The effect of temperature and breathing pattern on the surface activity of ground squirrel pulmonary surfactant.

This study investigates how hibernation affects the surface activity of pulmonary surfactant with respect to temperature and breathing pattern. Surfactant was isolated from a hibernating species, the 13-lined ground squirrel, and a homeotherm, the rabbit, and analysed for biophysical properties on a constrained sessile drop surfactometer. The results showed that surfactant from ground squirrels reduced surface tension better at low temperatures, including when mimicking episodic breathing, as compared with rabbit surfactant.

Science- and Risk-Based Stability Strategies to Support Product Lifecycle Changes.

ICH Q12 asserts that science- and risk-based approaches are applicable to stability studies supporting Chemistry, Manufacturing and Controls (CMC) post-approval changes (PAC) to enable more timely implementation; however, no guidance or specific examples are provided to demonstrate how prior knowledge of the product can inform the risk assessment for the proposed change(s). Ten diverse case studies are presented in this manuscript to demonstrate how science- and risk-based stability strategies were used to support drug substance and product CMC PAC and lifecycle management activities. The accumulated stability knowledge held by original manufacturers of marketed products is substantial, and different elements of this knowledge base were used to assess the risks and impact of the proposed changes for confident change management.

A technique for repeated blood and cerebrospinal fluid sampling from individual rats over time without the need for repeated anesthesia.

Ethical animal use follows the 3R's: Replacement, Reduction and Refinement. Here, we present the use of simultaneous jugular vein and cisterna magna catheterization via a port system in rats for repeated fluid sampling for 14 consecutive days without loss of catheter patency. This technique allows repeated intra-animal sampling without anesthesia and, if used with pooling samples from a cohort of animals, replaces the need for terminal collections for sufficient sample volumes.

Industry Perspective on Temperature Cycling Studies to Meet Regulatory Temperature Excursion Support Requirements: Survey Outcome and Recommendations.

Temperature cycling stability studies can be appropriately designed and utilized to ensure that drug product quality, efficacy, and safety are not compromised when materials are subjected to short term temperature excursions from intended storage that may occur during e.g., shipping, transport, or patient use.

E-cigarette aerosol exposure of pulmonary surfactant impairs its surface tension reducing function.

Introduction: E-cigarette (EC) and vaping use continue to remain popular amongst teenage and young adult populations, despite several reports of vaping associated lung injury. One of the first compounds that EC aerosols comes into contact within the lungs during a deep inhalation is pulmonary surfactant. Impairment of surfactant's critical surface tension reducing activity can contribute to lung dysfunction.

Alveolar epithelial glycocalyx degradation mediates surfactant dysfunction and contributes to acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure yet has few pharmacologic therapies, reflecting the mechanistic heterogeneity of lung injury. We hypothesized that damage to the alveolar epithelial glycocalyx, a layer of glycosaminoglycans interposed between the epithelium and surfactant, contributes to lung injury in patients with ARDS. Using mass spectrometry of airspace fluid noninvasively collected from mechanically ventilated patients, we found that airspace glycosaminoglycan shedding (an index of glycocalyx degradation) occurred predominantly in patients with direct lung injury and was associated with duration of mechanical ventilation.

Meeting Report: Vaccine Stability Considerations to Enable Rapid Development and Deployment.

The Stability Community of the American Association of Pharmaceutical Scientists (AAPS) held a virtual workshop on "Vaccine Stability Considerations to Enable Rapid Development and Deployment", on March 24-25, 2021. The workshop included distinguished speakers and panelists from across the industry, academia, regulatory agencies, as well as health care leaders. This paper presents a review of the topics covered.

Considerations for Updates to ICH Q1 and Q5C Stability Guidelines: Embracing Current Technology and Risk Assessment Strategies.

