Effects of cholestyramine and diet on small intestinal histomorphometry in rats.

Reports on the effects of cholestyramine on small intestinal structure of rats have produced contradictory data about changes in mucosal histomorphometry, perhaps due to interacting effects of dietary composition. In order to identify effects of cholestyramine and diet on structure of the small intestines, 40 male rats were divided into 4 groups of 10 and fed 1 of each of the following diets for 1 month: standard diet, purified fiber-free diet, standard diet + 2% cholestyramine, or purified fiber-free diet + 2% cholestyramine. Serum concentrations of cholesterol and triglycerides were moderately increased in rats fed the purified fiber-free diet versus the standard diet. Neither total length nor weight of small intestine were affected by either diet or cholestyramine. Mucosal weight was affected by interactions between cholestyramine and diet, indicating that outcome depended upon modulating effects of both variables. Significant interactions were similarly detected among the variables of anatomic site, diet, and cholestyramine for many histomorphometric parameters of intestinal mucosa. Cholestyramine reduced total mucosal thickness in both jejunum and ileum and reduced villus height and villus:crypt ratio in the ileum.

Pharmacokinetics of tiqueside (beta-tigogenin cellobioside) in dogs, rats, rabbits, and monkeys.

Tiqueside (CP-88,818, beta-tigogenin cellobioside) is an effective cholesterol absorption inhibitor that may be useful in the treatment of hypercholesteremia. We have investigated the pharmacokinetics of tiqueside in dogs, rats, rabbits, and monkeys. In dogs, the volume of distribution (Vdss) was 2.11 L/kg, clearance was 0.58 mL/min-kg, and half-life was 45 h following a 1.4 mg/kg intravenous dose. Absolute bioavailability in fed dogs decreased from 6.7% for a 30 mg/kg dose to 1.7% for a 375 mg/kg dose. The oral bioavailability at a dose of 375 mg/kg was approximately 4-fold lower in fasted dogs than fed dogs. AUC-(0-24) for doses up to 2000 mg/kg were only slightly greater than AUC-(0-24) for a 375 mg/kg dose. In rats dosed intravenously at 8.0 mg/kg, Vdss was 3.52 L/kg, clearance was 14.6 mL/min-kg, and half-life was 3.6 h. Estimated bioavailability for rats dosed in feed at 250-2000 mg/kg/day was less than 0.5%. In rabbits dosed at 4.0 mg/kg i.v., Vdss was 2.95 L/kg, clearance was 0.59 mL/min-kg, and half-life was 61 h. Bioavailability for rabbits dosed in feed at 62.5 or 125 mg/kg/day was approximately 7%. Systemic exposure in rhesus monkeys after oral dosing was lower than that for dogs and rabbits. Thus, low systemic exposure to tiqueside following oral administration has been demonstrated in several animal species.

Biliary excretion and enterohepatic cycling of zearalenone in immature pigs.

The disposition of the estrogenic mycotoxin, zearalenone (ZEN) in female, 10- to 14-week-old Yorkshire pigs was investigated. Pigs were administered [3H]ZEN intravenously (IV; n = 4; 5 mg/kg; 15 microCi/kg), orally (n = 4; 10 mg/kg; 30 microCi/kg), or intravenously with bile removal (IVB; n = 2; 5 mg/kg; 15 microCi/kg). Plasma, urine, feces, and bile (IVB pigs only) were serially collected and analyzed for radioactivity. Metabolite profiles were determined in plasma and bile by HPLC. The biological half-life of total plasma radioactivity in IV and orally dosed pigs (86.6 hr) was much larger than that of IVB animals (3.34 hr). Metabolite profiles of plasma concentration vs time demonstrated secondary peaks in concentration during the terminal elimination phase in IV and orally dosed pigs. In IVB pigs these peaks were absent, relative metabolite profiles were altered, and ZEN and metabolites were no longer detectable after 16 hr post-dosing. Biliary recovery of radioactivity, principally as glucuronide conjugates, was extensive (45.61 +/- 4.7%) in IVB pigs and significantly greater (p < 0.05) than that of fecal recovery of radioactivity in IV (6.56 +/- 0.78) or orally dosed (21.74 +/- 1.56%) pigs. Intraduodenal administration of bile containing [3H]ZEN and metabolites resulted in recovery of 64.56 +/- 4.89% of the dose in bile, 20.78 +/- 3.94% in urine, and the presence of glucuronide conjugates of ZEN and alpha-zearalenol (ZEL) in portal and jugular plasma. Differences in metabolite profiles between administered bile and sampled plasma suggest that the intestinal mucosa was active in reducing ZEN to ZEL and conjugating these metabolites with glucuronic acid. These studies provide evidence for extensive biliary secretion and enterohepatic cycling of ZEN and metabolites in pigs.

Evaluation of a superactivated charcoal paste and detergent and water in prevention of T-2 toxin-induced local cutaneous effects in topically exposed swine.

T-2 toxin (6 mg) dissolved in 90% DMSO was topically applied to nine 9-cm2 sites on the dorsum of each of nine young, crossbred, specific pathogen-free, female pigs, 20.6 +/- 1.9 kg in weight. A superactive charcoal paste (SAC) and/or a soap-and-water wash (SOAP) was applied to eight of the T-2-exposed sites on each animal. These treatments were applied at various times postexposure ranging from 5 to 65 min. The site that received T-2 alone served as a positive control. DMSO was applied to a tenth site on each pig as a negative control. Animals were killed 1, 3, or 6 days after treatment. Skin lesions were examined and graded grossly and histologically. No adverse systemic clinical signs were observed in any of the animals. Marked reddening and slight swelling of the T-2 toxin-treated positive control sites were present throughout the study. Ulceration of this site was first noted on Day 3. All therapeutic regimens effectively reduced lesion severity resulting from T-2 toxin application. Significant differences in relative effectiveness were also seen between treatments. In each significant pair, the ordering of mean lesion severity was SAC/SOAP less than SAC or SOAP and SOAP less than SAC. As a single treatment, SOAP appears to be more effective than SAC in reducing lesion severity. These results failed to provide unequivocal evidence of an additive therapeutic effect when SAC and SOAP were used sequentially on the same site.

Eurotium spp. and echinulin in feed refused by swine.

Feed refused by swine contained a high-propagule density of Eurotium chevalieri Mangin (anamorph, Aspergillus chevalieri (Mangin) Thom and Church), Eurotium amstelodami Mangin (anamorph, Aspergillus amstelodami (Mangin Thom and Church), and Aspergillus candidus Link. Echinulin (8 micrograms/g of feed) was detected in the feed. Isolates of E. chevalieri and E. amstelodami but not A. candidus produced echinulin on rice or cracked corn. Mice refused to drink water containing 90 micrograms of echinulin per ml. This is the first report of the alkaloid echinulin in feed refused by swine.