Benzodiazepines and other benzodiazepine receptor agonists, such as the “Z” drugs, are widely prescribed medications mainly used for treating anxiety and seizures, and for inducing sedation. Unfortunately, despite t...Benzodiazepines and other benzodiazepine receptor agonists, such as the “Z” drugs, are widely prescribed medications mainly used for treating anxiety and seizures, and for inducing sedation. Unfortunately, despite their popularity, benzodiazepine prescribing often exceeds recommendations and the consequences can be severe. On September 23, 2020, the United States FDA announced a new requirement for a Boxed Warning for benzodiazepines prescribing. Along with this announcement, the FDA stated that relevant information regarding the initiation, continuation, and discontinuation of benzodiazepines is lacking. Here, we describe initial pilot studies intended to investigate the questions 1) can animal models be developed that demonstrate benzodiazepine physical dependence and/or withdrawal symptoms, and 2) determine whether translocator protein (TSPO) plays a role in benzodiazepine dependence and/or withdrawal processes. The former was demonstrated, methodological limitations prevented the latter.展开更多
Polysubstance (combinations of substances) abuse and overdose deaths now surpass mono-substance abuse and overdose deaths. Several international and governmental organizations such as the WHO (World Health Organizatio...Polysubstance (combinations of substances) abuse and overdose deaths now surpass mono-substance abuse and overdose deaths. Several international and governmental organizations such as the WHO (World Health Organization), CDC (Centers for Disease Control and Prevention), several of the Institutes of the NIH (National Institutes of Health), Regulators, and Enforcement Agencies, among others, track and provide a valuable source of statistical information about drug (prescription and illicit) (mis)use and overdose. The information is disseminated free to stakeholders and the general public for use. Although the numeric presentations of the data are helpful and adequate for professionals, the non-expert and the visual learner often find visual representation more clear and more compelling. With this in mind, the aim of this study was to present polysubstance use and overdose using visual maps of the available data. This article considers the opioids.展开更多
Polysubstance Abuse (PSA) greatly complicates an attempt to implicate a single drug as sole cause of an overdose death. Since PSA now occurs in the majority of cases of drug overdoses, many or most overdose deaths are...Polysubstance Abuse (PSA) greatly complicates an attempt to implicate a single drug as sole cause of an overdose death. Since PSA now occurs in the majority of cases of drug overdoses, many or most overdose deaths are polysubstance overdose deaths. And since many of the substances involved in a polysubstance Overdose Death (POD) are Central Nervous System (CNS) depressants, many of which can cause overdose death themselves, or synergistically with opioids, it is somewhat puzzling that prescription opioids have been singled out as the cause of these deaths—without reference to PSA. This is particularly puzzling in light of the fact that the issues of PSA and POD have been recognized and discussed in the literature since at least the 1960’s and before. We therefore here consider the question: are we facing an “opioid” crisis or, instead, a “polysubstance crisis”? And we wonder if the issue has been over-simplified, to the detriment of the individuals affected, and to society more broadly. There is a need for an “agnostic” respiratory stimulant that can reverse polysubstance-induced respiratory depression.展开更多
Recent publications reveal the disturbing information that a minor edit to an algorithm being used for designing legitimate drug candidates redirected the program in a way that resulted in the surprising design of nov...Recent publications reveal the disturbing information that a minor edit to an algorithm being used for designing legitimate drug candidates redirected the program in a way that resulted in the surprising design of novel chemical warfare agent candidates. Although this outcome was not the result of nefarious intent, and appropriate chemical defense authorities were notified, the potential implications of some misapplication of a drug-design algorithm for nefarious purposes are clear. This Commentary summarizes how otherwise benign Artificial Intelligence (AI) algorithms used for drug discovery can be easily reversed to design novel chemical warfare agents for which no effective antidote will be available, or perhaps even envisioned.展开更多
