Attention deficit hyperactivity disorder is a developmental disorder with an age onset prior to 7 years. Children with ADHD have significantly lower ability to focus and sustain attention and also score higher on impulsivity and hyperactivity. Stimulants, such as methylphenidate, have remained the mainstay of ADHD treatment for decades with evidence supporting their use. However, recent years have seen emergence of newer drugs and drug delivery systems, like osmotic release oral systems and transdermal patches, to mention a few. The (...) use of nonstimulant drugs like atomoxetine and various other drugs, such as a-agonists, and a few antidepressants, being used in an off-label manner, have added to the pharmacotherapy of ADHD. This review discusses current trends in drug therapy of ADHD and highlights the promise pharmacogenomics may hold in the future. (shrink)

*The views represented in this article are those of the author and do not necessarily represent the views or policies of the American Medical Association.

The COVID-19 pandemic has resulted in more than 524 million cases and 6 million deaths worldwide. Various drug interventions targeting multiple stages of COVID-19 pathogenesis can significantly reduce infection-related mortality. The current within-host mathematical modeling study addresses the optimal drug regimen and efficacy of combination therapies in the treatment of COVID-19. The drugs/interventions considered include Arbidol, Remdesivir, Interferon and Lopinavir/ritonavir. It is concluded that these drugs, when administered singly or in combination, reduce the number of infected cells and (...) viral load. Four scenarios dealing with the administration of a single drug, two drugs, three drugs and all four are discussed. In all these scenarios, the optimal drug regimen is proposed based on two methods. In the first method, these medical interventions are modeled as control interventions and a corresponding objective function and optimal control problem are formulated. In this framework, the optimal drug regimen is derived. Later, using the comparative effectiveness method, the optimal drug regimen is derived based on the basic reproduction number and viral load. The average number of infected cells and viral load decreased the most when all four drugs were used together. On the other hand, the average number of susceptible cells decreased the most when Arbidol was administered alone. The basic reproduction number and viral load decreased the most when all four interventions were used together, confirming the previously obtained finding of the optimal control problem. The results of this study can help physicians make decisions about the treatment of the life-threatening COVID-19 infection. (shrink)

This article explores the translation and migration of illegal drugs, humanistic therapies and political ideologies by focusing on China’s first residential community drug treatment center, called Sunlight. I argue that the migration of contemporary treatment therapies from one continent to another initiates certain practices that re-appropriate and remake drug-using bodies that live and work at Sunlight. Reviewing Sunlight ethnographically also allows for broader theoretical exploration. When bodies do not operate under the common trope of possessive individualism different forms (...) of biopolitical and therapeutic power are at play. In keeping with the theme of this special issue, this article begins with a discussion of why migration is a useful rubric for understanding how therapeutics and bodies become global entities and practices through the movement of three things: heroin, humanistic therapy and political ideology. It then presents an ethnographic slice of life at Sunlight to demonstrate how these practices and ideologies play out in the everyday. It finally returns to the question of why these therapies re-appropriate the post-socialist drug user’s body and psyche through a discussion of the term ‘psycho-sociability’. Psycho-sociability can be read as a demand for becoming a good biological citizen, as well as a theoretical rubric for explaining non-Western biopolitics. (shrink)

Anthropology of Consciousness, Volume 32, Issue 1, Page 33-54, Spring 2021.

The development of photodynamic therapy and anti-vascular endothelial growth factor agents have revolutionized the treatment of retinal diseases, transforming the retina subspecialty by ushering in an age of pharmacological treatments for a wide range of diseases, including age-related macular degeneration.

Volume 20, Issue 4, May 2020, Page 102-103.

Oversight of human gene transfer research presents an important model with potential application to oversight of nanobiology research on human participants. Gene therapy oversight adds centralized federal review at the National Institutes of Health's Office of Biotechnology Activities and its Recombinant DNA Advisory Committee to standard oversight of human subjects research at the researcher's institution and at the federal level by the Office for Human Research Protections. The Food and Drug Administration's Center for Biologics Evaluation and Research oversees human (...) gene transfer research in parallel, including approval of protocols and regulation of products. This article traces the evolution of this dual oversight system; describes how the system is already addressing nanobiotechnology in gene transfer: evaluates gene therapy oversight based on public opinion, the literature, and preliminary expert elicitation; and offers lessons of the gene therapy oversight experience for oversight of nanobiotechnology. (shrink)

