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A major obstacle for topical and enteral drug delivery is the poor transport of macromolecular drugs through the epithelium. One potential solution is the use of permeation enhancers that alter epithelial structures. Piperazine derivatives are known permeation enhancers that modulate epithelial structures, reduce transepithelial electrical resistance, and augment the absorption of macromolecular drugs. The mechanism by which piperazine derivatives disrupt the structures of epithelial monolayers is not well understood. Here, the effects of 1-phenylpiperazine and 1-methyl-4-phenylpiperazine are modeled in the epithelial cell line NRK-52E. Live-cell imaging reveals a dose-dependent gross reorganization of monolayers at high concentrations, but reorganization differs based on the piperazine molecule. Results show that low concentrations of piperazine derivatives increase myosin force generation within the cells and do not disrupt the cytoskeletal structure. Also, cytoskeletally attached cadherin junctions are disrupted before tight junctions. In summary, piperazines appear to increase myosin-mediated contraction followed by disruption of cell–cell contacts. These results provide new mechanistic insight into how transient epithelial permeation enhancers act and will inform of the development of future generations of transepithelial delivery systems.

The resistivity, magnetization and ultrasonic properties of charge-ordered polycrystalline (Nd(0.75)Na(0.25))(x)(Nd(0.5)Ca(0.5))(1-x)MnO(3) have been investigated from 50 to 300 K. A considerable velocity softening accompanied by an attenuation peak was observed around the charge-ordering transition temperature (T(CO)) upon cooling. The simultaneous occurrence of the charge ordering (CO) and the ultrasonic anomaly implies strong electron-phonon coupling, which originates from the cooperative Jahn-Teller effect. At very low temperature, another broad attenuation peak was observed, which is attributed to the phase separation (PS) and gives a direct evidence of spin-phonon coupling in the compound. With increasing x, T(CO) shifts to lower temperature, the magnetization of the system is strengthened and the PS is enhanced. The temperature dependence of the longitudinal modulus shows that the Jahn-Teller coupling energy E(JT) decreases with increasing Na content. The analysis suggests that the charge mismatch effect may be the main reason for the suppression of the CO and enhancement of the PS.

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