: the writing of 64 subjects was evaluated by the Laboratory of Learning Disabilities of the Neurology Department of UNICAMP and diagnosed as showing some type of learning problem. Deficit of Attention / Hyperactivity disorder (28; School Difficulties (13; Learning Disabilities (7; Dyslexia (3; Associated Disorders (5 and Inconclusive Diagnosis (9. The ages varied between 8;2 and 13;4 years, with a 10;6 year-old average. Only subjects in alphabetical writing level without any type of intellectual deficit were included. The found mistakes were classified in eleven categories and quantified for ends of statistical analysis. RESULTS: the spelling mistakes found in each problem type correspond to those observed in children without learning complaint. The spelling mistakes through Multiple Representations, Omission of letters and Orality, are respectively, the three most frequent types in the cases Deficit of Attention and Hyperactivity disorder, School Difficulties, Associated Disorders and Unknown Diagnosis. In the Disturbance of Learning the sequence is of Multiple Representations, Omission, Other Mistakes and Voiced/Unvoiced mistakes. In the dyslexia we note the sequence of Multiple Representations, Orality, Omission and Other Mistakes. There is a trend, in each problem type, to the prevalence of orthographic nature mistakes, although with no statistically significant difference in relation to the phonological nature mistakes. CONCLUSION: the orthographic nature mistakes are the most frequent, although, there is no significant difference, in each group, in relation to the phonological nature mistakes. With contrary trend, the visual-spatial mistakes have low occurrence in general, which shows that the difficulty concerning all groups has fundamentally a linguistic
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.
New Zealand’s Drug Development Industry

Directory of Open Access Journals (Sweden)

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.
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.
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
Strategic mistakes (AVOIDABLE) The topicality of Michel Porter’s generic strategies

OpenAIRE

Viltard, Leandro Adolfo

2017-01-01

This article explores the topicality of Porter’s generic strategies, assessing about their applicability on two specific automotive industry projects: The Smart and the New Beetle. After performing a documentation analysis on these two projects, it was concluded that both of them may be considered avoidable strategic mistakes as they show the risks of higher differentiation that is not being paid by the customer, no matter how if it is about recognized brands or icon products. Hazards a...
Cystic fibrosis: myths. mistakes, and dogma.

Science.gov (United States)

Rubin, Bruce K

2014-03-01

As a student I recall being told that half of what we would learn in medical school would be proven to be wrong. The challenges were to identify the incorrect half and, often more challenging, be willing to give up our entrenched ideas. Myths have been defined as traditional concepts or practice with no basis in fact. A misunderstanding is a mistaken approach or incomplete knowledge that can be resolved with better evidence, while firmly established misunderstandings can become dogma; a point of view put forth as authoritative without basis in fact. In this paper, I explore a number of myths, mistakes, and dogma related to cystic fibrosis disease and care. Many of these are myths that have long been vanquished and even forgotten, while others are controversial. In the future, many things taken as either fact or "clinical experience" today will be proven wrong. Let us examine these myths with an open mind and willingness to change our beliefs when justified. Copyright © 2013 Elsevier Ltd. All rights reserved.
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
Fatal cardiac glycoside poisoning due to mistaking foxglove for comfrey.

Science.gov (United States)

Wu, I-Lin; Yu, Jiun-Hao; Lin, Chih-Chuan; Seak, Chen-June; Olson, Kent R; Chen, Hsien-Yi

2017-08-01

Accidental ingestion of foxglove (Digitalis purpurea) can cause significant cardiac toxicity. We report a patient who ingested foxglove mistaking it for comfrey and developed refractory ventricular arrhythmias. The patient died despite treatment with digoxin-specific antibody fragments (DSFab) and veno-arterial extracorporeal membrane oxygenation (VA-ECMO). A 55-year-old woman presented to the emergency department with nausea, vomiting and generalized weakness eight hours after drinking "comfrey" tea. She had bradycardia (54 beats/min) and hyperkalemia (7.6 mEq/L). Electrocardiogram revealed a first-degree atrioventricular conduction block with premature atrial contractions, followed by polymorphic ventricular tachycardia three hours after arrival. A serum digoxin level was 151.2 ng/mL. The patient developed ventricular fibrillation while waiting for Digibind infusion. Resuscitation was performed and an emergent VA-ECMO was set up. A total of eight vials of Digibind were given over the next 16 hours. She temporarily regained consciousness, but remained hemodynamically unstable and subsequently developed lower limb ischemia and multiple organ failure, and she expired on hospital day seven. A botanist confirmed that the plant was foxglove. The diagnosis of cardiac glycoside plant poisoning can be difficult in the absence of an accurate exposure history. In facilities where DSFab is unavailable or insufficient, early VA-ECMO might be considered in severely cardiotoxic patients unresponsive to conventional therapy.
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
Systemic mistakes in hand hygiene practice in Ukraine: detection, consequences and ways of elimination

Science.gov (United States)

Klymenko, Iryna; Kampf, Günter

2015-01-01

Aim: Every year, millions of people around the world suffer from different infectious diseases, considerable part of which are hospital-acquired infections. WHO considers hand hygiene as a priority measure aimed to reduce the level of infection. We evaluated various aspects related to the situational behavior and prioritization regarding hand hygiene measures among the healthcare workers of Ukraine. Method: Identification of system mistakes in hand hygiene was carried out first of all by direct and indirect observation of the activities of medical and pharmaceutical personnel in their everyday practice as well as during their participation in trainings on routine hand hygiene. Questionnaires also were used to estimate the level of hand hygiene compliance of participants of the study. During this period 112 training courses, 315 master-classes and presentations on proper hand hygiene were realized. The target audience included health care workers of medical centers, clinics, maternity hospitals, health care organizations and staff of pharmacies and pharmaceutical manufacturing enterprises in all regions of Ukraine. 638 respondents took part in anonymous survey on hand hygiene practice. Results: The most common mistakes were to regard hand washing and hand disinfection equally, to wash hands before doing a hand disinfection, to neglect the five moments for hand hygiene and to ignore hand hygiene before and after wearing protective gloves. Practitioners, medical attendants, pharmacy and pharmaceutical industry workers highlighted the need for practical and understandable instructions of various hand hygiene procedures, including the clarification of the possible technical mistakes. This became a ground for us to create individual master classes on hand hygiene for each cluster of healthcare workers. Conclusions: Changing hand hygiene behavior and attitude is possible by beginning to observe clinical practice and by involving healthcare workers in teaching and training
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...
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.
Prospective Mathematics Teachers' Ability to Identify Mistakes Related to Angle Concept of Sixth Grade Students

Science.gov (United States)

Arslan, Cigdem; Erbay, Hatice Nur; Guner, Pinar

2017-01-01

In the present study we try to highlight prospective mathematics teachers' ability to identify mistakes of sixth grade students related to angle concept. And also we examined prospective mathematics teachers' knowledge of angle concept. Study was carried out with 30 sixth-grade students and 38 prospective mathematics teachers. Sixth grade students…
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.)
Recombinase, chromosomal translocations and lymphoid neoplasia: targeting mistakes and repair failures.

Science.gov (United States)

Marculescu, Rodrig; Vanura, Katrina; Montpellier, Bertrand; Roulland, Sandrine; Le, Trang; Navarro, Jean-Marc; Jäger, Ulrich; McBlane, Fraser; Nadel, Bertrand

2006-09-08

A large number of lymphoid malignancies is characterized by specific chromosomal translocations, which are closely linked to the initial steps of pathogenesis. The hallmark of these translocations is the ectopic activation of a silent proto-oncogene through its relocation at the vicinity of an active regulatory element. Due to the unique feature of lymphoid cells to somatically rearrange and mutate receptor genes, and to the corresponding strong activity of the immune enhancers/promoters at that stage of cell development, B- and T-cell differentiation pathways represent propitious targets for chromosomal translocations and oncogene activation. Recent progress in the understanding of the V(D)J recombination process has allowed a more accurate definition of the translocation mechanisms involved, and has revealed that V(D)J-mediated translocations result both from targeting mistakes of the recombinase, and from illegitimate repair of the V(D)J recombination intermediates. Surprisingly, V(D)J-mediated translocations turn out to be restricted to two specific sub-types of lymphoid malignancies, T-cell acute lymphoblastic leukemias, and a restricted set of mature B-cell Non-Hodgkin's lymphomas.
Methodology for teaching technical pattern of lying, sport shooting. Mistakes often.

Directory of Open Access Journals (Sweden)

Yaydel Avila Gómez

2011-09-01

Full Text Available The next album we set out a summary of the key technical elements for a good development of the prone position, bearing in mind that sometimes violate some methodological steps for teaching the same in athletes who play sports Shooting sports Rifle mode, which creates bad habits in the teaching of the position are difficult to eradicate later. We proceeded to perform the following steps. Criteria for experts to determine methodological steps to be taken into account in the teaching of technical pattern prone position; query bibliographic elements of the sport, the explanation of the basic technical elements; survey a group of coaches in the form of Rifle for the determination of the most common mistakes in the process of teaching the technical pattern of the prone position. It came to the conclusion that teaching the correct technical pattern that position must be taken into account methodological steps which do not allow making any error that would create a dynamic stereotype wrong in athletes who subsequently would be difficult to resolve.
The phonological mistake and 5D paradigm

Directory of Open Access Journals (Sweden)

Piero Crispiani

2015-12-01

Full Text Available In the first part of this article I present a background in scientific studies on dyslexia, from cognitive science to the neuropedagogical perspective. In this investigation the analysis of mental processes is the most important thanks to comparison with genetic research. In the second part, the dyslexic condition is seen from the perspective of the neuro-motor approach, named the Praxic Motor Theory, which improves neural circuits and inter-hemispherical exchange, electrical transmission and evoked potentials. In this perspective, the dyslexia condition is a disorder related to lack of coordination, including disorganization in space-time and lateral dominance. The phonological hypothesis referring to a lack of sign-sound association in dyslexia is inappropriate, as the term phonology has been intended in English literature as a more complex process and not simply an association between phoneme and grapheme. It is related to access to the word, groups of sounds, rather than single sounds. In this sense the dyslexic reader does not make a phonological mistake in terms of association, but a kinetic-motor one, in space-time from left to right.
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:.
Four Points Beginner Risk Managers Should Learn from Jeff Holman's Mistakes in the Discussion of Antifragile

OpenAIRE

Nassim Nicholas Taleb

2014-01-01

Using Jeff Holman's comments in Quantitative Finance to illustrate 4 critical errors students should learn to avoid: 1) Mistaking tails (4th moment) for volatility (2nd moment), 2) Missing Jensen's Inequality, 3) Analyzing the hedging wihout the underlying, 4) The necessity of a numeraire in finance.
Errors and mistakes in breast ultrasound diagnostics

Directory of Open Access Journals (Sweden)

Wiesław Jakubowski

2012-09-01

Full Text Available Sonomammography is often the first additional examination performed in the diagnostics of breast diseases. The development of ultrasound imaging techniques, particularly the introduction of high frequency transducers, matrix transducers, harmonic imaging and finally, elastography, influenced the improvement of breast disease diagnostics. Neverthe‑ less, as in each imaging method, there are errors and mistakes resulting from the techni‑ cal limitations of the method, breast anatomy (fibrous remodeling, insufficient sensitivity and, in particular, specificity. Errors in breast ultrasound diagnostics can be divided into impossible to be avoided and potentially possible to be reduced. In this article the most frequently made errors in ultrasound have been presented, including the ones caused by the presence of artifacts resulting from volumetric averaging in the near and far field, artifacts in cysts or in dilated lactiferous ducts (reverberations, comet tail artifacts, lateral beam artifacts, improper setting of general enhancement or time gain curve or range. Errors dependent on the examiner, resulting in the wrong BIRADS‑usg classification, are divided into negative and positive errors. The sources of these errors have been listed. The methods of minimization of the number of errors made have been discussed, includ‑ ing the ones related to the appropriate examination technique, taking into account data from case history and the use of the greatest possible number of additional options such as: harmonic imaging, color and power Doppler and elastography. In the article examples of errors resulting from the technical conditions of the method have been presented, and those dependent on the examiner which are related to the great diversity and variation of ultrasound images of pathological breast lesions.
Writing a review article - Are you making these mistakes?

Science.gov (United States)

Daldrup-Link, Heike E

2018-01-01

An explosion of scientific publications over the last decades has increased the need for review articles: Carefully crafted scientific review articles can provide the novice reader with an overview of a new subject and provide the expert with a synthesis of scientific evidence, proof of reproducibility of published data and pooled estimates of common truth through meta-analyses. Unfortunately, while there are ample presentations and published guidelines for the preparation of scientific articles available, detailed information about how to properly prepare scientific review articles is relatively scarce. This perspective summarizes possible mistakes that can lead to misinformation in scientific review articles with the goal to help authors to improve the scientific contribution of their review article and thereby, increase the respective value of these articles for the scientific community.
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
[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.
[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.
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.
FDA's requirements for radiation dosimetry of radiopharmaceutical drug products

International Nuclear Information System (INIS)

Abel, N.M.

1986-01-01

The primary concern of the Office of Drug Research and Review of the Food and Drug Administration in the field of radiation dosimetry is to ensure that radiopharmaceutical drug products are safe when used as investigational drugs (INDs) and are both safe and effective when a new drug application (NDA) is approved. In order to accomplish this, the sponsor of either an IND or applicant in the case of NDA must provide information that clearly describes the radiation dose that a patient will receive from the administration of the drug. The submitted numerical estimates of the radiation dose should be based on an absorbed fraction method of radiation dose calculation, such as the system set forth by the Medical Internal Radiation Dose (MIRD) Committee of the Society of Nuclear Medicine or the system set forth by the International Commission on Radiological Protection (ICRP). This presentation will describe in detail the data that a sponsor of an IND needs to submit to satisfy the regulatory requirements. Examples will be given of common mistakes and omissions by sponsors in their presentation of data
Strategic mistakes (AVOIDABLE The topicality of Michel Porter’s generic strategies

Directory of Open Access Journals (Sweden)

Leandro Adolfo Viltard

2017-06-01

Full Text Available This article explores the topicality of Porter’s generic strategies, assessing about their applicability on two specific automotive industry projects: The Smart and the New Beetle. After performing a documentation analysis on these two projects, it was concluded that both of them may be considered avoidable strategic mistakes as they show the risks of higher differentiation that is not being paid by the customer, no matter how if it is about recognized brands or icon products. Hazards and risks, like big losses and negative margins, are applicable to every firm. This is a qualitative investigation with a not experimental and transversal research design.
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].

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.
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
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 antituberculous drugs: current status and future prospects].

Science.gov (United States)

Tomioka, Haruaki; Namba, Kenji

2006-12-01

Worldwide, tuberculosis (TB) remains the most frequent and important infectious disease causing morbidity and death. One-third of the world's population is infected with Mycobacterium tuberculosis (MTB), the etiologic agent of TB. The World Health Organization estimates that about eight to ten million new TB cases occur annually worldwide and the incidence of TB is currently increasing. In this context, TB is in the top three, with malaria and HIV being the leading causes of death from a single infectious agent, and approximately two million deaths are attributable to TB annually. In particular, pulmonary TB, the most common form of TB, is a highly contagious and life-threatening infection. Moreover, enhanced susceptibility to TB in HIV-infected populations is another serious health problem throughout the world. In addition, multidrug-resistant TB (MDR-TB) has been increasing in incidence in many areas, not only in developing countries but industrialized countries as well, during the past decade. These situations, particularly the global resurgence of TB and the rapid emergence of MDR-TB, underscore the importance of the development of new antituberculous drugs and new protocols for efficacious clinical control of TB patients using ordinary antimycobacterial drugs. Concerning the development of new antituberculous drugs, the following points are of particular importance. (1) Development of drugs which display lasting antimycobacterial activity in vivo is desirable, since they can be administered with long intervals and consequently facilitate directly observed therapy and enhance patient compliance. (2) Development of novel antituberculosis compounds to combat MDR-TB is urgently needed. (3) The eradication of slowly metabolizing and, if possible, dormant populations of MTB organisms that cause relapse, using new classes of anti-TB drugs is very promising for prevention of TB incidence, because it will markedly reduce the incidence of active TB from persons who are
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...
[A qualitative analysis of spelling mistakes and a systematic supportive learning instruction of spelling disorder].

Science.gov (United States)

Corvacho Del Toro, Irene M

2016-09-01

This paper explains how a qualitative analysis of spelling mistakes (Oldenburger Fehleranalyse, Thomé & Thomé, 2014) may be used to select learning materials according to individual needs. The pre-post design with control group serves to evaluate the effects of an intervention that is systematic and learning supportive for pupils with a diagnosed spelling disorder (ages 12 to 14; 6th-8th grade). Therapists of the experimental group were instructed to apply a series of linguistic and psycholinguistic criteria when creating the material for instruction and when carrying out the therapy. Therapists of the control group carried out the intervention without attending to these criteria, although they did have knowledge about the pupil’s profile in spelling mistakes. The intervention included 20 sessions. The ANOVA shows improvement for both groups (HSP, May 2012): (F(1, 14) = 15,05, p = .002, η2 = .518). For the experimental group it is stronger, and the difference in achievement gain is significant (F(1, 14) = 4,70, p = .048; η2 = .25). These results support a combination of qualitative analysis and a high qualification for therapists that relates specifically to orthography and its instruction. For some pupils the changes in the qualitative profiles reveal persistent support requirements in phonology or grammar instruction.
No Room for Mistakes: The Impact of the Social Unconscious on Organizational Learning in Kazakhstan

Directory of Open Access Journals (Sweden)

Indira Kjellstrand

2017-08-01

Full Text Available The aim of this paper is to add to existing work on the theme of power, emotion, and organizational learning. The study was undertaken in Kazakhstan, where tensions between old and new regimes provide an environment that is rich in emotion and power/politics; and offer an opportunity to study the interplay between emotion and power during individual and organizational attempts to learn. The social unconscious is used as a conceptual frame to identify underlying dynamics that impact on organizational learning. The empirical study illustrates a social fantasy concerning the fear of mistakes and its consequences. This fantasy is sustained through blaming and punishing the people who make mistakes, and through feelings of internalised embarrassment and guilt that are enacted through interpersonal relations of shaming and being ashamed. Our contribution to knowledge arises from employing a concept (social unconscious that has not been used to study organizational learning within a social and organizational context for organizational learning (Kazakhstan that has not yet been studied. The practical purpose of this paper is to improve our knowledge of the social and political context of organizational learning in post-Soviet Kazakhstan through understanding unconscious dynamics that both inform and undermine attempts to learn.
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.
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...
Mistakes and complications in the surgical treatment of ambulatory equino planovalgus foot deformities in patients with cerebral palsy using extra-articular subtalar arthrodesis

Directory of Open Access Journals (Sweden)

Valery V Umnov

2016-06-01

Full Text Available Aim. To evaluate the results of a modified technique for extra-articular arthrodesis of the subtalar joint for patients with cerebral palsy with an ambulatory form of equine-planovalgus deformity of the foot. The mistakes and complications that occurred during treatment with this technique are discussed. Materials and methods. Between 2005 and 2015, this surgical method for performing arthrodesis of the subtalar joint, was performed on 544 patients (989 feet between 4 and 15 years old. Correction of equinus contracture was performed using Achilles tendon plasty or dissection of the tendon of the gastrocnemius muscle. Abnormal muscle tone was reduced either by administering Dysport® in the calf muscle or by selective neurotomy of the tibial nerve. Results. Good results were achieved for 72% of cases, satisfactory for 23% of cases, and unsatisfactory for 5% of cases. Unsatisfactory results of treatment were associated with overvaluation of the degree of mobility of the deformity and with a number of technical and tactical mistakes. Conclusion. This analysis of mistakes and complications of extra-articular arthrodesis of the subtalar joint will allow surgeons to avoid these issues in the future and improve the quality of treatment for similar patients.
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.
Imbalanced decision hierarchy in addicts emerging from drug-hijacked dopamine spiraling circuit.

Directory of Open Access Journals (Sweden)

Mehdi Keramati

Full Text Available Despite explicitly wanting to quit, long-term addicts find themselves powerless to resist drugs, despite knowing that drug-taking may be a harmful course of action. Such inconsistency between the explicit knowledge of negative consequences and the compulsive behavioral patterns represents a cognitive/behavioral conflict that is a central characteristic of addiction. Neurobiologically, differential cue-induced activity in distinct striatal subregions, as well as the dopamine connectivity spiraling from ventral striatal regions to the dorsal regions, play critical roles in compulsive drug seeking. However, the functional mechanism that integrates these neuropharmacological observations with the above-mentioned cognitive/behavioral conflict is unknown. Here we provide a formal computational explanation for the drug-induced cognitive inconsistency that is apparent in the addicts' "self-described mistake". We show that addictive drugs gradually produce a motivational bias toward drug-seeking at low-level habitual decision processes, despite the low abstract cognitive valuation of this behavior. This pathology emerges within the hierarchical reinforcement learning framework when chronic exposure to the drug pharmacologically produces pathologicaly persistent phasic dopamine signals. Thereby the drug hijacks the dopaminergic spirals that cascade the reinforcement signals down the ventro-dorsal cortico-striatal hierarchy. Neurobiologically, our theory accounts for rapid development of drug cue-elicited dopamine efflux in the ventral striatum and a delayed response in the dorsal striatum. Our theory also shows how this response pattern depends critically on the dopamine spiraling circuitry. Behaviorally, our framework explains gradual insensitivity of drug-seeking to drug-associated punishments, the blocking phenomenon for drug outcomes, and the persistent preference for drugs over natural rewards by addicts. The model suggests testable predictions and

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.
Galileo's mistake a new look at the epic confrontation between galileo and the church

CERN Document Server

Rowland, Wade

2011-01-01

The modern understanding of the notorious 1633 trial of Galileo is that of Science and Reason persecuted by Ignorance and Superstition-of Galileo as a lonely, courageous freethinker oppressed by a reactionary and anti-intellectual institution fearful of losing its power and influence. But is this an accurate picture? In his provocative reexamination of one of the turning points in the history of science and thought, Wade Rowland contends that the dispute concerned an infinitely more profound question: What is truth and how can we know it? Rowland demonstrates that Galileo's mistak
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.
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.
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.
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.
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.
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.
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.
About errors, inaccuracies and sterotypes: Mistakes in media coverage - and how to reduce them

Science.gov (United States)

Scherzler, D.

2010-12-01

The main complaint made by scientists about the work of journalists is that there are mistakes and inaccuracies in TV programmes, radio or the print media. This seems to be an important reason why too few researchers want to deal with journalists. Such scientists regularly discover omissions, errors, exaggerations, distortions, stereotypes and sensationalism in the media. Surveys carried out on so-called accuracy research seem to concede this point as well. Errors frequently occur in journalism, and it is the task of the editorial offices to work very hard in order to keep the number of errors as low as possible. On closer inspection some errors, however, turn out to be simplifications and omissions. Both are obligatory in journalism and do not automatically cause factual errors. This paper examines the different kinds of mistakes and misleading information that scientists observe in the mass media. By giving a view from inside the mass media it tries to explain how errors come to exist in the journalist’s working routines. It outlines that the criteria of journalistic quality which scientists and science journalists apply differ substantially. The expectation of many scientists is that good science journalism passes on their results to the public in as “unadulterated” a form as possible. The author suggests, however, that quality criteria for journalism cannot be derived from how true to detail and how comprehensively it reports on science, nor to what extent the journalistic presentation is “correct” in the eyes of the researcher. The paper suggests in its main part that scientists who are contacted or interviewed by the mass media should not accept that errors just happen. On the contrary, they can do a lot to help preventing mistakes that might occur in the journalistic product. The author proposes several strategies how scientists and press information officers could identify possible errors, stereotypes and exaggeration by journalists in advance and
Identification of mistakes and their correction by a small group discussion as a revision exercise at the end of a teaching module in biochemistry.

Science.gov (United States)

Bobby, Zachariah; Nandeesha, H; Sridhar, M G; Soundravally, R; Setiya, Sajita; Babu, M Sathish; Niranjan, G

2014-01-01

Graduate medical students often get less opportunity for clarifying their doubts and to reinforce their concepts after lecture classes. The Medical Council of India (MCI) encourages group discussions among students. We evaluated the effect of identifying mistakes in a given set of wrong statements and their correction by a small group discussion by graduate medical students as a revision exercise. At the end of a module, a pre-test consisting of multiple-choice questions (MCQs) was conducted. Later, a set of incorrect statements related to the topic was given to the students and they were asked to identify the mistakes and correct them in a small group discussion. The effects on low, medium and high achievers were evaluated by a post-test and delayed post-tests with the same set of MCQs. The mean post-test marks were significantly higher among all the three groups compared to the pre-test marks. The gain from the small group discussion was equal among low, medium and high achievers. The gain from the exercise was retained among low, medium and high achievers after 15 days. Identification of mistakes in statements and their correction by a small group discussion is an effective, but unconventional revision exercise in biochemistry. Copyright 2014, NMJI.
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.
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.

Science.gov (United States)

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.

Science.gov (United States)

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.

Science.gov (United States)

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.
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.
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.
Risk management of new product development process

OpenAIRE

Aleixo, Gonçalo Granja

2009-01-01

Dissertation submitted to Faculdade de Ciências e Tecnologia of Universidade Nova de Lisboa for the achievement of Integrated Master´s degree in Industrial Management Engineering Winners in today´s global changing environment, are those who continuously pursuit innovations in order to guarantee their sustainability. If in the presence of a certain environment many enterprises makes enormous mistakes, in an uncertain environment as the development of innovations, these mistakes will be mult...
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.
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.

Sensory illusions: Common mistakes in physics regarding sound, light and radio waves

Science.gov (United States)

Briles, T. M.; Tabor-Morris, A. E.

2013-03-01

Optical illusions are well known as effects that we see that are not representative of reality. Sensory illusions are similar but can involve other senses than sight, such as hearing or touch. One mistake commonly noted among instructors is that students often mis-identify radio signals as sound waves and not as part of the electromagnetic spectrum. A survey of physics students from multiple high schools highlights the frequency of this common misconception, as well as other nuances on this misunderstanding. Many students appear to conclude that, since they experience radio broadcasts as sound, then sound waves are the actual transmission of radio signals and not, as is actually true, a representation of those waves as produced by the translator box, the radio. Steps to help students identify and correct sensory illusion misconceptions are discussed. School of Education
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
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...
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 ...
Development of a web-based tool for automated processing and cataloging of a unique combinatorial drug screen.

Science.gov (United States)

Dalecki, Alex G; Wolschendorf, Frank

2016-07-01

Facing totally resistant bacteria, traditional drug discovery efforts have proven to be of limited use in replenishing our depleted arsenal of therapeutic antibiotics. Recently, the natural anti-bacterial properties of metal ions in synergy with metal-coordinating ligands have shown potential for generating new molecule candidates with potential therapeutic downstream applications. We recently developed a novel combinatorial screening approach to identify compounds with copper-dependent anti-bacterial properties. Through a parallel screening technique, the assay distinguishes between copper-dependent and independent activities against Mycobacterium tuberculosis with hits being defined as compounds with copper-dependent activities. These activities must then be linked to a compound master list to process and analyze the data and to identify the hit molecules, a labor intensive and mistake-prone analysis. Here, we describe a software program built to automate this analysis in order to streamline our workflow significantly. We conducted a small, 1440 compound screen against M. tuberculosis and used it as an example framework to build and optimize the software. Though specifically adapted to our own needs, it can be readily expanded for any small- to medium-throughput screening effort, parallel or conventional. Further, by virtue of the underlying Linux server, it can be easily adapted for chemoinformatic analysis of screens through packages such as OpenBabel. Overall, this setup represents an easy-to-use solution for streamlining processing and analysis of biological screening data, as well as offering a scaffold for ready functionality expansion. Copyright © 2016 Elsevier B.V. All rights reserved.
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.
WHY CANT WE LEARN FROM OUR MISTAKES LEARN THE LESSON TELL THE STORY

International Nuclear Information System (INIS)

LANGSTAFF, D.C.

2005-01-01

Tell the story well and people can learn from the lesson. The United States Department of Energy (DOE) Office of Environmental Management (EM) and its contractors are pursuing environmental remediation at the Hanford Site. This endeavor has been underway for a number of years, both at Hanford and at other sites across the DOE complex. Independently, the occurrence of two fatalities on two Sites at opposite ends of the country within two weeks raised the question, ''What is going on in the Field?'' Corporate EM management communicated directly with Field Office Managers to answer the question. As a result of this intense interest and focused communication, EM identified four areas that need additional exploration. One of those is, ''EM's ability to learn from its mistakes.'' The need to cultivate the ability to learn from our mistakes is not unique to DOE. A quick review of EM Lessons Learned reports shows that most of the reports in the EM system originate at the sites with the largest budgets doing the most work. Not surprising. A second look, however, reveals that many reports are repetitive, that many people might consider many reports trivial, and that reports on some of the more significant events sometimes take a long time to get distributed across the DOE Complex. Spot checks of event reports revealed frequent identification of symptoms rather than root causes. With a high percentage of identified root causes in the questionable category, it is highly unlikely that the real root causes of many events are being corrected, thus leading to recurrences of events. To learn the lesson from an event, people need to be aware of the root causes of the event. Someone has to tell a story the reader can learn from, i.e., include all the information needed to understand what happened and why it happened. Most importantly, they need to understand the lesson to be learned
The danger of fixed drug combinations.

Science.gov (United States)

Herxheimer, H

1975-07-01

After the second world war a number of pharmaceutical firms which were not able to create new therapeutic substances by their own research, put a great number of fixed drug combinations on the market. Their number quickly increased, as the efficiency of these compounds required no legal proof and as, with appropriate propaganda, large profits could be earned. The number of firms doing this sort of production also increased, and in West Germany, for instance, more than 3/4 of all drugs on the official list are now fixed combinations. Our task is, therefore, to ask for regulations which limit fixed combinations to such preparation the efficiency of which has been shown and whose advantages more than outweigh their disadvantages. The advantages of these preparations are convenience to the patient, avoidance of potential mistakes made possible by too many drugs given on the same day and, perhaps, lower prices. The disadvantages are: 1. The individual optimum dose for a patient cannot be achieved, because in case of a change of dosis all components are changed. 2. Different components may have different duration of action. 3. Different components may have a different bioavailability. 4. Different components may interact. 5. Some components may create tolerance, others not. In many cases fixed combinations have been used to make drugs with poor efficiency financially viable by combining them with very efficient drugs. The existence of thousands of fixed combinations makes the drug market indiscernible and useless. They obscure the relatively few essential drugs and make it difficult for the doctor to find his way amongst the mass of offered medicaments. Few fixed combinations are justifiable. These are well known and they should be permitted as before. All others should be banned until it has been shown that their advantages are greater than their disadvantages.
[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.
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...
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
Medication errors in anaesthetic practice: A report of two cases and ...

