Central Nervous System Ischemia Associated with Bevacizumab: An Analysis of the Japanese Adverse Drug Event Report Database.

Bevacizumab is an inhibitor of vascular endothelial growth factor (VEGF) that prevents tumor growth. While bevacizumab is therapeutically effective, it induces several adverse events. Among these, central nervous system (CNS) ischemia can lead to death or permanent disability. In this study, we reviewed the Japanese Adverse Drug Event Report database to analyze the occurrence of CNS ischemia after bevacizumab administration. Significant associations between the occurrence of CNS ischemia and bevacizumab use were detected (adjusted reporting odds ratios (ROR): 2.68, 95% confidence interval (CI): 2.00-3.59, p < 0.001). Furthermore, an association between diagnosis of glioma and bevacizumab use was also detected (p < 0.001). These events occurred early after the start of treatment and then gradually decreased; however, more than half of CNS ischemia events were reported beyond 30 d after the first administration. In addition, a logistic regression suggested that CNS ischemia caused by bevacizumab was associated with glioma, underlying hypertension and aging. A poor prognosis was reported for several cases occurring in elderly patients (over 60 years of age). Although bevacizumab is a useful pharmacological treatment for cancer, caution should be taken to avoid severe adverse events. Accordingly, the patient's general and medical condition should be carefully examined before initiating treatment, and blood pressure should be continuously assessed throughout treatment with bevacizumab to prevent CNS ischemia.

Animal studies supporting the inhibition of mast cell activation by Eriobotrya japonica seed extract.

OBJECTIVES: The potent antioxidant activity of Eriobotrya japonica seed extract (ESE) and its usefulness in the prevention and treatment of various disorders has been reported previously. Its antioxidant activity associated with beta-sitosterol and polyphenols contained in the extract was also validated. In this study, anti-allergic activity of Eriobotrya japonica seed extract was investigated. METHODS: The inhibition of histamine release-mediated type 1 allergy by Eriobotrya japonica seed extract was used as an index. KEY FINDINGS: The administration of this extract inhibited histamine release from rat mast cells, suggesting its usefulness in allergic disease treatment. In an experiment using a guinea-pig allergic rhinitis model, this extract reduced the frequency of sneezing and nose-scratching. CONCLUSIONS: These results suggest that Eriobotrya japonica seed extract may contribute to the relief of allergic disease-related symptoms.

[Inhibitory effects of "Goishi-tea" as a post-fermented-tea on dietary-induced hypercholesteremia and atherosclerosis in rabbits].

Since lipid oxidation is involved in the deterioration of hypercholesterolemia-related atherosclerosis, ingestion of drinks and foods with antioxidant actions is useful for preventing lipid oxidation. Goishi-tea is a post-fermented-tea manufactured by a unique method in Japan, and may be useful for preventing various disorders. However, there is no scientific evidence. In this study, we compared the radical scavenging activity of goishi-tea with that of other teas, and administered this tea to a rabbit model of hypercholesteremia to evaluate its usefulness in the inhibition of hypercholesteremia and atherosclerosis. The radical scavenging activity of goishi-tea was similar to that of green-tea, and was higher than that of other types of fermented-teas. On the other hand, some difference of components was found between goishi-tea and green-tea. In cholesterol-fed rabbits, low-density lipoprotein (LDL)-cholesterol level in the goishi-tea-group was lower than that in the green-tea-group. Plasma lipidperoxide value was also lower in the goishi-tea-group than in the green-tea and tap-water-groups. On aortic endothelial staining, fat area in the goishi-tea-group was lower than that in the tap-water-group. Furthermore, fat accumulation in the aortic intima in the goishi-tea-group was very low. Goishi-tea has higher antioxidant activities than the other fermented-teas tested, which were generally low, and decreased serum lipid levels, suggesting that goishitea is a very peculiar fermented-tea with usefulness in the prevention of hypercholesterolemia and atherosclerosis.

Effect of orally administered Eriobotrya japonica seed extract on allergic contact dermatitis in rats.

