This month in Gastroenterology

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otential Dangers of Omeprazole herapy nzymes of the cytochrome P450 E superfamily participate in the oxiative metabolism of many drugs and rreign chemicals. Some drugs, inciudig a variety of imidazole derivatives, an both inhibit and induce these epatic enzymes. Noting that omepraale, a substituted benzimidazole, can npair the clearance of diazepam and henytoin (agents metabolized by cyjchrome P450 enzymes], Diaz et al. 3asoned that omeprazole also might iteract with cytochrome P450 enymes. In cultured human hepatocytes, meprazole was found to selectively educe certain members of the cychrome P450IA family. A similar elective induction of hepatic P450IA nzymes was found in five patients in Ihorn liver biopsy specimens were btained before and after treatment withomeprazole. This in vivo confirmaon of the in vitro results strongly upports the validity of the cultured .uman hepatocyte system for the study f drug-metabolizing enzymes in the .uman liver. Enzymes of the cyIchrome P450IA family are involved 1 the oxidative metabolism of acetminophen and in the biotransformaIon of carcinogens and procarcinoens. In theory, induction of synthesis f these enzymes might predispose to cetaminophen hepatotoxicity and to ertain types of cancer. In an accompalying editorial, Farrell and Murray ecommend caution in the use of cetaminophen for patients receiving ong-term omeprazole therapy. Beause enzymes of the P450IA family re induced by cigarette smoke and by aocarcinogenic polycyclic aromatic hyIrocarbons, which themselves are meabolized by these enzymes, patients eceiving omeprezole should be adised to avoid smoking and to abstain rom charcoal-broiled foods that may ontain aromatic hydrocarbons, . . . pages 737,885 Xetetic Candy Is An Oxymoron o assuage conscience rather than T hunger, many gourmands top off a negacalorie meal with a dietetic candy Ir beverage sweetened by an all-ogedly Inabsorbable sugar alcohol (e. g., sorb-

itol). Beaugerie et al. have studied the absorption of sorbitol and other sugar alcohols ingested postprandially by healthy volunteers. Surprisingly, only 21% of a postprandial dose of sorbitol was recovered by aspiration of intestinal contents through a tube positioned at the terminal ileum, indicating that most of the sugar alcohol had been absorbed by the small intestine. Furthermore. stool excretion of sorbitol was negligible, suggesting extensive metabolism of this molecule by colonic bacteria. The bacterial fermentation of sugar alcohols produces short-chain fatty acids and lactate which can be absorbed and metabolized by the host, and therefore passage of sorbitol into the colon is not tantamount to calorie loss. Indeed, the investigators estimate that the host can capture approxi. mately half of the energy stored in the sorbitol delivered to the colon. This unexpectedly efficient absorption of sorbitol by the small intestine, combined with the colonic salvage of its energy-rich metabolites, suggests that it is futile to consume foods containing sorbitol with the expectation of reduc. . . page 717 ing calories.

Dinnertime Cimetidine for GERD lthough histamine HZ-receptor blocking agents can improve the symptoms and endoscopic signs of gastroesophageal reflux disease (GERD), the optimal dose and treatment schedule for these agents remain unclear. In early studies on cimetidine therapy for GERD, the medication was administered four times per day with the assumption that round-the-clock acid suppression would be most effective therapeutically. For many patients, however, acid reflux occurs predominantly in the evening hours after dinner. Divided medication doses might not be neeesary in such cases, provided acid suppression is adequate after dinner. Tytgat et al. report the results of three large, double-blind, controlled trials comparing the following cimetidine regimens for patients with uncomplicated GERD: (a) 400 mg q.i.d. vs. 800 mg at bedtime, (b] 400 mg q.i.d. vs. 800 mg b.i.d. and (c) 800 mg at bedtime vs. 890 mg at dinnertime. After 6 and 12 weeks of therapy, the endoscopic grade

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of esophagitis improved from pretreatment values at rates that did not differ significantly among treatment groups. Heartburn also improved in most patie&, although best results were obtamed using either the q.i.d. or the dinnertime dosing schedule. These findings suggest that cimetidine administered in a single 800~mg dose at dinnertime is the most cost-effective of the cimetidine treatment regimens studied for patients with uncomphcated GERD. . , . page 629