African Journals Online (AJOL)

Background: Mistakes in the identification and administration of drugs may be fatal. This is especially so in the practice of anaesthesia. This is a report of 2 cases of near fatality due to mistakes in drug administration from look-alike medications. Objective: To highlight the significance of medication errors in our practice and ...
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.
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.
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.
Drug-diagnostics co-development in oncology

Directory of Open Access Journals (Sweden)

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.
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
When Mistake Rolls up Its Sleeves and Becomes Slang

Directory of Open Access Journals (Sweden)

Elisa Mattiello

2017-04-01

Full Text Available This study explores the semantic area of ‘mistake’ in contemporary English, with a special focus on slang in general English dictionaries (e.g. OED and dictionaries of modern slang (e.g. Green 2010/2016, Urban Dictionary 1999-2016. While the ‘mistake’ area already abounds in standard lexical items concerning misconceptions, misunderstandings, errors of judgement, gross mistakes, or even blunders, the negative connotations that it entails are even more evident in slang. Slang items designating ‘mistake’ range from regular formations, such as the compound party foul or the derived word floater, to extra-grammatical words, such as clippings (e.g. boob ← booby, acronyms (e.g. snafu ← situation normal, all fucked up, reduplicatives (e.g. boo-boo, and even to rhyming slang (e.g. penny banger for ‘clanger’ (Mattiello 2008, 2013. The origin of these items is often specialised or restricted to small speech communities – e.g. military world, theatre, students’ campus – but their use has extended to common language nowadays. The study both investigates the morphological peculiarities of slang items of the ‘mistake’ area, and shows how they are often tinged with offensiveness, vulgarity, and rudeness due to their semantic associations to negative, vulgar or abusive standard meanings. Diachronically, the emphasis is on the twentieth and twenty-first centuries.
Effectiveness of the different methods of inhalation drugs delivery in children with bronchial asthma

Directory of Open Access Journals (Sweden)

S.M. Nedelska

2017-02-01

Full Text Available Aim of the work — to evaluate the effectiveness of inhalation technique when using different types of inhalers (dry powder inhalers — Turbuhaler, Diskus, metered-dose inhalers, breath-actuated inhalers — Easyhaler. Materials and methods. 45 patients aged 6–17 years underwent the evaluation of inhalation technique accuracy with the use of In-Check-Dial — apparatus, which imitates the airway resistance that should be overcome during inspiration through different inhaler types, and measure inspiration velocity. Incidence of mistakes was studied in different age groups. Results. 80 % of children aged 6–7 years made mistakes while using Turbuhaler, 73.3 % — metered-dose inhaler, 60 % — Easyhaler. There were no mistakes in patients making inhalation by means of Diskhaler. 100 % of children aged 12–14 years incorrectly used metered-dose inhaler. Easyhaler was incorrectly used in 66.6 % of cases, Diskhaler — in 26.6 %. Among elder group, incidence of mistakes when making inhalations through Turbuhaler was lower — 40 % in 12–14-year-old group and 25 % — in 15–17-year-old (р < 0.05. Children of 15–17 years old are able to use Turbuhaler and Diskus (mistakes in 33.3 and 46.6 %, respectively. At the same time, none of the patients have done the correct inhalation by means of metered-dose inhaler, 93.3 % of the patients have mistakes when using Easyhaler. Conclusions. The incidence of mistakes depends on the age and inhaler type and reaches 26–100 %. Minimal quantity of mistakes is seen for Diskus (in all age groups, maximal — for metered-dose inhaler. For the purpose of optimal inhaler choice in a child with bronchial asthma, it is advisable to measure the inspiratory flow with the help of In-Check-Dial before therapy administration.
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 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.
On the Terminological Mistake in the Biography of the Astrakhan Cossack Regiment Commander, Major General P.S. Popov

OpenAIRE

Astafyev Evgeniy V.

2016-01-01

On the basis of authentic documents of the late 18th – early 19th centuries, stored in federal and regional archives of Russia, as well as published materials, the article analyzes the reasons of the terminological mistake made in the biography of commander of Astrakhan’s Cossack regiment, major general P.S. Popov, which had been reproduced in the scientific works for longer than 100 years. So well known person in the Lower Volga region, P.S. Popov was purposefully chosen as an object of hist...
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.
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.
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.
Guide to good practices for developing and conducting case studies: DOE handbook

Energy Technology Data Exchange (ETDEWEB)

NONE

1998-01-01

Learning from experience is often very costly to a facility in terms of injured personnel, damaged equipment, and wasted time. Learning from the experience gained at the facility and from industry can prevent repeating costly mistakes. This guide contains a method for learning from experience to prevent mistakes from occurring; that method is the case study. This guide describes how to develop and present case studies. This guide provides the instructional developer insight on the best kind of case study to use and includes examples of the various types of case studies.
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.
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.
6. Sınıf Öğrencilerinin Yazım Yanlışları Sıklığı ve Yazım Yanlışlarının Nedenlerine İlişkin Öğretmen Görüşleri 6th Grade Students’ Frequency Of Orthographic Mistakes And Teachers’ View About The Reasons For Orthographic Mistakes

Directory of Open Access Journals (Sweden)

Ahmet AKKAYA

2013-07-01

Full Text Available Orthographic mistake is one of the important elements leading to communication problems in written expression, and is generally one of the written expression acquisitions attempted to be taught students in educational institutions. This paper aims to reveal 6th grade students’ frequency of orthographic mistakes in their exam papers and to find out Turkish language teachers’ views about the reasons for orthographic mistakes. To do so, 336 exam papers of 6th grade students, collected both from two schools in Adıyaman city center and a village school, have been examined. 4142 orthographic mistakes have been identified. It is seen that students do not use symbols, acronyms/abbreviations, circumflex and proper nouns, do not miswrite complementary verb conjugations, and write accurately the words formed by such sound events as vowel shortening and epenthesis. It is identified that 6th grade students have made mistakes mostly in capitalization. Moreover, writing of consonants and vowels, syncopation, the conjunction of ‘de/da’ meaning ‘also’ in English are among other most repeated mistakes. In addition, the open-ended question “What are the 6th grade students’ reasons for orthographic mistakes?” has been asked to 16 Turkish language teachers so as to find out students’ reasons for orthographic mistakes. Content analysis method has been employed to analyze the acquired data. Those Turkish language teachers have responded that the 6th grade students’ reasons for orthographic mistakes are caused by lack of interest and attention, deficiency in basic language acquisition, lack of speaking in Turkish properly and efficiently outside school, exam types or teacher’s exam evaluations, and deficiency of either teachers or students in efficient utilization of sources about orthographic rules. Besides, this paper also suggests to identify the orthographic mistakes of students other than 6th grade, present the orthographic mistakes
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...
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.
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.
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.
Implementing diversity dozens of practical tips for leading the change effort, 12 classic mistakes most organizations make and how to avoid them

CERN Document Server

Loden, Marilyn

1996-01-01

This practical and provocative guide provides the strategies and tactics used by organizations committed to implementing diversity from the top down. Focusing on the necessity for a strategic change initiative, Loden discusses: how to position diversity initiatives for maximum buy-in and support; proven strategies for managing resistance to this important change; the 12 classic mistakes made when implementing diversity initiatives - and how to avoid them.
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...
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...
Gigabit ATM: another technical mistake?

Science.gov (United States)

Christ, Paul

1998-09-01

, many of the elements mentioned above are now being presented by standard 'Gigabit Ethernet and Gigabit ATM -- friends or foes' conferences. In- depth analyses are given concerning the canonical elements of such a setting: legacy, new use requirements, manageability, security LAN-WAN, architectures, standards, technologies and products, complexity, evolution-transition strategies, manufacturers, player organizations etc. Often in such conferences, Fiber Channel, being one of Gigabit Ethernet's physical media, is presented as the only other Gigabit LAN technology. In an attempt to sum up: Given the present state of ATM deployment measured in terms of functionalities and sophistication, after ten years of CCCITT/ITU and almost as many years of ATM Forum effort, does the question still being asked now represent the answer -- ATM is or was a mistake there some elements still missing? Here's a technical and a political example:
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.
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.
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.
Comparação dos erros ortográficos de alunos com desempenho inferior em escrita e alunos com desempenho médio nesta habilidade A comparison study of the orthographics mistakes of students with inferior and students with average writing performance

Directory of Open Access Journals (Sweden)

Patrícia Aparecida Zuanetti

2008-01-01

Full Text Available OBJETIVO: O objetivo deste estudo foi comparar se crianças com baixo desempenho em escrita cometem mais erros ortográficos que crianças da mesma série com desempenho satisfatório nesta tarefa, e quais os tipos de erros ortográficos mais freqüentes. MÉTODOS: Participaram deste estudo 24 crianças da 2ª série do ensino fundamental de uma escola pública, avaliadas individualmente. O teste aplicado foi o subteste de escrita do Teste de Desempenho Escolar, composto por 34 palavras que são ditadas aos alunos. RESULTADOS: Os alunos com desempenho inferior em escrita cometeram significativamente mais erros ortográficos que o grupo com desempenho satisfatório. Os erros que tiveram diferença estatisticamente significativa entre os dois grupos foram erros do tipo hipercorreção, dificuldade com marcadores de nasalização, relação fonografêmica irregular, omissões de sílabas e erros por troca de letras. Também houve correlação fortemente negativa entre erros ortográficos e desempenho em escrita. CONCLUSÕES: Quanto melhor o desempenho em escrita, menos erros ortográficos possui a elaboração gráfica do aluno. Os erros mais freqüentes no grupo com desempenho baixo, que os difere do outro grupo, dizem respeito aos erros de relação fonografêmica irregular, omissões de sílabas, dificuldade no uso de marcadores de nasalização, hipercorreção e erros por troca de letras. Com o avanço da capacidade de aprendizagem da criança, o desempenho ortográfico tende a melhorar.PURPOSE: The aim of this study was to verify whether children with poor writing performances make more orthographic mistakes than children of the same school grade with average performances, and what are the most frequent types of orthographic mistakes. METHODS: Twenty-four second grade children from a public school were individually analyzed in this study. The test used was the writing subtest of the School Performance Test, which is composed by 34 words that
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.
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

In the wake of a possible mistake: Security motivation, checking behavior, and OCD.

Science.gov (United States)

Hinds, Andrea L; Woody, Erik Z; Schmidt, Louis A; Van Ameringen, Michael; Szechtman, Henry

2015-12-01

In previous experiments, OCD washers did not differ significantly from controls in their initial level of activation in response to the potential threat of contamination; however, they were less able to reduce their activation by engaging in hand-washing, suggesting that the key problem in OCD is a faulty stopping mechanism. The main objectives of the present experiments were to develop a similar experimental paradigm for investigating checking behavior, and to use it to test the hypothesis that a faulty stopping mechanism also underlies OCD checking. Participants sorted pills under the guise of beta testing a new medication system and then were given suggestions of the possibility of having made mistakes with potentially serious consequences. Later, participants engaged in a 90-s checking period and an unlimited period of checking. At baseline and three other times during the experiment, security motivation was measured with respiratory sinus arrhythmia (RSA) and subjective ratings of confidence. Experiment 1 established the parameters of the paradigm in non-patient participants, and Experiment 2 contrasted OCD checkers with OCD washers and non-patients. Results for both subjective and physiological measures of security motivation closely replicated previous findings for washing behavior. Groups did not differ significantly in initial activation, but the OCD checkers were unable to reduce their activation by engaging in period of checking that was ample for returning controls to baseline. The sample size for the patient groups was modest. These results lend further support to the security-motivation theory of OCD. Copyright © 2015 Elsevier Ltd. All rights reserved.
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
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.
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.
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...
Retracted publications in the drug literature.

Science.gov (United States)

Samp, Jennifer C; Schumock, Glen T; Pickard, A Simon

2012-07-01

Recent studies have suggested an increase in the number of retracted scientific publications. It is unclear how broadly the issue of misleading and fraudulent publications pertains to retractions of drug therapy studies. Therefore, we sought to determine the trends and factors associated with retracted publications in drug therapy literature. A PubMed search was conducted to identify retracted drug therapy articles published from 2000-2011. Articles were grouped according to reason for retraction, which was classified as scientific misconduct or error. Scientific misconduct was further divided into data fabrication, data falsification, questions of data veracity, unethical author conduct, and plagiarism. Error was defined as duplicate publication, scientific mistake, journal error, or unstated reasons. Additional data were extracted from the retracted articles, including type of article, funding source, author information, therapeutic area, and retraction issue. A total of 742 retractions were identified from 2000-2011 in the general biomedical literature, and 102 drug studies met our inclusion criteria. Of these, 73 articles (72%) were retracted for a reason classified as scientific misconduct, whereas 29 articles (28%) were retracted for error. Among the 73 articles classified as scientific misconduct, those classified as unethical author conduct (32 articles [44%]) and data fabrication (24 articles [33%]) constituted the majority. The median time from publication of the original article to retraction was 31 months (range 1-130). Fifty percent of retracted articles did not state a funding source, whereas pharmaceutical manufacturer funding accounted for only 13 articles (13%) analyzed. Many retractions were due to repeat offenses by a small number of authors, with nearly 40% of the retracted studies associated with two individuals. We found that a greater proportion of drug therapy articles were retracted for reasons of misconduct and fraud compared with other
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.
Medication competency of nurses according to theoretical and drug calculation online exams: A descriptive correlational study.

Science.gov (United States)

Sneck, Sami; Saarnio, Reetta; Isola, Arja; Boigu, Risto

2016-01-01

Medication administration is an important task of registered nurses. According to previous studies, nurses lack theoretical knowledge and drug calculation skills and knowledge-based mistakes do occur in clinical practice. Finnish health care organizations started to develop a systematic verification processes for medication competence at the end of the last decade. No studies have yet been made of nurses' theoretical knowledge and drug calculation skills according to these online exams. The aim of this study was to describe the medication competence of Finnish nurses according to theoretical and drug calculation exams. A descriptive correlation design was adopted. Participants and settings All nurses who participated in the online exam in three Finnish hospitals between 1.1.2009 and 31.05.2014 were selected to the study (n=2479). Quantitative methods like Pearson's chi-squared tests, analysis of variance (ANOVA) with post hoc Tukey tests and Pearson's correlation coefficient were used to test the existence of relationships between dependent and independent variables. The majority of nurses mastered the theoretical knowledge needed in medication administration, but 5% of the nurses struggled with passing the drug calculation exam. Theoretical knowledge and drug calculation skills were better in acute care units than in the other units and younger nurses achieved better results in both exams than their older colleagues. The differences found in this study were statistically significant, but not high. Nevertheless, even the tiniest deficiency in theoretical knowledge and drug calculation skills should be focused on. It is important to identify the nurses who struggle in the exams and to plan targeted educational interventions for supporting them. The next step is to study if verification of medication competence has an effect on patient safety. Copyright © 2015 Elsevier Ltd. All rights reserved.
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
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.
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
Factors that motivate software developers in Nigerian's software ...

African Journals Online (AJOL)

It was also observed those courtesy, good reward systems, regular training, recognition, tolerance of mistakes and good leadership were high motivators of software developers. Keywords: Software developers, information technology, project managers, Nigeria International Journal of Natural and Applied Sciences, 6(4): ...
Phenotypic screening approaches to develop Aurora kinase inhibitors: Drug Discovery perspectives

Directory of Open Access Journals (Sweden)

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

Directory of Open Access Journals (Sweden)

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
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...
Personalized Medicine: Pharmacogenomics and Drug Development

Directory of Open Access Journals (Sweden)

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.
Blunder, Error, Mistake, Pitfall: Trawling the OED with the Help of the Historical Thesaurus

Directory of Open Access Journals (Sweden)

Jane Roberts

2017-04-01

Full Text Available The paper considers the lexis of error and examines its use across time in relation to the writing and spelling of English, to grammar and pronunciation. Discussion focuses first on the earliest records of notions of correctness in English language usage, from Ælfric forwards to the emergence of standard English, from the sixteenth century’s growing worries about copiousness and purity of diction to eighteenth-century concerns to prescribe and rule the language. The historical overview is complemented by consideration of the data drawn together by the Glasgow Historical Thesaurus project, its evidence taken from the Oxford English Dictionary and the Dictionary of Old English Corpus. For earlier centuries, there are by far fewer relevant citations, often buried within words wide in reference. With the help of the Historical Thesaurus we drill down to view how views of language mistakes and errors have changed over the centuries of the recorded history of English.
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.
Thirty Years of Orphan Drug Legislation and the Development of Drugs to Treat Rare Seizure Conditions: A Cross Sectional Analysis.

Science.gov (United States)

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

Directory of Open Access Journals (Sweden)

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.
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
Patient safety: numerical skills and drug calculation abilities of nursing students and registered nurses.

Science.gov (United States)

McMullan, Miriam; Jones, Ray; Lea, Susan

2010-04-01

This paper is a report of a correlational study of the relations of age, status, experience and drug calculation ability to numerical ability of nursing students and Registered Nurses. Competent numerical and drug calculation skills are essential for nurses as mistakes can put patients' lives at risk. A cross-sectional study was carried out in 2006 in one United Kingdom university. Validated numerical and drug calculation tests were given to 229 second year nursing students and 44 Registered Nurses attending a non-medical prescribing programme. The numeracy test was failed by 55% of students and 45% of Registered Nurses, while 92% of students and 89% of nurses failed the drug calculation test. Independent of status or experience, older participants (> or = 35 years) were statistically significantly more able to perform numerical calculations. There was no statistically significant difference between nursing students and Registered Nurses in their overall drug calculation ability, but nurses were statistically significantly more able than students to perform basic numerical calculations and calculations for solids, oral liquids and injections. Both nursing students and Registered Nurses were statistically significantly more able to perform calculations for solids, liquid oral and injections than calculations for drug percentages, drip and infusion rates. To prevent deskilling, Registered Nurses should continue to practise and refresh all the different types of drug calculations as often as possible with regular (self)-testing of their ability. Time should be set aside in curricula for nursing students to learn how to perform basic numerical and drug calculations. This learning should be reinforced through regular practice and assessment.
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.
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.
A peek into the drug development scenario of endometriosis - A systematic review.

Science.gov (United States)

Goenka, Luxitaa; George, Melvin; Sen, Maitrayee

2017-06-01

Endometriosis is a gynaecological disease that is characterised by the presence of endometrium like tissue-epithelium and stroma that develops outside the uterine cavity, which is responsible for pelvic pain and infertility. Even though several medical therapies exist for the treatment of endometriosis, each of the drug class has its own limitations such as cost of treatment, side-effects and its short-term effect on the symptoms of endometriosis. In this review, we have attempted to summarize the current status and challenges of drug development for endometriosis. A systematic review was done and all the RCTs were selected from the identified hits. We included studies that explored the usage of therapeutic drugs on endometriosis patients from inception till November 2016. The search term used was 'Endometriosis' using PubMed and Clinicaltrials.gov. For the final analysis, 60 articles were analyzed and we identified the newly emerging drug therapies for endometriosis treatment and have briefed their current status and challenges in drug development for endometriosis. The quality of the selected studies was assessed based on the degree of bias. The current classes of drugs that have shown promising therapeutic results include Gonadotropin- releasing hormone (GnRH) antagonists, aromatase inhibitors (AI), and selective progesterone and estrogen receptor modulators, dopamine receptor-2-agonists and statins. The drugs that failed midway during development include tanezumab, rosiglitazone, infliximab, pentoxifylline, telapristone acetate, asoprisnil and raloxifene. From the literature review, it appears that the most promising molecules for the treatment of endometriosis in the near future include elagolix, mifepristone, TAK-385, KLH-2109 and ASP1707 and cabergoline. It remains to be seen if these molecules would succeed large phase 3 clinical trials and overcome the regulatory hurdles to become an essential tool in the gynaecologist's armamentarium against endometriosis
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
Radiology errors: are we learning from our mistakes?

International Nuclear Information System (INIS)

Mankad, K.; Hoey, E.T.D.; Jones, J.B.; Tirukonda, P.; Smith, J.T.

2009-01-01

Aim: To question practising radiologists and radiology trainees at a large international meeting in an attempt to survey individuals about error reporting. Materials and methods: Radiologists attending the 2007 Radiological Society of North America (RSNA) annual meeting were approached to fill in a written questionnaire. Participants were questioned as to their grade, country in which they practised, and subspecialty interest. They were asked whether they kept a personal log of their errors (with an error defined as 'a mistake that has management implications for the patient'), how many errors they had made in the preceding 12 months, and the types of errors that had occurred. They were also asked whether their local department held regular discrepancy/errors meetings, how many they had attended in the preceding 12 months, and the perceived atmosphere at these meetings (on a qualitative scale). Results: A total of 301 radiologists with a wide range of specialty interests from 32 countries agreed to take part. One hundred and sixty-six of 301 (55%) of responders were consultant/attending grade. One hundred and thirty-five of 301 (45%) were residents/fellows. Fifty-nine of 301 (20%) of responders kept a personal record of their errors. The number of errors made per person per year ranged from none (2%) to 16 or more (7%). The majority (91%) reported making between one and 15 errors/year. Overcalls (40%), under-calls (25%), and interpretation error (15%) were the predominant error types. One hundred and seventy-eight of 301 (59%) of participants stated that their department held regular errors meeting. One hundred and twenty-seven of 301 (42%) had attended three or more meetings in the preceding year. The majority (55%) who had attended errors meetings described the atmosphere as 'educational.' Only a small minority (2%) described the atmosphere as 'poor' meaning non-educational and/or blameful. Conclusion: Despite the undeniable importance of learning from errors
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.
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.
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 ...
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.)

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.
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.
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
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...
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.
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.
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.
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.
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
Growing pains : how drug testing keeps workers and assets safe in a booming oil patch

Energy Technology Data Exchange (ETDEWEB)

Paulgaard, T.S.

2006-06-15

Drug abuse has become a subject of concern to the oil and gas industry, where mistakes in the operation of large machines can result in injury, death and the loss of millions of dollars. Pre-employment urine tests are becoming standard procedure in the oil field. Many supervisors refuse to let employees start work without a clear test. Urine samples are tested for the presence of cannabis, cocaine, opiates, amphetamines and phencyclidine. When a worker is injured or killed on the job, or after an uncommon error that causes significant damage, all parties involved are tested as soon as possible and a receipt of the results are expedited. The Alberta Human Rights and Citizenship Commission is now addressing the issue of drug testing, and has ascertained that drug and alcohol testing are only allowable in certain circumstances, and that it is discriminatory to test potential or existing employees for drug and alcohol use if the testing is not reasonable or justifiable. They have also suggested that there is a duty to accommodate persons with disabilities in the workplace. Drug and alcohol dependency fall within the meaning of disabled. Under the Construction Owner's Association of Alberta's Canadian Model for a Safe Workplace, testing must work in concert with treatment. Current employees are directed to seek help via an employee assistant plan. Workers and supervisors report that drug use is rampant in work camps. Industry-wide, fail rates for those who take part in drug testing are quoted by experts as ranging from between 2 to 14 per cent. 2 figs.
Growing pains : how drug testing keeps workers and assets safe in a booming oil patch

Energy Technology Data Exchange (ETDEWEB)

Paulgaard, T S

2006-06-15

Drug abuse has become a subject of concern to the oil and gas industry, where mistakes in the operation of large machines can result in injury, death and the loss of millions of dollars. Pre-employment urine tests are becoming standard procedure in the oil field. Many supervisors refuse to let employees start work without a clear test. Urine samples are tested for the presence of cannabis, cocaine, opiates, amphetamines and phencyclidine. When a worker is injured or killed on the job, or after an uncommon error that causes significant damage, all parties involved are tested as soon as possible and a receipt of the results are expedited. The Alberta Human Rights and Citizenship Commission is now addressing the issue of drug testing, and has ascertained that drug and alcohol testing are only allowable in certain circumstances, and that it is discriminatory to test potential or existing employees for drug and alcohol use if the testing is not reasonable or justifiable. They have also suggested that there is a duty to accommodate persons with disabilities in the workplace. Drug and alcohol dependency fall within the meaning of disabled. Under the Construction Owner's Association of Alberta's Canadian Model for a Safe Workplace, testing must work in concert with treatment. Current employees are directed to seek help via an employee assistant plan. Workers and supervisors report that drug use is rampant in work camps. Industry-wide, fail rates for those who take part in drug testing are quoted by experts as ranging from between 2 to 14 per cent. 2 figs.

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...
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.
Common characteristics of open source software development and applicability for drug discovery: a systematic review.

Science.gov (United States)

Ardal, Christine; Alstadsæter, Annette; Røttingen, John-Arne

2011-09-28

Innovation through an open source model has proven to be successful for software development. This success has led many to speculate if open source can be applied to other industries with similar success. We attempt to provide an understanding of open source software development characteristics for researchers, business leaders and government officials who may be interested in utilizing open source innovation in other contexts and with an emphasis on drug discovery. A systematic review was performed by searching relevant, multidisciplinary databases to extract empirical research regarding the common characteristics and barriers of initiating and maintaining an open source software development project. Common characteristics to open source software development pertinent to open source drug discovery were extracted. The characteristics were then grouped into the areas of participant attraction, management of volunteers, control mechanisms, legal framework and physical constraints. Lastly, their applicability to drug discovery was examined. We believe that the open source model is viable for drug discovery, although it is unlikely that it will exactly follow the form used in software development. Hybrids will likely develop that suit the unique characteristics of drug discovery. We suggest potential motivations for organizations to join an open source drug discovery project. We also examine specific differences between software and medicines, specifically how the need for laboratories and physical goods will impact the model as well as the effect of patents.
Optimization and Simulation in Drug Development - Review and Analysis

DEFF Research Database (Denmark)

Schjødt-Eriksen, Jens; Clausen, Jens

2003-01-01

We give a review of pharmaceutical R&D and mathematical simulation and optimization methods used to support decision making within the pharmaceutical development process. The complex nature of drug development is pointed out through a description of the various phases of the pharmaceutical develo...... development process. A part of the paper is dedicated to the use of simulation techniques to support clinical trials. The paper ends with a section describing portfolio modelling methods in the context of the pharmaceutical industry....
Use of radiopharmaceuticals in the development of drug delivery systems

International Nuclear Information System (INIS)

Frier, M.

1997-01-01

Full text. Nuclear medicine imaging techniques have great potential in the study of the behaviour of drug formulations and drug delivery systems in human subjects. No other technique can locate so precisely the site of disintegration of a tablet in the Gl tract, the depth of penetration of a nebulized solution into the lung, or the residence time of a drug on the cornea. By using the gamma camera to image the in vivo distribution of pharmaceutical formulations radio labelled with a suitable gamma emitting radionuclide, images may be used to quantify the biodistribution, release and kinetics of drug formulations and delivery from novel carrier systems and devices. Radionuclide tracer techniques allow correlation between the observed pharmacological effects and the precise site of delivery. The strength of the technique lies in the quantitative nature of radionuclide images. Example will be shown of studies which examine the rate of transit of orally-administered formulations through the GI tract, as well as describing the development of devices for specific targeting of drugs to the colon. Data will also demonstrate the effectiveness of devices such as spacers in pulmonary drug delivery, in both normal volunteers, and in asthmatic subjects. Such studies not only provide data on the nature and characteristics of a product, such as reliability and reproducibility but, may also be used in submission to Regulatory Authorities in product registration dossiers
The role of globalization in drug development and access to orphan drugs: orphan drug legislation in the US/EU and in Latin America [v1; ref status: indexed, http://f1000r.es/3ix

Directory of Open Access Journals (Sweden)

Renée J.G. Arnold

2015-02-01

Full Text Available 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.
The Rise, Fall and Subsequent Triumph of Thalidomide: Lessons Learned in Drug Development

Science.gov (United States)

Rehman, Waqas; Arfons, Lisa M.; Lazarus, Hillard M.

2011-01-01

Perhaps no other drug in modern medicine rivals the dramatic revitalization of thalidomide. Originally marketed as a sedative, thalidomide gained immense popularity worldwide among pregnant women because of its effective anti-emetic properties in morning sickness. Mounting evidence of human teratogenicity marked a dramatic fall from grace and led to widespread social, legal and economic ramifications. Despite its tragic past thalidomide emerged several decades later as a novel and highly effective agent in the treatment of various inflammatory and malignant diseases. In 2006 thalidomide completed its remarkable renaissance becoming the first new agent in over a decade to gain approval for the treatment of plasma cell myeloma. The catastrophic collapse yet subsequent revival of thalidomide provides important lessons in drug development. Never entirely abandoned by the medical community, thalidomide resurfaced as an important drug once the mechanisms of action were further studied and better understood. Ongoing research and development of related drugs such as lenalidomide now represent a class of irreplaceable drugs in hematological malignancies. Further, the tragedies associated with this agent stimulated the legislation which revamped the FDA regulatory process, expanded patient informed consent procedures and mandated more transparency from drug manufacturers. Finally, we review recent clinical trials summarizing selected medical indications for thalidomide with an emphasis on hematologic malignancies. Herein, we provide a historic perspective regarding the up-and-down development of thalidomide. Using PubMed databases we conducted searches using thalidomide and associated keywords highlighting pharmacology, mechanisms of action, and clinical uses. PMID:23556097
Developing and promoting an intranet site for a drug information service.

Science.gov (United States)

Costerison, Emily C; Graham, Angie S

2008-04-01

The development and promotion of a drug information service (DIS) intranet site are described. Stanford Hospital and Clinics (SHC) is an acute and tertiary care facility with 613 licensed inpatient beds and 48 outpatient clinics. A DIS intranet site was developed to allow better accessibility to pharmacy forms and products (e.g., drug shortage list, reference guides) and to reduce repetitive requests to the DIS. The goal was to continue to provide information to SHC health care providers but allow the drug information specialist to focus on answering clinical questions. The intranet site was completed over a four-month period. The intranet site was divided into seven webpages: DIS overview, pharmacy and therapeutics, frequently asked questions, quick drug reference guide, ask the pharmacist, drug information resources, and referral center. The preparation for and implementation of the promotional phase took approximately two months. Promotional strategies included the creation and dissemination of brochures and stickers. The intranet site went live on January 1, 2007, and the advertising campaign began one month later. The utility of the site was measured for five months by tracking the number of visits to the site, the number of visits to each webpage, and the number of downloaded files. Request volume, caller affiliation, and question types received by the DIS call center were also recorded. Establishing a DIS intranet site required a considerable time investment and a willingness to work with existing infrastructures, such as the marketing and communications department and Web marketing staff.
Research Ethics and Commercial Drug Development: When Integrity Threatens Profitability

Directory of Open Access Journals (Sweden)

Bélisle Pipon, Jean-Christophe

2016-05-01

Full Text Available This case, based on personal experiences and on those found in the literature, highlights the delicate tension faced by drug development companies having to balance research integrity and their profitability.
The development and maintenance of drug addiction.