The rise in “vaping”-associated deaths in the United States raises serious concerns. A justification for some level of risk is that e-cigarettes might pro</span><span style="font-family:Verdana;"&...The rise in “vaping”-associated deaths in the United States raises serious concerns. A justification for some level of risk is that e-cigarettes might pro</span><span style="font-family:Verdana;">vide a </span></span><span style="font-family:Verdana;">“</span><span style="font-family:Verdana;">reverse-gateway” from smoking traditional cigarettes to a less-harmful</span><span style="font-family:Verdana;"> alternative. But are users actually smokers? We developed an electronic on-line survey to gather data regarding e-cigarette usage in a target study population of pharmacy students. The survey was created using Google Forms to collect the responses anonymously. We surveyed medical-savvy healthcare students about their e-cigarette use, and whether or not their healthcare providers were aware of their e-cigarette use. Although nearly one-fourth of a convenience sampling of 134 pharmacy-student respondents (23.9%) reported using e-cigarettes, only 2.0% reported prior regular cigarette use, 28% used cartridges containing nicotine and only 11.2% had tried and wanted to quit. The majority (64.1%) reported that their healthcare providers did not ask about such use, and respondents did not volunteer this information. The results of this pilot survey reveal a significant e-cigarette use among health-aware pharmacy students, and they do not support the notion that the respondents do so to quit smoking. The observation that most of the students’ healthcare providers did not inquire about their e-cigarette use, coupled with the finding that users did not volunteer their vaping behavior</span><span style="font-family:Verdana;">,</span><span style="font-family:Verdana;"> suggests that the information should be included when getting a medical history. Further research is needed to determine what behavioral factors may play a role in this type of decision-making among student healthcare professionals.展开更多
<span style="font-family:Verdana;">The </span><span style="font-family:Verdana;">“</span><span style="font-family:Verdana;">opioid crisis</span><sp...<span style="font-family:Verdana;">The </span><span style="font-family:Verdana;">“</span><span style="font-family:Verdana;">opioid crisis</span><span style="font-family:Verdana;">”</span><span style="font-family:""><span style="font-family:Verdana;"> has had a tremendous impact not only on its victims, but also on the practice of medicine, pain patients, and society in general. Unfortunately, efforts to “stem the tide” have not been successful at reducing overdose deaths. Counterbalancing the many ardent efforts to eliminate overdose deaths (such as the current widespread availability and use of opioid-receptor antagonists such as naloxone) is influx of the illicit fentanoids (</span><i><span style="font-family:Verdana;">i.e</span></i><span style="font-family:Verdana;">., fentanyl and analogs). In addition to their high-potency, the fentanoids differ in surprising ways from more “traditional” opioids such as morphine and heroin. This uniqueness contributes to a reduced effectiveness of opioid receptor antagonists in the treatment of opioid overdose. Further greatly complicating overdose treatment is polysubstance abuse (e.g., an opioid plus a benzodiaze</span><span style="font-family:Verdana;">pine). The non-opioid in the combination is not responsive to an opio</span><span style="font-family:Verdana;">id-recep</span></span><span style="font-family:Verdana;">- </span><span style="font-family:""><span style="font-family:Verdana;">tor antagonist, which imparts additional challenges. Thus, the new reality in</span><span style="font-family:Verdana;">troduces complications that negatively impact efforts to reverse </span></span><span style="font-family:Verdana;">“</span><span style="font-family:Verdana;">opioid</span><span style="font-family:Verdana;">”</span><span style="font-family:""><span style="font-family:Verdana;"> overdose. New approaches to improve outcomes in individuals who experience </span><span style="font-family:Verdana;">respiratory depression due to fentanoid-induced or polysubstance-induced</span><span style="font-family:Verdana;"> over</span></span><span style="font-family:Verdana;">- </span><span style="font-family:Verdana;">dose are needed. Approaches that harmonize with the new reality, perhaps something like a non-opioid </span><span style="font-family:Verdana;">“</span><span style="font-family:Verdana;">agnostic</span><span style="font-family:Verdana;">”</span><span style="font-family:Verdana;"> pharmacologic ventilatory stimulant, would provide a welcome addition to the current choices.</span>展开更多
<span lang="EN-US" style="white-space:normal;font-family:Verdana;">The benzodiazepines were introduced into medical practice during the 1960s. At the time, they represented a safer alternativ...<span lang="EN-US" style="white-space:normal;font-family:Verdana;">The benzodiazepines were introduced into medical practice during the 1960s. At the time, they represented a safer alternative to extant therapies used for anxiety, such as the barbiturates. However, on September 23, 2020, the United States FDA indicated that more is needed to be known about the initiation, continuation, and discontinuation of </span><span lang="EN-US" style="white-space:normal;font-family:Verdana;">the </span><span lang="EN-US" style="white-space:normal;font-family:Verdana;">us</span><span lang="EN-US" style="white-space:normal;font-family:Verdana;">e of</span><span lang="EN-US" style="white-space:normal;font-family:Verdana;"> these widely-used drugs with publication of the announcement </span><span lang="EN-US" style="white-space:normal;font-family:Verdana;">“</span><span lang="EN-US" style="white-space:normal;font-family:Verdana;">to address the serious risks of abuse, addiction, physical dependence, and withdrawal reactions, the U.S. Food and Drug Administration (FDA) is requiring the Boxed Warning be updated for all benzodiazepine medicines.