Intraperitoneal administration of cabazitaxel-loaded nanoparticles in peritoneal metastasis models.

Colorectal and ovarian cancers frequently develop peritoneal metastases with few treatment options. Intraperitoneal chemotherapy has shown promising therapeutic effects, but is limited by rapid drug clearance and systemic toxicity. We therefore encapsulated the cabazitaxel taxane in poly(alkyl cyanoacrylate) (PACA) nanoparticles (NPs), designed to improve intraperitoneal delivery. Toxicity of free and encapsulated cabazitaxel was investigated in rats by monitoring clinical signs, organ weight and blood hematological and biochemical parameters. Pharmacokinetics, biodistribution and treatment response were evaluated in mice. Biodistribution was investigated by measuring both cabazitaxel and the 2-ethylbutanol NP degradation product. Drug encapsulation was shown to increase intraperitoneal drug retention, leading to prolonged intraperitoneal drug residence time and higher drug concentrations in peritoneal tumors. As a result, encapsulation of cabazitaxel improved the treatment response in two in vivo models bearing intraperitoneal tumors. Together, these observations indicate a strong therapeutic potential of NP-based cabazitaxel encapsulation as a novel treatment for peritoneal metastases.

Intraperitoneal administration of nanoparticles containing tocopheryl succinate prevents peritoneal dissemination.

Intraperitoneal administration of anticancer nanoparticles is a rational strategy for preventing peritoneal dissemination of colon cancer due to the prolonged retention of nanoparticles in the abdominal cavity. However, instability of nanoparticles in body fluids causes inefficient retention, reducing its anticancer effects. We have previously developed anticancer nanoparticles containing tocopheryl succinate, which showed high in vivo stability and multifunctional anticancer effects. In the present study, we have demonstrated that peritoneal dissemination derived from colon cancer was prevented by intraperitoneal administration of tocopheryl succinate nanoparticles. The biodistribution of tocopheryl succinate nanoparticles was evaluated using inductively coupled plasma mass spectroscopy and imaging analysis in mice administered quantum dot encapsulated tocopheryl succinate nanoparticles. Intraperitoneal administration of tocopheryl succinate nanoparticles showed longer retention in the abdominal cavity than by its intravenous (i.v.) administration. Moreover, due to effective biodistribution, tumor growth was prevented by intraperitoneal administration of tocopheryl succinate nanoparticles. Furthermore, the anticancer effect was attributed to the inhibition of cancer cell proliferation and improvement of the intraperitoneal microenvironment, such as decrease in the levels of vascular endothelial growth factor A, interleukin 10, and M2-like phenotype of tumor-associated macrophages. Collectively, intraperitoneal administration of tocopheryl succinate nanoparticles is expected to have multifaceted antitumor effects against colon cancer with peritoneal dissemination.

Polymeric Chloroquine as an Effective Antimigration Agent in the Treatment of Pancreatic Cancer.

Hydroxychloroquine (HCQ) has been the subject of multiple recent preclinical and clinical studies for its beneficial use in the combination treatments of different types of cancers. Polymeric HCQ (PCQ), a macromolecular multivalent version of HCQ, has been shown to be effective in various cancer models both in vitro and in vivo as an inhibitor of cancer cell migration and experimental lung metastasis. Here, we present detailed in vitro studies that show that low concentrations of PCQ can efficiently inhibit cancer cell migration and colony formation orders of magnitude more effectively compared to HCQ. After intraperitoneal administration of PCQ in vivo, high levels of tumor accumulation and penetration are observed, combined with strong antimetastatic activity in an orthotopic pancreatic cancer model. These studies support the idea that PCQ may be effectively used at low doses as an adjuvant in the therapy of pancreatic cancer. In conjunction with previously published literature, these studies further undergird the potential of PCQ as an anticancer agent.

Chronic intraperitoneal injection of polyethylene glycol 200 in mice induces hippocampal neuroinflammation.

