This book describes the theories, applications, and challenges for different oral controlled release formulations. This book differs from most in its focus on oral controlled release formulation ...design and process development. It also covers the related areas like preformulation, biopharmaceutics, in vitro-in vivo correlations (IVIVC), quality by design (QbD), and regulatory issues.
Agricultural fields are an important anthropogenic source of atmospheric nitrous oxide (N₂O) and nitric oxide (NO). Although many field studies have tested the effectiveness of possible mitigation ...options on N₂O and NO emissions, the effectiveness of each option varies across sites due to environmental factors and field management. To combine these results and evaluate the overall effectiveness of enhanced-efficiency fertilizers i.e., nitrification inhibitors (NIs), polymer-coated fertilizers (PCFs), and urease inhibitors (UIs) on N₂O and NO emissions, we performed a meta-analysis using field experiment data (113 datasets from 35 studies) published in peer-reviewed journals through 2008. The results indicated that NIs significantly reduced N₂O emissions (mean: -38%, 95% confidential interval: -44% to -31%) compared with those of conventional fertilizers. PCFs also significantly reduced N₂O emissions (-35%, -58% to -14%), whereas UIs were not effective in reducing N₂O. NIs and PCFs also significantly reduced NO (-46%, -65% to -35%; -40%, -76% to -10%, respectively). The effectiveness of NIs was relatively consistent across the various types of inhibitors and land uses. However, the effect of PCFs showed contrasting results across soil and land-use type: they were significantly effective for imperfectly drained Gleysol grassland (-77%, -88% to -58%), but were ineffective for well-drained Andosol upland fields. Because available data for PCFs were dominated by certain regions and soil types, additional data are needed to evaluate their effectiveness more reliably. NIs were effective in reducing N₂O emission from both chemical and organic fertilizers. Moreover, the consistent effect of NIs indicates that they are potent mitigation options for N₂O and NO emissions.
Recent advances in the pathophysiologic understanding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has indicated that patients with severe coronavirus disease 2019 ...(COVID-19) might experience cytokine release syndrome (CRS), characterized by increased interleukin (IL)-6, IL-2, IL-7, IL-10, etc. Therefore, the treatment of cytokine storm has been proposed as a critical part of rescuing severe COVID-19. Several of the cytokines involved in COVID-19 employ a distinct intracellular signaling pathway mediated by Janus kinases (JAKs). JAK inhibition, therefore, presents an attractive therapeutic strategy for CRS, which is a common cause of adverse clinical outcomes in COVID-19. Below, we review the possibilities and challenges of targeting the pathway in COVID-19.
Recent advances in the pathophysiologic understanding of COVID-19 infection have suggested a critical role of cytokine release syndrome (CRS) in severe COVID-19 patients.Several inflammatory cytokines that are involved in CRS and correlate with adverse clinical outcomes in COVID-19 employ a distinct intracellular signaling pathway mediated by Janus kinases (JAKs).JAK-STAT signaling may be an excellent therapeutic target for the development of much needed therapies for COVID-19.
A subset of patients with severe COVID-19 develop profound inflammation and multi-organ dysfunction consistent with a “Cytokine Storm Syndrome” (CSS). In this review we compare the clinical features, ...diagnosis, and pathogenesis of COVID-CSS with other hematological CSS, namely secondary hemophagocytic lymphohistiocytosis (sHLH), idiopathic multicentric Castleman disease (iMCD), and CAR-T cell therapy associated Cytokine Release Syndrome (CRS). Novel therapeutics targeting cytokines or inhibiting cell signaling pathways have now become the mainstay of treatment in these CSS. We review the evidence for cytokine blockade and attenuation in these known CSS as well as the emerging literature and clinical trials pertaining to COVID-CSS. Established markers of inflammation as well as cytokine levels are compared and contrasted between these four entities in order to establish a foundation for future diagnostic criteria of COVID-CSS.
With the exponential growth of the global population, the agricultural sector is bound to use ever larger quantities of fertilizers to augment the food supply, which consequently increases food ...production costs. Urea, when applied to crops is vulnerable to losses from volatilization and leaching. Current methods also reduce nitrogen use efficiency (NUE) by plants which limits crop yields and, moreover, contributes towards environmental pollution in terms of hazardous gaseous emissions and water eutrophication. An approach that offsets this pollution while also enhancing NUE is the use of controlled release urea (CRU) for which several methods and materials have been reported. The physical intromission of urea granules in an appropriate coating material is one such technique that produces controlled release coated urea (CRCU). The development of CRCU is a green technology that not only reduces nitrogen loss caused by volatilization and leaching, but also alters the kinetics of nitrogen release, which, in turn, provides nutrients to plants at a pace that is more compatible with their metabolic needs. This review covers the research quantum regarding the physical coating of original urea granules. Special emphasis is placed on the latest coating methods as well as release experiments and mechanisms with an integrated critical analyses followed by suggestions for future research.
Display omitted
RyR2 is a high-conductance intracellular calcium (Ca
) channel that controls the release of Ca
from the sarco(endo)plasmic reticulum of a variety of cells. Here, we report the structures of RyR2 from ...porcine heart in both the open and closed states at near-atomic resolutions determined using single-particle electron cryomicroscopy. Structural comparison reveals a breathing motion of the overall cytoplasmic region resulted from the interdomain movements of amino-terminal domains (NTDs), Helical domains, and Handle domains, whereas almost no intradomain shifts are observed in these armadillo repeats-containing domains. Outward rotations of the Central domains, which integrate the conformational changes of the cytoplasmic region, lead to the dilation of the cytoplasmic gate through coupled motions. Our structural and mutational characterizations provide important insights into the gating and disease mechanism of RyRs.
