Pyridine C-region analogs of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists.

A series of pyridine derivatives in the C-region of N-((6-trifluoromethyl-pyridin-3-yl)methyl) 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. The SAR analysis indicated that 6-difluorochloromethyl pyridine derivatives were the best surrogates of the C-region for previous leads. Among them, compound 31 showed excellent antagonism to capsaicin as well as to multiple hTRPV1 activators. It demonstrated strong analgesic activity in the formalin test in mice with full efficacy and it blocked capsaicin-induced hypothermia in vivo.

The effects of pH and surfactants on the absorption and fluorescence properties of ochratoxin A and zearalenone.

The pH and surfactant dependencies of the absorption and fluorescence properties of ochratoxin A (OTA) and zearalenone (ZEN), the main mycotoxins found as contaminants in foods and feeds, were evaluated. Three surfactants with different ionic properties were investigated, namely sodium dodecyl sulfate (SDS, anionic), Tween 20 (nonionic) and hexadecyltrimethylammonium bromide (CTAB, cationic). The results show that the effects of pH on the absorption wavelength maxima and fluorescence efficiencies of the mycotoxins, which are a consequence of the presence of acidic phenol and/or carboxyl containing fluorophores, are dependent on the ionic nature of the added surfactants. Specifically, the fluorescence responses to pH changes of OTA and ZEN are similar in the presence or absence of Tween 20 and SDS. By contrast, the pH-dependent fluorescence properties of these mycotoxins are altered when CTAB is present in the solutions. Moreover, unlike OTA, ZEN in aqueous solution displays almost no fluorescence. However, fluorescence enhancement takes place when surfactants are present in aqueous solutions of this mycotoxin. The results of this study demonstrate that the different microenvironments, present in the organized micellar systems created by the individual surfactants, can be potentially employed to modulate the sensitivities and selectivities of the fluorescence detection of OTA or ZEN.

α-Methylated simplified resiniferatoxin (sRTX) thiourea analogues as potent and stereospecific TRPV1 antagonists.

A series of α-methylated analogues of the potent sRTX thiourea antagonists were investigated as rTRPV1 ligands in order to examine the effect of α-methylation on receptor activity. The SAR analysis indicated that activity was stereospecific with the (R)-configuration of the newly formed chiral center providing high binding affinity and potent antagonism while the configuration of the C-region was not significant.

[A case of basaloid squamous cell carcinoma of rectosigmoid colon].

Basaloid squamous cell carcinoma is a rare and aggressive variant of squamous cell carcinoma, which mostly occurs in the upper aerodigestive tracts. Basaloid squamous cell carcinoma also typically arises in the anal canal, but is extremely rare in the lower gastrointestinal tract. A 70-year-old man presented with loose stool and intermittent hematochezia 2 months ago. Colonoscopy showed an ulceroinfiltrative mass on the rectosigmoid colon from 16 cm to 18 cm above the anal verge. Conventional colonoscope could not pass through the lesion but it was possible with pediatric colonoscope. Abdominal CT scan showed 1.6 cm sized wall thickening with circumferential luminal narrowing in the rectosigmoid colon and multiple ill-defined low density masses in both lobes of the liver. Therefore, colon cancer with liver metastasis was suspected. However, basaloid cells were noted on histologic examination, and they were weakly positive for synaptophysin on immunohistochemical study. After palliative lower anterior resection, histologic examination of the resected specimen revealed basaloid differentiation with keratin pearls, and tumor cells were positively stained with high molecular weighted cytokeratin (34BE12) and CK 5/6. Thus, the patient was finally diagnosed with basaloid squamous cell carcinoma of rectosigmoid colon with distant metastases.

Bedside index for severity in acute pancreatitis: comparison with other scoring systems in predicting severity and organ failure.

