The pharmacological effects of Daikenchuto, a traditional herbal medicine, on delayed gastrointestinal transit in rat postoperative ileus

The effect of Daikenchuto, a traditional herbal medicine, on gastrointestinal hypoperistalsis in postoperative ileus (POI) was investigated. POI was induced by laparotomy with manipulation of the gastrointestine under anesthesia, and gastrointestinal transit was calculated by migration of Evans blue. Daikenchuto (270 - 2,700 mg/kg, p.o.) dose-dependently improved the delayed gastrointestinal transit in POI. This effect of Daikenchuto was partially inhibited by SB204070 (1 mg/kg, s.c.), a 5-hydroxytriptamine(4) (5-HT(4))-receptor antagonist and completely abolished by atropine (1 mg/kg, s.c.), a muscarine-receptor antagonist. Among the constituents of Daikenchuto, the medical herb zanthoxylum fruit (60 mg/kg, p.o.) and maltose syrup (2,400 mg/kg, p.o.) significantly ameliorated the delayed gastrointestinal transit, but ginseng and processed ginger did not affect the gastrointestinal transit in the rat POI. The improvement induced by zanthoxylum fruit was also inhibited by atropine or SB204070. In addition, the high osmotic pressure of the maltose syrup (2400 mg/10 mL per kg) was related to the improvement of delayed gastrointestinal transit. These results demonstrated that Daikenchuto ameliorates postoperative hypoperistalsis via cholinergic nerves and 5-HT(4) receptors and that osmotic pressure also may be involved in this action. Moreover, zanthoxylum fruit and maltose syrup were crucial medical herbs contributing to the ability of Daikenchuto.     

Management of Living Donor Liver Transplant Patients Using Twice-Daily 4-Hour Intravenous Cyclosporine Therapy

Oral administration of cyclosporine (CsA) is the currently favored route in most liver transplant centers. From October 1998 to January 2008, 86 living donor liver transplantations (LDLTs) were performed in 85 patients (46 adults and 39 children) at our institution. Seventy-three patients received tacrolimus (Tac), and 12 intravenous CsA twice daily at a dose of 3 mg/kg/d as a 4-hour continuous infusion. Thirteen of 73 Tac-based patients were switched to CsA because of side effects. Five were switched to intravenous CsA because they were unable to take the drug orally because of severe Tac-related complications. The remaining eight patients switched to oral CsA. We evaluated patients (11 adults and three children), including 12 with induction therapy and two with conversion therapy within 2 weeks of LDLT. The patients were given a 4-hour intravenous infusion of CsA at an initial dose of 3 mg/kg/d. Stable and adequate blood CsA concentrations were achieved by 4-hour intravenous CsA administration. Among several factors, only graft-to-recipient weight ratio (r = .743, P < .0001) showed significant correlations with initial blood CsA concentration. No adverse effects were observed after intravenous CsA. No patients developed biopsy-proven acute cellular rejection (ACR) during intravenous CsA administration, whereas two patients had histopathologically diagnosed episodes of ACR after conversion from intravenous to oral CsA. Our findings suggest that immediate administration of a 4-hour intravenous infusion of CsA at an initial dose of 3 mg/kg/d is practical and effective for routine clinical use.     

Inhibition of Gastroesophageal Reflux by Semi‐solid Nutrients in Patients With Percutaneous Endoscopic Gastrostomy

