Extensive surgical resection or disease of the small intestine may result in short-bowel syndrome with malabsorption of nutrients and fluids. Patients with less than 200 cm of small intestine (with or without colon resection) usually are dependent on partial or complete parenteral nutritional support to maintain hydration and nutrition. Teduglutide is a glucagon-like peptide 2 analog that binds to enteric neurons and endocrine cells, stimulating release of a number of trophic hormones (including insulin-like growth factor) that stimulate mucosal epithelial growth and enhance fluid absorption. In clinical trials, 54% of patients treated with teduglutide (0.05 mg/kg once daily by subcutaneous injection) reduced their need for parenteral support by at least 1 day/ wk compared with 23% treated with placebo. Teduglutide may be associated with an increased risk of neoplasia, including colorectal polyps.
Ursodiol (ursodeoxycholic acid) is a naturally occurring bile acid that makes up less than 5% of the circulating bile salt pool in humans and a much higher percentage in bears. After oral administration, it is absorbed, conjugated in the liver with glycine
Drugs Used in the Treatment of Gastrointestinal Diseases 1113 or taurine, and excreted in the bile. Conjugated ursodiol undergoes extensive enterohepatic recirculation. The serum half-life is approximately 100 hours. With long-term daily administration, ursodiol constitutes 30–50% of the circulating bile acid pool. A small amount of unabsorbed conjugated or unconjugated ursodiol passes into the colon, where it is either excreted or undergoes dehydroxylation by colonic bacteria to lithocholic acid, a substance with potential hepatic toxicity.
The solubility of cholesterol in bile is determined by the relative proportions of bile acids, lecithin, and cholesterol. Although prolonged ursodiol therapy expands the bile acid pool, this does not appear to be the principal mechanism of action for dissolution of gallstones. Ursodiol decreases the cholesterol content of bile by reducing hepatic cholesterol secretion. Ursodiol also appears to stabilize hepatocyte canalicular membranes, possibly through a reduction in the concentration of other endogenous bile acids or through inhibition of immune-mediated hepatocyte destruction.
Ursodiol is used for dissolution of small cholesterol gallstones in patients with symptomatic gallbladder disease who refuse cholecystectomy or who are poor surgical candidates. At a dosage of 10 mg/kg/d orally for 12–24 months, dissolution occurs in up to 50% of patients with small (<5–10 mm) noncalcified gallstones. It is also effective for the prevention of gallstones in obese patients undergoing rapid weight loss therapy.
Ursodiol is also the first-line agent used for the treatment of early primary biliary cirrhosis (PBC). As a nontoxic bile acid, ursodiol is believed to reduce liver injury by replacement of more toxic endogenous bile acids and through anti-inflammatory effects. At a dose of 13–15 mg/kg/d, ursodiol improves liver biochemical abnormalities, slows the rate of clinical and histologic progression, reduces the need for liver transplantation, and improves long-term survival. Approximately 35% of patients with PBC do not respond to ursodiol.
Ursodiol is practically free of serious adverse effects. Bile salt-induced diarrhea is uncommon. Unlike its predecessor, chenodeoxycholate, ursodiol has not been associated with hepatotoxicity.