Formulation Pre-screening of Inhalation Powders Using Computational Atom–Atom Systematic Search Method

The synthonic modeling approach provides a molecule-centered understanding of the surface properties of crystals. It has been applied extensively to understand crystallization processes. This study aimed to investigate the functional relevance of synthonic modeling to the formulation of inhalation powders by assessing cohesivity of three active pharmaceutical ingredients (APIs, fluticasone propionate (FP), budesonide (Bud), and salbutamol base (SB)) and the commonly used excipient, α-lactose monohydrate (LMH). It is found that FP (−11.5 kcal/mol) has a higher cohesive strength than Bud (−9.9 kcal/mol) or SB (−7.8 kcal/mol). The prediction correlated directly to cohesive strength measurements using laser diffraction, where the airflow pressure required for complete dispersion (CPP) was 3.5, 2.0, and 1.0 bar for FP, Bud, and SB, respectively. The highest cohesive strength was predicted for LMH (−15.9 kcal/mol), which did not correlate with the CPP value of 2.0 bar (i.e., ranking lower than FP). High FP–LMH adhesive forces (−11.7 kcal/mol) were predicted. However, aerosolization studies revealed that the FP–LMH blends consisted of agglomerated FP particles with a large median diameter (∼4–5 μm) that were not disrupted by LMH. Modeling of the crystal and surface chemistry of LMH identified high electrostatic and H-bond components of its cohesive energy due to the presence of water and hydroxyl groups in lactose, unlike the APIs. A direct comparison of the predicted and measured cohesive balance of LMH with APIs will require a more in-depth understanding of highly hydrogen-bonded systems with respect to the synthonic engineering modeling tool, as well as the influence of agglomerate structure on surface–surface contact geometry. Overall, this research has demonstrated the possible application and relevance of synthonic engineering tools for rapid pre-screening in drug formulation and design

Luminescence spectra of lead tungstate, spodumene and topaz crystals

A detailed set of thermoluminescence, cathodoluminescence and radioluminescence (TL, CLTL and RLTL) data of lead tungstate, Spodumene and Topaz have been reported for the first time over a wide temperature range from 25 to 500K. Lead tungstate (PbWO_4), a widely known scintillating material, gives TL glow peaks which are related to complex defect centres. Doping of this crystal with trivalent rare earth ions (La"3"+, Y"3"+) reduces the slow component of the emission thereby making it more suitable for its applications. The pentavalent dopants on the other hand, enhance the green emission and quench the blue emission at temperatures 100K. The origin and the irradiation temperature definitely have an effect on the spectrum. No strong relationship could be derived from the dose dependence data. Two less studied minerals, Spodumene and Topaz have also been investigated with the luminescence techniques. The glow peak near 250degC is thought to have originated from Mn"2"+ centres. As there are no ESR data available, the assignment of defect centres is rather difficult. Cr"+ acts as the quencher in green spodumene. Topaz had the same treatment as the other two sets of samples and the defect centre characterisation looks complex as each coloured sample gave different patterns of glow peaks. Cathodoluminescence whilst heating (CLTL) of all these samples showed some unusual features in the form of a luminescence intensity step which is believed to have originated from the presence of ice. Water, in nanoparticle size quantities, is present as a contaminant in the lattice and undergoes a phase transition at 170K from hexagonal to cubic structures. This phase change influences the luminescence efficiency of the host material and is reflected in the spectrum as a discontinuity in intensity. (author)SIGLEAvailable from British Library Document Supply Centre- DSC:DXN056804 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Luminescence spectra of lead tungstate, spodumene and topaz crystals