Science.gov (United States)

Wise, Roy A; Koob, George F

2014-01-01

What is the defining property of addiction? We dust off a several-decades-long debate about the relative importance of two forms of reinforcement—positive reinforcement, subjectively linked to drug-induced euphoria, and negative reinforcement, subjectively linked to the alleviation of pain—both of which figure importantly in addiction theory; each of these forms has dominated addiction theory in its time. We agree that addiction begins with the formation of habits through positive reinforcement and that drug-opposite physiological responses often establish the conditions for negative reinforcement to come into play at a time when tolerance, in the form of increasing reward thresholds, appears to develop into positive reinforcement. Wise’s work has tended to focus on positive-reinforcement mechanisms that are important for establishing drug-seeking habits and reinstating them quickly after periods of abstinence, whereas Koob’s work has tended to focus on the negative-reinforcement mechanisms that become most obvious in the late stages of sustained addiction. While we tend to agree with each other about the early and late stages of addiction, we hold different views as to (i) the point between early and late at which the diagnosis of ‘addiction’ should be invoked, (ii) the relative importance of positive and negative reinforcement leading up to this transition, and (iii) the degree to which the specifics of negative reinforcement can be generalized across the range of addictive agents.
Adolescent neurocognitive development, self-regulation, and school-based drug use prevention.

Science.gov (United States)

Pokhrel, Pallav; Herzog, Thaddeus A; Black, David S; Zaman, Adnin; Riggs, Nathaniel R; Sussman, Steve

2013-06-01

Adolescence is marked by several key development-related changes, including neurocognitive changes. Cognitive abilities associated with self-regulation are not fully developed until late adolescence or early adulthood whereas tendencies to take risks and seek thrilling and novel experience seem to increase significantly throughout this phase, resulting in a discrepancy between increased susceptibility to poor regulation and lower ability to exercise self-control. Increased vulnerability to drug use initiation, maintenance, and dependence during adolescence may be explained based on this imbalance in the self-regulation system. In this paper, we highlight the relevance of schools as a setting for delivering adolescent drug use prevention programs that are based on recent findings from neuroscience concerning adolescent brain development. We discuss evidence from school-based as well as laboratory research that suggests that suitable training may improve adolescents' executive brain functions that underlie self-regulation abilities and, as a result, help prevent drug use and abuse. We note that considerable further research is needed in order (1) to determine that self-regulation training has effects at the neurocognitive level and (2) to effectively incorporate self-regulation training based on neuropsychological models into school-based programming.
Guidelines to PET measurements of the target occupancy in the brain for drug development

Energy Technology Data Exchange (ETDEWEB)

Takano, Akihiro; Varrone, Andrea; Gulyas, Balazs; Halldin, Christer [Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatric Research, Stockholm (Sweden); Salvadori, Piero [CNR Istituto di Fisiologia Clinica, Pisa (Italy); Gee, Antony [Kings College London, Department of Chemistry and Biology, Division of Imaging Sciences and Biomedical Engineering, London (United Kingdom); Windhorst, Albert; Lammertsma, Adriaan A. [VU University Medical Center, Department of Radiology and Nuclear Medicine, Amsterdam (Netherlands); Vercouillie, Johnny [Universite Francois Rabelais de Tours, UMR Inserm U930, Tours (France); Bormans, Guy [KU Leuven, Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, Leuven (Belgium)

2016-11-15

This guideline summarizes the current view of the European Association of Nuclear Medicine Drug Development Committee. The purpose of this guideline is to guarantee a high standard of PET studies that are aimed at measuring target occupancy in the brain within the framework of development programs of drugs that act within the central nervous system (CNS drugs). This guideline is intended to present information specifically adapted to European practice. The information provided should be applied within the context of local conditions and regulations. (orig.)
Stem cells: a model for screening, discovery and development of drugs.

Science.gov (United States)

Kitambi, Satish Srinivas; Chandrasekar, Gayathri

2011-01-01

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.
New paradigm for drug developments--from emerging market statistical perspective.

Science.gov (United States)

Quan, Hui; Chen, Xun; Zhang, Ji; Zhao, Peng-Liang

2013-11-01

Paradigm for new drug development has changed dramatically over the last decade. Even though new technology increases efficiency in many aspects, partially due to much more stringent regulatory requirements, it actually now takes longer and costs more to develop a new drug. To deal with challenge, some initiatives are taken by the pharmaceutical industry. These initiatives include exploring emerging markets, conducting global trials and building research and development centers in emerging markets to curb spending. It is particularly the current trend that major pharmaceutical companies offshore a part of their biostatistical support to China. In this paper, we first discuss the skill set for trial statisticians in the new era. We then elaborate on some of the approaches for acquiring statistical talent and capacity in general, particularly in emerging markets. We also make some recommendations on the use of the PDUFA strategy and collaborations among industry, health authority and academia from emerging market statistical perspective. © 2013.
Development and characterization of multifunctional nanoparticles for drug delivery to cancer cells

Science.gov (United States)

Nahire, Rahul Rajaram

Lipid and polymeric nanoparticles, although proven to be effective drug delivery systems compared to free drugs, have shown considerable limitations pertaining to their uptake and release at tumor sites. Spatial and temporal control over the delivery of anticancer drugs has always been challenge to drug delivery scientists. Here, we have developed and characterized multifunctional nanoparticles (liposomes and polymersomes) which are targeted specifically to cancer cells, and release their contents with tumor specific internal triggers. To enable these nanoparticles to be tracked in blood circulation, we have imparted them with echogenic characteristic. Echogenicity of nanoparticles is evaluated using ultrasound scattering and imaging experiments. Nanoparticles demonstrated effective release with internal triggers such as elevated levels of MMP-9 enzyme found in the extracellular matrix of tumor cells, decreased pH of lysosome, and differential concentration of reducing agents in cytosol of cancer cells. We have also successfully demonstrated the sensitivity of these particles towards ultrasound to further enhance the release with internal triggers. To ensure the selective uptake by folate receptor- overexpressing cancer cells, we decorated these nanoparticles with folic acid on their surface. Fluorescence microscopic images showed significantly higher uptake of folate-targeted nanoparticles by MCF-7 (breast cancer) and PANC-1 (pancreatic cancer) cells compared to particles without any targeting ligand on their surface. To demonstrate the effectiveness of these nanoparticles to carry the drugs inside and kill cancer cells, we encapsulated doxorubicin and/or gemcitabine employing the pH gradient method. Drug loaded nanoparticles showed significantly higher killing of the cancer cells compared to their non-targeted counterparts and free drugs. With further development, these nanoparticles certainly have potential to be used as a multifunctional nanocarriers for image
Clinical trials and late-stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014

Science.gov (United States)

Schneider, Lon S.; Mangialasche, Francesca; Andreasen, Niels; Feldman, Howard; Giacobini, Ezio; Jones, Roy; Mantua, Valentina; Mecocci, Patrizia; Pani, Luca; Winblad, Bengt; Kivipelto, Miia

2014-01-01

The modern era of drug development for Alzheimer’s disease began with the proposal of the cholinergic hypothesis of memory impairment and the 1984 research criteria for Alzheimer’s disease. Since then, despite the evaluation of numerous potential treatments in clinical trials, only four cholinesterase inhibitors and memantine have shown sufficient safety and efficacy to allow marketing approval at an international level. Although this is probably because the other drugs tested were ineffective, inadequate clinical development methods have also been blamed for the failures. Here we review the development of treatments for Alzheimer’s disease during the past 30 years, considering the drugs, potential targets, late-stage clinical trials, development methods, emerging use of biomarkers and evolution of regulatory considerations in order to summarize advances and anticipate future developments. We have considered late-stage Alzheimer’s disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta-analyses, methods, commentaries, position papers and guidelines. We then review the evolution of drugs in late clinical development, methods, biomarkers and regulatory issues. Although a range of small molecules and biological products against many targets have been investigated in clinical trials, the predominant drug targets have been the cholinergic system and the amyloid cascade. Trial methods have evolved incrementally: inclusion criteria have largely remained focused on mild to moderate Alzheimer’s disease criteria, recently extending to early or prodromal Alzheimer disease or ‘mild cognitive impairment due to Alzheimer’s disease’, for drugs considered to be disease modifying. The duration of trials has remained at 6 to 12 months for drugs intended to improve symptoms; 18- to 24-month trials have been established for drugs expected to attenuate clinical course. Cognitive performance, activities
PRELIMINARILY DEVELOPMENT OF A MOISTURE-ACTIVATED BIORESORBABLE POLYMERIC PLATFORM FOR DRUG DELIVERY

Directory of Open Access Journals (Sweden)

Renê O. do Couto

2015-08-01

Full Text Available Bioresorbable polymeric films were prepared by solvent casting using a tyrosine-derived polycarbonate and metronidazole (MDZ as the model drug at 2.5%, 5% and 10% (w/w. Drug loading did not affect the water uptake, drug release, polymer degradation or erosion profiles. All devices released approximately 85% (w/w of the drug within a 1.5 h period. This may be attributed to the rapid water uptake of the polymer. An increase in the water uptake correlated with a linear rate increase of the polymer degradation (0.968 ≤ R2 ≤ 0.999. Moreover, MDZ presented a remarkable plasticizing effect for the polymer and drug loading exerted a significant impact on the mechanical properties of the obtained films. The results obtained can be used to further the development of novel biocompatible and biodegradable polymeric platforms for the delivery of metronidazole and other drugs in a broad range of pharmaceutical applications.

Direct anti-atherosclerotic therapy; development of natural anti-atherosclerotic drugs preventing cellular cholesterol retention.

Science.gov (United States)

Orekhov, Alexander N

2013-01-01

The results of numerous clinical trials with statins and other drugs have demonstrated the principal possibility of the prevention and regression of atherosclerosis by pharmacotherapy. This review describes the use of cultured human arterial cells for the mass screening of anti-atherosclerotic substances, the investigation of the mechanisms responsible for their atherosclerosis-related effects, and the optimization of anti-atherosclerotic and anti-atherogenic drug and dietary therapies. Natural products can be considered promising drugs for anti-atherosclerotic therapy. Our basic studies have shown that cellular lipidosis is the principal event in the genesis of atherosclerotic lesions. Using cellular models and natural products, we have developed an approach to prevent lipid accumulation in arterial cells. Based on our knowledge of atherosclerosis, we developed drugs that possess direct anti-atherosclerotic activity. Two-year treatment with allicor (garlic powder) has a direct anti-atherosclerotic effect on carotid atherosclerosis in asymptomatic men. Inflaminat (calendula, elder, and violet), which possesses anti-cytokine activity, has been shown to cause the regression of carotid atherosclerosis following the treatment of asymptomatic men for one year. The phytoestrogen-rich drug karinat (garlic powder, extract of grape seeds, green tea leaves, hop cones, β-carotene, α-tocopherol, and ascorbic acid) prevents the development of carotid atherosclerosis in postmenopausal women. Thus, our basic findings were successfully translated into clinical practice. Because of this translation, a novel approach to antiatherosclerotic therapy was developed. Our clinical trial confirmed the efficacy of both the novel approach and the novel drugs.
Sortase A: an ideal target for anti-virulence drug development.

Science.gov (United States)

Cascioferro, Stella; Totsika, Makrina; Schillaci, Domenico

2014-12-01

Sortase A is a membrane enzyme responsible for the anchoring of surface-exposed proteins to the cell wall envelope of Gram-positive bacteria. As a well-studied member of the sortase subfamily catalysing the cell wall anchoring of important virulence factors to the surface of staphylococci, enterococci and streptococci, sortase A plays a critical role in Gram-positive bacterial pathogenesis. It is thus considered a promising target for the development of new anti-infective drugs that aim to interfere with important Gram-positive virulence mechanisms, such as adhesion to host tissues, evasion of host defences, and biofilm formation. The additional properties of sortase A as an enzyme that is not required for Gram-positive bacterial growth or viability and is conveniently located on the cell membrane making it more accessible to inhibitor targeting, constitute additional reasons reinforcing the view that sortase A is an ideal target for anti-virulence drug development. Many inhibitors of sortase A have been identified to date using high-throughput or in silico screening of compound libraries (synthetic or natural), and while many have proved useful tools for probing the action model of the enzyme, several are also promising candidates for the development into potent inhibitors. This review is focused on the most promising sortase A inhibitor compounds that are currently in development as leads towards a new class of anti-infective drugs that are urgently needed to help combat the alarming increase in antimicrobial resistance. Copyright © 2014 Elsevier Ltd. All rights reserved.
Biomarkers as drug development tools: discovery, validation, qualification and use.

Science.gov (United States)

Kraus, Virginia B

2018-06-01

The 21st Century Cures Act, approved in the USA in December 2016, has encouraged the establishment of the national Precision Medicine Initiative and the augmentation of efforts to address disease prevention, diagnosis and treatment on the basis of a molecular understanding of disease. The Act adopts into law the formal process, developed by the FDA, of qualification of drug development tools, including biomarkers and clinical outcome assessments, to increase the efficiency of clinical trials and encourage an era of molecular medicine. The FDA and European Medicines Agency (EMA) have developed similar processes for the qualification of biomarkers intended for use as companion diagnostics or for development and regulatory approval of a drug or therapeutic. Biomarkers that are used exclusively for the diagnosis, monitoring or stratification of patients in clinical trials are not subject to regulatory approval, although their qualification can facilitate the conduct of a trial. In this Review, the salient features of biomarker discovery, analytical validation, clinical qualification and utilization are described in order to provide an understanding of the process of biomarker development and, through this understanding, convey an appreciation of their potential advantages and limitations.
Next generation human skin constructs as advanced tools for drug development.

Science.gov (United States)

Abaci, H E; Guo, Zongyou; Doucet, Yanne; Jacków, Joanna; Christiano, Angela

2017-11-01

Many diseases, as well as side effects of drugs, manifest themselves through skin symptoms. Skin is a complex tissue that hosts various specialized cell types and performs many roles including physical barrier, immune and sensory functions. Therefore, modeling skin in vitro presents technical challenges for tissue engineering. Since the first attempts at engineering human epidermis in 1970s, there has been a growing interest in generating full-thickness skin constructs mimicking physiological functions by incorporating various skin components, such as vasculature and melanocytes for pigmentation. Development of biomimetic in vitro human skin models with these physiological functions provides a new tool for drug discovery, disease modeling, regenerative medicine and basic research for skin biology. This goal, however, has long been delayed by the limited availability of different cell types, the challenges in establishing co-culture conditions, and the ability to recapitulate the 3D anatomy of the skin. Recent breakthroughs in induced pluripotent stem cell (iPSC) technology and microfabrication techniques such as 3D-printing have allowed for building more reliable and complex in vitro skin models for pharmaceutical screening. In this review, we focus on the current developments and prevailing challenges in generating skin constructs with vasculature, skin appendages such as hair follicles, pigmentation, immune response, innervation, and hypodermis. Furthermore, we discuss the promising advances that iPSC technology offers in order to generate in vitro models of genetic skin diseases, such as epidermolysis bullosa and psoriasis. We also discuss how future integration of the next generation human skin constructs onto microfluidic platforms along with other tissues could revolutionize the early stages of drug development by creating reliable evaluation of patient-specific effects of pharmaceutical agents. Impact statement Skin is a complex tissue that hosts various
Drug Repositioning: An Opportunity to Develop Novel Treatments for Alzheimer’s Disease

Directory of Open Access Journals (Sweden)

Clive Ballard

2013-10-01

Full Text Available Alzheimer’s Disease (AD is the most common cause of dementia, affecting approximately two thirds of the 35 million people worldwide with the condition. Despite this, effective treatments are lacking, and there are no drugs that elicit disease modifying effects to improve outcome. There is an urgent need to develop and evaluate more effective pharmacological treatments. Drug repositioning offers an exciting opportunity to repurpose existing licensed treatments for use in AD, with the benefit of providing a far more rapid route to the clinic than through novel drug discovery approaches. This review outlines the current most promising candidates for repositioning in AD, their supporting evidence and their progress through trials to date. Furthermore, it begins to explore the potential of new transcriptomic and microarray techniques to consider the future of drug repositioning as a viable approach to drug discovery.
The development of multiple drug use among anabolic-androgenic steroid users: six subjective case reports

Directory of Open Access Journals (Sweden)

Nyberg Fred

2008-11-01

Full Text Available Abstract Background The inappropriate use of anabolic androgenic steroids (AAS was originally a problem among athletes but AAS are now often used in nonsport situations and by patients attending regular addiction clinics. The aim of this study was to improve understanding of the development of multiple drug use in patients seeking treatment at an addiction clinic for AAS-related problems. Methods We interviewed six patients (four men and two women with experience of AAS use who were attending an addiction clinic for what they believed were AAS-related problems. The patients were interviewed in-depth about their life stories, with special emphasis on social background, substance use, the development of total drug use and subjective experienced psychological and physical side effects. Results There was significant variation in the development of drug use in relation to social background, onset of drug use, relationship to AAS use and experience of AAS effects. All patients had initially experienced positive effects from AAS but, over time, the negative experiences had outweighed the positive effects. All patients were dedicated to excess training and took AAS in combination with gym training, indicating that the use of these drugs is closely related to this form of training. Use of multiple drugs was common either in parallel with AAS use or serially. Conclusion The study shows the importance of understanding how AAS use can develop either with or without the concomitant use of other drugs of abuse. The use of AAS can, however, progress to the use of other drugs. The study also indicates the importance of obtaining accurate, comprehensive information about the development of AAS use in designing treatment programmes and prevention strategies in this area.
Recommendations for adaptation and validation of commercial kits for biomarker quantification in drug development.

Science.gov (United States)

Khan, Masood U; Bowsher, Ronald R; Cameron, Mark; Devanarayan, Viswanath; Keller, Steve; King, Lindsay; Lee, Jean; Morimoto, Alyssa; Rhyne, Paul; Stephen, Laurie; Wu, Yuling; Wyant, Timothy; Lachno, D Richard

2015-01-01

Increasingly, commercial immunoassay kits are used to support drug discovery and development. Longitudinally consistent kit performance is crucial, but the degree to which kits and reagents are characterized by manufacturers is not standardized, nor are the approaches by users to adapt them and evaluate their performance through validation prior to use. These factors can negatively impact data quality. This paper offers a systematic approach to assessment, method adaptation and validation of commercial immunoassay kits for quantification of biomarkers in drug development, expanding upon previous publications and guidance. These recommendations aim to standardize and harmonize user practices, contributing to reliable biomarker data from commercial immunoassays, thus, enabling properly informed decisions during drug development.
The impact of nanobiotechnology on the development of new drug delivery systems

NARCIS (Netherlands)

Kayser, Oliver; Lemke, A.; Hernandez-Trejo, N.

2005-01-01

Nanotechnology, or systems/devices manufactured at the molecular level, is a multidisciplinary scientific field undergoing explosive development. A part of this field is the development of nanoscaled drug delivery devices. Nanoparticles have been developed as an important strategy to deliver
Review on potential phytocompounds in drug development for Parkinson disease: A pharmacoinformatic approach

Directory of Open Access Journals (Sweden)

S. Vijayakumar

Full Text Available Parkinson's disease (PD is caused by human physiological function and is ranked as the second most common neurodegenerative disorder. One of the prominent therapies currently available for PD is the use of dopamine agonists which mimic the natural action of dopamine in the brain and stimulate dopamine receptors directly. Currently, available pharmaceutical drugs provide only temporary relief of the disease. Phytocompounds have been identified as promising target of research in the quest for new pharmaceutical compounds as they can produce secondary metabolites with novel chemical structure. In this review the drug development of Parkinson disease has been analyzed using computational tools. Keywords: Parkinson disease, Phytocompounds, Computational methods, Drug development and design
Biofuels development and the policy regime.

Science.gov (United States)

Philp, Jim C; Guy, Ken; Ritchie, Rachael J

2013-01-01

Any major change to the energy order is certain to provoke both positive and negative societal responses. The current wave of biofuels development ignited controversies that have re-shaped the thinking about their future development. Mistakes were made in the early support for road transport biofuels in Organisation for Economic Co-operation and Development (OECD) countries. This article examines some of the policies that shaped the early development of biofuels and looks to the future. Copyright © 2012 Elsevier Ltd. All rights reserved.
Emerging technologies, recent developments, and novel applications for drug metabolite identification.

Science.gov (United States)

Lu, Wenjie; Xu, Youzhi; Zhao, Yinglan; Cen, Xiaobo

2014-01-01

Drug metabolite identification and metabolic characteristics analysis play a crucial role in new drug research and development, because they can lead to varied efficacy, severe adverse reactions, and even toxicity. Classical methodologies for metabolite identification have mainly been based on mass spectrometry (MS) coupled with gas chromatography (GC) or liquid chromatography (LC), and some other techniques are used as complementary approaches, such as nuclear magnetic resonance (NMR). Over the past decade, more and more newly emerging techniques or technologies have been applied to metabolite identification, and are making the procedure easier and more robust, such as LC-NMR-MS, ion mobility MS, ambient ionization techniques, and imaging MS. A novel application of drug metabolite identification based on "omics" known as pharmacometabonomics is discussed, which is an interdisciplinary field that combines pre-dose metabolite profiling and chemometrics methods for data analysis and modeling, aiming to predict the responses of individuals to drugs.
[Development of anti-Alzheimer's disease drug based on beta-amyloid hypothesis].

Science.gov (United States)

Sugimoto, Hachiro

2010-04-01

Currently, there are five anti-Alzheimer's disease drugs approved. These are tacrine, donepezil, rivastigmine, galantamine, and memantine. The mechanism of the first four drugs is acetylcholinesterase inhibition, while memantine is an NMDA-receptor antagonist. However, these drugs do not cure Alzheimer's, but are only symptomatic treatments. Therefore, a cure for Alzheimer's disease is truly needed. Alzheimer's disease is a progressive neurodegenerative disease characterized by cognitive deficits. The cause of the disease is not well understood, but research indicates that the aggregation of beta-amyloid is the fundamental cause. This theory suggests that beta-amyloid aggregation causes neurotoxicity. Therefore, development of the next anti-Alzheimer's disease drug is based on the beta-amyloid theory. We are now studying natural products, such as mulberry leaf extracts and curcumin derivatives, as potential cure for Alzheimer's disease. In this report, we describe some data about these natural products and derivatives.
Developing a Molecular Roadmap of Drug-Food Interactions

DEFF Research Database (Denmark)

Jensen, Kasper; Ni, Yueqiong; Panagiotou, Gianni

2015-01-01

therapeutic interventions, a systematic approach for identifying, predicting and preventing potential interactions between food and marketed or novel drugs is not yet available. The overall objective of this work was to sketch a comprehensive picture of the interference of ∼ 4,000 dietary components present...... view of the associations between diet and dietary molecules with drug targets, metabolic enzymes, drug transporters and carriers currently deposited in Drug-Bank. Moreover, we identified disease areas and drug targets that are most prone to the negative effects of drug-food interactions, showcasing......Recent research has demonstrated that consumption of food -especially fruits and vegetables-can alter the effects of drugs by interfering either with their pharmacokinetic or pharmacodynamic processes. Despite the recognition of such drug-food associations as an important element for successful...
Development, use and evaluation of drugs

DEFF Research Database (Denmark)

Hansen, E H; Launsø, Laila

1987-01-01

. Drugs offer a standard solution to health problems independent of the individuals' social life. Thus drugs become a tool which function in agreement with the disintegrated and achievement-orientated approach to disease as it is organized today. In general the statements in this article are not limited...
Investigating Nature's Mysteries for Drug Development

Science.gov (United States)

More than half of the drugs approved to treat cancer come from a natural product or a natural product prototype. Scientists in NCI-Frederick's Natural Products Branch are exploring ways to harness chemicals produced by marine invertebrates, other animals, plants, and microbes for cancer drug discovery.
78 FR 32667 - Draft Guidance for Industry on Rheumatoid Arthritis: Developing Drug Products for Treatment...

Science.gov (United States)

2013-05-31

... products. This guidance revises the guidance for industry entitled ``Clinical Development Programs for... Information, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave... (HFM-40), Center for Biologics Evaluation and Research, Food and Drug Administration, 1401 Rockville...
Development and evaluation of diclofenac sodium thermorevesible subcutaneous drug delivery system.

Science.gov (United States)

Nasir, Fazli; Iqbal, Zafar; Khan, Jamshaid A; Khan, Abad; Khuda, Fazli; Ahmad, Lateef; Khan, Amirzada; Khan, Abbas; Dayoo, Abdullah; Roohullah

2012-12-15

The objective of current work was to develop and evaluate thermoreversible subcutaneous drug delivery system for diclofenac sodium. The poloxamer 407, methyl cellulose, hydroxypropyl methyl cellulose and polyethylene glycol were used alone and in combination in different ratios to design the delivery system. The physical properties like Tsol-gel, viscosity, clarity of solution and gel were evaluated. The in vitro release of the drug delivery system was evaluated using membrane less method and the drug release kinetics and mechanism was predicted by applying various mathematical models to the in vitro dissolution data. Rabbits were used as in vivo model following subcutaneous injection to predict various pharmacokinetics parameters by applying Pk-Summit software. The in vitro and in vivo data revealed that the system consisting of the poloxamer 407 in concentration of 20% (DP20) was the most capable formulation for extending the drug release and maintaining therapeutic blood level of DS for longer duration (144 h). The data obtained for drug content after autoclaving the solutions indicate that autoclaving results in 6% degradation of DS. The data also suggested that the studied polymers poloxamer, MC and PG are good candidate to extend the drug release possessing a unique thermoreversible property. Copyright © 2012 Elsevier B.V. All rights reserved.
In silico tools used for compound selection during target-based drug discovery and development.

Science.gov (United States)

Caldwell, Gary W

2015-01-01

The target-based drug discovery process, including target selection, screening, hit-to-lead (H2L) and lead optimization stage gates, is the most common approach used in drug development. The full integration of in vitro and/or in vivo data with in silico tools across the entire process would be beneficial to R&D productivity by developing effective selection criteria and drug-design optimization strategies. This review focuses on understanding the impact and extent in the past 5 years of in silico tools on the various stage gates of the target-based drug discovery approach. There are a large number of in silico tools available for establishing selection criteria and drug-design optimization strategies in the target-based approach. However, the inconsistent use of in vitro and/or in vivo data integrated with predictive in silico multiparameter models throughout the process is contributing to R&D productivity issues. In particular, the lack of reliable in silico tools at the H2L stage gate is contributing to the suboptimal selection of viable lead compounds. It is suggested that further development of in silico multiparameter models and organizing biologists, medicinal and computational chemists into one team with a single accountable objective to expand the utilization of in silico tools in all phases of drug discovery would improve R&D productivity.
Patient-Reported Outcomes in Cancer Drug Development and US Regulatory Review: Perspectives From Industry, the Food and Drug Administration, and the Patient.

Science.gov (United States)

Basch, Ethan; Geoghegan, Cindy; Coons, Stephen Joel; Gnanasakthy, Ari; Slagle, Ashley F; Papadopoulos, Elektra J; Kluetz, Paul G

2015-06-01

Data reported directly by patients about how they feel and function are rarely included in oncology drug labeling in the United States, in contrast to Europe and to nononcology labeling in the United States, where this practice is more common. Multiple barriers exist, including challenges unique to oncology trials, and industry's concerns regarding cost, logistical complexities, and the Food and Drug Administration's (FDA's) rigorous application of its 2009 guidance on the use of patient-reported outcome (PRO) measures. A panel consisting of representatives of industry, FDA, the PRO Consortium, clinicians, and patients was assembled at a 2014 workshop cosponsored by FDA to identify practical recommendations for overcoming these barriers. Key recommendations included increasing proactive encouragement by FDA to clinical trial sponsors for including PROs in drug development programs; provision of comprehensive PRO plans by sponsors to FDA early in drug development; promotion of an oncology-specific PRO research agenda; development of an approach to existing ("legacy") PRO measures, when appropriate (focused initially on symptoms and functional status); and increased FDA and industry training in PRO methodology. FDA has begun implementing several of these recommendations.
Synthesis and applications of radiolabelled drugs in pharmaceutical development

International Nuclear Information System (INIS)

Landvatter, S.W.; Heys, J.R.; Garner, K.T.; Mack, J.F.; Senderoff, S.G.; Shu, A.Y.; Villani, A.J.; Saunders, D.

1994-01-01

Radiolabelled drugs play a vital role in the development of new pharmaceuticals including application in drug discovery, pre-clinical development and clinical development. The synthesis of these pharmaceuticals in tritium or carbon-14 labelled form poses many challenges for the synthetic organic chemist. The actual choice of synthetic route must take into account the small scale, limited choice and high cost of labelled precursors, and the positioning of the label into a metabolically stable position. There are, however, a number of synthetic strategies available for overcoming these constraints. Although in some C-14 syntheses the requisite labelled raw material can be purchased and the existing synthesis adapted for labelling, frequently the synthetic challenge is the synthesis of a structurally simple, yet commercially unavailable, labelled precursor (e.g., γ-butyrolactone-[2- 14 C], cyclohexanone-[ 3 H], CuCN-[ 14 C], 2-furancarboxaldehyde-[ 14 C]). Another useful strategy in C-14 synthesis is the conversion of an advanced intermediate, or perhaps the unlabelled product itself, into a precursor which can then be reconverted into the labelled version of the intermediate. Occasionally, a new total synthesis must be developed. In addition to these strategies, tritium labelling can uniquely take advantage of exchange labelling techniques, synthesis and reduction of unsaturated precursors, or tritium-halogen replacement reactions. Examples of these strategies and use of the labelled products are discussed

Development of Bioadhesive Chitosan Superporous Hydrogel Composite Particles Based Intestinal Drug Delivery System

Directory of Open Access Journals (Sweden)

Hitesh Chavda

2013-01-01

Full Text Available Bioadhesive superporous hydrogel composite (SPHC particles were developed for an intestinal delivery of metoprolol succinate and characterized for density, porosity, swelling, morphology, and bioadhesion studies. Chitosan and HPMC were used as bioadhesive and release retardant polymers, respectively. A 32 full factorial design was applied to optimize the concentration of chitosan and HPMC. The drug loaded bioadhesive SPHC particles were filled in capsule, and the capsule was coated with cellulose acetate phthalate and evaluated for drug content, in vitro drug release, and stability studies. To ascertain the drug release kinetics, the drug release profiles were fitted for mathematical models. The prepared system remains bioadhesive up to eight hours in intestine and showed Hixson-Crowell release with anomalous nonfickian type of drug transport. The application of SPHC polymer particles as a biomaterial carrier opens a new insight into bioadhesive drug delivery system and could be a future platform for other molecules for intestinal delivery.
A long and winding road; evolution of antimicrobial drug development - crisis management.

