Synthetic Cathinones: A New Public Health Problem

New psychoactive substances (NPS) have completely modified the drug scene and the current landscape of addiction. Synthetic substances, such as substituted or synthetic cathinones, also known as « legal highs », are often produced and used to mimic the effects of controlled drugs such as cocaine, methylenedioxymethamphetamine (MDMA, ecstasy), and methamphetamine. The overwhelming majority of synthetic cathinones are produced in China and South East Asian countries. The Internet has emerged as the new marketplace for NPS, playing a major role in providing information on acquisition, synthesis, extraction, identification, and substance use. All these compounds are intentionally mislabeled and sold on-line under slang terms such as bath salts, plant food, plant feeders and research chemicals. They are sometimes labeled « not for human use » or « not tested for hazards or toxicity ». The rapid spread of NPS forces member countries of the European Union to adapt their response to the potential new dangers that may cause. To date, not only health actors but also the general public need to be clearly informed and aware of dangers resulting from NPS spread and use. Here, we review the major clinical effects of synthetic cathinones to highlight their impact on public health. A literature search was conducted from 2009 to 2014 based on PubMed, Google Scholar, Erowid, and governmental websites, using the following keywords alone or in combination: “new psychoactive substances”, “synthetic cathinones”, “substituted cathinones”, “mephedrone”, “methylone”, “MDPV”, “4-MEC”, “addiction”, and “substance use disorder”.     

Cathinone Neurotoxicity (“The “3Ms”)

Synthetic cathinones are designer drugs of the phenethylamine class, structurally and pharmacologically similar to amphetamine, 3,4-methylenedioxymethamphetamine (MDMA), cathinone and other related substances. New analogues, legal at least, until formally banned (a time consuming process), are introduced almost daily The United Nations estimates nearly 250 new drug analogues are produced per year. Various combinations of these drugs are sold under the name of “bath salts”. They can be ingested by any route and some appear capable of causing great harm, mostly behavioral. One drug in particular, MDVP, appears to frequently cause symptoms indistinguishable from the classic findings in Excited Delirium Syndrome (ExDS). Little is known about the pathology or clinical toxicology of these drugs but their molecular mechanism of action seems to be identical with that of cocaine. This mini-review examines what little is known on the subject and explains the suspected mechanisms of excited delirium syndrome.     

Mechanisms of Action of Antipsychotic Drugs of Different Classes,Refractoriness to Therapeutic Effects of Classical Neuroleptics,and Individual Variation in Sensitivity to their Actions: PART II

Rapid-onset psychotic rebound is uncommon on discontinuation of most antipsychotic drugs, as might be expected for antipsychotic drugs with (hypothetically) indirect actions at their final target receptors. Rapid-onset psychosis is more common on withdrawal of clozapine, which might be expected if its action is direct. Drugs other than clozapine (notably thioridazine) may have hitherto unrecognised similarities to clozapine (but without danger of agranulocytosis), and may be useful in treatment of refractory psychosis. Quetiapine fulfils only some criteria for a clozapine-like drug. Clinical response to neuroleptics varies widely at any given plasma level. Haase’s “neuroleptic threshold” concept suggests that the dose producing the slightest motor side effects produces most or all of the therapeutic benefit, but analyses presented here suggest that antipsychotic actions are not subject to a sharp “all-or-none” threshold but increase over a small dose range. This concept could provide a method for quantitative determination of individualized optimal doses.Key Words: Antipsychotic drugs, neuroleptic drugs, cholinergic interneurones, D1 receptors, D2 receptors, muscarinic M1 receptors, muscarinic M4 receptors, neuroleptic threshold, individualized dose, atypical antipsychotic agents.     

