sirolimus and fasudil

Benign biliary stricture (BBS) is highly refractory. Currently, there is no effective strategy for prevention of BBS recurrence. The aim of this study is to establish a novel BBS rabbit model and to investigate the efficacy of biliary infusion with anti-proliferative medications for treating BBS.. A BBS model was established via surgical injury and biliary infection. The biliary infusion tube was inserted into the common bile duct via the stump of cystic duct after cholecystectomy. Biliary infusions with Rapamycin, Pirfenidone and Fasudil were performed daily during the 4 weeks following the surgery. The wall thickness and luminal area of the bile duct were assessed.. All rabbits formed BBS after surgery. The mortality rate was 13% (8/60) and tube withdrawal rate was 4% (2/48). The thickness of the bile duct wall was significantly reduced; whereas the luminal area of the bile duct was dramatically enlarged in the Rapamycin or the Pirfenidone treated group, compared to the saline treated group. Furthermore, the local treatment significantly decreased the levels of proliferation makers, including PCNA, Collagen I and fibrogenic mediators, including ACTA2 and TGF-beta.. We have established a novel animal model for BBS formation. We have further demonstrated that biliary infusion with Rapamycin or Pirfenidone limits the biliary strictures through inhibiting the proliferation of the bile duct wall in this model. This may represent a new avenue for preventing biliary restenosis.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Antineoplastic Agents; Biliary Tract Diseases; Constriction, Pathologic; Disease Models, Animal; Drug Evaluation, Preclinical; Pyridones; Rabbits; Secondary Prevention; Sirolimus; Vasodilator Agents

The specificities of 28 commercially available compounds reported to be relatively selective inhibitors of particular serine/threonine-specific protein kinases have been examined against a large panel of protein kinases. The compounds KT 5720, Rottlerin and quercetin were found to inhibit many protein kinases, sometimes much more potently than their presumed targets, and conclusions drawn from their use in cell-based experiments are likely to be erroneous. Ro 318220 and related bisindoylmaleimides, as well as H89, HA1077 and Y 27632, were more selective inhibitors, but still inhibited two or more protein kinases with similar potency. LY 294002 was found to inhibit casein kinase-2 with similar potency to phosphoinositide (phosphatidylinositol) 3-kinase. The compounds with the most impressive selectivity profiles were KN62, PD 98059, U0126, PD 184352, rapamycin, wortmannin, SB 203580 and SB 202190. U0126 and PD 184352, like PD 98059, were found to block the mitogen-activated protein kinase (MAPK) cascade in cell-based assays by preventing the activation of MAPK kinase (MKK1), and not by inhibiting MKK1 activity directly. Apart from rapamycin and PD 184352, even the most selective inhibitors affected at least one additional protein kinase. Our results demonstrate that the specificities of protein kinase inhibitors cannot be assessed simply by studying their effect on kinases that are closely related in primary structure. We propose guidelines for the use of protein kinase inhibitors in cell-based assays.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Acetophenones; Alkaloids; Amides; Animals; Benzamides; Benzophenanthridines; Benzopyrans; Butadienes; Cell Line; Enzyme Inhibitors; Flavonoids; Humans; Imidazoles; Indoles; Inhibitory Concentration 50; Isoquinolines; Lithium; Magnesium; Nitriles; Phenanthridines; Phosphorylation; Potassium Chloride; Protein Kinase Inhibitors; Protein Kinases; Pyridines; Sirolimus; Substrate Specificity; Sulfonamides