Science.gov (United States)

Echols, Roger M

2012-11-01

The development of antimicrobial drugs has evolved from observational case reports to complex randomized prospective clinical trials in specific treatment indications. Beginning around the year 2000, the US FDA has evolved its approach on study design and other study characteristics, which has made the conduct of these studies more difficult and the outcomes for sponsors more risky. This has contributed to the decline in the discovery and development of new antimicrobials, which are needed to address the increasing problem of bacterial resistance to existing marketed products. This study reviews the historical basis for the current regulatory climate including the various crises that have led to considerable political pressures on the agency. Recent efforts to resolve development uncertainties and to provide economic incentives for future antimicrobial drug development are presented.
Nanotechnology and Drug Delivery Part 2: Nanostructures for Drug ...

African Journals Online (AJOL)

Some challenges associated with the technology as it relates to drug effectiveness, toxicity, stability, pharmacokinetics and drug regulatory control are discussed in this review. Clearly, nanotechnology is a welcome development that is set to transform drug delivery and drug supply chain management, if optimally developed ...
The practice of pre-marketing safety assessment in drug development.

Science.gov (United States)

Chuang-Stein, Christy; Xia, H Amy

2013-01-01

The last 15 years have seen a substantial increase in efforts devoted to safety assessment by statisticians in the pharmaceutical industry. While some of these efforts were driven by regulations and public demand for safer products, much of the motivation came from the realization that there is a strong need for a systematic approach to safety planning, evaluation, and reporting at the program level throughout the drug development life cycle. An efficient process can help us identify safety signals early and afford us the opportunity to develop effective risk minimization plan early in the development cycle. This awareness has led many pharmaceutical sponsors to set up internal systems and structures to effectively conduct safety assessment at all levels (patient, study, and program). In addition to process, tools have emerged that are designed to enhance data review and pattern recognition. In this paper, we describe advancements in the practice of safety assessment during the premarketing phase of drug development. In particular, we share examples of safety assessment practice at our respective companies, some of which are based on recommendations from industry-initiated working groups on best practice in recent years.
Drug discovery and development tomorrow -- changing the mindset.

Science.gov (United States)

Coleman, Robert A

2009-09-01

Today's drug discovery and development paradigm is not working, and something needs to be done about it. There is good reason to believe that a move away from reliance on animal surrogates for human subjects in the Pharma Industry's R&D programmes could provide an important step forward. However, no serious move will be made in that direction until there is some hard evidence that it will be rewarded with improved productivity outcomes. The Safer Medicines Trust are proposing that a study be undertaken, involving a range of drugs that have been approved for human use, but have subsequently proved to have limitations in terms of safety and/or efficacy. The aim is to determine the efficiency of a battery of human-based test methods to identify a compound's safety and efficacy profiles, and to compare this with that of the more traditional, largely animal-based methods that were employed in their original development. Should such an approach prove more reliable, the authorities will be faced with important decisions relating to the role of human biological test data in regulatory submissions, while the Pharma Industry will be faced with the key logistical issue of how to acquire the human biomaterials necessary to make possible the routine application of such test methods. 2009 FRAME.
Predicting drug?drug interactions through drug structural similarities and interaction networks incorporating pharmacokinetics and pharmacodynamics knowledge

OpenAIRE

Takeda, Takako; Hao, Ming; Cheng, Tiejun; Bryant, Stephen H.; Wang, Yanli

2017-01-01

Drug?drug interactions (DDIs) may lead to adverse effects and potentially result in drug withdrawal from the market. Predicting DDIs during drug development would help reduce development costs and time by rigorous evaluation of drug candidates. The primary mechanisms of DDIs are based on pharmacokinetics (PK) and pharmacodynamics (PD). This study examines the effects of 2D structural similarities of drugs on DDI prediction through interaction networks including both PD and PK knowledge. Our a...
Repurposing pharma assets: an accelerated mechanism for strengthening the schistosomiasis drug development pipeline.

Science.gov (United States)

Ramamoorthi, Roopa; Graef, Katy M; Dent, Jennifer

2015-01-01

Schistosomiasis, one of 17 diseases deemed to be neglected by the World Health Organization, has received little attention from the biopharmaceutical industry. Due to this, only a handful of drugs have been developed to treat schistosomiasis, with only one, praziquantel, used in most endemic regions. Growing concern over resistance coupled with praziquantel's incomplete efficacy across all stages of the Schistosoma platyhelminth life cycle highlights the urgent need for new drugs. The WIPO Re:Search consortium is a platform whereupon biopharmaceutical company compounds are being repurposed to efficiently and cost-effectively develop new drugs for neglected diseases such as schistosomiasis. This article summarizes recent clinical-stage efforts to identify new antischistosomals and highlights biopharmaceutical company compounds with potential for repurposing to treat schistosomiasis.
Exosomes in development, metastasis and drug resistance of breast cancer.

Science.gov (United States)

Yu, Dan-dan; Wu, Ying; Shen, Hong-yu; Lv, Meng-meng; Chen, Wei-xian; Zhang, Xiao-hui; Zhong, Shan-liang; Tang, Jin-hai; Zhao, Jian-hua

2015-08-01

Transport through the cell membrane can be divided into active, passive and vesicular types (exosomes). Exosomes are nano-sized vesicles released by a variety of cells. Emerging evidence shows that exosomes play a critical role in cancers. Exosomes mediate communication between stroma and cancer cells through the transfer of nucleic acid and proteins. It is demonstrated that the contents and the quantity of exosomes will change after occurrence of cancers. Over the last decade, growing attention has been paid to the role of exosomes in the development of breast cancer, the most life-threatening cancer in women. Breast cancer could induce salivary glands to secret specific exosomes, which could be used as biomarkers in the diagnosis of early breast cancer. Exosome-delivered nucleic acid and proteins partly facilitate the tumorigenesis, metastasis and resistance of breast cancer. Exosomes could also transmit anti-cancer drugs outside breast cancer cells, therefore leading to drug resistance. However, exosomes are effective tools for transportation of anti-cancer drugs with lower immunogenicity and toxicity. This is a promising way to establish a drug delivery system. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.
Methodological Study to Develop Standard Operational Protocol on Oral Drug Administration for Children.

Science.gov (United States)

Bijarania, Sunil Kumar; Saini, Sushma Kumari; Verma, Sanjay; Kaur, Sukhwinder

2017-05-01

To develop standard operational protocol (SOP) on oral drug administration and checklist to assess the implementation of the developed SOP. In this prospective methodological study, SOPs were developed in five phases. In the first phase, the preliminary draft of SOPs and checklists were prepared based on literature review, assessment of current practices and focus group discussion (FGD) with bedside working nurses. In the second phase, content validity was checked with the help of Delphi technique (12 experts). Total four drafts were prepared in stages and necessary modifications were made as per suggestions after each Delphi round. Fourth Delphi round was performed after conducting a pilot study. In the fourth phase, all bedside nurses were trained as per SOPs and asked to practice accordingly and observation of thirty oral drug administrations in children was done to check reliability of checklists for implementation of SOPs. In Phase-V, 7 FGDs were conducted with bedside nurses to assess the effectiveness of SOPs. The Content Validity Index (CVI) of SOP and checklists was 99.77%. Overall standardized Cronbach's alpha was calculated as 0.94. All the nurses felt that the SOP is useful. Valid and feasible SOP for drug administration to children through oral route along with valid and reliable checklist were developed. It is recommended to use this document for drug administration to children.
A systematic review of patient medication error on self-administering medication at home.

Science.gov (United States)

Mira, José Joaquín; Lorenzo, Susana; Guilabert, Mercedes; Navarro, Isabel; Pérez-Jover, Virtudes

2015-06-01

Medication errors have been analyzed as a health professionals' responsibility (due to mistakes in prescription, preparation or dispensing). However, sometimes, patients themselves (or their caregivers) make mistakes in the administration of the medication. The epidemiology of patient medication errors (PEs) has been scarcely reviewed in spite of its impact on people, on therapeutic effectiveness and on incremental cost for the health systems. This study reviews and describes the methodological approaches and results of published studies on the frequency, causes and consequences of medication errors committed by patients at home. A review of research articles published between 1990 and 2014 was carried out using MEDLINE, Web-of-Knowledge, Scopus, Tripdatabase and Index Medicus. The frequency of PE was situated between 19 and 59%. The elderly and the preschooler population constituted a higher number of mistakes than others. The most common were: incorrect dosage, forgetting, mixing up medications, failing to recall indications and taking out-of-date or inappropriately stored drugs. The majority of these mistakes have no negative consequences. Health literacy, information and communication and complexity of use of dispensing devices were identified as causes of PEs. Apps and other new technologies offer several opportunities for improving drug safety.
Investigation of toxic metabolites during drug development

International Nuclear Information System (INIS)

Park, Kevin; Williams, Dominic P.; Naisbitt, Dean J.; Kitteringham, Neil R.; Pirmohamed, Munir

2005-01-01

Adverse drug reactions (ADRs) are a significant human health problem. Any organ system can be affected, including the liver, skin and kidney. Drug-induced liver injury is the most frequent reason for the withdrawal of an approved drug from the market, and it also accounts for up to 50% of cases of acute liver failure. The clinical picture is often diverse, even for the same drug. Mild, asymptomatic effects occur at a relatively high frequency with a number of drugs. Idiosyncratic toxicity is rare but potentially life-threatening. Many serious ADRs that occur in man are unpredictable from routine pathology and clinical chemistry in laboratory animals and are therefore poorly understood. The drug metabolist can determine the propensity of a novel chemical entity to either accumulate in the hepatocyte or undergo bioactivation in numerous model systems, from expressed enzymes, genetically engineered cells to whole animals. Bioactivation can be measured using trapping experiments with model nucleophiles or by measurement of non-specific covalent binding. The chemistry of the process is defined and the medicinal chemist can address the issue by seeking a metabolically stable pharmacophore to replace the potential toxicophore. However, we require a more fundamental understanding of the role of drug chemistry and biochemistry in ADRs. This requires knowledge of the ultimate toxin, signalling in cell defense and the sequence of molecular events, which ultimately lead to cell and tissue damage. It is imperative that such studies have a clinical level, but then translated into laboratory-based molecular studies. This will provide a deeper understanding of potential toxicophores for drug design and define candidate genes for pharmacogenomic approaches to individualized medicines
Incorporation of in silico biodegradability screening in early drug development--a feasible approach?

Science.gov (United States)

Steger-Hartmann, Thomas; Länge, Reinhard; Heuck, Klaus

2011-05-01

The concentration of a pharmaceutical found in the environment is determined by the amount used by the patient, the excretion and metabolism pattern, and eventually by its persistence. Biological degradation or persistence of a pharmaceutical is experimentally tested rather late in the development of a pharmaceutical, often shortly before submission of the dossier to regulatory authorities. To investigate whether the aspect of persistence of a compound could be assessed early during drug development, we investigated whether biodegradation of pharmaceuticals could be predicted with the help of in silico tools. To assess the value of in silico prediction, we collected results for the OECD 301 degradation test ("ready biodegradability") of 42 drugs or drug synthesis intermediates and compared them to the prediction of the in silico tool BIOWIN. Of these compounds, 38 were predictable with BIOWIN, which is a module of the Estimation Programs Interface (EPI) Suite™ provided by the US EPA. The program failed to predict the two drugs which proved to be readily biodegradable in the degradation tests. On the other hand, BIOWIN predicted two compounds to be readily biodegradable which, however, proved to be persistent in the test setting. The comparison of experimental data with the predicted one resulted in a specificity of 94% and a sensitivity of 0%. The results of this study do not indicate that application of the biodegradation prediction tool BIOWIN is a feasible approach to assess the ready biodegradability during early drug development.
[Orphan drugs].

Science.gov (United States)

Golocorbin Kon, Svetlana; Vojinović, Aleksandra; Lalić-Popović, Mladena; Pavlović, Nebojsa; Mikov, Momir

2013-01-01

Drugs used for treatment of rare diseases are known worldwide under the term of orphan drugs because pharmaceutical companies have not been interested in "adopting" them, that is in investing in research, developing and producing these drugs. This kind of policy has been justified by the fact that these drugs are targeted for small markets, that only a small number of patients is available for clinical trials, and that large investments are required for the development of drugs meant to treat diseases whose pathogenesis has not yet been clarified in majority of cases. The aim of this paper is to present previous and present status of orphan drugs in Serbia and other countries. THE BEGINNING OF ORPHAN DRUGS DEVELOPMENT: This problem was first recognized by Congress of the United States of America in January 1983, and when the "Orphan Drug Act" was passed, it was a turning point in the development of orphan drugs. This law provides pharmaceutical companies with a series of reliefs, both financial ones that allow them to regain funds invested into the research and development and regulatory ones. Seven years of marketing exclusivity, as a type of patent monopoly, is the most important relief that enables companies to make large profits. There are no sufficient funds and institutions to give financial support to the patients. It is therefore necessary to make health professionals much more aware of rare diseases in order to avoid time loss in making the right diagnosis and thus to gain more time to treat rare diseases. The importance of discovery, development and production of orphan drugs lies in the number of patients whose life quality can be improved significantly by administration of these drugs as well as in the number of potential survivals resulting from the treatment with these drugs.
Developing a molecular roadmap of drug-food interactions.

Directory of Open Access Journals (Sweden)

Kasper Jensen

2015-02-01

Full Text Available Recent research has demonstrated that consumption of food -especially fruits and vegetables- can alter the effects of drugs by interfering either with their pharmacokinetic or pharmacodynamic processes. Despite the recognition of such drug-food associations as an important element for successful therapeutic interventions, a systematic approach for identifying, predicting and preventing potential interactions between food and marketed or novel drugs is not yet available. The overall objective of this work was to sketch a comprehensive picture of the interference of ∼ 4,000 dietary components present in ∼1800 plant-based foods with the pharmacokinetics and pharmacodynamics processes of medicine, with the purpose of elucidating the molecular mechanisms involved. By employing a systems chemical biology approach that integrates data from the scientific literature and online databases, we gained a global view of the associations between diet and dietary molecules with drug targets, metabolic enzymes, drug transporters and carriers currently deposited in DrugBank. Moreover, we identified disease areas and drug targets that are most prone to the negative effects of drug-food interactions, showcasing a platform for making recommendations in relation to foods that should be avoided under certain medications. Lastly, by investigating the correlation of gene expression signatures of foods and drugs we were able to generate a completely novel drug-diet interactome map.
Development in Assay Methods for in Vitro Antimalarial Drug Efficacy Testing: A Systematic Review

Directory of Open Access Journals (Sweden)

Shweta Sinha

2017-10-01

Full Text Available The emergence and spread of drug resistance are the major challenges in malaria eradication mission. Besides various strategies laid down by World Health Organization, such as vector management, source reduction, early case detection, prompt treatment, and development of new diagnostics and vaccines, nevertheless the need for new and efficacious drugs against malaria has become a critical priority on the global malaria research agenda. At several screening stages, millions of compounds are screened (1,000–2,000,000 compounds per screening campaign, before pre-clinical trials to select optimum lead. Carrying out in vitro screening of antimalarials is very difficult as different assay methods are subject to numerous sources of variability across different laboratories around the globe. Despite this, in vitro screening is an essential part of antimalarial drug development as it enables to resource various confounding factors such as host immune response and drug–drug interaction. Therefore, in this article, we try to illustrate the basic necessity behind in vitro study and how new methods are developed and subsequently adopted for high-throughput antimalarial drug screening and its application in achieving the next level of in vitro screening based on the current approaches (such as stem cells.
Development and evaluation of an electronic drug and therapeutics bulletin.

Science.gov (United States)

Alderman, Christopher P

2002-10-01

To describe the development, implementation, and initial evaluation of a paperless drug and therapeutics bulletin that is distributed by electronic mail from the pharmacy department of an Australian teaching hospital. A standardized format for the bulletin was designed and approved in February 2001. The aim of the bulletin is to facilitate the timely dissemination of concise, factual information about issues of current interest in therapeutics, drug safety, and the cost-effective use of medicines. A simple and attractive graphic design was chosen, and the hospital's clinical pharmacists and drug information staff developed an initial bank of content during the period immediately preceding the launch. The bulletin is presented as a 1-page, read-only file in Word for Windows format and was initially distributed by electronic mail to all users of the hospital's computerized communication network. As the popularity of the bulletin increased, healthcare practitioners from outside of the hospital began to request permission for inclusion on the circulation list, and the content was frequently forwarded by E-mail to workers in other hospitals and community-based settings. The bulletin is now distributed to pharmacists around Australia via 2 separate moderated discussion lists, one of which provides an archive site for previous editions. Healthcare workers in Singapore, the US, Canada, and New Zealand also receive the bulletin, which is now also abstracted by a major Australian pharmacy journal. A readership survey (also electronically distributed) was used to seek feedback after the publication of the first 12 editions. Readers indicated a high level of satisfaction with the content, format, and frequency of distribution of the materials. Although the concept and execution of this project was relatively simple, an extensive literature review did not reveal any previously published reports describing this type of approach to the distribution of a pharmacy bulletin. The
Ask the experts: the challenges and benefits of flow chemistry to optimize drug development.

Science.gov (United States)

Anderson, Neal; Gernaey, Krist V; Jamison, Timothy F; Kircher, Manfred; Wiles, Charlotte; Leadbeater, Nicholas E; Sandford, Graham; Richardson, Paul

2012-09-01

Against a backdrop of a struggling economic and regulatory climate, pharmaceutical companies have recently been forced to develop new ways to provide more efficient technology to meet the demands of a competitive drug industry. This issue, coupled with an increase in patent legislation and a rising generics market, makes these themes common issues in the growth of drug development. As a consequence, the importance of process chemistry and scale-up has never been more under the spotlight. Future Medicinal Chemistry wishes to share the thoughts and opinions of a variety of experts from this field, discussing issues concerning the use of flow chemistry to optimize drug development, the potential regulatory and environmental challenges faced with this, and whether the academic and industrial sectors could benefit from a more harmonized system relevant to process chemistry.
Tailored approaches in drug development and diagnostics : from molecular design to biological model systems

NARCIS (Netherlands)

Sahlgren, C.M.; Meinander, A.; Zhang, H.; Cheng, F.; Preis, Maren; Xu, C.; Salminen, T.A.; Toivola, D.M.; Abankwa, D.; Rosling, A.; Karaman, D.Ş.; Salo-Ahen, O.M.H.; Österbacka, R.; Eriksson, J.E.; Willför, S.; Petre, I.; Peltonen, J.; Leino, R.; Johnson, M.; Rosenholm, J.; Sandler, N.

2017-01-01

Approaches to increase the efficiency in developing drugs and diagnostics tools, including new drug delivery and diagnostic technologies, are needed for improved diagnosis and treatment of major diseases and health problems such as cancer, inflammatory diseases, chronic wounds, and antibiotic
Development and evaluation of 'Pure Rush': An online serious game for drug education.

Science.gov (United States)

Stapinski, Lexine A; Reda, Bill; Newton, Nicola C; Lawler, Siobhan; Rodriguez, Daniel; Chapman, Catherine; Teesson, Maree

2018-04-01

Learning is most effective when it is active, enjoyable and incorporates feedback. Past research demonstrates that serious games are prime candidates to utilise these principles, however the potential benefits of this approach for delivering drug education are yet to be examined in Australia, a country where drug education in schools is mandatory. The serious game 'Pure Rush' was developed across three stages. First, formative consultation was conducted with 115 students (67% male, aged 15-17 years), followed by feasibility and acceptability testing of a prototype of the game (n = 25, 68% male). In the final stage, 281 students (62% female, aged 13-16 years) were randomly allocated to receive a lesson involving Pure Rush or an active control lesson. The lessons were compared in terms of learning outcomes, lesson engagement and future intentions to use illicit drugs. Students enjoyed playing Pure Rush, found the game age-appropriate and the information useful to them. Both the Pure Rush and the active control were associated with significant knowledge increase from pre to post-test. Among females, multi-level mixed-effects regression showed knowledge gain was greater in the Pure Rush condition compared to control (β = 2.36, 95% confidence interval 0.36-4.38). There was no evidence of between condition differences in lesson engagement or future intentions to use illicit drugs. Pure Rush is an innovative online drug education game that is well received by students and feasible to implement in schools. [Stapinski LA, Reda B, Newton NC, Lawler S, Rodriguez D, Chapman C, Teesson M. Development and evaluation of 'Pure Rush': An online serious game for drug education. Drug Alcohol Rev 2017]. © 2017 Australasian Professional Society on Alcohol and other Drugs.
[The trend of new drug development for the treatment of diabetes mellitus].

Science.gov (United States)

Kaku, Kohei

2015-12-01

The trend of new drug development in the field of diabetes mellitus is overviewed. The hypoglycemic drugs such as glucagon receptor antagonists, glucokinase activators, and GPR agonists and oral medication of GLP-1 receptor agonist are under phase 2 trial in Japan. As for therapeutic medicines for diabetic nephropathy, atrasentan as an endothelin A receptor antagonist is in phase 3 trial, and bardoxolone methyl as Nrf2 activator in phase 2 in Japan. Canagliflozin, a SGLT2 inhibitor, is in phase 3 study to obtain new indication of diabetic nephropathy. An environment surrounding development of therapeutic medicines for diabetes has been tough since FDA guidance in 2008.

Spurious and counterfeit drugs: a growing industry in the developing world.

Science.gov (United States)

Gautam, C S; Utreja, A; Singal, G L

2009-05-01

Spread of spurious/counterfeit/substandard drugs is a modern day menace which has been recognised internationally, especially so in developing countries. The problem assumes added significance in view of rapid globalisation. The market of spurious and counterfeit drugs is a well-organised, white collar crime. Poverty, high cost of medicines, lack of an official supply chain, legislative lacunae, easy accessibility to computerised printing technology, ineffective law enforcement machinery, and light penalties provide the counterfeiters with an enormous economic incentive without much risk. The consequences of the use of such medicines may vary from therapeutic failure to the occurrence of serious adverse events and even death. Proper drug quality monitoring, enforcement of laws and legislation, an effective and efficient regulatory environment, and awareness and vigilance on part of all stakeholders can help tackle this problem.
Application of in situ polymerization for design and development of oral drug delivery systems.

Science.gov (United States)

Ngwuluka, Ndidi

2010-12-01

Although preformed polymers are commercially available for use in the design and development of drug delivery systems, in situ polymerization has also been employed. In situ polymerization affords the platform to tailor and optimize the drug delivery properties of polymers. This review brings to light the benefits of in situ polymerization for oral drug delivery and the possibilities it provides to overcome the challenges of oral route of administration.
Application of In Situ Polymerization for Design and Development of Oral Drug Delivery Systems

OpenAIRE

Ngwuluka, Ndidi

2010-01-01

Although preformed polymers are commercially available for use in the design and development of drug delivery systems, in situ polymerization has also been employed. In situ polymerization affords the platform to tailor and optimize the drug delivery properties of polymers. This review brings to light the benefits of in situ polymerization for oral drug delivery and the possibilities it provides to overcome the challenges of oral route of administration.
[New drug developments of snake venom polypeptides and progress].

Science.gov (United States)

Fu, Sihai; Feng, Mei; Xiong, Yan

2017-11-28

The value of snake venom polypeptides in clinical application has drawn extensive attention, and the development of snake polypeptides into new drugs with anti-tumor, anti-inflammatory, antithrombotic, analgesic or antihypertensive properties has become the recent research hotspot. With the rapid development of molecular biology and biotechnology, the mechanisms of snake venom polypeptides are also gradually clarified. Numerous studies have demonstrated that snake venom polypeptides exert their pharmacological effects by regulating ion channels, cell proliferation, apoptosis, intracellular signaling pathway, and expression of cytokine as well as binding to relevant active sites or receptors.
78 FR 15371 - Drug Development for Chronic Fatigue Syndrome and Myalgic Encephalomyelitis; Public Workshop

Science.gov (United States)

2013-03-11

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-N-0962] Drug Development for Chronic Fatigue Syndrome and Myalgic Encephalomyelitis; Public Workshop AGENCY... therapies to treat signs and symptoms related to chronic fatigue syndrome (CFS) and myalgic...
The Influence of Big (Clinical) Data and Genomics on Precision Medicine and Drug Development.

Science.gov (United States)

Denny, Joshua C; Van Driest, Sara L; Wei, Wei-Qi; Roden, Dan M

2018-03-01

Drug development continues to be costly and slow, with medications failing due to lack of efficacy or presence of toxicity. The promise of pharmacogenomic discovery includes tailoring therapeutics based on an individual's genetic makeup, rational drug development, and repurposing medications. Rapid growth of large research cohorts, linked to electronic health record (EHR) data, fuels discovery of new genetic variants predicting drug action, supports Mendelian randomization experiments to show drug efficacy, and suggests new indications for existing medications. New biomedical informatics and machine-learning approaches advance the ability to interpret clinical information, enabling identification of complex phenotypes and subpopulations of patients. We review the recent history of use of "big data" from EHR-based cohorts and biobanks supporting these activities. Future studies using EHR data, other information sources, and new methods will promote a foundation for discovery to more rapidly advance precision medicine. © 2017 American Society for Clinical Pharmacology and Therapeutics.
Challenges and opportunities for the development of new antipsychotic drugs.

Science.gov (United States)

Forray, Carlos; Buller, Raimund

2017-11-01

In spite of the significant impact that the serendipitous discovery of drugs with antipsychotic properties had on the care of patients with psychotic disorders, there are significant challenges when aiming at therapeutic goals such as remission, recovery, improved health-related quality of life and functioning. The efficacy and effectiveness of existing antipsychotic drugs fail to address the full spectrum of symptoms and functional deficits that currently prevent patients with psychotic disorders from achieving fulfilling lives. The study of the pharmacological mechanism of action has increased our knowledge on molecular targets and brain circuits related to the antipsychotic properties of this drug class. However, our understanding of how these molecular targets and brain circuits relate to other aspects of disease pathophysiology like cognitive impairment and negative symptoms is incomplete although these are significant clinical unmet needs. Currently, there is still an important knowledge gap between psychopathology and pathophysiology in schizophrenia research. This may have contributed to some recent costly failures of large clinical development programs for drugs targeted at glutamatergic function and nicotinic receptors. The lack of success of these pharmacological approaches to achieve clinical validation raises important questions concerning the underlying hypothesis that guided the choice of molecular targets, and about the predictive validity of translational models that supported the rationale for testing these drugs in clinical studies. From a clinical perspective there is a need to more strongly consider the disease heterogeneity linked to the use of the current diagnostic classification of subjects and to the validity of the psychopathological constructs and assessments that are used to assess clinical outcomes. A paradigm shift in the development of drugs for schizophrenia is needed. This will require among other addressing: the shortcomings of a
MALDI imaging facilitates new topical drug development process by determining quantitative skin distribution profiles.

Science.gov (United States)

Bonnel, David; Legouffe, Raphaël; Eriksson, André H; Mortensen, Rasmus W; Pamelard, Fabien; Stauber, Jonathan; Nielsen, Kim T

2018-04-01

Generation of skin distribution profiles and reliable determination of drug molecule concentration in the target region are crucial during the development process of topical products for treatment of skin diseases like psoriasis and atopic dermatitis. Imaging techniques like mass spectrometric imaging (MSI) offer sufficient spatial resolution to generate meaningful distribution profiles of a drug molecule across a skin section. In this study, we use matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to generate quantitative skin distribution profiles based on tissue extinction coefficient (TEC) determinations of four different molecules in cross sections of human skin explants after topical administration. The four drug molecules: roflumilast, tofacitinib, ruxolitinib, and LEO 29102 have different physicochemical properties. In addition, tofacitinib was administrated in two different formulations. The study reveals that with MALDI-MSI, we were able to observe differences in penetration profiles for both the four drug molecules and the two formulations and thereby demonstrate its applicability as a screening tool when developing a topical drug product. Furthermore, the study reveals that the sensitivity of the MALDI-MSI techniques appears to be inversely correlated to the drug molecules' ability to bind to the surrounding tissues, which can be estimated by their Log D values. Graphical abstract.
The development of high-content screening (HCS) technology and its importance to drug discovery.

Science.gov (United States)

Fraietta, Ivan; Gasparri, Fabio

2016-01-01

High-content screening (HCS) was introduced about twenty years ago as a promising analytical approach to facilitate some critical aspects of drug discovery. Its application has spread progressively within the pharmaceutical industry and academia to the point that it today represents a fundamental tool in supporting drug discovery and development. Here, the authors review some of significant progress in the HCS field in terms of biological models and assay readouts. They highlight the importance of high-content screening in drug discovery, as testified by its numerous applications in a variety of therapeutic areas: oncology, infective diseases, cardiovascular and neurodegenerative diseases. They also dissect the role of HCS technology in different phases of the drug discovery pipeline: target identification, primary compound screening, secondary assays, mechanism of action studies and in vitro toxicology. Recent advances in cellular assay technologies, such as the introduction of three-dimensional (3D) cultures, induced pluripotent stem cells (iPSCs) and genome editing technologies (e.g., CRISPR/Cas9), have tremendously expanded the potential of high-content assays to contribute to the drug discovery process. Increasingly predictive cellular models and readouts, together with the development of more sophisticated and affordable HCS readers, will further consolidate the role of HCS technology in drug discovery.
Leveling the playing field: bringing development of biomarkers and molecular diagnostics up to the standards for drug development.

Science.gov (United States)

Poste, George; Carbone, David P; Parkinson, David R; Verweij, Jaap; Hewitt, Stephen M; Jessup, J Milburn

2012-03-15

Molecular diagnostics are becoming increasingly important in clinical research to stratify or identify molecularly profiled patient cohorts for targeted therapies, to modify the dose of a therapeutic, and to assess early response to therapy or monitor patients. Molecular diagnostics can also be used to identify the pharmacogenetic risk of adverse drug reactions. The articles in this CCR Focus section on molecular diagnosis describe the development and use of markers to guide medical decisions regarding cancer patients. They define sources of preanalytic variability that need to be minimized, as well as the regulatory and financial challenges involved in developing diagnostics and integrating them into clinical practice. They also outline a National Cancer Institute program to assist diagnostic development. Molecular diagnostic clinical tests require rigor in their development and clinical validation, with sensitivity, specificity, and validity comparable to those required for the development of therapeutics. These diagnostics must be offered at a realistic cost that reflects both their clinical value and the costs associated with their development. When genome-sequencing technologies move into the clinic, they must be integrated with and traceable to current technology because they may identify more efficient and accurate approaches to drug development. In addition, regulators may define progressive drug approval for companion diagnostics that requires further evidence regarding efficacy and safety before full approval can be achieved. One way to accomplish this is to emphasize phase IV postmarketing, hypothesis-driven clinical trials with biological characterization that would permit an accurate definition of the association of low-prevalence gene alterations with toxicity or response in large cohorts.
Sex, gender, and pharmaceutical politics: From drug development to marketing.