A detailed set of thermoluminescence, cathodoluminescence and radioluminescence (TL, CLTL and RLTL) data of lead tungstate, Spodumene and Topaz have been reported for the first time over a wide temperature range from 25 to 500K. Lead tungstate (PbWO_4), a widely known scintillating material, gives TL glow peaks which are related to complex defect centres. Doping of this crystal with trivalent rare earth ions (La"3"+, Y"3"+) reduces the slow component of the emission thereby making it more suitable for its applications. The pentavalent dopants on the other hand, enhance the green emission and quench the blue emission at temperatures 100K. The origin and the irradiation temperature definitely have an effect on the spectrum. No strong relationship could be derived from the dose dependence data. Two less studied minerals, Spodumene and Topaz have also been investigated with the luminescence techniques. The glow peak near 250degC is thought to have originated from Mn"2"+ centres. As there are no ESR data available, the assignment of defect centres is rather difficult. Cr"+ acts as the quencher in green spodumene. Topaz had the same treatment as the other two sets of samples and the defect centre characterisation looks complex as each coloured sample gave different patterns of glow peaks. Cathodoluminescence whilst heating (CLTL) of all these samples showed some unusual features in the form of a luminescence intensity step which is believed to have originated from the presence of ice. Water, in nanoparticle size quantities, is present as a contaminant in the lattice and undergoes a phase transition at 170K from hexagonal to cubic structures. This phase change influences the luminescence efficiency of the host material and is reflected in the spectrum as a discontinuity in intensity. (author)SIGLEAvailable from British Library Document Supply Centre- DSC:DXN056804 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Hyper-Expression of PD-1 Is Associated with the Levels of Exhausted and Dysfunctional Phenotypes of Circulating CD161(++)TCR iV alpha 7.2(+) Mucosal-Associated Invariant T Cells in Chronic Hepatitis B Virus Infection

Mucosal-associated invariant T (MAIT) cells, defined as CD161(++) TCR iV alpha 7.2(+) T cells, play an important role in the innate defense against bacterial infections, and their functionality is impaired in chronic viral infections. Here, we investigated the frequency and functional role of MAIT cells in chronic hepatitis B virus (HBV) infection. The peripheral CD3(+)CD161(++)TCR iV alpha 7.2(+) MAIT cells in chronic HBV-infected patients and healthy controls were phenotypically characterized based on CD57, PD-1, TIM-3, and CTLA-4, as well as HLA-DR and CD38 expression. The frequency of MAIT cells was significantly decreased among chronic HBV-infected individuals as compared to controls. Expression of CD57, PD-1, CTLA-4, as well as HLA-DR and CD38 on MAIT cells was significantly elevated in chronic HBV-infected individuals relative to controls. The percentage of T cell receptor (TCR) iVa7.2+ CD161(+) MAIT cells did not correlate with HBV viral load but inversely with HLA-DR on CD4(+) T cells and MAIT cells and with CD57 on CD8(+) T cells suggesting that decrease of MAIT cells may not be attributed to direct infection by HBV but driven by HBV-induced chronic immune activation. The percentage and expression levels of PD-1 as well as CTLA-4 on MAIT cells inversely correlated with plasma HBV-DNA levels, which may suggest either a role for MAIT cells in the control of HBV infection or the effect of HBV replication in the liver on MAIT cell phenotype. We report that decrease of TCR iV alpha 7.2(+) MAIT cells in the peripheral blood and their functions were seemingly impaired in chronic HBV-infected patients likely because of the increased expression of PD-1.Funding Agencies|Frontier Research Grant (FRG) [FG019-17AFR]</p

Hyper-Expression of PD-1 Is Associated with the Levels of Exhausted and Dysfunctional Phenotypes of Circulating CD161++TCR iVα7.2+ Mucosal-Associated Invariant T Cells in Chronic Hepatitis B Virus Infection

Mucosal-associated invariant T (MAIT) cells, defined as CD161++TCR iVα7.2+ T cells, play an important role in the innate defense against bacterial infections, and their functionality is impaired in chronic viral infections. Here, we investigated the frequency and functional role of MAIT cells in chronic hepatitis B virus (HBV) infection. The peripheral CD3+CD161++TCR iVα7.2+ MAIT cells in chronic HBV-infected patients and healthy controls were phenotypically characterized based on CD57, PD-1, TIM-3, and CTLA-4, as well as HLA-DR and CD38 expression. The frequency of MAIT cells was significantly decreased among chronic HBV-infected individuals as compared to controls. Expression of CD57, PD-1, CTLA-4, as well as HLA-DR and CD38 on MAIT cells was significantly elevated in chronic HBV-infected individuals relative to controls. The percentage of T cell receptor (TCR) iVα7.2+ CD161+ MAIT cells did not correlate with HBV viral load but inversely with HLA-DR on CD4+ T cells and MAIT cells and with CD57 on CD8+ T cells suggesting that decrease of MAIT cells may not be attributed to direct infection by HBV but driven by HBV-induced chronic immune activation. The percentage and expression levels of PD-1 as well as CTLA-4 on MAIT cells inversely correlated with plasma HBV-DNA levels, which may suggest either a role for MAIT cells in the control of HBV infection or the effect of HBV replication in the liver on MAIT cell phenotype. We report that decrease of TCR iVα7.2+ MAIT cells in the peripheral blood and their functions were seemingly impaired in chronic HBV-infected patients likely because of the increased expression of PD-1