</span><span lang="EN-US" style="white-space:normal;font-family:Verdana;">”</span><span lang="EN-US" style="white-space:normal;font-family:Verdana;"> Because for many years</span><span lang="EN-US" style="white-space:normal;font-family:Verdana;">, </span><span lang="EN-US" style="white-space:normal;font-family:Verdana;">there has been a sparsity </span><span lang="EN-US" style="white-space:normal;font-family:Verdana;">of </span><span lang="EN-US" style="white-space:normal;font-family:Verdana;">research on these drugs, relevant information is unfortunately lacking at this critical time. It is therefore valuable to (re)establish animal models and begin to collect relevant data. We here use a model of conditioned place</span><span lang="EN-US" style="white-space:normal;" "=""> </span><span lang="EN-US" style="white-space:normal;font-family:Verdana;">preference (CPP) </span><span lang="EN-US" style="white-space:normal;font-family:Verdana;">which </span><span lang="EN-US" style="white-space:normal;font-family:Verdana;">suggests that the representative benzodiazepine alprazolam induces positive place preference in female rats.</span>展开更多
Abuse of drug substances and resultant overdose deaths are no longer very straightforward—viz., attributable to a single chemical entity of known purity. The reality is that most overdose deaths involve polysubstance...Abuse of drug substances and resultant overdose deaths are no longer very straightforward—viz., attributable to a single chemical entity of known purity. The reality is that most overdose deaths involve polysubstance use (i.e., the use of combinations of substances). Further, the combinations are often of unknown purity, and even of unknown composition. Overdose deaths are at all-time highs. The depressing statistics are monitored and reported by several international and governmental organizations such as the WHO (World Health Organization), CDC (Centers for Disease Control and Prevention), several Institutes of the NIH (National Institutes of Health), Regulators, and Enforcement Agencies (e.g., DEA). The information is disseminated for free for review and use. But it is our observation that although numeric presentation is helpful and adequate for professionals, the non-expert and the visual learner often find a visual representation clearer and compelling. With this in mind, we present the “gestalt” of polysubstance use and overdose using available maps of the data. The previous article in the series considered the opioids. This one considers amphetamines and cocaine, and places the rise in opioid-associated overdose deaths in the context of other abused drugs.展开更多
General anesthetics constitute some of the most important and widely-used therapeutic drugs in the pharmacotherapeutic armamentarium. They are routinely used effectively and with adequate precaution-safety throughout ...General anesthetics constitute some of the most important and widely-used therapeutic drugs in the pharmacotherapeutic armamentarium. They are routinely used effectively and with adequate precaution-safety throughout the world for a multitude of clinical applications, predominantly as adjunctive agents for surgical procedures. Nevertheless, they have potential adverse effects (such as a drop in blood pressure and the inhibition of steroid production), particularly in vulnerable populations such as the very young and the frail elderly. It would be desirable therefore to have alternative agents that are just as efficacious, but have a better safety profile in a broader spectrum of patients. Toward this end, an anesthetic based on a unique chemical core (viz., an N-arylpyrrole derivative) has been reported in preclinical models to produce anesthetic effects without hemodynamic suppression. This lead could pave the way for new general anesthetics that are safer and easier to use.展开更多
Falls represent a significant contribution to the morbidity and mortality of the elderly population. Because vitamin D is important in bone physiology, the use of vitamin D to restore deficient bone and ameliorate the...Falls represent a significant contribution to the morbidity and mortality of the elderly population. Because vitamin D is important in bone physiology, the use of vitamin D to restore deficient bone and ameliorate the effects of bone fractures due to falls has become a common practice in recent years. Following introduction of widespread use, reports began to emerge that vitamin D not only aided in repair of fall-induced bone fractures, but that it also reduced the occurrence of falls. Vitamin D now has become a routine intervention as a fall-prevention measure. Early analyses found evidence of prevention efficacy (reduced falls), but recent analyses are more equivocal. We retrospectively examined the records of 350 patients in a long-term care facility in which vitamin D administration and the number of falls were recorded as part of a comprehensive database of care. We found a dramatic rise in vitamin D use over the period covered (2006 – 2011) and a corresponding dramatic decrease in the number of falls. However, the number of falls continued to decline after 2008, despite a plateau in number of patients on vitamin D, particularly females. It appears that other factors contribute to the overall decline.展开更多