BACKGROUND: The early identification of severe acute pancreatitis is important for the management and for improving outcomes. The bedside index for severity in acute pancreatitis (BISAP) has been considered as an accurate method for risk stratification in patients with acute pancreatitis. This study aimed to evaluate the comparative usefulness of the BISAP. METHODS: We retrospectively analyzed 303 patients with acute pancreatitis diagnosed at our hospital from March 2007 to December 2010. BISAP, APACHE-II, Ranson criteria, and CT severity index (CTSI) of all patients were calculated. We stratified the number of patiants with severe pancreatitis, pancreatic necrosis, and organ failure as well as the number of deaths by BISAP score. We used the area under the receiver-operating curve (AUC) to compare BISAP with other scoring systems, C-reactive protein (CRP), hematocrit, and body mass index (BMI) with regard to prediction of severe acute pancreatitis, necrosis, organ failure, and death. RESULTS: Of the 303 patiants, 31 (10.2%) were classified as having severe acute pancreatitis. Organ failure occurred in 23 (7.6%) patients, pancreatic necrosis in 40 (13.2%), and death in 6 (2.0%). A BISAP score of 2 was a statistically significant cutoff value for the diagnosis of severe acute pancreatitis, organ failure, and mortality. AUCs for BISAP predicting severe pancreatitis and death were 0.80 and 0.86, respectively, which were similar to those for APACHE-II (0.80, 0.87) and Ranson criteria (0.74, 0.74) and greater than AUCs for CTSI (0.67, 0.42). The AUC for organ failure predicted by BISAP, APACHE-II, Ranson criteria, and CTSI was 0.93, 0.95, 0.84 and 0.57, respectively. AUCs for BISAP predicting severity, organ failure, and death were greater than those for CRP (0.69, 0.80, 0.72), hematocrit (0.45, 0.35, 0.14), and BMI (0.41, 0.47, 0.17). CONCLUSION: The BISAP predicts severity, death, and especially organ failure in acute pancreatitis as well as APACHE-II does and better than Ranson criteria, CTSI, CRP, hematocrit, and BMI.

Differentiation of mucinous cystic neoplasm and cystic changes associated with pancreatic adenocarcinoma.

A 63-year-old woman presented to the hospital with persistent nausea, dyspepsia and weight loss for 6 months. Abdomen CT showed a low-attenuation mass, approximately 7.6 cm diameter, in the region of the body and tail of the pancreas. Cystic lesions, 5.5×4.9 cm and 4.6×3.7 cm in size, were observed in the body and tail of the pancreas, respectively, associated with the low-attenuation mass. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) revealed fetal carcinoembryonic antigen levels of >1000 ng/mL and necrotic cells with no malignant cells. On the basis of the imaging and EUS-FNA results, a putative diagnosis of mucinous cystadenoma accompanying pancreatic adenocarcinoma was made, and distal pancreatectomy and splenectomy were performed. Final biopsy using the surgical specimen confirmed pancreatic adenocarcinoma with moderate differentiation accompanied by degenerative cystic changes.

TRPV1 antagonist with high analgesic efficacy: 2-Thio pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides.

A series of 2-thio pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Among them, compound 24S showed stereospecific and excellent TRPV1 antagonism of capsaicin-induced activation. Further, it demonstrated strong anti-allodynic in a rat neuropathic pain model. Consistent with its action in vitro being through TRPV1, compound 24S blocked capsaicin-induced hypothermia in mice. Docking analysis of 24S with our hTRPV1 homology model was performed to identify its binding mode.

The carbonate analogues of 5'-halogenated resiniferatoxin as TRPV1 ligands.

A series of carbonate analogues of 5'-halogenated RTX have been investigated in order to examine the effect of the carbonate group as a linker and the role of halogens in the reversal of activity from agonism to antagonism for rat and human TRPV1 heterologously expressed in Chinese hamster ovary cells. The carbonate analogues showed similar activities to the corresponding RTX derivatives in rat TRPV1 but lower potency in human TRPV1. 5-Halogenation converted the agonists to partial agonists or full antagonists and the extent of antagonism reflected the order of I>Br>Cl>F, with a somewhat greater extent of antagonism for the derivatives of the 4-amino RTX surrogates compared to the corresponding derivatives of RTX itself. The carbonate analogues of I-RTX (60) and 5-bromo-4-amino-RTX (66) were potent and full antagonists with Ki(ant)=2.23 and 2.46 nM, respectively, for rat TRPV1, which were ca. 5-fold more potent than I-RTX (2) under our conditions. The conformational analysis of the I-RTX-carbonate (60) indicated that its bent conformation was similar to that of I-RTX, consistent with compound 60 and I-RTX showing comparable potent antagonism.