The making and taking of psychotropic drugs, whether on medical prescription or as self-medication, whether marketed by pharmaceutical companies or clamoured for by an anxious population, has been an integral part of the twentieth century. In this modern era of speed, uncertainty, pleasure and anguish the boundaries between healing and enhancing the mind by chemical means have been redefined. Long before Prozac would become a household name for an ‘emotional aspirin’ did consumers embrace the idea and practice of taking psychotropics (...) not only to treat mental illness but also to make them feel better about living in a modern world. The Freudian promise that each individual can remake him- or herself in the pursuit of health and happiness was helpful in promoting and legitimizing the idea and practice of seeking wellness on prescription. We will argue that the modern consumer-driven political culture of medicine will continue to transverse the boundaries of therapy and enhancement of the mind into the largely unexplored territories of human cognition and behaviour. However exciting, this endeavour will come at the cost of further widening the problem of iatrogenic addiction in the age of happiness pills as ‘botox’ for the mind. (shrink)

Direct brain intervention based mental capacity restoration techniques-for instance, psycho-active drugs-are sometimes used in criminal cases to promote the aims of justice. For instance, they might be used to restore a person's competence to stand trial in order to assess the degree of their responsibility for what they did, or to restore their competence for punishment so that we can hold them responsible for it. Some also suggest that such interventions might be used for therapy or reform in criminal legal (...) contexts-i.e. to make non-responsible and irresponsible people more responsible. However, I argue that such interventions may at least sometimes fail to promote these responsibility-related legal aims. This is because responsibility hinges on other factors than just what mental capacities a person has-in particular, it also hinges on such things as authenticity, personal identity, and mental capacity ownership-and some ways of restoring mental capacity may adversely affect these other factors. Put one way, my claim is that what might suffice for the restoration of competence need not necessarily suffice for the restoration of responsibility, or, put another way, that although responsibility indeed tracks mental capacity it may not always track restored mental capacities. (shrink)

Improvements in the health capital of citizens are central to the development of countries. By exploiting steep decreases in antiretroviral drug prices and the subsequent increases in antiretroviral therapy (ART) coverage, we test whether the resulting improvements in the health of the population are associated with the prevalence of entrepreneurial activity and whether entrepreneurial activity strengthens the relationship between ART coverage and a country’s development. Drawing on a sample of 87 low- and middle-income countries (2006–2019), we find that a (...) 1% increase in ART coverage is associated with a 1.5% increase in the number of newly registered limited liability firms; however, there is no significant relationship with (male or female) self-employment. Higher ART coverage is particularly associated with development—as proxied by gross domestic product (GDP) per capita and the Human Development Index—in countries with low levels of new business formation and high proportions of self-employment. (shrink)

BackgroundAt present, tic disorder has attracted the attention of medical researchers in many countries. More clinicians choose non-drug therapy, especially cognitive-behavioral therapy because of the cognitive side effects of drug therapy. However, few studies had assessed its efficacy. It is necessary to have a more comprehensive understanding of the literature quality of CBT and its intervention effect.MethodsIn this study, MEDLINE, Embase, and Cochrane were searched from the beginning to June 15, 2021 to study the efficacy of -CBT on (...) tic disorder. Only studies using the Yale Global Tic Severity Scale and the control group were included.ResultsA total of 12 randomized controlled trials, including 536 patients with tic disorders, were identified. The results showed that the effect of CBT was better than that of the control group. The pooled standardized mean difference was −0.34. The effect size of CBT differs from different intervention conditions. In seven studies, the subjects’ motor tic scores were counted. The sample size of the experimental group was 224 and that of the control group was 218. The pooled SMD was −0.43. Seven studies counted the vocal tic scores of subjects, 224 in the experimental group and 218 in the control group. The pooled SMD was −0.22. Seven studies counted the tic impairment scores of subjects, 220 in the experimental group and 214 in the control group. The pooled SMD was −0.48.ConclusionThe literature shows that different CBTs can significantly reduce the total score of tic disorder and the score of motor tic, but cannot significantly reduce the score of vocal tic. In the future, more new interventions were needed to improve the symptoms of different patients, especially vocal tic. (shrink)

In the historical context of a crisis in biological psychiatry, psychedelic drugs paired with psychotherapy are globally re-emerging in research clinics as a potential transdiagnostic therapy for treating mood disorders, addictions, and other forms of psychological distress. The treatments are poised to soon shift from clinical trials to widespread service delivery in places like Australia, North America, and Europe, which has prompted ethical questions by social scientists and bioethicists. Taking a broader view, we argue that the ethics of psychedelic therapy (...) concerns not simply how psychotherapies are different when paired with psychedelic drugs, but how psychedelic therapies shape and are shaped by different values, norms, and metaphysical commitments. Drawing from the published literature and interviews with seven psychedelic therapists working in clinical trials in the United States, Germany, Switzerland, and Australia, this article opens the black box of the treatments to consider the values and informal debates currently animating the therapies. Considering questions of patient autonomy, mechanisms of therapeutic action, and which therapies are best suited to pair with psychedelic substances, we examine the ethics of psychedelic therapy as an emergent form of life. To bring this form of life out in fuller relief, we conclude by comparing and contrasting it with ayahuasca use in Amazonian shamanism. (shrink)

A study of the international pharmaceutical industry discusses the uses and abuses of prescription drugs and details the dangers and adverse impact of disease treatment with drugs.

