Enzastaurin cardiotoxicity: QT interval prolongation, negative inotropic responses and negative chronotropic action.

Several clinical trials observed that enzastaurin prolonged QT interval in cancer patients. However, the mechanism of enzastaurin-induced QT interval prolongation is unclear. Therefore, this study aimed to assess the effect and mechanism of enzastaurin on QT interval and cardiac function. The Langendorff and Ion-Optix MyoCam systems were used to assess the effects of enzastaurin on QT interval, cardiac systolic function and intracellular Ca2+ transient in guinea pig hearts and ventricular myocytes. The effects of enzastaurin on the rapid delayed rectifier (IKr), the slow delayed rectifier K+ current (IKs), transient outward potassium current (Ito), action potentials, Ryanodine Receptor 2 (RyR2) and the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) expression and activity in HEK 293 cell system and primary cardiomyocytes were investigated using whole-cell recording technique and western blotting. We found that enzastaurin significantly prolonged QT interval in guinea pig hearts and increased the action potential duration (APD) in guinea pig cardiomyocytes in a dose-dependent manner. Enzastaurin potently inhibited IKr by binding to the human Ether-à-go-go-Related gene (hERG) channel in both open and closed states, and hERG mutant channels, including S636A, S631A, and F656V attenuated the inhibitory effect of enzastaurin. Enzastaurin also moderately decreased IKs. Additionally, enzastaurin also induced negative chronotropic action. Moreover, enzastaurin impaired cardiac systolic function and reduced intracellular Ca2+ transient via inhibition of RyR2 phosphorylation. Taken together, we found that enzastaurin prolongs QT, reduces heart rate and impairs cardiac systolic function. Therefore, we recommend that electrocardiogram (ECG) and cardiac function should be continuously monitored when enzastaurin is administered to cancer patients.

Evaluating the Role of Hydrophobic and Cationic Appendages on the Laundry Performance of Modified Hydroxyethyl Celluloses.

Soil-release polymers (SRPs) are essential additives of laundry detergents whose function is to enable soil release from fabric and to prevent soil redeposition during the washing cycle. The currently used SRPs are petrochemical-based; however, SRPs based on biorenewable polymers would be preferred from an environmental and regulatory perspective. To explore this possibility, we have synthesized SRPs based on hydroxyethyl cellulose (amphiphilic HEC) appended with controlled compositions of hydrophobic and cationic appendages and assessed their cleaning abilities. The results demonstrate that the introduction of hydrophobic lauryl appendages onto the HEC backbone is essential to deliver anti-redeposition and soil-release performance. Conversely, further introduction of cationic groups onto hydrophobic modified HECs had no clear impact on soil-release performance but caused significant disadvantages on anti-redeposition performance. We speculate that this poor performance arises on account of coacervation formation between the cationic HEC polymer and the anionic surfactant in the detergent, negatively impacting soil suspension and suggests that the inclusion of cationic appendages on HECs can ultimately lead to detrimental effects on performance. Interestingly, in contrast to conventional SPRs that exhibit good soil-release performance exclusively on synthetic fabrics, amphiphilic HEC displayed encouraging results on both synthetic and cotton-based textiles, possibly as a result of a good chemical affinity with natural fabrics. This work highlights that the nature and hydrophobic content of HEC ethers are key variables that govern HEC applicability as SRPs, thus paving the way for the design and synthesis of new SRPs.