Use of a Fundamental Approach to Spray-Drying Formulation Design to Facilitate the Development of Multi-Component Dry Powder Aerosols for Respiratory Drug Delivery

Purpose

A fundamental approach incorporating current theoretical models into aerosol formulation design potentially reduces experimental work for complex formulations. A D-amino acid mixture containing D-Leucine (D-Leu), D-Methionine, D-Tryptophan, and D-Tyrosine was selected as a model formulation for this approach.

Methods

Formulation design targets were set, with the aim of producing a highly dispersible D-amino acid aerosol. Particle formation theory and a spray dryer process model were applied with boundary conditions to the design targets, resulting in a priori predictions of particle morphology and necessary spray dryer process parameters. Two formulations containing 60% w/w trehalose, 30% w/w D-Leu, and 10% w/w remaining D-amino acids were manufactured.

Results

The design targets were met. The formulations had rugose and hollow particles, caused by deformation of a crystalline D-Leu shell while trehalose remained amorphous, as predicted by particle formation theory. D-Leu acts as a dispersibility enhancer, ensuring that both formulations: 1) delivered over 40% of the loaded dose into the in vitro lung region, and 2) achieved desired values of lung airway surface liquid concentrations based on lung deposition simulations.

Conclusions

Theoretical models were applied to successfully achieve complex formulations with design challenges a priori. No further iterations to the design process were required.     

Synthesis of Zn3(VO4)2/BiVO4 heterojunction composite for the photocatalytic degradation of methylene blue organic dye and electrochemical detection of H2O2

In this study, a Zn₃(VO₄)₂/BiVO₄ heterojunction nanocomposite photocatalyst was prepared using a hydrothermal route with different molar concentration ratios. The as-synthesized nanophotocatalyst was characterized using XRD, SEM, EDS, XPS, FT-IR, Raman, BET, UV-vis DRS, EPR and PL. The effect of molar ratio on composition and morphology was studied. The as-prepared nanocomposite exhibited excellent photocatalytic response by completely degrading the model pollutant methylene blue (MB) dye in 60 min at molar concentration ratio of 2 : 1. In basic medium at pH 12, the Zn₃(VO₄)₂/BiVO₄ nanocomposite degrades MB completely within 45 min. The nanocomposite was also successfully used for the electrochemical detection of an important analyte hydrogen peroxide (H₂O₂). This study opens up a new horizon for the potential applications of Zn₃(VO₄)₂/BiVO₄ nanocomposite in environmental wastewater remediation as well as biosensing sciences.

In this study, a Zn₃(VO₄)₂/BiVO₄ heterojunction nanocomposite photocatalyst was prepared using a hydrothermal route with different molar concentration ratios.     

Assessment of safety of performing percutaneous coronary intervention after a recent episode of gastrointestinal bleeding

Background: Little literature exists on the risk of performing coronary intervention (PCI) on patients who have had recent gastrointestinal bleeding (GIB), although bleeding after PCI has been identified as a risk factor for long-term mortality. Methods: Patients within the Cleveland Clinic PCI database who had acute GIB within 30 days preceding PCI during the same hospitalization (n = 79) were retrospectively compared to those who had PCI without recent GIB (n = 10 979) for mortality and need for revascularization. Baseline characteristics, laboratory values, procedures, morbidities, and mortality were compared using chi-square test for categorical variables and using Wilcoxon rank sum test for continuous variables. Mortality data was obtained using Social Security Death Index and demonstrated using Kaplan–Meier method. Results: The GIB group had more prevalent history of peptic ulcer disease, GIB, gastrointestinal or liver disease (P < 0.0001), transient ischemic accident (P = 0.017), peripheral vascular disease (P = 0.0002), significant carotid artery occlusion (P = 0.023), and myocardial infarction (P < 0.0001). 47% of patients had upper GIB with 20% needing endoscopic intervention. This group had more anemia (P < 0.0001), heart failure (P = 0.0001), cardiogenic shock (10% versus 1.4%, P < 0.001), cardiac arrest (7.6% versus 1%, P < 0.001). GIB group had worse in-hospital mortality (P < 0.0001), long-term mortality (P < 0.001), and a 7.6% re-bleeding incidence. Conclusions: Overall, the patients who had GIB preceding PCI had higher in-hospital mortality and long-term mortality compared with those without GIB before PCI.     