In consideration of the recent ICH Quality Discussion Group (QDG) recommended revision to the ICH series of stability guidelines, the IQ Consortium (International Consortium for Innovation and Quality in Pharmaceutical Development) Science- and Risk-based Stability Working Group conducted a comprehensive review of ICH Q1A, Q1B, Q1C, Q1D, Q1E, and Q5C to identify areas where the guidelines could be clarified, updated, and amended to reflect the potential knowledge gained from current risk-based predictive stability tools and to consider other science- and risk-based stability strategies in accordance with ICH Q8-12. The recommendations propose a holistic approach to stability understanding, utilizing historical data, prior knowledge, modeling, and a risk assessment process to expand the concept of what could be included (or would be acceptable) in the core stability data package, including type and amount of stability evidence, assignment of retest period and shelf-life for a new product, and assessment of the impact of post-approval changes.

The impact of maternal protein restriction during perinatal life on the response to a septic insult in adult rats.

Although abundant evidence exists that adverse events during pregnancy lead to chronic conditions, there is limited information on the impact of acute insults such as sepsis. This study tested the hypothesis that impaired fetal development leads to altered organ responses to a septic insult in both male and female adult offspring. Fetal growth restricted (FGR) rats were generated using a maternal protein-restricted diet.

Exogenous Surfactant as a Pulmonary Delivery Vehicle for Budesonide In Vivo.

Background: Lung inflammation is associated with many respiratory conditions. Consequently, anti-inflammatory medications, like glucocorticoids, have become mainstay intrapulmonary therapeutics. However, their effectiveness for treating inflammation occurring in the alveolar regions of the lung is limited by suboptimal delivery.

The effect of maternal protein restriction during perinatal life on the inflammatory response in pediatric rats.

Fetal growth restriction can affect health outcomes in postnatal life. This study tested the hypothesis that the response to an inflammatory pulmonary insult is altered in pediatric fetal growth restricted rats. Using a low-protein diet during gestation and postnatal life, growth-restricted male and female rats and healthy control rats were exposed to an inflammatory insult via the intratracheal instillation of heat-killed bacteria.

Protective effects of aerosolized pulmonary surfactant powder in a model of ventilator-induced lung injury.

Mechanical ventilation may contribute to the impairment of the pulmonary surfactant system, which is one of the mechanisms leading to the progression of acute lung injury. To investigate the potential protective effects of pulmonary surfactant in a rat model of ventilator-induced lung injury, the surfactant powder was aerosolized using an in-house made device designed to deliver the aerosolized powder to the inspiratory line of a rodent ventilator circuit. Rats were randomized to (i) administration of aerosolized recombinant surfactant protein C based pulmonary surfactant, (ii) intratracheally instillation of the same surfactant re-constituted in saline, and (iii) no treatment.

The effects of aging and exercise on lung mechanics, surfactant and alveolar macrophages.

Advancing age leads to changes to the respiratory system associated with increased susceptibility to lung diseases, and exercise may counteract this effect. To explore the underlying processes, we investigated the effects of aging and exercise on lung mechanics, alveolar macrophage function, and surfactant pools and activity, in mice. It was hypothesized that aging would impact lung mechanics, macrophage polarization, and the status of the surfactant system, and that these changes would be mitigated by exercise.

Maternal protein restriction during perinatal life affects lung mechanics and the surfactant system during early postnatal life in female rats.

Limited information is available on how fetal growth retardation (FGR) affects the lung in the neonatal period in males and females. This led us to test the hypothesis that FGR alters lung mechanics and the surfactant system during the neonatal period. To test this hypothesis a model of FGR was utilized in which pregnant rat dams were fed a low protein diet during both the gestation and lactation period.

Mental Health-related Physician Office Visits by Adults Aged 18 and Over: United States, 2012-2014.

In 2016, mental illness affected about 45 million U.S. adults (1).

Effective in vivo treatment of acute lung injury with helical, amphipathic peptoid mimics of pulmonary surfactant proteins.

Acute lung injury (ALI) leads to progressive loss of breathing capacity and hypoxemia, as well as pulmonary surfactant dysfunction. ALI's pathogenesis and management are complex, and it is a significant cause of morbidity and mortality worldwide. Exogenous surfactant therapy, even for research purposes, is impractical for adults because of the high cost of current surfactant preparations.

The effect of diet-induced serum hypercholesterolemia on the surfactant system and the development of lung injury.