Drug Repurposing and the Medicinal Chemist

Drug repurposing is an approach to finding new uses for older drugs and has been gaining popularity in recent years. The role of traditional medicinal chemistry in the context of these efforts is considered.Every practicing medicinal chemist labors under an assumption that is almost never stated out loud: not all potentially useful drugs for human use have yet been found. It certainly seems like a reasonable viewpoint, given the number of medical conditions either for which there is no pharmacotherapy available or for which existing treatments leave much to be desired. However, another way of addressing this need has gained steam in recent years. “Drug repurposing” is the practice of looking for new clinical uses of existing drugs, which contrasts sharply from de novo drug discovery approaches to therapeutics. The purpose of this essay will be to consider this approach, contrast it to traditional medicinal chemistry, and consider how the two approaches could positively complement each other.The primary concern of all who engage in applied biomedical research should be helping patients in the absence of disciplinary bias. For the medicinal chemist, this means that the goal is to identify the best drug regardless of provenance or commercial concerns (including the recognition that drug therapy itself is not always the best course of action). Of course, pragmatic compromises must usually be considered, whether scientific or economic in nature. “Best” has a temporal connotation as well: the “best” drug today can change as new agents are introduced or as new information is obtained in and beyond clinical trials. For example, there are numerous conditions for which patients would gladly accept an imperfect cure, especially if one does not presently exist. In such cases, the lives of those who suffer improve to some degree, immediately. The state-of-the-art therapies in such areas as Alzheimer’s or Parkinson’s disease, as well as many types of cancer, can very much be viewed in this way. Attaining such a status quo does not mean that all research toward better treatments will stop. To the contrary, this is one area where the self-correcting nature of science flowers best, as scientists and clinicians work together to build a better tomorrow on top of yesterday’s achievements.One of the hardest parts of a de novo drug discovery campaign is starting out, in part due to the challenges of selecting and establishing initial structure–activity relationships on a given chemical series to explore. The short-term assessment of chemical series may be relatively easy to uncover through the selection of appropriate assays and biological models selection, but selecting the right series—i.e., one able to surmount all of the hurdles between discovery chemistry and the clinic—is much harder for the nonclairvoyant. Conventional wisdom has deemed most of the innovations meant to increase passage from early- to late-stage drug discovery wanting, especially the coupling of combinatorial chemistry with high-throughput screening.¹ Although the idea that combinatorial chemistry or any other individual approach has failed is debatable, one thing that everyone can agree on is that it is harder than ever to develop a new drug and that these challenges have negatively impacted the global pharmaceutical enterprise.Enter drug repurposing.Generically, drug repurposing is a collection of approaches that collectively seek to adapt the current pharmacopeia for new uses.²⁻⁴ Included in the complicated taxonomy that is being developed for such approaches⁵ is “drug rescue”, in which promising compounds that have been developed for one indication but have failed to reach the clinic are redirected toward another. For the purposes of this discussion, I will not attempt to differentiate between different flavors of drug repurposing but consider the concept in broad strokes.The proponents of drug repurposing cite numerous scientific advantages of the idea. To my mind, foremost among these is related to a prime challenge in moving a molecule discovered by target-centric biology forward, namely establishing the validity of a new biological target in the treatment of disease. In this view, a considerable amount of time may be saved, as clinical trials would have been facilitated by the fact that the fictional repurposed candidate would have already been approved for use in humans. Other advantages attributed to repurposed drugs accrue from the fact that so much is known about them relative to newly synthesized molecules. As a class, they have at least tolerable safety and pharmacokinetic profiles, or they would not have been approved in the first place; minimally, one knows what one is dealing with (although it must be noted that, for drug rescue programs, one also knows that one is dealing with drug candidates that have, in fact, failed to reach the clinic). There are no hidden issues with respect to manufacturing or stability issues, and indeed, many drugs are off patent and may provide relatively inexpensive solutions for new problems. And they are available. Pragmatically, one can dovetail a repurposing effort with screening by the modest expedient of replacing a traditional screening library, which often contains hundreds of thousands of compounds, with a much smaller library of approved drug candidates. Such a library is a key component of one important approach to drug repurposing/rescue being carried out under the banner of the newly formed National Center for Advancing Translational Science.⁶⁻⁹ Careful combinatorialization of the screening effort might uncover novel combinations of agents that are superior to single compounds, an approach that would be harder to apply to larger numbers of relatively unknown compound streams that would still require optimization (as might the repurposed drugs as well, but more about that shortly).Other, nonscience-based factors have been partly responsible for the uptick in drug repurposing efforts, especially in academic- or foundation-based drug discovery efforts, many of which do not have at their beck and call a team of highly skilled medicinal chemists. For universities and research institutes seeking to establish themselves as bona fide players in drug discovery, a significant milestone is entry of a compound into clinical trials. The attractiveness of the repurposing approach for that milestone is obvious, even if the validity of entry into clinical trials as the primary measure of success (as opposed to successful passage through clinical trials into the clinic) is subject for discussion. Moreover, when confronted with the recognized difficulties and crushing expense of bringing a molecule all the way from discovery/design/optimization and into the clinic, the allure of a repurposing approach is understandable.What does all of this say about the role of the medicinal chemist in the twenty-first century? Some are quick to point out the downsides of repurposing, ranging from the lack of understanding of how the molecules are working (i.e., when the repurposed drug arose from a phenotypic or alternative assay lacking resolution vis-à-vis target) to the challenges of formulating a workable business model for patenting and employing a treatment that someone already owns. However, to defend traditional drug discovery by pointing to these concerns would be a cop-out. If real cures are to be found through drug repurposing of any ilk, creative solutions to its problems will not be far behind. And we owe it to patients to provide help regardless from which scientific approach the help arises or who benefits. (Remember that stuff about “identifying the best drug regardless of provenance”? I meant it.)It is always dangerous to make predictions and doubly so to do it in print, but here goes. I suspect that drug repurposing, from a strictly scientific perspective, will grow in popularity as its potential is demonstrated and successes are seen. But like combinatorial chemistry and nearly every other “new” technology or approach, it is likely to reach a point where limits become more and more clear. At this point, discovery tools tend to reach their appropriate equilibrium and become accepted, warts and all, for what they are. Unless, in the process, it becomes clear that every useful drug molecule has indeed already been discovered (which is so unlikely, given the vastness of chemical space and the diversity of both target- and nontarget-based challenges in negotiating the biological milieu), de novo and repurposing approaches to drug therapy discovery will coexist.While giving drug repurposing its chance to succeed or fail on its own merits, I’d like to advocate for maintaining a strong pipeline of drugs discovered and developed through de novo medicinal chemistry. This is due to the unique ability of synthetic medicinal chemistry to provide and optimize novel chemical matter and my strong sense that the need for such compounds is not going to end anytime soon. Drug repurposing’s or, especially, drug rescue’s reliance on finding a molecule in just the right chemical spot to cross the goal line is analogous to scoring in American football via pass interception or fumble recovery near the goal line. It is great when it happens, but successful football teams need a diversified strategy that also includes the long game, as tough as it can be. To this point, a case can be made that the additional time needed to optimize a given agent through SAR may not be the overwhelming cost driver in current drug development when compared to the cost of clinical studies.Moreover, far from feeling threatened by drug purposing as a competing strategy, the medicinal chemist should use this tool when it makes sense to do so. Two limiting conditions can be envisioned for a successful repurposing project. In one, the drug acts at the same single target but with different outcomes that depend on the physical site of biological action. Even if the same drug were to be useful in both contexts, one can easily envision different distribution or metabolism issues that would require additional structural tweaking of the compound. Taking advantage of such a situation does require that the medicinal chemist come ready to ply her or his trade in the service of manipulating pharmaceutic properties—which I would argue ought to be part of every discovery scientist’s personal toolbox in any circumstance.The opposite end of the spectrum leads to even more clear-cut conclusions. If the “old” purpose of the drug and the “new” one have different biochemical targets, it is extremely unlikely that the repurposed drug has been preoptimized for the latter situation. In other words, there is no reason to suppose that a structure–activity relationship campaign carried out to optimize a compound for target A would be identical to that needed for compound B. This leads to the familiar situation, described above, where the repurposed drug, even if first-in-class to the clinic, represents a tentative solution that would eventually be rendered obsolete by a subsequent drug that would be even better. Medicinal chemists should feel enabled to tackle such a “fast follow-on” approach to new chemical matter, but to do so, they will have to come to grips with the understanding that the best way forward may not allow them to have the satisfaction of having invented the whole scaffold from the project’s inception (IP attorneys will have to deal with the business and legal aspects of the same realization as well). Some solace may be taken from the fact that, if the repurposed drug is a member of a privileged class of chemical matter, many of the synthetic analogues needed may well already exist in the physical universe and be available at relatively modest expense.As long as the field has existed, medicinal chemistry has sought to incorporate new tools and approaches to accomplish its mission of providing society with new and better drugs. Drug resourcing need not deter us from this path, even if it means that the mission statement will sometimes be edited to read “providing society with better drugs that are not necessarily so new”. So long as the field of medicinal chemistry continues to demonstrate its worth by providing novel solutions to important problems, and so long as these efforts are supported by the business and academic research communities, we will earn our place in the global biomedical research community.     

