Water distribution studies within microcrystalline cellulose and chitosan using differential scanning calorimetry and dynamic vapor sorption analysis

The objective of the study was to assess and compare the interaction and distribution of water within microcrystalline cellulose (MCC) and chitosan by differential scanning calorimetry (DSC) and dynamic vapor sorption analysis. The amounts of nonfreezing and freezing water in hydrated samples were determined from melting endotherms obtained by DSC. After accounting for the percent crystallinity of MCC and chitosan, no statistically significant difference was observed in their ability to bind water molecules per repeating unit at the minimum water content at which freezing water is evident. Exposure of chitosan to water for 30 min was sufficient to achieve equilibration at 61% w/w actual water content. The moisture sorption profiles were analyzed according to the GAB and Young and Nelson equations. The adsorbed monolayer, externally adsorbed moisture, and internally absorbed moisture were not statistically different for MCC and chitosan after accounting for the amorphous content of the polymers. These studies suggest that chitosan can act as a "molecular sponge," and thus aid in the production of beads by extrusion and spheronization.     

The new oral adenosine A1 receptor agonist capadenoson in male patients with stable angina

Background

Anti-ischaemic effect of A1 adenosine receptor agonists was shown in animal and preclinical studies. The present proof-of-concept study aimed at evaluation of the efficacy and safety of a new adenosine A1 receptor agonist capadenoson in patients with stable angina.

Methods

This was a randomized, double-blind, placebo-controlled, single dose-escalating, multicenter trial comparing the effect of capadenoson at 1, 2.5, 5, 10, and 20?mg versus placebo. For each dose step patients were randomized to receive single doses of either capadenoson or matching placebo in a 5:1 ratio. The primary efficacy variable was the absolute difference in heart rate (HR) at maximum comparable level of workload between baseline and post dose exercise tolerance test at maximum concentration of capadenoson. Capadenoson effect on total exercise time and time to 1-mm ST-segment depression were also measured.

Results

Sixty-two male patients with stable angina were enrolled in the study. There was a consistent trend for HR reduction at comparable maximum work load in active treatment groups, with significant differences against placebo for 10 and 20?mg (HR reduction by 12.2 and 6.8 beats per min, p?=?0.0002 and p?=?0.032, respectively). A statistically significant trend (p?=?0.0003) for a reduction in HR with increasing doses of capadenoson was shown. Increases in total exercise time and time to 1-mm ST-segment depression were also observed.

Conclusions

In patients with stable angina capadenoson lowers exercise HR at comparable maximum workload, which is associated with improved total exercise time and prolongation of time to ischaemia.     

Cyclin‐dependent kinase inhibitor p21, via its C‐terminal domain,is essential for resolution of murine inflammatory arthritis

Objective

The mechanism responsible for persistent synovial inflammation in rheumatoid arthritis (RA) is unknown. Previously, we demonstrated that expression of the cyclin‐dependent kinase inhibitor p21 is reduced in synovial tissue from RA patients compared to osteoarthritis patients and that p21 is a novel suppressor of the inflammatory response in macrophages. The present study was undertaken to investigate the role and mechanism of p21‐mediated suppression of experimental inflammatory arthritis.

Methods

Experimental arthritis was induced in wild‐type or p21^−/− (C57BL/6) mice, using the K/BxN serum–transfer model. Mice were administered p21 peptide mimetics as a prophylactic for arthritis development. Lipopolysaccharide‐induced cytokine and signal transduction pathways in macrophages that were treated with p21 peptide mimetics were examined by Luminex‐based assay, flow cytometry, or enzyme‐linked immunosorbent assay.

Results

Enhanced and sustained development of experimental inflammatory arthritis, associated with markedly increased numbers of macrophages and severe articular destruction, was observed in p21^−/− mice. Administration of a p21 peptide mimetic suppressed activation of macrophages and reduced the severity of experimental arthritis in p21‐intact mice only. Mechanistically, treatment with the p21 peptide mimetic led to activation of the serine/threonine kinase Akt and subsequent reduction of the activated isoform of p38 MAPK in macrophages.

Conclusion

These are the first reported data to reveal that p21 has a key role in limiting the activation response of macrophages in an inflammatory disease such as RA. Thus, targeting p21 in macrophages may be crucial for suppressing the development and persistence of RA.

     

Curcumin and its analogues: Potential anticancer agents

This review chronicles the exploration of the curcumin in terms of development of analogues for the anticancer activity over the last century. Curcumin is a natural phytochemical obtained from dried root and rhizome of Turmeric (Curcuma Longa). It has been shown to interfere with multiple cell signaling pathways, including apoptosis (activation of caspases and downregulation of antiapoptotic gene products), proliferation (HER‐2, EGFR, and AP‐1), angiogenesis (VEGF), and inflammation (NF‐κB, TNF, IL‐6, IL‐1, COX‐2, and 5‐LOX). In the last decade it has been much explored and various synthetic analogues have been prepared and evaluated for various pharmacological activities. Most of the analogues have shown very good anticancer activity in various models and various cell lines. However, some analogues have also shown antioxidant, anti‐HIV, antimutagenic, antiangiogenic, antimalarial, antitubercular, antiandrogenic, COX inhibitory activities. Few analogues have shown very potent results and may be considered as clinical candidates for the development of future anticancer agent. This review contains 728 curcumin analogues and covers the literature from 1815 to mid 2009 and 93 references are cited. © 2009 Wiley Periodicals, Inc. Med Res Rev, 30, No. 5, 818–860, 2010