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.     

The effect of prostagiandin F2alpha on canine hepatic bile flow and biliary cyclic AMP secretion.

This study evaluates the effects of prostaglandin F_2α (PGF_2α) on canine hepatic bile flow and gastric hydrogen ion output and on biliary cyclic AMP excretion. During the experiments the enterohepatic circulation was maintained by intravenous bile salt infusion. PGF_2α was administered through either a separate intravenous or intra-arterial line in doses of 1, 2, 4, and 8 μ/kg/min. PGF_2α produced progressive increases in bile output and gastric hydrogen ion output. The choleresis was characterized by increased bile salt and chloride secretion suggesting that PGF_2α altered bile flow at the canalicular level. There was no greater response produced when the prostaglandins were administered intra-arterially compared to the response produced by intravenous PGF_2α. Bile cyclic AMP and cyclic GMP concentrations were measured by radioimmunoassay. Cyclic AMP concentrations were decreased by all doses of PGF_2α administered while cyclic AMP output was significantly decreased only by 8 μ/kg/min of PGF_2α. Cyclic GMP levels were consistently less than 0.8 pmol/ml and were not changed by PGF_2α. The results indicate that PFG_2α stimulates hepatic bile flow and gastric hydrogen ion output in a dose-related manner, the choleresis may be canalicular in nature, and metabolic degradation of PGF_2α by the lungs in these studies did not greatly influence the results obtained. Biliary cyclic AMP levels were decreased, suggesting that PGF_2α does not produce its response by stimulating the adenyl cyclase-cyclic AMP system.     

Adrenergic and cholinergic contributions to decreased gastric emptying,small intestinal transit,and colonic transit in the postoperative ileus rat

The depression of gastric emptying (GE), small intestinal transit (SIT), and colonic transit (CT) was studied in laparotomized rats 45 min after surgery to systematically determine neuronal contributions to postoperative ileus in this species. Chemical sympathectomy by intravenous 6-hydroxydopamine (100 mg/kg) 48 hr prior to surgery normalized CT and increased GE and SIT. If GE was measured 5 hr instead of 45 min after laparotomy, sympathectomized values were normal, but those of vehicle-treated controls were still depressed. Subcutaneous atropine (6 mg/ kg) administered 20 min prior to laparotomy prevented the augmentation of GE and CT by prior sympathectomy. Intraperitoneal phentolamine (0.25 mg/kg) but not propranolol (0.25 mg/kg) 20 min prior to surgery mimicked the effects of 6-hydroxydopamine pretreatment. Subcutaneous bethanechol (0.05, 0.1, or 1.0 mg/kg), neostigmine (0.01, 0.05, or 0.1 mg/kg), or guanethidine (1.0, 5.0, or 10.0 mg/kg) 20 min prior to laparotomy normalized CT and increased GE as compared to vehicle-treated controls. SIT was slightly augmented by neostigmine or bethanechol treatment. Combining chemical sympathectomy with carbachol (0.03 mg/kg) or neostigmine (0.03 mg/kg) normalized GE and increased CT and SIT more than with either compound alone. Subcutaneous methysergide (20 mg/kg) or naloxone (0.5 mg/kg) 20 min prior to surgery had no effect on transit. Subcutaneous indomethacin (10 mg/kg) 3 hr prior to laparotomy was likewise ineffective in increasing propulsion. These results suggest that postoperative ileus is caused both by increased α, but not β sympathetic activity in the stomach, small intestine, and possibly the colon, as well as depression of propulsive stimuli in stomach, small intestine, and the colon. Recovery of propulsive stimuli occurred prior to diminution of sympathetic activity in the stomach. Combination therapy with compounds to reverse both these phenomena appear to normalize propulsion most effectively. Some discrepancies in past reports on this subject were resolved.     