Over the past few years several drugs that target epigenetic modifications have shown clinical benefits, thus seemingly validating epigenetic cancer therapy. More recently, however, it has become clear that these drugs are either characterized by low specificity or that their target enzymes have low substrate specificity. As such, clinical proof‐of‐concept for epigenetic cancer therapies remains to be established. Human cancers are characterized by widespread changes in their genomic DNA methylation and histone modification patterns. Epigenetic cancer therapy aims to restore normal (...) epigenetic modification patterns through the inhibition of epigenetic modifier enzymes. In this review, we provide an overview about the known functional roles of DNA methyltransferases, histone deacetylases, histone methyltransferases, and demethylases in cancer development. The available data identify several examples that warrant further consideration as drug targets. Future research should be directed toward targeted enzyme inhibition and toward exploring interactions between epigenetic pathways to maximize cancer specificity. (shrink)

The emphasis in human pluripotent stem cell (hPSC) technologies has shifted from cell therapy to in vitro disease modelling and drug screening. This review examines why this shift has occurred, and how current technological limitations might be overcome to fully realise the potential of hPSCs. Details are provided for all disease‐specific human induced pluripotent stem cell lines spanning a dozen dysfunctional organ systems. Phenotype and pharmacology have been examined in only 17 of 63 lines, primarily those that model neurological (...) and cardiac conditions. Drug screening is most advanced in hPSC‐cardiomyocytes. Responses for almost 60 agents include examples of how careful tests in hPSC‐cardiomyocytes have improved on existing in vitro assays, and how these cells have been integrated into high throughput imaging and electrophysiology industrial platforms. Such successes will provide an incentive to overcome bottlenecks in hPSC technology such as improving cell maturity and industrial scalability whilst reducing cost. (shrink)

A mathematical model of the dynamics of the immune system is considered to illustrate the effect of its response to HIV infection, i.e. on viral growth and on T-cell dynamics. The specific immune response is measured by the levels of cytotoxic lymphocytes in a human body. The existence and stability analyses are performed for infected steady state and uninfected steady state. In order to keep infection under control, roles of drug therapies are analyzed in the presence of efficient immune (...) response. Numerical simulations are computed and exhibited to illustrate the support of the immune system to drug therapies, so as to ensure the decay of infection and to maintain the level of healthy cells. (shrink)

The use of opioid contracts, which often require patients to submit to random drug screens, have become widespread amongst physicians using opioids to treat chronic pain. The main purpose of the contract is to improve care through better adherence to opioid therapy but there is little evidence as to its efficacy. The author suggests the use of opioid contracts and random drug testing destroys patients' trust which impacts health outcomes, and that physicians' motivation for their use are concerns (...) about prosecution, medication abuse and misuse, and addiction. Statistics are provided to counter fears, and evidence is offered suggesting opioid contracts are unenforceable and lack efficacy; random drug testing is often inconclusive, and a patient's trust improves adherence to treatment. (shrink)

It is common for physicians who prescribe opioids for chronic pain to have their patients sign an opioid contract in order to receive opioid therapy. A vast majority of these contracts contain a stipulation requiring patients to submit to random drug testing which screens for both licit and illicit drugs. Physicians who prescribe opioids may be concerned about prosecution and disciplinary actions; medication abuse and misuse; and addiction. Steven Passik et al. write, “…physicians still fear the risk of abuse (...) or addiction as well as the potential legal consequences of their prescribing.”Issues surrounding OC/RDT need a closer look with a focus on enforceability and efficacy of the opioid contract; accuracy and complications of drug screens and their interpretation; and the importance of trust between patient and physician. In addition, it is vital to dispel fears with facts regarding prosecutions, nonmedical use of prescription opioids, and addiction. (shrink)

Heroin use poses a significant health and economic burden to society, and individuals with heroin dependence are responsible for a significant amount of crime. Owing to its efficacy and cost-effectiveness, methadone maintenance therapy (MMT) is offered as an optional alternative to imprisonment for drug offenders in several jurisdictions. Some object to such 'MMT offers' on the basis that they involve coercion and thus invalidate the offender's consent to MMT. While we find these arguments unpersuasive, we do not attempt to (...) build a case against them here. Instead, we explore whether administration of MMT following acceptance of an MMT offer might be permissible even on the assumption that MMT offers are coercive, and in such a way that the resulting MMT is non-consensual. We argue that non-consensual MMT following an MMT offer is typically permissible. We first offer empirical evidence to demonstrate the substantial benefits to the offender and society of implementing non-consensual MMT in the criminal justice system. We then explore and respond to potential objections to such uses of MMT. These appeal respectively to harm, autonomy, bodily and mental interference, and penal theoretic considerations. Finally, we introduce and dismiss a potential response to our argument that takes a revisionist position, rejecting prevailing incarceration practices. (shrink)

