Discovery and pharmacological characterization of novel positive allosteric modulators acting on skeletal muscle-type nicotinic acetylcholine receptors.

Skeletal muscle-type nicotinic acetylcholine receptors (m-nAChRs) are ligand-gated ion channels that open after activation by ACh and whose signals cause muscle contraction. Defects in neurotransmission are reported in disorders such as myasthenia gravis (MG) and congenital myasthenia syndromes (CMS). Although treatments for these disorders exist, therapies which significantly increase muscle strength have yet to be reported.

Discovery of highly potent and selective biphenylacylsulfonamide-based beta3-adrenergic receptor agonists and molecular modeling based on the solved X-ray structure of the beta2-adrenergic receptor: part 6.

As an extension of research, we have investigated modification of left-hand side (LHS) of biphenyl analogues containing an acylsulfonamide moiety in the development of potent and selective human beta(3)-adrenergic receptor (AR) agonists. Result of structure-activity relationships (SAR) and cassette-dosing evaluation in dogs showed that the hydroxynorephedrine analogue 16 had an excellent balance of in vitro and in vivo potency with pharmacokinetic profiles. In addition, to facilitate structure-based drug design (SBDD), we also have performed a docking study of biphenyl analogues based on the X-ray structure of the beta(2)-adrenergic receptor.

Discovery of highly potent and selective biphenylacylsulfonamide-based beta3-adrenergic receptor agonists and evaluation of physical properties as potential overactive bladder therapies: part 5.

As an extension of research conducted on beta(3)-adrenergic receptor agonists as potential drugs for treating overactive bladder (OAB), novel series containing an acylsulfonamide moiety instead of the carboxylic acid moiety were evaluated. These compounds have been identified as potent and selective human beta(3)-AR agonists with improved oral bioavailability compared to the previous series. Results of structure-activity relationship (SAR) studies and cassette dosing evaluation in dogs showed several analogues (namely, 6h, 6j, 6o, 7e, and 9e) to have an excellent balance of in vitro potency and selectivity, pharmacokinetic (PK) profile, and an in vivo OAB model.

Discovery of novel series of benzoic acid derivatives containing biphenyl ether moiety as potent and selective human beta(3)-adrenergic receptor agonists: Part IV.

Identification and SAR study of novel series of beta(3)-AR agonists with benzoic acid are described. Conversion of ether linkage position of phenoxybenzoic acid derivative 2b led to compound 7b with moderate beta(3)-AR activity. Further modification in right, center and left parts of compound 7b was investigated to improve the beta(3)-AR potency and selectivity.

Discovery of a novel series of benzoic acid derivatives as potent and selective human beta3 adrenergic receptor agonists with good oral bioavailability. 3. Phenylethanolaminotetraline (PEAT) skeleton containing biphenyl or biphenyl ether moiety.

We designed a series of benzoic acid derivatives containing the biphenyl ether or biphenyl template on the RHS and a phenylethanolaminotetraline (PEAT) skeleton, which was prepared by highly stereoselective synthesis, to generate two structurally different lead compounds ( 10c, 10m) with a good balance of potency, selectivity, and pharmacokinetic profile. Further optimization of the two lead compounds to improve potency led to several potential candidates (i.e.

Discovery of a novel series of biphenyl benzoic acid derivatives as highly potent and selective human beta3 adrenergic receptor agonists with good oral bioavailability. Part II.

The left-hand side (LHS) and central part of our first generation biphenyl (FGB) series was modified to improve in vitro and in vivo beta3-AR potency without loss of oral bioavailability. First, in this study, we focused our efforts on replacement of the 3-chlorophenyl moiety in the LHS of FGB analogues with 3-pyridyl ring analogues to adjust the lipophilicity. Second, we investigated the replacement of the central part of this series and discovered that introduction of a methyl group into the alpha-position of the phenethylamine moiety greatly enhanced potency keeping good oral availability.