Science.gov (United States)

Fisher, Jill A; Ronald, Lorna M

2010-08-01

Biological sex differences and sociocultural gender norms affect the provision of health care products and services, but there has been little explicit analysis of the impact of sex differences and gender norms on the regulation of pharmaceutical development and marketing. This article provides an overview of the regulation of pharmaceuticals and examines the ways that regulatory agencies account for sex and gender in their review of scientific data and marketing materials. The primary focus is on the US context, but information is also included about regulatory models in Europe, Canada, and Japan for comparative purposes. Specific examples show how sex differences and gender norms influence scientific and policy decisions about pharmaceuticals. The United States and Canada were found to be the only countries that have explicit requirements to include women in clinical trials and to perform sex-based subgroup analysis on study results. The potential influence of politics on regulatory decisions may have led to an uneven application of standards, as seen through the examples of mifepristone (for abortion) and sildenafil citrate (for erectile dysfunction). Three detailed case studies illustrate the importance of considering sex and gender in pharmaceutical development and marketing: Phase I clinical trials; human papillomavirus quadrivalent vaccine; and tegaserod, a drug for irritable bowel syndrome. Sex and gender play important roles in pharmaceutical regulation, from the design of clinical trials and the approval of new drugs to advertising and postmarketing surveillance. However, regulatory agencies pay insufficient attention to both biological sex differences and sociocultural gender norms. This disregard perpetuates inequalities by ignoring drug safety problems that predominate in women and by allowing misleading drug marketing that reinforces gender stereotypes. Recommendations have been made to improve the regulation of pharmaceuticals in regard to sex and
Drug development and manufacturing

Science.gov (United States)

Warner, Benjamin P.; McCleskey, T. Mark; Burrell, Anthony K.

2015-10-13

X-ray fluorescence (XRF) spectrometry has been used for detecting binding events and measuring binding selectivities between chemicals and receptors. XRF may also be used for estimating the therapeutic index of a chemical, for estimating the binding selectivity of a chemical versus chemical analogs, for measuring post-translational modifications of proteins, and for drug manufacturing.
Data-driven prediction of adverse drug reactions induced by drug-drug interactions.

Science.gov (United States)

Liu, Ruifeng; AbdulHameed, Mohamed Diwan M; Kumar, Kamal; Yu, Xueping; Wallqvist, Anders; Reifman, Jaques

2017-06-08

The expanded use of multiple drugs has increased the occurrence of adverse drug reactions (ADRs) induced by drug-drug interactions (DDIs). However, such reactions are typically not observed in clinical drug-development studies because most of them focus on single-drug therapies. ADR reporting systems collect information on adverse health effects caused by both single drugs and DDIs. A major challenge is to unambiguously identify the effects caused by DDIs and to attribute them to specific drug interactions. A computational method that provides prospective predictions of potential DDI-induced ADRs will help to identify and mitigate these adverse health effects. We hypothesize that drug-protein interactions can be used as independent variables in predicting ADRs. We constructed drug pair-protein interaction profiles for ~800 drugs using drug-protein interaction information in the public domain. We then constructed statistical models to score drug pairs for their potential to induce ADRs based on drug pair-protein interaction profiles. We used extensive clinical database information to construct categorical prediction models for drug pairs that are likely to induce ADRs via synergistic DDIs and showed that model performance deteriorated only slightly, with a moderate amount of false positives and false negatives in the training samples, as evaluated by our cross-validation analysis. The cross validation calculations showed an average prediction accuracy of 89% across 1,096 ADR models that captured the deleterious effects of synergistic DDIs. Because the models rely on drug-protein interactions, we made predictions for pairwise combinations of 764 drugs that are currently on the market and for which drug-protein interaction information is available. These predictions are publicly accessible at http://avoid-db.bhsai.org . We used the predictive models to analyze broader aspects of DDI-induced ADRs, showing that ~10% of all combinations have the potential to induce ADRs
Detecting drug-drug interactions using a database for spontaneous adverse drug reactions : an example with diuretics and non-steroidal anti-inflammatory drugs

NARCIS (Netherlands)

van Puijenbroek, E P; Egberts, A C; Heerdink, E R; Leufkens, H G

2000-01-01

OBJECTIVE: Drug-drug interactions are relatively rarely reported to spontaneous reporting systems (SRSs) for adverse drug reactions. For this reason, the traditional approach for analysing SRS has major limitations for the detection of drug-drug interactions. We developed a method that may enable
Journal of Research in National Development - Vol 8, No 2 (2010)

African Journals Online (AJOL)

Mystifying development policy strategies in the Niger Delta: The unending mistake · EMAIL FULL TEXT EMAIL FULL TEXT DOWNLOAD FULL TEXT ... Academic achievement and self-concept of secondary school students in Nigeria's federal capital territory · EMAIL FULL TEXT EMAIL FULL TEXT DOWNLOAD FULL TEXT ...
77 FR 69634 - International Conference on Harmonisation; Guidance on Q11 Development and Manufacture of Drug...

Science.gov (United States)

2012-11-20

...] International Conference on Harmonisation; Guidance on Q11 Development and Manufacture of Drug Substances... Administration (FDA) is announcing the availability of a guidance entitled ``Q11 Development and Manufacture of... guidance is intended to apply only to the manufacture of drug substance, not the manufacture of finished...
Development of a standardized, citywide process for managing smart-pump drug libraries.

Science.gov (United States)

Walroth, Todd A; Smallwood, Shannon; Arthur, Karen; Vance, Betsy; Washington, Alana; Staublin, Therese; Haslar, Tammy; Reddan, Jennifer G; Fuller, James

2018-06-15

Development and implementation of an interprofessional consensus-driven process for review and optimization of smart-pump drug libraries and dosing limits are described. The Indianapolis Coalition for Patient Safety (ICPS), which represents 6 Indianapolis-area health systems, identified an opportunity to reduce clinically insignificant alerts that smart infusion pumps present to end users. Through a consensus-driven process, ICPS aimed to identify best practices to implement at individual hospitals in order to establish specific action items for smart-pump drug library optimization. A work group of pharmacists, nurses, and industrial engineers met to evaluate variability within and lack of scrutiny of smart-pump drug libraries. The work group used Lean Six Sigma methodologies to generate a list of key needs and barriers to be addressed in process standardization. The group reviewed targets for smart-pump drug library optimization, including dosing limits, types of alerts reviewed, policies, and safety best practices. The work group also analyzed existing processes at each site to develop a final consensus statement outlining a model process for reviewing alerts and managing smart-pump data. Analysis of the total number of alerts per device across ICPS-affiliated health systems over a 4-year period indicated a 50% decrease (from 7.2 to 3.6 alerts per device per month) after implementation of the model by ICPS member organizations. Through implementation of a standardized, consensus-driven process for smart-pump drug library optimization, ICPS member health systems reduced clinically insignificant smart-pump alerts. Copyright © 2018 by the American Society of Health-System Pharmacists, Inc. All rights reserved.
Preventing Drug Abuse Among Hispanic Adolescents: Developing a Responsive Intervention Approach.

Science.gov (United States)

Schinke, Steven P; Schwinn, Traci M; Hursh, Hilary A

2015-10-01

Intervention research is essential to help Hispanic American adolescents avoid drug use. This article describes an intervention research program aimed at preventing drug use among these youths. Grounded in salient epidemiological data, the program is informed by bicultural competence, social learning, and motivational interviewing theories. The program, called Vamos, is aimed at the risk and protective factors as well as the cultural prerogatives that demark the adolescent years of Hispanic American youths. Innovative in its approach, the program is delivered through a smartphone application (app). By interacting with engaging content presented via the app, youths can acquire the cognitive-behavioral skills necessary to avoid risky situations, urges, and pressures associated with early drug use. The intervention development process is presented in detail, and an evaluation plan to determine the program's efficacy is outlined. Lessons for practice and intervention programming are discussed.
Bird Flu Fears: Is There a Better Way to Develop Drugs?

OpenAIRE

Dean Baker

2005-01-01

Government-granted patent monopolies have limited the ability to produce and stockpile large quantities of the drugs deemed most effective in treating the Avian Flu. This report examines alternative mechanisms for financing the development of pharmaceutical products.
Quasi-Drugs Developed in Japan for the Prevention or Treatment of Hyperpigmentary Disorders

Directory of Open Access Journals (Sweden)

Hideya Ando

2010-06-01

Full Text Available Excess production of melanin or its abnormal distribution, or both, can cause irregular hyperpigmentation of the skin, leading to melasma and age spots. To date, various quasi-drugs that prevent or improve hyperpigmentary disorders have been developed and officially approved by the Ministry of Health, Labor and Welfare of Japan. Many of these inhibit the activity of tyrosinase, an enzyme required for melanin synthesis, for example, by competitive or non-competitive inhibition of its catalytic activity, by inhibiting its maturation, or by accelerating its degradation. In this review, we categorize the quasi-drugs developed in Japan to prevent or treat hyperpigmentary disorders, or both, and discuss perspectives for future development.

From research on rare diseases to new orphan drug development

NARCIS (Netherlands)

Heemstra, H.E.

2010-01-01

Rare diseases have a prevalence of lower than 5 in 10,000 inhabitants and are life-threatening or chronically debilitating. It is estimated that worldwide more than 5000 rare diseases exist, which account for over 55 million patients in the EU and the US together. However, the development of drugs
Crowdfunding drug development: the state of play in oncology and rare diseases.

Science.gov (United States)

Dragojlovic, Nick; Lynd, Larry D

2014-11-01

In this article, we present descriptive data on 125 crowdfunding campaigns aimed at financing research in oncology (including basic research, drug discovery, and clinical trials). We also describe five campaigns that have succeeded in raising substantial funds to support the development of treatments for ultrarare diseases. The data suggest that crowdfunding is a viable approach to supporting early proof-of-concept research that could allow researchers in oncology and rare diseases to succeed in traditional grant competitions or to attract private investment. The data also suggest that such an approach could become a valuable additional source of funding for early-stage innovators in the drug development arena. Copyright © 2014 Elsevier Ltd. All rights reserved.
Di-22:6-bis(monoacylglycerol)phosphate: A clinical biomarker of drug-induced phospholipidosis for drug development and safety assessment

International Nuclear Information System (INIS)

Liu, Nanjun; Tengstrand, Elizabeth A.; Chourb, Lisa; Hsieh, Frank Y.

2014-01-01

The inability to routinely monitor drug-induced phospholipidosis (DIPL) presents a challenge in pharmaceutical drug development and in the clinic. Several nonclinical studies have shown di-docosahexaenoyl (22:6) bis(monoacylglycerol) phosphate (di-22:6-BMP) to be a reliable biomarker of tissue DIPL that can be monitored in the plasma/serum and urine. The aim of this study was to show the relevance of di-22:6-BMP as a DIPL biomarker for drug development and safety assessment in humans. DIPL shares many similarities with the inherited lysosomal storage disorder Niemann–Pick type C (NPC) disease. DIPL and NPC result in similar changes in lysosomal function and cholesterol status that lead to the accumulation of multi-lamellar bodies (myeloid bodies) in cells and tissues. To validate di-22:6-BMP as a biomarker of DIPL for clinical studies, NPC patients and healthy donors were classified by receiver operator curve analysis based on urinary di-22:6-BMP concentrations. By showing 96.7-specificity and 100-sensitivity to identify NPC disease, di-22:6-BMP can be used to assess DIPL in human studies. The mean concentration of di-22:6-BMP in the urine of NPC patients was 51.4-fold (p ≤ 0.05) above the healthy baseline range. Additionally, baseline levels of di-22:6-BMP were assessed in healthy non-medicated laboratory animals (rats, mice, dogs, and monkeys) and human subjects to define normal reference ranges for nonclinical/clinical studies. The baseline ranges of di-22:6-BMP in the plasma, serum, and urine of humans and laboratory animals were species dependent. The results of this study support the role of di-22:6-BMP as a biomarker of DIPL for pharmaceutical drug development and health care settings. - Highlights: • A reliable biomarker of drug-induced phospholipidosis (DIPL) is needed for humans. • Di-22:6-BMP is specific/sensitive for DIPL in animals as published in literatures. • The di-22:6-BMP biomarker can be validated for humans via NPC patients. • DIPL
Di-22:6-bis(monoacylglycerol)phosphate: A clinical biomarker of drug-induced phospholipidosis for drug development and safety assessment

Energy Technology Data Exchange (ETDEWEB)

Liu, Nanjun; Tengstrand, Elizabeth A.; Chourb, Lisa; Hsieh, Frank Y., E-mail: frank.hsieh@nextcea.com

2014-09-15

The inability to routinely monitor drug-induced phospholipidosis (DIPL) presents a challenge in pharmaceutical drug development and in the clinic. Several nonclinical studies have shown di-docosahexaenoyl (22:6) bis(monoacylglycerol) phosphate (di-22:6-BMP) to be a reliable biomarker of tissue DIPL that can be monitored in the plasma/serum and urine. The aim of this study was to show the relevance of di-22:6-BMP as a DIPL biomarker for drug development and safety assessment in humans. DIPL shares many similarities with the inherited lysosomal storage disorder Niemann–Pick type C (NPC) disease. DIPL and NPC result in similar changes in lysosomal function and cholesterol status that lead to the accumulation of multi-lamellar bodies (myeloid bodies) in cells and tissues. To validate di-22:6-BMP as a biomarker of DIPL for clinical studies, NPC patients and healthy donors were classified by receiver operator curve analysis based on urinary di-22:6-BMP concentrations. By showing 96.7-specificity and 100-sensitivity to identify NPC disease, di-22:6-BMP can be used to assess DIPL in human studies. The mean concentration of di-22:6-BMP in the urine of NPC patients was 51.4-fold (p ≤ 0.05) above the healthy baseline range. Additionally, baseline levels of di-22:6-BMP were assessed in healthy non-medicated laboratory animals (rats, mice, dogs, and monkeys) and human subjects to define normal reference ranges for nonclinical/clinical studies. The baseline ranges of di-22:6-BMP in the plasma, serum, and urine of humans and laboratory animals were species dependent. The results of this study support the role of di-22:6-BMP as a biomarker of DIPL for pharmaceutical drug development and health care settings. - Highlights: • A reliable biomarker of drug-induced phospholipidosis (DIPL) is needed for humans. • Di-22:6-BMP is specific/sensitive for DIPL in animals as published in literatures. • The di-22:6-BMP biomarker can be validated for humans via NPC patients. • DIPL
Formulation and development of a self-nanoemulsifying drug delivery system of irbesartan

Directory of Open Access Journals (Sweden)

Jaydeep Patel

2011-01-01

Full Text Available Irbesartan (IRB is an angiotensin II receptor blocker antihypertensive agent. The aim of the present investigation was to develop a self-nanoemulsifying drug delivery system (SNEDDS to enhance the oral bioavailability of poorly water-soluble IRB. The solubility of IRB in various oils was determined to identify the oil phase of SNEDDS. Various surfactants and co-surfactants were screened for their ability to emulsify the selected oil. Pseudoternary phase diagrams were constructed to identify the efficient self-emulsifying region. The optimized SNEDDS formulation contained IRB (75 mg, Cremophor® EL (43.33%, Carbitol® (21.67% and Capryol® 90 (32%. SNEDDS was further evaluated for its percentage transmittance, emulsification time, drug content, phase separation, dilution, droplet size and zeta potential. The optimized formulation of IRB-loaded SNEDDS exhibited complete in vitro drug release in 15 min as compared with the plain drug, which had a limited dissolution rate. It was also compared with the pure drug solution by oral administration in male Wister rats. The in vivo study exhibited a 7.5-fold increase in the oral bioavailability of IRB from SNEDDS compared with the pure drug solution. These results suggest the potential use of SNEDDS to improve dissolution and oral bioavailability of poorly water-soluble IRB.
Development of a rational scale to assess the harm of drugs of potential misuse.

Science.gov (United States)

Nutt, David; King, Leslie A; Saulsbury, William; Blakemore, Colin

2007-03-24

Drug misuse and abuse are major health problems. Harmful drugs are regulated according to classification systems that purport to relate to the harms and risks of each drug. However, the methodology and processes underlying classification systems are generally neither specified nor transparent, which reduces confidence in their accuracy and undermines health education messages. We developed and explored the feasibility of the use of a nine-category matrix of harm, with an expert delphic procedure, to assess the harms of a range of illicit drugs in an evidence-based fashion. We also included five legal drugs of misuse (alcohol, khat, solvents, alkyl nitrites, and tobacco) and one that has since been classified (ketamine) for reference. The process proved practicable, and yielded roughly similar scores and rankings of drug harm when used by two separate groups of experts. The ranking of drugs produced by our assessment of harm differed from those used by current regulatory systems. Our methodology offers a systematic framework and process that could be used by national and international regulatory bodies to assess the harm of current and future drugs of abuse.
Management of premature rupture of membranes at term: the need to correct a recurring mistake in articles, chapters, and recommendations of professional organizations.

Science.gov (United States)

Krispin, Eyal

2017-12-01

Recommendations about the management of premature rupture of membranes at term are based, in part, on a large, randomized controlled trial published in 1996: the TERMPROM trial. The original article contained an error in Table 1, in which "Interval from membrane rupture to delivery" was listed instead of "Interval from membrane rupture to study entry." While the authors and journal corrected this error, the mistake published in the original paper has made its way into subsequent publications and even in guidelines or practice bulletins issued by professional organizations, textbooks, and other publications around the world. The mistake, that half of women with premature rupture of membranes at term who were managed expectantly delivered within 5 hours and 95% delivered within 28 hours of membrane rupture, should be replaced with the actual fact that half of women with premature rupture of membranes at term who were managed expectantly delivered within 33 hours, and 95% delivered within 94-107 hours of membrane rupture. Correcting this error in contemporary health care information and publications is important to counsel patients accurately and to optimize the clinical care of women with premature rupture of membranes at term. Copyright © 2017 Elsevier Inc. All rights reserved.
Development of an opioid self-administration assay to study drug seeking in zebrafish.

Science.gov (United States)

Bossé, Gabriel D; Peterson, Randall T

2017-09-29

The zebrafish (Danio rerio) has become an excellent tool to study mental health disorders, due to its physiological and genetic similarity to humans, ease of genetic manipulation, and feasibility of small molecule screening. Zebrafish have been shown to exhibit characteristics of addiction to drugs of abuse in non-contingent assays, including conditioned place preference, but contingent assays have been limited to a single assay for alcohol consumption. Using inexpensive electronic, mechanical, and optical components, we developed an automated opioid self-administration assay for zebrafish, enabling us to measure drug seeking and gain insight into the underlying biological pathways. Zebrafish trained in the assay for five days exhibited robust self-administration, which was dependent on the function of the μ-opioid receptor. In addition, a progressive ratio protocol was used to test conditioned animals for motivation. Furthermore, conditioned fish continued to seek the drug despite an adverse consequence and showed signs of stress and anxiety upon withdrawal of the drug. Finally, we validated our assay by confirming that self-administration in zebrafish is dependent on several of the same molecular pathways as in other animal models. Given the ease and throughput of this assay, it will enable identification of important biological pathways regulating drug seeking and could lead to the development of new therapeutic molecules to treat addiction. Copyright © 2017 Elsevier B.V. All rights reserved.
Discovery and development of new antibacterial drugs: learning from experience?

Science.gov (United States)

Jackson, Nicole; Czaplewski, Lloyd; Piddock, Laura J V

2018-06-01

Antibiotic (antibacterial) resistance is a serious global problem and the need for new treatments is urgent. The current antibiotic discovery model is not delivering new agents at a rate that is sufficient to combat present levels of antibiotic resistance. This has led to fears of the arrival of a 'post-antibiotic era'. Scientific difficulties, an unfavourable regulatory climate, multiple company mergers and the low financial returns associated with antibiotic drug development have led to the withdrawal of many pharmaceutical companies from the field. The regulatory climate has now begun to improve, but major scientific hurdles still impede the discovery and development of novel antibacterial agents. To facilitate discovery activities there must be increased understanding of the scientific problems experienced by pharmaceutical companies. This must be coupled with addressing the current antibiotic resistance crisis so that compounds and ultimately drugs are delivered to treat the most urgent clinical challenges. By understanding the causes of the failures and successes of the pharmaceutical industry's research history, duplication of discovery programmes will be reduced, increasing the productivity of the antibiotic drug discovery pipeline by academia and small companies. The most important scientific issues to address are getting molecules into the Gram-negative bacterial cell and avoiding their efflux. Hence screening programmes should focus their efforts on whole bacterial cells rather than cell-free systems. Despite falling out of favour with pharmaceutical companies, natural product research still holds promise for providing new molecules as a basis for discovery.
77 FR 35028 - Bill Alexander, M.D.; Decision and Order

Science.gov (United States)

2012-06-12

... characterized as a mistake, he was transporting marijuana for a drug trafficking organization because he needed... occasions he transported large quantities of marijuana for a drug trafficking organization, is not... marijuana for a drug trafficking organization and was paid to do so. GX 7, at 2-3. This conduct also...
Development of the generic drug industry in the US after the Hatch-Waxman Act of 1984

Directory of Open Access Journals (Sweden)

Garth Boehm

2013-09-01

Full Text Available The key events in the development of the US generic drug industry after the Hatch-Waxman Act of 1984 are systematically reviewed, including the process of approval for generic drugs, bioequivalence issues including “switchability”, bioequivalence for complicated dosage forms, patent extension, generic drug safety, generic substitution and low-cost generics. The backlog in generic review, generic drug user fees, and “quality by design” for generic drugs is also discussed. The evolution of the US generic drug industry after the Hatch-Waxman Act in 1984 has afforded several lessons of great benefit to other countries wishing to establish or re-establish a domestic generic drug industry.
Current status in development of new EXFOR editor

International Nuclear Information System (INIS)

Sarsembayeva, A.; Ebata, S.; Kato, K.; Aikawa, M.; Imai, S.; Chiba, M.; Otuka, N.

2016-01-01

A new stand-alone type editor for EXFOR is being developed in Hokkaido University Nuclear Reaction Data Centre (JCPRG). The new editor is designed to allow compilers to save time and to avoid mistakes by using its advanced features. The features included in the latest release are described such as filterable and dynamic suggestion fields. (author)
Discovery and Development of Therapeutic Drugs against Lethal Human RNA Viruses: a Multidisciplinary Assault.

Science.gov (United States)

1991-07-16

AD-A239 742 AD GRANT NO: DAMD17-89-Z-9021 TITLE: DISCOVERY AND DEVELOPMENT OF THERAPEUTIC DRUGS AGAINST LETHAL HUMAN RNA VIRUSES: A MULTIDISCIPLINARY...62787A871 AB WrJDA317987 11. TITLE (Include Securty Classification) DISCOVERY AND DEVELOPMENT OF THERAPEUTIC DRUGS AGAINST LETHAL HUMAN RNA VIRUSES: A...G. R. Pettit, III, D.-S. Huang, and G. R. Pettit, 23rd Int’l. Horticulture Congress, Italy, 8/27 - 9/1/90. "Bryostatins Define the Role of Protein
Collaboration with Pharma Will Introduce Nanotechnologies in Early Stage Drug Development | Poster

Science.gov (United States)

The Frederick National Lab has begun to assist several major pharmaceutical companies in adopting nanotechnologies in early stage drug development, when the approach is most efficient and cost-effective.
Development and evaluation of accelerated drug release testing methods for a matrix-type intravaginal ring.

Science.gov (United States)

Externbrink, Anna; Eggenreich, Karin; Eder, Simone; Mohr, Stefan; Nickisch, Klaus; Klein, Sandra

2017-01-01

Accelerated drug release testing is a valuable quality control tool for long-acting non-oral extended release formulations. Currently, several intravaginal ring candidates designed for the long-term delivery of steroids or anti-infective drugs are being in the developing pipeline. The present article addresses the demand for accelerated drug release methods for these formulations. We describe the development and evaluation of accelerated release methods for a steroid releasing matrix-type intravaginal ring. The drug release properties of the formulation were evaluated under real-time and accelerated test conditions. Under real-time test conditions drug release from the intravaginal ring was strongly affected by the steroid solubility in the release medium. Under sufficient sink conditions that were provided in release media containing surfactants drug release was Fickian diffusion driven. Both temperature and hydro-organic dissolution media were successfully employed to accelerate drug release from the formulation. Drug release could be further increased by combining the temperature effect with the application of a hydro-organic release medium. The formulation continued to exhibit a diffusion controlled release kinetic under the investigated accelerated conditions. Moreover, the accelerated methods were able to differentiate between different prototypes of the intravaginal ring that exhibited different release profiles under real-time test conditions. Overall, the results of the present study indicate that both temperature and hydro-organic release media are valid parameters for accelerating drug release from the intravaginal ring. Variation of either a single or both parameters yielded release profiles that correlated well with real-time release. Copyright © 2016 Elsevier B.V. All rights reserved.
Orphan drugs

OpenAIRE

Goločorbin-Kon, Svetlana; Vojinović, Aleksandra; Lalić-Popović, Mladena; Pavlović, Nebojša; Mikov, Momir

2013-01-01

Introduction. Drugs used for treatment of rare diseases are known worldwide under the term of orphan drugs because pharmaceutical companies have not been interested in ”adopting” them, that is in investing in research, developing and producing these drugs. This kind of policy has been justified by the fact that these drugs are targeted for small markets, that only a small number of patients is available for clinical trials, and that large investments are required for the development of ...
78 FR 66744 - Draft Guidance for Industry on Pulmonary Tuberculosis: Developing Drugs for Treatment; Availability

Science.gov (United States)

2013-11-06

...] Draft Guidance for Industry on Pulmonary Tuberculosis: Developing Drugs for Treatment; Availability...) is announcing the availability of a draft guidance for industry entitled ``Pulmonary Tuberculosis... of antimycobacterial drugs for the treatment of pulmonary tuberculosis. This guidance applies to the...
Interdisciplinary researches for potential developments of drugs and natural products

Directory of Open Access Journals (Sweden)

Arunrat Chaveerach

2017-04-01

Full Text Available Developments of drugs or natural products from plants are possibly made, simple to use and lower cost than modern drugs. The development processes can be started with studying local wisdom and literature reviews to choose the plants which have long been used in diverse areas, such as foods, traditional medicine, fragrances and seasonings. Then those data will be associated with scientific researches, namely plant collection and identification, phytochemical screening by gas chromatography-mass spectrometry, pharmacological study/review for their functions, and finally safety and efficiency tests in human. For safety testing, in vitro cell toxicity by cell viability assessment and in vitro testing of DNA breaks by the comet assay in human peripheral blood mononuclear cells can be performed. When active chemicals and functions containing plants were chosen with safety and efficacy for human uses, then, the potential medicinal natural products will be produced. Based on these procedures, the producing cost will be cheaper and the products can be evaluated for their clinical properties. Thus, the best and lowest-priced medicines and natural products can be distributed worldwide.
Interdisciplinary researches for potential developments of drugs and natural products

Institute of Scientific and Technical Information of China (English)

Arunrat Chaveerach; Runglawan Sudmoon; Tawatchai Tanee

2017-01-01

Developments of drugs or natural products from plants are possibly made,simple to use and lower cost than modern drugs.The development processes can be started with studying local wisdom and literature reviews to choose the plants which have long been used in diverse areas,such as foods,traditional medicine,fragrances and seasonings.Then those data will be associated with scientific researches,namely plant collection and identification,phytochemical screening by gas chromatography-mass spectrometry,pharmacological study/review for their functions,and finally safety and efficiency tests in human.For safety testing,in vitro cell toxicity by cell viability assessment and in vitro testing of DNA breaks by the comet assay in human peripheral blood mononuclear cells can be performed.When active chemicals and functions containing plants were chosen with safety and efficacy for human uses,then,the potential medicinal natural products will be produced.Based on these procedures,the producing cost will be cheaper and the products can be evaluated for their clinical properties.Thus,the best and lowest-priced medicines and natural products can be distributed worldwide.
Exploring Professional Identity Development in Alcohol and Drug Counselors in the 21st Century

Science.gov (United States)

Simmons, Lori; Haas, Deborah; Massella, John; Young, Jared; Toth, Paul

2017-01-01

Professional identity development is an emerging area for alcohol and drug counselors. Few studies have investigated professional identity in alcohol and drug counselors (Ogborne, Braun, & Schmidt, 2001; Massella, Simons, Young, Haas, & Toth 2013). The goal of the current study is to add to this area of research. A total of 1,333 certified…

What does systems biology mean for drug development?

Science.gov (United States)

Schrattenholz, André; Soskić, Vukić

2008-01-01

regard to a new focus on agents that modulate multiple targets simultaneously. Targeting cellular function as a system rather than on the level of the single protein molecule significantly increases the size of the drugable proteome and is expected to introduce novel classes of multi-target drugs with fewer adverse effects and toxicity. Multiple target approaches have recently been used to design medications against atherosclerosis, cancer, depression, psychosis and neurodegenerative diseases. A focussed approach towards "systemic" drugs will certainly require the development of novel computational and mathematical concepts for appropriate modelling of complex data and extraction of "screenable" information from biological systems essentially ruled by deterministic chaotic processes on a background of individual stochasticity.
Scientific and Regulatory Considerations in Solid Oral Modified Release Drug Product Development.

Science.gov (United States)

Li, Min; Sander, Sanna; Duan, John; Rosencrance, Susan; Miksinski, Sarah Pope; Yu, Lawrence; Seo, Paul; Rege, Bhagwant

2016-11-01

This review presents scientific and regulatory considerations for the development of solid oral modified release (MR) drug products. It includes a rationale for patient-focused development based on Quality-by-Design (QbD) principles. Product and process understanding of MR products includes identification and risk-based evaluation of critical material attributes (CMAs), critical process parameters (CPPs), and their impact on critical quality attributes (CQAs) that affect the clinical performance. The use of various biopharmaceutics tools that link the CQAs to a predictable and reproducible clinical performance for patient benefit is emphasized. Product and process understanding lead to a more comprehensive control strategy that can maintain product quality through the shelf life and the lifecycle of the drug product. The overall goal is to develop MR products that consistently meet the clinical objectives while mitigating the risks to patients by reducing the probability and increasing the detectability of CQA failures.
Drugs in development for toxoplasmosis: advances, challenges, and current status.

