Layered Tablets: A Novel Oral Solid Dosage Form

Oral solid dosage forms hold a predominant position in the drug delivery system. Tablets are the most widely used and convenient dosage form. Due to their ease of manufacturing, the minimum cost of production, easy handling and storage, and better stability, tablets are most preferred. Patients who are prescribed more than one drug are in a situation to consume multiple tablets. To minimize the counts, one or more drugs are cast into layers to form a single tablet, thus called layered tablets. Layered tablets tend to improve patient compliance and reduce the cost of production by half. Layers can be of multiple drugs or the same drug at different doses or drugs with release enhancers or drugs with fillers. Layered tablets hold a greater potential with better patient outcomes as well as stay production-friendly

Stereoselective synthesis of a natural product inspired tetrahydroindolo[2,3-a]-quinolizine compound library

AbstractA natural product-inspired synthesis of a compound collection embodying the tetrahydroindolo[2,3-a]quinolizine scaffold was established with a five step synthesis route. An imino-Diels–Alder reaction between Danishefsky’s diene and the iminoesters derived from tryptamines was used as a key reaction. Reductive amination of the ketone function and amide synthesis with the carboxylic acid derived from the ethyl ester, were used to decorate the core scaffold. Thus a compound library of 530 tetrahydroindolo[2,3-a]quinolizines was generated and submitted to European lead factory consortium for various biological screenings

Chorioamnionitis disrupts erythropoietin and melatonin homeostasis through the placental-fetal-brain axis during critical developmental periods

Introduction: Novel therapeutics are emerging to mitigate damage from perinatal brain injury (PBI). Few newborns with PBI suffer from a singular etiology. Most experience cumulative insults from prenatal inflammation, genetic and epigenetic vulnerability, toxins (opioids, other drug exposures, environmental exposure), hypoxia-ischemia, and postnatal stressors such as sepsis and seizures. Accordingly, tailoring of emerging therapeutic regimens with endogenous repair or neuro-immunomodulatory agents for individuals requires a more precise understanding of ligand, receptor-, and non-receptor-mediated regulation of essential developmental hormones. Given the recent clinical focus on neurorepair for PBI, we hypothesized that there would be injury-induced changes in erythropoietin (EPO), erythropoietin receptor (EPOR), melatonin receptor (MLTR), NAD-dependent deacetylase sirtuin-1 (SIRT1) signaling, and hypoxia inducible factors (HIF1α, HIF2α). Specifically, we predicted that EPO, EPOR, MLTR1, SIRT1, HIF1α and HIF2α alterations after chorioamnionitis (CHORIO) would reflect relative changes observed in human preterm infants. Similarly, we expected unique developmental regulation after injury that would reveal potential clues to mechanisms and timing of inflammatory and oxidative injury after CHORIO that could inform future therapeutic development to treat PBI.Methods: To induce CHORIO, a laparotomy was performed on embryonic day 18 (E18) in rats with transient uterine artery occlusion plus intra-amniotic injection of lipopolysaccharide (LPS). Placentae and fetal brains were collected at 24 h. Brains were also collected on postnatal day 2 (P2), P7, and P21. EPO, EPOR, MLTR1, SIRT1, HIF1α and HIF2α levels were quantified using a clinical electrochemiluminescent biomarker platform, qPCR, and/or RNAscope. MLT levels were quantified with liquid chromatography mass spectrometry.Results: Examination of EPO, EPOR, and MLTR1 at 24 h showed that while placental levels of EPO and MLTR1 mRNA were decreased acutely after CHORIO, cerebral levels of EPO, EPOR and MLTR1 mRNA were increased compared to control. Notably, CHORIO brains at P2 were SIRT1 mRNA deficient with increased HIF1α and HIF2α despite normalized levels of EPO, EPOR and MLTR1, and in the presence of elevated serum EPO levels. Uniquely, brain levels of EPO, EPOR and MLTR1 shifted at P7 and P21, with prominent CHORIO-induced changes in mRNA expression. Reductions at P21 were concomitant with increased serum EPO levels in CHORIO rats compared to controls and variable MLT levels.Discussion: These data reveal that commensurate with robust inflammation through the maternal placental-fetal axis, CHORIO impacts EPO, MLT, SIRT1, and HIF signal transduction defined by dynamic changes in EPO, EPOR, MLTR1, SIRT1, HIF1α and HIF2α mRNA, and EPO protein. Notably, ligand-receptor mismatch, tissue compartment differential regulation, and non-receptor-mediated signaling highlight the importance, complexity and nuance of neural and immune cell development and provide essential clues to mechanisms of injury in PBI. As the placenta, immune cells, and neural cells share many common, developmentally regulated signal transduction pathways, further studies are needed to clarify the perinatal dynamics of EPO and MLT signaling and to capitalize on therapies that target endogenous neurorepair mechanisms

