7196 research outputs found
Sort by
Immediate Release 3D-Printed Dosage Forms for Poorly Soluble Drugs: Development and Exploration of Morphology-Dissolution Relationship
No full text3D-printing technologies such as Fused Deposition Modeling (FDM) bring a unique opportunity for personalized and flexible near patient production of pharmaceuticals, potentially improving safety and efficacy for some medications. However, FDM-printed tablets often exhibit tendency for slow dissolution due to polymer erosion based dissolution mechanisms. Development of Immediate Release 3D-printed dosage with poorly water-soluble model compounds is even more challenging, but required to ensure wide applicability of the technology within pharmaceutical development portfolios. In this work, morphology and process for a selected formulation were considered, using BCS class IV compound lumefantrine as a model drug. Basic butylated methacrylate copolymer (Eudragit EPO) as matrix former, as well as hydrophilic plasticizer xylitol and pore former maltodextrin were selected as a promising formulation approach to achieve fast dissolution rates. Tablets of size 9 x 5 x 4 mm, i.e. acceptable for children from 6 years old, were successfully 3D-printed. Tablets with 5% lumefantrine and corresponding placebo were printed, higher drug load as required for clinically relevant dosage strength however lead to increased brittleness incompatible with FDM printing. Residual crystallinity in manufactured tablets and filaments was explored by highly sensitive Raman mapping technique. Lumefantrine was present in the fully amorphous state in the tablets as intended. Grid-designed 3D-printed tablets with 65% infill density met rapid release criteria, while 80% and 100% showed slower dissolution. For the first time, the critical structural characteristics of 3D-printed tablets with non-continuous surface such as accessible porosity, specific surface area by weight and by volume were quantified by an automated micro-CT based methodology, and were confirmed to be responsible for the dissolution rate acceleration. Increase in accessible porosity, total surface area, specific surface area by weight and by volume and decrease in relative density appeared to be critical factors for modification of lumefantrine dissolution rate, whereas increase in closed pores volume did not contribute to accelerating dissolution rate. To conclude, Immediate Release FDM-tablets with BCS class IV compound were developed and key dissolution parameters were detected with non-destructive accurate morphological analysis
Sequestosome 1/p62 enhances chronic skin inflammation
No full textBackground: The molecular control of inflammation and
epidermal thickening in skin lesions of patients with atopic
dermatitis (AD) is not known. Sequestosome 1/p62 is a
multifunctional adapter protein implicated in the control of key
regulators of cellular homeostasis, such as proinflammatory and
mechanistic target of rapamycin signaling.
Objective: We sought to determine whether p62 plays a role in
the cutaneous and systemic manifestations of an AD-like mouse
model.
Methods: AD-like skin lesions were induced by deletion of
JunB/AP-1, specifically in epidermal keratinocytes (JunBDep).
The contribution of p62 to pathological changes was determined
by inactivation of p62 in JunBDep p622/2 double knockout mice.