Discovery of a novel series of biphenyl benzoic acid derivatives as potent and selective human beta3-adrenergic receptor agonists with good oral bioavailability. Part I.

A novel class of biphenyl analogues containing a benzoic acid moiety based on lead compound 8i have been identified as potent and selective human beta 3 adrenergic receptor (beta 3-AR) agonists with good oral bioavailability and long plasma half-life. After further substituent effects were investigated at the terminal phenyl ring of lead compound 8i, we have discovered that more lipophilic substitution at the R position improved potency and selectivity. As a result of these studies, 10a and 10e were identified as the leading candidates with the best balance of potency, selectivity, and pharmacokinetic profiles.

Inhibitory effect of zacopride on Cisplatin-induced delayed emesis in ferrets.

We evaluated the antiemetic effect of zacopride, a potent 5-HT3-receptor antagonist with 5-HT4-receptor agonist properties, on delayed emesis caused by cisplatin (5 mg/kg, i.p.) in ferrets, compared with granisetron, a selective 5-HT3-receptor antagonist.

Hepatic arterial infusion of paclitaxel for liver metastasis from gastric cancer.

Little is known about hepatic arterial infusion (HAI) of paclitaxel for hepatic malignancies. The authors administered paclitaxel via the HAI port in two patients with liver metastases from gastric cancer. Both patients were uneventfully treated without any serious complications, and its anti-tumor effect on 5-fluouracil resistant liver metastases was confirmed.

[Two cases of recurrent lung cancer successfully treated with concurrent radiochemotherapy with vinorelbine plus cisplatin].

Case 1:A 62-year-old man, who had undergone right upper lobectomy for lung squamous cell carcinoma (pT2pN2M0, stage IIA) 4 months earlier, was diagnosed as mediastinal lymph node recurrence by chest CT. Case 2: A 63-year-old woman, who had undergone right middle-lower lobectomy for lung squamous cell carcinoma (pT2pN1M0, stage IIB) 16 months earlier, was diagnosed as hilar lymph node recurrence by chest CT. Both patients underwent radiochemotherapy with 2 cycles of cisplatin (CDDP) 80 mg/m2 on day 1 and vinorelbine (VNR) 15 mg/m2 on day 1 and another day (day 8-16), and concurrent radiation (60 Gy/30 fr) for mediastinum.

The selective Na+-Ca2+ exchange inhibitor attenuates brain edema after radiofrequency lesion in rats.

2-[4-[(2,5-Difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400), a specific inhibitor of the Na+-Ca2+ exchanger, exerts cytoprotective action and reduces brain infarct volume after cerebral ischemia. We examined the effect of SEA0400 on vasogenic brain edema in rats. Histological observations showed that radiofrequency current caused brain infarct and extravasation of endogenous albumin in the brain.

Efficacy of absorbable clips compared with metal clips for cystic duct ligation in laparoscopic cholecystectomy.

Purpose: This study was conducted to examine the usefulness and safety of absorbable clips in laparoscopic cholecystectomy (LC).

Methods: We retrospectively compared the clinical data of 328 patients who underwent LC using absorbable clips for cystic duct ligation and 444 patients who underwent LC using metal clips for cystic duct ligation.

Results: The mean operative time in the absorbable clip group was significantly shorter than that in the metal clip group.

Additional right parasternal incision without thoracotomy provides alternative access for hepatic resection.

Background: Although hepatic resections are performed with various access approaches according to the location of the tumor, the extent of resection and patient's physical constitution, the exposure of the root of the hepatic veins is not optimal in some patients by any conventional incision.

Methods: An additional 5 cm of right parasternal skin incision followed by division of two costal cartilages was performed in 8 patients, which demonstrated poor exposure of the upper part of the liver by abdominal incision.

Results: In all cases, satisfactory exposure of the operative area was obtained without thoracotomy, and hepatic resection procedure was carried out without significant events.