The anti-allergic activity of Eriobotrya japonica seeds extract (ESE) was investigated. Oral administration of ESE dramatically inhibited ear swelling due to allergic contact dermatitis caused by repeated application of two antigens, 4-ethoxymethylene-2-phenyl-2-oxazolin-5-one (oxazolone) and dinitrofluorobenzene (DNFB), respectively. The increase of histamine content in inflamed ear tissue induced by oxazolone and DNFB was significantly antagonized by orally administered ESE. Eosinophil peroxidase and myeloperoxidase activity in both models was suppressed by orally administered ESE. Tumour necrosis factor-alpha in the inflamed region caused by repeated application of DNFB was also significantly suppressed. The findings suggest that ESE may be effective for treating allergic contact dermatitis.

Eriobotrya japonica seed extract and deep sea water protect against indomethacin-induced gastric mucosal injury in rats.

We have previously reported that Eriobotrya japonica seed extract (ESE) is effective for the treatment of various gastric mucosal injuries. For the pharmaceutical preparation of ESE, we are evaluating deep sea water (DSW), which contains trace elements and has a homeostasis-enhancing effect, as the solvent. In this study, we prepared DSW containing ESE (ESE + DSW) and evaluated its usefulness for the prevention of gastric mucosal injuries using non-steroidal anti-inflammatory drug-induced acute gastric mucosal injury models in male Wistar/ST rats. Gastric mucosal injury models were prepared by administering indomethacin at 30 mg/kg orally to the rats after a 24-h fast. ESE was prepared by a routine procedure and administered at the same concentration as in the administration to humans. The rats were divided into the following 6 groups: ESE, DSW, ESE + DSW, tap water (control), rebamipide (positive control), or untreated. Gastric mucosal injuries were evaluated by measuring the injury area, lipid peroxide (LPO) level, antioxidative enzyme level, and volume of mucus. The injury area and LPO levels in plasma and gastric tissue were significantly reduced in the ESE and ESE + DSW groups compared with the control and DSW group. The plasma and gastric tissue antioxidative enzyme levels were significantly higher in the ESE and ESE + DSW groups than in the control group. These results suggest that DSW, when combined with ESE, inhibits antioxidative enzymes, and enhances the gastric mucosal protecting effect of ESE.

Gastroprotective activity of Eriobotrya japonica seed extract on experimentally induced gastric lesions in rats.

The effect of Eriobotrya japonica seed extract (ESE) prepared with 70% ethanol on gastric mucosal injury was investigated. Six experimental models with different action mechanisms were used for the evaluation. Three concentrations of ESE were prepared for each model. ESE administration was initiated 14 days before induction of gastric mucosal injury, and its effect was investigated. ESE inhibited formation of gastric mucosal injury.

Effect of Eriobotrya japonica seed extract on 5-fluorouracil-induced mucositis in hamsters.

In this study, we investigated the effects of an Eriobotrya japonica seed extract (ESE) on mucositis using a 5-fluorouracil (5-FU)-induced mucositis hamster model. This model was prepared by intraperitoneally administering 90 mg/kg of 5-FU to hamsters on Day 1, scratching 1 cm(2) of the left cheek pouch of hamsters with a wire brush on Days 2, 3, and 4, and intraperitoneally administering 60 mg/kg of 5-FU on Day 5. Mucositis was evaluated based on the mucositis score at the mucositis site, left cheek pouch thickness, histological findings on HE staining, and plasma lipid peroxide levels. On Day 10, the mucositis score and left cheek pouch thickness in the ESE group were significantly lower than those in the tap water group. Histologically, the two groups showed a defect of the cheek pouch epithelium on Day 6. On Day 10, epithelial injury and bacterial infection were noted in the tap water group. However, in the ESE group, similar findings were not observed. On Day 6, the plasma lipid peroxide level in the tap water group was significantly higher than that in the normal group. In the ESE group, the plasma lipid peroxide level was significantly lower than that in the tap water group. These results suggest that ESE is useful for treating chemotherapy-induced mucositis.

Scavenging of reactive oxygen species by Eriobotrya japonica seed extract.

