A possible mechanism of choleretic action of 3-(2,4,5-triethoxybenzoyl)-propionic acid (AA-149) in dogs

The choleretic action of 3-(2,4,5-triethoxybenzoyl)propionic acid (AA-149) was studied in anesthetized dogs. AA-149 produced a dose-dependent increase of the bile flow with both i.v. and intrajejunal administration of doses 1 mg/kg and higher. Biliary clearance of 14C-erythritol showed that AA-149 stimulated canalicular bile formation without enhancement of water secretion and/or inhibition of bile reabsorption in the biliary ductules and ducts. AA-149 did not increase the excretion of bile acids into the bile, but enhanced the excretion of the biliary electrolytes, in particular sodium ion, in proportion to an increase of the bile flow. About 3--4% of AA-149 administered i.v. was excreted into the bile during the first 1 h period, so that biliary AA-149 was insufficient to increase the bile flow via its osmotic effect. These results strongly suggest that the choleretic action of AA-149 is attributable to stimulation of a bile acid-independent bile formation in the canaliculi coupled with an active sodium transport system.     

Experimental study of the biliary excretion of antibiotic (cefotiam) in the presence of biliary tract obstruction (author's transl)

Excretion of a new semisynthetic analogue of cephalosporin, cefotiam (CTM), and cefazolin (CEZ) in bile was investigated in dogs with experimental obstruction of biliary tract. In the control group, peak concentrations of antibiotics in bile after 50 mg/kg intravenous administration were as follows: In CTM administrated groups, 5,302 micrograms/ml at one hour after administration; and in CEZ administrated group, 1,249 micrograms/ml after one hour. The total biliary excretory rates summed to 6 hours after administration of antibiotics were 7.8% in the CTM group, and 2.1% in the CEZ group. On the other hand, in the biliary tract obstruction group, the peak concentration in bile in CTM group was 65.7 micrograms/ml after 1 hours, and in CEZ group, 62.4 micrograms/ml after 2 hours. The total biliary excretory rate in the CTM group was 0.202%, while in the CEZ group 0.12%. The peak concentration and the excretory rate of CTM in bile was four times higher than that of CEZ in the control group. No significant difference was revealed in the peak concentration and the excretory rate in bile between CTM and CEZ in the biliary tract obstruction group.     

Pharmacokinetics of ceftazidime in patients with biliary tract disease

Summary After administration of ceftazidime as a 1 g i.v. bolus injection, its concentration was measured by HPLC at frequent intervals in serum, bile and tissue from different parts of the biliary tract in 32 patients undergoing operation for biliary tract disease. In bile from the functioning gallbladder and common bile duct, a high concentration of ceftazidime was found, mean 18.5 and 26.6 mg/l, respectively. In bile from the non-functioning gallbladder, a very low concentration was found (<1.5 mg/l). Ceftazidime in the gallbladder wall varied considerably with the type and degree of inflammation judged histologically; the mean level was 21.3 mg/kg. The elimination half-life of ceftazidime was 1.74 h, apparent volume of distribution 20.01 and total plasma clearance 133 ml/min. In bile from T-tube specimens a high concentration was found, the mean peak values being 27.2 mg/l. However, biliary excretion of the drug was low at less than 0.5% of the administered dose. These concentrations of ceftazidime were sufficient to inhibit the in-vitro growth of pathogens, namely theEnterobacteriaecae commonly responsible for biliary tract infection.     

Effects of neurotensin on the motility of the isolated gallbladder, bile duct and ampulla in guinea-pigs

Neurotensin induced dose-dependent contraction in the isolated gallbladder, bile duct and ampulla of guinea-pigs, which were usually reduced by atropine and tetrodotoxin. In all cases, the neurotensin-induced contraction of the gallbladder was reversed to relaxation by indomethacin after administration of atropine and tetrodotoxin. The neurotensin-induced contraction of bile duct and ampulla was reduced by indomethacin, atropine and tetrodotoxin, and was slightly enhanced in some experiments after guanethidine administration. Ganglion-, alpha- and beta-adrenoceptor, serotonin- and histamine-blocking agents did not affect the neurotensin-induced contraction in any of the preparations. These results suggest the following; (1) the contractile effects are due to excitement of cholinergic neurons in the myenteric plexus of the biliary tract, (2) the direct action of neurotensin on the smooth muscle of the bile duct and ampulla results in a small contraction, (3) the contraction in the gallbladder is partly caused by stimulation of prostaglandin synthesis.     

Technique for assessment of local effects of substances found in bile upon opening pressure of choledochoduodenal junction.

