Serofendic acid is a low-molecular-weight compound extracted from fetal calf serum. We previously reported that intracerebroventricular administration of serofendic acid prevents cerebral ischemia-reperfusion injury. However, the effect of peripheral administration of serofendic acid on cerebral ischemia-reperfusion injury has not been examined. In the present study, we investigated the effect of intravenous administration of serofendic acid against cerebral ischemia-reperfusion injury using transient middle cerebral artery occlusion model rats. Serofendic acid (10mg/kg) administrated three times, including 30min before the onset of ischemia, just after the onset of ischemia and just before reperfusion reduced the infarct volume and improved the neurological dysfunction induced by ischemia-reperfusion without affecting regional cerebral blood flow or physiological parameters. However, there were no protective effects when serofendic acid (30mg/kg) was only administered once at 30min before the onset of ischemia, just after the onset of ischemia, or just before reperfusion. Our results reveal the importance of maintaining the blood concentration of serofendic acid for preventing cerebral ischemia-reperfusion injury.

Abstract. We previously reported that serofendic acid, a lipophilic extract of fetal calf serum, protects against oxidative stress in primary culture of neonatal rat cardiomyocytes. However, the effect of serofendic acid on myocardial ischemia-reperfusion injury in vivo is yet to be determined. In the present study, we investigated the effect of intravenous administration of serofendic acid on ischemia-reperfusion injury induced by transient occlusion of the left coronary artery in rats. The rat heart was subjected to 25min ischemia followed by 2h reperfusion. Bolus intravenous administration of serofendic acid (1 -10 mg/kg) given twice reduced the infarct volume in a dose dependent manner. The protective effect of serofendic acid was abolished by pretreatment with 5hydroxydecanoate, a blocker of mitochondrial ATPsensitive potassium channels. For further testing of the protective effect of serofendic acid at the subcellular level, we monitored mitochon drial membrane potential (MMP) in individual cells using realtime twophoton imaging of Langendorffperfused rat heart. A 25min noflow ischemia, followed by reperfusion caused progressive MMP loss. Serofendic acid significantly reduced the number of cells undergoing MMP loss. These results suggest that serofendic acid protected cardiac myocytes against myocardial ischemia-reperfusion injury by preserving the functional integrity of mitochondria.

Purpose The clinical application of gemcitabine (GEM) is limited by its pharmacokinetic properties. The aim of this study was to characterize the stability in circulating plasma, tumor targeting, and payload release of liposome-encapsulated GEM, FF-10832. Methods Antitumor activity was assessed in xenograft mouse models of human pancreatic cancer. The pharmacokinetics of GEM and its active metabolite dFdCTP were also evaluated. Results In mice with Capan-1 tumors, the dose-normalized areas under the curve (AUCs) after FF-10832 administration in plasma and tumor were 672 and 1047 times higher, respectively, than after using unencapsulated GEM. The tumor-to-bone marrow AUC ratio of dFdCTP was approximately eight times higher after FF-10832 administration than after GEM administration. These results indicated that liposomal encapsulation produced long-term stability in circulating plasma and tumor-selective targeting of GEM. In mice with Capan-1, SUIT-2, and BxPC-3 tumors, FF-10832 had better antitumor activity and tolerability than GEM. Internalization of FF-10832 in tumor-associated macrophages (TAMs) was revealed by flow cytometry and confocal laser scanning microscopy, and GEM was efficiently released from isolated macrophages of mice treated with FF-10832. These results suggest that TAMs are one of the potential reservoirs of GEM in tumors. Conclusion This study found that FF-10832 had favorable pharmacokinetic properties. The liposomal formulation was more effective and tolerable than unencapsulated GEM in mouse xenograft tumor models. Hence, FF-10832 is a promising candidate for the treatment of pancreatic cancer.