[Reasonable approach for prophylactic hepatic arterial infusion chemotherapy after potentially curative surgery for colorectal liver metastases].

The authors discuss the reasonable management of implantable ports and catheters after cessation of adjuvant hepatic arterial infusion (HAI) chemotherapy following curative resection of colorectal liver metastases. Local recurrence in the residual liver was observed in only 4 patients of thirty-two patients (13%). Although heparin administration into the port was regularly performed in 17 patients to prevent its occlusion, the ports were successfully maintained in only 9 patients at a median time of 11.

[A case of postoperative hepatic metastasis from gastric cancer responding to hepatic arterial infusion chemotherapy of paclitaxel].

A 70-year-old man underwent total gastrectomy for advanced gastric cancer in January 2000. He was treated with UFT of 300 mg/day after surgery. In December 2000, liver metastasis was detected.

[Hepatectomy with an additional parasternal incision without thoracotomy].

A 74-year-old woman was diagnosed with hepatocellular carcinoma in S8 and underwent partial hepatectomy. A 5-cm right parasternal skin incision was added to the median incision, followed by division of the two costal cartilages, which resulted in excellent exposure of the subphrenic portion of the liver including the root of hepatic veins. The authors used this access technique in 7 patients over the past 12 months, and a satisfactory operative field was achieved in all cases.

Laparoscopic wedge resection for gastric perforation after endoscopic mucosal resection: report of a case.

We performed laparoscopic wedge resection to treat gastric perforation that occurred as a complication of endoscopic mucosal resection (EMR) in a 53-year-old man. We believe this is an appropriate procedure to treat gastric perforation after EMR for early gastric cancer because it is safe and minimally invasive, and faster recovery can be expected than after conservative therapy.

Importance of the retro-mammary space as a route of breast cancer metastasis.

Background: There are many cases of breast cancer with axillary lymph node metastases without lymphatic invasion. We hypothesized that in these cases cancer cells may pass through the retro-mammary space (RS) into lymph nodes and that axillary lymph node metastases may correlate with the tumor invasion of the RS.

Methods: A total of 127 patients who had undergone radical operation between April 1997 and April 2001 were studied.

Solitary splenic metastasis from ovarian cancer successfully treated by hand-assisted laparoscopic splenectomy: report of a case.

Solitary splenic metastasis is an extremely rare phenomenon for which splenectomy is generally indicated because a good prognosis can be achieved if chemotherapy is given postoperatively. We report herein a case of solitary splenic metastasis from ovarian cancer, which was completely removed by hand-assisted laparoscopic surgery.

An oral anticancer drug, TS-1, enabled a patient with advanced gastric cancer with Virchow's metastasis to receive curative resection.

We encountered a patient with advanced gastric cancer, with Virchow's lymph node metastasis, who subsequently underwent curative resection after neoadjuvant chemotherapy with the newly developed oral anticancer drug, TS-1. The patient was a 67-year-old woman who had a type 2 tumor in the middle third of the stomach, and Virchow's lymph node metastasis, which was diagnosed by fine-needle aspiration cytology; she also had swollen paraaortic lymph nodes. Curative resection was considered impossible, and TS-1 (100 mg/day) was administered for 28 days in one course, mainly in the outpatient clinic.

Primary squamous cell carcinoma of the stomach.

Primary squamous cell carcinoma (SCC) of the stomach is extremely rare; only 32 cases are found in the Japanese literature. The pathogenesis of this neoplasm remains obscure and controversial. Furthermore, the optimal treatment, including adjuvant chemotherapy, remains unclear.

Mast cell infiltration around gastric cancer cells correlates with tumor angiogenesis and metastasis.

BACKGROUND: Increased numbers of mast cells are found in various solid tumors. To investigate the role of mast cells in the vicinity of gastric cancer cells, we used special staining and an immunohistochemical technique.METHODS: Specimens were surgically obtained from 102 patients with gastric cancer.