In vivo treatment of hydrophobic substances requires the use of organic solvents, which are often toxic. Consequently, polyethylene glycols (PEGs), which are considered as nontoxic, have been widely used for many years in chemistry and biology. We used PEG 200, which was administrated by intraperitoneal (i.p.) injection once a week to mice. After 4 months of injections, at the dose of 1.67 mL/kg, a surprising increase in expression of GFAP (glial fibrillary acidic protein) and IBA1 (ionized calcium binding adaptor molecule 1), glial markers of astrocytes and microglia respectively, was observed in the mice's hippocampus. These results were associated with a dramatic increase in pro-inflammatory cytokine interleukin-1ß (IL-1ß) expression, all together suggesting an inflammatory process. It is important to communicate these results to the scientific community to provide awareness of this potential effect when PEG 200 is used under similar conditions as a vehicle in mice.

Intraperitoneal siRNA Nanoparticles for Augmentation of Gemcitabine Efficacy in the Treatment of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma is a deadly disease with limited treatment options due to late diagnosis and resistance to conventional chemotherapy. Among emerging therapeutic targets, the CXCR4 chemokine receptor and polo-like kinase 1 (PLK1) play critical roles in the progression, metastasis, and chemoresistance of pancreatic cancer. Here, we tested the hypothesis that combining CXCR4 inhibition by a polymeric CXCR4 antagonist PAMD-CHOL with PLK1 knockdown by siRNA will enhance the therapeutic effect of gemcitabine (GEM) in the orthotopic model of metastatic pancreatic cancer. We formulated nanoparticles with cholesterol-modified PAMD and siPLK1 and found strong synergism when combined with GEM treatment in vitro in both murine and human pancreatic cancer cell lines. The biodistribution of the nanoparticles in orthotopic pancreatic cancer models revealed strong accumulation in primary and metastatic tumors, with limited hepatic disposition. The cholesterol-containing nanoparticles showed not only increased tumor accumulation than the cholesterol-lacking control but also deeper penetration into the tumors. In a therapeutic study in vivo, the triple combination of PAMD-CHOL/siPLK1 and GEM showed superior anticancer activity when compared with single and dual combination controls. In conclusion, PAMD-CHOL/siPLK1 nanoparticles synergistically enhance anticancer activity of GEM in pancreatic cancer and represent a promising addition to the treatment arsenal.

Efficacy of intraperitoneally administered paclitaxel for colorectal cancer with peritoneal metastases.

PURPOSE: Prognosis after peritoneal metastases in colorectal cancer is worse than that after lung or liver metastases. Previously, we demonstrated the safety of intraperitoneal (ip) administration of paclitaxel (PTX) combined with mFOLFOX6/CapeOX plus bevacizumab for colorectal cancer with peritoneal metastasis in a phase-I trial. Here, we evaluated the efficacy of this chemotherapy. METHODS: We enrolled six patients with histologically confirmed peritoneal metastases secondary to colorectal cancer. PTX was administered through a peritoneal access port, in combination with oxaliplatin-based systematic chemotherapy. Response rate, progression-free survival, 1-year survival rate, frequency of improvement in peritoneal cancer index (PCI), and cytology in peritoneal lavage were evaluated. This study was registered in the University Hospital Medical Information Network Clinical Trial Registry on July 1, 2016 (UNIN000022924). RESULTS: Three patients received the mFOLFOX6-bevacizumab regimen, whereas the other three received the CapeOX-bevacizumab regimen. The response rate was 25%. PCI score improved in 50% of the cases. Peritoneal lavage cytology that was positive in five patients before initiating the chemotherapy turned negative during chemotherapy in all patients. One-year survival rate was 100%, progression-free survival was 8.8 months (range, 6.8-12 months), and median survival time was 29.3 months. CONCLUSION: The ip administration of PTX with systemic chemotherapy can potentially control peritoneal metastases in colorectal cancer.

Lymphatic Uptake of Liposomes after Intraperitoneal Administration Primarily Occurs via the Diaphragmatic Lymphatics and is Dependent on Liposome Surface Properties.

