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
The first “deuterated” drug has recently been approved by the U.S. FDA (Food & Drug Administration). A “deuterated” drug is a drug in which the hydrogen atom in one or more of the carbon-hydrogen bonds in its ...The first “deuterated” drug has recently been approved by the U.S. FDA (Food & Drug Administration). A “deuterated” drug is a drug in which the hydrogen atom in one or more of the carbon-hydrogen bonds in its chemical structure is replaced by deuterium (“heavy hydrogen”, a hydrogen isotope that has a neutron, i.e., one neutron instead of the usual no neutrons). A carbon-deuterium (C-D) bond is more stable in the body than a carbon-hydrogen (C-H) bond. If the deuterium is strategically located in a drug’s chemical structure, the extra stability of the bond will be more resistant to metabolic breakdown, and the duration of drug action will be prolonged. We review the general concept of deuterated drugs, historical examples of the classes of application, and the new approval.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
There is accumulating evidence that the subfamily of large-conductance potassium (“big”, “BK”) channels are involved in diverse, and perhaps coordinated, protective or counteractive responses to local or generaliz...There is accumulating evidence that the subfamily of large-conductance potassium (“big”, “BK”) channels are involved in diverse, and perhaps coordinated, protective or counteractive responses to local or generalized ischemia and hypoxia. Although widely distributed, the physiological differences among BK channels which results from posttranslational modification (alternative splicing) and co-assembly with auxiliary modulatory subunits (<em>β</em><sub>1-4</sub> and <em>γ</em><sub>1-4</sub>), bestows localized differences in subunit composition, distribution, 2<sup>nd</sup>-messenger coupling, and pharmacologic properties. Due to the ubiquitous nature of BK channels and the multiplicity of subtypes, they have many potential therapeutic applications in the maintenance of oxygen homeostasis, cerebro- and cardio-protection, and stimulation of respiration in response to drug-induced respiratory depression. BK channels may also offer other potentially broad and underrecognized promising targets for novel pharmaceutical development.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
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
Between the illicit use of opioids and attendant overdoses, and accidental overdoses with prescribed drugs, overuse of opioids has become a serious problem. At the same time, finding that fine balance between minimizi...Between the illicit use of opioids and attendant overdoses, and accidental overdoses with prescribed drugs, overuse of opioids has become a serious problem. At the same time, finding that fine balance between minimizing the risk of opioid misuse and abuse while at the same time providing access to treatment for patients who need pain control presents an ongoing challenge. Efforts to discover and develop better agents have led to what we term “new-look” opioids. We summarize here one such approach—known as biased ligands. By targeting a subset of GPCR signal transduction, this approach attempts to increase the separation between therapeutic and adverse effects.展开更多
<span style="font-family:Verdana;"><strong>Introduction:</strong></span><span><span><span style="font-family:""><span style="font-family:Verda...<span style="font-family:Verdana;"><strong>Introduction:</strong></span><span><span><span style="font-family:""><span style="font-family:Verdana;"> The inflammatory mechanisms of COVID-19 suggest that corticosteroids may be beneficial, but their benefits must outweigh their potential risks. The RECOVERY trial results suggest that dexamethasone 6 mg/day </span><span style="font-family:Verdana;">(but not other steroids) may confer mortality benefits on ventilated COVID-19 </span><span style="font-family:Verdana;">patients.</span></span></span></span><span><span><span style="font-family:""> </span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><b><span style="font-family:Verdana;">Methods:</span></b></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;"> This is a narrative review of the literature about the use of ciclesonide and dexamethasone for COVID-19 patients. Literature is being created rapidly and this review is offered as a state-of-the-science narration.</span></span></span><span><span><span style="font-family:""> </span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><b><span style="font-family:Verdana;">Results:</span></b></span></span><span><span><span style="font-family:""><span style="font-family:Verdana;"> The SARS-CoV-2 virus is an RNA virus whose RNA is transcribed via open reading frames, making its elimination difficult. Coronaviruses have evolved multiple strategies for proteolytic activation of the spike;viral replication occurs entirely in the cytoplasm. In this connection, the RNA-cleaving endoribonuclease (NSP-15 also known as EndoU) may play a key role by facilitating viral double-stranded RNA recognition by the host’s macrophages. </span><span style="font-family:Verdana;">Furthermore, the virus is able to undergo RNA recombination rapidly,</span><span style="font-family:Verdana;"> enabling it to evade host immunity and develop drug resistance. Ciclesonide is an inhaled corticosteroid that reduces lung inflammation and blocks the activity of specific kinases which may explain its anti-inflammatory effect. Dexamethasone is known to reduce mortality in ventilated COVID-19 patients.