Image_1.tif

<p>Mucosal-associated invariant T (MAIT) cells, defined as CD161⁺⁺TCR iVα7.2⁺ T cells, play an important role in the innate defense against bacterial infections, and their functionality is impaired in chronic viral infections. Here, we investigated the frequency and functional role of MAIT cells in chronic hepatitis B virus (HBV) infection. The peripheral CD3⁺CD161⁺⁺TCR iVα7.2⁺ MAIT cells in chronic HBV-infected patients and healthy controls were phenotypically characterized based on CD57, PD-1, TIM-3, and CTLA-4, as well as HLA-DR and CD38 expression. The frequency of MAIT cells was significantly decreased among chronic HBV-infected individuals as compared to controls. Expression of CD57, PD-1, CTLA-4, as well as HLA-DR and CD38 on MAIT cells was significantly elevated in chronic HBV-infected individuals relative to controls. The percentage of T cell receptor (TCR) iVα7.2⁺ CD161⁺ MAIT cells did not correlate with HBV viral load but inversely with HLA-DR on CD4⁺ T cells and MAIT cells and with CD57 on CD8⁺ T cells suggesting that decrease of MAIT cells may not be attributed to direct infection by HBV but driven by HBV-induced chronic immune activation. The percentage and expression levels of PD-1 as well as CTLA-4 on MAIT cells inversely correlated with plasma HBV-DNA levels, which may suggest either a role for MAIT cells in the control of HBV infection or the effect of HBV replication in the liver on MAIT cell phenotype. We report that decrease of TCR iVα7.2⁺ MAIT cells in the peripheral blood and their functions were seemingly impaired in chronic HBV-infected patients likely because of the increased expression of PD-1.</p

Image_2.tif

<p>Mucosal-associated invariant T (MAIT) cells, defined as CD161⁺⁺TCR iVα7.2⁺ T cells, play an important role in the innate defense against bacterial infections, and their functionality is impaired in chronic viral infections. Here, we investigated the frequency and functional role of MAIT cells in chronic hepatitis B virus (HBV) infection. The peripheral CD3⁺CD161⁺⁺TCR iVα7.2⁺ MAIT cells in chronic HBV-infected patients and healthy controls were phenotypically characterized based on CD57, PD-1, TIM-3, and CTLA-4, as well as HLA-DR and CD38 expression. The frequency of MAIT cells was significantly decreased among chronic HBV-infected individuals as compared to controls. Expression of CD57, PD-1, CTLA-4, as well as HLA-DR and CD38 on MAIT cells was significantly elevated in chronic HBV-infected individuals relative to controls. The percentage of T cell receptor (TCR) iVα7.2⁺ CD161⁺ MAIT cells did not correlate with HBV viral load but inversely with HLA-DR on CD4⁺ T cells and MAIT cells and with CD57 on CD8⁺ T cells suggesting that decrease of MAIT cells may not be attributed to direct infection by HBV but driven by HBV-induced chronic immune activation. The percentage and expression levels of PD-1 as well as CTLA-4 on MAIT cells inversely correlated with plasma HBV-DNA levels, which may suggest either a role for MAIT cells in the control of HBV infection or the effect of HBV replication in the liver on MAIT cell phenotype. We report that decrease of TCR iVα7.2⁺ MAIT cells in the peripheral blood and their functions were seemingly impaired in chronic HBV-infected patients likely because of the increased expression of PD-1.</p