Reconsidering Sports Pharmacists and Anti-Doping Education as the World Celebrates the Olympic and Paralympic Games

The Tokyo Olympic and Paralympic Games in 2021 presented an opportunity for pharmacists to recognize the uniqueness of sports pharmacy as a developing field and to understand the importance of anti-doping education among patient-athletes. Patient-athletes make up a distinct patient population, and pharmacists are well positioned to support athletes’ therapeutic decisions. Pharmacists need to be able to search for and interpret drug information to take care of this special population appropriately. The purpose of this commentary is to facilitate a discussion on what changes or reinforcement might help train pharmacists to become equipped with adequate knowledge and skills to support safe use of drugs among patient-athletes. While effective resources and tools have become more widely available, pharmacists’ awareness of and training in the field of sports pharmacy continue to be needed. No matter where they practice, pharmacists should be ready to promote “the spirit of sport” and defend the importance of “clean” sport for their patient-athletes.     

Regulatory Considerations for Approval of Generic Inhalation Drug Products in the US,EU, Brazil,China, and India

This article describes regulatory approaches for approval of “generic” orally inhaled drug products (OIDPs) in the United States, European Union, Brazil, China and India. While registration of a generic OIDP in any given market may require some documentation of the formulation and device similarity to the “original” product as well as comparative testing of in vitro characteristics and in vivo performance, the specific documentation approaches, tests and acceptance criteria vary by the country. This divergence is due to several factors, including unique cultural, historical, legal and economic circumstances of each region; the diverse healthcare and regulatory systems; the different definitions of key terms such as “generic” and “reference” drug; the acknowledged absence of in vitro in vivo correlations for OIDPs; and the scientific and statistical issues related to OIDP testing (such as how best to account for the batch-to-batch variability of the Reference product, whether to use average bioequivalence or population bioequivalence in the statistical analysis of results, whether to use healthy volunteers or patients for pharmacokinetic studies, and which pharmacodynamic or clinical end-points should be used). As a result of this discrepancy, there are ample opportunities for the regulatory and scientific communities around the world to collaborate in developing more consistent, better aligned, science-based approaches. Moving in that direction will require both further research and further open discussion of the pros and cons of various approaches.     