Many therapeutic drugs are racemates;i.e. they are chiral molecules consisting of “left”- and “right-handed” enantiomers (stereoisomers that are mirror images of each other, and are non-superimposable). In some ca...Many therapeutic drugs are racemates;i.e. they are chiral molecules consisting of “left”- and “right-handed” enantiomers (stereoisomers that are mirror images of each other, and are non-superimposable). In some cases, both enantiomers of the drug contribute to some extent (or equally) to the therapeutic effect;in other cases they contribute not at all. The same is true for the adverse effects of racemate drugs: the adverse effects of a racemate drug can be greater-than, less-than, or equal to one or the other enantiomer. An unusual situation arises when a drug consists of “atropisomers”, stereoisomers arising because of hindered rotation about a single chemical bond. We summarize the concept of atropisomerism, and give examples.展开更多
Treatment of health problems that accompany aging often includes pharmacotherapy. It is thus common for older adults—and, increasingly, younger adults—to be on multiple medications, either prescription or over-the-c...Treatment of health problems that accompany aging often includes pharmacotherapy. It is thus common for older adults—and, increasingly, younger adults—to be on multiple medications, either prescription or over-the-counter (OTC). With the consumption of multiple medications, drug-drug interactions (DDIs) are a concern. The site of drug-drug interactions is often at the level of drug metabolism. If a drug inhibits (or enhances) the metabolism of another, the blood level (therapeutic effect) can be decreased below the required level, or adverse effects can increase. Because most currently used drugs are metabolized via cytochrome P450-catalyzed pathways, drug discovers seek drugs that are metabolized by alternate pathways. Medicinal chemists have come upon a strategy—the incorporation of oxetane rings in the drug structure—that increases the likelihood that a drug will not be metabolized via CYP450. The same modification gives other desirable physical properties to the molecule. Although there are no guarantees that there will be fewer DDIs or an absence of other unexpected problems, the strategy could pave the way for new drugs that are safer and easier to use with concomitant medications.展开更多
As aging comes, an increased prevalence of medical maladies and chronic pain independently or interactively disrupt sleep, which in turn can exacerbate either one. Furthermore, anxiety about pain can further negativel...As aging comes, an increased prevalence of medical maladies and chronic pain independently or interactively disrupt sleep, which in turn can exacerbate either one. Furthermore, anxiety about pain can further negatively impact sleep. Fortunately, good quality sleep can improve pain management. Because benzodiazepine receptor agonists (including the “Z” drugs) can reduce anxiety and improve sleep, they seem a convenient choice. However, their use in this population, particularly for more than short-term (guidelines range from 2 to 6 weeks max), is not recommended because of increased likelihood of falls, further disruption of sleep, dependence, and problems with discontinuation (withdrawal). Besides, this population is often likely to take concomitant medication for pain or other central nervous system depressants leading to potentially serious and even life-threatening interactions involving synergistic amplification of respiratory depression (opioids being a particularly dangerous interaction). Therefore, insomnia in older adults should ideally be treated with a non-benzodiazepine receptor agonist;if indicated, they may be used, but should be closely monitored and tapered to avoid long-term adverse problems (direct or from withdrawal). Older adult patients with insomnia may be more optimally treated with sleep aids that do not interact with the GABAA receptor.展开更多
Two selective phosphodiesterase-4 (PDE4) inhibitors—viz., crisaborole (Eucrisa®, Pfizer) and apremilast (Otezla®, Celgene)—have recently received approval by the United States Food and Drug Administr...Two selective phosphodiesterase-4 (PDE4) inhibitors—viz., crisaborole (Eucrisa®, Pfizer) and apremilast (Otezla®, Celgene)—have recently received approval by the United States Food and Drug Administration for the treatment of related but different dermatologic skin conditions (viz., atopic dermatitis and plaque psoriasis, respectively). The purpose of this review is to summarize the underlying biochemistry and pathophysiology associated with these dermatologic conditions, review the chemistry, pharmacology and safety of each of these products, and present preclinical and clinical evidence that may help explain why these two PDE4 inhibitors offer new treatment options for these skin conditions.展开更多
Opioids are a treatment option for a variety of chronic pain conditions. But long-term opioid use can be associated with side effects, including hypogonadism. Opioid-induced hypogonadism (OIhG) is associated with the ...Opioids are a treatment option for a variety of chronic pain conditions. But long-term opioid use can be associated with side effects, including hypogonadism. Opioid-induced hypogonadism (OIhG) is associated with the alteration of the hypothalamic-pituitary-gonadal axis (HPG). In males, hypogonadism can result in erectile dysfunction, reduced libido, fatigue, worsening mood, and increased risk of osteoporosis;in females, it can result in changes in the menstrual cycle and reduced libido, among other effects. A current treatment option for these patients is hormone replacement therapy. In this report, we discuss the problem of opioid-induced hypogonadism, and the therapeutic approach and the potential complications of treating pain patients using hormone replacement therapy.展开更多