Acute respiratory distress syndrome (ARDS) is a pulmonary disorder associated with alterations to the pulmonary surfactant system. Recent studies showed that supra-physiological levels of cholesterol in surfactant contribute to impaired function. Since cholesterol is incorporated into surfactant within the alveolar type II cells which derives its cholesterol from serum, it was hypothesized that serum hypercholesterolemia would predispose the host to the development of lung injury due to alterations of cholesterol content in the surfactant system.

Impact of ventilation-induced lung injury on the structure and function of lamellar bodies.

Alterations to the pulmonary surfactant system have been observed consistently in ventilation-induced lung injury (VILI) including composition changes and impairments in the surface tension reducing ability of the isolated extracellular surfactant. However, there is limited information about the effects of VILI on the intracellular form of surfactant, the lamellar body. It is hypothesized that VILI leads to alterations of lamellar body numbers and function.

Emergency Department Visits for Injury and Illness Among Adults Aged 65 and Over: United States, 2012-2013.

Data from the National Hospital Ambulatory Medical Care Survey ● During 2012-2013, adults aged 65 and over had an emergency department (ED) visit rate of 12 per 100 persons for injury and 36 per 100 persons for illness. ● Among adults aged 65 and over, women had a higher ED visit rate for injury (14 per 100 women) compared with men (10 per 100 men).There was no difference between women and men in the visit rate for illness.

A respiratory-gated micro-CT comparison of respiratory patterns in free-breathing and mechanically ventilated rats.

In this study, we aim to quantify the differences in lung metrics measured in free-breathing and mechanically ventilated rodents using respiratory-gated micro-computed tomography. Healthy male Sprague-Dawley rats were anesthetized with ketamine/xylazine and scanned with a retrospective respiratory gating protocol on a GE Locus Ultra micro-CT scanner. Each animal was scanned while free-breathing, then intubated and mechanically ventilated (MV) and rescanned with a standard ventilation protocol (56 bpm, 8 mL/kg and PEEP of 5 cm HO) and again with a ventilation protocol that approximates the free-breathing parameters (88 bpm, 2.

Lack of matrix metalloproteinase 3 in mouse models of lung injury ameliorates the pulmonary inflammatory response in female but not in male mice.

Background: The acute respiratory distress syndrome (ARDS) is a complex pulmonary disorder in which the local release of cytokines and chemokines appears central to the pathophysiology.

Objective: Based on the known role of matrix metalloproteinase-3 (MMP3) in inflammatory processes, the objective was to examine the role of MMP3 in the pathogenesis of ARDS through the modulation of pulmonary inflammation.

Materials And Methods: Female and male, wild type (MMP3) and knock out (MMP3) mice were exposed to two, clinically relevant models of ARDS including (i) lipopolysaccharide (LPS)-induced lung injury, and (ii) hydrochloric acid-induced lung injury.

The effect of matrix metalloproteinase-3 deficiency on pulmonary surfactant in a mouse model of acute lung injury.

The acute respiratory distress syndrome (ARDS) is characterized by arterial hypoxemia accompanied by severe inflammation and alterations to the pulmonary surfactant system. Published data has demonstrated a protective effect of matrix metalloproteinase-3 (Mmp3) deficiency against the inflammatory response associated with ARDS; however, the effect of Mmp3 on physiologic parameters and alterations to surfactant have not been previously studied. It was hypothesized that Mmp3 deficient (Mmp3(-/-)) mice would be protected against lung dysfunction associated with ARDS and maintain a functional pulmonary surfactant system.

Toward a More Complete Picture of Outpatient, Office-Based Health Care in the U.S.

The healthcare system in the U.S., particularly outpatient, office-based care, has been shifting toward service delivery by advanced practice providers, particularly nurse practitioners (NPs) and physician assistants (PAs).

Emergency Department Visits Related to Schizophrenia Among Adults Aged 18-64: United States, 2009-2011.

ED care is important for the treatment of acute presentations of schizophrenia and may serve as a safety net for schizophrenic patients not otherwise receiving care (4,5). This analysis of National Hospital Ambulatory Medical Care Survey (NHAMCS) data indicates that during 2009-2011, an average of 382,000 ED visits related to schizophrenia occurred each year among adults aged 18-64, corresponding to an overall visit rate of 20.1 per 10,000 adults.