Theoretical and Experimental in vitro Antifungal and Antitumor Activities of Organotin(IV) Derivatives of 3-(4-nitrophenyl)-2-methylacrylic acid

Pharmaceutical Chemistry Journal - Di- and triorganotin(IV) derivatives of 3-(4-nitrophenyl)-2-methylacrylic acid (HL), i.e., [n-Bu2SnL2] (1), [Me2SnL2] (2), [n-Bu3SnL]n (3) [Me3SnL]n (4) and...     

Synchronous gist,colon and breast adenocarcinoma with double colonic polyp metastases

INTRODUCTION

Long term survivors of breast cancer are at risk of developing distant metastasis years after the initial treatment. We report a case of breast adenocarcinoma with colonic polyp metastases, as well as synchronous primary colonic adenocarcinoma and a gastric GIST.

PRESENTATION OF CASE

An 83 year old female underwent colonoscopy for rectal bleeding. This showed a primary colonic adenocarcinoma, a pedunculated polyp in the ascending colon and two polyps in the sigmoid colon. A staging CT scan did not show distant metastasis, but revealed a small gastric GIST which was managed conservatively. A right hemicolectomy showed a T3N0 colonic adenocarcinoma and a polyp contained metastatic adenocarcinoma from a breast primary. The patient had undergone surgery 30 years ago for an invasive lobular carcinoma. Further clinical assessment demonstrated an impalpable grade II Invasive ductal carcinoma in the contralateral breast. She was started on hormonal treatment and at 18 months follow-up, she was well with stable disease.

DISCUSSION

Invasive lobular cancer is the most common histological type of breast cancer that metastasizes to the colon. There is no consensus on the management of breast cancer metastasis to the gastrointestinal tract. Co-existence of a GIST and an adenocarcinoma at two separate locations is uncommon. These are two different cancer entities and it is unclear whether these two are related by as causal relationship.

CONCLUSION

This is a rare case of three distinct tumours; association between them is unlikely. However, the case highlights the importance of a multidisciplinary approach to cancer treatment.     

A series of lanthanide–quinoxaline-2,3(1H,4H)-dione complexes containing 1D chiral Ln2O3 (Ln = Eu,Tb, Sm,Dy) chains: luminescent properties and response to small molecules

Five new isostructural lanthanide–organic complexes, [Ln₂O₂(OH)(HQXD)(H₂QXD)₂]·H₂O (Ln = Eu 1, Tb 2, Sm 3 Dy 4 and Gd 5; H₂QXD = quinoxaline-2,3(1H,4H)-dione), have been synthesized under hydrothermal conditions. These complexes are characterized by powder X-ray diffraction (PXRD), infrared spectroscopy (IR), elemental analysis (EA), thermogravimetric-differential thermal analysis (TG-DTA) and photo-luminescent spectroscopy. Single crystal X-ray diffraction analysis of complex 1 revealed that the structure featured in 1D chiral “Eu₂O₃” chains surrounded by coordinating organic ligands. These chains are interconnected via hydrogen bonding and offset π⋯π stacking interactions of the ligands to form the 3D supramolecular frameworks. The photo-luminescence studies for complexes 1–5 disclosed that the ligand (H₂QXD) showed an antenna effect to transfer energy toward the lanthanide cations. The energy transfer mechanism investigations show that the energy transition from the triplet energy level (³ππ*) of ligand H₂QXD to the Tb³⁺ cation is more effective than to the Eu³⁺, Sm³⁺ and Dy³⁺ ions; therefore it has been selected as a representative to examine the potential for sensing small molecules. Complex 2′, which was obtained by the heating treatment of 2 at 150 °C, displayed a high luminescence sensitivity towards small solvent molecules. Tertiary butanol (t-butanol) was found to be an excellent sensitizer, while tetrahydrofuran (THF) was a highly quenching species. Complex 2′ could regain a higher photo-luminescence intensity after treating for 5 cycles with t-butanol, revealing a prospect for reusability.

A series of isostructural lanthanide–quinoxaline-2,3(1H,4H)-dione containing 1D chiral chains shows high sensing effect toward the small solvent molecules, in which tertiary butanol was an excellent sensitizer, while tetrahydrofuran was a highly quenching species.     

iRhom2 controls the substrate selectivity of stimulated ADAM17-dependent ectodomain shedding

