The tissue effect of argon-plasma coagulation with prior submucosal injection (Hybrid-APC) versus standard APC: A randomized ex-vivo study.

BACKGROUND: Thermal ablation for Barrett's oesophagus has widely been established in gastrointestinal endoscopy during the last decade. The mainly used methods of radiofrequency ablation (RFA) and argon-plasma coagulation (APC) carry a relevant risk of stricture formation of up to 5-15%. Newer ablation techniques that are able to overcome this disadvantage would therefore be desirable. The aim of the present study was to compare the depth of tissue injury of the new method of Hybrid-APC versus standard APC within a randomized study in a porcine oesophagus model. METHODS: Using a total of eight explanted pig oesophagi, 48 oesophageal areas were ablated either by standard or Hybrid-APC (APC with prior submucosal fluid injection) using power settings of 50 and 70 W. The depth of tissue injury to the oesophageal wall was analysed macroscopically and histopathologically. RESULTS: Using 50 W, mean coagulation depth was 937 ± 469 µm during standard APC, and 477 ± 271 µm during Hybrid-APC (p = 0.064). Using 70 W, coagulation depth was 1096 ± 320 µm (standard APC) and 468 ± 136 µm (Hybrid-APC; p = 0.003). During all settings, damage to the muscularis mucosae was observed. Using standard APC, damage to the submucosal layer was observed in 4/6 (50 W) and 6/6 cases (70 W). During Hybrid-APC, coagulation of the submucosal layer occurred in 2/6 (50 W) and 1/6 cases (70 W). The proper muscle layer was only damaged during conventional APC (50 W: 1/6; 70 W: 3/6). LIMITATIONS: Ex-vivo animal study with limited number of cases. CONCLUSIONS: Hybrid-APC reduces coagulation depth by half in comparison with standard APC, with no thermal injury to the proper muscle layer. It may therefore lead to a lower rate of stricture formation during clinical application.

Ablation of residual Barrett's epithelium after endoscopic resection: a randomized long-term follow-up study of argon plasma coagulation vs. surveillance (APE study).

BACKGROUND AND STUDY AIM: It is commonly assumed that ablation of any remaining Barrett's epithelium after endoscopic resection of early Barrett's neoplasia improves outcome by reducing the rate of metachronous lesions, but this has not yet been evaluated in a randomized trial. The aim of this study was to compare argon plasma coagulation (APC) with surveillance only for the management of residual Barrett's epithelium following endoscopic resection. PATIENTS AND METHODS: Patients in whom focal early Barrett's neoplasia (high grade intraepithelial neoplasia [HGIN] or mucosal cancer) had been curatively resected by endoscopy were randomly assigned to undergo ablation of the residual Barrett's segment by APC or surveillance only; pH-metry-adjusted proton pump inhibitor therapy was administered in both groups. The main outcome parameter was recurrence-free survival. Follow-up endoscopies with biopsies in cases of further residual Barrett's epithelium were carried out at 6-monthly intervals in both groups. RESULTS: A total of 63 patients (57 male [90.5%]) were included in the study (ablation group n=33; surveillance group n=30). For complete Barrett's ablation, a mean number of 4±1.6 APC sessions were required (range 2-7). The mean follow-up duration did not differ significantly between ablation (28.2±13.7 months, range 0-44) and surveillance patients (24.7±14.8 months, range 0-45; P=0.159). The number of secondary lesions was 1 in the ablation group (3%), and 11 in the surveillance group (36.7%), leading to significantly higher recurrence-free survival for the patients undergoing ablation (P=0.005). CONCLUSIONS: Thermal ablation of residual Barrett's epithelium leads to a significant reduction in neoplasia recurrence rate compared with a surveillance strategy during a limited follow-up of 2 years. A longer follow-up duration may have led to a relatively higher rate of secondary neoplasia in both groups of patients.

Profiling at recombinant homomeric and heteromeric rat P2X receptors identifies the suramin analogue NF449 as a highly potent P2X1 receptor antagonist.

