A combination treatment with a mood stabilizer and an antipsychotic drug is often used in as many as 90% of subjects with acute mania. Recently, augmentation therapy with atypical antipsychotics has been investigated in both the acute and long-term treatment of bipolar disorder with or without psychosis. In the present study, the authors investigated the efficacy of risperidone treatment for both acute manic and depressive episodes in bipolar disorder. Eighteen patients (M/F: 8/10, age: 34 +/- 15 yr) who met the DSM-IV criteria for bipolar I disorder (12 cases of manic episodes, 6 cases of depressive episodes) with risperidone treatment were evaluated regarding their clinical improvement using the Young Mania rating Scale (YMRS) and the Hamilton rating Scale for Depression (Ham-D). Plasma concentrations of HVA and MHPG were analyzed by HPLC-ECD and plasma brain-derived neurotrophic factor (BDNF) levels were detected by sandwich ELISA. The mean scores of the YMRS were 22, 18, 12, 8, and 5 at time points before and 1, 2, 3, and 4 weeks after the risperidone administration, respectively. The mean scores of the Ham-D were 24, 25, 21, 21, and 19 at time points before and 1, 2, 3, and 4 weeks after the risperidone administration, respectively. The plasma levels of HVA and 3-methoxy-4-hydroxyphenylglycol (MHPG) were observed to have decreased 4 weeks after risperidone administration in manic patients. The levels did not change in depressive patients. The plasma levels of BDNF were decreased in depressive patients compared with manic patients or healthy controls. However, the administration of risperidone did not alter plasma BDNF levels.

We investigated the effect of a peroxisome proliferator-activated receptor alpha (PPARα) agonist ophthalmic solution in wound healing using a rat corneal alkali burn model. After instillation of a selective agonist of PPARα, fenofibrate, onto the burned cornea, PPARα-positive cells were observed in vascular endothelial cells, and there was upregulation of mRNA of PPARα in corneal stroma. Fenofibrate suppressed expression of neutrophils and macrophages during the early phase, and development of neovascularization and myofibroblast generation during the late phase. Fenofibrate reduced not only mRNA expression of vascular endothelial growth factor-A but also angiopoietin-1 and angiopoietin-2. Furthermore, fenofibrate suppressed scar formation by reducing type III collagen expression. These data suggest that a PPARα agonist ophthalmic solution might be a new strategy for treating corneal wounds through not only anti-inflammatory effects but also by preventing neovascularization.

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Evidence suggests that the use of angiotensin-converting enzyme inhibitors potentially reduces the risk of cancer, though the mechanism is unclear. To clarify a potential involvement of angiotensin II (Ang II) signaling in cancer risk, we have examined the effect of Ang II receptor deficiency on azoxymethane (AOM)-induced colon tumorigenesis. Male Ang II type 2 receptor gene-disrupted (AT(2)-null) mice with a 129/Ola and C57BL/6J genetic background, AT(2)-null mice with an SWR/J genetic background, and their corresponding control wild type mice were treated once a week with AOM (10 mg/kg, i.p., 4 consecutive weeks) or saline vehicle. All mice were killed 23-26 weeks after the initial injection of AOM, and tumor burdens were examined. AOM treatment caused the development of colon tumors in all wild type control mice regardless of genetic background (100% tumor prevalence), but only one tumor was present in AT(2)-null mice with a 129/Ola and C57BL/6J genetic background (11.1% tumor prevalence). Although the introduction of the AOMsusceptible SWR/J genetic background induced AOM susceptibility in AT(2) null mice, the tumor multiplicity (6.3) and tumor size (19.8 +/- 3.0 mm(3)) were significantly smaller than those in wild type mice (multiplicity, 12.0 and size, 36.8 +/- 3.2 mm(3)). AOM efficiently downregulated cytochrome P450 2E1 (CYP2E1) in the liver of wild type mice significantly more than in AT(2)-null mice. The levels of DNA methyl adducts formed in wild type mouse colon epithelium by AOM treatment were also significantly higher than in AT(2)-null mice. These results imply that the AT(2) receptor functions to augment AOM-induced downregulation of CYP2E1 expression in the liver, and thus increases AOM-induced tumorigenesis in the colon. The AT(2) receptor function in the liver may be a potential determinant of tumor susceptibility in chemical carcinogen-induced colon tumorigenesis.

Nitric oxide (NO) is involved in pathophysiology of psychiatric disorders such as depression and schizophrenia. We hypothesize that plasma levels of NO and its metabolites (NO(x)) are decreased in patients with schizophrenia. To examine the hypothesis, we compared plasma NO(x) levels between 30 schizophrenic patients (M/F: 18/12, age: 38 +/- 15 years) and age- and sex-matched 30 healthy controls (M/F: 18/12, age: 41 +/- 19 years), and we also examined the effects of risperidone on plasma NO(x) levels in schizophrenic patients. The baseline plasma NO(x) levels were significantly lower in the schizophrenia group (1.85 +/- 0.70 microM) than those in control group (3.37 +/- 2.27 microM). A significantly negative correlation was found between plasma NO(x) levels and PANSS-N scores before risperidone administration (rho = -0.385, p = 0.0416). Treatment with risperidone significantly increased the plasma NO(x) levels by 8 weeks (before; 1.85 +/- 0.70 microM, after; 2.25 +/- 1.00 microM, p = 0.0491). These results suggest that NO might be one of the candidates factors which are associated with the pathophysiology of negative symptoms of schizophrenia.