Protein ectodomain shedding by ADAM17 (a disintegrin and metalloprotease 17), a principal regulator of EGF-receptor signaling and TNFα release, is rapidly and posttranslationally activated by a variety of signaling pathways, and yet little is known about the underlying mechanism. Here, we report that inactive rhomboid protein 2 (iRhom2), recently identified as essential for the maturation of ADAM17 in hematopoietic cells, is crucial for the rapid activation of the shedding of some, but not all substrates of ADAM17. Mature ADAM17 is present in mouse embryonic fibroblasts (mEFs) lacking iRhom2, and yet ADAM17 is unable to support stimulated shedding of several of its substrates, including heparin-binding EGF and Kit ligand 2 in this context. Stimulated shedding of other ADAM17 substrates, such as TGFα, is not affected in iRhom2^−/− mEFs but can be strongly reduced by treating iRhom2^−/− mEFs with siRNA against iRhom1. Activation of heparin-binding EGF or Kit ligand 2 shedding by ADAM17 in iRhom2^−/− mEFs can be rescued by wild-type iRhom2 but not by iRhom2 lacking its N-terminal cytoplasmic domain. The requirement for the cytoplasmic domain of iRhom2 for stimulated shedding by ADAM17 may help explain why the cytoplasmic domain of ADAM17 is not required for stimulated shedding. The functional relevance of iRhom2 in regulating shedding of EGF receptor (EGFR) ligands is established by a lack of lysophasphatidic acid/ADAM17/EGFR-dependent crosstalk with ERK1/2 in iRhom2^−/− mEFs, and a significant reduction of FGF7/ADAM17/EGFR-stimulated migration of iRhom2^−/− keratinocytes. Taken together, these findings uncover functions for iRhom2 in the regulation of EGFR signaling and in controlling the activation and substrate selectivity of ADAM17-dependent shedding events.     

Living donor liver transplantation in patients with portal vein thrombosis: a survey and review of technical issues

BACKGROUND: Unlike cadaveric liver transplantation, current attitudes in living donor liver transplantation (LDLT) quote increased risk factors in the potential recipient such as retransplantation, multiple previous surgeries, or preexisting recipient portal vein thrombosis (PVT) as absolute or relative contraindications to this procedure. METHODS: An international survey was performed to examine the attitude of transplant teams relative to LDLT in the setting of preexisting PVT in the potential recipient. A questionnaire was sent to a total of 80 transplant centers performing LDLT in the United States, Europe, Canada, Japan, Southeast Asia, and Australia. RESULTS: A response was obtained from 47 transplant centers (59% response rate). This included 2146 LDLT procedures that combined both left and right lobe allografts. The incidence of acute preexisting recipient PVT was 18 (0.8%) and of chronic PVT was 26 (1.2%). Thrombectomy was performed in 28 (64%), a jump graft in 13 (29.5%), and a combination of both thrombectomy and a jump graft in 2 (4.5%) cases. With reference to the presence of preexisting PVT in the potential recipient, 5 centers considered this to be an absolute contraindication (10.7%), 24 centers as a relative contraindication (51%), and 18 as not being a contraindication (38.3%) to LDLT. CONCLUSIONS: The overall response to our questionnaire reflected a cautious attitude within the transplant community. Ethical criteria pertaining to risk undertaken by a healthy donor in situations of higher recipient morbidity risk does seem to impact on the decision to undertake LDLT in this group of patients.     

Early nutrition and leptin concentrations in later life

BACKGROUND: Formula feeding or overweight in infancy may increase the later risk of obesity, but the mechanisms involved are uncertain. Because obesity is associated with high leptin concentrations relative to fat mass, programming of leptin concentrations may be one mechanism by which early nutrition influences later obesity. OBJECTIVE: We tested the hypothesis that high nutrient intake or formula feeding in infancy programs greater leptin concentrations relative to fat mass in later life. DESIGN: Serum leptin concentrations were measured by radioimmunoassay in 197 adolescents aged 13-16 y who were born preterm and randomly assigned at birth to receive either a nutrient-enriched preterm formula or banked donated breast milk (trial 1) or a preterm formula or a standard formula (trial 2). Fat mass was estimated with the use of bioelectrical impedance analysis. RESULTS: After combining the results of trials 1 and 2 as planned, the ratio of leptin to fat mass was significantly greater in the children who received the preterm formula (geometric : 0.84 microg x L(-1) x kg(-1)) than in those who received standard formula or banked breast milk (0.62 microg x L(-1) x kg(-1); mean difference: 30.8%; 95% CI for difference: 8.4%, 53.2%; P = 0.007). The difference between the diet groups remained significant after adjustment for age, sex, Tanner stage, social class, and fat mass. Human milk intake was significantly associated with lower leptin concentrations relative to fat mass in adolescence (P = 0.023), independent of potential confounding factors. CONCLUSION: Programming of relative leptin concentrations by early diet may be one mechanism that links early nutrition with later obesity.