Drugs are commonly administered via the intraperitoneal (IP) route to treat localized infections and cancers in patients and to test drug efficacy and toxicity in preclinical studies. Despite this, there remain large gaps in our understanding of drug absorption routes (lymph vs blood) and pharmacokinetics following IP administration. This is particularly true when drugs are administered in complex delivery systems such as liposomes which are the main marketed formulation for several drugs that are administered intraperitoneally. This study investigated the impact of liposome surface properties (charge and PEGylation) on absorption into lymph and blood, and lymphatic disposition patterns, following IP administration. To achieve this, stable 3H-dipalmitoyl-phosphatidylcholine (DPPC) and 14C-sucrose-radiolabeled liposomes of 100-150 nm diameter with negative, neutral, or positive surface charge, or a PEGylated surface, were prepared and administered intraperitoneally to rats. Radiolabel concentrations were measured in lymph, blood, and lymph nodes (LNs). Lymph was collected from the thoracic lymph duct at either the abdomen (ABD) or the jugular-subclavian junction (JSJ). The lymphatic recovery of the radiolabels was substantially lower after administration in positively charged compared to the neutral, negative, or PEGylated liposomes. Radiolabel recovery was substantially greater (up to 18-fold) in the thoracic lymph collected at the JSJ when compared to that at the ABD, suggesting that liposomes entered the lymphatics at the diaphragm. Consistent with this, the concentration of the liposome labels was substantially higher (up to seven-fold) in mediastinal than in mesenteric LNs. Overall, this study shows how the peritoneal absorption and lymphatic disposition of drugs administered intraperitoneally can be manipulated through a careful selection of the drug delivery system and may thus be optimized to treat localized conditions such as cancers, infections, inflammatory diseases, and acute and critical illness.

High Pressure Nebulization (PIPAC) Versus Injection for the Intraperitoneal Administration of mRNA Complexes.

PURPOSE: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel technique delivering drugs into the abdominal cavity as an aerosol under high pressure. It is hypothesized to have advantages such as enhancing tissue uptake, distributing drugs homogeneously within the closed and expanded abdominal cavity and higher local concentration of drugs in the peritoneal cavity. However, the clinical trials of PIPAC so far are limited to liquid chemotherapeutic solution, and the applicability of biomolecules (such as mRNA, siRNA and oligonucleotide) is not known. We aimed to investigate the feasibility of administrating mRNA lipoplexes to the peritoneal cavity via high pressure nebulization. METHODS: We firstly investigated the influences of nebulization on physicochemical properties and in vitro transfection efficiency of mRNA lipoplexes. Then, mRNA lipoplexes were delivered to healthy rats through intravenous injection, intraperitoneal injection and PIPAC, respectively. RESULTS: mRNA lipoplexes can withstand the high pressure applied during the PIPAC procedure in vitro. Bioluminescence localized to the peritoneal cavity of rats after administration by IP injection and nebulization, while intravenous injection mainly induced protein expression in the spleen. CONCLUSION: This study demonstrated that local nebulization is feasible to apply mRNA complexes in the peritoneal cavity during a PIPAC procedure.

New insight in beryllium toxicity excluding exposure to beryllium-containing dust: accumulation patterns, target organs, and elimination.

There is much contradiction between different experimental studies on beryllium (Be) toxicity. The majority of studies focus on occupational pathologies, caused by the exposure to Be dust. However, Be pollution may affect wide population groups through other exposure routes. The discrepancies between experimental studies may be attributed to the lack of adequate Be toxicity model since conventional administration routes are hampered by high acidity and low solubility of Be compounds. This study was aimed to develop a novel way to implement Be toxicity avoiding side effects, related to high acidity or low solubility of Be salts. Intraperitoneal injection of Be-glycine composition (containing BeSO4, glycine, purified water, pH adjusted to 5.5 with NaOH) was tested in the dose range 238-7622 µmol Be kg-1 (body weight, b/w) in full-grown Wistar male rats. The model provided reliable uptake of Be from the peritoneum into general circulation for at least 48 h. LD50 was found to be 687 µmol Be kg-1 (b/w). The established LD50 value differed from previous data on gastrointestinal, intramuscular or intravenous administration of Be compounds. The liver was found to act as a primary elimination route for Be and related to the highest Be content in the animal. However, it had no signs of morphological damage, which was observed only in the testes (deterioration of germinal epithelium). At the same time, the lungs, stated as a primary target tissue for Be in the models of chronic beryllium disease, did not show strong Be accumulation nor morphological changes. Survived animals showed behavioral changes, including increased motor activity and aggressive reactions in some cases, and complete spasticity in other. The obtained data show the applicability of the established modeling protocol and testified for the independence of chronic beryllium disease on Be2+ ion toxicity per se.