This paper applies basic concepts of Logic-Based Therapy (LBT) to the case of a person in recovery from drug and alcohol addiction after relapse. The paper has been written in partial fulfillment of the requirements for the online Practical Reasoning course taught by Dr. Elliot D. Cohen at Indian River State College.

As a response to the opioid epidemic in the United States, the Centers for Disease Control and Prevention (CDC) published the CDC Guideline for Prescribing Opioids for Chronic Pain in 2016. This document served as a means to reduce risks and address harms of opioid use by recommending that clinicians conduct periodic urine drug testing for patients on chronic opioid therapy. As an unintended result of this recommendation, providers began using unexpected urine drug test results as a reason (...) to dismiss patients from practice, both out of concern for their patients’ wellbeing as well as their own legal risks. Using Husserl’s and Heidegger’s phenomenology, we argue that this science-based, black-and-white practice does not heed the patient as a whole person. Instead, we recommend a more contextual, patient-centered approach that can help us to better understand and manage patient needs in such contexts. (shrink)

Introduction In 2013, Dr. J. Muizelaar and Dr. R. Schrot, two neurosurgeons at the University of California Davis Medical Center (UCDMC), were found guilty of research misconduct due to failure to comply with institutional policies as well as Food and Drug Administration (FDA) regulations governing human subjects research. At issue here, however, is the difference between research and innovative therapy in the clinical setting of patient care where clinical judgment is reasonably to be privileged. Methods The UCDMC investigative document (...) is reviewed along with standard literature on clinical ethics and clinical data about glioblastoma multiforme (GBM) cancer. Results In this paper I argue that, by tendentiously focusing on policies, regulations, and procedures governing human subjects research, the UCDMC investigation failed to account for the centrality of clinical judgment and clinical ethics pertinent to judicious review of this matter, especially given the unique clinical context of terminally ill patients having exhausted standard care treatment options for glioblastoma multiforme (GBM) cancer. Conclusions The UCDMC investigation raises serious problems for clinicians who are engaged in innovative therapy in the clinical setting, requiring a regulatory framework separate from the normal Institutional Review Board (IRB) process. (shrink)

Psychoactive drugs are being prescribed to millions of Americans at an increasing rate. In many cases these drugs are necessary in order to overcome debilitating emotional problems. Yet in other instances, these drugs are used to supplant, not supplement, interpersonal therapy. The process of overcoming emotional obstacles by introspection and the attainment of self knowledge is gradually being eroded via the gratuitous use of psychoactive medication in order to rapidly attain a release from the common problems that life inevitably presents (...) us with. In this paper, I argue that Kant’s formula of humanity, which maintains that persons ought never to treat others or themselves soley as a means to an end, proscribes this. Moreover, Kant argues that we have an imperfect duty of self development, and I argue that we fail to adhere to such a duty whenever we seek to evade the process of introspection and self knowledge in favour of the expedient results that drugs may provide us with as we attempt to overcome the emotional hurdles in our lives. (shrink)

Step therapy is an insurance company policy whereby patients must try a less costly treatment and fail-first before the insurer will cover another, more costly treatment. This article argues that there are relevant and well-established principles of medical ethics—the duty to practice evidenced-based medicine and the duty to consider cost-effectiveness when treating patients—that constrain and guide physician behavior with respect to step therapy; clinical practice guidelines promulgated by authoritative physician groups attempt to incorporate and reconcile the competing demands of evidenced-based (...) and cost-effective medicine, although it is unclear whether they do so in a manner that appropriately considers all relevant ethical factors relating to cost-effectiveness; and despite the potential shortcomings of CPGs, the ethical principles guiding and constraining physician behavior can help demarcate the ethical boundaries for other actors in the drug prescribing and reimbursement matrix, including insurance companies and benefit managers. (shrink)

During tumor evolution, cancer cells use the tumor‐stroma crosstalk to reorganize the microenvironment for maximum robustness of the tumor. The success of immune checkpoint therapy foretells a new cancer therapy paradigm: an effective cancer treatment should not aim to influence the individual components of super complex intracellular interactomes (molecular targeting), but try to disrupt the intercellular interactions between cancer and stromal cells, thus breaking the tumor as a whole. Arguments are provided in favor of a hypothesis that such interactions include (...) formation of synapse‐like structures (interfaces) where the interacting cells are located at a distance of ∼10–15 nm. Within these interfaces, molecules initiating and strengthening the interaction are organized, and allow optimum cross‐signaling; a very confined intercellular space facilitates the concentration of secreted cytokines, enhancing the paracrine cross‐communication. These features of tumors form a druggable cancer hallmark the tumor‐stroma symbiotic crosstalk—which represents a new target for efficient cancer drug discovery. (shrink)