MDMA (3,4-Methylenedioxymethamphetamine) Analogues as Tools to Characterize MDMA-Like Effects: An Approach to Understand Entactogen Pharmacology

Besides stimulants and hallucinogens, whose psychotropic effects are shared by many structurally related molecules exhibiting different efficacies and potencies in humans, the phenylisopropylamine MDMA (3,4-methylenedioxymethamphetamine, XTC, “Ecstasy”) is the prototypical representative of a separate class of psychotropic substance, able to elicit the so-called entactogenic syndrome in healthy humans. This reversible altered state of consciousness, usually described as an “open mind state”, may have relevant therapeutic applications, both in psychotherapy and as a pharmacological support in many neuropsychiatric disorders with a high rate of treatment failure. Nevertheless, a comprehensive and systematic exploration of the structure-activity relationships associated with entactogenic activity has remained incomplete and controversial, highlighting the possibility that MDMA might represent a pharmacological rarity in the field of psychotropics. As the latter is still an open question, the pharmacological characterization of MDMA analogues remains the logical strategy to attempt the elucidation of the structural requirements needed to elicit typical MDMA-like effects. Intriguingly, almost no experimental evidence supports the existence of actual MDMA analogues that truly resemble the whole pharmacological profile of MDMA, probably due to its complex (and partially not fully understood) mechanism of action that includes a disruption of monoaminergic neurotransmission. The present review presents a brief summary of the pharmacology of MDMA, followed by the evidence accumulated over the years regarding the characterization of classical structurally related MDMA analogues in different models and how this state of the art highlights the need to develop new and better MDMA analogues.     

Increased psychotropic drug consumption by children in the Netherlands during 1995–2001 is caused by increased use of methylphenidate by boys

Objective The aim of the study was to determine the changes in consumption of psychotropic drugs by children aged less than 18 years during the years 1995 to 2001 in the Netherlands.Methods The year prevalence of antipsychotics, benzodiazepines, antidepressants and psychostimulants for boys and girls under 18 years was determined using electronic pharmacy dispensing records obtained from the PHARMO database.Results The overall prevalence of psychotropic drugs increased from 11.1 per 1000 in 1995 to 22.9 per 1000 in 2001. This increase could almost completely be attributed to the increase in the use of psychostimulants, i.e. methylphenidate, which increased from 1.7 per 1000 children in 1995 to 10.0 per 1000 in 2001. For the other psychotropic drugs, no or only a small increase was seen. For both boys and girls, the use of psychostimulants was highest in the age group of 5–14 years.Conclusion During the years 1995–2001, the consumption of psychotropic drugs by children in the Netherlands has more than doubled. This increase could largely be attributed to an increased use of the psychostimulant methylphenidate by boys of the age 5–14 years.     

Differences in Anxiety-Like Behavior within a Batch of Wistar Rats Are Associated with Differences in Serotonergic Transmission,Enhanced by Acute SRI Administration,and Abolished By Serotonin Depletion

Background:

The anxiety-reducing effect of long-term administration of serotonin reuptake inhibitors is usually seen only in subjects with anxiety disorders, and such patients are also abnormally inclined to experience a paradoxical anxiety-enhancing effect of acute serotonin reuptake inhibition. These unique responses to serotonin reuptake inhibitors in anxiety-prone subjects suggest, as do genetic association studies, that inter-individual differences in anxiety may be associated with differences in serotonergic transmission.

Methods:

The one-third of the animals within a batch of Wistar rats most inclined to spend time on open arms in the elevated plus maze were compared with the one-third most inclined to avoid them with respect to indices of brain serotonergic transmission and how their behavior was influenced by serotonin-modulating drugs.

Results:

“Anxious” rats displayed higher expression of the tryptophan hydroxylase-2 gene and higher levels of the tryptophan hydroxylase-2 protein in raphe and also higher levels of serotonin in amygdala. Supporting these differences to be important for the behavioral differences, serotonin depletion obtained by the tryptophan hydroxylase-2 inhibitor p-chlorophenylalanine eliminated them by reducing anxiety in “anxious” but not “non-anxious” rats. Acute administration of a serotonin reuptake inhibitor, paroxetine, exerted an anxiety-enhancing effect in “anxious” but not “non-anxious” rats, which was eliminated by long-term pretreatment with another serotonin reuptake inhibitor, escitalopram.

Conclusions:

Differences in an anxiogenic impact of serotonin, which is enhanced by acute serotonin reuptake inhibitor administration, may contribute to differences in anxiety-like behavior amongst Wistar rats.     

Four Lessons from Global Health Drug Discovery: Medicine for an Ailing Industry?