Repolarization of Tumor-Associated Macrophages in a Genetically Engineered Nonsmall Cell Lung Cancer Model by Intraperitoneal Administration of Hyaluronic Acid-Based Nanoparticles Encapsulating MicroRNA-125b.

Tumor-associated macrophages (TAMs) acquire a pro-tumor (M2) phenotype, which promotes tumor growth, angiogenesis, and metastasis. Certain microRNAs (miRs), such as miR-125b, can reprogram TAMs into an antitumor/pro-inflammatory (M1) phenotype. Using CD44 targeting hyaluronic acid-poly(ethylenimine) (HA-PEI)-based nanoparticles encapsulating miR-125b, we have herein shown macrophage-specific delivery and transfection upon intraperitoneal (i.p.) administration. We have exploited the inherent ability of peritoneal macrophages to migrate toward the inflammation/injury and demonstrated that following intraperitoneal administration of HA-PEI nanoparticles, there is an accumulation of HA-PEI nanoparticles in the macrophage-ablated lung tissues of both naïve and KRAS/p53 double mutant genetically engineered (KP-GEM) nonsmall cell lung cancer (NSCLC) mouse model. Additionally, upon transfection with miR-125b, we observed a >6-fold increase in the M1 to M2 macrophage ratio and 300-fold increase in the iNOS (M1 marker)/Arg-1 (M2 marker) ratio in TAMs as compared to the untreated control group. The results of these studies show that i.p. administered macrophage-specific HA-PEI nanoparticles can successfully transfect TAMs in lung tissues of both naïve mice and a KP-GEM NSCLC mouse model. Successful TAM repolarization toward the M1 phenotype has significant implication in anticancer immunotherapy.

A randomized phase II multicenter trial to explore efficacy of weekly intraperitoneal in comparison with intravenous paclitaxel administered immediately after gastrectomy to the patients with high risk of peritoneal recurrence: final results of the INPACT trial.

BACKGROUND: Intraperitoneal administration of paclitaxel had been considered a promising option to treat peritoneal metastasis, the most frequent pattern of recurrence in gastric cancer after D2 gastrectomy, but its safety and efficacy after gastrectomy had not been fully explored. METHODS: A phase II randomized comparison of postoperative intraperitoneal (IP) vs. intravenous (IV) paclitaxel was conducted. Patients with resectable gastric linitis plastica, cancer with minimal amount of peritoneal deposits (P1), or cancer positive for the peritoneal washing cytology (CY1) were eligible. After intraoperative confirmation of the above disease status and of resectability, patients were randomized to be treated either by the IP therapy (paclitaxel 60 mg/m2 delivered intraperitoneally on days 0, 14, 21, 28, 42, 49, and 56) or the IV therapy (80 mg/m2 administered intravenously using the identical schedule) before receiving further treatments with evidence-based systemic chemotherapy. The primary endpoint was 2-year survival rate. RESULTS: Of the 86 patients who were randomized intraoperatively, 83 who actually started the protocol treatment were eligible for analysis (n = 39, IP group; n = 44, IV group). The 2-year survival rate of the IP and IV groups was 64.1% (95% CI 47.9-76.9) and 72.3% (95% CI 56.3-83.2%), respectively (p = 0.5731). The IP treatment did not confer significant overall or progression-free survival benefits, and was associated with particularly poor performance in patients with residual disease, including the CY1 P0 population. CONCLUSIONS: We were unable to prove superiority of the IP paclitaxel over IV paclitaxel delivered after surgery to control advanced gastric cancer with high risk of peritoneal recurrence.

