Ionic liquids for oral insulin delivery Banerjee, Amrita; Ibsen, Kelly; Brown, Tyler ...
Proceedings of the National Academy of Sciences,
07/2018, Volume:
115, Issue:
28
Journal Article
Peer reviewed
Open access
With the rise in diabetes mellitus cases worldwide and lack of patient adherence to glycemia management using injectable insulin, there is an urgent need for the development of efficient oral insulin ...formulations. However, the gastrointestinal tract presents a formidable barrier to oral delivery of biologics. Here we report the development of a highly effective oral insulin formulation using choline and geranate (CAGE) ionic liquid. CAGE significantly enhanced paracellular transport of insulin, while protecting it from enzymatic degradation and by interacting with the mucus layer resulting in its thinning. In vivo, insulin-CAGE demonstrated exceptional pharmacokinetic and pharmacodynamic outcome after jejunal administration in rats. Low insulin doses (3–10 U/kg) brought about a significant decrease in blood glucose levels, which were sustained for longer periods (up to 12 hours), unlike s.c. injected insulin. When 10 U/kg insulin-CAGE was orally delivered in enterically coated capsules using an oral gavage, a sustained decrease in blood glucose of up to 45% was observed. The formulation exhibited high biocompatibility and was stable for 2 months at room temperature and for at least 4 months under refrigeration. Taken together, the results indicate that CAGE is a promising oral delivery vehicle and should be further explored for oral delivery of insulin and other biologics that are currently marketed as injectables.
Abstract
Mortality from coronavirus disease 2019 (COVID-19) is strongly associated with cardiovascular disease, diabetes, and hypertension. These disorders share underlying pathophysiology related to ...the renin-angiotensin system (RAS) that may be clinically insightful. In particular, activity of the angiotensin-converting enzyme 2 (ACE2) is dysregulated in cardiovascular disease, and this enzyme is used by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to initiate the infection. Cardiovascular disease and pharmacologic RAS inhibition both increase ACE2 levels, which may increase the virulence of SARS-CoV-2 within the lung and heart. Conversely, mechanistic evidence from related coronaviruses suggests that SARS-CoV-2 infection may downregulate ACE2, leading to toxic overaccumulation of angiotensin II that induces acute respiratory distress syndrome and fulminant myocarditis. RAS inhibition could mitigate this effect. With conflicting mechanistic evidence, we propose key clinical research priorities necessary to clarify the role of RAS inhibition in COVID-19 mortality that could be rapidly addressed by the international research community.
The association between coronavirus disease 2019 (COVID-19) mortality and cardiovascular disease is likely mediated by dysregulation of the renin-angiotensin system (RAS). Pharmacoepidemiologic studies are needed to clarify whether RAS inhibition mediates this association and is helpful or harmful.
The coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 that has significant implications for the cardiovascular care of patients. ...First, those with COVID-19 and pre-existing cardiovascular disease have an increased risk of severe disease and death. Second, infection has been associated with multiple direct and indirect cardiovascular complications including acute myocardial injury, myocarditis, arrhythmias, and venous thromboembolism. Third, therapies under investigation for COVID-19 may have cardiovascular side effects. Fourth, the response to COVID-19 can compromise the rapid triage of non-COVID-19 patients with cardiovascular conditions. Finally, the provision of cardiovascular care may place health care workers in a position of vulnerability as they become hosts or vectors of virus transmission. We hereby review the peer-reviewed and pre-print reports pertaining to cardiovascular considerations related to COVID-19 and highlight gaps in knowledge that require further study pertinent to patients, health care workers, and health systems.
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•Patients with pre-existing CVD appear to have worse outcomes with COVID-19.•CV complications include biomarker elevations, myocarditis, heart failure, and venous thromboembolism, which may be exacerbated by delays in care.•Therapies under investigation for COVID-19 may have significant drug-drug interactions with CV medications.•Health care workers and health systems should take measures to ensure safety while providing high-quality care for COVID-19 patients.
The delivery of therapeutics to the brain in an efficient, noninvasive manner continues to be a major unmet need in the field of drug delivery. One significant impediment to brain delivery results ...from the existence of the physical yet dynamic blood-brain barrier (BBB). Despite the many, often complex strategies that currently exist to breach the BBB, adequate delivery of effective therapeutics from the bloodstream continues to remain quite low. Nanotechnology has emerged as a promising tool for brain delivery, but little is known about the important particle parameters that influence delivery. Here, we synthesized and characterized a library of nanoparticles with distinct properties ranging from size, shape, stiffness, and composition to investigate and identify the key attributes influencing particle uptake and transport for brain delivery. To accomplish this task, an
human BBB model was developed and validated using human cerebral microvascular endothelial cells (hCMEC/D3). Particle uptake and apparent permeability coefficients (
) were then determined for each particle group. To elucidate the roles of different parameters on particle uptake and transport across the BBB, the predominant mechanisms of endocytosis were also investigated. Our results show that particle composition yielded the greatest impact on penetration across the BBB model. This work lays the foundation and provides new insights into the role of particle parameters on penetration across the BBB.