Homogenization of parabolic equation in an evolving domain with an oscillating boundary

International audienc

Divergent organ-specific isogenic metastatic cell lines identified using multi-omics exhibit differential drug sensitivity.

BackgroundMonitoring and treating metastatic progression remains a formidable task due, in part, to an inability to monitor specific differential molecular adaptations that allow the cancer to thrive within different tissue types. Hence, to develop optimal treatment strategies for metastatic disease, an important consideration is the divergence of the metastatic cancer growing in visceral organs from the primary tumor. We had previously reported the establishment of isogenic human metastatic breast cancer cell lines that are representative of the common metastatic sites observed in breast cancer patients.MethodsHere we have used proteomic, RNAseq, and metabolomic analyses of these isogenic cell lines to systematically identify differences and commonalities in pathway networks and examine the effect on the sensitivity to breast cancer therapeutic agents.ResultsProteomic analyses indicated that dissemination of cells from the primary tumor sites to visceral organs resulted in cell lines that adapted to growth at each new site by, in part, acquiring protein pathways characteristic of the organ of growth. RNAseq and metabolomics analyses further confirmed the divergences, which resulted in differential efficacies to commonly used FDA approved chemotherapeutic drugs. This model system has provided data that indicates that organ-specific growth of malignant lesions is a selective adaptation and growth process.ConclusionsThe insights provided by these analyses indicate that the rationale of targeted treatment of metastatic disease may benefit from a consideration that the biology of metastases has diverged from the primary tumor biology and using primary tumor traits as the basis for treatment may not be ideal to design treatment strategies

Diversity-oriented synthesis of useful chiral building blocks from D-mannitol

A diversity-oriented synthesis is described for functionalized chiral building blocks (i.e., 7, 9, 10, 16, and 17) and the biologically active iminosugar, fucosidase inhibitor (2S,3R,4R,5R)-2-(hydroxymethyl)-5-methylpyrrolidine-3,4-diol (22), starting from common chiral intermediate 1a which is obtained through a regioselective reductive cleavage of a bis(benzylidene) acetal

A Comparison of PET Tracers in Recurrent High-Grade Gliomas: A Systematic Review

Humans with high-grade gliomas have a poor prognosis, with a mean survival time of just 12–18 months for patients who undergo standard-of-care tumor resection and adjuvant therapy. Currently, surgery and chemoradiotherapy serve as standard treatments for this condition, yet these can be complicated by the tumor location, growth rate and recurrence. Currently, gadolinium-based, contrast-enhanced magnetic resonance imaging (CE-MRI) serves as the predominant imaging modality for recurrent high-grade gliomas, but it faces several drawbacks, including its inability to distinguish tumor recurrence from treatment-related changes and its failure to reveal the entirety of tumor burden (de novo or recurrent) due to limitations inherent to gadolinium contrast. As such, alternative imaging modalities that can address these limitations, including positron emission tomography (PET), are worth pursuing. To this end, the identification of PET-based markers for use in imaging of recurrent high-grade gliomas is paramount. This review will highlight several PET radiotracers that have been implemented in clinical practice and provide a comparison between them to assess the efficacy of these tracers

Stereoselective Cascade Double-Annulations Provide Diversely Ring-Fused Tetracyclic Benzopyrones

A cascade double-annulation strategy employing diverse pairs of zwitterions with 3-formylchromones is presented that provides stereoselective access to complex tetracyclic benzopyrones. Different zwitterions incorporated different rings that include aza-, oxa-, and carbocycles fused to a common benzopyrone scaffold and in the process created three contiguous chiral centers including an all-carbon-quaternary center with high efficiency and excellent stereoselectivity