Aim To explore the way people living with HIV and healthcare providers in Togo judge the priority of HIV-infected patients regarding the allocation of antiretroviral drugs. Method From June to September 2015, 200 adults living with HIV and 121 healthcare providers living in Togo were recruited for the study. They were presented with stories of a few lines depicting the situation of an HIV-infected patient and were instructed to judge the extent to which the patient should be given priority for (...) antiretroviral drugs. The stories were composed by systematically varying the levels of four factors: the severity of HIV infection, the financial situation of the patient, the patient's family responsibilities and the time elapsed since the first consultation. Results Five clusters were identified: 65% of the participants expressed the view that patients who are poor and severely sick should be treated as a priority, 13% prioritised treatment of patients who are poor and parents of small children, 12% expressed the view that the poor should be treated as a priority, 4% preferred that the sickest be treated as a priority and 6% wanted all patients to get treatment. Conclusions WHO's guideline regarding antiretroviral therapy allocation currently in use in many African countries does not reflect the preferences of Togolese people living with HIV. For most HIV-infected patients in Togo, patients who cannot get treatment on their own should be treated as a priority. (shrink)

Pharmacoresistant schizophrenia is a significant impediment to the successful management of the disease. The expression and function of P‐glycoprotein (P‐gp) has recently been implicated in this phenomenon. P‐gp is a multidrug efflux transporter that prevents drug substrates from crossing the blood–brain barrier (BBB). Although the direct interaction between individual antipsychotic agents and P‐gp has been demonstrated, the effect of antipsychotic drug combinations used in disease management on P‐gp transport function remains to be elucidated. This could have important clinical (...) implications in some individuals as dosage adjustments based on plasma drug concentration changes may not always be appropriate if drug–drug interactions and the resulting changes in drug concentration in the brain are not considered. This paper introduces the potential impact that combination antipsychotic therapy may have on P‐gp function at the BBB and discusses the consequences of this in the prevention and circumvention of unfavourable therapeutic response in schizophrenic disorders. BioEssays 30:183–188, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

In this paper we analyse some ethical and philosophical questions related to the development of memory enhancing drugs (MEDs) and anti-dementia drugs. The world of memory enhancement is coloured by utopian thinking and by the desire for quicker, sharper, and more reliable memories. Dementia is characterized by decline, fragility, vulnerability, a loss of the most important cognitive functions and even a loss of self. While MEDs are being developed for self-improvement, in Alzheimer’s Disease (AD) the self is being lost. Despite (...) this it is precisely those patients with AD and other forms of dementia that provide the subjects for scientific research on memory improvement. Biomedical research in the field of MEDs and anti-dementia drugs appears to provide a strong impetus for rethinking what we mean by ‘memory’, ‘enhancement’, ‘therapy’, and ‘self’. We conclude (1) that the enhancement of memory is still in its infancy, (2) that current MEDs and anti-dementia drugs are at best partially and minimally effective under specific conditions, (3) that ‘memory᾿and ‘enhancement᾿are ambiguous terms, (4) that there is no clear-cut distinction between enhancement and therapy, and (5) that the research into MEDs and anti-dementia drugs encourages a reductionistic view of the human mind and of the self. (shrink)

Although the use of ECT has declined dramatically from its inception, this decrease has recently shown signs of leveling out because of ECT's powerful therapeutic effect in severely ill depressed individuals who either do not respond to pharmacologic alternatives or are too ill to tolerate a relatively lengthy drug trial. Notwithstanding its therapeutic benefits, ECT has also remained a controversial treatment modality, particularly in the eye of the public. Given the unsavory qualities associated with the word “electroconvulsive,” claims of (...) possible, probable, or even certain brain damage with ECT have easily found listeners. A careful, nonselective assessment of data covering the areas of pathology, radiology, electrophysiology, biochemistry, and neuropsychology leads both to certain conclusions and to certain unanswered questions. ECT is not the devastating purveyor of wholesale brain damage that some of its detractors claim. For the typical individual receiving ECT, no detectable correlates of irreversible brain damage appear to occur. Still, there remains the possibility that either subtle, objectively undetectable persistent deficits, particularly in the area of autobiographic memory function, occur, or that a rarely occurring syndrome of more pervasive persistent deficits related to ECT use may be present. Clearly, more research directed toward answering these questions needs to be carried out so that the role of ECT can be more rigorously defined. While such research is pending, however, we cannot expect that the conditions that predispose to clinical referrals for ECT will disappear. Given the misery, anguish, and risk of death by suicide, starvation, or debilitation associated with severe depressive illness, for example, it still appears that ECT, at least for the present, must continue to be available. (shrink)

