Binding specificity is a centrally important concept in molecular biology, yet it has received little philosophical attention. Here I aim to remedy this by analyzing binding specificity as a causal property. I focus on the concept’s role in drug design, where it is highly prized and hence directly studied. From a causal perspective, understanding why binding specificity is a valuable property of drugs contributes to an understanding of causal selection—of how and why scientists distinguish between causes, not just (...) causes from noncauses. In particular, the specificity of drugs is precisely what underwrites their value as experimental interventions on biological processes. (shrink)

Rational drug design is a method for developing new pharmaceuticals that typically involves the elucidation of fundamental physiological mechanisms. It thus combines the quest for a scientific understanding of natural phenomena with the design of useful technology and hence integrates epistemic and practical aims of research and development. Case studies of the rational design of the cardiovascular drugs propranolol, captopril and losartan provide insights into characteristics and conditions of this integration. Rational drug design became (...) possible in the 1950s when theoretical knowledge of drug-target interaction and experimental drug testing could interlock in cycles of mutual advancement. The integration does not, however, diminish the importance of basic research for pharmaceutical development. Rather, it can be shown that still in the 1990s, linear processes of innovation and the close combination of practical and epistemic work were interdependent. (shrink)

Rational drug design is a method for developing new pharmaceuticals that typically involves the elucidation of fundamental physiological mechanisms. It thus combines the quest for a scientific understanding of natural phenomena with the design of useful technology and hence integrates epistemic and practical aims of research and development. Case studies of the rational design of the cardiovascular drugs propranolol, captopril and losartan provide insights into characteristics and conditions of this integration. Rational drug design became (...) possible in the 1950s when theoretical knowledge of drug-target interaction and experimental drug testing could interlock in cycles of mutual advancement. The integration does not, however, diminish the importance of basic research for pharmaceutical development. Rather, it can be shown that still in the 1990s, linear processes of innovation and the close combination of practical and epistemic work were interdependent. (shrink)

Drug design methods have made significant new advances over the last ten years, mainly in the areas of molecular modelling. In more recent times important developments in theory have led to a different type of modelling becoming possible, the so‐called de novo or automated design algorithms. In this new method the programs perform much of the chemist's thinking, in finding appropriately sized chemical groups to fit into a target site. However this is a combinatoric problem which has (...) no general analytical solution; it is ripe for optimization. Other advances, such as combinatorial chemical synthesis and screening, will dramatically influence the search for new lead structures for target sites, which at present are poorly understood. Already these methods are being applied to peptide libraries. Peptides do not make good drug compounds because of their poor bioavailability; further, their flexibility reduces their affinity. In some cases peptide backbones can be removed and replaced with rigid non‐peptide scaffolds. (shrink)

We review the findings of Cho et al.(1) on the crystal structure of a p53 tumor suppressor‐DNA complex. The core DNA binding domain of p53 folds into a structure termed a β‐sandwich, which organizes two loops and a loop‐sheet‐helix structure on one surface of p53 to interact with the consensus DNA recognition sequence of p53. These structures help to explain the functions of wild‐type p53 and the effects of tumor‐associated mutations on p53 DNA binding, transactivation and suppression of cellular proliferation.

Optogenetics and DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) are important research tools in recent neurobiology. These tools allow unprecedented control over activity in specifically targeted neurons in behaving animals. Two approaches in philosophy of neuroscience, mechanism and ruthless reductionism, provide explicit accounts of experiments and results using tools like these, but each offers a different picture about how levels of mechanisms relate. I argue here that the ruthless reductionist’s direct mind‐to‐cellular/molecular activities linkages “in a single bound” better fits (...) with both the experimental designs using these tools and some of the scientists’ own judgments about their results than does the mechanist’s “nested hierarchies of mechanisms‐within‐mechanisms.” So at least some important work in current neuroscience appears to be ruthlessly reductive. Mechanism may not correctly characterize all current work in neuroscience, despite its recent popularity. (shrink)

