Comparative formation of lithocholic acid from chenodeoxycholic and ursodeoxycholic acids in the colon.

The comparative rate of formation of lithocholic acid from chenodeoxycholic acid and its 7 beta epimer, ursodeoxycholic acid, was studied in human subjects and in a rhesus monkey. [24-14C]Chenodeoxycholic acid and [24-14C]ursodeoxycholic acid were incubated in vitro, under anaerobic conditions, in fecal samples from 7 control and 7 asymptomatic gallstone subjects. The incubations were carried out for 0, 0.5, 1, 4, and 12 h. In addition, the labeled precursors were instilled into the colon of 4 asymptomatic gallstone patients and a rhesus monkey in which a bile duct fistula had been created. Radioactive metabolites were analyzed by thin-layer chromatography in the in vitro fecal incubates and in the in vivo colonic aspirates, stool, and bile. The biotransformation of the unlabeled material was analyzed by gas-liquid chromatography in the in vitro incubates and in the in vivo fecal samples of the rhesus monkey. There was no statistical difference between chenodeoxycholic and ursodeoxycholic acids in their rate of biotransformation to lithocholic acid, when the total group of 14 subjects was compared. However, among these 14, a subgroup of 4 subjects (2 controls and 2 with gallstones) was identified in whom the rate of degradation to lithocholic acid was significantly faster for chenodeoxycholic than for ursodeoxycholic acid. Increases in the concentrations of the precursors led to a decrease in the rate, but not a change in the comparative pattern of lithocholic acid formation. At the lower concentrations, the conversion of both bile acids to lithocholic acid was almost complete after 12 h. In the in vivo studies, the formation of lithocholic acid from chenodeoxycholic and ursodeoxycholic acids was comparable both in the 4 human subjects and in the rhesus monkey. The results of this study indicate that, in most cases, the risk of liver damage from lithocholic acid formation should be similar for both epimers. However, there appears to be a small population in which this risk could be higher during chenodeoxycholic acid than during ursodeoxycholic acid treatment due to a more rapid formation of lithocholic acid.

Tracheal reconstruction by resection and end-to-end anastomosis in the horse.

A surgical technique for resection of a portion of the trachea followed by end-to-end anastomosis was developed on 4 clinically normal horses. The trachea healed without complications in 3 of the horses in which 3 tracheal cartilages were removed. Five tracheal cartilages were removed from the 4th horse. It had to be euthanatized because of excessive suture line tension and wound disruption, which occurred during recovery from anesthesia. Suture line tension was measured on 3 other clinically normal horses positioned in dorsal recumbency immediately after euthanasia after 3 and 5 tracheal cartilages had been removed and before and after flexion of the neck to 90 degrees. Suture line tension was reduced by approximately 50% when the neck was flexed. Similarly, the force required to appose the cut ends of the trachea was nearly doubled when 5 rather than 3 tracheal cartilages were removed. The surgical technique was performed on 1 horse and 1 pony with partial obstruction of the trachea. In the pony, 5 tracheal cartilages were resected. It was able to return to successful show competition. In the horse, 4 tracheal cartilages were removed. This horse died of complications resulting from bilateral hindlimb myositis, but the tracheal anastomosis was intact, sealed, and healing well.

Comparison of the effects between ursodeoxycholic and chenodeoxycholic acids on liver function and structure and bile acid composition in the Rhesus Monkey.

The hepatotoxic potential of the cholelitholytic bile acids, chenodeoxycholic (chenic), and ursodeoxycholic acids, was compared in the rhesus monkey. A placebo-controlled treatment trial with 40 and 120 mg/kg/day doses of chenic acid and ursodeoxycholic acid, respectively, was conducted in 20 animals. Both chenic and ursodeoxycholic acids induced comparable abnormalities of liver function and structure. Liver biopsies, performed before and after 6 mo of treatment, showed the development of distinct light microscopic changes, including inflammation, fibrosis, and ductular proliferation in the portal fields as well as lobular rearrangement with formation of septa and regenerative nodules. Electron microscopy confirmed light microscopy, but showed no specific changes of cell organelles. Light microscopic examination of the kidneys, lungs, heart, intestine, and brain in 10 monkeys, which were sacrificed after 6 mo of controlled bile acid treatment, showed no abnormalities. Biliary lithocholic acid, all of which was unsulfated, increased several-fold to comparable levels in the bile acid-treated groups. Follow-up studies 6 mo after termination of bile acid treatment showed normalization of liver function tests and of bile acid composition as well as a considerable improvement of the histologic abnormalities. However, the restitution of normal liver structure was incomplete, with fibrosis and mild inflammation persisting in the portal fields. Our studies show that, in this primate species, chenic and ursodeoxycholic acids have comparable hepatotoxic effects, which are associated with similar increases of unsulfated lithocholic acid in bile.

The pony as a model for septic shock.

This study was conducted to determine the feasibility of using alert, conscious ponies as a model for septic shock in man. Ten ponies were given 0.7-5 X 10(9) organisms/kg of body weight of live E coli intravenously over one hour. All ponies died and exhibited signs of low cardiac output septic shock. significant decreases were found in cardiac index to 3.15 +/- 0.1 liters/min/m2 (P less than 0.05), white blood cell count to 1,930 +/- 100 cells/m3 (P less than 0.05), preterminal blood glucose to 75 +/- 5 mg/dl (P less than 0.05), PaO2 to 75.7 +/- 5.7 mm Hg (P less than 0.05), and pH to 7.15 +/- 0.5 (P less than 0.05). Increases were noted in systemic resistance to 3,869 +/- 322 dynes/dic/cm-5 (P less than 0.05), pulmonary resistance to 770.8 +/- 11.12 dynes/sec/cm-5 (P less than 0.05), pulmonary arterial pressure to 41 +/- 7 mm Hg (P less than 0.05), pulmonary wedge pressure to 19.5 +/- 2.5 mm Hg (P less than 0.05), intrapulmonary shunt to 16.43 +/- l.73% (P less than 0.05), early blood glucose to 204 +/- 9.0 mg/dl (P less than 0.05), and excess lactate concentration to 53.06 +/- 5.3 mg/dl (P less than 0.05). From these data it appears that the septic pony shows changes similar to low output septic shock documented in man.