The rapid evolution of drug resistance remains a major obstacle for HIV therapy. The capacity of the virus for recombination is widely believed to facilitate the evolution of drug resistance. Here, we challenge this intuitive view. We develop a population genetic model of HIV replication that incorporates the processes of mutation, cellular superinfection, and recombination. We show that cellular superinfection increases the abundance of low fitness viruses at the expense of the fittest strains due to the mixing of (...) viral proteins during virion assembly. Moreover, we argue that whether recombination facilitates the evolution of drug resistance depends critically on how resistance mutations interact to determine viral fitness. Contrary to the commonly held belief, we find that, under the most plausible biological assumptions, recombination is expected to slow down the rate of evolution of multi‐drug‐resistant virus during therapy. BioEssays 26:180–188, 2004. © 2004 Wiley Periodicals, Inc. (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)

The recent tragic and widely publicised death of Jesse Gelsinger in a gene therapy trial has many important lessons for those engaged in the ethical review of research. One of the most important lessons is that ethics committees can give too much weight to ensuring informed consent and not enough attention to minimising the harm associated with participation in research. The first responsibility of ethics committees should be to ensure that the expected harm associated with participation is reasonable. Jesse was (...) an 18-year-old man with a mild form of ornithine transcarbamylase (OTC) deficiency, a disorder of nitrogen metabolism. His form of the disease could be controlled by diet and drug treatment. On September 13 1999 a team of researchers lead by James Wilson at the University of Pennsylvania's Institute for Human Gene Therapy (IHGT) injected 3.8 X 1013 adenovirus vector particles containing a gene to correct the genetic defect. He was the eighteenth and final patient in the trial. The virus particles were injected directly into the liver. He received the largest number of virus particles in a gene therapy trial.1 Four days later he was dead from what was probably an immune reaction to the virus vector. This was the first death directly attributed to gene therapy. It resulted in worldwide publicity, an independent investigation, the Federal Drug Administration (FDA) suspending all trials at the IHGT, an FDA, and a senate subcommittee investigation. At a special public meeting at the National Institutes of Health (NIH) in December 1999, James Wilson, also the director of the IHGT, said they still did not understand fully what had gone wrong.2 Even though a massive dose had been used, only 1% of transferred genes reached the target cells. (None of the patients in the trial showed significant gene expression. Art …. (shrink)

Cancer drugs are broadly classified into two categories: cytotoxic chemotherapies and targeted therapies that specifically modulate the activity of one or more proteins involved in cancer. Major advances have been achieved in targeted cancer therapies in the past few decades, which is ascribed to the increasing understanding of molecular mechanisms for cancer initiation and progression. Consequently, monoclonal antibodies and small molecules have been developed to interfere with a specific molecular oncogenic target. Targeting gain‐of‐function mutations, in general, has been productive. However, (...) it has been a major challenge to use standard pharmacologic approaches to target loss‐of‐function mutations of tumor suppressor genes. Novel approaches, including synthetic lethality and collateral vulnerability screens, are now being developed to target gene defects in p53, PTEN, and BRCA1/2. Here, we review and summarize the recent findings in cancer genomics, drug development, and molecular cancer biology, which show promise in targeting tumor suppressors in cancer therapeutics. (shrink)

The U.S. Food and Drug Administration's drug advisory committees provide expert assessments of the safety and efficacy of new therapies considered for approval. A committee hears from a variety of speakers, from six groups, including voting members of the committee, FDA staff members, employees of the pharmaceutical company seeking approval of a therapy, patient and consumer representatives, expert speakers invited by the company, and public participants. The committees convene at the request of the FDA when the risks and (...) harms of novel products are not immediately clear, and their final decisions carry significant weight, as most therapies that receive advisory committee approval are subsequently approved by the FDA. In recent years, across a series of diverse publications, the financial conflicts of interest of each category of participants in the meetings have been investigated. Here, we summarize these findings and their ethical implications, focusing on the FDA Oncologic Drugs Advisory Committee, and we suggest ways to move toward more transparent and impartial advisory committee meetings. (shrink)

