Sensitivity of Pharmacokinetics to Differences in the Particle Size Distribution for Formulations of Locally Acting Mometasone Furoate Suspension-Based Nasal Sprays.

To assess bioequivalence of locally acting suspension-based nasal sprays, the U.S. FDA currently recommends a weight-of-evidence approach. In addition to in vitro and human pharmacokinetic (PK) studies, this includes a comparative clinical endpoint study to ensure equivalent bioavailability of the active pharmaceutical ingredient (API) at the site of action. The present study aimed to assess, within an in vitro/in vivo correlation paradigm, whether PK studies and dissolution kinetics are sensitive to differences in drug particle size for a locally acting suspension-based nasal spray product. Two investigational suspension-based nasal formulations of mometasone furoate (MF-I and MF-II; delivered dose: 180 µg) differed in API particle size and were compared in a single-center, double-blind, single-dose, randomized, two-way crossover PK study in 44 healthy subjects with oral charcoal block. Morphology-directed Raman spectroscopy yielded volume median diameters of 3.17 µm for MF-I and 5.50 µm for MF-II, and dissolution studies showed that MF-II had a slower dissolution profile than MF-I. The formulation with larger API particles (MF-II) showed a 45% smaller Cmax and 45% smaller AUC0-inf compared to those of MF-I. Systemic bioavailability of MF-I (2.20%) and MF-II (1.18%) correlated well with the dissolution kinetics, with the faster dissolving formulation yielding the higher bioavailability. This agreement between pharmacokinetics and dissolution kinetics cross-validated both methods and supported their use in assessing potential differences in slowly dissolving suspension-based nasal spray products.

Characteristics and outcomes of patients with sepsis who had cortisol level measurements or received hydrocortisone during their intensive care unit management: A retrospective single center study.

Objectives: The current guidelines for managing patients with sepsis include the early cultures, administration of antibiotics, and fluid resuscitation. Several clinical trials have tried to determine whether or not the administration of corticosteroids improves outcomes in these patients. This study analyzed the characteristics of a large group of critically ill patients who either had cortisol levels drawn during their intensive care unit management or had hydrocortisone administered during their management. Methods: A list of patients who had cortisol levels measured or who had hydrocortisone administered empirically for the treatment of sepsis was identified by the medical record department at University Medical Center in Lubbock, Texas. The primary outcome was in-hospital mortality. Secondary outcomes included the need for mechanical ventilation, the need for renal replacement therapy, the need for vasopressors, length of stay, and the development of nosocomial infections. Results: This study included 351 patients, including 194 women (55.3%). The mean age was 62.9 ± 16.1 years. The mean admission SOFA score was 9.3 ± 3.63, the mean APACHE 2 score was 18.15 ± 7.7, and the mean lactic acid level was 3.8 ± 4.0 mmol/L. One hundred sixty-two patients required intubation, 262 required vasopressors, 215 developed acute kidney injury, and 319 had cortisol levels measured. The mean length of stay was 11.5 ± 13.7 days; the mortality rate was 32.2%. Multiple variable analysis demonstrated that higher cortisol levels were associated with increased mortality (44.1% if cortisol ⩾20 µg/dL versus 17.5% if cortisol <20 µg/dL). One hundred forty-five patients received corticosteroids, and multivariable analysis demonstrated that these patients had increased mortality (40.0% versus 26.7%). Conclusion: In this study, higher cortisol levels were associated with increased mortality. The administration of hydrocortisone was associated with increased mortality possibly reflecting the use of this medication in patients who had a higher likelihood of poor outcomes.

Can Pharmacokinetic Studies Assess the Pulmonary Fate of Dry Powder Inhaler Formulations of Fluticasone Propionate?

In the context of streamlining generic approval, this study assessed whether pharmacokinetics (PK) could elucidate the pulmonary fate of orally inhaled drug products (OIDPs). Three fluticasone propionate (FP) dry powder inhaler (DPI) formulations (A-4.5, B-3.8, and C-3.7), differing only in type and composition of lactose fines, exhibited median mass aerodynamic diameter (MMAD) of 4.5 µm (A-4.5), 3.8 µm (B-3.8), and 3.7 µm (C-3.7) and varied in dissolution rates (A-4.5 slower than B-3.8 and C-3.7). In vitro total lung dose (TLDin vitro) was determined as the average dose passing through three anatomical mouth-throat (MT) models and yielded dose normalization factors (DNF) for each DPI formulation X (DNFx = TLDin vitro,x/TLDin vitro,A-4.5). The DNF was 1.00 for A-4.5, 1.32 for B-3.8, and 1.21 for C-3.7. Systemic PK after inhalation of 500 µg FP was assessed in a randomized, double-blind, four-way crossover study in 24 healthy volunteers. Peak concentrations (Cmax) of A-4.5 relative to those of B-3.8 or C-3.7 lacked bioequivalence without or with dose normalization. The area under the curve (AUC0-Inf) was bio-IN-equivalent before dose normalization and bioequivalent after dose normalization. Thus, PK could detect differences in pulmonary available dose (AUC0-Inf) and residence time (dose-normalized Cmax). The differences in dose-normalized Cmax could not be explained by differences in in vitro dissolution. This might suggest that Cmax differences may indicate differences in regional lung deposition. Overall this study supports the use of PK studies to provide relevant information on the pulmonary performance characteristics (i.e., available dose, residence time, and regional lung deposition).

Maternal and perinatal outcomes related to COVID-19 and pregnancy: An overview of systematic reviews.

