ABSTRACT
Proton pump inhibitors (PPIs) are widely used for treating acid-related disorders. For an "ideal PPI," achieving maximal absorption and sustaining pharmacodynamic effects through the 24-h dosing cycle are critical features. Dexlansoprazole offers a relevant case study on how an improved PPI was developed capitalizing on the rational optimization of a precursor molecule-in this case, using lansoprazole as a starting point, leveraging its chemical properties on pharmacokinetics, and exploring optimized formulations. Dexlansoprazole is the R(+)-enantiomer of lansoprazole and shows stereoselective differences in absorption and metabolism compared with the racemic mixture of lansoprazole. The formulation was further refined to use pulsate-type granules with enteric coating to withstand acidic gastric conditions, while allowing prolonged absorption in the proximal and distal small intestine. As a result, the dual delayed-release formulation of dexlansoprazole has a plasma concentration-time profile characterized by 2 distinct peaks, leading to an extended duration of therapeutic plasma drug concentrations compared with the conventional delayed-release lansoprazole formulation. The dual delayed-release formulation maintains plasma drug concentrations longer than the lansoprazole delayed-release formulation at all doses.
Subject(s)
Capsules/chemistry , Delayed-Action Preparations/chemistry , Dexlansoprazole/chemistry , Proton Pump Inhibitors/chemistry , Capsules/pharmacokinetics , Chemistry, Pharmaceutical/methods , Delayed-Action Preparations/pharmacokinetics , Dexlansoprazole/pharmacokinetics , Humans , Intestine, Small/metabolism , Lansoprazole/chemistry , Lansoprazole/pharmacokinetics , Proton Pump Inhibitors/pharmacokineticsABSTRACT
Background: Anti-tumor necrosis factor alpha (anti-TNFα) therapy has become the mainstay of therapy for Crohn's disease (CD). However, post-therapy, the recurrence rate is still high. The aim of this study was to dissect the molecular mechanism for recurrence of CD treated with anti-TNFα therapy and investigate novel therapeutic options that could induce complete remission. Methods: We re-analyzed publicly available mucosal gene expression data from CD patients pre- and post-infliximab therapy to extract the transcriptional differences between responders and healthy controls. We used a systematic computational approach based on identified differences to discover novel therapies and validated this prediction through in vitro and in vivo experimentation. Results: We identified a set of 3545 anti-TNFα therapy-untreatable genes (TUGs) that are significantly regulated in intestinal epithelial cells, which remain altered during remission. Pathway enrichment analysis of these genes clearly showed excessive growth state and suppressed terminal differentiation, whereas immune components were clearly resolved. Through in silico screening strategy, we observed that MEK inhibitors were predicted to revert expression of genes dysregulated in infliximab responders. In vitro transcriptome analysis demonstrated that selective MEK1/2 inhibitor significantly normalized reference genes from TUGs. In addition, in vitro functional study proved that MEK1/2 inhibitor facilitated intestinal epithelial differentiation. Finally, using murine colitis model, administration of MEK1/2 inhibitor significantly improved diarrhea and histological score. Conclusions: Our data revealed the abnormalities in anti-TNFα responders' CD colons that would be cause of recurrence of CD. Also, we provided evidence regarding MEK1/2 inhibitor as a potential treatment against CD to achieve sustainable remission.
Subject(s)
Crohn Disease/drug therapy , MAP Kinase Kinase 1/antagonists & inhibitors , MAP Kinase Kinase 2/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adalimumab , Animals , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Caco-2 Cells , Colon/pathology , Crohn Disease/metabolism , Disease Models, Animal , Female , Gene Expression Regulation/drug effects , Humans , Infliximab , MAP Kinase Kinase 1/metabolism , MAP Kinase Kinase 2/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Recurrence , Remission InductionABSTRACT
Drug delivery systems maximize the efficacy of drugs by improving their pharmacokinetic profiles, pharmacodynamic effects, or both and reducing their adverse effects. One of the most advanced, clinically available formulations are liposome-encapsulated drugs. In this study, we aimed to determine if liposomes can selectively deliver compounds in gastrointestinal diseases. Initially, we evaluated the correlation between the diarrhea score and accumulation of fluorescence (FL)-labeled liposome using in vivo imaging systems in various disease states of an inflammatory bowel disease mouse model. The result showed that FL-labeled liposome accumulation and colon tissue weight, which reflect the disease state were highly and positively correlated. Then, to confirm the accumulation of liposomes at injured sites of the colon, we administered both FL-labeled liposomes and luminescence probes for detecting reactive oxygen species (ROS) to the mouse model. The imaging data showed that liposome accumulation tended to coincide with ROS detected sites and the correlation coefficient indicated a significantly positive correlation between liposome accumulation and ROS detection levels. Finally, we evaluated the involvement of macrophages in the uptake mechanism of the liposomes by analyzing the relationship between FL-labeled liposome accumulation and macrophage marker gene expression levels. The result showed that the expression of each macrophage marker gene and liposome accumulation showed a significant positive correlation. Therefore, the macrophages considerably contributed to the uptake mechanism of the liposomes. These data suggest that liposomes could be an attractive delivery tool for enhancing the accumulation of drug candidates through macrophages in injured colonic tissues. This approach is expected to provide new treatment options for patients with colitis.
Subject(s)
Colon/metabolism , Drug Delivery Systems , Inflammatory Bowel Diseases/drug therapy , Adoptive Transfer , Animals , Antigens, CD/genetics , Antigens, Differentiation/genetics , Antigens, Differentiation, Myelomonocytic/genetics , Colon/injuries , Disease Models, Animal , Female , Fluorescent Dyes/administration & dosage , Fluorescent Dyes/pharmacokinetics , Genetic Markers , Inflammatory Bowel Diseases/etiology , Inflammatory Bowel Diseases/metabolism , Liposomes , Macrophages/metabolism , Mice , Mice, Inbred BALB C , Nanomedicine , Reactive Oxygen Species/metabolism , Scavenger Receptors, Class A/genetics , T-Lymphocytes/immunologyABSTRACT
The basic structure of alpha-LiFeO2, lithium iron oxide, is a cubic NaCl-type structure with a lattice constant of 0.42 nm; some short-range ordering characterized by octahedral clusters exists. The local structure of the short-range ordering was investigated by transmission electron microscopy and electron diffraction. A new short-range ordering structure was found in local areas. The local structure has a cubic lattice with a doubled lattice constant. The occupation factors of cations on Wyckoff sites 4(a) and 4(b) are different from those on 24(d) sites, but the stoichiometric composition in cubic clusters is the same as the macroscopic composition. The number of pairs in which iron cations exist in nearest-neighbor sites and next nearest-neighbor sites is reduced in the structure. This means that a magnetic interaction between the iron cations is reduced by cation ordering even without spin ordering at room temperature.