Parent@r!al Nutr&‘& in IniIammatmy Bowel Disease any clinicians prescribe parenteral nutrition for clinically malnourished patients who have exacerbations of inflammatory bowel disease, even though the efficacy of such treatment has not been established. The study of Christie and Hi11 provides some support for this common practice. These investigators studied respiratory and skeletal muscle function, and estimated total body protein in 19 patients who received parenteral nutrition during hospitalization for flares of inflammatory bowel disease. All patients had clinical signs of malnutrition and had received steroids for at least 8 weeks before hospital admission. During 14 days of parenteral nutrition, there were no significant changes in total body protein. Nevertheless, significant improvements were observed in the function of respiratory and skeletal muscles during the same period. These findings suggest that parenteral nutrition causes rapid improvement in muscle function for malnourished patients with imflammatory bowel disease by mechanisms other than repletion of total body protein. . . . page 730

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Sh@rt-c&& Fatty Acid Transport by the Colon ngested carbohydrate that escapes absorption by the small intestine can be metabolized by colonie bacteria to short-chain fatty acids such as propionate. It has been estimated that colonic bacteria produce approximately 360 mmol of short-chain fatty acids each

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day, yet only 10 mmol is excreted daily in the feces. Although the colon apparently absorbs large quantities of shortchain fatty acids in vivo, several in vitro studies paradoxically have shown net secretion of propionate by the colonic mucosa. These in vitro studies were performed using mucosal bathing solutions at pH 7.4. At this pH, propionate is predominantly an anion that may not diffuse across cell membranes as readily as the electrically neutral acid form of the molecule. Sellin and DeSoignie have found that relatively small changes in pH affect propionate transport by rabbit proximal colon substantially in vitro. Under certain experimental conditions, a change in the pH of the mucosal bathing solution from pH 7.4 to pH 8.8 resulted in a change in propionate transport from net secretion to net absorption. The investigators also found evidence for active transport of propionate that is linked to electroneutral Na absorption mechanisms. This study suggests that colonic regulation of short-chain fatty acid transport is complex and is influenced substantially by the pH and electrolyte composition of the fluid bathing the mucosa. . . page 676

concentrations might influence bile lipid composition, investigators have sought an association between serum lipid levels and cholesterol gallstones. Because bile cholesterol saturation generally is not considered a pathogenetic factor for pigment gallstones, few data are available on serum lipid levels in patients with these stones. In a casecontrol study, Thijs et al. have found that patients with gallstones had lower levels of total serum cholesterol and high-density lipoprotein cholesterol than control subjects, whereas serum triglyceride levels were higher in gallstone patients than in controls. These results confirm those of other studies on patients with cholesterol gallstones. Surprisingly, however, patients with pigment gallstones exhibited the same serum lipid patterns as those with cholesterol stones (viz. lower total and high-density lipoprotein cholesterol levels, and higher triglyceride levels than control subjects). These findings suggest that abnormalities in serum lipid concentrations might influence the formation of both cholesterol and pigment gallstones. . . . page 843

Serum

hysicians concerned about survival in a hostile and overregulated environment would do well to consider the cunning Helicobacter pyiori, organisms that thrive in such a climate. Gastric acid handily kills most bacteria, yet H. pylori swim in it. Although the

Lipids and Pigment Stones

bnormalities in the lipid composition of bile that result in cholesterol supersaturation play an important role in the pathogenesis of cholesterol gallstones. Reasoning that serum lipid

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An H. Pylori Story

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organisms commonly are found adjacent to gastric epithelial cells where they are shielded from huninal acid by a layer of pH-neutral mucus, viable H. pylori have been cultured from acidic gastric juice, suggesting that the bacteria have intrinsic mechanisms for protection from H’. One such mechanism might involve the bacterial enzyme urease that catalyzes the hydrolysis of urea, thereby generating ammonia and bicarbonate for acid neutralization. Marshall et al. found that H. pylori incubated in a medium devoid of urea were killed by acidic solutions, whereas the organisms survived when incubated with the same solutions in the presence of urea. These findings suggest that urease activity protects H. pylori from acid-induced injury. In addition to neutralizing ambient acid, urease activity generates NH,’ which. by reacting with intermediates of the citric acid cycle, can interfere with adenosine triphosphate production by gastric epithelial cells. The authors speculate that these two effects of urease activity (viz. acid neutralization and interference with energy production by parietal cells] might contribute to the hypochlorhydria associated with acute H. pylori infection. The authors also propose that urease activity might protect swallowed H. pylori from injury by huninal acid, enabling the bacteria to reach the shelter of the gastric mucus layer, where they establish residence and a base for infection. . . page 697