Results: Expression of p62 was elevated in skin lesions of
JunBDep mice, resembling upregulation of p62 in AD and
psoriasis. When p62 was inactivated, JunBDep-associated defects
in the differentiation of keratinocytes, epidermal thickening,
skin infiltration by mast cells and neutrophils, and the
development of macroscopic skin lesions were significantly
reduced. p62 inactivation had little effect on circulating
cytokines, but decreased serum IgE. Signaling through
mechanistic target of rapamycin and natural factor kappa B
was increased in JunBDep but not in JunBDep p622/2 double
knockout skin, indicating an important role of p62 in enhancing
these signaling pathways in the skin during AD-like
inflammation
Identification of monoclonal antibody variants involved in aggregate formation – Part 2: Hydrophobicity variants
No full textMonoclonal antibodies (mAbs) are valuable tools both in therapy and in diagnostic. Their tendency to aggregate is a serious concern. Since a mAb drug substance (DS) is composed of different variants, it is important for manufacturers to know the behavior and stability not only of the mAb as a whole, but also of the variants contained in the product. We present a method to separate hydrophobicity variants of a mAb and subsequently analyzed these variants for stability and aggregation propensity. We identified a potentially aggregation prone hydrophilic variant which is interrelated with another previously identified aggregation prone acidic charge variant. Additionally, we assessed the risk posed by the aggregation prone variant to the DS by spiking hydrophobicity variants into DS and did not observe an enhanced aggregation propensity. Thus we present an approach to separate, characterize and analyze the criticality of aggregation prone variants in protein DS which is a step forward to further assure drug safety
Mammalian SWI/SNF continuously restores local accessibility to chromatin
No full textChromatin accessibility is a hallmark of regulatory regions, entails transcription factor (TF) binding and requires nucleosomal reorganization. However, it remains unclear how dynamic this process is. In the present study, we use small-molecule inhibition of the catalytic subunit of the mouse SWI/SNF remodeler complex to show that accessibility and reduced nucleosome presence at TF-binding sites rely on persistent activity of nucleosome remodelers. Within minutes of remodeler inhibition, accessibility and TF binding decrease. Although this is irrespective of TF function, we show that the activating TF OCT4 (POU5F1) exhibits a faster response than the repressive TF REST. Accessibility, nucleosome depletion and gene expression are rapidly restored on inhibitor removal, suggesting that accessible chromatin is regenerated continuously and in a largely cell-autonomous fashion. We postulate that TF binding to chromatin and remodeler-mediated nucleosomal removal do not represent a stable situation, but instead accessible chromatin reflects an average of a dynamic process under continued renewal
Mammalian SWI/SNF continuously restores local accessibility to chromatin
No full textChromatin accessibility is a hallmark of regulatory regions, entails transcription factor (TF) binding and requires nucleosomal reorganization. However, it remains unclear how dynamic this process is. In the present study, we use small-molecule inhibition of the catalytic subunit of the mouse SWI/SNF remodeler complex to show that accessibility and reduced nucleosome presence at TF-binding sites rely on persistent activity of nucleosome remodelers. Within minutes of remodeler inhibition, accessibility and TF binding decrease. Although this is irrespective of TF function, we show that the activating TF OCT4 (POU5F1) exhibits a faster response than the repressive TF REST. Accessibility, nucleosome depletion and gene expression are rapidly restored on inhibitor removal, suggesting that accessible chromatin is regenerated continuously and in a largely cell-autonomous fashion. We postulate that TF binding to chromatin and remodeler-mediated nucleosomal removal do not represent a stable situation, but instead accessible chromatin reflects an average of a dynamic process under continued renewal
Nanochannels in Photoactive Cu(I) Polymer for Selective Oxidations in Aqueous Micelles
No full textwe have performed catalytic redox events using heterogenous copper-based polymeric material in water as a sustainable reaction medium. The catalyst is recyclable, and their nanochannels allow the micelle of PS-750-M to travel through to perform catalysis, avoiding the need for toxic dipolar-aprotic solvents. The computational studies assisted in establishing reaction conditions, which are reproducible at variable scales. The need to develop this sustainable heterogeneous catalyst that only uses molecular oxygen as an oxidant meets all the standards established by the ACS GCIPR. More reports on visible light-mediated heterogenous micellar catalysis will be published soon
Regioselective Difunctionalization of Pyridines via 3,4-Pyridynes
No full textA new regioselective 3,4-difunctionalization of 3 chloropyridines via 3,4-pyridyne intermediates is reported. Regioselective lithiation of 3-chloro-2-ethoxypyridine and a related 2-thio-derivative followed by treatment with aryl- and alkylmagnesium halides as well as magnesium thiolates at 78 °C produced 3,4-pyridynes during heating to 75 °C. Regioselective addition of the Grignard moiety in position 4 followed by an electrophilic quench in position 3 led to various 2,3,4-trisubstituted pyridines. This method was adapted into a continuous flow set-up. As an application, we have prepared a key intermediate for the antidepressant (±) paroxetine
A Randomized Phase II Study of Anti-CSF-1 Monoclonal Antibody Lacnotuzumab (MCS110) Combined with Gemcitabine and Carboplatin in Advanced Triple Negative Breast Cancer.
