Oxfendazole kinetics in pigs: In vivo assessment of its pattern of accumulation in Ascaris suum.

Ascaris suum is a widespread parasitic nematode that causes infection in pigs with high prevalence rates. Oxfendazole (OFZ) is effective against A. suum when used at a single high oral dose of 30 mg/kg. The aim of this study was to assess the pattern of distribution/accumulation of OFZ and its metabolites, in bloodstream (plasma), mucosal tissue and contents from small and large intestine and adult specimens of A. suum collected from infected and treated pigs. The activity of glutathione-S-transferases (GSTs) in A. suum was also investigated. Infected pigs were orally treated with OFZ (30 mg/kg) and sacrificed at 0, 3, 6 and 12 h after treatment. Samples of blood, mucosa and contents from both small and large intestine as well as adult worms were obtained and processed for quantification of OFZ/metabolites by HPLC. OFZ was the main analyte measured in all of the evaluated matrixes. The highest drug concentrations were determined in small (AUC0-t 718.7 ±â€¯283.5 µg h/g) and large (399.6 ±â€¯110.5 µg h/g) intestinal content. Concentrations ranging from 1.35 to 2.60 µg/g (OFZ) were measured in adult A. suum. GSTs activity was higher after exposure to OFZ both in vivo and ex vivo. The data obtained here suggest that the pattern of OFZ accumulation in A. suum would be more related to the concentration achieved in the fluid and mucosa of the small intestine than in other tissues/fluids. It is expected that increments in the amount of drug attained in the tissues/fluids of parasite location will correlate with increased drug concentration within the target parasite, and therefore with the resultant treatment efficacy. The results are particularly relevant considering the potential of OFZ to be used for soil transmitted helminths (STH) control programs and the advantages of pigs as a model to assess drug treatment to be implemented in humans.

In vitro assessment of intestinal IGF-I stability.

Insulin-like growth factor (IGF-I) is a 7648-Da polypeptide consisting of 70 amino acids. Clinically, IGF-I might be used in type II diabetes, which requires a life-long treatment. Therefore, delivery routes other than parenteral injections are highly desirable. For convenience, the peroral route is the most attractive. Therefore, in an attempt to answer the feasibility of oral delivery of IGF-I we examined the metabolism of this polypeptide in the gut in the presence of crude porcine pancreatic enzymes (CPPE) and flushings of the small and large intestine from pig, rat, and dog. Moreover, incubation studies with purified pancreatic enzymes that are present in the intestine were performed to determine the most active enzymes responsible for the intestinal cleavage of IGF-I. IGF-I was mainly degraded by chymotrypsin (t(1/2) = 2.7 min) and trypsin (t(1/2) = 34.6 min), whereas in the presence of aminopeptidase M and carboxypeptidase A IGF-I was stable up to 90 min. IGF-I was degraded in flushings from the jejunum, ileum, and colon. However, there were no significant differences in the stability of IGF-I between the examined intestinal segments. The addition of serine protease inhibitors such as a combination of aprotinin, soybean trypsin inhibitor, and Nalpha-p-tosyl-L-lysine chloromethyl ketone (TLCK), as well as casein profoundly improved the stability. Because we were able to improve the stability of IGF-I in vitro in all species at the same degree we speculate that a similar extension of half-life might also be possible in the human intestinal system.

Comparative assessment of D-xylose absorption between small intestine and large intestine.

The present study aimed to evaluate the absorption of D-xylose, a passively absorbed five-carbon monosaccharide, from the large intestine compared with the small intestine, in order to explore the absorption potential of the large intestine. D-Xylose absorption was evaluated in the intestinal loop and everted sacs in rats and comparisons were made between small intestine (mid-gut) and large intestine (colon). The absorption of D-xylose was smaller, by an order of magnitude or more, after administration into the loop of large intestine than after administration into that of small intestine, based on appearance in plasma and disappearance from the intestinal loop. D-Xylose absorption was practically insignificant (nominal 4.9%) in 60 min in the large intestine, whereas it was moderate (57.0%) in the small intestine. Consistently, the uptake of D-xylose in everted sacs was about 20 times larger in the small intestine than in the large intestine. Thus the passive membrane permeability of D-xylose was demonstrated to be negligible in the large intestine, even though the small intestine was fairly permeable. This result helps rationalize kinetic modelling strategies assuming the small intestine as the sole absorption site for gastrointestinal absorption in-vivo. It also suggests that hydrophilic drugs with molecular size similar to or larger than D-xylose may not be good candidates for colonic drug delivery by controlled release.

Assessment of fermentation in growing pigs given unmolassed sugar-beet pulp: a stoichiometric approach.

In four experiments growing pigs were given a cereal-based diet alone or supplemented with unmolassed sugar-beet pulp (SBP), used as a model substrate for fermentation. The rates of production of methane and gaseous hydrogen were measured and, together with the molar proportions of volatile fatty acids (VFA) in the digesta, used in stoichiometric calculations of fermentation. The resulting estimates were only one-sixth of the observed extent of digestion of SBP. Bacteriostatic levels of antibiotics reduced fermentation by more than half, as judged from the digestion of non-starch polysaccharides: allowing for the incomplete suppression of fermentation it was estimated that the production of methane and VFA could account completely for the digested SBP. The potential contribution of various routes of hydrogen disposal to the error of the stoichiometric calculations is discussed.