In recent years, the pharmaceutical industry has faced many challenges to its business model, undergoing tremendous change and turmoil to survive. Are there any lessons to be drawn from drug discovery focused on Global Health, where there is little market incentive?The pharmaceutical industry is in trouble. Although unlikely he had drug discovery in mind, baseball player/manager Yogi Berra may have gotten it right when he said, “We made too many wrong mistakes.” No doubt playing baseball is different from drug discovery (at least in baseball you know you have a home run even before you round first base), but it doesn''t take a genius to know when something is not going well. The intellectual part comes later, when deciding what to do about it.Most in the industry will readily admit too many wrong mistakes were made, and the data supporting this point of view (we are scientists, after all) are overwhelming. One need only pick up the business section of the newspaper to find a proliferation of articles describing companies pulling out of therapeutic areas, downsizing, reorganizing, and merging—all visible signs of the turmoil within the industry. In a growing trend, Pharma CEOs and heads of R&D publicly admit failure, loss of productivity, lack of innovation, and a need for renewal. The picture is stark and undeniable: current trends make the industry unsustainable, as poignantly illustrated by Figure ​Figure1,1, showing how many drugs one gets for $1B charted between 1950 and 2010. A billion dollars doesn''t go very far in drug development today or, as Yogi put it, “A nickel ain''t worth a dime anymore.” One could spend weeks arguing over the causes—who''s to blame, how it could have been avoided—but sometimes, a picture says it all. The rest is moot.Open in a separate windowFigure 1The number of drugs per billion U.S.$ R&D spending over time.¹However, the more pertinent question is not what the wrong mistakes were, but what are the correct corrections? Perhaps we can use our understanding of evolution to guide us—building off the knowledge that only the strongest survive under stringent and restricted conditions. Maybe if we are looking for examples of where R&D has succeeded, we should look where the conditions are most stringent, the funding most restricted, and (hence) the evolutionary pressure the most intense—at Global Health drug discovery.Really, Global Health drug discovery? Granted, here too, there has been failure, and there is still much work to be done. However, take a closer look at the organizations and institutions doing this work, and you will find highly honed and motivated research and development groups (there is no fat when it comes to these diseases) developing products on a fraction of a big Pharma R&D budget. Visit the Web sites of Product Development Partnerships (PDPs) such as Medicines for Malaria Venture (MMV), Drugs for Neglected Diseases Initiative (DNDi), and the Global Alliance for TB Drug Development (TB Alliance) to view the drug development pipelines that they have established, and you will hopefully be convinced that they must be doing something right, but what are they doing, and what lessons can be drawn?The PDPs have retained many of the best aspects of big Pharma. Like big Pharma, they employ experienced drug discoverers to guide their programs and build collaborative partnerships with a wide variety of groups, but equally important, they have assiduously avoided the aspects of big Pharma that work less well and have adapted new approaches, platforms, and collaborative models that are foreign (or anathema) to big Pharma. This is where the lessons are to be found.Lesson #1 is obvious but often goes unheeded: go after compounds, not targets. GlaxoSmithKline embraced the genomics approach in its antibacterial program and learned this lesson the hard way, pursuing novel targets with 70 HTS target-based screens. For these heroic efforts, they were repaid with only 16 screens providing hits, and only 5 screens yielding leads.² Likewise, a plethora of obesity targets were pursued in the pharmaceutical industry during the early 2000s—many of them chemogenomically “validated” in a rodent model, only to fall out in clinical development.³ Here, we learned a hard lesson that any toxicologist could have told us long ago—there is more than one way to stop a rat from eating, and not all of them are good. As scientists, we do not like to admit it, but reductionism does not always work well in drug discovery. Consider MMV, which partnered to screen over 5 million compounds in a phenotypic blood-stage malaria assay and identified 25,000 hits with <1 μM activity. In follow up biochemical assays, scientists were unable to link these hits to any of the top targets everyone in the field was working on. This brings up an embarrassing point; we simply are not very good at picking drug targets.Lesson #2, a suggestion, might be considered heretical by some. Maybe some things, such as chemical libraries and HTS hits, should be considered as precompetitive. “Our compound library, the best in the industry, is unique and is the engine that drives our drug discovery program” is the retort. However, closer inspection of the published journal and patent literature belies this: your chemical library and hits are not as unique are you think they are, and there is more to be gained by sharing these than by hiding them. The PDPs have shown this to be true. “Ah, but they work in a nonprofit area, and do not need to rely on commercial return,” comes the refrain. True, but increased efficiency behooves nonprofit and for-profit endeavors alike, and the truly innovative and inventive steps (and IP) come not from the hit but from what is done with it. Medicinal chemists know this—show a group of them a hit structure, and there will be as many ideas as there are chemists. Once you accept the distinction between precompetitive and competitive, a world of new possibilities suddenly opens up. Maybe other things, like computational tools, predictive models, molecular probes and reagents, technical know-how—even technology platforms—might be shared. “This would be risky” some might say. True, but Figure ​Figure11 suggests that continuing business as usual is even riskier.Lesson #3 is simple: be open-minded, and do not be afraid to take risks. For example, Lipinski''s rules, originally developed to flag risk, have been mistranslated into “thou shalt not” rules. For some good examples of what “thou shalt not”, take a look at the chemical structure of some of the leading drugs used in the Global Health drug armamentarium (Figure ​(Figure2,2, disease treatment in parentheses). Amphotericin B, Ivermectin, Rifampin, and Artemisinin—these do not look like “drugs”—many would claim they are downright ugly. Nonetheless, millions of lives have been saved using these compounds, ugly as they are, and the world would be much worse off without them. The lesson is simple: if you work in a risky business and risk is essential for success, then embrace it. There are many ways to do this. For example, the Foundation has established a Discovery program specifically designed to take risks, entitled Grand Challenges Explorations,⁴ which specifically encourages (and funds) high-risk approaches and ideas that have the potential to be game-changing. To achieve this, we are willing to accept failure—after all, how many transformational advances do you need to succeed?Open in a separate windowFigure 2Structures of select Global Health drugs.Lesson #4 is to have a long-term strategic vision and stay with it. For example, our PDP partners have identified therapeutic areas where this is great unmet medical need and are committed to their cause until the problem is solved. Patient need, not NPV based upon a series of assumptions, drives their programs and sustains their commitment. No doubt the situation is tricky in big Pharma—where the economic and leadership stability conducive to long-term vision is rapidly fading (some might argue gone) and market forces favor short-term returns over long-term success. Nonetheless, a strong argument can be made that some of the most successful companies are those that have had a sustained vision. It is not hard to find areas of unmet medical need; Alzheimer''s disease, cancer, diabetes (to name a few)—why not pick a few and stay with them until the vision is fulfilled?Drug discovery is an amazing endeavor, requiring incredible science, technology, intellect, collaboration, hard work, and perseverance. However, these qualities alone are not enough to ensure continued success—such virtues are engraved on many a mossy tombstone of now long-gone endeavors. Monks hand-scribing books, sailors hunting down whales on the open seas, photographic film developing—these all were once thriving industries. Then, the world changed— the Gutenberg printing press, oil wells, and digital cameras emerged, and these once robust industries died. Will the pharmaceutical industry suffer a similar fate? It is hard to imagine this happening, given the tremendous skill, intellect, and opportunities available. However, what is clear is that the pharmaceutical industry has come to a point where it must address some key and fundamental questions, and they must be willing and able to adjust their model and forge new paths forward. This is by no means an easy thing to achieve, but the big Pharma CEOs and Research Heads must summon their courage to voyage out into these unexplored and uncertain areas. Yogi might have some sage advice for them—“if you come to a fork in the road, take it.”     

