Short Review of Ischemia- and Hypoxia-Protective Roles of “Big Potassium” (BK) Channels

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 (β1-4 and γ1-4), bestows localized differences in subunit composition, distribution, 2nd-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.

Ciclesonide Use in COVID-19: Not All Steroids Are the Same

Introduction: 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 (but not other steroids) may confer mortality benefits on ventilated COVID-19 patients. Methods: 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. Results: 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. Furthermore, the virus is able to undergo RNA recombination rapidly, 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. Discussion: 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. Conclusion: 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.

Survey of Students Regarding Zika Infection: Is the Next Generation Aware of the Dangers?

In 2016 and 2017 an outbreak of the Zika virus in new locales shocked populations 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 the 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 ± 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.

The First Approved “Deuterated” Drug: A Short Review of the Concept

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.

The Place of Community Rescue Naloxone in a Public Health Crisis of Opioid Overdose

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.

“New-Look” Opioids: Biased Ligands

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.

Differences in the Receptor Binding Profile of Lofexidine Compared to Clonidine

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).

<i>Commentary</i>: Benzodiazepine (BZD) and Related BZD-Receptor Agonists: Basic Science Reasons to Limit to Four Weeks or Less

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.

Persistence of Healthcare-Associated (Nosocomial) Infections Due to Inadequate Hand Hygiene: Part 3—Application of Human Factors Engineering to an Ozone Hand Sanitizer

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.

Persistence of Healthcare-Associated (Nosocomial) Infections Due to Inadequate Hand Hygiene: Part 1—Biological and Treatment Factors

The most frequent adverse event in the healthcare delivery system is acquisition of an infection within a healthcare facility. Since infection control measures are known, simple, and low-cost, we examine why the problem of healthcare-associated infections persists. Hundreds of millions of patients each year are affected by a healthcare-associated infection, with negative medical outcome and financial cost. It is a major public health problem even in countries with advanced healthcare systems. This is a bit perplexing, given that hygienic practices have been known and actively promoted. The objective is to address the question: doesn’t the use of disinfection, sterilization, handwashing, and alcohol rubs prevent the spread of pathogenic organisms? We conclude that 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 in Part 2). A new approach is presented in Part 3.

Persistence of Healthcare-Associated (Nosocomial) Infections Due to Inadequate Hand Hygiene: Part 2—Human Factors

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.