Size-dependent acute toxicity of silver nanoparticles in mice.

In this study, we aimed to evaluate changes in the acute toxicity of intraperitoneally administered silver nanoparticles (AgNPs) of varying sizes in BALB/c mice. Seven-week-old female BALB/c mice were intraperitoneally administered AgNPs measuring 10, 60, or 100 nm in diameter (0.2 mg/mouse) and then sacrificed 1, 3, or 6 h after treatment. In mice administered 10 nm AgNPs, reduced activity and piloerection were observed at 5 h post administration, and lowered body temperature was observed at 6 h post administration, with histopathological changes of congestion, vacuolation, single cell necrosis, and focal necrosis in the liver; congestion in the spleen; and apoptosis in the thymus cortex. These histopathological changes were not evident following administration of either 60 or 100 nm AgNPs. These results suggested that smaller AgNPs, e.g., those measuring 10 nm in diameter, had higher acute toxicity in mice.

Human umbilical cord Wharton jelly cells promote extra-pancreatic insulin formation and repair of renal damage in STZ-induced diabetic mice.

BACKGROUND: We evaluated the therapeutic effect and fate of high doses of human umbilical cord Wharton jelly cells (hUCWJCs) after IP administration to streptozotocin (STZ)-induced diabetic mice. METHODS: Type 1 diabetes (T1D) was induced in Kunming mice via IP injection of STZ. hUCWJCs were labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI). Diabetic animals with sustained hyperglycemia for at least 2 weeks were administered 1 × 107 Dil-hUCWJCs via intraperitoneal injection. Insulin, glucagon and PDX-1 were detected by immunofluorescence with confocal microscopy. Serum mouse and human C-peptide was assayed in blood collected via intracardiac puncture. Specific ß-cell differentiation markers and human DNA were assessed using qPCR performed with 200 ng of target DNA. RESULTS: hUCWJCs migrated to the STZ-damaged organs and contributed to lower blood glucose levels in 30% of the treated mice. Confocal microscopy revealed the presence of resident insulin-positive cells in the liver and kidneys. hUCWJC-treated mice with restored hyperglycemia also showed increased serum mouse C-peptide levels. The qPCR results, particularly in the liver, revealed that after transplantation hUCWJCs upregulated genes of endocrine precursors but failed to express endocrine stage markers. Mice with restored hyperglycemia had reduced urinary volume and lacked glomerular hypertrophy, exhibiting a morphology resembling that of normal glomeruli. Moreover, we also verified that one of the possible mechanisms by which hUCWJCs exert immunosuppressive effects is through down-regulation of the cell surface receptor HLA-1. CONCLUSIONS: We confirmed the potential of IP administration of hUCWJCs and the capability of these cells to migrate to damaged tissues and promote insulin secretion from non-pancreatic local cells and to improve renal damage. These findings confer unique therapeutic properties to hUCWJCs, suggesting a promising future in the treatment of diabetes mellitus.

Synthesis and SAR studies of 3,6-disubstituted indazole derivatives as potent hepcidin production inhibitors.

Hepcidin has emerged as the central regulatory molecule of systemic iron homeostasis. Inhibition of hepcidin could be a strategy favorable to treating anemia of chronic disease (ACD). We report herein the synthesis and structure-activity relationships (SARs) of a series of indazole compounds as hepcidin production inhibitors. The optimization study of compound 1 led to a potent hepcidin production inhibitor 45, which showed serum hepcidin lowering effects in a mouse IL-6 induced acute inflammatory model.

Feasibility of weekly intraperitoneal versus intravenous paclitaxel therapy delivered from the day of radical surgery for gastric cancer: a preliminary safety analysis of the INPACT study, a randomized controlled trial.

