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treatment and survival among colorectal carcinoma patients in an equal-access medical system. Cancer 1998;82:2312–20. 3. Lin DY, Psaty BM, Kronmal RA. Assessing the sensitivity of regression results to unmeasured confounders in observational studies. Biometrics 1998;54:948 –63. Reprint requests and correspondence: Deborah A. Fisher, M.D., Duke University Medical Center, GI Outcomes Research, 508 Fulton Street, Building 16, Room 70, Durham, NC 27705. Received Aug. 28, 2003; accepted Sep. 2, 2003.

Betaine and Nonalcoholic Steatohepatitis TO THE EDITOR: In a recent issue of The American Journal of Gastroenterology, Dr. Mark Milliard provided a brief review of the current clinical evidence that betaine (trimethylglycine) might provide hepatoprotective effects in the treatment of such conditions as nonalcoholic steatohepatitis (NASH) (1). He suggests that the availability of a dietary supplement provides a source of betaine for the treatment of hepatotoxic liver disease; however, this requires some clarification. In the pilot study cited (2), betaine anhydrous was investigated for the treatment of NASH, and more rigorous studies are currently being conducted to further assess the safety and efficacy of betaine anhydrous for the treatment of this disease. As indicated by Dr. Mailliard, other investigators have also evaluated betaine anhydrous for the treatment of other hepatotoxic disease states (3, 4). These studies have been performed with betaine anhydrous, an approved, pharmaceutical form of this substance, and the purpose of this letter is to distinguish it from betaine hydrochloride, currently available as a dietary supplement. The U.S. Food and Drug Administration (FDA) regulates dietary supplements under a different set of regulations than those used for approving prescription and over-the-counter medications. Under the Dietary Supplement Health and Education Act of 1994, the manufacturer of a dietary supplement is only responsible for ensuring product safety. Generally, these manufacturers are not required to register with the FDA or to obtain FDA approval before marketing their product. If the dietary supplement label promotes a statement of nutritional support, the produce label must also indicate that the statement has not been evaluated by the FDA and that the product is not intended to diagnose, treat, cure, or prevent any disease. In addition, the contents of nutritional supplements are not held to the same standards for product potency and purity normally imposed in the manufacture of FDA-approved medications (5). Betaine anhydrous is approved for the treatment of homocystinuria, most commonly the result of several congenital metabolic defects, including cystathionine ␤-synthase deficiency (6); 5,10-methylenetetrahydrofolate reductase deficiency (7); or defects in cobalamin cofactor metabolism

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(7). In patients with homocystinuria, disruption of the methionine/homocysteine cycle leads to toxic concentrations of plasma homocystine resulting in myriad clinical effects (6, 7). By acting as a methyl donor in the remethylation of homocysteine to methionine, betaine anhydrous significantly reduces blood homocysteine concentrations, thereby decreasing the morbidity associated with these incurable diseases (6, 7). The pharmaceutical form of betaine is known as Cystadane (betaine anhydrous) for oral solution (Orphan Medical, Minnetonka, MN) and was approved by the FDA for the treatment of homocystinuria in 1996. Since that time, the safety and efficacy of betaine anhydrous for the treatment of homocystinuria remains well established. William C. Houghton, M.D. Orphan Medical, Inc. Minnetonka, Minnesota

REFERENCES 1. Mailliard M. What is betaine and why could it prevent liver damage? Cytoprotection and the liver. Am J Gastroenterol 2003;98:726. 2. Abdelmalek MF, Angula P, Jorgensen RA, et al. Betaine, a promising new agent for patients with nonalcoholic steatohepatitis. Results of a pilot study. Am J Gastroenterol 2001;96: 2711–7. 3. Barak AJ, Beckenhauer HC, Badakhsh S, et al. The effect of betaine in reversing alcoholic steatosis. Alcohol Clin Exp Res 1997;21:1100 –2. 4. Graf D, Kurz AK, Reinehr, et al. Prevention of bile acidinduced apoptosis by betaine in rat liver. Hepatology 2002;36: 829⫺39. 5. US Department of Health and Human Services, Center for Food Safety and Applied Nutrition. Dietary supplements. Available at: http://vm.cfsan.fda.gov/⬃dms/supplmnt.html. Accessed August 27, 2003. 6. Mudd SH, Levy HL, Kraus JP. Disorders of transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. 8th ed, vol 2. New York: McGraw-Hill, 2001:1278 –327. 7. Rosenblatt DS, Fenton WA. Inherited disorders of folate and cobalamin transport and metabolism. In: Scriver CR, Beaudet Al, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill, 2001:3897–933. Reprint requests and correspondence: William C. Houghton, M.D., Orphan Medical, Inc., Medical Affairs, 13911 Ridgedale Drive, Suite 250, Minnetonka, MN 55305. Received June 2, 2003; accepted July 15, 2003.