The U.S. Food and Drug Administration's rationale for supporting the development and approval of BiDil for heart failure specifically in black patients was based on under-powered, post hoc subgroup analyses of two relatively old trials , which were further complicated by substantial covariate imbalances between racial groups. Indeed, the only statistically significant difference observed between black and white patients was found without any adjustment for potential confounders in samples that were unlikely to have been adequately randomized. Meanwhile, because the (...) accepted baseline therapy for heart failure has substantially improved since these trials took place, their results cannot be combined with data from the more recent trial amongst black patients alone. There is therefore little scientific evidence to support the approval of BiDil only for use in black patients, and the FDA's rationale fails to consider the ethical consequences of recognizing racial categories as valid markers of innate biological difference, and permitting the development of group-specific therapies that are subject to commercial incentives rather than scientific evidence or therapeutic imperatives. This paper reviews the limitations in the scientific evidence used to support the approval of BiDil only for use in black patients; calls for further analysis of the V-HeFT I and II data which might clarify whether responses to H-I vary by race; and evaluates the consequences of commercial incentives to develop racialized medicines. We recommend that the FDA revise the procedures they use to examine applications for race-based therapies to ensure that these are based on robust scientific claims and do not undermine the aims of the 1992 Revitalization Act. (shrink)

The left ventricular assist device was originally designed to be surgically implanted as a bridge to transplantation for patients with chronic end-stage heart failure. On the basis of the REMATCH trial, the US Food and Drug Administration and the US Centers for Medicare & Medicaid Services approved permanent implantation of the left ventricular assist device as a destination therapy in Medicare beneficiaries who are not candidates for heart transplantation. The use of the left ventricular assist device as a destination (...) therapy raises certain ethical challenges. Left ventricular assist devices can prolong the survival of average recipients compared with optimal medical management of chronic end-stage heart failure. However, the overall quality of life can be adversely affected in some recipients because of serious infections, neurologic complications, and device malfunction. Left ventricular assist devices alter end-of-life trajectories. The caregivers of recipients may experience significant burden (e.g., poor physical health, depression, anxiety, and posttraumatic stress disorder) from destination therapy with left ventricular assist devices. There are also social and financial ramifications for recipients and their families. We advocate early utilization of a palliative care approach and outline prerequisite conditions so that consenting for the use of a left ventricular assist device as a destination therapy is a well informed process. These conditions include: (1) direct participation of a multidisciplinary care team, including palliative care specialists, (2) a concise plan of care for anticipated device-related complications, (3) careful surveillance and counseling for caregiver burden, (4) advance-care planning for anticipated end-of-life trajectories and timing of device deactivation, and (5) a plan to address the long-term financial burden on patients, families, and caregivers. Short-term mechanical circulatory devices (e.g. percutaneous cardiopulmonary bypass, percutaneous ventricular assist devices, etc.) can be initiated in emergency situations as a bridge to permanent implantation of ventricular assist devices in chronic end-stage heart failure. In the absence of first-person (patient) consent, presumed consent or surrogate consent should be used cautiously for the initiation of short-term mechanical circulatory devices in emergency situations as a bridge to permanent implantation of left ventricular assist devices. Future clinical studies of destination therapy with left ventricular assist devices should include measures of recipients' quality of end-of-life care and caregivers' burden. (shrink)

Recent political developments and disclosures of serious adverse events in human gene therapy (HGT) with the death of 18‐year old Jesse Gelsinger in the USA have shown that the clinical application of HGT raises some severe ethical issues. These have either been neglected or not yet been discussed to a satisfactory extent. In this paper, we will address this deficiency and develop strategies for a safer application of HGT. Such a study must first look closely at the science of HGT (...) itself. We will evaluate the latest preclinical research, especially data on the viruses that are used as vectors and on modes of administration of vectors. We will put forward new arguments concerning the toxicity assessment of so‐called ‘gene drugs‘, the tissue and cell type specificity of the vectors, and the duration and on‐set of gene expression. Secondly, we will look at procedural aspects of applied research ethics on the way to clinical application of HGT. There, informed consent (IC) and the patient‐researcher relationship are of utmost concern. Furthermore, we will explore the problem of expertise in risk assessment and will show how current regulations foster conflicts of interests that create dilemma situations even for those researchers who act in the best interest of the patients. We will conclude the article with a set of questions for ethicists who have to decide about the quality of HGT protocols. This may contribute to the safety of patients participating in HGT trials and to achieving the aim of efficient application of HGT. (shrink)

Mucopolysaccharidosis type I (MPS I) is a rare lysosomal storage disorder treated with bone marrow transplantation or enzyme replacement therapy with laronidase, a high-cost orphan drug. Laronidase was approved by the US Food and Drug Administration and the European Medicines Agency in 2003 and by the Brazilian National Health Surveillance Agency in 2005. Many Brazilian MPS I patients have been receiving laronidase despite the absence of a governmental policy regulating access to the drug. Epidemiological and treatment data (...) concerning MPS I are scarce. This study aims to present a demographic profile of Brazilian patients with MPS I, describe the routes of access to laronidase in Brazil, and discuss associated ethical issues relating to public funding of orphan drugs. (shrink)