An assessment of the localized influences of various chemicals found in bile was made by applying them to the interior of the canine choledochoduodenal junction. Test agents were isolated by air bubbles and introduced into the terminal lumen of the intramural portion of the common bile duct via the pressure measurement catheter; they remained in the duct for approximately 1.5 min. The system was flushed and opening pressures were then measured. Responses were measured in terms of alterations in ductal opening pressures generated by a linear pressure ramp. Histamine, serotonin, and bethanechol markedly increased ductal opening pressures, whereas epinephrine and norepinephrine decreased opening pressures. None of the agents affected either cardiovascular or small intestinal motor activity in the vicinity of the sphincter when administered in the manner. The results suggest that the presence in bile of certain neurohumoral transmitters and neurohumoral-like agents may directly affect the canine choledochoduodenal sphincter function.     

Concentrations of cefmenoxime and cefotiam in the bile and gallbladder tissue following intravenous administration in patients with biliary tract diseases

To test the effectiveness of cefmenoxime (CMX) and cefotiam (CTM) in patients with biliary tract diseases, concentrations of either antibiotic were measured after an intravenous bolus injection of 1.0 g of CMX or CTM, or simultaneous injection of both (1.0 g each). CMX or CTM was injected in 76 patients with biliary tract diseases (mostly cholelithiasis) prior to a cholecystectomy and concentrations of CMX or CTM were measured by the bioassay (agar well) method at 30 to 60 minutes after the injection. Average concentrations of both CMX and CTM in gallbladder bile and gallbladder tissue sufficiently exceeded the minimal inhibitory concentration (MIC) against main causative organisms of biliary tract infections. Concentrations of both antibiotics in gallbladder bile were significantly higher in patients with patent cystic ducts than with obstructed cystic ducts. Concentrations of both antibiotics in the gallbladder tissue reached at a similar high level regardless of the patency of the cystic ducts, but concentrations were lower in severely inflamed gallbladders. CMX and CTM were administered alternatively (cross-over fashion), or simultaneously (combined) to 13 patients with T-tube drainage or percutaneous transhepatic cholangio-drainage, and concentrations of both antibiotics in bile from the drainage tube were measured by high performance liquid chromatography at hourly intervals after the injection. Concentrations of both antibiotics were far greater than MICs against main attributable microorganisms in biliary tract infections. The concentration of CMX slightly exceeded that of CTM. Concentrations of both antibiotics were lower in bile of patients showing abnormally high serum GTP, A1-P, and total bilirubin levels than in bile of patients with normal values of these variables. It is speculated that the secretion of both antibiotics in the bile may decrease in cases with severe hepatic failure, but effective concentrations of both antibiotics in the gallbladder tissue should be maintained as long as the blood circulation in the gallbladder was maintained.     

Effect of Tilorone Hydrochloride on Hepatic Disposition of Sulphobromophthalein (BSP) in the Rat

1. Biliary excretion of sulphobromophthalein (BSP) was studied in male rats after oral administration of tilorone HCl, an anti-viral and anti-tumour agent.

2. The stimulation of bile flow by BSP was decreased 1?h after tilorone administration; this decrease was no longer apparent 24?h later but a fall of basal bile flow was noted at that time. No changes in bile flow were observed 7 days after this single dose.

3. Repeated dosing with tilorone produced a dose-dependent increase in hepatic concentration of unchanged and metabolized tilorone. This was associated with a dose-dependent decrease of bile formation and BSP excretion. Bile acid excretion was depressed as well.

4. BSP metabolism was not significantly affected by tilorone administration.     

Clinical studies on the transference of cephem-type antibiotics into bile and gallbladder tissues with special reference to cefotiam and cefmenoxime

Cefotiam (CTM) and cefmenoxime (CMX) were studied for their serum concentrations and transference into bile in patients with PTCD or T-tube. One gram of CTM or either 1 g or 2 g of CMX was administered by an intravenous drip infusion for over 30 minutes. These drugs were also studied for their serum concentrations, bile concentrations, and tissue concentrations in the walls of the gallbladder of patients operated on for cholelithiasis. Intravenous drip infusion (over 30 minutes) was used to administer 1 g of CTM or 1 g or 2 g CMX immediately before surgery. Both CTM and CMX were readily transferred into bile. Their bile concentrations, however, varied greatly among patients, and extremely low levels were detected in some patients. A crossover analysis of concentrations of CMX in bile of patients given doses of 1 g and 2 g revealed a dose-response relationship. The crossover analysis of drug concentrations in bile of patients given CTM and CMX showed that CMX is transferred more readily to bile. The relationship between liver functions and drug transfer to bile was examined by plotting the total bilirubin level against drug concentrations in bile. The plots formed an exponential curve with a correlation coefficient (r) being -0.52 in cases when each subjects received 1 g of CTM and -0.72 in cases when each subjects received 1 g of CMX. A study of 3 patients given CMX at a dose of 1 g suggested that bile levels of CMX may be correlated to ICG. Concentrations of CTM and CMX in tissues of the gallbladder wall were fairly high, with unexpectedly small variance among patients. Even in patients with low bile concentrations of these drugs, drug levels in the tissues of the gallbladder wall were high. Drug levels in the noninflammatory tissues were higher than those in inflammatory lesions. The above findings suggest that CTM should be the antibiotic of choice for patients with ordinary biliary tract infections and after the surgery of the liver and biliary tract system, while CMX should be the antibiotic of choice for patients with severe biliary tract infections, and for compromised hosts after the surgery of the liver and biliary tract system.     