When any type of product has been ordered to be removed from the marketplace by a governmental regulatory body, that action is a powerful indicator that the product has been determined to be unsafe for further use, th...When any type of product has been ordered to be removed from the marketplace by a governmental regulatory body, that action is a powerful indicator that the product has been determined to be unsafe for further use, thereby branding the product as defective and opening up the possibility of product liability litigation. When the product is a drug or medical device, it is especially serious since the possibility of personal injury (acute and/or chronic) or death may occur. Needless to say, in these situations, product injury litigation will almost surely follow. We review the definition and requisite claims needed to establish drug product liability, and the role that the medical literature, clinical trial data, and even experimental research data can play in product (drug)-injury litigation. We show how each of these resources played a significant role in two well-known cases: Fen-Phen and thimerosal. The ultimate goal of such knowledge is to make better informed decisions about drug safety.展开更多
文摘Benzodiazepines and other benzodiazepine receptor agonists, such as the “Z” drugs, are widely prescribed medications mainly used for treating anxiety and seizures, and for inducing sedation. Unfortunately, despite their popularity, benzodiazepine prescribing often exceeds recommendations and the consequences can be severe. On September 23, 2020, the United States FDA announced a new requirement for a Boxed Warning for benzodiazepines prescribing. Along with this announcement, the FDA stated that relevant information regarding the initiation, continuation, and discontinuation of benzodiazepines is lacking. Here, we describe initial pilot studies intended to investigate the questions 1) can animal models be developed that demonstrate benzodiazepine physical dependence and/or withdrawal symptoms, and 2) determine whether translocator protein (TSPO) plays a role in benzodiazepine dependence and/or withdrawal processes. The former was demonstrated, methodological limitations prevented the latter.
文摘Polysubstance (combinations of substances) abuse and overdose deaths now surpass mono-substance abuse and overdose deaths. Several international and governmental organizations such as the WHO (World Health Organization), CDC (Centers for Disease Control and Prevention), several of the Institutes of the NIH (National Institutes of Health), Regulators, and Enforcement Agencies, among others, track and provide a valuable source of statistical information about drug (prescription and illicit) (mis)use and overdose. The information is disseminated free to stakeholders and the general public for use. Although the numeric presentations of the data are helpful and adequate for professionals, the non-expert and the visual learner often find visual representation more clear and more compelling. With this in mind, the aim of this study was to present polysubstance use and overdose using visual maps of the available data. This article considers the opioids.
文摘Polysubstance Abuse (PSA) greatly complicates an attempt to implicate a single drug as sole cause of an overdose death. Since PSA now occurs in the majority of cases of drug overdoses, many or most overdose deaths are polysubstance overdose deaths. And since many of the substances involved in a polysubstance Overdose Death (POD) are Central Nervous System (CNS) depressants, many of which can cause overdose death themselves, or synergistically with opioids, it is somewhat puzzling that prescription opioids have been singled out as the cause of these deaths—without reference to PSA. This is particularly puzzling in light of the fact that the issues of PSA and POD have been recognized and discussed in the literature since at least the 1960’s and before. We therefore here consider the question: are we facing an “opioid” crisis or, instead, a “polysubstance crisis”? And we wonder if the issue has been over-simplified, to the detriment of the individuals affected, and to society more broadly. There is a need for an “agnostic” respiratory stimulant that can reverse polysubstance-induced respiratory depression.
文摘Recent publications reveal the disturbing information that a minor edit to an algorithm being used for designing legitimate drug candidates redirected the program in a way that resulted in the surprising design of novel chemical warfare agent candidates. Although this outcome was not the result of nefarious intent, and appropriate chemical defense authorities were notified, the potential implications of some misapplication of a drug-design algorithm for nefarious purposes are clear. This Commentary summarizes how otherwise benign Artificial Intelligence (AI) algorithms used for drug discovery can be easily reversed to design novel chemical warfare agents for which no effective antidote will be available, or perhaps even envisioned.