Development of a Sensitive Activity Assay for High-Volume Evaluation of Human Renin Inhibitory Peptides in Rat Serum: Results with U-71,038

A sensitive activity assay for high volume evaluation of human renin inhibitory peptides (RIPs) in rat sera (range 2–80 ng/ml) was developed based on the low affinity of RIPs to rat renin and their high affinity to human renin. The utility of this activity assay was tested by measuring concentrations of a human RIP, U-71,038 (BOC-Pro-Phe-N-MeHis-Leu [CHOHCH₂]Val-Ile-Amp), in rat sera, determined by the activity assay, by a sensitive radioimmunoassay (RIA), and by tracking tritiated drug. Rats were given radiolabeled drug as an intravenous bolus, and blood samples were collected at various times after dosing. The serum level of U-71,038 equivalents was determined by the three techniques. Whole blood was also counted for total radioactivity to evaluate the potential for U-71,038 incorporation into red blood cells. Results from the three serum assays indicate good agreement between the calculated U-71,038 equivalents for the 30 min and 1 hr collection times. The 2 and 4 hr collection times show excellent agreement for the activity assay and RIA; [³H]-U-71,038 determinations gave substantially higher values. Serum levels for U-71,038 determined 30 min after dosing averaged less than 300 ng equivalents/ml suggesting that less than 1% of the administered dose was in the systemic circulation at that time. Thus, U-71,038 was rapidly cleared. At the 4 hr collection time, the level of U-71,038 equivalents, as determined by activity assay and RIA, was ten times the in vitro IC₅₀ for the renin inhibitory activity of U-71,038. Analysis of whole blood levels of ³[H]-U-71,038 indicated little or no incorporation of drug related material into red blood cells. In addition to predicting pharmacological response, the activity assay can be used to quantify human RIPs in rat serum when biotransformation is absent.     

Clonidine delays small intestinal transit in the rat

Subcutaneous clonidine (0.01--1.0 mg/kg) was found to delay small intestinal transit but not gastric emptying in the unanesthetized rat, with a maximal effect seen at 0.1 mg/kg. Gastric emptying was expressed as the percentage of intragastrically administered 51Cr emptied into the small intestine after 45 min. Small intestinal transit was the percentage of the small intestinal length traveled 45 min after oral or duodenal administration of black ink. The depression of small intestinal transit by clonidine to 20 to 30% of control values was blocked by phentolamine and yohimbine, but not by prazosin or phenoxybenzamine, suggesting a presynaptic (alpha-2) agonist action of clonidine. Pretreatment of rats with 6-hydroxydopamine, propranolol, atropine, methysergide, naloxone, mepyramine or metiamide failed to alter the effects of clonidine. These results suggest that an alpha adrenergic receptor, possibly presynaptic, regulates small bowel propulsion in rat without involvement of acetylcholine, norepinephrine, endorphins, histamine or serotonin.     

Prazosin inhibits small intestinal transit in the rat

Gastric emptying, small intestinal transit, and colonic transit were measured in fasted rats preimplanted with either duodenal or colonic cannulae. At the doses stated, prazosin (given subcutaneously) had no effect on gastric emptying or colonic transit, whereas small intestinal transit was significantly delayed.     

16,16-Dimethyl prostaglandin E2 delays collagen formation in nutritional injury in rat liver

Chronic nutritional injury was induced in rats by a high-fat, lipotrope-deficient diet. The hepatoprotective effect of 16,16-dimethyl prostaglandin E2 on the deposition of collagen and fat was assessed by histological evaluation and measurement of hydroxyproline. Dose-response studies established that optimal protection was achieved by the twice daily administration of 16,16-dimethyl prostaglandin E2 at 100 micrograms per kg (subcutaneous) or 250 micrograms per kg (oral). 16,16-Dimethyl prostaglandin E2 and a crystalline analog [(p-acetamidobenzamido)phenyl ester of 16,16-dimethyl prostaglandin E2 significantly delayed both the deposition of collagen and the increase in hepatic hydroxyproline content. There was an excellent correlation between the histological assessment of collagen and the biochemical measurement of hydroxyproline. These data provide a rationale for the evaluation of prostaglandins in the treatment of human liver disease.