Studies on penetration of antibiotics to gallbladder tissue and bile, its surgical significance. Mainly with cefmenoxime

Basic and clinical studies in 37 patients with biliary tract disease on comparison between cefmenoxime (CMX) and cefotiam (CTM) were studied and the following results were obtained. In vitro antibacterial activities of CMX and CTM against 25 strains (15 organisms) isolated from bile of patients with biliary tract disease were stronger than that of cefazolin (CEZ). In cholecystectomized patients, CMX (2 g) or CTM (2 g) was injected intravenously, followed by determination of concentration in bile and gallbladder tissue about 2 hours after administration. In CMX administration, the mean concentration in gallbladder bile was 812.1 micrograms/ml, and the mean concentration in duct bile was 1,050.6 micrograms/ml, and the mean concentration in gallbladder tissue was 100.7 micrograms/g. In CTM administration, the mean values were, 1,092.5 micrograms/ml, 1,287.8 micrograms/ml, 28.5 micrograms/g, respectively. The concentration of CMX and CTM were almost similarly. The bile concentration of CMX (i.v.) was compared with CTM (i.v.) by cross-over method in cases of T-tube drainage. The peak bile concentrations of CMX and CTM were as high as 172.4 micrograms/ml and 182.2 micrograms/ml, respectively, 1 approximately 2 hours after 2 g intravenous administrations. Furthermore, the concentration of them were highly gained, 16.1 micrograms/ml of CMX and 33.8 micrograms/ml of CTM, even at 5 approximately 6 hours. In choledochostomized patients, CMX (4 g/day) was injected intravenously, followed by determination of concentration in intraperitoneal exudate. The mean concentration of CMX was 15.3 micrograms/ml on the first day after the operation, and 6.0 micrograms/ml even on the third day after the operation. Those results suggest that the high antibacterial activity of CMX against organism in bile and, the high penetration of CMX to bile, gallbladder tissue and intraperitoneal exudate will promise its important role in treatment of biliary tract infections.     

Chemotherapy of biliary tract infections (XXXVII). Excretion into bile and gallbladder tissue levels of levofloxacin and its clinical effect in biliary tract infections]

Evaluations were made on biliary excretion and penetration into the gallbladder tissue of levofloxacin (LVFX, DR-3355), a new quinolone antibacterial agent, and its clinical efficacy in biliary tract infections. 1. Gallbladder tissue concentrations and biliary concentrations of LVFX at 2-6 hours at oral administration of 100 mg were 0.58-1.99 micrograms/g and 0.49-5.63 micrograms/ml, respectively. These tissue and biliary levels are almost equal or somewhat higher than the serum levels (0.55-1.63 micrograms/ml) of the compound. 2. The concentrations of LVFX and optical isomer DR-3354 in the serum, gallbladder tissue, and bile were determined after a single or a concomitant administration of LVFX 100 mg and/or ofloxacin (OFLX) 100 to 200 mg. The concentration ratio of LVFX to DR-3354 paralleled with the ratio of the 2 compounds administrated. 3. At a dose of 100 mg, the glucuronide of LVFX in the common duct bile was detected at proportions between 0.9 and 36.0%. 4. A total of 11 patients with biliary tract infections, including 6 cholecystitis 3 cholangitis, and 1 each of cholecystocholangitis and liver abscess was treated with LVFX at 100-200 mg t.i.d. for 3-14 days. Clinical results were excellent or good in 8 cases and fair in 3 cases, resulting in an efficacy rate of 72.7%. 5. A side effect and an abnormal change in laboratory findings were observed in both 1 case each and they were both mild. It was concluded that LVFX showed good penetration to the biliary tract as does OFLX, and that it would be a useful oral agent for the treatment of biliary tract infections.     