文摘The rise in “vaping”-associated deaths in the United States raises serious concerns. A justification for some level of risk is that e-cigarettes might pro</span><span style="font-family:Verdana;">vide a </span></span><span style="font-family:Verdana;">“</span><span style="font-family:Verdana;">reverse-gateway” from smoking traditional cigarettes to a less-harmful</span><span style="font-family:Verdana;"> alternative. But are users actually smokers? We developed an electronic on-line survey to gather data regarding e-cigarette usage in a target study population of pharmacy students. The survey was created using Google Forms to collect the responses anonymously. We surveyed medical-savvy healthcare students about their e-cigarette use, and whether or not their healthcare providers were aware of their e-cigarette use. Although nearly one-fourth of a convenience sampling of 134 pharmacy-student respondents (23.9%) reported using e-cigarettes, only 2.0% reported prior regular cigarette use, 28% used cartridges containing nicotine and only 11.2% had tried and wanted to quit. The majority (64.1%) reported that their healthcare providers did not ask about such use, and respondents did not volunteer this information. The results of this pilot survey reveal a significant e-cigarette use among health-aware pharmacy students, and they do not support the notion that the respondents do so to quit smoking. The observation that most of the students’ healthcare providers did not inquire about their e-cigarette use, coupled with the finding that users did not volunteer their vaping behavior</span><span style="font-family:Verdana;">,</span><span style="font-family:Verdana;"> suggests that the information should be included when getting a medical history. Further research is needed to determine what behavioral factors may play a role in this type of decision-making among student healthcare professionals.
文摘<span style="font-family:Verdana;">The </span><span style="font-family:Verdana;">“</span><span style="font-family:Verdana;">opioid crisis</span><span style="font-family:Verdana;">”</span><span style="font-family:""><span style="font-family:Verdana;"> has had a tremendous impact not only on its victims, but also on the practice of medicine, pain patients, and society in general. Unfortunately, efforts to “stem the tide” have not been successful at reducing overdose deaths. Counterbalancing the many ardent efforts to eliminate overdose deaths (such as the current widespread availability and use of opioid-receptor antagonists such as naloxone) is influx of the illicit fentanoids (</span><i><span style="font-family:Verdana;">i.e</span></i><span style="font-family:Verdana;">., fentanyl and analogs). In addition to their high-potency, the fentanoids differ in surprising ways from more “traditional” opioids such as morphine and heroin. This uniqueness contributes to a reduced effectiveness of opioid receptor antagonists in the treatment of opioid overdose. Further greatly complicating overdose treatment is polysubstance abuse (e.g., an opioid plus a benzodiaze</span><span style="font-family:Verdana;">pine). The non-opioid in the combination is not responsive to an opio</span><span style="font-family:Verdana;">id-recep</span></span><span style="font-family:Verdana;">- </span><span style="font-family:""><span style="font-family:Verdana;">tor antagonist, which imparts additional challenges. Thus, the new reality in</span><span style="font-family:Verdana;">troduces complications that negatively impact efforts to reverse </span></span><span style="font-family:Verdana;">“</span><span style="font-family:Verdana;">opioid</span><span style="font-family:Verdana;">”</span><span style="font-family:""><span style="font-family:Verdana;"> overdose. New approaches to improve outcomes in individuals who experience </span><span style="font-family:Verdana;">respiratory depression due to fentanoid-induced or polysubstance-induced</span><span style="font-family:Verdana;"> over</span></span><span style="font-family:Verdana;">- </span><span style="font-family:Verdana;">dose are needed. Approaches that harmonize with the new reality, perhaps something like a non-opioid </span><span style="font-family:Verdana;">“</span><span style="font-family:Verdana;">agnostic</span><span style="font-family:Verdana;">”</span><span style="font-family:Verdana;"> pharmacologic ventilatory stimulant, would provide a welcome addition to the current choices.</span>
