Memory Enhancement by Oral Administration of Extract of Eleutherococcus senticosus Leaves and Active Compounds Transferred in the Brain.

The pharmacological properties of Eleutherococcus senticosus leaf have not been clarified although it is taken as a food item. In this study, the effects of water extract of Eleutherococcus senticosus leaves on memory function were investigated in normal mice. Oral administration of the extract for 17 days significantly enhanced object recognition memory. Compounds absorbed in blood and the brain after oral administration of the leaf extract were detected by LC-MS/MS analyses. Primarily detected compounds in plasma and the cerebral cortex were ciwujianoside C3, eleutheroside M, ciwujianoside B, and ciwujianoside A1. Pure compounds except for ciwujianoside A1 were administered orally for 17 days to normal mice. Ciwujianoside C3, eleutheroside M, and ciwujianoside B significantly enhanced object recognition memory. These results demonstrated that oral administration of the leaf extract of E. senticosus enhances memory function, and that active ingredients in the extract, such as ciwujianoside C3, eleutheroside M, and ciwujianoside B, were able to penetrate and work in the brain. Those three compounds as well as the leaf extract had dendrite extension activity against primary cultured cortical neurons. The effect might relate to memory enhancement.

Calcium channel blockers reduce oxaliplatin-induced acute neuropathy: a retrospective study of 69 male patients receiving modified FOLFOX6 therapy.

Oxaliplatin-based chemotherapy has been widely used for colorectal cancer. However, it causes severe acute and chronic peripheral neuropathies. Recently, we reported that calcium channel blockers prevent the oxaliplatin-induced cold hyperalgesia in rats. The purpose of this study was to determine whether the treatment with calcium channel blockers prevents the peripheral neuropathy during oxaliplatin therapy. The electronic medical charts for patients who received modified FOLFOX6 regimen from January 2008 to December 2010 were evaluated. Of the 200 patients who received modified FOLFOX6 therapy, 84 patients were excluded due to the exclusion criteria. Calcium channel blockers had been taken by 26 of 69 male patients, but only three of 47 female patients. Therefore, in the present analysis, the male data of the groups with and without calcium channel blockers (n=26 and 43, respectively) were compared. The cumulative incidence curve of acute neuropathy was significantly lower in the group with calcium channel blockers (P=0.0438, log-rank test), whereas there was no difference between these groups in the cumulative incidence curve of chronic neuropathy (P=0.4919, log-rank test). The present study indicated that calcium channel blockers inhibit the development of acute peripheral neuropathy in patients receiving modified FOLFOX6 therapy.

Change of formulation decreases venous irritation in breast cancer patients receiving epirubicin.

PURPOSE: Epirubicin is an antitumor drug, particularly used in the treatment of the breast cancer. The peripheral intravenous infusion of epirubicin frequently causes venous irritation such as, erythema, injection site pain, and phlebitis. The purpose of the present study was to investigate the risk factor associated with the epirubicin-induced venous irritation and to establish a suitable administration method of epirubicin. METHODS: The phlebitis scores (Visual Infusion Phlebitis score) were evaluated retrospectively using the collected nursing record. We analyzed the risk factor associated with venous irritation in 97 patients administered with epirubicin from December 2004 to September 2008. We subsequently changed the regimen of epirubicin and examined the incidence of venous irritation in 26 patients administered with epirubicin from August 2009 to March 2010. RESULTS: The phlebitis scores were significantly higher in the patients treated with ready-to-use solution compared with lyophilized powder (P = 0.04). Based on this result, we switched the formulation of epirubicin to lyophilized powder. After the intervention, the phlebitis scores were significantly decreased (P = 0.003). An ordinal logistic regression analysis revealed that use of ready-to-use solution was a significant predictor for venous irritation (odds ratio = 3.70; 95%, confidence intervals, 1.29-11.45; P = 0.02). CONCLUSIONS: The use of ready-to-use solution was a risk factor for epirubicin-induced venous irritation. The change of formulation by pharmacist intervention decreased the risk of venous irritation.