</span></span></span></span><span><span><span style="font-family:""> </span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><b><span style="font-family:Verdana;">Discussion:</span></b></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;"> Systemic corticosteroids were used in previous coronavirus epidemics (SARS and MERS) and pulmonary histology of these patients is similar to those in COVID-19 patients. Acute respiratory distress syndrome is the main cause of death in most COVID-19 infections and steroids may be effective in addressing that condition, brought on by cytokine storm. However, it should be noted that inhaled steroids likely have a narrower window for effect than systemic regimens.</span></span></span><span><span><span style="font-family:""> </span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><b><span style="font-family:Verdana;">Conclusion:</span></b></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;"> Dexamethasone has been proven to confer mortality benefits on ventilated COVID-19 patients and may be used with inhaled ciclesonide, which has few side effects and can be locally metabolized. Further study is needed.</span></span></span>展开更多
Lucemyra? (lofexidine hydrochloride) has recently been approved by the US FDA for the mitigation of withdrawal symptoms to facilitate abrupt discontinuation of opioids in adults. Lofexidine is an alpha-2 adrenoceptor ...Lucemyra? (lofexidine hydrochloride) has recently been approved by the US FDA for the mitigation of withdrawal symptoms to facilitate abrupt discontinuation of opioids in adults. Lofexidine is an alpha-2 adrenoceptor agonist. However, the clinical attributes of lofexidine differ in advantageous ways from the classical alpha-2 adrenoceptor agonist clonidine. In the present study, we measured the receptor binding profile of lofexidine and clonidine in an effort to gain an insight into the clinical difference(s).展开更多
The recent large increase in deaths involving opioids (whether prescription or illicit, pure or adulterated, alone or in combination with other drugs) is the manifestation of a complex, and multifaceted problem consis...The recent large increase in deaths involving opioids (whether prescription or illicit, pure or adulterated, alone or in combination with other drugs) is the manifestation of a complex, and multifaceted problem consisting of psychological, psychosocial, medical, legal, regulatory, economic, cultural, and political components, among others. Because the problem involves issues related to both supply and demand, the solution is not obvious, simple, or quick. There is no easy fix. Preventing and treating opioid misuse and abuse requires a comprehensive, time-intensive, and expensive intervention supported by public policy and support through coordinated medical, regulatory, legal, and financial guidelines and practice. But until the long-term problems can be fixed, the immediate crisis of overdose deaths can be ameliorated by making available an opioid receptor antagonist to reverse the respiratory depression that is the cause of death to those who are in the best position to administer it in time (professionals, untrained bystanders, and even fellow drug abusers). The statistics overwhelmingly demonstrate that this is a life-saving medical intervention. Yet, there is still uncertainty about this intervention, and even some opposition to it. We describe the scientific basis for the approach and the issues surrounding its use to treat accidental or intentional overdose by pain patients, recreational opioid users, and addicts. We also describe the calls to limit the number of times it should be available to a user and the limitations of its effectiveness—mainly that it only addresses the acute death crisis, not the underlying problems that led to it.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
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
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
Compliance to hand-hygiene guidelines in healthcare facilities remains disappointingly low for a variety of human-factors (HF) reasons. A device HF-engineered for convenient and effective use even under high-workload ...Compliance to hand-hygiene guidelines in healthcare facilities remains disappointingly low for a variety of human-factors (HF) reasons. A device HF-engineered for convenient and effective use even under high-workload conditions could contribute to better compliance, and consequently to reduction in healthcare-acquired infections. We present an overview of the efficacy of a passive hand-spray device that uses solubilized ozone—a strong, safe, non-irritant biocide having broad-spectrum antimicrobial properties—on glass surface, pigskin, and synthetic human skin matrix.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
A healthcare-associated infection (defined as an infection acquired within a healthcare facility), such as due to transmission via medical equipment or by healthcare providers is the most frequent adverse event in the...A healthcare-associated infection (defined as an infection acquired within a healthcare facility), such as due to transmission via medical equipment or by healthcare providers is the most frequent adverse event in the healthcare delivery system. But why does the problem persist, when infection control measures are known, simple, and low-cost? We reviewed some biological- and treatment-factors in Part 1, and we now review some human-factors. Healthcare-associated infections are a major public health problem even in advanced healthcare systems. They affect hundreds of millions of patients each year, and are responsible for increased morbidity, mortality, and financial burden. This is perplexing, since good-hygiene practices are known and promoted. Disinfection, sterilization, handwashing, and alcohol rubs should be more effective, but human-factors interfere. The persistent high prevalence of nosocomial infections, despite known hygienic practices, is attributable to two categories of factors: biological and inherent shortcomings of some practices (considered in Part 1), and human factors (considered here). A new approach is considered in Part 3.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