Equality before the law is one of the fundamental guarantees citizens expect in a just and fair society. We argue that recent trend toward mass incarceration, which has had vastly disproportionate impact on African Americans, is undermining this claim to fairness and raises a serious legitimacy problem for the legal system as a whole. Using original data from the Race, Crime and Public Opinion study we show that African Americans view the 'War on Drugs" as racially biased in its implementation. (...) This perception of bias consequentially undermines legal system legitimacy by lowering blacks' expectations for police performance in their communities and encouraging receptivity to appeals for jury nullification based on race. (shrink)

Today's clinical AIDS research is in trouble. Principal investigators are confronted with young and frequently highly knowledgeable patients. Many of these people with AIDS are often unwilling to adhere to the trial protocols. These PWAs believe they are ethically justified in breaching trial protocols because they do not consider themselves true volunteers in such trials. PWAs argue that they do not really volunteer because existing legislation prevents them from buying and using experimental drugs or from testing alternative treatment strategies. Their (...) only access to such agents is participation in clinical trials. (shrink)

Although applications are being developed and have reached the market, nanopharmacy to date is generally still conceived as an emerging technology. Its concept is ill-defined. Nanopharmacy can also be construed as a converging technology, which combines features of multiple technologies, ranging from nanotechnology to medicine and ICT. It is still debated whether its features give rise to new ethical issues or that issues associated with nanopharma are merely an extension of existing issues in the underlying fields. We argue here that, (...) regardless of the alleged newness of the ethical issues involved, developments occasioned by technological advances affect the roles played by stakeholders in the field of nanopharmacy to such an extent that this calls for a different approach to responsible innovation in this field. Specific features associated with nanopharmacy itself and features introduced to the associated converging technologies- bring about a shift in the roles of stakeholders that call for a different approach to responsibility. We suggest that Value Sensitive Design is a suitable framework to involve stakeholders in addressing moral issues responsibly at an early stage of development of new nanopharmaceuticals. (shrink)

Promotion of prescription drugs may appear to be severely limited in some jurisdictions due to restrictions on direct-to-consumer advertising. However, in most jurisdictions, strategies exist to raise consumer awareness about prescription drugs, notably through the deployment of direct-to-consumer information campaigns that encourage patients to seek help for particular medical conditions. In Canada, DTCI is presented by industry and regulated by Health Canada as being purely informational activities, but their design and integration in broader promotional campaigns raise very similar ethical (...) concerns as those associated with DTCA. Specifically, DTCI can be an effective means of familiarizing the public with the scope and benefits of a particular prescription drug and so, like DTCA, can promote increased patient-consumer demand and thus a problematic rise in the prescribing and use of medications that may be neither the most appropriate nor the most cost-effective. Yet, with DTCI the industry is playing within the existing rules and regulations set by health regulators. To respond appropriately to this regulatory incoherence, we argue that DTCI should be regulated as a type of direct-to-consumer indirect advertising. Even if the case and specific regulations presented here are Canadian, the implications extend to every country that has a partial or total prohibition on DTCA. (shrink)

In purity and holiness I will guard my life and my art.Every physician-patient encounter is a conflict of interest. Every physician-payer encounter is also a conflict of interest.Wide-spread criticism of the pharmaceutical industry’s extravagant marketing practices and some doctors’ undignified, even appalling eagerness to stuff themselves, their pockets and their offices with the industry’s “stuff,” prompted physician groups, the drug and device industry itself to institute reforms designed better to limit industry influence on physicians.But according to Troyen Brennan and (...) his coauthors, the reforms, while reducing some of the most egregious instances of industry influence peddling and physicians’ self-debasement, were doomed fundamentally, for three reasons. First, they were based on common sense but incorrect assumptions about the mechanism of industry influence and on myths about the efficacy of disclosure as an ethical disinfectant. Second, they relied on voluntary adherence and so failed to pinpoint responsibility for monitoring compliance and enforcement. (shrink)