I welcome with great enthusiasm Meling and Scheidegger’s (2023; henceforth “M&S”) timely contribution to advance an enactive approach to psychedelic therapy, especially to the complex causality involved. Their two main research questions concerned:(i) the causal interaction between the psychedelic molecule and brain activity; and (ii) the causal interaction between brain activity and the psychedelic experience. While I largely agree with and celebrate much of what is proposed by M&S, especially their employment of key enactive concepts to advance our understanding of (...) the first research question, in the following, I will present some worries regarding their answers to the second. Although I agree that there is probably a two-way reciprocal relationship between neural activity and experience, I have several points of contention regarding M&S’s proposal. My hope is to stimulate discussion on M&S’s important contribution, and to help advance a much-needed enactive science of psychedelics. (shrink)

Limited research has been done among pregnant people participating in investigational drug trials. To enhance the ethical understanding of pregnant people’s perspectives on research participation, we sought to describe motives and risk perceptions of participants in a phase 1 trial of ledipasvir/sofosbuvir treatment for chronic Hepatitis C virus during pregnancy. Pregnant people with chronic HCV infection enrolled in an open-label, phase 1 study of LDV/SOF participated in semi-structured, in-depth interviews to explore their reasons for participation and experiences within the (...) study. Pregnant people took 12 weeks of LDV/SOF and were interviewed at enrollment and at the end of study. We recorded the interviews, transcribed them verbatim, coded them using NVivo software, and performed inductive thematic analysis. Nine women completed the study yielding 18 interview transcripts. We identified two themes regarding motives and one regarding risk perception. Motives— Women conceptualized study participation as part of the caregiving role they associate with motherhood; participating was viewed as an act of caregiving for their infants, their families, themselves, and other pregnant women with chronic HCV. Women also noted that they faced multiple barriers to treatment prior to pregnancy that created a desire to receive therapy through trial participation. Risk perception— Women acknowledged personal and fetal risk associated with participation. Acceptance of risk was influenced by women’s concepts of motherhood, preexisting knowledge of HCV and medical research, family members, intimate partners, or by the study design. Women enrolled in a phase 1 trial for chronic HCV therapy during pregnancy acknowledged risks of participation and were motivated by hopes for fetal and personal benefit and by lack of prenatal access to treatment. Ethical inclusion of pregnant people in research should acknowledge structural factors that contribute to vulnerability and data deficiencies for treatment in pregnancy. (shrink)

Effective therapies are now available that can stop the progression of HIV infection and significantly delay the onset of AIDS. The “highly active antiretroviral therapy” (HAART) is a combination of potent antiretroviral drugs such as viral protease inhibitors or nucleoside-analogue reverse-transcriptase inhibitors, that has a variety of serious side effects, including lipodystrophy, a pathology characterized by accumulation of visceral fat, breast adiposity, cervical fat-pads, hyperlipidemia, insulin resistance as well as fat wasting in face and limbs. There is still an open (...) debate that concerns the precise responsibility of HAART as well as metabolic pathways and mechanisms that are involved in the onset of lipodystrophy. The similarities with multiple symmetric lipomatosis (MSL), in which mitochondria impairment plays a crucial role, lead to the hypothesis that drug-induced damages to mitochondrial DNA are able to alter mitochondria functionality to an extent that is similar to what occurs in MSL. In addition, several evidences indicate that HAART is also linked to a deregulated production of tumour necrosis factor-α, which uses mitochondria as intracellular targets. In this paper, we review data concerning the role of mitochondria in the pathogenesis of lipodystrophy, and advance a unifying hypothesis involving either direct or indirect effects of the drugs employed during HAART. BioEssays 23:1070–1080, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

In applying statutory safeguards, the FDA must not regulate investigational new products so stringently that a life‐saving therapy is unavailable. But the agency must also protect dying patients from exploitation by unscrupulous or overzealous researchers. The balance between individual choice and public protection has been questioned in cases involving experimental AIDS drugs and an artificial heart.

Our understanding of the neurochemical bases of human love and attachment, as well as of the genetic, epigenetic, hormonal, and experiential factors that conspire to shape an individual's sexual orientation, is increasing exponentially. This research raises the vexing possibility that we may one day be equipped to modify such variables directly, allowing for the creation of “high-tech” conversion therapies or other suspect interventions. In this article, we discuss the ethics surrounding such a possibility, and call for the development of legal (...) and procedural safeguards for protecting vulnerable children from the application of such technology. We also consider the more difficult case of voluntary, adult “conversion” and argue that in rare cases, such attempts might be permissible under strict conditions. (shrink)