Biliary tract infections and antibiotics concentration of cefotiam in gallbladder tissue and bile (author's transl)

In 12 patients undergoing operation, 1 g of cefotiam (CTM) was administered intravenously and CTM levels in gallbladder tissue and gallbladder bile were examined. CTM concentration in gallbladder bile was high in patients with patent cystic duct, while very low in those with cystic duct obstruction. CTM concentration in gallbladder tissue was low in patients with chronic inflammatory gallbladder. CTM activities of T-tube bile were compared with those of CMZ by cross over method in 2 cases. CTM showed extremely higher concentration in bile than CMZ. In a case with excessive output of bile, CTM activity, total bile acids concentration and canalicular flow/ductal flow ratio were low. It can be presumed that CTM was diluted by increased ductal secretion.     

Application of biliary stents in endoscopic stenting of biliary ducts

Extra hepatic bile ducts with the gallbladder are the center place for many disease processes. In extreme cases of significant strictures of bile ducts and impairment of bile flow, obstructive jaundice occurs. There are benign and malignant biliary strictures. The treatment of obstructive jaundice depends on the removal of blockage using endoscopic and surgical methods which return the efficient bile flow to the digestive tract. The endoscopic treatment from Vater's papilla access using plastic and metal stents is the method of choice. The choice of proper prosthesis depends on the reason for biliary strictures. The plastic stents (straight, pigtail) are applied the most. Due to their low cost, easy insertion to biliary ducts and exchangeability, they are applied in benign and malignant strictures. However, metal stents (Wallstent, Diamond, Z-stent, InStent), due to the wide diameter after expansion and no possibility of removal, are applied only in malignant strictures. Endoscopic insertion of biliary endoprostheses can be burdened with complications. There have been reports of occlusion, migration with duodenal wall injury and hemorrhaging.     

On the spasmolytic action of 3-butoxy-1-phenoxy-propanol-(2) (febuprol) on the biliary tract (author's transl)

The spasmolytic activity of 3-butoxy-1-phenoxy-propanol-(2) (febuprol) on the biliary tract is demonstrated in two different experimental arrangements in anesthetized dogs. This effect on the spasm provoked by morphine or prostigmine is illustrated by measuring the alteration of pressure in the choledochal duct. The spasmolytic efficacy of febuprol is significant and indicates a favourable secondary therapeutic effect of this substance.     

Clinical studies on excretion in biliary tract with the antibiotic cefotiam

Cefotiam (CTM) was administered through 1 hour intravenous drip infusion for the patients performed biliary tract surgery. The concentration of CTM in serum, gallbladder tissue and the excretion in bile of the choledochus were measured. Twenty-one patients performed cholecystectomy were followed the concentration of CTM in the gallbladder tissue and the results were studied with pharmacokinetic analysis. The simulation curve, which was described by computer system in two-compartment open model, showed the maximal concentration of CTM in the serum was 60.3 micrograms/ml at 1 hour after infusion and that in the gallbladder tissue was 27.1 micrograms/g at 1.07 hours. The concentration of CTM in the gallbladder tissue was presumed to be in proportion to that of CTM in the serum. Six patients performed bile drainage were followed the concentration of CTM in bile of the choledochus for 6 hours after infusion. The maximal concentration was 215.2 +/- 62.7 micrograms/ml at 3 hours after injection, and the mean biliary recovery was 1.66 +/- 0.55% through 6 hours. Neither any side effects nor any abnormal values in the laboratory analysis of samples were observed for CTM.     

Therapeutic effects of cefotiam in biliary tract infections

As useful antibiotics for biliary tract infections, smooth transmigration to lesion and potent antibacterial activities will be demanded. Usually the antibiotics having potent antibacterial activities against E. coli and Klebsiella, which are considered to be main causative organisms of biliary tract infections, will be used for treatment. The concentrations of cefotiam (CTM) in bile and gallbladder wall tissue were investigated, and CTM showed very high concentrations in these tissues for several hours. And very good correlation between concentration of CTM in bile and laboratory findings, especially ICG R15 value, was obtained. CTM showed also very potent antibacterial activities against E. coli and Klebsiella. These results suggest that CTM will be useful agent for the treatment of biliary tract infections.     