Our drug policy has been widely deemed a failure because the criminalization of drug use has not succeeded in reducing prevalence rates. I contend that the most promising basis to defend the justifiability of drug offenses is to construe them as proxy crimes: offenses designed to prevent the commission of other, more serious crimes. I make a case that many law enforcement officials use drug proscriptions for this purpose in the real world. When construed as proxy (...) crimes, drug prohibitions are less vulnerable to some of the familiar objections brought against their legitimacy. Nonetheless, the justification for punishing those who violate drug proscriptions remains unpersuasive. (shrink)

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 the prospects for a reasonable profit and 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 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 bulk buying. (shrink)

Artificial intelligency can bring speed and reliability to drug discovery process. It represents an additional intelligence, which in any case can replace the strategic and logic creative insight of the medicinal chemist who remains the architect and molecule master designer. In terms of drug design, artificial intelligency, deep learning machines, and other revolutionary technologies will match with the medicinal chemist’s natural intelligency, but for sure never go beyond. This manuscript tries to assess the impact of the artificial (...) intelligency on drug discovery today. (shrink)

Access to students’ perspectives on substance abuse is essential for effective youth intervention projects development. This study aimed to explore students’ perspectives on abuse of drugs and alcohol with probable development of student-led intervention strategies. The study was conducted at public universities in Zambia. Student’s perspectives on drugs and alcohol abuse were documented using a mixed method design that employed purposive and snowball sampling to select 200 respondents to questionnaires and 10 to in-depth interviews. A humanistic theory approach was (...) applied in the interpretation and analysis of the data collected. The findings showed that cannabis (30%) and codeine contained in Benylin (17%) were commonly abused. Further findings showed that students’ academic pressure was the leading cause of substance abuse (27%), followed by peer pressure (20%). Students knew that abuse of drugs and alcohol led to low academic performance, violence and theft, risks of contracting sexually transmitted infections (STIs), and other social maladjustments. The study recommends that institutions of learning increase student-led awareness campaigns, security surveillance on campus, and collaboration with government drug enforcement agencies. Institutions of learning should involve students in the planning of programmes to deal with drug and alcohol abuse. Contribution: The study will inform amendment of drug and alcohol abuse policies in institutions of learning. The study will contribute towards the UNESCO O3 PLUS project goal of making campuses safe and inclusive, and overall, the Sustainable Development Goal 3 and 4. The study serves as basis for scholars in the field of biblical theology engaged with justice, health and human development. The article is a contribution to the research project Biblical Theology and Hermeneutics. The results of this research can especially be utilised by scholars in the field of psychology of religion, the sociology of religion and practical theologians focusing on youth ministry. (shrink)

New technologies regularly bring about profound changes in our daily lives. Romantic relationships are no exception to these transformations. Some philosophers expect the emergence in the near future of love drugs: a theoretically achievable biotechnological intervention that could be designed to strengthen and maintain love in romantic relationships. We investigated laypeople’s resistance to the use of such technologies and its sources. Across two studies (Study 1, French and Peruvian university students, N after exclusion = 186; Study 2, Amazon Mechanical Turk (...) sample, N after exclusion = 693, pre-registered), we found that the use of love drugs designed to strengthen and maintain love in romantic relationships are considered as more morally problematic than psychological therapy with the same aim. In Study 2, we show that this last effect is partially due to the fact that the love resulting from the use of love drugs is perceived as less authentic, intense, and durable. We discuss the specific role of authenticity in the relative moral disapproval of love drugs. (shrink)

Conflicts of interest are common and exist in academia, government, and many industries, including pharmaceutical development. Medical journal editors and others have recently criticized “the pharmaceutical industry,” citing concerns over investigator access to data, approaches to analysis of clinical trial data, and publication practices. Merck & Co., Inc. is a global, research-driven pharmaceutical company that discovers, develops, manufactures, and markets a broad range of human and animal health products, directly and through its joint ventures. Although part of its mission is (...) to provide a superior rate of return to its investors, Merck does not believe this creates an irreconcilable conflict of interest, particularly in activities concerning clinical drug development. We employ rigorous scientific methods to design, conduct, analyze, and report results of clinical trials in the development of innovative drugs and vaccines, with a focus on meeting unmet medical needs and with an ethic that puts the interests of the patient first. This article describes Merck’s approaches to potential conflicts of interest in drug development, particularly with regard to clinical trials. We believe that proprietary interests of the Company can be respected while observing objectivity and transparency in communicating clinical research results. The standards for the review of manuscripts reporting such trials for peer-reviewed publication should be the same, whether they are from Merck or elsewhere. (shrink)

