Novel potassium channel openers: synthesis and pharmacological evaluation of new N-(substituted-3-pyridyl)-N'-alkylthioureas and related compounds.

This report describes the synthesis and pharmacological evaluation of a series of novel potassium channel openers related to the pinacidil-type compounds. Thioureas, cyanoguanidines, and pyridine N-oxides were systematically evaluated for their effects on both the inhibition of spontaneous mechanical activity in rat portal vein (in vitro) and their antihypertensive activity (in vivo), and the structure-activity relationship for this series of compounds was discussed. Good correlation between in vitro and iv antihypertensive activity was observed for these compounds. Among them, cyanoguanidines bearing a conformationally rigid unit such as a norbornyl group generally possessed potent activity in both in vitro and in vivo studies. Especially, N-(6-amino-3-pyridyl)-N'-cyano-N"-(1-methyl-2-norbornyl)guanidine (23d) was identified as a more potent potassium channel opener in vitro (EC100 = 3 x 10(-8) M) than pinacidil (EC100 = 10(-7) M).

Repeated piezoelectric lithotripsy for gallstones with and without ursodeoxycholic acid dissolution: a multicenter study.

The use of bile acid dissolution therapy in extracorporeal shockwave lithotripsy of gallstones, remains controversial. Our study examined whether chemolitholysis after sufficient disintegration enhanced stone clearance within 6 months of the first lithotripsy. A total of 143 patients who developed one to three radiolucent stones measuring < or = 30 mm in diameter were randomly separated into two treatment groups: 47% were given lithotripsy alone, and 53% lithotripsy plus ursodeoxycholic acid (UDCA). Repeated piezoelectric lithotripsy was given, with no limit on the total number of treatment sessions, to pulverize or disintegrate stones into fragments < 3 mm. Stones were disintegrated in 97% of all patients, and the fragments were < or = 2 mm in 50% of these patients. According to an intention-to-treat analysis, 52% in the lithotripsy alone group and 58% in the UDCA group were free of stones 6 months after the first lithotripsy (P = 0.61). Of the patients with fragments < or = 2 mm, 71% in the former and 86% in the latter group were free of stones 6 months after the first lithotripsy, with no significant difference between the groups. Biliary pain occurred in 25% of all patients, including 3 with acute cholecystitis. We concluded that the sufficient disintegration of gallstones achieved with repeated lithotripsy enhanced the early clearance of fragments, regardless of whether chemolitholysis was employed.

The effect of bilirubin on biliary lipid secretion: analysis by horseradish peroxidase associated intrahepatic vesicular transport system.

The mechanism of biliary lipid secretion is still controversial and there is no definite information regarding how bilirubin inhibits biliary phospholipid and cholesterol secretions without affecting bile salt secretion. In this study, the effects of bilirubin on intrahepatic vesicular transport and biliary lipid secretion were examined using bile-fistula rats. Horseradish peroxidase (HRP) was used as a tracer of intrahepatic vesicular transport. Bilirubin (5 mg/100 g BW) and/or HRP (5 mg/100 gBW) were injected through the mesenteric vein. Bile flow, biliary bile acid, biliary phospholipid and cholesterol outputs were examined in saline, HRP and HRP + bilirubin groups, respectively. Bile flow and biliary bile acid output were not affected by bilirubin administration. Biliary phospholipid and cholesterol as well as biliary HRP outputs were inhibited just after bilirubin administration, 42.8 +/- 6.1 SD% 47.7 +/- 5.1 SD%, and 33.4 +/- 3.8 SD%, respectively. These results suggested the participation of intrahepatic vesicular transport system in the inhibition of biliary lipid secretion by bilirubin and in its secretory mechanism.