P2X receptors are cation channels gated by extracellular ATP and related nucleotides. Because of the widespread distribution of P2X receptors and the high subtype diversity, potent and selective antagonists are needed to dissect their roles in intact tissues. Based on suramin as a lead compound, several derivates have been described that block recombinant P2X receptors with orders of magnitude higher potency than suramin. Here we characterized the suramin analogue 4,4',4'',4'''-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis-benzene-1,3-disulfonic acid (NF449) with respect to its potency to antagonize ATP or alphabeta-methyleneadenosine 5'-trisphosphate-induced inward currents of homomeric rat P2X(1)-P2X(4) receptors or heteromeric P2X(1 + 5) and P2X(2+3) receptors, respectively. NF449 most potently blocked P2X(1) and P2X(1 + 5) receptors with IC(50) values of 0.3 nM and 0.7 nM, respectively. Three to four orders of magnitude higher NF449 concentrations were required to block homomeric P2X(3) or heteromeric P2X(2 + 3) receptors (IC(50) 1.8 and 0.3 microM, respectively). NF449 was least potent at homomeric P2X(2) receptors (IC(50) 47 microM) and homomeric P2X(4) receptors (IC(50) > 300 microM). Altogether, these results characterize NF449 as the so far most potent and selective antagonist of receptors incorporating the P2X(1) subunit such as the P2X(1) homomer and the P2X(1 + 5) heteromer.

Structure-activity relationships of analogues of NF449 confirm NF449 as the most potent and selective known P2X1 receptor antagonist.

NF449 [4,4',4",4"'-(carbonylbis(imino-5,1,3-benzenetriyl-bis(carbonylimino)))tetrakisbenzene-1,3-disulfonic acid-octasodiumsalt)] was recently described to inhibit recombinant rP2X(1) receptors (Naunyn Schmiedeberg's Arch. Pharmacol. 364 (2001) 285). The purpose of this study was to examine structure-activity-relationships at P2 receptors of a series of NF449 analogues. Thus, compounds containing various arylaminemono-, di-, or trisulfonic acids and a replacement of the central urea bridge were synthesized. NF449 displayed a pIC(50) at P2X(1) receptors (rat vas deferens) of 6.31 +/- 0.04 being at least 19-fold more potent at P2X(1) than at P2X(3), P2Y(1), P2Y(2), or P2Y(11). Any deletion or change of position of sulfonic acid groups or replacing the central urea bond by the bisamide of terephthalic acid reduced the potency at P2X(1) by at least 90%. All compounds were very weak antagonists at P2Y(2) or P2Y(11) receptors (pIC(50) < 4.5). In conclusion, NF449 remains the most potent and selective P2X(1) antagonist known. Potential lead compounds among the suramin class for P2X(3) (16d) and P2Y(1) (16a) receptors were identified.

Structure-activity relationships of suramin and pyridoxal-5'-phosphate derivatives as P2 receptor antagonists.

Extracellular adenine and uracil 5'-nucleotides are important signalling molecules that exert a great variety of effects in numerous tissues and cell types through the activation of P2 receptors. In the past eight years, an extended series of P2 receptors (P2X(17), ionotropic subunits; P2Y(1,2,4,6,11,12), metabotropic receptors) has been cloned from vertebrate tissues. In this rapidly expanding field, one of the main current challenges is to relate the cloned P2 receptor subtypes to the diverse physiological responses mediated by the pharmacological phenotypes of native P2 receptors. Unfortunately, subtype-selective P2 ligands, especially potent and selective antagonists, have been only slowly forthcoming, and this acts as a considerable impediment to progress. However, a number of new P2 receptor antagonists have recently been described which to some degree are more potent and more selective than earlier antagonists like suramin or pyridoxal-5'-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS). This work moves us closer to the ideal goal of classifying the recombinant and native P2 receptor subtypes on the basis of antagonist profiles. This review begins with a brief account of the current status of P2 receptors and their ligands. It then focuses on structure-activity relationships of PPADS and suramin analogues and will finish with a brief discussion of some related therapeutic possibilities.