Design research programs attempt to bring together the properties of available materials and the demands derived from intended applications. The logic of problem states and state transitions in such programs, including assessment criteria and heuristic principles, is described in settheoretic terms, starting with a naive model comprising an intended profile and the operational profile of a prototype. In a first concretization the useful distinction between structural and functional properties is built into the model. In two further concretizations the inclusion (...) of potential applications is motivated and described for the case of drug research as well as the inclusion of potential realizations for the case of complex products. Next, another line of concretization of the naive model, the incorporation of potentially relevant properties, is sketched. Then the partial analogy between product- and truth-approximation is indicated. We conclude with some remarks about the usefulness of our models for products reaching the market in comparison to the the so-called social construction of technology approach. (shrink)

Drug development regularly has to deal with complex circumstances on two levels: the local level of pharmacological intervention on specific target proteins, and the systems level of the effects of pharmacological intervention on the organism. Different development strategies in the recent history of early drug development can be understood as competing attempts at coming to grips with these multi-level complexities. Both rational drug design and high-throughput screening concentrate on the local level, while traditional empirical search strategies (...) as well as recent systems biology approaches focus on the systems level. The analysis of these strategies reveals serious obstacles to integrating the study of interventive and systems complexity in a systematic, methodical way. Due to some fairly general properties of biological networks and the available options for pharmaceutical intervention, drug development is captured in an obstinate methodological dilemma. It is argued that at least in typical cases, drug development therefore remains dependent on coincidence, serendipity or plain luck to bridge the gap between development methodology and actual therapeutic success. (shrink)

This paper seeks to understand the treatment effect of Prescription Drug Monitoring Programs on opioid prescription rates. Using county-level panel data on all opioid prescriptions in the U.S. between 2006 and 2015, we investigate whether state interventions like PDMPs have heterogeneous treatment effects at the sub-state level, based on regional and temporal variations in policy design, extent of urbanization, race, and income. Our models comprehensively control for a set of county and time fixed effects, countyspecific and time-varying demographic (...) controls, potentially endogenous time-series trends in prescription rates, and other state-level opioid interventions such as Naloxone Access and Good Samaritan laws, Medicaid expansion, and the provision of Methadone Assistance Treatment. We find that PDMPs are only effective in reducing prescription rates if they obligate doctors to check for patients' history prior to filling out a prescription, but the frequency at which a state requires its PDMP to be updated is irrelevant to its effectiveness. Moreover, the significant treatment effects of PDMPs are almost exclusively driven by urban and predominantly white counties, with the relatively more affluent regions showing greater responsiveness than their less affluent counterparts. (shrink)

An increasing number of drugs removed from the market because of unacceptable toxicity raises concerns regarding preapproval testing of drug safety. In the present paper it is postulated that the non-inferiority type of trial should be abandoned in favor of the superiority trial with active controls and less stringent (p<0.1, both for efficacy and toxicity) statistics. This approach will increase sensitivity of detection of drug-induced adverse effects at the expense of increasing false positive results regarding the difference in (...) efficacy between the tested and reference drug. Such a move will increase the protection of future patients. In addition, the proposed design is far more acceptable from the clinical (e.g. no need to specify the statistically expected “unimportant” number of deaths) and ethical points of view, as well as being favored by the strong incentive of involved parties. In the second part of this paper arguments are presented in favor of the hypothesis that placebo (still used in some superiority trials) does not induce adverse effects. The assertion that placebo may induce adverse effects is probably biased by the nature of the clinical experiment. Such a conclusion is supported by studies indicating that placebo-induced adverse effects are disease — and treatment — specific. The modification of clinical trials according to the proposed changes may increase the trials’ sensitivity at detecting adverse effects of drugs. (shrink)