Science.gov (United States)

Alday, P Holland; Doggett, Joseph Stone

2017-01-01

Toxoplasma gondii causes fatal and debilitating brain and eye diseases. Medicines that are currently used to treat toxoplasmosis commonly have toxic side effects and require prolonged courses that range from weeks to more than a year. The need for long treatment durations and the risk of relapsing disease are in part due to the lack of efficacy against T. gondii tissue cysts. The challenges for developing a more effective treatment for toxoplasmosis include decreasing toxicity, achieving therapeutic concentrations in the brain and eye, shortening duration, eliminating tissue cysts from the host, safety in pregnancy, and creating a formulation that is inexpensive and practical for use in resource-poor areas of the world. Over the last decade, significant progress has been made in identifying and developing new compounds for the treatment of toxoplasmosis. Unlike clinically used medicines that were repurposed for toxoplasmosis, these compounds have been optimized for efficacy against toxoplasmosis during preclinical development. Medicines with enhanced efficacy as well as features that address the unique aspects of toxoplasmosis have the potential to greatly improve toxoplasmosis therapy. This review discusses the facets of toxoplasmosis that are pertinent to drug design and the advances, challenges, and current status of preclinical drug research for toxoplasmosis.
Drug use trajectory patterns among older drug users

Directory of Open Access Journals (Sweden)

Tyndall B

2011-05-01

Full Text Available Miriam Boeri, Thor Whalen, Benjamin Tyndall, Ellen BallardKennesaw State University, Department of Sociology and Criminal Justice, Kennesaw GA, USAAbstract: To better understand patterns of drug use trajectories over time, it is essential to have standard measures of change. Our goal here is to introduce measures we developed to quantify change in drug use behaviors. A secondary goal is to provide effective visualizations of these trajectories for applied use. We analyzed data from a sample of 92 older drug users (ages 45 to 65 to identify transition patterns in drug use trajectories across the life course. Data were collected for every year since birth using a mixed methods design. The community-drawn sample of active and former users were 40% female, 50% African American, and 60% reporting some college or greater. Their life histories provided retrospective longitudinal data on the diversity of paths taken throughout the life course and changes in drug use patterns that occurred over time. Bayesian analysis was used to model drug trajectories displayed by innovative computer graphics. The mathematical techniques and visualizations presented here provide the foundation for future models using Bayesian analysis. In this paper we introduce the concepts of transition counts, transition rates and relapse/remission rates, and we describe how these measures can help us better understand drug use trajectories. Depicted through these visual tools, measurements of discontinuous patterns provide a succinct view of individual drug use trajectories. The measures we use on drug use data will be further developed to incorporate contextual influences on the drug trajectory and build predictive models that inform rehabilitation efforts for drug users. Although the measures developed here were conceived to better examine drug use trajectories, the applications of these measures can be used with other longitudinal datasets.Keywords: drug use, trajectory patterns
Framework programmable platform for the advanced software development workstation. Integration mechanism design document

Science.gov (United States)

Mayer, Richard J.; Blinn, Thomas M.; Mayer, Paula S. D.; Reddy, Uday; Ackley, Keith; Futrell, Mike

1991-01-01

The Framework Programmable Software Development Platform (FPP) is a project aimed at combining effective tool and data integration mechanisms with a model of the software development process in an intelligent integrated software development environment. Guided by this model, this system development framework will take advantage of an integrated operating environment to automate effectively the management of the software development process so that costly mistakes during the development phase can be eliminated.
Clinical Drug-Drug Pharmacokinetic Interaction Potential of Sucralfate with Other Drugs: Review and Perspectives.

Science.gov (United States)

Sulochana, Suresh P; Syed, Muzeeb; Chandrasekar, Devaraj V; Mullangi, Ramesh; Srinivas, Nuggehally R

2016-10-01

Sucralfate, a complex of aluminium hydroxide with sulfated sucrose, forms a strong gastrointestinal tract (GIT) mucosal barrier with excellent anti-ulcer property. Because sucralfate does not undergo any significant oral absorption, sucralfate resides in the GIT for a considerable length of time. The unabsorbed sucralfate may alter the pharmacokinetics of the oral drugs by impeding its absorption and reducing the oral bioavailability. Because of the increased use of sucralfate, it was important to provide a reappraisal of the published clinical drug-drug interaction studies of sucralfate with scores of drugs. This review covers several category of drugs such as non-steroidal anti-inflammatory drugs, fluoroquinolones, histamine H2-receptor blockers, macrolides, anti-fungals, anti-diabetics, salicylic acid derivatives, steroidal anti-inflammatory drugs and provides pharmacokinetic data summary along with study design, objectives and key remarks. While the loss of oral bioavailability was significant for the fluoroquinolone class, it generally varied for other classes of drugs, suggesting that impact of the co-administration of sucralfate is manageable in clinical situations. Given the technology advancement in formulation development, it may be in order feasible to develop appropriate formulation strategies to either avoid or minimize the absorption-related issues when co-administered with sucralfate. It is recommended that consideration of both in vitro and preclinical studies may be in order to gauge the level of interaction of a drug with sucralfate. Such data may aid in the development of appropriate strategies to navigate the co-administration of sucralfate with other drugs in this age of polypharmacy.
When ubiquitin meets NF-κB: a trove for anti-cancer drug development.

Science.gov (United States)

Wu, Zhao-Hui; Shi, Yuling

2013-01-01

During the last two decades, the studies on ubiquitination in regulating transcription factor NF-κB activation have elucidated the expanding role of ubiquitination in modulating cellular events by non-proteolytic mechanisms, as well as by proteasomal degradation. The significance of ubiquitination has also been recognized in regulating gene transcription, epigenetic modifications, kinase activation, DNA repair and subcellular translocation. This progress has been translated into novel strategies for developing anti-cancer therapeutics, exemplified by the success of the first FDA-approved proteasome inhibitor drug Bortezomib. Here we discuss the current understanding of the ubiquitin-proteasome system and how it is involved in regulating NF-κB signaling pathways in response to a variety of stimuli. We also focus on the recent progress of anti-cancer drug development targeting various steps of ubiquitination process, and the potential of these drugs in cancer treatment as related to their impact on NF-κB activation.
Innovator Organizations in New Drug Development: Assessing the Sustainability of the Biopharmaceutical Industry.

Science.gov (United States)

Kinch, Michael S; Moore, Ryan

2016-06-23

The way new medicines are discovered and brought to market has fundamentally changed over the last 30 years. Our previous analysis showed that biotechnology companies had contributed significantly to the US Food and Drug Administration approval of new molecular entities up to the mid-1980s, when the trends started to decline. Although intriguing, the focus on biotechnology necessarily precluded the wider question of how the biopharmaceutical industry has been delivering on its goals to develop new drugs. Here, we present a comprehensive analysis of all biopharmaceutical innovators and uncover unexpected findings. The present biopharmaceutical industry grew steadily from 1800 to 1950 and then stagnated for two decades, before a burst of growth attributable to the biotechnology revolution took place; but consolidation has reduced the number of active and independent innovators to a level not experienced since 1945. The trajectories and trends we observe raise fundamental questions about biopharmaceutical innovators and the sustainability of the drug-development enterprise. Copyright © 2016 Elsevier Ltd. All rights reserved.
Is Popper's Falsificationist Heuristic a Helpful Resource for Developing Critical Thinking?

Science.gov (United States)

Lam, Chi-Ming

2007-01-01

Based on a rather simple thesis that we can learn from our mistakes, Karl Popper developed a falsificationist epistemology in which knowledge grows through falsifying, or criticizing, our theories. According to him, knowledge, especially scientific knowledge, progresses through conjectures (i.e. tentative solutions to problems) that are controlled…
A drug's life: the pathway to drug approval.

Science.gov (United States)

Keng, Michael K; Wenzell, Candice M; Sekeres, Mikkael A

2013-10-01

In the United States, drugs and medical devices are regulated by the US Food and Drug Administration (FDA). A drug must undergo rigorous testing prior to marketing to and medical use by the general public. The FDA grants marketing approval for drug products based on a comprehensive review of safety and efficacy data. This review article explains the history behind the establishment of the FDA and examines the historical legislation and approval processes for drugs, specifically in the fields of medical oncology and hematology. The agents imatinib (Gleevec, Novartis) and decitabine (Dacogen, Eisai) are used to illustrate both the current FDA regulatory process-specifically the orphan drug designation and accelerated approval process-and why decitabine failed to gain an indication for acute myeloid leukemia. The purpose and construct of the Oncologic Drugs Advisory Committee are also discussed, along with examples of 2 renal cell cancer drugs-axitinib (Inlyta, Pfizer) and tivozanib-that used progression-free survival as an endpoint. Regulatory approval of oncology drugs is the cornerstone of the development of new treatment agents and modalities, which lead to improvements in the standard of cancer care. The future landscape of drug development and regulatory approval will be influenced by the new breakthrough therapy designation, and choice of drug will be guided by genomic insights.
78 FR 9396 - Draft Guidance for Industry on Alzheimer's Disease: Developing Drugs for the Treatment of Early...

Science.gov (United States)

2013-02-08

...] Draft Guidance for Industry on Alzheimer's Disease: Developing Drugs for the Treatment of Early Stage... ``Alzheimer's Disease: Developing Drugs for the Treatment of Early Stage Disease.'' This guidance outlines FDA... trials that are specifically focused on the treatment of patients with established Alzheimer's disease...
The impact of the Orphan Drug Act on drug discovery.

Science.gov (United States)

Haffner, Marlene E; Maher, Paul D

2006-11-01

For nearly a quarter of a century the FDA Office of Orphan Products Development has administered the US Orphan Drug Act, which assists in bringing a wide variety of drug and biological (drug) products to treat rare diseases to market. Enthusiasm for rare disease product development has been sustained, seen throughout a wide spectrum of product types and disease conditions, and has resulted in clinically meaningful medical advances. Development of programmes for rare disease treatment worldwide, coupled with the development of drugs for diseases affecting developing countries, attests to the strength of this legislation. The marketing of almost 300 products in the US for rare diseases also testifies to the depth and intensity of scientific endeavour in this area.
Developing new drugs for ovarian cancer: a challenging task in a changing reality.

Science.gov (United States)

Canetta, R M; Carter, S K

1984-01-01

Recent therapeutic and technological advances have profoundly modified the parameters of new drug testing in ovarian cancer. The potential of compounds tested today in this disease therefore needs to be assessed according to this changing reality. Previous treatment with or without cisplatin is the criterion we have applied in our review of the single agent clinical data. Results obtained with older compounds have also been, when possible, reassessed in order to facilitate a comparative interpretation of recent trials. A brief overview of the most recently developed laboratory screening models has been conducted in order to stress their close relationship and their crucial role in future new drug development.
Development of PET and SPECT radiopharmaceuticals to study multi-drug resistance (MDR)

International Nuclear Information System (INIS)

Katsififs, A.; Dikic, B.; Greguric, I.; Knott, R.; Mattner, F.

2002-01-01

Full text: Cellular resistance or Multidrug Resistance (MDR) to cytotoxic agents is the major cause of treatment failure in many human cancers. P-glycoprotein (Pgp), a Mr 17,0000 transmembrane protein and Multi Resistance Protein (MRP) are two proteins that are over expressed and confer resistance to a large number of chemotherapeutic agents by enhancing their extracellular transport. P-glycoprotein is expressed at a relative high level in treated and untreated human malignant tumours, including renal, colonic, adrenal, hepatocellular carcinoma and a considerable percentage of breast carcinomas. 99m Tc-Sestamibi, a lipophilic cationic complex is a transport substrate for Pgp. In clinical studies of human neoplasms it was found that tumour uptake and clearance of this tracer correlate with Pgp expression and may be used for the phenotypic assessment of MDR. However, new tracers with better substrate specificity for Pgp and other drug transporters would greatly assist in optimising chemotherapeutic treatment and improving patient management by predicting tumour response to therapy and to assist in the development of antagonists, which may reverse or halt MDR. The aim of this project is therefore to develop PET and SPECT radiopharmaceuticals with improved affinity and selectivity for Pgp and MRP for the clinical evaluation of MDR in cancer patients. To optimise cellular transport characteristics, a number of chemical families that have been found to be substrates of Pgp and other drug efflux pumps, will be investigated. In the first instance, a series of drugs based on the flavonol natural product, Quercetin will be developed, screened for MDR and radiolabelled with PET and SPECT isotopes. Quercetin and related flavonol derivatives have been selected for this project because of their moderate to good affinity for Pgp. With the assistance of molecular modeling and in vitro studies, structural modification will be undertaken to improve the specificity and affinity for
[Drug-Drug Interactions with Consideration of Pharmacogenetics].

Science.gov (United States)

Ozawa, Shogo

2018-01-01

　Elderly patients often suffer from a variety of diseases and therefore may be prescribed several kinds of drugs. Interactions between these drugs may cause problems in some patients. Guidelines for drug interactions were released on July 8, 2014 "Drug Interaction Guideline for Drug Development and Labeling Recommendations (Final Draft)". These guidelines include the theoretical basis for evaluating the mechanisms of drug interaction, the possible extent of drug interactions, and take into consideration special populations (e.g., infants, children, elderly patients, patients with hepatic or renal dysfunction, and subjects with minor deficient alleles for drug metabolizing enzymes and drug transporters). In this symposium article, I discuss this last special population: altered drug metabolism and drug interactions in subjects with minor alleles of genes encoding deficient drug metabolizing enzymes. I further discuss a drug label for eliglustat (Cerdelga) with instructions for patients with ultra-rapid, extensive, intermediate, and poor metabolizer phenotypes that arise from different CYP2D6 gene alleles.
Medication Development of Ibogaine as a Pharmacotherapy for Drug Dependencea.

Science.gov (United States)

Mash, Deborah C; Kovera, Craig A; Buck, Billy E; Norenberg, Michael D; Shapshak, Paul; Hearn, W Lee; Sanchez-Ramos, Juan

1998-05-01

The potential for deriving new psychotherapeutic medications from natural sources has led to renewed interest in rain forest plants as a source of lead compounds for the development of antiaddiction medications. Ibogaine is an indole alkaloid found in the roots of Tabernanthe iboga (Apocynaceae family), a rain forest shrub that is native to equatorial Africa. Ibogaine is used by indigenous peoples in low doses to combat fatigue, hunger and in higher doses as a sacrament in religious rituals. Members of American and European addict self-help groups have claimed that ibogaine promotes long-term drug abstinence from addictive substances, including psychostimulants and cocaine. Anecdotal reports attest that a single dose of ibogaine eliminates withdrawal symptoms and reduces drug cravings for extended periods of time. The purported antiaddictive properties of ibogaine require rigorous validation in humans. We have initiated a rising tolerance study using single administration to assess the safety of ibogaine for the treatment of cocaine dependency. The primary objectives of the study are to determine safety, pharmacokinetics and dose effects, and to identify relevant parameters of efficacy in cocaine-dependent patients. Pharmacokinetic and pharmacodynamic characteristics of ibogaine in humans are assessed by analyzing the concentration-time data of ibogaine and its desmethyl metabolite (noribogaine) from the Phase I trial, and by conducting in vitro experiments to elucidate the specific disposition processes involved in the metabolism of both parent drug and metabolite. The development of clinical safety studies of ibogaine in humans will help to determine whether there is a rationale for conducting efficacy trials in the future.
Medication development of ibogaine as a pharmacotherapy for drug dependence.

Science.gov (United States)

Mash, D C; Kovera, C A; Buck, B E; Norenberg, M D; Shapshak, P; Hearn, W L; Sanchez-Ramos, J

1998-05-30

The potential for deriving new psychotherapeutic medications from natural sources has led to renewal interest in rain forest plants as a source of lead compounds for the development of antiaddiction medications. Ibogaine is an indole alkaloid found in the roots of Tabernanthe iboga (Apocynaceae family), a rain forest shrub that is native to equatorial Africa. Ibogaine is used by indigenous peoples in low doses to combat fatigue, hunger and in higher doses as a sacrament in religious rituals. Members of American and European addict self-help groups have claimed that ibogaine promotes long-term drug abstinence from addictive substances, including psychostimulants and cocaine. Anecdotal reports attest that a single dose of ibogaine eliminates withdrawal symptoms and reduces drug cravings for extended periods of time. The purported antiaddictive properties of ibogaine require rigorous validation in humans. We have initiated a rising tolerance study using single administration to assess the safety of ibogaine for treatment of cocaine dependency. The primary objectives of the study are to determine safety, pharmacokinetics and dose effects, and to identify relevant parameters of efficacy in cocaine-dependent patients. Pharmacokinetic and pharmacodynamic characteristics of ibogaine in humans are assessed by analyzing the concentration-time data of ibogaine and its desmethyl metabolite (noribogaine) from the Phase I trial, and by conducting in vitro experiments to elucidate the specific disposition processes involved in the metabolism of both parent drug and metabolite. The development of clinical safety studies of ibogaine in humans will help to determine whether there is a rationale for conducting efficacy trials in the future.
Re-Inventing Infectious Disease: Antibiotic Resistance and Drug Development at the Bayer Company 1945-80.

Science.gov (United States)

Gradmann, Christoph

2016-04-01

This paper analyses how research on antibiotic resistance has been a driving force in the development of new antibiotics. Drug resistance, while being a problem for physicians and patients, offers attractive perspectives for those who research and develop new medicines. It imposes limits on the usability of older medicines and simultaneously modifies pathologies in a way that opens markets for new treatments. Studying resistance can thus be an important part of developing and marketing antibiotics. The chosen example is that of the German pharmaceutical company Bayer. Before World War Two, Bayer had pioneered the development of anti-infective chemotherapy, sulpha drugs in particular, but had missed the boat when it came to fungal antibiotics. Exacerbated by the effects of war, Bayer's world market presence, which had been considerable prior to the war, had plummeted. In this critical situation, the company opted for a development strategy that tried to capitalise on the problems created by the use of first-generation antibiotics. Part and parcel of this strategy was monitoring what can be called the structural change of infectious disease. In practice, this meant to focus on pathologies resulting from resistance and hospital infections. In addition, Bayer also focused on lifestyle pathologies such as athlete's foot. This paper will follow drug development and marketing at Bayer from 1945 to about 1980. In this period, Bayer managed to regain some of its previous standing in markets but could not escape from the overall crisis of anti-infective drug development from the 1970s on.
The Development of Videos in Culturally Grounded Drug Prevention for Rural Native Hawaiian Youth

Science.gov (United States)

Okamoto, Scott K.; Helm, Susana; McClain, Latoya L.; Dinson, Ay-Laina

2012-01-01

The purpose of this study was to adapt and validate narrative scripts to be used for the video components of a culturally grounded drug prevention program for rural Native Hawaiian youth. Scripts to be used to film short video vignettes of drug-related problem situations were developed based on a foundation of pre-prevention research funded by the…
Moving forward in uveitis therapy: preclinical to phase II clinical trial drug development.

Science.gov (United States)

Salazar-Méndez, Raquel; Yilmaz, Taygan; Cordero-Coma, Miguel

2016-01-01

Several advances have been made in the diagnostic approach and therapeutic management of patients with immune-mediated uveitis over the last few decades, which have to lead to an improvement in the visual prognosis of patients. However, the use of available therapies, including steroids and immunosuppressive drugs, is still associated with limited efficacy and potentially serious side effects. Consequently, efforts have been made to develop novel therapeutic alternatives including new molecules and innovative therapeutic approaches. Herein, the authors provide an updated review of those drugs in the initial phases of evaluation for the treatment of immune-mediated uveitides as well as the latest evidence from basic research. Enhanced understanding of the pathogenic mechanisms leading to immune-mediated uveitis has led to the identification of new therapeutic targets and thus to the development of more specific drugs. In addition, considering that the eye is a semi-enclosed chamber and that local therapy has the benefit of sparing the rest of the body from potentially toxic exposure, several attempts of establishing direct ophthalmologic avenues for delivery of the established and emerging drugs have also been made. All these advances have been an unquestionable step forward in the challenging management of uveitis patients.

The teaching of drug development to medical students: collaboration between the pharmaceutical industry and medical school.

Science.gov (United States)

Stanley, A G; Jackson, D; Barnett, D B

2005-04-01

Collaboration between the medical school at Leicester and a local pharmaceutical company, AstraZeneca, led to the design and implementation of an optional third year special science skills module teaching medical students about drug discovery and development. The module includes didactic teaching about the complexities of the drug discovery process leading to development of candidate drugs for clinical investigation as well as practical experience of the processes involved in drug evaluation preclinically and clinically. It highlights the major ethical and regulatory issues concerned with the production and testing of novel therapies in industry and the NHS. In addition it helps to reinforce other areas of the medical school curriculum, particularly the understanding of clinical study design and critical appraisal. The module is assessed on the basis of a written dissertation and the critical appraisal of a drug advertisement. This paper describes the objectives of the module and its content. In addition we outline the results of an initial student evaluation of the module and an assessment of its impact on student knowledge and the opinion of the pharmaceutical industry partner. This module has proven to be popular with medical students, who acquire a greater understanding of the work required for drug development and therefore reflect more favourably on the role of pharmaceutical companies in the UK.
The development of a value based pricing index for new drugs in metastatic colorectal cancer.

Science.gov (United States)

Dranitsaris, George; Truter, Ilse; Lubbe, Martie S

2011-06-01

Worldwide, prices for cancer drugs have been under downward pressure where several governments have mandated price cuts of branded products. A better alternative to government mandated price cuts would be to estimate a final price based on drug performance, cost effectiveness and a country's ability to pay. We developed a global pricing index for new cancer drugs in patients with metastatic colorectal cancer (mCRC) that encompasses all of these attributes. A pharmacoeconomic model was developed to simulate mCRC patients receiving chemotherapy plus a 'new drug' that improves survival by 1.4, 3 and 6months, respectively. Cost and utility data were obtained from cancer centres and oncology nurses (n=112) in Canada, Spain, India, South Africa and Malaysia. Multivariable analysis was then used to develop the pricing index, which considers survival benefit, per capita GDP and income dispersion (as measured by the Gini coefficient) as predictor variables. Higher survival benefits were associated with elevated drug prices, especially in higher income countries such as Canada. For Argentina with a per capita GDP of $15,000 and a Gini coefficient of 51, the index estimated that for a drug which provides a 4month survival benefit in mCRC, the value based price would be $US 630 per dose. In contrast, the same drug in a wealthier country like Norway (per capita GDP=$50,000) could command a price of $US 2,775 per dose. The application of this index to estimate a price based on cost effectiveness and the wealth of a nation would be important for opening dialogue between the key stakeholders and a better alternative to government mandated price cuts. Copyright © 2011 Elsevier Ltd. All rights reserved.
The development of a value based pricing index for new drugs in metastatic colorectal cancer

OpenAIRE

Lubbe, Martha Susanna; Dranitsaris, George; Truter, Ilse

2011-01-01

Background Worldwide, prices for cancer drugs have been under downward pressure where several governments have mandated price cuts of branded products. A better alternative to government mandated price cuts would be to estimate a final price based on drug performance, cost effectiveness and a country’s ability to pay. We developed a global pricing index for new cancer drugs in patients with metastatic colorectal cancer (mCRC) that encompasses all of these attributes. Methods ...
Targeting DNA repair systems in antitubercular drug development.

Science.gov (United States)

Minias, Alina; Brzostek, Anna; Dziadek, Jaroslaw

2018-01-28

Infections with Mycobacterium tuberculosis, the causative agent of tuberculosis, are difficult to treat using currently available chemotherapeutics. Clinicians agree on the urgent need for novel drugs to treat tuberculosis. In this mini review, we summarize data that prompts the consideration of DNA repair-associated proteins as targets for the development of new antitubercular compounds. We discuss data, including gene expression data, that highlight the importance of DNA repair genes during the pathogenic cycle as well as after exposure to antimicrobials currently in use. Specifically, we report experiments on determining the essentiality of DNA repair-related genes. We report the availability of protein crystal structures and summarize discovered protein inhibitors. Further, we describe phenotypes of available gene mutants of M. tuberculosis and model organisms Mycobacterium bovis and Mycobacterium smegmatis. We summarize experiments regarding the role of DNA repair-related proteins in pathogenesis and virulence performed both in vitro and in vivo during the infection of macrophages and animals. We detail the role of DNA repair genes in acquiring mutations, which influence the rate of drug resistance acquisition. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
Which Benefits Are Mentioned Most Often in Drug Development Publications?

Directory of Open Access Journals (Sweden)

Vanessa Strüver, MSc

2017-01-01

Conclusions: Both theoretically expected and actually reported benefits in the majority of the included publications emphasized the importance of individual patient benefits from drug development rather than the collective benefits to society in general. The authors of these publications emphasized the right of each individual patient or subject to look for and expect some personal benefit from participating in a clinical trial rather than considering societal benefit as a top priority. From an ethical point of view, the benefits each individual patient receives from his or her participation in a clinical trial might also be seen as a societal benefit, especially when the drug or device tested, if approved for marketing, would eventually be made available for other similar patients from the country in which the clinical trial was conducted.
Using multicriteria decision analysis during drug development to predict reimbursement decisions.

Science.gov (United States)

Williams, Paul; Mauskopf, Josephine; Lebiecki, Jake; Kilburg, Anne

2014-01-01

Pharmaceutical companies design clinical development programs to generate the data that they believe will support reimbursement for the experimental compound. The objective of the study was to present a process for using multicriteria decision analysis (MCDA) by a pharmaceutical company to estimate the probability of a positive recommendation for reimbursement for a new drug given drug and environmental attributes. The MCDA process included 1) selection of decisions makers who were representative of those making reimbursement decisions in a specific country; 2) two pre-workshop questionnaires to identify the most important attributes and their relative importance for a positive recommendation for a new drug; 3) a 1-day workshop during which participants undertook three tasks: i) they agreed on a final list of decision attributes and their importance weights, ii) they developed level descriptions for these attributes and mapped each attribute level to a value function, and iii) they developed profiles for hypothetical products 'just likely to be reimbursed'; and 4) use of the data from the workshop to develop a prediction algorithm based on a logistic regression analysis. The MCDA process is illustrated using case studies for three countries, the United Kingdom, Germany, and Spain. The extent to which the prediction algorithms for each country captured the decision processes for the workshop participants in our case studies was tested using a post-meeting questionnaire that asked the participants to make recommendations for a set of hypothetical products. The data collected in the case study workshops resulted in a prediction algorithm: 1) for the United Kingdom, the probability of a positive recommendation for different ranges of cost-effectiveness ratios; 2) for Spain, the probability of a positive recommendation at the national and regional levels; and 3) for Germany, the probability of a determination of clinical benefit. The results from the post
Model-Informed Drug Development for Ixazomib, an Oral Proteasome Inhibitor.

Science.gov (United States)

Gupta, Neeraj; Hanley, Michael J; Diderichsen, Paul M; Yang, Huyuan; Ke, Alice; Teng, Zhaoyang; Labotka, Richard; Berg, Deborah; Patel, Chirag; Liu, Guohui; van de Velde, Helgi; Venkatakrishnan, Karthik

2018-02-15

Model-informed drug development (MIDD) was central to the development of the oral proteasome inhibitor ixazomib, facilitating internal decisions (switch from body surface area (BSA)-based to fixed dosing, inclusive phase III trials, portfolio prioritization of ixazomib-based combinations, phase III dose for maintenance treatment), regulatory review (model-informed QT analysis, benefit-risk of 4 mg dose), and product labeling (absolute bioavailability and intrinsic/extrinsic factors). This review discusses the impact of MIDD in enabling patient-centric therapeutic optimization during the development of ixazomib. © 2017 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.
The role of health technology assessment bodies in shaping drug development

Directory of Open Access Journals (Sweden)

Ciani O

2014-11-01

Full Text Available Oriana Ciani,1,3 Claudio Jommi1,2 1Centre for Research on Health and Social Care Management (CERGAS, Bocconi University, Milan, Italy; 2Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara, Italy; 3University of Exeter Medical School, Exeter, UK Abstract: The use of health technology assessment (HTA to inform policy-making is established in most developed countries. Compared to licensing agencies, HTA agencies have different interests and, therefore, different evidence requirements. Criteria for coverage or reimbursement decisions on pharmaceutical compounds vary; however, it is common to include, as part of the HTA, a comparative effectiveness evaluation. This type of clinical data might go beyond that required for market authorization, thus creating an additional evidence gap between the regulatory and the reimbursement submission. The relevance of submissions to HTA agencies is consistently increasing in a pharmaceutical company’s perspective, as market prospects are strongly influenced by third-party payers’ coverage. In this study, we aim to describe current HTA activities with a potential impact throughout the drug development process of pharmaceuticals, with a comparative emphasis on the systems in place in Italy and in the UK. Based on an extensive literature and website review, we identified three major classes of HTA activities, beyond mainstream HTA, with the potential to influence the drug development program: 1 horizon scanning and early HTA; 2 bipartite and tripartite early dialogue between manufacturers, regulators, and HTA assessors; and 3 managed market entry agreements. From early stages of clinical research up to postauthorization studies, there is a trend toward increased collaboration between parties, anticipation of market access evidence collection, and postmarketing risk-sharing. Heterogeneity of HTA practices increases the complexity of the market access environment. Overall, there are
Pharmacokinetic-Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance.

Science.gov (United States)

Germovsek, Eva; Barker, Charlotte I S; Sharland, Mike; Standing, Joseph F

2018-04-19

Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects. This paper discusses the principles of PKPD modeling in the context of pediatric drug development, summarizing how important PK parameters, such as clearance (CL), are scaled with size and age, and highlights a standardized method for CL scaling in children. One standard scaling method would facilitate comparison of PK parameters across multiple studies, thus increasing the utility of existing PK models and facilitating optimal design of new studies.
New drug developments in the Latin Americas (Argentina, Costa Rica, Mexico and Panama).