BACKGROUND: Peritoneal carcinomatosis is common after curative resection of gastric cancer. Intraperitoneal administration of paclitaxel (PTX) is known to control ovarian peritoneal metastases. PATIENTS AND METHODS: Patients with either linitis plastica or T4 cancer with high risk of peritoneal metastasis or recurrence but whose cancer was considered resectable were preregistered. After their cancer had been confirmed intraoperatively as resectable, the patients were randomized into either group A (PTX at 60 mg/m2 intraperitoneally on the day of surgery and on days 14, 21, 28, 42, 49, and 56) or group B (PTX at 80 mg/m2 administered intravenously by the identical schedule) before being treated by evidence-based chemotherapy. The primary end point was the 2-year survival rate. Safety, the secondary end point, was also analyzed. The study has been registered as UMIN000002957. RESULTS: Of 177 preregistered patients, 83 underwent treatment (39 by intraperitoneal administration and 44 by intravenous administration). There was no difference in patient demographics between the two groups. The incidences of surgical complications were similar between the groups, except for transient bowel obstruction observed exclusively in group A. The relative dose intensity of PTX was 81.4 % for group A and 76.3 % for group B. There was one death due to pulmonary thrombosis and a case of anaphylaxis that led to termination of the protocol treatment (group B). Other adverse events were mild and manageable. CONCLUSIONS: Intraperitoneal administration of PTX from the day of gastrectomy did not result in a higher incidence of surgical complications and adverse reactions when compared with intravenous administration of PTX.

Biochemical and molecular modulation of CCl4-induced peripheral and central damage by Tilia americana var. mexicanaextracts.

Around the world, species from the genus Tilia are commonly used because of their peripheral and central medicinal effects; they are prepared as teas and used as tranquilizing, anticonvulsant, and analgesic agents. In this study, we provide evidence of the protective effects of organic and aqueous extracts (100 mg/kg, i.p.) obtained from the leaves of Tilia americana var. mexicana on CCl4-induced liver and brain damage in the rat. Protection was observed in the liver and brain (cerebellum, cortex and cerebral hemispheres) by measuring the activity of antioxidant enzymes and levels of malondialdehyde (MDA) using spectrophotometric methods. Biochemical parameters were also assessed in serum samples from the CCl4-treated rats. The T. americana var. mexicana leaf extracts provided significant protection against CCl4-induced peripheral and central damage by increasing the activity of antioxidant enzymes, diminishing lipid peroxidation, and preventing alterations in biochemical serum parameters, such as the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-globulin (γ-GLOB), serum albumin (ALB), total bilirubin (BB), creatinine (CREA) and creatine kinase (CK), relative to the control group. Additionally, we correlated gene expression with antioxidant activity in the experimental groups treated with the organic and aqueous Tilia extracts and observed a non-statistically significant positive correlation. Our results provide evidence of the underlying biomedical properties of T. americana var. mexicana that confer its neuro- and hepatoprotective effects.

Cyclosporine A disposition, hepatic and renal tolerance in Wistar rat.

Cyclosporine A, a potent calcineurin inhibitor, has been widely used in organ transplantation and in the treatment of autoimmune diseases. It has, however, been shown to induce serious renal and hepatic side effects. The drug is also used in preclinical studies, but with little published information on the optimal dose and route of administration in rodents. Objectives of this study were to identify efficient and safe doses of cyclosporine A in rodent and to assess its effects on hepatic and renal functions. For this purpose, we tested the effects of different doses and administration routes of cyclosporine A (5, 2.5 and 1 mg/kg) administered during 28 days intraperitoneally, or by gastric feeding on Wistar rats. Our data indicate that rats injected intraperitoneally with 5 mg/kg/2d (every two days) exhibited trough cyclosporine A levels within known therapeutic range in human, but were subject to blood cyclosporine A accumulation, whereas the 5 mg/kg/d gavage resulted in only a small cyclosporine A accumulation over time. In both cases this accumulation was not deleterious to renal and hepatic functions, as shown by transaminase, urea, creatinine and bilirubin measurements.

A phase II trial of perioperative chemotherapy involving a single intraperitoneal administration of paclitaxel followed by sequential S-1 plus intravenous paclitaxel for serosa-positive gastric cancer.