Background: Aspiration is one of the major complications after percutaneous endoscopic gastrostomy (PEG). The administration of semi‐solid nutrients by means of gastrostomy tube has recently been reported to be effective in preventing aspiration pneumonia. The effects of semi‐solid nutrients on gastroesophageal reflux, intragastric distribution, and gastric emptying were evaluated. Methods: Semi‐solid nutrients were prepared by liquid nutrients mixed with agar at the concentration of 0.5%. The distribution of the administered radiolabeled liquid and semi‐solid nutrients was monitored by a scintillation camera for 15 post‐PEG patients. The percentage of esophageal reflux, the distribution of the proximal and distal stomach, and the gastric emptying time were evaluated. Results: The percentage of gastroesophageal reflux was significantly decreased in semi‐solid nutrients (0.82 ± 1.27%) compared with liquid nutrients (3.75 ± 4.25%), whereas the gastric emptying time was not different. The distribution of semi‐solid nutrients was not different from liquid nutrients in the early phase, whereas higher retention of liquid nutrients in the proximal stomach was observed in the late phase. Conclusions: Gastroesophageal reflux was significantly inhibited by semi‐solid nutrients. One of the mechanisms of the inhibition is considered to be an improvement in the transition from the proximal to distal stomach in semi‐solid nutrients.     

PCR classification of CTX-M-type beta-lactamase genes identified in clinically isolated gram-negative bacilli in Japan

Of 1,456 strains isolated from 2001 to 2003 demonstrating resistance to either oxyimino-cephalosporin, 317 strains, isolated in 57 of 132 clinical facilities, were found to harbor bla(CTX-M) genes by PCR. Fifty-seven, 161, and 99 strains harbored bla(CTX-M) genes belonging to the bla(CTX-M-1), bla(CTX-M-2), and bla(CTX-M-9) clusters, respectively.     

Role of Insulin-Like Growth Factor Binding Protein 2 in Lung Adenocarcinoma : IGF-Independent Antiapoptotic Effect Via Caspase-3

Insulin-like growth factor (IGF) signaling plays a pivotal role in cell proliferation and mitogenesis. Secreted IGF-binding proteins (IGFBPs) are important modulators of IGF bioavailability; however, their intracellular functions remain elusive. We sought to assess the antiapoptotic properties of intracellular IGFBP-2 in lung adenocarcinomas. IGFBP-2 overexpression resulted in a decrease in procaspase-3 expression; however, it did not influence the phosphorylation status of either IGF receptor or its downstream targets, including Akt and extracellular signal-regulated kinase. Apoptosis induced by camptothecin was significantly inhibited by IGFBP-2 overexpression in NCI-H522 cells. Conversely, selective knockdown of IGFBP-2 using small-interfering RNA resulted in an increase in procaspase-3 expression and sensitization to camptothecin-induced apoptosis in NCI-H522 cells. {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002, an inhibitor of phosphatidyl-inositol 3-kinase, caused a decrease in IGFBP-2 levels and enhanced apoptosis in combination with camptothecin. Immunohistochemistry demonstrated that intracellular IGFBP-2 was highly expressed in lung adenocarcinomas compared with normal epithelium. Intracellular IGFBP-2 and procaspase-3 were expressed in a mutually exclusive manner. These findings suggest that intracellular IGFBP-2 regulates caspase-3 expression and contributes to the inhibitory effect on apoptosis independent of IGF. IGFBP-2, therefore, may offer a novel therapeutic target and serve as an antiapoptotic biomarker for lung adenocarcinoma.Insulin-like growth factor-I and -II (IGF-I and -II) are important regulators of cellular metabolism, growth, and survival. When IGFs bind to their receptors, the type I and type II IGF receptors (IGF-IR or IGF-IIR), they activate the downstream signaling cascades via the phosphorylation of tyrosine kinase. Activated IGF-1R transmits signals to the major distinct pathways mitogen-activated protein kinase and phosphatidyl inositol 3-kinase (PI3K), signaling pathways that are highly implicated in the development and progression of neoplasia. IGF’s bioavailability is regulated by six high affinity IGF binding proteins (IGFBPs). Secreted IGFBPs by cancer cells interfere primarily with IGF-I or -II through the formation of IGF-IGFBPs complex, which in turn exert an inhibitory effect on IGF-mediated biological functions.IGF-independent functions of extracellular IGFBPs have long been discussed. Secreted and membrane-associated IGFBP-2 directly binds to proteoglycans and integrins,^1,2,3,4,5 demonstrating IGFBP-2 as a negative or positive regulator of cell adhesion, migration, and invasion in an IGF-independent manner. In the same way, IGFBP-2 positively or negatively regulates cell growth and survival in certain types of cancers in vitro.^{2,6,7,8,9,10,11} In in vivo studies, the growth of mice colorectal adenomas induced by chemical carcinogen was inhibited when they were crossed with IGFBP-2 transgenic mice¹²; however, in contrast, IGFBP-2 exerts oncogenic effects in brain-specific transgenic mice.¹³ Thus, increased IGFBP-2 confers advantage or disadvantage for tumor growth, depending on cell type and physiological conditions.^2,14Despite these two opposite effects of IGFBP-2 on biological behaviors of cancers, biochemistry and molecular pathology have demonstrated that IGFBP-2 is overexpressed in a wide variety of human malignancies, including glioma,¹⁵ prostate cancer,¹⁶ lung cancer,^17,18,19 colorectal cancer,²⁰ ovarian cancer,²¹ adrenocortical tumor,²² breast cancer,²³ and leukemia.²⁴ Importantly, IGFBP-2 is frequently overexpressed in advanced cancers and is suggested to be involved in the metastatic process.²⁵ Several potential mechanisms of cancer progression mediated by secreted IGFBP-2 are discussed,¹⁴ but little study has been conducted to the analysis of intracellular-IGFBP-2 functions.Our aim for this study is to examine the effect of intracellular IGFBP-2 on apoptosis in lung cancer cells and elucidate its molecular mechanism. We also examine the significance of intracellular IGFBP-2 and procaspase-3 in clinical samples and explore the therapeutic implications.     