Identifying and Addressing Technology Challenges Among Older Adults

It is sometimes surprising to learn about the challenges patients face in maintaining health and wellness. Many of their challenges are things we may not commonly consider. Additionally, our preconceived ideas of what a patient experiences can often be off the mark. This month, we explore the segment of the population that is most commonly encountered in US hospitals.Have you ever been sick? If you answered “no,” we would love to talk to you to learn your secret; our e-mails are at the end of this article. Otherwise, we expect that most – if not everyone – reading this likely scoffed at our question with a hearty “of course.” The reality is that health and wellness challenges (as we will call them) are constantly encountered in our daily activities. The media does a thorough job of keeping us informed about the latest challenges to healthy living. These challenges are not necessarily found exclusively in our environment, however, as some are found in our genes. These challenges can be much more difficult to pinpoint and address.Regardless of the source of the challenges we face to better health, we know that, in general, we are confronted with more challenges as we get older. A quick stroll through the halls of any general medical-surgical facility in this country will demonstrate that the majority of patients are 65 years of age or older. In fact, data from the Centers for Disease Control and Prevention show a more than doubling in the rate of hospitalization for individuals over 65 compared to those 45 to 64 years old. Clearly, it is important to address health and wellness issues in this segment of the population.When thinking about the “over 64” crowd, we may be tempted to classify them as Luddites (see the July-August 2014 column) when it comes to general information technology use. And while many of us can easily identify those older adults in our lives who have been broadly hesitant, or even resistant to technology, we are beginning to see that this generalization is not completely accurate. We remember in the mid-1990s to mid-2000s when we literally received 2 to 3 AOL CDs in the mail each week. PC World readers actually named this practice of mass CD mailing as the most annoying tech product ever. Such a waste! Meanwhile, the older adults in our lives were also receiving these CDs, and we remember stories of large numbers of older adults accessing AOL’s services and bogging down their systems. The point is that older adults’ disdain for technology does not necessarily apply across the board.We have data to support our personal observations that the older adult segment of the population is not exclusively composed of technophobes; in fact, some are even technophiles. For these data, we turn to a proven source of current, valid research on trends in the US population. The Pew Research Center Internet and American Life Project (www.pewinternet.org) conducts surveys on how the Internet impacts American lives. In a recent survey, Pew identified 2 distinct groups among the older adult population in terms of technology usage.¹ Among the older adult population, those who are older and less affluent are often “physically and psychologically” disconnected from digital tools and services. In many cases, this group of the population has health or disability issues that impact their use of technology. The other group of older adults, which is composed of those who are younger, better educated, and more affluent, positively view technology and have many tools at their disposal.Drilling down into the results, we find that physical and health issues pose distinct challenges for 2 in 5 older adults, directly impacting their ability to read or to participate in activities of daily living. Overall, this group is less likely to go online, have broadband Internet access at home, or to own common digital technologies. For this portion of the older adult population, many of the tools your institution has implemented or is considering implementing that can be used to engage patients may not provide any real value. For example, online portals, app-based communication, home monitoring devices, and even SMS messaging may miss the mark for those who do not have Internet access or cannot read. The digital divide does still exist for this group of patients, and its implications should be carefully considered in the implementation of any technology-based solutions. Some data suggest that phone calls are effective at reducing unnecessary readmissions. Could low-tech solutions such as the traditional phone call be best in this group of patients?To adopt technology, older adults need the tools (ie, Internet access) and skills (ie, reading ability), but these are not the only factors influencing technology use. Other challenges include skepticism and difficulty with learning to use new technology. It seems logical that those who currently do not use the Internet are skeptical about the importance of Internet access, and this was found in the Pew report. Additionally, fewer than 20% of respondents indicated feeling comfortable learning to use new technology without assistance. This segment of older US adults may not adopt technology just because it is available.We have a multifaceted challenge, which requires a multifaceted solution. Although providing broadband access at a patient’s home or teaching someone to read in the short time they are in the hospital are not within the pharmacists’ capabilities, their awareness of the challenges that patients face can impact the actions they take. For example, for a patient who cannot read and does not have Internet access at home, the discharge process can include visual education tools that do not require reading. These tools can be low tech and paper-based or high-tech videos. Patients who can read but do not have Internet access can be referred to local libraries or community centers that provide free Internet access. Involving more tech-savvy family members and friends in the caregiving process is another possibility. The range of measures to address the challenges of technology use among older adults is as broad as the challenges themselves. The good news is that the Pew report found that 71% of older adults who use the Internet go online every day, or almost every day. We welcome your experiences of what has and has not worked in addressing the use of technology tools by older adults (Brent, ude.nrubua@nerbxof; Bill, ude.nrubua@gbeklef).     