BACKGROUND AND OBJECTIVES: We carried out a phase II trial to evaluate the feasibility, efficacy, and tolerability of perioperative chemotherapy including single intraperitoneal(IP) administration of paclitaxel(PTX) followed by intravenous(IV) administrations of PTX with S-1 in a neoadjuvant setting for serosa-positive gastric cancer. METHODS: Patients with cT4a gastric cancer were enrolled. A laparoscopic survey was performed before study inclusion for the confirmation of serosal invasion, negative lavage cytology, and negative peritoneal metastasis. IP PTX (80 mg/m(2)) was administered, followed by systemic chemotherapy. Surgery was performed after the completion of chemotherapy. The primary endpoint was the treatment completion rate. RESULTS: 37 patients were recruited. The treatment completion rate was 67.6% (25/37; 90% CI, 52.8-80.1%), which was significantly higher than 50%; we set this as a threshold value (P = 2.4% [one-sided]). 14 patients had target lesions; of these, 10 showed a partial response (71.4%), three had stable disease (21.4%), and one had progressive disease(7.2%). The response rate was 71.4% (10/14). All patients underwent gastrectomy with D2 lymph node dissection. The 3- and 5-year OS rates were 78.0 and 74.9%, respectively. CONCLUSIONS: Perioperative chemotherapy including neoadjuvant IP PTX followed by sequential IV PTX with S-1 for serosa-positive gastric cancer is feasible, safe, and efficient.

Relationship Between Emotional Behavior in Mice and the Concentration of (+)-α-Santalol in the Brain.

We previously reported finding anxiolytic-like activity for sandalwood oil after administration in mice. In this report, we further investigated the emotional behavior associated with inhaled or intraperitoneally administered (+)-α-santalol, the main component of sandalwood oil, in addition to examining whether pharmacological or neurological transfers are responsible for this behavior. After administration of (+)-α-santalol by inhalation or intraperitoneal injection, we assessed anxiolytic-like and locomotor activities using elevated-plus maze tests. We also examined the relationship between the emotional behavior and the (+)-α-santalol brain concentration. Anxiolytic-like activity was not observed immediately after administration or after water-immersion stress for 24 h for either the (+)-α-santalol 2 µL/L air inhalation or the (+)-α-santalol 0.03 mL/kg (i.p.) administration. However, mice administered (+)-α-santalol 0.03 mL/kg intraperitoneally exhibited a significant decrease in the locomotor activity after exposure to water-immersion stress for 24 h. The brain (+)-α-santalol concentration was 2.6 µg/g tissue after (+)-α-santalol 0.03 mL/kg (i.p.) administration. The observed shift of (+)-α-santalol to the brain suggests that this component acts via pharmacological transfer and is responsible for the sedative effect but not the anxiolytic-like activity.

Intraperitoneal administration of α-melanocyte stimulating hormone (α-MSH) suppresses food intake and induces anxiety-like behavior via the brain MC4 receptor-signaling pathway in goldfish.

α-Melanocyte stimulating hormone (α-MSH) is a peptide hormone released from the intermediate lobe of the pituitary which regulates body pigmentation. In addition to the pituitary, α-MSH is also produced in the midbrain, and exerts both anorexigenic and an anxiogenic actions. Acyl ghrelin and cholecystokinin are peripheral hormones derived from the digestive tract which affect the brain to control food intake and feeding behavior in vertebrates. In the present study, hypothesizing that plasma α-MSH may also stimulate the brain and exert central effects, we examined whether peripherally administered α-MSH affects food intake and psychomotor activity using a goldfish model. Intraperitoneal (IP) administration of α-MSH at 100 pmol g-1 body weight (BW) reduced food consumption and enhanced thigmotaxis. These α-MSH-induced actions were blocked by intracerebroventricular administration of HS024, an antagonist of the melanocortin 4 receptor (MC4R), at 50 pmol g-1 BW, whereas these actions were not attenuated by pretreatment with an IP-injected excess amount of capsaicin, a neurotoxin that destroys primary sensory (vagal and splanchnic) afferents, at 160 nmol g-1 BW. Transcripts for the MC4R showed higher expression in the diencephalon in other regions of the brain. These results suggest that, in goldfish, IP administered α-MSH is taken up by the brain, and also acts as anorexigenic and anxiogenic factor via the MC4R signaling pathway.