Benzodiazepines and related benzodiazepine-receptor agonists such as the pyrazolopyrimidinezalepl -on;?the imidazopyridine zolpidem;and the cyclopyrroloneszopiclone and eszopiclone, are among the most widely prescribe...Benzodiazepines and related benzodiazepine-receptor agonists such as the pyrazolopyrimidinezalepl -on;?the imidazopyridine zolpidem;and the cyclopyrroloneszopiclone and eszopiclone, are among the most widely prescribed drugs, and for a variety of conditions. Surprisingly: 1) there are only a few conditions for which there is a good evidence basis, 2) efficacy has only been well demonstrated for short-term use (i.e., less than 4 weeks), and 3) much less is known about the basic science of these drugs than is widely believed. We suggest that the use of these drugs beyond four or less weeks exceeds the available knowledge base, so best-practice use suggests that the prescribing of these drugs for most patients should be limited to only short-term use until more is known about the basic pharmacology of their actions in the brain and in the periphery.展开更多
In 2016 and 2017 an outbreak of the Zika virus</span><span style="font-family:""> </span><span style="font-family:Verdana;">in new locales shocked populations</span&...In 2016 and 2017 an outbreak of the Zika virus</span><span style="font-family:""> </span><span style="font-family:Verdana;">in new locales shocked populations</span><span style="font-family:""> </span><span style="font-family:Verdana;">into awareness of the disease and of its imputed ability to cause serious fetal abnormalities, particularly microcephaly. There was a major reduction in travel by people of child-bearing age. But the temporary regression in </span><span style="font-family:Verdana;">the </span><span style="font-family:Verdana;">spread, and preoccupation with COVID-19, seem to have overshadowed concern about Zika virus. In order to investigate this phenomenon, we conducted an online survey of 157 high-school students from four schools in different parts of the United States regarding their knowledge, practices, and attitudes about Zika virus. The mean age of the respondents was 16.4 </span><span style="font-family:""><span style="font-family:Verdana;">±</span><span style="font-family:Verdana;"> 1.1 years, 55% were girls, and 60% attended public (rather than private) schools. Most students (70%) had taken no steps to prevent Zika, but said they would tell their parents or a physician if they were exposed. They relied primarily on school and the internet (76% and 72%, respectively) as trusted sources of information about the virus. The majority (73%) said they would spend some time to learn more about Zika;girls exhibited more concern than did boys. Half (50%) of respondents knew the signs and symptoms of Zika, but only 20% knew all the ways Zika could be transmitted and 31% why Zika prevention was crucial for pregnant women and their partners. The results of this study suggest that comprehensive national preventive healthcare educational programs are needed.展开更多
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.
文摘The first “deuterated” drug has recently been approved by the U.S. FDA (Food & Drug Administration). A “deuterated” drug is a drug in which the hydrogen atom in one or more of the carbon-hydrogen bonds in its chemical structure is replaced by deuterium (“heavy hydrogen”, a hydrogen isotope that has a neutron, i.e., one neutron instead of the usual no neutrons). A carbon-deuterium (C-D) bond is more stable in the body than a carbon-hydrogen (C-H) bond. If the deuterium is strategically located in a drug’s chemical structure, the extra stability of the bond will be more resistant to metabolic breakdown, and the duration of drug action will be prolonged. We review the general concept of deuterated drugs, historical examples of the classes of application, and the new approval.
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There is accumulating evidence that the subfamily of large-conductance potassium (“big”, “BK”) channels are involved in diverse, and perhaps coordinated, protective or counteractive responses to local or generalized ischemia and hypoxia. Although widely distributed, the physiological differences among BK channels which results from posttranslational modification (alternative splicing) and co-assembly with auxiliary modulatory subunits (<em>β</em><sub>1-4</sub> and <em>γ</em><sub>1-4</sub>), bestows localized differences in subunit composition, distribution, 2<sup>nd</sup>-messenger coupling, and pharmacologic properties. Due to the ubiquitous nature of BK channels and the multiplicity of subtypes, they have many potential therapeutic applications in the maintenance of oxygen homeostasis, cerebro- and cardio-protection, and stimulation of respiration in response to drug-induced respiratory depression. BK channels may also offer other potentially broad and underrecognized promising targets for novel pharmaceutical development.