INTRODUCTION: Evidence about coronavirus disease 2019 (COVID-19) and pregnancy has rapidly increased since December 2019, making it difficult to make rigorous evidence-based decisions. The objective of this overview of systematic reviews is to conduct a comprehensive analysis of the current evidence on prognosis of COVID-19 in pregnant women. MATERIAL AND METHODS: We used the Living OVerview of Evidence (L·OVE) platform for COVID-19, which continually retrieves studies from 46 data sources (including PubMed/MEDLINE, Embase, other electronic databases, clinical trials registries, and preprint repositories, among other sources relevant to COVID-19), mapping them into PICO (population, intervention, control, and outcomes) questions. The search covered the period from the inception date of each database to 13 September 2020. We included systematic reviews assessing outcomes of pregnant women with COVID-19 and/or their newborns. Two authors independently screened the titles and abstracts, assessed full texts to select the studies that met the inclusion criteria, extracted data, and appraised the risk of bias of each included systematic review. We measured the overlap of primary studies included among the selected systematic reviews by building a matrix of evidence, calculating the corrected covered area, and assessing the level of overlap for every pair of systematic reviews. RESULTS: Our search yielded 1132 references. 52 systematic reviews met inclusion criteria and were included in this overview. Only one review had a low risk of bias, three had an unclear risk of bias, and 48 had a high risk of bias. Most of the included reviews were highly overlapped among each other. In the included reviews, rates of maternal death varied from 0% to 11.1%, admission to intensive care from 2.1% to 28.5%, preterm deliveries before 37 weeks from 14.3% to 61.2%, and cesarean delivery from 48.3% to 100%. Regarding neonatal outcomes, neonatal death varied from 0% to 11.7% and the estimated infection status of the newborn varied between 0% and 11.5%. CONCLUSIONS: Only one of 52 systematic reviews had a low risk of bias. Results were heterogeneous and the overlap of primary studies was frequently very high between pairs of systematic reviews. High-quality evidence syntheses of comparative studies are needed to guide future clinical decisions.

Living systematic review: new inputs and challenges. / La revisión sistemática viva: nuevos aportes y desafíos.

This is the second article from a collaborative methodological series of biostatistics and clinical epidemiology narrative reviews. This review aims to describe living systematic reviews relevance, the considerations that should be taken when producing one, and the challenges proper of this type of review. The living systematic review is a continuous update that maintains a systematic reviews rigor and methodological quality. The living format is appropriate when the review aims to answer a priority question in terms of health decision-making, the existent certainty of the evidence for this question is low or very low, and new evidence will likely appear soon. To carry out a successful living systematic review, researchers should consider different things, such as: having a continuous and automated search, having update criteria, evaluating how to update the meta-analysis and how to perform the editorial process, and publishing in a friendly format, among others. As living systematic reviews are a new proposal, they will likely change in the future to improve their performance, so we will have to keep an eye on its future updates.

Este artículo es el segundo de una serie metodológica colaborativa de revisiones narrativas sobre temáticas de bioestadística y epidemiología clínica. El objetivo de este trabajo es describir la pertinencia, las consideraciones y los desafíos de las revisiones sistemáticas vivas. La revisión sistemática viva es una propuesta de actualización continua, que conserva el rigor y la calidad metodológica de una revisión sistemática. El modelo vivo es adecuado cuando la revisión busca responder una pregunta prioritaria para la toma de decisiones en salud, la certeza de la evidencia para esa pregunta es baja y es muy probable que surja nueva evidencia al respecto. Para que una revisión sistemática viva sea exitosa debe considerar varios aspectos, por ejemplo: que la búsqueda sea continua y automatizada, que existan criterios de actualización de la revisión, que se evalúe cómo se llevará a cabo la actualización del metanálisis y cómo será el proceso editorial, y que la publicación se amigable, entre otras. Al ser una propuesta relativamente nueva deberá enfrentar múltiples cambios que permitan su mejor funcionamiento, por lo que debemos estar atentos a estos cambios venideros.

La revisión sistemática viva: nuevos aportes y desafíos / Living systematic review: new inputs and challenges

Este artículo es el segundo de una serie metodológica colaborativa de revisiones narrativas sobre temáticas de bioestadística y epidemiología clínica. El objetivo de este trabajo es describir la pertinencia, las consideraciones y los desafíos de las revisiones sistemáticas vivas. La revisión sistemática viva es una propuesta de actualización continua, que conserva el rigor y la calidad metodológica de una revisión sistemática. El modelo vivo es adecuado cuando la revisión busca responder una pregunta prioritaria para la toma de decisiones en salud, la certeza de la evidencia para esa pregunta es baja y es muy probable que surja nueva evidencia al respecto. Para que una revisión sistemática viva sea exitosa debe considerar varios aspectos, por ejemplo: que la búsqueda sea continua y automatizada, que existan criterios de actualización de la revisión, que se evalúe cómo se llevará a cabo la actualización del metanálisis y cómo será el proceso editorial, y que la publicación se amigable, entre otras. Al ser una propuesta relativamente nueva deberá enfrentar múltiples cambios que permitan su mejor funcionamiento, por lo que debemos estar atentos a estos cambios venideros.

This is the second article from a collaborative methodological series of biostatistics and clinical epidemiology narrative reviews. This review aims to describe living systematic reviews' relevance, the considerations that should be taken when producing one, and the challenges proper of this type of review. The living systematic review is a continuous update that maintains a systematic review's rigor and methodological quality. The living format is appropriate when the review aims to answer a priority question in terms of health decision-making, the existent certainty of the evidence for this question is low or very low, and new evidence will likely appear soon. To carry out a successful living systematic review, researchers should consider different things, such as: having a continuous and automated search, having update criteria, evaluating how to update the meta-analysis and how to perform the editorial process, and publishing in a friendly format, among others. As living systematic reviews are a new proposal, they will likely change in the future to improve their performance, so we will have to keep an eye on its future updates.