How does aspirin reduce pain and inflammation? How does it prevent heart attacks? Why does it upset the stomach? How do scientists discover the answers? This article examines research and development in the history from willow bark to aspirin to “super aspirins” Celebrex and Vioxx. Scientists adopt various approaches: trial and error, laboratory experiment, clinical test, elucidation of underlying mechanisms, concept-directed research, and rational drug design. Each approach is limited, but they complement each other in unraveling the mystery (...) of a wonder drug. (shrink)

Drug‐resistant bacterial infections constitute a major threat to global public health. Several key bacteria that are becoming increasingly resistant are among those that are ubiquitously carried by human beings and usually cause no symptoms (i.e. individuals are asymptomatic carriers) until and/or unless a precipitating event leads to symptomatic infection (and thus disease). Carriers of drug‐resistant bacteria can also transmit resistant pathogens to others, thus putting the latter at risk of resistant infections. Accumulating evidence suggests that such transmission occurs (...) not only in hospital settings but also in the general community, although considerably more data are needed to assess the extent of this problem. Asymptomatic carriage of drug‐resistant bacteria raises important ethical questions regarding the appropriate public health response, including the degree to which it would be justified to impose burdens on asymptomatic carriers (and others) in order to prevent transmission. In this paper, we (i) summarize current evidence regarding the carriage of key drug‐resistant bacteria, noting important knowledge gaps; and (ii) explore the particular implications of existing public health ethics frameworks for policy‐making regarding asymptomatic carriers. Inter alia, we argue that the relative burdens imposed by public health measures on healthy carriers (as opposed to sick individuals) warrant careful consideration and should be proportionate to the expected public health benefits in terms of risks averted. We conclude that more surveillance and research regarding community transmission will be needed in order to clarify relevant risks and design proportionate policies, although extensive community surveillance itself would also require careful ethical consideration. (shrink)

With the human genome mapped, and with the mapping of more than one hundred animal genomes in progress, the amount of genetic data available is increasing exponentially. This exponential increase in data is having an immediate impact on the process of drug development. By using techniques of information technology to manipulate data regarding the genes, proteins, and biochemical pathways associated with various diseases, scientists are beginning to be able to design drugs in a systematic fashion. In the context (...) of any given disease, scientists look to see whether a gene, a protein for which the gene codes, or another protein in the relevant biochemical pathway could be the “target” biological molecule, the “knocking out” of which would halt or slow the disease's progression. Once a target molecule has been identified and characterized structurally, drug therapies that would be likely to knock out this target can be identified and tested systematically. The merger of information technology and genetic technology has changed the process of pharmaceutical development so much that a new term—bioinformatics—has been coined to describe this new approach to such development. (shrink)

We are unlikely to stop seeking pleasure, as this would prejudice our health and well-being. Yet many psychoactive substances providing pleasure are outlawed as illicit recreational drugs, despite the fact that only some of them are addictive to some people. Efforts to redress their prohibition, or to reform legislation so that penalties are proportionate to harm have largely failed. Yet, if choices over seeking pleasure are ethical insofar as they avoid harm to oneself or others, public health strategies should foster (...) ethical choice by moving beyond current risk management practices embodied in the harm reduction movement. The neuroscience of pleasure has much to offer neuroethics and public health strategies. Distinguishing between ‘wanting’ and ‘liking’ fosters new understandings of addiction. These hold promise for directing the search for pharmacotherapies which prevent addiction and relapse or disrupt associated neuromechanisms. They could inform new research into creating lawful psychoactive substances which give us pleasure without provoking addiction. As the health and well being of human and other animals rests upon the experience of pleasure, this would be an ethical objective within public health strategy. Were ethical and neurobiological obstacles to ending addiction to be overcome, problems associated with excessive consumption, the lure of unlawful psychoactive substances and the paucity of lawful means to achieve pleasurable altered states would remain. Non-addictive designer drugs, which reliably provided lawful access to pleasures and altered states, would ameliorate these public health concerns insofar as they fostered citizens’ informed, ethical choices according to a neurobiological taxonomy of pleasures. (shrink)

