Survey of chemotherapy-induced nausea and vomiting in patients with urothelial carcinoma.

Chemotherapy-induced nausea and vomiting (CINV) can cause anorexia, weight loss and deterioration of patient quality of life. It is one of the most unpleasant adverse effects of chemotherapy treatment regimens. For the optimal treatment of gastrointestinal symptoms during urothelial carcinoma chemotherapy, the present study investigated the association between gastrointestinal symptoms and therapeutic effects of gemcitabine plus platinum [cisplatin (GC) or carboplatin (GCa)] therapies. The incidence and frequency of nausea/vomiting with GC split therapy (gemcitabine, 1,000 mg/m2 on days 1 and 8; split-dose cisplatin, 35 mg/m2 on days 1 and 8; 21-day schedule) and GCa therapy [gemcitabine, 750-1,000 mg/m2 on days 1, 8 and 15; carboplatin, area under the blood concentration-time curve=5 mg min/ml (Calvert formula) on day 2; 28-day schedule] were lower compared with those of GC therapy (gemcitabine, 1,000 mg/m2 on days 1, 8 and 15; single-dose cisplatin 70 mg/m2 on day 2; 28-day schedule). However, no differences in therapeutic outcomes were observed among therapies. GCa therapy, regardless of renal function, and GC split therapy demonstrated significant increases compared with GC therapy in alleviating gastrointestinal symptoms associated with cancer chemotherapy in patients with urothelial carcinoma. Overall, these results suggested that split-dose cisplatin administration or the use of carboplatin instead of cisplatin may be useful in patients who experience CINV without compromising treatment effectiveness.

Involvement of the histamine H4 receptor in clozapine-induced hematopoietic toxicity: Vulnerability under granulocytic differentiation of HL-60 cells.

Clozapine is an effective antipsychotic for treatment-resistant schizophrenia, but can cause fatal hematopoietic toxicity as agranulocytosis. To elucidate the mechanism of hematopoietic toxicity induced by clozapine, we developed an in vitro assay system using HL-60 cells, and investigated the effect on hematopoiesis. HL-60 cells were differentiated by all-trans retinoic acid (ATRA) into three states according to the following hematopoietic process: undifferentiated HL-60 cells, those undergoing granulocytic ATRA-differentiation, and ATRA-differentiated granulocytic cells. Hematopoietic toxicity was evaluated by analyzing cell survival, cell proliferation, granulocytic differentiation, apoptosis, and necrosis. In undifferentiated HL-60 cells and ATRA-differentiated granulocytic cells, both clozapine (50 and 100µM) and doxorubicin (0.2µM) decreased the cell survival rate, but olanzapine (1-100µM) did not. Under granulocytic differentiation for 5days, clozapine, even at a concentration of 25µM, decreased survival without affecting granulocytic differentiation, increased caspase activity, and caused apoptosis rather than necrosis. Histamine H4 receptor mRNA was expressed in HL-60 cells, whereas the expression decreased under granulocytic ATRA-differentiation little by little. Both thioperamide, a histamine H4 receptor antagonist, and DEVD-FMK, a caspase-3 inhibitor, exerted protection against clozapine-induced survival rate reduction, but not of live cell counts. 4-Methylhistamine, a histamine H4 receptor agonist, decreased the survival rate and live cell counts, as did clozapine. HL-60 cells under granulocytic differentiation are vulnerable under in vitro assay conditions to hematopoietic toxicity induced by clozapine. Histamine H4 receptor is involved in the development of clozapine-induced hematopoietic toxicity through apoptosis, and may be a potential target for preventing its occurrence through granulocytic differentiation.

Behavioral phenotypes in schizophrenic animal models with multiple combinations of genetic and environmental factors.

Schizophrenia is a multifactorial psychiatric disorder in which both genetic and environmental factors play a role. Genetic [e.g., Disrupted-in-schizophrenia 1 (DISC1), Neuregulin-1 (NRG1)] and environmental factors (e.g., maternal viral infection, obstetric complications, social stress) may act during the developmental period to increase the incidence of schizophrenia. In animal models, interactions between susceptibility genes and the environment can be controlled in ways not possible in humans; therefore, such models are useful for investigating interactions between or within factors in the pathogenesis and pathophysiology of schizophrenia. We provide an overview of schizophrenic animal models investigating interactions between or within factors. First, we reviewed gene-environment interaction animal models, in which schizophrenic candidate gene mutant mice were subjected to perinatal immune activation or adolescent stress. Next, environment-environment interaction animal models, in which mice were subjected to a combination of perinatal immune activation and adolescent administration of drugs, were described. These animal models showed interaction between or within factors; behavioral changes, which were obscured by each factor, were marked by interaction of factors and vice versa. Appropriate behavioral approaches with such models will be invaluable for translational research on novel compounds, and also for providing insight into the pathogenesis and pathophysiology of schizophrenia.