Cardiovascular effects of 1-(3,4-dimethoxyphenyl)-2-(4-diphenylmethylpiperazinyl) ethanol and possible mechanisms involved

Cardiovascular effects of NC-1100 (1-(3,4-dimethoxyphenyl)-2-(4-diphenylmethylpiperazinyl)ethanol and possible modes of action were studied in dogs and guinea pigs. 1. In pentobarbital-anesthetized dogs, intravenous administration of NC-1100 (0.05-1.6 mg/kg) induced a dose-dependent fall of blood pressure, a bradycardia followed by temporal tachycardia, a slight and transient stimulation of respiration and a prolongation of the R-R interval with slight augmentations of P, R and T waves in ECG. 2. In pentobarbital-anesthetized dogs, NC-1100 (2.5-80 micrograms/kg) administered to the maxillary and vertebral artery dose-dependently increased the blood flow in the respective artery. 3. Intravenous administration of NC-1100 (0.05-1.6 mg/kg) also exhibited dose-dependent increases of the maxillary and vertebral blood flow, though the increase in maxillary flow was a little reduced at a high dose of 1.6 mg/kg. Intravenous administration of NC-1100 (0.1-1.6 mg/kg) caused a slight increase in the aortic and coronary blood flow, a decrease in renal flow and a slight and transient decrease followed by an increase in femoral flow. 4. In pentobarbital-anesthetized dogs, NC-1100 (1 mg/kg) administered i.v. did not affect responses of blood pressure and heart rate to norepinephrine and isoprenaline (isoproterenol) but slightly inhibited hypotensive responses to acetylcholine. NC-1100 had no effect on hypertension elicited by carotid sinus reflex and on bradycardia by vagus stimulation. NC-1100 slightly inhibited the tachycardia elicited by pre- as well as postganglionic stellate stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of butylated hydroxytoluene (BHT) on biliary excretion of xenobiotics and bile flow in rats

A significant enhancement in the biliary excretion of iv injected sulfobromophthalein (BSP), phenol- 3,6 -dibromphthalein disulfonate (DBSP), procaine amide ethobromide (PAEB) and ouabain was observed in rats maintained on diets containing 0.25% BHT for periods of 10 days. The enhanced biliary excretion of these drugs in BHT treated rats appears to be correlated with the increase in bile flow produced by BHT. The increased bile flow was due to an increase in canalicular bile production rather than a change in net ductular secretion or reabsorption of fluid since bile to plasma concentration ratios of erythritol were unchanged and no permeability change in the biliary tree was observed when mannitol was administered by retrograde intrabiliary injection. The increase in bile flow was not due to an enhanced excretion of bile salts into bile, because both the biliary bile acid concentration and total biliary excretion of bile acids were lower in BHT-treated rats than in control rats. It appears that the increase in bile flow produced by BHT is due to the osmotic choleresis related to the secretion of BHT and its metabolites into bile.     

Evaluation of lincomycin as a cholesterol gallstone dissolution rate accelerator

These studies were undertaken to test the hypothesis that interfacial resistance may be an important rate-limiting factor in cholesterol gallstone dissolution. The addition of lincomycin hydrochloride to the gallbladder bile of dogs in an in vitro bath system resulted in an acceleration in the rate of dissolution of a compressed cholesterol monohydrate pellet incubating in the bile. However, the constant infusion of lincomycin for 13 d directly into the gallbladders of conscious, unrestrained dogs, which resulted in biliary lincomycin concentrations comparable to that of the in vitro tests, did not alter the dissolution rate of a compressed cholesterol monohydrate pellet which had been surgically placed into the gallbladder. We therefore conclude that the interfacial resistance between the cholesterol monohydrate pellet and the bile may be reduced by the addition of lincomycin to the gallbladder bile which, in the in vitro environment, results in an acceleration in the rate of dissolution of compressed cholesterol pellets. However, the ineffectiveness of lincomycin in accelerating the dissolution of cholesterol pellets in vivo suggests that interfacial resistance is not the only rate-limiting factor in gallstone dissolution. Other factors, such as mixing, may also be critical.     

Inhibitory action of 6-ethyl-3-(1H-tetrazol-5-YL)chromone (AA-344) on IgE, IgGa- or chemical agent-induced histamine release from isolated rat mast cells.

The antiallergic action of 6-ethyl-3-(1H-tetrazol-5-yl)chromone (AA-344) was studied on isolated rat peritoneal mast cells. AA-344 clearly inhibited the IgE-mediated release of histamine caused by various concentrations of antigen and the 50% inhibitory concentration was 0.1 microM. On the IgGa-mediated release of histamine, a peak inhibition of AA-344 was observed at 10 microM. The histamine release induced by chemical agents such as concanavalin A, dextran and compound 48/80 was depressed by AA-344 at the range of 0.1--1 mM. The results obtained in this study indicate that the antiallergic action of AA-344 is due to selective inhibition on the immunological release of the chemical mediator from mast cells.