No country has yet implemented a pilot to ensure access to or the innovation of new antibiotics for multi-drug infections. A team from national health agencies in Norway, with the support of the Innovative Medicine Initiative-funded project DRIVE-AB, designed a model suitable for the national context, including the selection of the antibiotics, the potential value, and the operational model.

Hospital systems commonly face the challenge of determining just ways to allocate scarce drugs during national shortages. There is no standardised approach of how this should be instituted, but principles of distributive justice are commonly used so that patients who are most likely to benefit from the drug receive it. As a result, clinical indications, in which the evidence for the drug is assumed to be established, are often prioritised over research use. In this manuscript, we present a (...) case of a phase II investigational trial of intravenous thiamine for delirium prevention in patients undergoing haematopoietic stem cell transplantation to emphasise several shortcomings in the overarching prioritisation of clinical over research uses of scarce drugs. Specifically, we present the following considerations: clinical use may not have stronger evidence than research use; a strong scientific rationale for research use may outweigh the claim for clinical indications in which there is weak evidence; treatment within the context of a clinical trial may be the standard of care; and research use may not only benefit patients receiving the treatment but also offers the prospect of improving future clinical care. In summary, we argue against allocation schemes that prohibit all research uses of scarce drugs and instead recommend that allocation schemes include a balanced approach that weighs risks and benefits of access to scarce drugs irrespective of the research versus clinical use designation. (shrink)

Regulatory agencies vary widely in their classification of FMT, with significant impact on patient access. This article conducts a global survey of national regulations and collates existing FMT classification statuses, ultimately suggesting that the human cell and tissue product designation best fits FMT's characteristics and that definitional objectives to that classification may be overcome.

The ethical issues in conducting research on preventing HIV infection are among the most complex of any area of human subjects research. This article is an update of a 1987 article that addressed potential conflicts between research design and ethics with respect to AIDS prevention among injecting drug users. The present article reviews current ethical issues that arise in the design and conduct of HIV/AIDS prevention research focused on injecting drug users.

Efforts to foster transparency in biopharmaceutical regulation are well underway: drug manufacturers are, for example, legally required to register clinical trials and share research results in the United States and Europe. Recently, the policy conversation has shifted toward the disclosure of clinical trial data, not just trial designs and basic results. Here, I argue that clinical trial registration and disclosure of clinical trial data are necessary but insufficient. There is also a need to ensure that regulatory decisions that flow (...) from clinical trials — whether positive (i.e., product approvals) or negative (i.e., abandoned products, product refusals, and withdrawals) — are open to outside scrutiny. Further, a jurisprudence of drug regulation is needed. I develop two arguments motivated by (1) innovation concerns and (2) the value of good governance in support of openly publishing all final decisions for approved, abandoned, refused, and withdrawn products. After articulating why greater transparency in regulatory decision-making is needed, I distil four essential features of a jurisprudence of drug regulation that prescribe policy changes in terms not only of the transparency of regulatory outcomes and the underlying reasoning, but also regulatory organization. (shrink)

Efforts to ensure greater transparency in the regulation of “drugs” are well underway. For example, laws in the United States and Europe now require registration of most clinical trials beyond phase 1. Yet instances of avoidable harm to patients continue to arise. In response, calls for disclosure of clinical trial data in the form of “clinical study reports,” not just trial designs and basic results, are growing. In this paper, I argue that disclosure of clinical trial data is necessary but (...) insufficient. Rather, the regulatory decisions that flow from those trial data —whether positive or negative —should also be open to outside scrutiny provided they are final in nature. (shrink)

