Development of Clinically Optimized Sitagliptin and Dapagliflozin Complex Tablets: Pre-Formulation, Formulation, and Human Bioequivalence Studies.

The purpose of this study is to derive an optimal drug release formulation with human clinical bioequivalence in developing a sitagliptin phosphate monohydrate-dapagliflozin propanediol hydrate fixed-dose combination (FDC) tablet as a treatment for type 2 diabetes mellitus. As a treatment for type 2 diabetes mellitus, the combined prescription of dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose cotransporter-2 (SGLT-2) inhibitors is common. Therefore, this study simplified the number of individual drugs taken and improved drug compliance by developing FDC tablets containing sitagliptin phosphate monohydrate as a DPP-4 inhibitor and dapagliflozin propanediol hydrate as an SGLT-2 inhibitor. To derive the optimal dosage form, we prepared single-layer tablets, double-layer tablets, and dry-coated tablets and evaluated the drug control release ability, tableting manufacturability, quality, and stability. Single-layer tablets caused problems with stability and drug dissolution patterns. When the dissolution test was performed on the dry-coated tablets, a corning effect occurred, and the core tablet did not completely disintegrate. However, in the quality evaluation of the double-layer tablets, the hardness was 12-14 kilopond, the friability was 0.2%, and the disintegration was within 3 min. In addition, the stability test revealed that the double-layer tablet was stable for 9 months under room temperature storage conditions and 6 months under accelerated storage conditions. In the drug release test, only the FDC double-layer tablet showed the optimal drug release pattern that satisfied each drug release rate. In addition, the FDC double-layer tablet showed a high dissolution rate of over 80% in the form of immediate-release tablets within 30 min in a pH 6.8 dissolution solution. In the human clinical trial, we co-administered a single dose of a sitagliptin phosphate monohydrate-dapagliflozin propanediol hydrate FDC double-layered tablet and the reference drug (Forxiga®, Januvia®) in healthy adult volunteers. This study showed clinically equivalent results in the stability and pharmacodynamic characteristics between the two groups.

Identification of Novel Aryl Carboxamide Derivatives as Death-Associated Protein Kinase 1 (DAPK1) Inhibitors with Anti-Proliferative Activities: Design, Synthesis, In Vitro, and In Silico Biological Studies.

Death-associated protein kinase 1 (DAPK1) is a serine/threonine protein kinase involved in diverse fundamental cellular processes such as apoptosis and autophagy. DAPK1 isoform plays an essential role as a tumor suppressor and inhibitor of metastasis. Consequently, DAPK1 became a promising target protein for developing new anti-cancer agents. In this work, we present the rational design and complete synthetic routes of a novel series of eighteen aryl carboxamide derivatives as potential DAPK1 inhibitors. Using a custom panel of forty-five kinases, a single dose of 10 µM of the picolinamide derivative 4a was able to selectively inhibit DAPK1 kinase by 44.19%. Further investigations revealed the isonicotinamide derivative 4q as a promising DAPK1 inhibitory lead compound with an IC50 value of 1.09 µM. In an in vitro anticancer activity assay using a library of 60 cancer cell lines including blood, lung, colon, CNS, skin, ovary, renal, prostate, and breast cancers, four compounds (4d, 4e, 4o, and 4p) demonstrated high anti-proliferative activity with mean % GI ~70%. Furthermore, the most potent DAPK1 inhibitor (4q) exhibited remarkable activity against leukemia (K-562) and breast cancer (MDA-MB-468) with % GI of 72% and 75%, respectively.

Anatomical structures in the maxillary sinus related to lateral sinus elevation: a cone beam computed tomographic analysis.

OBJECTIVES: The objective of this study is to evaluate the anatomical structures in the maxillary sinus with relation to lateral approach sinus elevation utilizing cone beam computed tomography (CT) scans taken prior to sinus elevation surgery. MATERIALS AND METHODS: A total of 150 CT images were acquired from 150 patients (90 men and 60 women; mean age, 49.4 years, range 23-86 years) who were being treated with implant-supported restorations in the posterior edentulous maxilla. Of the 150 CT scans, 65 were of the right sinus and 85 of the left sinus. Measurements of the anatomical structures in the maxillary sinus were conducted on the CT images. RESULTS: In the mean width of the lateral wall, there were statistically significant values among the measurement points (P < 0.05). The anterior area of the sinus lateral wall was thicker than the posterior lateral wall. There was a statistically significant difference between the vessel diameter and lateral wall width (P < 0.05). As sinus lateral wall width increased, so did the vessel diameter. The mean distance to the inferior border of the vessel from the sinus floor and from the alveolar crest was 8.25 and 17.03 mm, respectively. The intraosseous group among the vessel position was 64.3%, so the intraosseous vessel could be visualized in CT scans at 64.3%. In angle A, the group of less than 30° was 4.8%. Schneiderian membrane perforation by narrow angle had a low risk. The prevalence of the septa related to Schneiderian membrane perforation was 44%. The distance to the inferior border of the vessel from the alveolar crest being less than 15 mm was 31%. The vessel diameter greater than 1 mm was 37.8%. CONCLUSIONS: Based on present research about utilizing cone beam CT scans for sinus elevation, the alteration of the lateral approach sinus elevation technique is highly recommended if complications such as membrane perforation or bleeding are expected.

Negative self-synchronization: will I change to be like you when it is bad for me?

The current research examined whether people will attempt to modify internal aspects of the self to make them congruent with others, even when those modifications have negative implications for the self, a phenomenon we refer to as negative self-synchronization. We proposed that negative self-synchronization will occur only for individuals who are securely attached. Across 4 experiments, participants who were high in secure attachment were more likely than those low in attachment security to engage in negative self-synchronization (Experiments 1-4). Attachment style did not moderate positive self-synchronization (Experiments 1 and 2). In addition, priming secure attachment increased negative self-synchronization among insecure participants (Experiments 2 and 3). Conversely, priming insecure attachment decreased negative self-synchronization among secure participants (Experiment 4). Implications of these findings for social synchronization processes, the need to belong, and attachment security are discussed.

Defensive pride and consensus: strength in imaginary numbers.

Failure (Study 1) and attachment separation thoughts (Study 2) caused exaggerated consensus estimates for personal beliefs about unrelated social issues. This compensatory consensus effect was most pronounced among defensively proud individuals, that is, among those with the combination of high explicit and low implicit self-esteem (Study 1) and the combination of high attachment avoidance and low attachment anxiety (Study 2). In Study 3, another form of defensive pride, narcissism, was associated with exaggerated consensual worldview defense after a system-injustice threat. In Study 4, imagined consensus reduced subjective salience of proud individuals' troubling thoughts. Compensatory consensus is seen as a kind of defensive self-affirmation that defensively proud people turn to for insulation from distressing thoughts.