文摘<span lang="EN-US" style="white-space:normal;font-family:Verdana;">The benzodiazepines were introduced into medical practice during the 1960s. At the time, they represented a safer alternative to extant therapies used for anxiety, such as the barbiturates. However, on September 23, 2020, the United States FDA indicated that more is needed to be known about the initiation, continuation, and discontinuation of </span><span lang="EN-US" style="white-space:normal;font-family:Verdana;">the </span><span lang="EN-US" style="white-space:normal;font-family:Verdana;">us</span><span lang="EN-US" style="white-space:normal;font-family:Verdana;">e of</span><span lang="EN-US" style="white-space:normal;font-family:Verdana;"> these widely-used drugs with publication of the announcement </span><span lang="EN-US" style="white-space:normal;font-family:Verdana;">“</span><span lang="EN-US" style="white-space:normal;font-family:Verdana;">to address the serious risks of abuse, addiction, physical dependence, and withdrawal reactions, the U.S. Food and Drug Administration (FDA) is requiring the Boxed Warning be updated for all benzodiazepine medicines.</span><span lang="EN-US" style="white-space:normal;font-family:Verdana;">”</span><span lang="EN-US" style="white-space:normal;font-family:Verdana;"> Because for many years</span><span lang="EN-US" style="white-space:normal;font-family:Verdana;">, </span><span lang="EN-US" style="white-space:normal;font-family:Verdana;">there has been a sparsity </span><span lang="EN-US" style="white-space:normal;font-family:Verdana;">of </span><span lang="EN-US" style="white-space:normal;font-family:Verdana;">research on these drugs, relevant information is unfortunately lacking at this critical time. It is therefore valuable to (re)establish animal models and begin to collect relevant data. We here use a model of conditioned place</span><span lang="EN-US" style="white-space:normal;" "=""> </span><span lang="EN-US" style="white-space:normal;font-family:Verdana;">preference (CPP) </span><span lang="EN-US" style="white-space:normal;font-family:Verdana;">which </span><span lang="EN-US" style="white-space:normal;font-family:Verdana;">suggests that the representative benzodiazepine alprazolam induces positive place preference in female rats.</span>
文摘Abuse of drug substances and resultant overdose deaths are no longer very straightforward—viz., attributable to a single chemical entity of known purity. The reality is that most overdose deaths involve polysubstance use (i.e., the use of combinations of substances). Further, the combinations are often of unknown purity, and even of unknown composition. Overdose deaths are at all-time highs. The depressing statistics are monitored and reported by several international and governmental organizations such as the WHO (World Health Organization), CDC (Centers for Disease Control and Prevention), several Institutes of the NIH (National Institutes of Health), Regulators, and Enforcement Agencies (e.g., DEA). The information is disseminated for free for review and use. But it is our observation that although numeric presentation is helpful and adequate for professionals, the non-expert and the visual learner often find a visual representation clearer and compelling. With this in mind, we present the “gestalt” of polysubstance use and overdose using available maps of the data. The previous article in the series considered the opioids. This one considers amphetamines and cocaine, and places the rise in opioid-associated overdose deaths in the context of other abused drugs.
文摘General anesthetics constitute some of the most important and widely-used therapeutic drugs in the pharmacotherapeutic armamentarium. They are routinely used effectively and with adequate precaution-safety throughout the world for a multitude of clinical applications, predominantly as adjunctive agents for surgical procedures. Nevertheless, they have potential adverse effects (such as a drop in blood pressure and the inhibition of steroid production), particularly in vulnerable populations such as the very young and the frail elderly. It would be desirable therefore to have alternative agents that are just as efficacious, but have a better safety profile in a broader spectrum of patients. Toward this end, an anesthetic based on a unique chemical core (viz., an N-arylpyrrole derivative) has been reported in preclinical models to produce anesthetic effects without hemodynamic suppression. This lead could pave the way for new general anesthetics that are safer and easier to use.
文摘Falls represent a significant contribution to the morbidity and mortality of the elderly population. Because vitamin D is important in bone physiology, the use of vitamin D to restore deficient bone and ameliorate the effects of bone fractures due to falls has become a common practice in recent years. Following introduction of widespread use, reports began to emerge that vitamin D not only aided in repair of fall-induced bone fractures, but that it also reduced the occurrence of falls. Vitamin D now has become a routine intervention as a fall-prevention measure. Early analyses found evidence of prevention efficacy (reduced falls), but recent analyses are more equivocal. We retrospectively examined the records of 350 patients in a long-term care facility in which vitamin D administration and the number of falls were recorded as part of a comprehensive database of care. We found a dramatic rise in vitamin D use over the period covered (2006 – 2011) and a corresponding dramatic decrease in the number of falls. However, the number of falls continued to decline after 2008, despite a plateau in number of patients on vitamin D, particularly females. It appears that other factors contribute to the overall decline.