Previous conversation analytic studies of institutional interaction included analyses of empathy in interaction. These studies revealed that professionals may use empathy displays not only to validate the client’s worry, but also to perform actions oriented to other institutional goals and tasks such as closing off a troubles-telling sequence. In this article, we present an analysis of empathically designed responses in Dutch telephone counseling. The data consist of 36 calls from the Alcohol and Drugs Info Line. In some of the calls, (...) clients’ troubles-telling includes ‘emotion discourse’, that is, descriptions of their feelings/emotions. Counselors may respond to these descriptions using conventional empathy displays like ‘I can imagine that’ and ‘I understand that’ in a range of verbal and prosodic variations. The analysis reveals that these responses open up advice sequences that vary in the extent to which they treat the client’s articulated feelings as valid. Most are affiliating, treating the client’s feelings as the basis for advice, while some are less affiliative, putting the client’s feelings into perspective or implicitly questioning their legitimacy. Hence, empathically designed responses are pivots to advice-giving. (shrink)

In the last few years, annexins have been discovered in several nematodes and other parasites, and distinct differences between the parasite annexins and those of the hosts make them potentially attractive targets for anti‐parasite therapeutics. Annexins are ubiquitous proteins found in almost all organisms across all kingdoms. Here, we present an overview of novel annexins from parasitic organisms, and summarize their phylogenetic and biochemical properties, with a view to using them as drug or vaccine targets. Building on structural and (...) biological information that has been accumulated for mammalian and plant annexins, we describe a predicted additional secondary structure element found in many parasite annexins that may confer unique functional properties, and present a specific antigenic epitope for use as a vaccine. (shrink)

Prescribing drugs for uses that the FDA has not approved — off-label drug use — can sometimes be justified but is typically not supported by substantial evidence of effectiveness. At the root of inappropriate off-label drug use lie perverse incentives for pharmaceutical firms and flawed oversight of prescribing physicians. Typical reform proposals such as increased sanctions for manufacturers might reduce the incidence of unjustified off-label use, but they do not remove the source of the problem. Public policy should (...) address the cause and control the practice. To manage inappropriate off-label drug use, off-label prescriptions must be tracked in order to monitor the risks and benefits and the manufacturers’ conduct. Even more important, reimbursement rules should be changed so that manufacturers cannot profit from off-label sales. When off-label sales pass a critical threshold, manufacturers should also be required to pay for independent testing of the safety and effectiveness of off-label drug uses and for the FDA to review the evidence. Manufacturers should also finance, under FDA supervision, programs designed to warn physicians and the public about the risks of off-label drug use. (shrink)

The potential of the folic acid biosynthesis pathway as a target for the development of antibiotics has been acknowledged for many years and validated by the clinical use of several drugs. Recently, the crystal structures of all but one of the enzymes in the pathway from GTP to dihydrofolate have been determined. Given that structure‐based drug design strategies are now widely employed, these recent developments have prompted a re‐evaluation of the potential of each of the enzymes in the (...) pathway as a target for development of specific inhibitors. Here, we review the current knowledge of the structure and mechanism of each enzyme in the bacterial folic acid biosynthesis pathway from GTP to dihydrofolate and draw conclusions regarding the potential of each enzyme as a target for therapeutic intervention. BioEssays 24:637–648, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

There is consensus that children have questionable decisional capacity and, therefore, in general a parent or a guardian must give permission to enroll a child in a research study. Moreover, freedom from duress and coercion, the cardinal rule in research involving adults, is even more important for children. This principle is embodied prominently in the Nuremberg Code (1947) and is embodied in various federal human research protection regulations. In a program named "SATURN" (Student Athletic Testing Using Random Notification), each school (...) in the Oregon public-school system may implement a mandatory drug-testing program for high school student athletes. A prospective study to identify drug use among student-athletes, SATURN is designed both to evaluate the influence of random drug testing and to validate the survey data through identification of individuals who do not report drug use. The enrollment of students in the drug-testing study is a requirement for playing a school sport. In addition to the coercive nature of this study design, there were ethically questionable practices in recruitment, informed consent, and confidentiality. This article concerns the question of whether research can be conducted with high school students in conjunction with a mandatory drug-testing program, while adhering to prevailing ethical standards regarding human-subjects research and specifically the participation of children in research. (shrink)

