Development of a New Benzophenone–Diketopiperazine-Type Potent Antimicrotubule Agent Possessing a 2-Pyridine Structure

相似文献   

Disruptive neuronal development by acrylamide in the hippocampal dentate hilus after developmental exposure in rats

To examine whether developmental exposure to acrylamide (AA) impairs neuronal development, pregnant Sprague–Dawley rats were treated with AA at 0, 25, 50 or 100 ppm in drinking water from gestational day 6 until weaning on postnatal day 21. Offspring were immunohistochemically examined at the end of exposure. We investigated the expression of Reelin (a molecule regulating neuronal migration and positioning) in the hilus of the hippocampal dentate gyrus. As a positive control for direct exposure, AA (50 mg/kg body weight) was administered to pups by intraperitoneal injection 3 times per week during the lactation period. As well as pups directly injected with AA, maternally exposed offspring decreased body weight at 100 ppm; increased dose-dependently the number of Reelin-immunoreactive cells (from 25 ppm AA) and glutamic acid decarboxylase 67-immunoreactive cells (from 50 ppm AA), confirming an increase in γ-aminobutyric acid-ergic interneurons. We also noted decreased apoptosis in the neuroblast-producing subgranular zone of the dentate gyrus of maternally exposed pups at 100 ppm, as well as in directly AA-injected pups. These results suggest that a compensatory regulatory mechanism exists to correct impaired neurogenesis and mismigration caused by maternal exposure to AA during neuronal development. The lowest-observed-adverse-effect level of AA was determined to be 25 ppm (3.72 mg/kg body weight/day).     

The effect of dopamine depletion on the H2O2 production in the rat striatum following transient middle cerebral artery occlusion

The changes in the extracellular concentrations of rat striatal H₂O₂, dopamine (DA) and its metabolites during middle cerebral artery (MCA) occlusion and reperfusion were simultaneously examined by microdialysis, and the relationship between the ischemia-induced release of DA and the generation of H₂O₂ was estimated by assessing the effect of the lesion of the substantia nigra (SN). In the rats without SN lesions, a significant increase in the striatal H₂O₂ level was observed during the ischemia and reperfusion phases. In the rats with SN lesions, the ischemia-induced H₂O₂ production was not attenuated. These results suggest that DA is not an important source of H₂O₂ in cerebral ischemia and reperfusion.     

Second-phase validation study of short time exposure test for assessment of eye irritation potency of chemicals

A Short Time Exposure (STE) test is a cytotoxicity test that uses SIRC cells (rabbit corneal cell line) to assess eye irritation potency following a 5-min chemical exposure. This second-phase validation study assessed the predictive capacity of the STE test using 40 coded test substances at three laboratories. A Validation Management Team (VMT) then evaluated the predictivity of the STE test for United Nation (UN) Globally Harmonized System (GHS) categories using 63 test substances including the results of the first-phase validation study.The STE test can assess not only the severe or corrosive ocular irritants (corresponding to the UN GHS Category 1) but also non-irritant (corresponding to UN GHS Non Category) from other toxicity classes, especially for limited types of test substances. The predictivity by STE test, however, was insufficient for identification of UN GHS categories (Category 1, Category 2, or Non Category).These results suggest that the STE test can be recommended as an initial step in a top-down approach to identification of severe irritants and test substances that require classification for eye irritation (UN GHS Category 1) as well as an initial step in a bottom-up approach to identification of test substances that do not require classification for eye irritation (UN GHS Non Category) from other toxicity classes, especially for limited types of test substances. On the other hand, the STE test is not considered adequate for the identification of mild or moderate irritants (i.e., UN GHS Categories 2A and 2B) and severe irritants (UN GHS Category 1).     

A stage-dependent follow-up strategy after radical cystectomy for bladder carcinoma

With the aim of developing stage-dependent follow-up strategy after radical cystectomy for bladder carcinoma, the records of 111 patients with bladder carcinoma who underwent radical cystectomy during the period between 1986 and 2003, were reviewed for the date and site of recurrence. Intrapelvic recurrence developed in 3 out of 56 patients with pT1> or =, 1 of 22 with pT2 and 6 out of 33 with pT3< or = at a median of 34 (range 32-58), 28, 8 (4-51) months, respectively. Extrapelvic recurrence developed in 20 patients with pT1> or =, 4 with pT2 and 14 with pT3< or = at a median of 43 (20-66), 15.5 (13-20), 8 (2-46) months, respectively. Recurrence developed earlier and more frequently in patients with pT3< or = and pT2 than those with pT1> or =. A stage-specific approach to tumor surveillance after radical cystectomy for bladder carcinoma, taking into consideration the risk of recurrence, represents a new approach for efficiently detecting recurrence and reducing medical costs. Our results offer the possibility of a new stage-specific approach to tumor surveillance after radical cystectomy for bladder carcinoma, for efficiently detecting recurrence and reducing medical costs, taking into consideration the risk of recurrence.     

Effect of high dose methylprednisolone pulse therapy followed by oral prednisolone administration on the production of anti-TSH receptor antibodies and clinical outcome in Graves' disease

Little is known about the immunosuppressive effect of glucocorticoids on TSH receptor antibodies. We observed the long-term prognosis and serum TSH binding inhibitor immunoglobulin (TBII) levels in patients with Graves' ophthalmopathy who had received intravenous methylprednisolone pulse therapy (pulse therapy) followed by oral prednisolone administration in order to ascertain how long the immunosuppressive effect of glucocorticoids continued. This is the first report on the effect of pulse therapy on Graves' disease outcome. We observed 67 patients who were treated by antithyroid drugs (ATD) alone for 2 years after pulse therapy. TBII was evaluated before and 3, 6, 12, 18, and 24 months after pulse therapy. The mean TBII decreased significantly 3 months after pulse therapy (p<0.001), and was maintained until 24 months. There were 24 patients whose TBII was positive (>15%) at 24 months, in whom the mean TBII decreased significantly 3 to 6 months after pulse therapy (p<0.001), but increased again at 12 to 24 months (p<0.05). Thus, the immunosuppressive effect of glucocorticoids may be lost at 12 months after pulse therapy in these patients. The remission rate in the pulse therapy group was 40.98%, and that of the control patient group was 48.57%. There was no significant difference between the two. These results suggest that the immunosuppressive effect of pulse therapy was temporary, and that pulse therapy did not increase remission rate of Graves' disease.