文摘Many therapeutic drugs are racemates;i.e. they are chiral molecules consisting of “left”- and “right-handed” enantiomers (stereoisomers that are mirror images of each other, and are non-superimposable). In some cases, both enantiomers of the drug contribute to some extent (or equally) to the therapeutic effect;in other cases they contribute not at all. The same is true for the adverse effects of racemate drugs: the adverse effects of a racemate drug can be greater-than, less-than, or equal to one or the other enantiomer. An unusual situation arises when a drug consists of “atropisomers”, stereoisomers arising because of hindered rotation about a single chemical bond. We summarize the concept of atropisomerism, and give examples.
文摘Treatment of health problems that accompany aging often includes pharmacotherapy. It is thus common for older adults—and, increasingly, younger adults—to be on multiple medications, either prescription or over-the-counter (OTC). With the consumption of multiple medications, drug-drug interactions (DDIs) are a concern. The site of drug-drug interactions is often at the level of drug metabolism. If a drug inhibits (or enhances) the metabolism of another, the blood level (therapeutic effect) can be decreased below the required level, or adverse effects can increase. Because most currently used drugs are metabolized via cytochrome P450-catalyzed pathways, drug discovers seek drugs that are metabolized by alternate pathways. Medicinal chemists have come upon a strategy—the incorporation of oxetane rings in the drug structure—that increases the likelihood that a drug will not be metabolized via CYP450. The same modification gives other desirable physical properties to the molecule. Although there are no guarantees that there will be fewer DDIs or an absence of other unexpected problems, the strategy could pave the way for new drugs that are safer and easier to use with concomitant medications.
文摘As aging comes, an increased prevalence of medical maladies and chronic pain independently or interactively disrupt sleep, which in turn can exacerbate either one. Furthermore, anxiety about pain can further negatively impact sleep. Fortunately, good quality sleep can improve pain management. Because benzodiazepine receptor agonists (including the “Z” drugs) can reduce anxiety and improve sleep, they seem a convenient choice. However, their use in this population, particularly for more than short-term (guidelines range from 2 to 6 weeks max), is not recommended because of increased likelihood of falls, further disruption of sleep, dependence, and problems with discontinuation (withdrawal). Besides, this population is often likely to take concomitant medication for pain or other central nervous system depressants leading to potentially serious and even life-threatening interactions involving synergistic amplification of respiratory depression (opioids being a particularly dangerous interaction). Therefore, insomnia in older adults should ideally be treated with a non-benzodiazepine receptor agonist;if indicated, they may be used, but should be closely monitored and tapered to avoid long-term adverse problems (direct or from withdrawal). Older adult patients with insomnia may be more optimally treated with sleep aids that do not interact with the GABAA receptor.
文摘Two selective phosphodiesterase-4 (PDE4) inhibitors—viz., crisaborole (Eucrisa®, Pfizer) and apremilast (Otezla®, Celgene)—have recently received approval by the United States Food and Drug Administration for the treatment of related but different dermatologic skin conditions (viz., atopic dermatitis and plaque psoriasis, respectively). The purpose of this review is to summarize the underlying biochemistry and pathophysiology associated with these dermatologic conditions, review the chemistry, pharmacology and safety of each of these products, and present preclinical and clinical evidence that may help explain why these two PDE4 inhibitors offer new treatment options for these skin conditions.
文摘Opioids are a treatment option for a variety of chronic pain conditions. But long-term opioid use can be associated with side effects, including hypogonadism. Opioid-induced hypogonadism (OIhG) is associated with the alteration of the hypothalamic-pituitary-gonadal axis (HPG). In males, hypogonadism can result in erectile dysfunction, reduced libido, fatigue, worsening mood, and increased risk of osteoporosis;in females, it can result in changes in the menstrual cycle and reduced libido, among other effects. A current treatment option for these patients is hormone replacement therapy. In this report, we discuss the problem of opioid-induced hypogonadism, and the therapeutic approach and the potential complications of treating pain patients using hormone replacement therapy.
文摘When any type of product has been ordered to be removed from the marketplace by a governmental regulatory body, that action is a powerful indicator that the product has been determined to be unsafe for further use, thereby branding the product as defective and opening up the possibility of product liability litigation. When the product is a drug or medical device, it is especially serious since the possibility of personal injury (acute and/or chronic) or death may occur. Needless to say, in these situations, product injury litigation will almost surely follow. We review the definition and requisite claims needed to establish drug product liability, and the role that the medical literature, clinical trial data, and even experimental research data can play in product (drug)-injury litigation. We show how each of these resources played a significant role in two well-known cases: Fen-Phen and thimerosal. The ultimate goal of such knowledge is to make better informed decisions about drug safety.