Drug abuse has been and continues to be, a common social issue worldwide, yet the efficiency of widely adopted sweeping speech for anti-drug campaigns has proven inefficient. To provide students with a safe and efficient learning situation related to drug refusal skills, we used a novel approach rooted in a serious learning game and concept map during a brief extracurricular period to help students understand drugs and their negative effects. The proposed game-based situational learning system allowed all (...) students to participate simultaneously and individually in multiple scenarios of drug temptation posed by peers and classmates to practice responding and refusing drugs in school and community settings. Moreover, to explore whether different personality traits result in different anti-drug responses, we used a serious game to conduct an anti-drug experiment on 53 junior middle school students aged 13–15. Each participant’s decision-making process was recorded in the serious game as behavioral patterns for lag sequential analysis. The outcomes revealed seven behavioral patterns including differentiation, acceptance, effective and ineffective responses, effective and ineffective solution-seeking, and failure to refuse. The GSEQ which is a computer program for analyzing sequential observational data was used. The results indicated the following: Neuroticism was performed at a relatively low level under the guidance of a concept map. “Neuroticism” was associated with the lowest risk of accepting drugs. Students with “openness to experiences” were at high risk of accepting drugs. Almost all personality behavioral transition diagrams showed that failure to refuse drugs was followed by inefficient seeking of help and inefficient refusal. These findings provide reference points for designing adaptive anti-drug education programs. (shrink)

The paper presents major ethical, legal and methodological problems related to the use of placebo in mental disorders, especially in depression. It is pointed out that although authoritative groups of experts and numerous publications in the field of psychopharmacology indicate advisability of the double blind design with placebo in clinical trials of antidepressants, in recent years there have been more and more voices questioning legitimacy of this method. Objections of an ethical nature are raised, and reliability of this approach (...) is put into doubt from the methodological viewpoint. These issues are discussed in more detail in the paper. Available alternative solutions should be implemented in psychotropic drug studies. The author shares these objections and doubts of an ethical nature, and believes that the placebo procedure is not a necessity in clinical trials of antidepressants. (shrink)

Many drugs used in paediatric medicine are off-label. There is a rising call for the use of adaptive clinical trial designs in responding to the need for safe and effective drugs given their potential to offer efficiency and cost-effective benefits compared with traditional clinical trials. ADs have a strong appeal in paediatric clinical trials given the small number of available participants, limited understanding of age-related variability and the desire to limit exposure to futile or unsafe interventions. Although the ethical value (...) of adaptive trials has increasingly come under scrutiny, there is a paucity of literature on the ethical dilemmas that may be associated with paediatric adaptive designs. This paper highlights some of these ethical concerns around safety, scientific/social value and caregiver/guardian comprehension of the trial design. Against this background, the paper develops a non-static conceptual lens for understanding PADs. It shows that ADs are epistemically open and reduce some of the knowledge-associated uncertainties inherent in clinical trials as well as fast-track the time to draw conclusions about the value of evaluated drugs/treatments. On this note, the authors argue that PADs are ethically justifiable given they have multiple layers of safety, exposing enrolled children to lesser potential risks, create social/scientific value generally and for paediatric populations in particular, specifically foster the flourishing of paediatric populations and can significantly improve paediatric trial efficiency when properly designed and implemented. However, because PADs are relatively new and their regulatory, ethical and logistical characteristics are yet to be clarified in some jurisdictions, the cooperation of various public and private stakeholders is required to ensure that the interests of children, their caregivers and parents/guardians are best served while exposing paediatric research subjects to the most minimal of risks when they are enrolled in paediatric trials that use ADs. Data sharing not applicable as no datasets generated and/or analysed for this study. Not applicable. (shrink)