Role of oxidative stress in vinorelbine-induced vascular endothelial cell injury.

Vinorelbine (VNR), a vinca alkaloid anticancer drug, often causes vascular injury such as venous irritation, vascular pain, phlebitis, and necrotizing vasculitis. The purpose of this study was to identify the mechanisms that mediate the cell injury induced by VNR in porcine aorta endothelial cells (PAECs). PAECs were exposed to VNR for 10 min followed by further incubation in serum-free medium without VNR. The exposure to VNR (0.3-30 microM) decreased the cell viability concentration and time dependently. The incidence of apoptotic cells significantly increased at 12 h after transient exposure to VNR. At the same time, VNR increased the activity of caspases. Interestingly, VNR rapidly depleted intracellular glutathione (GSH) and increased intracellular reactive oxygen species (ROS) production. Moreover, VNR depolarized the mitochondrial membrane potential and decreased cellular ATP levels. These VNR-induced cell abnormalities were almost completely inhibited by GSH and N-acetylcysteine. On the other hand, L-buthionine-(S,R)-sulfoximine, a specific inhibitor of GSH synthesis, aggravated the VNR-induced loss of cell viability. These results clearly demonstrate that VNR induces oxidative stress by depleting intracellular GSH and increasing ROS production in PAECs, and oxidative stress plays an important role in the VNR-induced cell injury.

Protective effects of amino acids against gabexate mesilate-induced cell injury in porcine aorta endothelial cells.

Gabexate mesilate (GM), a serine protease inhibitor, often causes severe vascular injury. We previously reported that GM induced necrotic cell death via injury of the cell membrane in porcine aorta endothelial cells (PAECs). In the present study, we investigated the protective effects of amino acids against this GM-induced cell injury in PAECs. L-Cysteine (Cys), glycine (Gly), L-serine, L-glutamine (Gln), L-glutamate (Glu), L-proline, L-methionine, L-threonine, and L-isoleucine significantly inhibited the GM-induced decrease of cell viability. Gly showed the most potent effect among these amino acids. Gly, L-Cys, L-Glu, and L-Gln also inhibited the GM-induced increase in the number of necrotic cells stained by propidium iodide (PI). However, these amino acids had no effect on the GM-induced inhibition of trypsin activity. Strychnine, MK-801, or dichlorokynurenic acid did not affect the protective effect of Gly. Gly completely suppressed the GM-induced increase in PI uptake, which occurred immediately after exposure to GM. These findings suggest that Gly exerts protection against GM-induced cellular membrane injury, and several amino acids such as Gly may be useful for prophylaxis of the GM-induced severe vascular injury.

Characteristics of gabexate mesilate-induced cell injury in porcine aorta endothelial cells.

Gabexate mesilate (GM), a serine protease inhibitor, often causes severe vascular injury, when injected in high concentration. In the present study, we investigated the mechanisms for the cytotoxicity of GM on porcine aorta endothelial cells (PAECs). GM (0.5 - 5.0 mM) decreased cell viability in a dose-dependent manner and caused cell injury, whilst nafamostat mesilate (NM), another serine protease inhibitor, or mesilate itself had no effect on cell viability. zVAD-fmk, a pancaspase inhibitor, or zDEVD-fmk, a caspase-3 inhibitor, did not affect the GM (1.5 mM)-induced decrease of cell viability. Apoptotic cells or DNA fragmentation were also not observed after GM treatment. Moreover, Ca(2+) chelators, a nitric oxide (NO) synthase inhibitor, antioxidants, and radical scavengers had no effect on the GM-induced cell injury. On the other hand, cellular ATP content was decreased in the GM (2.0 mM)-treated cells. Surprisingly, GM (2.0 mM) immediately increased cellular uptake of propidium iodine. These findings suggest that GM induces necrotic cell death via injury of the cell membrane.