Beneficial and adverse psychotropic effects of antiepileptic drugs in patients with epilepsy: a summary of prevalence, underlying mechanisms and data limitations

Antiepileptic drugs (AEDs) can have both beneficial and adverse psychotropic effects. They act on neurotransmitter systems, neuronal ion permeability and other targets, although the exact mechanisms are not generally fully elucidated. A systematic review of the literature reveals evidence for both positive and negative effects on depression, anxiety, aggression, psychosis and sleep in patients with epilepsy. Topiramate, vigabatrin, levetiracetam, tiagabine and zonisamide have been associated primarily with adverse psychotropic effects, whilst gabapentin, pregabalin, lacosamide and lamotrigine, in particular, have demonstrated a more beneficial psychotropic profile, especially with regard to affective symptoms. This review, however, identifies specific methodological issues with studies that have reported on the psychotropic effects of AEDs, suggesting that some of the findings might be inconclusive or unreliable because of confounding factors, particularly the presence of psychiatric history. More rigorous double-blind, randomized, placebo-controlled trials on larger numbers of patients with epilepsy, with clear inclusion/exclusion criteria, that are specifically designed to investigate psychotropic changes are more likely to produce results that inform clinical practice and direct future research.     

The response of the isolated skin of rats to drugs and electrical stimulation

A new method of transmural stimulation (Hellmann, 1963b) has been used to examine the responses of the rat panniculus carnosus, a skeletal muscle which lines the skin. This preparation responded to drugs and to electrical excitation in the same way as other mammalian skeletal muscle preparations. The relaxation phase, when examined with fast recording systems, was complicated by what appeared to be the “tone” of the muscle.     

To what extent does the indicator “concurrent use of three or more psychotropic drugs” capture use of potentially inappropriate psychotropics among the elderly?

Purpose  The indicator “concurrent use of three or more psychotropic drugs” has been used as a measure of quality in drug use among the elderly. The aim of our study was to assess to what extent the indicator captures the use of specific psychotropics associated with an increased risk of adverse events among the elderly, i.e., potentially inappropriate psychotropic drugs (PIP). Methods  All individuals aged 75 years and older in Sweden purchasing prescribed psychotropic drugs in 2006 constituted the study population (n = 384,904). Data on purchased psychotropic drugs from the Swedish Prescribed Drug Register were used. The overlap between individuals with the indicator and individuals using PIP was assessed with sensitivity, specificity, positive and negative predictive values and likelihood ratio as outcome measures. Results  Among the psychotropic drug users, 15% had the indicator and 39% used PIP. The proportion of individuals with the indicator among all individuals using PIP was 27% (sensitivity). The proportion of individuals without the indicator among all individuals not using PIP was 93% (specificity). The positive predictive value was 72%, and the negative predictive value was 67%. Differences in outcome measures were observed between different categories of PIP. Conclusions  The indicator “concurrent use of three or more psychotropics” can be technically easy to use, but PIP is more specific. Three quarters of all individuals who used PIP in this study were not captured by the indicator. However, two thirds of all individuals with the indicator used PIP. When selecting instruments to assess appropriateness in drug therapy in the elderly, clinical relevance should be balanced against convenience of use.     