No full textThis phase II study determined the efficacy of lacnotuzumab added to gemcitabine plus carboplatin (gem-carbo) in patients with advanced triple-negative breast cancer (TNBC).Female patients with advanced TNBC, with high levels of tumor-associated macrophages, and not amenable to curative treatment by surgery or radiotherapy, were enrolled. Lacnotuzumab was dosed at 10 mg/kg every 3 weeks (Q3W), {plus minus} a dose on Cycle 1, Day 8. Gem and carbo were given at 1000 mg/m2 and area under curve 2 dose in mg, respectively, Q3W. Treatment continued until unacceptable toxicity, disease progression, or discontinuation by physician/patient.Patients received lacnotuzumab+gem-carbo (n=34) or gem-carbo (n=15). Enrollment was halted due to recruitment challenges owing to rapid evolution of the therapeutic landscape; formal hypothesis testing of the primary endpoint, was therefore not performed. Median progression-free survival was 5.6 months (90% CI: 4.47, 8.64) in the lacnotuzumab+gem-carbo arm and 5.5 months (90% CI: 3.45, 7.46) in the gem-carbo arm. Hematologic adverse events were common in both treatment arms; however, patients treated with lacnotuzumab experienced more frequent aspartate aminotransferase, alanine aminotransferase, and creatine kinase elevations. Pharmacokinetic results showed that free lacnotuzumab at 10 mg/kg exhibited a typical IgG pharmacokinetic profile and target engagement of circulating CSF-1 ligand.Despite successful target engagement and anticipated pharmacokinetic profile, lacnotuzumab+gem-carbo showed comparable antitumor activity to gem-carbo alone, with slightly poorer tolerability. However, the data presented in this manuscript would be informative for future studies testing agents targeting the CSF-1-CSF-1R pathway in TNBC
Ribociclib Population Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Analysis of Neutrophils in Cancer Patients
No full textThe population pharmacokinetics (popPK) of ribociclib and population pharmacokinetic/pharmacodynamic (PK/PD) relationship between ribociclib and absolute neutrophil count (ANC) were characterized in patients with cancer. PopPK and ANC PK/PD modeling were both conducted in 2 rounds per data availability. Initial models were developed based on data sets from early-phase trials and qualified using external data from the phase III MONALEESA-2 trial. The second round of analyses was performed using updated data sets that included 2 more phase III trials (MONALEESA-3 and -7). The popPK and ANC PK/PD models adequately described the data and demonstrated reasonable predictive ability. Covariate analysis showed that ribociclib PK were not affected by age, sex, race, baseline Eastern Cooperative Oncology Group (ECOG) status (grade 1), mild/moderate renal impairment, mild hepatic impairment, or concomitant use of combination partners, including aromatase inhibitors (letrozole, anastrozole) or fulvestrant, proton-pump inhibitors, or weak cytochrome P450 3A4/5 inhibitors. Body weight had no impact on ribociclib clearance to warrant dose adjustment. The ANC PK/PD relationship was not affected by age, weight, sex, race, baseline ECOG status (grade 1), or concomitant use of letrozole, anastrozole, or fulvestrant. The PK/PD analysis confirmed reversibility of ribociclib's effect on ANC; it also suggested that lowering the dose of ribociclib would mitigate ANC decrease and neutropenia risk. The popPK and ANC PK/PD analyses support the use of ribociclib in combination with an aromatase inhibitor or fulvestrant in patients with hormone receptor–positive, human epidermal growth factor receptor-2–negative advanced or metastatic breast cancer without dose adjustment in subpopulations, and the use of dose interruption/reduction to mitigate potential treatment-emergent neutropenia