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Between the illicit use of opioids and attendant overdoses, and accidental overdoses with prescribed drugs, overuse of opioids has become a serious problem. At the same time, finding that fine balance between minimizing the risk of opioid misuse and abuse while at the same time providing access to treatment for patients who need pain control presents an ongoing challenge. Efforts to discover and develop better agents have led to what we term “new-look” opioids. We summarize here one such approach—known as biased ligands. By targeting a subset of GPCR signal transduction, this approach attempts to increase the separation between therapeutic and adverse effects.
文摘<span style="font-family:Verdana;"><strong>Introduction:</strong></span><span><span><span style="font-family:""><span style="font-family:Verdana;"> The inflammatory mechanisms of COVID-19 suggest that corticosteroids may be beneficial, but their benefits must outweigh their potential risks. The RECOVERY trial results suggest that dexamethasone 6 mg/day </span><span style="font-family:Verdana;">(but not other steroids) may confer mortality benefits on ventilated COVID-19 </span><span style="font-family:Verdana;">patients.</span></span></span></span><span><span><span style="font-family:""> </span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><b><span style="font-family:Verdana;">Methods:</span></b></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;"> This is a narrative review of the literature about the use of ciclesonide and dexamethasone for COVID-19 patients. Literature is being created rapidly and this review is offered as a state-of-the-science narration.</span></span></span><span><span><span style="font-family:""> </span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><b><span style="font-family:Verdana;">Results:</span></b></span></span><span><span><span style="font-family:""><span style="font-family:Verdana;"> The SARS-CoV-2 virus is an RNA virus whose RNA is transcribed via open reading frames, making its elimination difficult. Coronaviruses have evolved multiple strategies for proteolytic activation of the spike;viral replication occurs entirely in the cytoplasm. In this connection, the RNA-cleaving endoribonuclease (NSP-15 also known as EndoU) may play a key role by facilitating viral double-stranded RNA recognition by the host’s macrophages. </span><span style="font-family:Verdana;">Furthermore, the virus is able to undergo RNA recombination rapidly,</span><span style="font-family:Verdana;"> enabling it to evade host immunity and develop drug resistance. Ciclesonide is an inhaled corticosteroid that reduces lung inflammation and blocks the activity of specific kinases which may explain its anti-inflammatory effect. Dexamethasone is known to reduce mortality in ventilated COVID-19 patients.</span></span></span></span><span><span><span style="font-family:""> </span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><b><span style="font-family:Verdana;">Discussion:</span></b></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;"> Systemic corticosteroids were used in previous coronavirus epidemics (SARS and MERS) and pulmonary histology of these patients is similar to those in COVID-19 patients. Acute respiratory distress syndrome is the main cause of death in most COVID-19 infections and steroids may be effective in addressing that condition, brought on by cytokine storm. However, it should be noted that inhaled steroids likely have a narrower window for effect than systemic regimens.</span></span></span><span><span><span style="font-family:""> </span></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><b><span style="font-family:Verdana;">Conclusion:</span></b></span></span><span style="font-family:Verdana;"><span style="font-family:Verdana;"><span style="font-family:Verdana;"> Dexamethasone has been proven to confer mortality benefits on ventilated COVID-19 patients and may be used with inhaled ciclesonide, which has few side effects and can be locally metabolized. Further study is needed.</span></span></span>
文摘Lucemyra? (lofexidine hydrochloride) has recently been approved by the US FDA for the mitigation of withdrawal symptoms to facilitate abrupt discontinuation of opioids in adults. Lofexidine is an alpha-2 adrenoceptor agonist. However, the clinical attributes of lofexidine differ in advantageous ways from the classical alpha-2 adrenoceptor agonist clonidine. In the present study, we measured the receptor binding profile of lofexidine and clonidine in an effort to gain an insight into the clinical difference(s).