Pharmacological properties of thalidomide (α-phthalimido glutarimide), a new sedative hypnotic drug

Thalidomide (α-phthalimidoglutarimide, “Distaval,” “Contergan”) is a new sedative hypnotic drug which produces no toxic effects when administered orally to animals in massive doses. This lack of toxicity may be due to limited absorption. The drug has a quietening effect on the central nervous system, reducing the voluntary activity of laboratory animals and promoting sleep. Unlike the barbiturate drugs it does not cause an initial excitation in mice, incoordination or narcosis. It potentiates the actions of other central nervous system depressants, in particular the barbiturates. Its sedative effects are counteracted by central nervous system stimulants. It has no deleterious side effects and does not affect the heart, respiration or autonomic nervous system.     

Manganese Toxicity Associated With Total Parenteral Nutrition: A Review

Objective: To review hypermanganesemia-induced toxicities in adult patients receiving parenteral nutrition (PN) therapy. Data Sources: A comprehensive literature review was conducted from June 2020 to May 2021 on PubMED, MEDLINE, Scopus, ProQuest, the Cumulative Index of Nursing and Allied Health Literature (CINAHL), and Web of Science. Study Selection and Data Extraction: Keyword and Boolean phrase searches were conducted using the following terminology: “manganese” OR “manganesemia” OR “manganism” or “hypermanganesemia” AND “total parenteral nutrition” OR “PN” or “parenteral nutrition” AND “toxicity” OR “accumulation.” Appropriate filters, including “humans” and “English” and NOT “reviews,” were utilized on all databases to improve search outcomes. Data Synthesis: A total of 4 reports detailing hypermanganesemia in 57 patient encounters were included in this review. Significant heterogeneity exists with regard to the duration of manganese supplementation and the dose of manganese. Toxicity associated with manganese was observed in as few as 15 days. The dose of manganese, though likely governed by content in commercially available products, may regularly exceed the recommendations of clinical guidelines and should be limited to 55 µg/day. Select patients with underlying malignancy, those with significant and prolonged Vitamin D deficiency, or those who have acquired a SLC30A10 genetic mutation may be at an increased risk of developing manganese toxicity. Conclusions: Clinicians must be cognizant of the concentration of trace elements added to PN, as manganese, and perhaps other biometals, may accumulate when dosed above the recommended daily allowances.     

Social Pharmacology: Expanding horizons

In the current modern and global society, social changes are in constant evolution due to scientific progress (technology, culture, customs, and hygiene) and produce the freedom in individuals to take decisions by themselves or with their doctors toward drug consumption. In the arena of marketed drug products which includes society, individual, administration, and pharmaceutical industry, the young discipline emerged is social pharmacology or sociopharmacology. This science arises from clinical pharmacology, and deals with different parameters, which are important in creating knowledge on marketed drugs. However, the scope of “social pharmacology” is not covered by the so-called “Phase IV” alone, but it is the science that handles the postmarketing knowledge of drugs. The social pharmacology studies the “life cycle” of any marketed pharmaceutical product in the social terrain, and evaluates the effects of the real environment under circumstances totally different in the drug development process. Therefore, there are far-reaching horizons, plural, and shared predictions among health professionals and other, for beneficial use of a drug, toward maximizing the benefits of therapy, while minimizing negative social consequences.KEY WORDS: Clinical pharmacology, drug abuse, Phase IV, post marketing period, sociopharmacology     

Evaluation of a procedure to assess the adverse effects of illicit drugs

The assessment procedure of new synthetic illicit drugs that are not documented in the UN treaty on psychotropic drugs was evaluated using a modified Electre model. Drugs were evaluated by an expert panel via the open Delphi approach, where the written score was discussed on 16 items, covering medical, health, legal, and criminalistic issues of the drugs. After this face-to-face discussion the drugs were scored again. Taking the assessment of ketamine as an example, it appeared that each expert used its own scale to score, and that policymakers do not score deviant from experts trained in the medical-biological field. Of the five drugs evaluated by the panel, p-methoxy-metamphetamine (PMMA), gamma-hydroxybutyric acid (GHB), and 4-methylthio-amphetamine (MTA) were assessed as more adverse than ketamine and psilocine and psilocybine-containing mushrooms. Whereas some experts slightly adjusted during the assessment procedure their opinion on ketamine and PMMA, the opinion on mushrooms was not affected by the discussion held between the two scoring rounds. All experts rank the five drugs in a similar way on the adverse effect scale i.e., concordance scale of the Electre model, indicating unanimity in the expert panel with respect to the risk classification of these abused drugs.