Science.gov (United States)

Ban, T A; Galvan, L; Udabe, R U; Vergara, L; Zoch, C

1974-07-01

New drug developments in four Latin American countries, i.e. Argentina, Costa Rica, Mexico and Panama and the United States were compared. In contradistinction to the United States, clinical investigations with newly developed drugs in the four countries are based on contracts between individual investigators and the pharmaceutical industry without governmental interference. There are no adequate facilities to develop new psychoactive preparation in the four Latin American countries. Nevertheless, psychopharmacological practices are essentially the same as in the United States or Canada and all important psychoactive preparations used in the United States are available in the Latin Americas. Some of the newer-thioxanthene, butyrophenone and diphenylbutylpiperidine preparations which are still under clinical investigation in the United States are already available for clinical use in Argentina, Costa Rica, Mexico and Panama. While there is less governmental control than in the United States or Canada, with regard to clinical investigations of drugs or with regard to marketing newly developed preparations, there is no evidence of abuse. Finally, it should be noted that the introduction of psychotropic drugs brought about a new era in psychiatry in the Latin Americas. It becomes increasingly obvious that psychiatry today is practiced on the basis of knowledge derived from clinical impressions and on the basis of findings verified in clinical testings, i.e. on the basis of two different standards. Accordingly, as in Europe and North America, a re-examination of traditional concepts has begun in the Latin Americas. There are indications that biological psychiatry in general, and psychopharmacology in particular, are gaining increasing importance in the Latin Americas. This has led to the creation of a training program in biological psychiatry by the World Health Organization in Montreal, in cooperation with the Division of Psychopharmacology of the Department of
Kinase-Centric Computational Drug Development

NARCIS (Netherlands)

Kooistra, Albert J.; Volkamer, Andrea

2017-01-01

Kinases are among the most studied drug targets in industry and academia, due to their involvement in a majority of cellular processes and, upon dysregulation, in a variety of diseases including cancer, inflammation, and autoimmune disorders. The high interest in this druggable protein family
Target-mediated drug disposition with drug-drug interaction, Part I: single drug case in alternative formulations.

Science.gov (United States)

Koch, Gilbert; Jusko, William J; Schropp, Johannes

2017-02-01

Target-mediated drug disposition (TMDD) describes drug binding with high affinity to a target such as a receptor. In application TMDD models are often over-parameterized and quasi-equilibrium (QE) or quasi-steady state (QSS) approximations are essential to reduce the number of parameters. However, implementation of such approximations becomes difficult for TMDD models with drug-drug interaction (DDI) mechanisms. Hence, alternative but equivalent formulations are necessary for QE or QSS approximations. To introduce and develop such formulations, the single drug case is reanalyzed. This work opens the route for straightforward implementation of QE or QSS approximations of DDI TMDD models. The manuscript is the first part to introduce DDI TMDD models with QE or QSS approximations.
Smarter Drugs: How Protein Crystallography Revolutionizes Drug Design

International Nuclear Information System (INIS)

Smith, Clyde

2005-01-01

According to Smith, protein crystallography allows scientists to design drugs in a much more efficient way than the standard methods traditionally used by large drug companies, which can cost close to a billion dollars and take 10 to 15 years. 'A lot of the work can be compressed down,' Smith said. Protein crystallography enables researchers to learn the structure of molecules involved in disease and health. Seeing the loops, folds and placement of atoms in anything from a virus to a healthy cell membrane gives important information about how these things work - and how to encourage, sidestep or stop their functions. Drug design can be much faster when the relationship between structure and function tells you what area of a molecule to target. Smith will use a timeline to illustrate the traditional methods of drug development and the new ways it can be done now. 'It is very exciting work. There have been some failures, but many successes too.' A new drug to combat the flu was developed in a year or so. Smith will tell us how. He will also highlight drugs developed to combat HIV, Tuberculosis, hypertension and Anthrax.
Opportunities and Challenges for Drug Development: Public-Private Partnerships, Adaptive Designs and Big Data.

Science.gov (United States)

Yildirim, Oktay; Gottwald, Matthias; Schüler, Peter; Michel, Martin C

2016-01-01

Drug development faces the double challenge of increasing costs and increasing pressure on pricing. To avoid that lack of perceived commercial perspective will leave existing medical needs unmet, pharmaceutical companies and many other stakeholders are discussing ways to improve the efficiency of drug Research and Development. Based on an international symposium organized by the Medical School of the University of Duisburg-Essen (Germany) and held in January 2016, we discuss the opportunities and challenges of three specific areas, i.e., public-private partnerships, adaptive designs and big data. Public-private partnerships come in many different forms with regard to scope, duration and type and number of participants. They range from project-specific collaborations to strategic alliances to large multi-party consortia. Each of them offers specific opportunities and faces distinct challenges. Among types of collaboration, investigator-initiated studies are becoming increasingly popular but have legal, ethical, and financial implications. Adaptive trial designs are also increasingly discussed. However, adaptive should not be used as euphemism for the repurposing of a failed trial; rather it requires carefully planning and specification before a trial starts. Adaptive licensing can be a counter-part of adaptive trial design. The use of Big Data is another opportunity to leverage existing information into knowledge useable for drug discovery and development. Respecting limitations of informed consent and privacy is a key challenge in the use of Big Data. Speakers and participants at the symposium were convinced that appropriate use of the above new options may indeed help to increase the efficiency of future drug development.
Opportunities and challenges for drug development: public-private partnerships, adaptive designs and big data

Directory of Open Access Journals (Sweden)

Oktay Yildirim

2016-12-01

Full Text Available Drug development faces the double challenge of increasing costs and increasing pressure on pricing. To avoid that lack of perceived commercial perspective will leave existing medical needs unmet, pharmaceutical companies and many other stakeholders are discussing ways to improve the efficiency of drug Research & Development. Based on an international symposium organized by the Medical School of the University of Duisburg-Essen (Germany and held in January 2016, we discuss the opportunities and challenges of three specific areas, i.e. public-private partnerships, adaptive designs and big data. Public-private partnerships come in many different forms with regard to scope, duration and type and number of participants. They range from project-specific collaborations to strategic alliances to large multi-party consortia. Each of them offers specific opportunities and faces distinct challenges. Among types of collaboration, investigator-initiated studies are becoming increasingly popular but have legal, ethical and financial implications. Adaptive trial designs are also increasingly discussed. However, adaptive should not be used as euphemism for the repurposing of a failed trial; rather it requires carefully planning and specification before a trial starts. Adaptive licensing can be a counter-part of adaptive trial design. The use of Big Data is another opportunity to leverage existing information into knowledge useable for drug discovery and development. Respecting limitations of informed consent and privacy is a key challenge in the use of Big Data. Speakers and participants at the symposium were convinced that appropriate use of the above new options may indeed help to increase the efficiency of future drug development.
Opportunities and Challenges for Drug Development: Public–Private Partnerships, Adaptive Designs and Big Data

Science.gov (United States)

Yildirim, Oktay; Gottwald, Matthias; Schüler, Peter; Michel, Martin C.

2016-01-01

Drug development faces the double challenge of increasing costs and increasing pressure on pricing. To avoid that lack of perceived commercial perspective will leave existing medical needs unmet, pharmaceutical companies and many other stakeholders are discussing ways to improve the efficiency of drug Research and Development. Based on an international symposium organized by the Medical School of the University of Duisburg-Essen (Germany) and held in January 2016, we discuss the opportunities and challenges of three specific areas, i.e., public–private partnerships, adaptive designs and big data. Public–private partnerships come in many different forms with regard to scope, duration and type and number of participants. They range from project-specific collaborations to strategic alliances to large multi-party consortia. Each of them offers specific opportunities and faces distinct challenges. Among types of collaboration, investigator-initiated studies are becoming increasingly popular but have legal, ethical, and financial implications. Adaptive trial designs are also increasingly discussed. However, adaptive should not be used as euphemism for the repurposing of a failed trial; rather it requires carefully planning and specification before a trial starts. Adaptive licensing can be a counter-part of adaptive trial design. The use of Big Data is another opportunity to leverage existing information into knowledge useable for drug discovery and development. Respecting limitations of informed consent and privacy is a key challenge in the use of Big Data. Speakers and participants at the symposium were convinced that appropriate use of the above new options may indeed help to increase the efficiency of future drug development. PMID:27999543
The effects of Psychotropic drugs On Developing brain (ePOD) study : methods and design

NARCIS (Netherlands)

Bottelier, Marco A; Schouw, Marieke L J; Klomp, Anne; Tamminga, Hyke G H; Schrantee, Anouk G M; Bouziane, Cheima; de Ruiter, Michiel B; Boer, Frits; Ruhé, Henricus G; Denys, D.; Rijsman, Roselyne; Lindauer, Ramon J L; Reitsma, Hans B; Geurts, Hilde M; Reneman, Liesbeth

2014-01-01

BACKGROUND: Animal studies have shown that methylphenidate (MPH) and fluoxetine (FLX) have different effects on dopaminergic and serotonergic system in the developing brain compared to the developed brain. The effects of Psychotropic drugs On the Developing brain (ePOD) study is a combination of
The effects of psychotropic drugs on developing brain (ePOD) study: methods and design

NARCIS (Netherlands)

Bottelier, M.A.; Schouw, M.L.J.; Klomp, A.; Tamminga, G.H.; Schrantee, A.G.M.; Bouziane, C.; de Ruiter, M.B.; Boer, F.; Ruhé, H.G.; Denys, D.; Rijsman, R.; Lindauer, R.J.L.; Reitsma, H.B.; Geurts, H.M.; Reneman, L.

2014-01-01

Background: Animal studies have shown that methylphenidate (MPH) and fluoxetine (FLX) have different effects on dopaminergic and serotonergic system in the developing brain compared to the developed brain. The effects of Psychotropic drugs On the Developing brain (ePOD) study is a combination of
The effects of Psychotropic drugs On Developing brain (ePOD) study : methods and design

NARCIS (Netherlands)

Bottelier, Marco A.; Schouw, Marieke L. J.; Klomp, Anne; Tamminga, Hyke G. H.; Schrantee, Anouk G. M.; Bouziane, Cheima; de Ruiter, Michiel B.; Boer, Frits; Ruhe, Henricus G.; Denys, Damiaan; Rijsman, Roselyne; Lindauer, Ramon J. L.; Reitsma, Hans B.; Geurts, Hilde M.; Reneman, Liesbeth

2014-01-01

Background: Animal studies have shown that methylphenidate (MPH) and fluoxetine (FLX) have different effects on dopaminergic and serotonergic system in the developing brain compared to the developed brain. The effects of Psychotropic drugs On the Developing brain (ePOD) study is a combination of
The effects of Psychotropic drugs On Developing brain (ePOD) study: methods and design

NARCIS (Netherlands)

Bottelier, Marco A.; Schouw, Marieke L. J.; Klomp, Anne; Tamminga, Hyke G. H.; Schrantee, Anouk G. M.; Bouziane, Cheima; de Ruiter, Michiel B.; Boer, Frits; Ruhé, Henricus G.; Denys, Damiaan; Rijsman, Roselyne; Lindauer, Ramon J. L.; Reitsma, Hans B.; Geurts, Hilde M.; Reneman, Liesbeth

2014-01-01

Animal studies have shown that methylphenidate (MPH) and fluoxetine (FLX) have different effects on dopaminergic and serotonergic system in the developing brain compared to the developed brain. The effects of Psychotropic drugs On the Developing brain (ePOD) study is a combination of different

Increased Risk of Autism Development in Children Whose Mothers Experienced Birth Complications or Received Labor and Delivery Drugs

Directory of Open Access Journals (Sweden)

Melissa Smallwood

2016-07-01

Full Text Available Autism spectrum disorder (ASD is a perplexing and pervasive developmental disorder characterized by social difficulties, communicative deficits, and repetitive behavior. The increased rate of ASD diagnosis has raised questions concerning the genetic and environmental factors contributing to the development of this disorder; meanwhile, the cause of ASD remains unknown. This study surveyed mothers of ASD and non-ASD children to determine possible effects of labor and delivery (L&D drugs on the development of ASD. The survey was administered to mothers; however, the results were analyzed by child, as the study focused on the development of autism. Furthermore, an independent ASD dataset from the Southwest Autism Research and Resource Center was analyzed and compared. Indeed, L&D drugs are associated with ASD (p = .039. Moreover, the Southwest Autism Research and Resource Center dataset shows that the labor induction drug, Pitocin, is significantly associated with ASD (p = .004. We also observed a synergistic effect between administrations of L&D drugs and experiencing a birth complication, in which both obstetrics factors occurring together increased the likelihood of the fetus developing ASD later in life (p = .0003. The present study shows the possible effects of L&D drugs, such as Pitocin labor-inducing and analgesic drugs, on children and ASD.
Methodologies Related to Computational models in View of Developing Anti-Alzheimer Drugs: An Overview.

Science.gov (United States)

Baheti, Kirtee; Kale, Mayura Ajay

2018-04-17

Since last two decades, there has been more focus on the development strategies related to Anti-Alzheimer's drug research. This may be attributed to the fact that most of the Alzheimer's cases are still mostly unknown except for a few cases, where genetic differences have been identified. With the progress of the disease, the symptoms involve intellectual deterioration, memory impairment, abnormal personality and behavioural patterns, confusion, aggression, mood swings, irritability Current therapies available for this disease give only symptomatic relief and do not focus on manipulations of biololecular processes. Nearly all the therapies to treat Alzheimer's disease, target to change the amyloid cascade which is considered to be an important in AD pathogenesis. New drug regimens are not able to keep pace with the ever-increasing understanding about dementia at molecular level. Looking into these aggravated problems, we though to put forth molecular modeling as a drug discovery approach for developing novel drugs to treat Alzheimer disease. The disease is incurable and it gets worst as it advances and finally causes death. Due to this, the design of drugs to treat this disease has become an utmost priority for research. One of the most important emerging technologies applied for this has been Computer-assisted drug design (CADD). It is a research tool that employs large scale computing strategies in an attempt to develop a model receptor site which can be used for designing of an anti-Alzheimer drug. The various models of amyloid-based calcium channels have been computationally optimized. Docking and De novo evolution are used to design the compounds. These are further subjected to absorption, distribution, metabolism, excretion and toxicity (ADMET) studies to finally bring about active compounds that are able to cross BBB. Many novel compounds have been designed which might be promising ones for the treatment of AD. The present review describes the research
Research and development in drug innovation: reflections from the 2013 bioeconomy conference in China, lessons learned and future perspectives.

Science.gov (United States)

Liu, Changxiao; Constantinides, Panayiotis P; Li, Yazhuo

2014-04-01

The enormous progress biotechnology, bioinformatics and nanotechnology made in recent years provides opportunities and scientific framework for development of biomedicine and constitutes a paradigm shift in pharmaceutical R&D and drug innovation. By analyzing the data and related information at R&D level over the past decades, developmental tendency and R&D patterns were summarized. We found that a growing number of biologics in the pipeline of pharma companies with successful products already in the market though, small molecular entities have primarily dominated drug innovation. Additionally, small/medium size companies will continue to play a key role in the development of small molecule drugs and biologics in a multi-channel integrated process. More importantly, modern and effective R&D strategies in biomedicine development to predict and evaluate efficacy and/or safety of 21st century therapeutics are urgently needed. To face new challenges, developmental strategies were proposed, in terms of molecular targeted medicine, generic drugs, new drug delivery system and protein-based drugs. Under the current circumstances, interdisciplinary cooperation mode and policy related to drug innovation in China were deeply discussed as well.
Click chemistry, 3D-printing, and omics: the future of drug development.

Science.gov (United States)

Kurzrock, Razelle; Stewart, David J

2016-01-19

Genomics is a disruptive technology, having revealed that cancers are tremendously complex and differ from patient to patient. Therefore, conventional treatment approaches fit poorly with genomic reality. Furthermore, it is likely that this type of complexity will also be observed in other illnesses. Precision medicine has been posited as a way to better target disease-related aberrations, but developing drugs and tailoring therapy to each patient's complicated problem is a major challenge. One solution would be to match patients to existing compounds based on in silico modeling. However, optimization of complex therapy will eventually require designing compounds for patients using computer modeling and just-in-time production, perhaps achievable in the future by three-dimensional (3D) printing. Indeed, 3D printing is potentially transformative by virtue of its ability to rapidly generate almost limitless numbers of objects that previously required manufacturing facilities. Companies are already endeavoring to develop affordable 3D printers for home use. An attractive, but as yet scantily explored, application is to place chemical design and production under digital control. This could be accomplished by utilizing a 3D printer to initiate chemical reactions, and print the reagents and/or the final compounds directly. Of interest, the Food and Drug Administration (FDA) has recently approved a 3D printed drug-levetiracetam-indicated for seizures. Further, it is now increasingly clear that biologic materials-tissues, and eventually organs-can also be "printed." In the near future, it is plausible that high-throughput computing may be deployed to design customized drugs, which will reshape medicine.
GPCR homomers and heteromers: a better choice as targets for drug development than GPCR monomers?

Science.gov (United States)

Casadó, Vicent; Cortés, Antoni; Mallol, Josefa; Pérez-Capote, Kamil; Ferré, Sergi; Lluis, Carmen; Franco, Rafael; Canela, Enric I

2009-11-01

G protein-coupled receptors (GPCR) are targeted by many therapeutic drugs marketed to fight against a variety of diseases. Selection of novel lead compounds are based on pharmacological parameters obtained assuming that GPCR are monomers. However, many GPCR are expressed as dimers/oligomers. Therefore, drug development may consider GPCR as homo- and hetero-oligomers. A two-state dimer receptor model is now available to understand GPCR operation and to interpret data obtained from drugs interacting with dimers, and even from mixtures of monomers and dimers. Heteromers are distinct entities and therefore a given drug is expected to have different affinities and different efficacies depending on the heteromer. All these concepts would lead to broaden the therapeutic potential of drugs targeting GPCRs, including receptor heteromer-selective drugs with a lower incidence of side effects, or to identify novel pharmacological profiles using cell models expressing receptor heteromers.
Medication errors in anesthesia: unacceptable or unavoidable?

Directory of Open Access Journals (Sweden)

Ira Dhawan

Full Text Available Abstract Medication errors are the common causes of patient morbidity and mortality. It adds financial burden to the institution as well. Though the impact varies from no harm to serious adverse effects including death, it needs attention on priority basis since medication errors' are preventable. In today's world where people are aware and medical claims are on the hike, it is of utmost priority that we curb this issue. Individual effort to decrease medication error alone might not be successful until a change in the existing protocols and system is incorporated. Often drug errors that occur cannot be reversed. The best way to ‘treat' drug errors is to prevent them. Wrong medication (due to syringe swap, overdose (due to misunderstanding or preconception of the dose, pump misuse and dilution error, incorrect administration route, under dosing and omission are common causes of medication error that occur perioperatively. Drug omission and calculation mistakes occur commonly in ICU. Medication errors can occur perioperatively either during preparation, administration or record keeping. Numerous human and system errors can be blamed for occurrence of medication errors. The need of the hour is to stop the blame - game, accept mistakes and develop a safe and ‘just' culture in order to prevent medication errors. The newly devised systems like VEINROM, a fluid delivery system is a novel approach in preventing drug errors due to most commonly used medications in anesthesia. Similar developments along with vigilant doctors, safe workplace culture and organizational support all together can help prevent these errors.
Application of methyl methacrylate copolymers to the development of transdermal or loco-regional drug delivery systems.

Science.gov (United States)

Cilurzo, Francesco; Selmin, Francesca; Gennari, Chiara G M; Montanari, Luisa; Minghetti, Paola

2014-07-01

Methyl methacrylate copolymers (Eudragit®) have been exploited to develop transdermal patches, medicated plasters (hereinafter patches) and, more recently, film-forming sprays, microsponges and nanoparticles intended to be applied on the skin. The article reviews the information regarding the application of Eudragits in the design and development of these dosage forms focusing on the impact of formulative variables on the skin drug penetration and the patch adhesive properties. Eudragits combined with a large amount of plasticizers are used to design the pressure-sensitive adhesives, specialized materials used in the patch development. They have to assure the drug skin penetration and the contact with the skin. Most of the studies mainly deal with the former aspect. The authors used a Eudragit type opportunely plasticized to merely investigate the in vitro or in vivo skin permeability of a loaded drug. However, the summa of these data evidenced that a strict connection between the matrix hydrophilicity and drug penetration probably exists. The criticisms of adhesion are addressed in a limited number of papers reporting data on technological properties, namely tack, shear adhesion and peel adhesion, while the structural data of the Eudragit adhesives, rheology and surface free energy are not described, excepting the case of Eudragit E. Among other applications, micro- and nanosystems exploiting the ionizable nature of some Eudragits can offer novel opportunities to develop pH-sensitive drug delivery systems suitable for triggering its release onto the skin.
IMPROVING ACCESS TO DRUGS

Directory of Open Access Journals (Sweden)

Max Joseph Herman

2012-11-01

Full Text Available Although essentially not all therapies need drug intervention, drugs is still an important components in health sector, either in preventive, curative, rehabilitative or promotion efforts. Hence the access to drugs is a main problem, either in international or national scale even to the smallest unit. The problem on access to drugs is very complicated and cannot be separated especially from pharmacy management problems; moreover in general from the overall lack of policy development and effective of health policy, and also the implementation process. With the policy development and effective health policy, rational drug uses, sufficient health service budget so a country can overcome the health problems. Besides infrastructures, regulations, distribution and cultural influences; the main obstacles for drug access is drugs affordability if the price of drugs is an important part and determined by many factors, especially the drug status whether is still patent orgenerics that significantly decrease cost of health cares and enhance the drugs affordability. The determination of essential drug prices in developing countries should based on equity principal so that poor people pay cheaper and could afford the essential drugs. WHO predicts two third of world population can not afford the essential drugs in which in developing countries, some are because of in efficient budget allocation in consequence of drug distribution management, including incorrect selection and allocation and also irrational uses. In part these could be overcome by enhancing performances on the allocation pharmacy needs, including the management of information system, inventory management, stock management and the distribution. Key words: access, drugs, essential drugs, generic drugs
A development perspective on adolescent drug abuse.

Science.gov (United States)

Baumrind, D; Moselle, K A

1985-01-01

Adolescent drug use is placed in an historical and developmental perspective. Existing evidence concerning causes and consequences of adolescent drug use is inconclusive. In the absence of conclusive empirical evidence and cogent theories, we present a prima facie case against early adolescent drug use by defending six propositions which posit specific cognitive, conative, and affective negative consequences including impairment of attention and memory; developmental lag imposing categorical limitations on the level of maximum functioning available to the user in cognitive, moral and psychosocial domains; amotivational syndrome; consolidation of diffuse or negative identity; and social alienation and estrangement. We call for a program of research which could provide credible evidence to support or rebut these propositions, and thus address the factual claims underlying the sociomoral concerns of social policy planners.
Nanomedicine: towards development of patient-friendly drug-delivery systems for oncological applications

Directory of Open Access Journals (Sweden)

Ranganathan R

2012-02-01

Full Text Available Ramya Ranganathan1,*, Shruthilaya Madanmohan1,*, Akila Kesavan1, Ganga Baskar1, Yoganathan Ramia Krishnamoorthy2, Roy Santosham3, D Ponraju4, Suresh Kumar Rayala2, Ganesh Venkatraman1 1Department of Human Genetics, Sri Ramachandra University, Porur, 2Department of Biotechnology, Indian Institute of Technology, Madras, 3Department of Radiology and Imaging Sciences, Sri Ramachandra University, Porur, Chennai, 4Safety Engineering Division, Nuclear and Engineering Safety Group, Indira Gandhi Center for Atomic Research, Kalpakkam, India*Authors contributed equally to this workAbstract: The focus on nanotechnology in cancer treatment and diagnosis has intensified due to the serious side effects caused by anticancer agents as a result of their cytotoxic actions on normal cells. This nonspecific action of chemotherapy has awakened a need for formulations capable of definitive targeting with enhanced tumor-killing. Nanooncology, the application of nanobiotechnology to the management of cancer, is currently the most important area of nanomedicine. Currently several nanomaterial-based drug-delivery systems are in vogue and several others are in various stages of development. Tumor-targeted drug-delivery systems are envisioned as magic bullets for cancer therapy and several groups are working globally for development of robust systems.Keywords: patient-friendly, drug-delivery systems, cancer, nanomedicine
Applying insights from biofilm biology to drug development - can a new approach be developed?

DEFF Research Database (Denmark)

Bjarnsholt, Thomas; Ciofu, Oana; Molin, Søren

2013-01-01

Most of the research on bacterial pathogenesis has focused on acute infections, but much less is known about the pathogenesis of infections caused by bacteria that grow as aggregates in biofilms. These infections tend to be chronic as they resist innate and adaptive immune defence mechanisms...... and pathology, and discuss how a deep insight into the physical and biological characteristics of biofilms can inform therapeutic strategies and molecular targets for the development of anti-biofilm drugs....
Developing the Pedagogical Culture of Parents by Means of Social Partnership with a Supplementary Education Institution

Science.gov (United States)

Zakirova, Venera G.; Nikitina, Ekaterina L.

2016-01-01

The urgency of the research is due to the current requirements to develop the pedagogical culture of parents, which can help them to be successful parents, to effectively interact with their children avoiding family upbringing mistakes. In this respect, the article aims to identify the conditions for development of the pedagogical culture of…
Metabolism-Activated Multitargeting (MAMUT): An Innovative Multitargeting Approach to Drug Design and Development.

Science.gov (United States)

Mátyus, Péter; Chai, Christina L L

2016-06-20

Multitargeting is a valuable concept in drug design for the development of effective drugs for the treatment of multifactorial diseases. This concept has most frequently been realized by incorporating two or more pharmacophores into a single hybrid molecule. Many such hybrids, due to the increased molecular size, exhibit unfavorable physicochemical properties leading to adverse effects and/or an inappropriate ADME (absorption, distribution, metabolism, and excretion) profile. To avoid this limitation and achieve additional therapeutic benefits, here we describe a novel multitargeting strategy based on the synergistic effects of a parent drug and its active metabolite(s). The concept of metabolism-activated multitargeting (MAMUT) is illustrated using a number of examples. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
The effect of mimicking febrile temperature and drug stress on malarial development

Directory of Open Access Journals (Sweden)

Adisakwattana Poom

2009-06-01

Full Text Available Abstract Background Malaria remains one of the most important tropical diseases of human with 1–2 million deaths annually especially caused by P. falciparum. During malarial life cycle, they exposed to many environmentally stresses including wide temperature fluctuation and pharmacological active molecules. These trigger malarial evolutionarily adaptive responses. The effect of febrile temperature on malarial growth, development and drug susceptibility by mimicking patient in treatment failure before and after drug uptake was examined. Methods Sensitivities of P. falciparum to antimalarial drug (chloroquine, mefloquine, quinine and artesunate were investigated based on the incorporation of [3H] hypoxanthine into parasite nucleic acids or radioisotopic technique. The number of parasites was examined under microscope following Giemsa staining and the parasite development at the end of each phase was counted and comparison of parasite number was made. The proteome was separated, blotted and hybridized with anti-Hsp70s primary antibody. The hybridized proteins were separately digested with trypsin and identified by MALDI-TOF peptide mass fingerprint. Results The results show that febrile temperature is capable of markedly inhibiting the growth of field isolate P. falciparum but not to K1 and 3D7 standard strains. K1 and 3D7 grown under heat shock developed greater and the reinfection rate was increased up to 2-folds when compared to that of non-heat shock group. The IC50 value of K1 toward chloroquine, mefloquine and quinine under heat shock was higher than that of K1 under non-heat shock which is opposite to that of 3D7. Heat shock caused death in field isolated parasite. It was also found that the febrile temperature coped with chloroquine uptake had no effect to the development, drug sensitivity and the parasite number of K1 strain. In the opposite way, heat shock and chloroquine shows extremely effect toward 3D7 and field isolate PF91 as shown
Development of PEGylated PLGA nanoparticle for controlled and sustained drug delivery in cystic fibrosis

Directory of Open Access Journals (Sweden)

Mazur Steven

2010-09-01

Full Text Available Abstract Background The mutation in the cystic fibrosis transmembrane conductance regulator (CFTR gene results in CF. The most common mutation, ΔF508-CFTR, is a temperature-sensitive, trafficking mutant with reduced chloride transport and exaggerated immune response. The ΔF508-CFTR is misfolded, ubiquitinated, and prematurely degraded by proteasome mediated- degradation. We recently demonstrated that selective inhibition of proteasomal pathway by the FDA approved drug PS-341 (pyrazylcarbonyl-Phe-Leuboronate, a.k.a. Velcade or bortezomib ameliorates the inflammatory pathophysiology of CF cells. This proteasomal drug is an extremely potent, stable, reversible and selective inhibitor of chymotryptic threonine protease-activity. The apprehension in considering the proteasome as a therapeutic target is that proteasome inhibitors may affect proteostasis and consecutive processes. The affect on multiple processes can be mitigated by nanoparticle mediated PS-341 lung-delivery resulting in favorable outcome observed in this study. Results To overcome this challenge, we developed a nano-based approach that uses drug loaded biodegradable nanoparticle (PLGA-PEGPS-341 to provide controlled and sustained drug delivery. The in vitro release kinetics of drug from nanoparticle was quantified by proteasomal activity assay from days 1-7 that showed slow drug release from day 2-7 with maximum inhibition at day 7. For in vivo release kinetics and biodistribution, these drug-loaded nanoparticles were fluorescently labeled, and administered to C57BL6 mice by intranasal route. Whole-body optical imaging of the treated live animals demonstrates efficient delivery of particles to murine lungs, 24 hrs post treatment, followed by biodegradation and release over time, day 1-11. The efficacy of drug release in CF mice (Cftr-/- lungs was determined by quantifying the changes in proteasomal activity (~2 fold decrease and ability to rescue the Pseudomonas aeruginosa LPS (Pa
Review on research of suppression male fertility and male contraceptive drug development by natural products.

Science.gov (United States)

Bajaj, Vijay Kumar; Gupta, Radhey S

2013-08-01

Male contraceptive development in the present scenario is most viable aspect of research due to uncontrolled population growth in the world. In this respect investigators are busy to find out a safe male contraceptive drug. Researchers have started their finding for a suitable drug from natural sources because these are safe and easily acceptable for common man, most of natural sources are plants and their products. In this review 137 plants and their effects on reproduction and reproductive physiology are summarized. Some of them have intense effect on male reproductive system and do not produce any side effects. Reproductive toxicological studies are also important aspects of these kinds of researches, so it is important that drugs are safe and widely acceptable. An ideal male contraceptive can influence semen, testes, hormone level, accessory reproductive organs and general physiology of animals and produced some alterations. Many plants in this review are showing antifertility as well as antispermatogenic effects, so these may be used for further study for contraceptives development but it is important to find out the mechanism of reaction and further laboratory and clinical research on some plants are needed for final male contraceptive drug development. In conclusion this review will help for finding suitable plant products for male contraceptive clinical and laboratory studies.
Development of buccal drug delivery systems based on a thiolated polymer.