We have clarified that Eriobotrya japonica seed extract has strong antioxidative activity, and is effective for the prevention and treatment of various diseases, such as hepatopathy and nephropathy. In this study, to investigate the influences of components of Eriobotrya japonica seed extract on its antioxidative activity, extracts were prepared using various solvents (n-hexane (Hex), ethyl acetate (EtOAc), n-butanol (n-BuOH), methanol (MeOH) and H2O) and the antioxidative activity of the solvent fractions and components was evaluated based on the scavenging of various radicals (DPPH and O2(-)) measured by the ESR method and the inhibition of Fe3+-ADP induced NADPH dependent lipid peroxidation in rat liver microsomes. The radical scavenging activities and inhibitory activities on lipid peroxidation differed among the solvent fractions and components. In the n-BuOH, MeOH and H2O fractions, radical scavenging activity and inhibitory activity on lipid peroxidation were high. In addition, these fractions contained abundant polyphenols, and the radical scavenging activity increased with the polyphenol content. In the low-polar Hex and EtOAc fractions, the radical scavenging activity was low, but the lipid peroxidation inhibition activity was high. These fractions contained beta-sitosterol, and the inhibitory activity on lipid peroxidation was high. Based on these findings, the antioxidative activity of Eriobotrya japonica seed extract may be derived from many components involved in a complex mechanism, resulting in high activity.

The effect of Eriobotrya japonica seed extract on oxidative stress in adriamycin-induced nephropathy in rats.

Eriobotrya japonica has been used as a medicinal plant for a long time, and its leaves are known to have many physiological actions such as anti-inflammatory, antitussive, and expectoran. In contrast, Eriobotrya japonica seeds are only known to contain amygdalin, and almost no investigations of its pharmacological action have been performed. Moreover, some anticancer agents such as adriamycin cause renal disorders as an adverse effect, and the mechanism of the adverse effect is considered to involve oxidative stress. We have reported that Eriobotrya japonica seed extract has an inhibitory effect on liver disorders. In this study, we prepared a 70% ethanol extract of Eriobotrya japonica seeds and administered the extract to rats with renal disorder induced by a single administration of 7 mg/kg body weight adriamycin, and investigated the usefulness of the extract. Increases in indices of renal function, plasma urea nitrogen, were significantly inhibited in rats treated with the Eriobotrya japonica extract compared to rats treated with tap water. In addition, the renal tissue level of reduced glutathione was significantly high in rats that ingested the extract, while the lipid peroxide levels in plasma and renal tissue were significantly low. However, no effect on renal tissue antioxidative enzymes was observed, suggesting that Eriobotrya japonica seed extract has direct antioxidative action. Based on these findings, Eriobotrya japonica seed extract may be effective in reducing the oxidative stress of adriamycin-induced renal disorder. Therefore, ingestion of Eriobotrya japonica seed extract may contribute to a reduction of the adverse effects of adriamycin.

Difference between deep seawater and surface seawater in the preventive effect of atherosclerosis.

Using surface and deep seawater collected in the sea area of Muroto Cape (Kochi, Japan), desalinated drinking samples of about 1200 hardness were prepared and examined for the effects on the prevention of atherosclerosis in dietary induced hyperlipidemia rabbits. The plasma LDL cholesterol level was lower in the deep seawater group than in the surface seawater group. GPx activity was significantly higher in the deep seawater group than in the control group, while there was no difference between the surface seawater and control groups. The level of LPO was also significantly lower in the deep seawater group than in the control group. The Sudan IV lipid stained area ratio on the inner surface of the aorta was significantly lower in the deep seawater groups than in the control group, while there was no difference between the surface seawater and control groups. The oil red O stained cross section of the aorta in the control and surface seawater administration group foam cells had accumulated to form thick layers, while in the deep seawater administration group, the degree of their accumulation was very low. These results suggested that the deep seawater was useful for the prevention of hyperlipidemia and arteriosclerosis compared to the surface seawater, and it was found that reduction of the LDL cholesterol level and enhancement of GPx activity were involved in its effects.