文摘The recent large increase in deaths involving opioids (whether prescription or illicit, pure or adulterated, alone or in combination with other drugs) is the manifestation of a complex, and multifaceted problem consisting of psychological, psychosocial, medical, legal, regulatory, economic, cultural, and political components, among others. Because the problem involves issues related to both supply and demand, the solution is not obvious, simple, or quick. There is no easy fix. Preventing and treating opioid misuse and abuse requires a comprehensive, time-intensive, and expensive intervention supported by public policy and support through coordinated medical, regulatory, legal, and financial guidelines and practice. But until the long-term problems can be fixed, the immediate crisis of overdose deaths can be ameliorated by making available an opioid receptor antagonist to reverse the respiratory depression that is the cause of death to those who are in the best position to administer it in time (professionals, untrained bystanders, and even fellow drug abusers). The statistics overwhelmingly demonstrate that this is a life-saving medical intervention. Yet, there is still uncertainty about this intervention, and even some opposition to it. We describe the scientific basis for the approach and the issues surrounding its use to treat accidental or intentional overdose by pain patients, recreational opioid users, and addicts. We also describe the calls to limit the number of times it should be available to a user and the limitations of its effectiveness—mainly that it only addresses the acute death crisis, not the underlying problems that led to it.
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Compliance to hand-hygiene guidelines in healthcare facilities remains disappointingly low for a variety of human-factors (HF) reasons. A device HF-engineered for convenient and effective use even under high-workload conditions could contribute to better compliance, and consequently to reduction in healthcare-acquired infections. We present an overview of the efficacy of a passive hand-spray device that uses solubilized ozone—a strong, safe, non-irritant biocide having broad-spectrum antimicrobial properties—on glass surface, pigskin, and synthetic human skin matrix.
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A healthcare-associated infection (defined as an infection acquired within a healthcare facility), such as due to transmission via medical equipment or by healthcare providers is the most frequent adverse event in the healthcare delivery system. But why does the problem persist, when infection control measures are known, simple, and low-cost? We reviewed some biological- and treatment-factors in Part 1, and we now review some human-factors. Healthcare-associated infections are a major public health problem even in advanced healthcare systems. They affect hundreds of millions of patients each year, and are responsible for increased morbidity, mortality, and financial burden. This is perplexing, since good-hygiene practices are known and promoted. Disinfection, sterilization, handwashing, and alcohol rubs should be more effective, but human-factors interfere. The persistent high prevalence of nosocomial infections, despite known hygienic practices, is attributable to two categories of factors: biological and inherent shortcomings of some practices (considered in Part 1), and human factors (considered here). A new approach is considered in Part 3.
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Benzodiazepines and related benzodiazepine-receptor agonists such as the pyrazolopyrimidinezalepl -on;?the imidazopyridine zolpidem;and the cyclopyrroloneszopiclone and eszopiclone, are among the most widely prescribed drugs, and for a variety of conditions. Surprisingly: 1) there are only a few conditions for which there is a good evidence basis, 2) efficacy has only been well demonstrated for short-term use (i.e., less than 4 weeks), and 3) much less is known about the basic science of these drugs than is widely believed. We suggest that the use of these drugs beyond four or less weeks exceeds the available knowledge base, so best-practice use suggests that the prescribing of these drugs for most patients should be limited to only short-term use until more is known about the basic pharmacology of their actions in the brain and in the periphery.
文摘In 2016 and 2017 an outbreak of the Zika virus</span><span style="font-family:""> </span><span style="font-family:Verdana;">in new locales shocked populations</span><span style="font-family:""> </span><span style="font-family:Verdana;">into awareness of the disease and of its imputed ability to cause serious fetal abnormalities, particularly microcephaly. There was a major reduction in travel by people of child-bearing age. But the temporary regression in </span><span style="font-family:Verdana;">the </span><span style="font-family:Verdana;">spread, and preoccupation with COVID-19, seem to have overshadowed concern about Zika virus. In order to investigate this phenomenon, we conducted an online survey of 157 high-school students from four schools in different parts of the United States regarding their knowledge, practices, and attitudes about Zika virus. The mean age of the respondents was 16.4 </span><span style="font-family:""><span style="font-family:Verdana;">±</span><span style="font-family:Verdana;"> 1.1 years, 55% were girls, and 60% attended public (rather than private) schools. Most students (70%) had taken no steps to prevent Zika, but said they would tell their parents or a physician if they were exposed. They relied primarily on school and the internet (76% and 72%, respectively) as trusted sources of information about the virus. The majority (73%) said they would spend some time to learn more about Zika;girls exhibited more concern than did boys. Half (50%) of respondents knew the signs and symptoms of Zika, but only 20% knew all the ways Zika could be transmitted and 31% why Zika prevention was crucial for pregnant women and their partners. The results of this study suggest that comprehensive national preventive healthcare educational programs are needed.