Tocilizumab, an IL-6 receptor antagonist, can be used to treat cytokine release syndrome (CRS), with observed improvements in a coronavirus disease 2019 (COVID-19) case series.
The goal of this study ...was to determine if tocilizumab benefits patients hospitalized with COVID-19.
This observational study of consecutive COVID-19 patients hospitalized between March 10, 2020, and March 31, 2020, and followed up through April 21, 2020, was conducted by chart review. Patients were treated with tocilizumab using an algorithm that targeted CRS. Survival and mechanical ventilation (MV) outcomes were reported for 14 days and stratified according to disease severity designated at admission (severe, ≥ 3 L supplemental oxygen to maintain oxygen saturation > 93%). For tocilizumab-treated patients, pre/post analyses of clinical response, biomarkers, and safety outcomes were assessed. Post hoc survival analyses were conducted for race/ethnicity.
Among the 239 patients, median age was 64 years; 36% and 19% were black and Hispanic, respectively. Hospital census increased exponentially, yet MV census did not. Severe disease was associated with lower survival (78% vs 93%; P < .001), greater proportion requiring MV (44% vs 5%; P < .001), and longer median MV days (5.5 vs 1.0; P = .003). Tocilizumab-treated patients (n = 153 64%) comprised 90% of those with severe disease; 44% of patients with nonsevere disease received tocilizumab for evolving CRS. Tocilizumab-treated patients with severe disease had higher admission levels of high-sensitivity C-reactive protein (120 vs 71 mg/L; P < .001) and received tocilizumab sooner (2 vs 3 days; P < .001), but their survival was similar to that of patients with nonsevere disease (83% vs 91%; P = .11). For tocilizumab-treated patients requiring MV, survival was 75% (95% CI, 64-89). Following tocilizumab treatment, few adverse events occurred, and oxygenation and inflammatory biomarkers (eg, high-sensitivity C-reactive protein, IL-6) improved; however, D-dimer and soluble IL-2 receptor (also termed CD25) levels increased significantly. Survival in black and Hispanic patients, after controlling for age, was significantly higher than in white patients (log-rank test, P = .002).
A treatment algorithm that included tocilizumab to target CRS may influence MV and survival outcomes. In tocilizumab-treated patients, oxygenation and inflammatory biomarkers improved, with higher than expected survival. Randomized trials must confirm these findings.
•SBA-15 and NH2/SBA-15 mesoporous were synthesized and modified with amino groups.•Curcumin was loaded onto mesoporous surfaces and pores by Adsorption method.•Method of loading with amino groups was ...influenced with curcumin release.•The results revealed curcumin bonding to the SBA-15 and NH2/SBA-15 Nano carriers.•NH2/SBA-15was found very active for loading and release of curcumin.
In this work, mesoporous silica SBA-15 was prepared and functionalized with amine groups (i.e., NH2) to form NH2/SBA-15. The curcumin (CUR) was encapsulated into the surface and pore of NH2/SBA-15 to create CUR@NH2/SBA-15 as an efficient carrier in drug delivery systems (DDSs). The three samples (i.e., SBA-15, NH2/SBA-15, and CUR@NH2/SBA-15) were characterized. The study investigated the effect of the carrier dose, initial CUR concentration, pH, and contact time on the CUR loading efficiency (DLE%) via adsorption. The best DLE% for the SBA-15 and NH2/SBA-15 were found to be 45% and 89.7%, respectively. The Langmuir isotherm had a greater correlation coefficient (R2) of 0.998 for SBA-15. A pseudo-second-order kinetic model seemed to fit well with R2 = 0.9998 for SBA-15 and R2 = 0.9993 for NH2/SBA-15. A phosphate buffer solution (PBS) with a pH of 7.4 was utilized to study the CUR release behavior. As a result, the full release after 72 h was found to have a maximum of 82.6% and 41.2% for SBA-15 and NH2/SBA-15, respectively. The first-order, Weibull, Hixson-Crowell, Korsmeyer-Peppas, and Higuchi kinetic release models were applied. The Weibull model estimated the kinetics of the CUR release from SBA-15 and NH2/SBA-15 with R2 = 0.814 and 0.808, respectively.
Display omitted .
Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To ...elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.
•COVID-19 severe outcomes is associated with the respiratory failure and cytokine release syndrome with elevated IL-6 as a predicting parameter.•Chronic inflammation, associated with elevated ...inflammatory serum cytokines, including IL-6, may exacerbate SARS-CoV-2 induced pathology.•IL-6 is a promising therapeutic target for the anti-cytokine therapy of SARS-CoV-2 severe cases.
COVID-19 mortality is strongly associated with the development of severe pneumonia and acute respiratory distress syndrome with the worst outcome resulting in cytokine release syndrome and multiorgan failure. It is becoming critically important to identify at the early stage of the infection those patients who are prone to develop the most adverse effects. Elevated systemic interleukin-6 levels in patients with COVID-19 are considered as a relevant parameter in predicting most severe course of disease and the need for intensive care. This review discusses the mechanisms by which IL-6 may possibly contribute to disease exacerbation and the potential of therapeutic approaches based on anti-IL-6 biologics.
PDF