Abstract
Student debt in the United States is at historically high levels and poses an excessive burden on medical graduates. Studies suggest that financial limitations dissuade some medical trainees ...from pursuing careers in infectious diseases (ID) and other cognitive specialties, despite their interest in the subject matter. Addressing student debt may have a transformative impact on ID recruitment, diversification of the ID workforce, and contributions of ID physicians to underserved public health needs. Relief of student debt also has the potential to narrow the racial wealth gap because nonwhite students are more likely to finance their postsecondary education, including medical school, with student loans, yet they have a lower earning potential following graduation. An executive order from the Biden-Harris administration announced in August 2022 presents a first step toward student debt relief, but the policy would need to be expanded in volume and scope to effectively achieve these goals.
Addressing medical student debt is important for infectious diseases recruitment, workforce diversification, physician well-being, and addressing underserved healthcare needs. While a recently announced executive order is unlikely to have substantial impact, it is a promising step in the right direction.
Nanoparticle‐based therapeutic formulations are being increasingly explored for the treatment of various ailments. Despite numerous advances, the success of nanoparticle‐based technologies in ...treating brain diseases has been limited. Translational hurdles of nanoparticle therapies are attributed primarily to their limited ability to cross the blood–brain barrier (BBB), which is one of the body's most exclusive barriers. Several efforts have been focused on developing affinity‐based agents and using them to increase nanoparticle accumulation at the brain endothelium. Very little is known about the role of fundamental physical parameters of nanoparticles such as size, shape, and flexibility in determining their interactions with and penetration across the BBB. Using a three‐dimensional human BBB microfluidic model (μHuB), we investigate the impact of these physical parameters on nanoparticle penetration across the BBB. To gain insights into the dependence of transport on nanoparticle properties, two separate parameters were measured: the number of nanoparticles that fully cross the BBB and the number that remain associated with the endothelium. Association of nanoparticles with the brain endothelium was substantially impacted by their physical characteristics. Hard particles associate more with the endothelium compared to soft particles, as do small particles compared to large particles, and spherical particles compared to rod‐shaped particles. Transport across the BBB also exhibited a dependence on nanoparticle properties. A nonmonotonic dependence on size was observed, where 200 nm particles exhibited higher BBB transport compared to 100 and 500 nm spheres. Rod‐shaped particles exhibited higher BBB transport when normalized by endothelial association and soft particles exhibited comparable transport to hard particles when normalized by endothelial association. Tuning nanoparticles' physical parameters could potentially enhance their ability to cross the BBB for therapeutic applications.
Universal Masking in Health Care Settings Brown, Tyler S; Mohareb, Amir M; LaRocque, Regina C
Annals of internal medicine,
12/2023, Volume:
176, Issue:
12
Journal Article
The global space industry is growing rapidly, with an increasing number of annual rocket launches. Gases and particulates are emitted by rockets directly into the middle and upper atmosphere, where ...the protective ozone layer resides. These emissions have been shown to damage ozone - highlighting the need for proper management of the upper atmosphere environment. We summarise the emission byproducts from rocket launches and discuss their involvement in chemical and radiative processes in the stratosphere, along with potential implications for the ozone layer due to an anticipated increase in rocket launch emissions in the future. We then present a potential vision for sustainable launches, including tractable pathways for both the aerospace industry and the ozone research community. We canvass international and domestic environmental regulation to consider how existing frameworks might be applied to rocket launches. We further identify gaps in aerospace industry practice where cooperation with environmental management and atmospheric science fields could lead to best-practise outcomes.
The current study proposes an extension of theory and research on the effect of status threat specific to heterosexual men’s anti-gay slurs usage. Drawing on both the Precarious Manhood Thesis and ...the Coalitional Value Theory, the current study investigates whether masculine personality traits moderate the association between status threat and men’s readiness to use anti-gay slurs. A sample of heterosexual male university students (
N
= 139) was recruited from two English-speaking universities in Montreal, Quebec, and Houston, Texas. Participants completed questionnaires and randomly received either status threatening or status confirming feedback. Next, after reading vignettes describing heterosexual men behaving in ways that might jeopardize their status, participants reported their estimated probability of calling the target character a “fag” or “faggot.” Findings revealed a significant interaction effect. That is, only among participants high in masculine personality traits, those in the threat condition indicated significantly greater readiness to use anti-gay slurs relative to those in the status affirmation group. These findings contribute to a more comprehensive understanding of men’s anti-gay slur usage grounded in a status striving motive paired with distinct personality features. Future research directions are discussed.
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