Antipsychotic potential of quinazoline ErbB1 inhibitors in a schizophrenia model established with neonatal hippocampal lesioning

Hyper-signaling of the epidermal growth factor receptor family (ErbB) is implicated in the pathophysiology of schizophrenia. Various quinazoline inhibitors targeting ErbB1 or ErbB2 - 4 have been developed as anti-cancer agents and might be useful for antipsychotic treatment. In the present study, we used an animal model of schizophrenia established by neonatal hippocampal lesioning and evaluated the neurobehavioral consequences of ErbB1-inhibitor treatment. Subchronic administration of the ErbB1 inhibitor ZD1839 to the cerebroventricle of rats receiving neonatal hippocampal lesioning ameliorated deficits in prepulse inhibition as well as those in the latent inhibition of tone-dependent fear learning. There were no apparent adverse effects on basal learning scores or locomotor activity, however. The administration of other ErbB1 inhibitors, PD153035 and OSI-774, similarly attenuated the prepulse inhibition impairment of this animal model. In parallel, there were decreases in ErbB1 phosphorylation in animals treated with ErbB1 inhibitors. These results indicate an antipsychotic potential of quinazoline ErbB1 inhibitors. ErbB receptor tyrosine kinases may be novel therapeutic targets for schizophrenia or its related psychotic symptoms.     

Feasibility and response to 1-(4-amino-2-methyl-5-pyrimidynyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride chemotherapy with pre-treated procarbazine for elderly patients with newly diagnosed glioblastoma

Purpose To evaluate the feasibility of 1-(4-amino- 2-methyl-5-pyrimidynyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) of pre-treated procarbazine for elderly patients with newly diagnosed glioblastomas. Patients and methods From January 2004 to March 2005, 7 patients with glioblastoma were enrolled. After maximal surgical resection, patients were treated with two to four cycles of procarbazine (100 mg/m² for day 1 to 5), ACNU (80 mg/m²/day¹ for day 5), cepharantine (70 mg for day 5 and 12) and vincristine (1.4 mg/m² for day 5 and 12). Results Significant toxicities of this regimen, including infectious toxicities, are described. Among the 7 patients enrolled, there were 6 patients were died, and one was still alive with disease at 13 months. The 6-month progression-free survival and 1-year overall survival are 29% (95% CI, 16% to 73%) and 29% (95% CI, 16% to 73%), respectively. Conclusion The chemotherapy regimen is active but too toxic for elderly patients with newly diagnosed glioblastoma.