Science.gov (United States)

Langoth, Nina; Kalbe, Jochen; Bernkop-Schnürch, Andreas

2003-02-18

The purpose of the present study was to investigate the benefit of thiolated polymers (thiomers) for the development of buccal drug delivery systems. L-Cysteine was thereby covalently attached to polycarbophil (PCP) mediated by a carbodiimide. The resulting conjugate displayed 140.5+/-8.4 microM thiol groups per gram polymer. Disintegration studies were carried out with tablets based on unmodified polymer and conjugated polymer, respectively. Due to the formation of disulfide bonds within the thiolated polymer, the stability of matrix-tablets based on this polymer was strongly improved. Additionally tensile studies were carried out, which were in good correlation with further results obtained by mucoadhesion studies, using the rotating cylinder method. These results showed that tablets based on thiolated PCP remained attached on freshly excised porcine mucosa 1.8 times longer than the corresponding control. Moreover, the enzyme inhibitory properties of polymers were evaluated as well. Thiolated PCP increased the stability of the synthetic substrate for aminopeptidase N-leu-p-nitroanilide (N-leu-pNA) and the model drug leucin-enkephalin (leu-enkephalin) against enzymatic degradation on buccal mucosa. Due to the use of thiolated polymers also a controlled drug release for leu-enkephalin was guaranteed over a time period for more than 24 h. Results of the present studies suggest that thiolated polymers represent a very useful tool for buccal delivery of peptide drugs.
Reliability of Soft Tissue Model Based Implant Surgical Guides; A Methodological Mistake.

Science.gov (United States)

Sabour, Siamak; Dastjerdi, Elahe Vahid

2012-08-20

Abstract We were interested to read the paper by Maney P and colleagues published in the July 2012 issue of J Oral Implantol. The authors aimed to assess the reliability of soft tissue model based implant surgical guides reported that the accuracy was evaluated using software. 1 I found the manuscript title of Maney P, et al. incorrect and misleading. Moreover, they reported twenty-two sites (46.81%) were considered accurate (13 of 24 maxillary and 9 of 23 mandibular sites). As the authors point out in their conclusion, Soft tissue models do not always provide sufficient accuracy for implant surgical guide fabrication.Reliability (precision) and validity (accuracy) are two different methodological issues in researches. Sensitivity, specificity, PPV, NPV, likelihood ratio positive (true positive/false negative) and likelihood ratio negative (false positive/ true negative) as well as odds ratio (true results\\false results - preferably more than 50) are among the tests to evaluate the validity (accuracy) of a single test compared to a gold standard.2-4 It is not clear that the reported twenty-two sites (46.81%) which were considered accurate related to which of the above mentioned estimates for validity analysis. Reliability (repeatability or reproducibility) is being assessed by different statistical tests such as Pearson r, least square and paired t.test which all of them are among common mistakes in reliability analysis 5. Briefly, for quantitative variable Intra Class Correlation Coefficient (ICC) and for qualitative variables weighted kappa should be used with caution because kappa has its own limitation too. Regarding reliability or agreement, it is good to know that for computing kappa value, just concordant cells are being considered, whereas discordant cells should also be taking into account in order to reach a correct estimation of agreement (Weighted kappa).2-4 As a take home message, for reliability and validity analysis, appropriate tests should be
Approaches to modernize the combination drug development paradigm

Directory of Open Access Journals (Sweden)

Daphne Day

2016-10-01

Full Text Available Abstract Recent advances in genomic sequencing and omics-based capabilities are uncovering tremendous therapeutic opportunities and rapidly transforming the field of cancer medicine. Molecularly targeted agents aim to exploit key tumor-specific vulnerabilities such as oncogenic or non-oncogenic addiction and synthetic lethality. Additionally, immunotherapies targeting the host immune system are proving to be another promising and complementary approach. Owing to substantial tumor genomic and immunologic complexities, combination strategies are likely to be required to adequately disrupt intricate molecular interactions and provide meaningful long-term benefit to patients. To optimize the therapeutic success and application of combination therapies, systematic scientific discovery will need to be coupled with novel and efficient clinical trial approaches. Indeed, a paradigm shift is required to drive precision medicine forward, from the traditional “drug-centric” model of clinical development in pursuit of small incremental benefits in large heterogeneous groups of patients, to a “strategy-centric” model to provide customized transformative treatments in molecularly stratified subsets of patients or even in individual patients. Crucially, to combat the numerous challenges facing combination drug development—including our growing but incomplete understanding of tumor biology, technical and informatics limitations, and escalating financial costs—aligned goals and multidisciplinary collaboration are imperative to collectively harness knowledge and fuel continual innovation.
Developing a Dissociative Nanocontainer for Peptide Drug Delivery

Directory of Open Access Journals (Sweden)

Patrick Kelly

2015-10-01

Full Text Available The potency, selectivity, and decreased side effects of bioactive peptides have propelled these agents to the forefront of pharmacological research. Peptides are especially promising for the treatment of neurological disorders and pain. However, delivery of peptide therapeutics often requires invasive techniques, which is a major obstacle to their widespread application. We have developed a tailored peptide drug delivery system in which the viral capsid of P22 bacteriophage is modified to serve as a tunable nanocontainer for the packaging and controlled release of bioactive peptides. Recent efforts have demonstrated that P22 nanocontainers can effectively encapsulate analgesic peptides and translocate them across blood-brain-barrier (BBB models. However, release of encapsulated peptides at their target site remains a challenge. Here a Ring Opening Metathesis Polymerization (ROMP reaction is applied to trigger P22 nanocontainer disassembly under physiological conditions. Specifically, the ROMP substrate norbornene (5-Norbornene-2-carboxylic acid is conjugated to the exterior of a loaded P22 nanocontainer and Grubbs II Catalyst is used to trigger the polymerization reaction leading to nanocontainer disassembly. Our results demonstrate initial attempts to characterize the ROMP-triggered release of cargo peptides from P22 nanocontainers. This work provides proof-of-concept for the construction of a triggerable peptide drug delivery system using viral nanocontainers.

Analysis of Drug Development Paradigms for Immune Checkpoint Inhibitors.

Science.gov (United States)

Jardim, Denis L; de Melo Gagliato, Débora; Giles, Francis J; Kurzrock, Razelle

2018-04-15

Immune checkpoint inhibitors have unique toxicities and response kinetics compared with cytotoxic and gene-targeted anticancer agents. We investigated the impact of innovative/accelerated immunotherapy drug development/approval models on the accuracy of safety and efficacy assessments by searching the FDA website. Initial phase I trials for each agent were reviewed and safety and efficacy data compared with that found in later trials leading to regulatory approvals of the same agents. As of June 2017, the FDA approved six checkpoint inhibitors for a variety of cancer types. All checkpoint inhibitors received a priority review status and access to at least two additional FDA special access programs, more often breakthrough therapy designation and accelerated approval. Median clinical development time (investigational new drug application to approval) was 60.77 months [avelumab had the shortest timeline (52.33 months)]. Response rates during early phase I trials (median = 16%) are higher than for phase I trials of other agents (with the exception of gene-targeted agents tested with a biomarker). Doses approved were usually not identical to doses recommended on phase I trials. Approximately 50% of types of immune-related and 43% of types of clinically relevant toxicities from later trials were identified in early-phase trials. Even so, treatment-related mortality remains exceedingly low in later studies (0.33% of patients). In conclusion, efficacy and safety of immune checkpoint inhibitors appear to be reasonably predicted from the dose-finding portion of phase I trials, indicating that the fast-track development of these agents is safe and justified. Clin Cancer Res; 24(8); 1785-94. ©2017 AACR . ©2017 American Association for Cancer Research.
Legislating thresholds for drug trafficking: a policy development case study from New South Wales, Australia.

Science.gov (United States)

Hughes, Caitlin Elizabeth; Ritter, Alison; Cowdery, Nicholas

2014-09-01

Legal thresholds are used in many parts of the world to define the quantity of illicit drugs over which possession is deemed "trafficking" as opposed to "possession for personal use". There is limited knowledge about why or how such laws were developed. In this study we analyse the policy processes underpinning the introduction and expansion of the drug trafficking legal threshold system in New South Wales (NSW), Australia. A critical legal and historical analysis was undertaken sourcing data from legislation, Parliamentary Hansard debates, government inquiries, police reports and research. A timeline of policy developments was constructed from 1970 until 2013 outlining key steps including threshold introduction (1970), expansion (1985), and wholesale revision (1988). We then critically analysed the drivers of each step and the roles played by formal policy actors, public opinion, research/data and the drug trafficking problem. We find evidence that while justified as a necessary tool for effective law enforcement of drug trafficking, their introduction largely preceded overt police calls for reform or actual increases in drug trafficking. Moreover, while the expansion from one to four thresholds had the intent of differentiating small from large scale traffickers, the quantities employed were based on government assumptions which led to "manifest problems" and the revision in 1988 of over 100 different quantities. Despite the revisions, there has remained no further formal review and new quantities for "legal highs" continue to be added based on assumption and an uncertain evidence-base. The development of legal thresholds for drug trafficking in NSW has been arbitrary and messy. That the arbitrariness persists from 1970 until the present day makes it hard to conclude the thresholds have been well designed. Our narrative provides a platform for future policy reform. Copyright © 2014 Elsevier B.V. All rights reserved.
DrugSig: A resource for computational drug repositioning utilizing gene expression signatures.

Directory of Open Access Journals (Sweden)

Hongyu Wu

Full Text Available Computational drug repositioning has been proved as an effective approach to develop new drug uses. However, currently existing strategies strongly rely on drug response gene signatures which scattered in separated or individual experimental data, and resulted in low efficient outputs. So, a fully drug response gene signatures database will be very helpful to these methods. We collected drug response microarray data and annotated related drug and targets information from public databases and scientific literature. By selecting top 500 up-regulated and down-regulated genes as drug signatures, we manually established the DrugSig database. Currently DrugSig contains more than 1300 drugs, 7000 microarray and 800 targets. Moreover, we developed the signature based and target based functions to aid drug repositioning. The constructed database can serve as a resource to quicken computational drug repositioning. Database URL: http://biotechlab.fudan.edu.cn/database/drugsig/.
Characterising and comparing drug-dispensing practices at animal health outlets in the Rift Valley, Kenya: an exploratory analysis (part II).

Science.gov (United States)

Higham, L E; Ongeri, W; Asena, K; Thrusfield, M V

2016-12-01

A mixed-method study was conducted in the Rift Valley of Kenya to characterise drug-dispensing practices amongst staff at animal health outlets and to explore perceptions of veterinary medicines amongst pastoralists and farmers. Forty structured questionnaires were administered to staff at animal health outlets, including franchise outlets of 'Sidai Africa Ltd.', and two focus group discussions were facilitated to explore the perceptions of local animal health services by a Maasai pastoralist group and a dairy farmer cooperative. Differences were detected in the characteristics of Sidai outlets, agrovets, pharmacies and dukas. A greater proportion of Sidai outlet staff selected drugs based on principles of responsible drug use than staff at other types of outlet, and technical qualifications and training were associated with responsible drug use. Across all outlet types, staff knowledge and training gaps were identified, including in the correct administration of medicines. The majority of drug sales are accompanied by verbal advice to farmers. Members of the Maasai pastoralist group were concerned about accidental self-medication, withdrawal periods, drug residues and the misuse of drugs due to a lack of quality information and advice. The dairy farmer group raised similar concerns, reporting under-dosing as a common mistake amongst farmers. This study concludes that current knowledge, attitudes and practices of many service providers and livestock owners in the sale, purchase and use of veterinary medicines present risks of drug misuse and therefore the emergence of antimicrobial resistance. There is a clear demand from livestock keepers for accessible, affordable and quality animal health services and products in Kenya, and animal health practitioners have the potential to provide increased support to livestock-based livelihoods and act as stewards of our existing portfolio of animal and human medicines.
Knowledge of drug prescription in dentistry students

Directory of Open Access Journals (Sweden)

Guzmán-Álvarez R

2012-06-01

Full Text Available R Guzmán-Álvarezv,1 M Medeiros,2,3 LI Reyes Lagunes,4 AE Campos-Sepúlveda11Pharmacology Department, UNAM School of Medicine and Dentistry, Mexico City, 2Pharmacology Clinical Seminar, UNAM School of Medicine, Mexico City, 3Medical Sciences Department, Mexico Federico Gómez Children's Hospital, Mexico City, 4Measuring and Evaluation Unit, UNAM School of Psychology, Mexico City, MexicoBackground: Students in schools of dentistry attend to patients with illnesses, and often prescribe medication. Because students are still learning, they are influenced by a variety of factors: the different teaching approaches of the professors at the clinics and in the pharmacology course, fellow students, and even the information provided by the pharmaceutical industry.Objectives: The aim of this pilot study was to assess the prescription knowledge and common mistakes in fourth-year students at the School of Dentistry at the Universidad Nacional Autónoma de México.Methods: In March 2010, a survey was conducted among 66 fourth-year students at the School of Dentistry, applying a previously validated questionnaire consisting of six open-ended questions The following factors were assessed: the most frequent illness requiring dental prescription; the most prescribed nonsteroidal anti-inflammatory drugs and antibiotics; the most frequent errors; sources of information used for prescribing drugs; and whether the students knew and followed the World Health Organization Guide to Good Prescribing.Results: The most frequent response for each question was considered the most significant. The most common reason for prescribing medication was infection (n = 37, 56%, followed by pain (n = 24, 38%; the most used painkillers were ibuprofen and acetaminophen at equal levels (n = 25, 37.8%, followed by ketorolac (n = 7, 10.6%, naproxen (n = 6, 9.1%, diclofenac (n = 2, 3%, and aspirin (n = 1, 1.5%; the most widely prescribed antibiotics were amoxicillin (n = 52, 78
The Role of Neoadjuvant Trials in Drug Development for Solid Tumors.

Science.gov (United States)

Funt, Samuel A; Chapman, Paul B

2016-05-15

The relatively low success rate of phase II oncology trials in predicting success of novel drugs in phase III trials and in gaining regulatory approval may be due to reliance on the endpoint of response rate defined by the RECIST. The neoadjuvant treatment paradigm allows the antitumor activity of a novel therapy to be determined on a pathologic basis at the time of surgery instead of by RECIST, which was not developed to guide clinical decision making or correlate with long-term outcomes. Indeed, the FDA endorsed pathologic complete response (pCR) as a surrogate for overall survival (OS) in early-stage breast cancer and granted accelerated approval to pertuzumab based on this endpoint. We propose that pCR is a biologically rational method of determining treatment effect that may be more likely to predict OS. We discuss some advantages of the neoadjuvant trial design, review the use of neoadjuvant therapy as standards of care, and consider the neoadjuvant platform as a method for drug development. Clin Cancer Res; 22(10); 2323-8. ©2016 AACR. ©2016 American Association for Cancer Research.
TERATOGENIC EFFECTS OF DRUGS ON THE ORGANISM OF A FUTURE CHILD DURING FETAL STAGE OF DEVELOPMENT

Directory of Open Access Journals (Sweden)

S.A. Sher

2011-01-01

Full Text Available Article assesses the impact of adverse factors on intrauterine development of the child, first of all, drugs. The author stresses that the importance of drug safety (D is due to the large number of unintended pregnancies worldwide. A list of the D, providing proven teratogenic effects on a child organism is presenting. It is shown that the D teratogenic effect in humans can not be assessed on the basis of experimental data obtained in animals due to the difference between metabolic and detoxification processes in a different mammals and individuals. Key words: drugs, safety, teratogenic effects, fetal development, the unborn child. (Pediatric pharmacology. — 2011; 8 (6: 57–60.
Strategic Regulatory Evaluation and Endorsement of the Hollow Fiber Tuberculosis System as a Novel Drug Development Tool.

Science.gov (United States)

Romero, Klaus; Clay, Robert; Hanna, Debra

2015-08-15

The first nonclinical drug development tool (DDT) advanced by the Critical Path to TB Drug Regimens (CPTR) Initiative through a regulatory review process has been endorsed by leading global regulatory authorities. DDTs with demonstrated predictive accuracy for clinical and microbiological outcomes are needed to support decision making. Regulatory endorsement of these DDTs is critical for drug developers, as it promotes confidence in their use in Investigational New Drug and New Drug Application filings. The in vitro hollow fiber system model of tuberculosis (HFS-TB) is able to recapitulate concentration-time profiles (exposure) observed in patients for single drugs and combinations, by evaluating exposure measures for the ability to kill tuberculosis in different physiologic conditions. Monte Carlo simulations make this quantitative output useful to inform susceptibility breakpoints, dosage, and optimal combination regimens in patients, and to design nonclinical experiments in animal models. The Pre-Clinical and Clinical Sciences Working Group within CPTR executed an evidence-based evaluation of the HFS-TB for predictive accuracy. This extensive effort was enabled through the collaboration of subject matter experts representing the pharmaceutical industry, academia, product development partnerships, and regulatory authorities including the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). A comprehensive analysis plan following the regulatory guidance documents for DDT qualification was developed, followed by individual discussions with the FDA and the EMA. The results from the quantitative analyses were submitted to both agencies, pursuing regulatory DDT endorsement. The EMA Qualification Opinion for the HFS-TB DDT was published 26 January 2015 (available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000319.jsp). © The Author 2015. Published by Oxford University Press on behalf of the
Turning theory into practice: the development of modern transdermal drug delivery systems and future trends.

Science.gov (United States)

Perumal, O; Murthy, S N; Kalia, Y N

2013-01-01

Despite its remarkable barrier function, the skin remains an attractive site for systemic drug delivery given its easy accessibility, large surface area and the possibility to bypass the gastrointestinal tract and the liver and so modify drug absorption kinetics. The pioneering work of Scheuplein, Higuchi and others in the 1960s helped to explain the processes involved in passive percutaneous absorption and led to the development of mathematical models to describe transdermal drug delivery. The intervening years have seen these theories turned to practice and a significant number of transdermal systems are now available including some that employ active drug delivery. This review briefly discusses the evolution of transdermal therapeutic systems over the years and the potential of newer transdermal technologies to deliver hydrophilic drugs and macromolecules through the skin. © 2013 S. Karger AG, Basel.
The current status of community drug testing via the analysis of drugs and drug metabolites in sewage

Directory of Open Access Journals (Sweden)

Malcolm J. Reid

2011-12-01

Full Text Available Over the past few years the analysis of drug residues in sewage has been promoted as a means of estimating the level of drug use in communities. Measured drug residue concentrations in the sewage are used to determine the load (total mass of the drug being used by the entire community. Knowledge of the size or population of the community then allows for the calculation of drug-use relative to population (typically drug-mass/day/1000 inhabitants which facilitates comparisons between differing communities or populations. Studies have been performed in many European countries, including Norway, as well as in the US and Australia. The approach has successfully estimated the use of cocaine, amphetamine, methamphetamine, MDMA, cannabis, nicotine and alcohol. The analysis of biomarkers of drug use in sewage has great potential to support and complement existing techniques for estimating levels of drug use, and as such has been identified as a promising development by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA; www.emcdda.europa.eu/wastewater-analysis. The approach is not without its challenges, and ongoing collaboration across Europe aims at agreeing upon best-practice and harmonising the methods being used. In Norway development is being performed through the NFR RUSMIDDEL funded DrugMon (www.niva.no/drugmon project that has led to the development of many new techniques, significantly improved our understanding of the uncertainties associated with the approach and allowed the coordination of Europe wide collaboration which has included all important intercalibration exercises. Application of the technique can provide evidence-based and real-time estimates of collective drug use with the resulting data used to improve the much needed estimates of drug use and dependency.
Organs-on-Chips in Drug Development: The Importance of Involving Stakeholders in Early Health Technology Assessment

NARCIS (Netherlands)

Middelkamp, Heleen H.T.; van der Meer, Andries Dirk; Hummel, J. Marjan; Stamatialis, Dimitrios; Mummery, Christine Lindsay; Passier, Petrus Christianus Johannes Josephus; IJzerman, Maarten Joost

2016-01-01

Organs-on-chips are three-dimensional, microfluidic cell culture systems that simulate the function of tissues and organ subunits. Organ-on-chip systems are expected to contribute to drug candidate screening and the reduction of animal tests in preclinical drug development and may increase
Rational drug design paradigms: the odyssey for designing better drugs.

Science.gov (United States)

Kellici, Tahsin; Ntountaniotis, Dimitrios; Vrontaki, Eleni; Liapakis, George; Moutevelis-Minakakis, Panagiota; Kokotos, George; Hadjikakou, Sotiris; Tzakos, Andreas G; Afantitis, Antreas; Melagraki, Georgia; Bryant, Sharon; Langer, Thierry; Di Marzo, Vincenzo; Mavromoustakos, Thomas

2015-01-01

Due to the time and effort requirements for the development of a new drug, and the high attrition rates associated with this developmental process, there is an intense effort by academic and industrial researchers to find novel ways for more effective drug development schemes. The first step in the discovery process of a new drug is the identification of the lead compound. The modern research tendency is to avoid the synthesis of new molecules based on chemical intuition, which is time and cost consuming, and instead to apply in silico rational drug design. This approach reduces the consumables and human personnel involved in the initial steps of the drug design. In this review real examples from our research activity aiming to discover new leads will be given for various dire warnings diseases. There is no recipe to follow for discovering new leads. The strategy to be followed depends on the knowledge of the studied system and the experience of the researchers. The described examples constitute successful and unsuccessful efforts and reflect the reality which medicinal chemists have to face in drug design and development. The drug stability is also discussed in both organic molecules and metallotherapeutics. This is an important issue in drug discovery as drug metabolism in the body can lead to various toxic and undesired molecules.
Scale development on consumer behavior toward counterfeit drugs in a developing country: a quantitative study exploiting the tools of an evolving paradigm.

Science.gov (United States)

Alfadl, Abubakr A; Ibrahim, Mohamed Izham b Mohamed; Hassali, Mohamed Azmi Ahmad

2013-09-11

Although desperate need and drug counterfeiting are linked in developing countries, little research has been carried out to address this link, and there is a lack of proper tools and methodology. This study addresses the need for a new methodological approach by developing a scale to aid in understanding the demand side of drug counterfeiting in a developing country. The study presents a quantitative, non-representative survey conducted in Sudan. A face-to-face structured interview survey methodology was employed to collect the data from the general population (people in the street) in two phases: pilot (n = 100) and final survey (n = 1003). Data were analyzed by examining means, variances, squared multiple correlations, item-to-total correlations, and the results of an exploratory factor analysis and a confirmatory factor analysis. As an approach to scale purification, internal consistency was examined and improved. The scale was reduced from 44 to 41 items and Cronbach's alpha improved from 0.818 to 0.862. Finally, scale items were assessed. The result was an eleven-factor solution. Convergent and discriminant validity were demonstrated. The results of this study indicate that the "Consumer Behavior Toward Counterfeit Drugs Scale" is a valid, reliable measure with a solid theoretical base. Ultimately, the study offers public health policymakers a valid measurement tool and, consequently, a new methodological approach with which to build a better understanding of the demand side of counterfeit drugs and to develop more effective strategies to combat the problem.
Problems associated with substandard and counterfeit drugs in developing countries: a review article on global implications of counterfeit drugs in the era of antiretroviral (ARVs) drugs in a free market economy.

Science.gov (United States)

Nsimba, Stephen E D

2008-12-01

To review the global implications associated with the use of substandard and or counterfeit drugs in developing and may be developed countries. The focus of this review is particularly on antiretroviral (ARVs), antimalarials and other drugs. Review of various literatures through Pub-Med, Medline, Google and Internet search to retrieve and download published materials was done by the author of this review paper. When patients receive a counterfeit medicines, they are subjected to multiple risks. They often suffer more than just an inconvenience; as they become victims of fraud medicines and are all put at risk of adverse effects from unprescribed medicines or substandard ingredients. Additionally, patients may lose confidence in health care professionals including their physician and pharmacist, and potentially modern medicine or the pharmaceutical industry in general. Counterfeit or substandard (poor quality) drugs pose threats to society; not only to the individual in terms of the health side effects experienced, but also to the public in terms of trade relations, economic implications, and the effects on global pandemics. It is vital for suppliers, providers, and patients to be aware of current trends in counterfeiting in order to best prepare for encounters with suspicious products. Furthermore, this is an issue that needs to be continually dealt with on national and international policy levels. Developing countries should try their level best to establish good laboratories for monitoring and checking quality of all pharmaceuticals manufactured locally and those imported or donated to these countries. The Ministries of Health and all stakeholders involved in this issue must ensure that all drugs meet the set or established international standards and national standards. Failure to do so will be to misuse the hard earned forex that is normally borrowed from banks for the procurement and distribution of drugs to its people. Indeed sub-standard medications do more
Development of novel alkylating drugs as anticancer agents.

Science.gov (United States)

Izbicka, Elzbieta; Tolcher, Anthony W

2004-06-01

Although conventional alkylating drugs have proven efficacy in the treatment of malignancies, the agents themselves are not selective. Therefore, non-specific alkylation of cellular nucleophilic targets may contribute to many of the observed toxic effects. Novel approaches to drug discovery have resulted in candidate agents that are focused on 'soft alkylation'--alkylators with greater target selectivity. This review highlights the discovery of small molecule drugs that bind to DNA with higher selectivity, act in a unique hypoxic tumor environment, or covalently bind specific protein targets overexpressed in cancer, such as topoisomerase II, glutathione transferase pi1, beta-tubulin and histone deacetylase.
[Giving medico-legal opinions in cases with suspicion of medical mistake.part 1. between medicine and justice.

Science.gov (United States)

Chowaniec, Czesław; Chowaniec, Małgorzata; Wilk, Mateusz

2017-01-01

Creating medico-legal opinion is a sophisticated investigative, analytical, decision-making and creative process. Forensic medicine specialist in cooperation with clinical medicine consultants, on the basis of evidence analysis, which was gathered during procedures and contained in the acts has to create an objective and essential opinion. This opinion is a vital, very important and irreplaceable proof in every case. Judicial body consults with forensic medicine specialist or specialists if there are circumstances for settlement of which there is a need of classified informations - art. 193 of Penalty Code. Forensic medicine specialists face many difficulties which may have effect on quality, positiveness of opinion, compliance with the deadline, increasing expectancy of judicial body or sides. It is very difficult to find clinical specialists which except their clinical knowledge have basic knowledge about law, the role and duties of an court expert. In this article we discuss creating-opinion problems, role and position of court expert in confrontation with expectations of judicial body and the Justice with particular emphasis on medical mistakes and assessment of medical proceedings. We show the complexity of creating of medical opinions, especially these institutional.
Drug repositioning: Re-investigating existing drugs for new therapeutic indications

Directory of Open Access Journals (Sweden)

B M Padhy

2011-01-01

Full Text Available Drug discovery and development is an expensive, time-consuming, and risky enterprise. In order to accelerate the drug development process with reduced risk of failure and relatively lower costs, pharmaceutical companies have adopted drug repositioning as an alternative. This strategy involves exploration of drugs that have already been approved for treatment of other diseases and/or whose targets have already been discovered. Various techniques including data mining, bioinformatics, and usage of novel screening platforms have been used for identification and screening of potential repositioning candidates. However, challenges in clinical trials and intellectual property issues may be encountered during the repositioning process. Nevertheless, such initiatives not only add value to the portfolio of pharmaceutical companies but also provide an opportunity for academia and government laboratories to develop new and innovative uses of existing drugs for infectious and neglected diseases, especially in emerging countries like India.
Drug repositioning: re-investigating existing drugs for new therapeutic indications.

Science.gov (United States)

Padhy, B M; Gupta, Y K

2011-01-01

Drug discovery and development is an expensive, time-consuming, and risky enterprise. In order to accelerate the drug development process with reduced risk of failure and relatively lower costs, pharmaceutical companies have adopted drug repositioning as an alternative. This strategy involves exploration of drugs that have already been approved for treatment of other diseases and/or whose targets have already been discovered. Various techniques including data mining, bioinformatics, and usage of novel screening platforms have been used for identification and screening of potential repositioning candidates. However, challenges in clinical trials and intellectual property issues may be encountered during the repositioning process. Nevertheless, such initiatives not only add value to the portfolio of pharmaceutical companies but also provide an opportunity for academia and government laboratories to develop new and innovative uses of existing drugs for infectious and neglected diseases, especially in emerging countries like India.
Drugs for cardiovascular disease in India: perspectives of pharmaceutical executives and government officials on access and development-a qualitative analysis.

Science.gov (United States)

Newman, Charles; Ajay, Vamadevan S; Srinivas, Ravi; Bhalla, Sandeep; Prabhakaran, Dorairaj; Banerjee, Amitava

2016-01-01

India shoulders the greatest global burden of cardiovascular diseases (CVDs), which are the leading cause of mortality worldwide. Drugs are the bedrock of treatment and prevention of CVD. India's pharmaceutical industry is the third largest, by volume, globally, but access to CVD drugs in India is poor. There is a lack of qualitative data from government and pharmaceutical sectors regarding CVD drug development and access in India. By purposive sampling, we recruited either Indian government officials, or pharmaceutical company executives. We conducted a stakeholder analysis via semi-structured, face-to-face interviews in India. Topic guides allow for the exploration of key issues across multiple interviews, along with affording the interviewer the flexibility to examine matters arising from the discussions themselves. After transcription, interviews underwent inductive thematic analysis. Ten participants were interviewed (Government Officials: n = 5, and Pharmaceutical Executives: n = 5). Two themes emerged: i) 'Policy-derived Factors'; ii) 'Patient- derived Factors' with three findings. First, both government and pharmaceutical participants felt that the focus of Indian pharma is shifting to more complex, high-quality generics and to new drug development, but production of generic drugs rather than new molecular entities will remain a major activity. Second, current trial regulations in India may restrict India's potential role in the future development of CVD drugs. Third, it is likely that the Indian government will tighten its intellectual property regime in future, with potentially far-reaching implications on CVD drug development and access. Our stakeholder analysis provides some support for present patent regulations, whilst suggesting areas for further research in order to inform future policy decisions regarding CVD drug development and availability. Whilst interviewees suggested government policy plays an important role in shaping the industry, a
Characteristics and drug utilization patterns for heavy users of prescription drugs among the elderly

DEFF Research Database (Denmark)

Øymoen, Anita; Pottegård, Anton; Almarsdóttir, Anna Birna

2015-01-01

drug users accounted for 75.4% of their use in 2012, and five of these were cardiovascular drugs. The development over time for the ten most used drug classes followed the same pattern among heavy drug users and in the general population. CONCLUSION: There is a skewed utilization of prescription drugs...... frequently used drugs among heavy drug users and development in use over time. METHOD: This is a descriptive study. Heavy drug users were defined as the accumulated top 1 percentile who accounted for the largest share of prescription drug use measured in number of dispensed defined daily doses (DDDs...

Some links on this page may take you to non-federal websites. Their policies may differ from this site.