Dosage of Intravenous Pantoprazole TO THE EDITOR: The use of a proton pump inhibitor (PPI) for acid reduction has become the standard of care in the patient who has undergone therapeutic endoscopy to achieve hemostasis in the setting of a bleeding peptic ulcer (1, 2). A pH ⬎ 6 has been suggested as optimal for clot stabilization, although the exact regimen to achieve this

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remains unclear (3). To achieve continuous suppression of acid production, both de novo activated pumps, as well as reactivated pumps resulting from the dissociation of the PPI–membrane complex, must be inactivated. A comparison of two regimens given for 3 days after endoscopic hemostasis showed that a once-daily dose of 40 mg of pantoprazole is clinically equivalent to a 40-mg bolus followed by a continuous infusion of 8 mg/h (4). However, neither of these regimens would be expected to result in a gastric pH ⬎ 6 (5). A study of omeprazole given as a 80-mg bolus followed by an infusion of 8 mg/h resulted in fewer episodes of rebleeding after therapeutic endoscopy as compared with control (1, 6). Indeed, a study in healthy normal subjects of pantoprazole given as an 80-mg bolus followed by an infusion of 8 mg/h resulted in a pH ⬎ 6 for 84% of the time (5). These findings, coupled with the apparent therapeutic equivalence of single doses of omeprazole and pantoprazole, have led to the suggestion of a similar regimen of an 80-mg bolus followed by an infusion rate of 8 mg/h for pantoprazole (7). However, the half life to acid recovery after acid suppression with omeprazole is 27.5 h, compared with the half life of acid recovery after pantoprazole suppression of 45 h (8). This is explained by the irreversible nature of the pantoprazole binding as compared with some degree of reversibility of the omeprazole binding (9). Thus, with omeprazole, both newly activated pumps as well as pumps that are regenerated by the dissociation of omeprazole from the pump must be inactivated to achieve pH control. With pantoprazole, only newly activated pumps require inactivation because the combination of pantoprazole with the potassium– hydrogen exchange pump seems to be irreversible. Therefore, on a theoretic basis, although the bolus dose of omeprazole and pantoprazole should be identical, a lower infusion rate of pantoprazole as compared with omeprazole should be adequate to achieve the same degree of acid suppression. If the assumption is made that the rate of de novo pump activation is the same whether omeprazole or pantoprazole is used, then one can estimate the new pump formation in the pantoprazole case by: P共 pant兲 ⫽ S ⴱ t where S ⫽ mean rate of new pump synthesis (independent of PPI), P(pant) ⫽ pumps requiring neutralization by pantoprazole, and t ⫽ time (h). With a half life of 45 h, we obtain: S ⫽ P共max兲/90 where P(max) ⫽ pumps after complete recovery. For omeprazole, the corresponding equations are P共ome兲 ⫽ S ⴱ t ⫹ R ⴱ t and P共ome兲 ⫽ 共P共max兲/90兲 ⴱ t ⫹ R ⴱ t. where P(ome) ⫽ pumps requiring neutralization by ome-

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prazole and R ⫽ mean rate of new pump formation by dissociation of omeprazole from pump. Because the half life for recovery for omeprazole is 27.5 h, we obtain: P共max)/ 2 ⫽ 共P共max兲/90兲 ⴱ 27.5 ⫹ R ⴱ 27.5 which results in: R ⫽ 0.007 ⴱ P共max兲. Combining the above equations, we obtain: 共dP共ome兲/dt兲/共dP共 pant兲/dt兲 ⫽ 1.63. Because the half life of recovery of acid secretion with omeprazole (27.5 h) is greater than the half life to acid recovery with use of pantoprazole (45 h), the above ratio is greater than 1. Eight mg/h infusion of omeprazole has been shown sufficient to decrease rebleeding after therapeutic endoscopy. From the above equation, the corresponding infusion rate of pantoprazole is estimated at 8/1.63 ⫽ 5 mg/h. Charles Maltz, M.D., Ph.D. Division of Gastroenterology and Hepatology Weill Cornell Medical School New York, New York

REFERENCES 1. Lau JYW, Sung JJY, Lee KKC, et al. Effect of intravenous omeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers. N Engl J Med 2000;343:310 –6. 2. Lee KKC, You JHS, Wong ICK, et al. Cost-effectiveness analysis of high-dose omeprazole infusion as adjuvant therapy to endoscopic treatment of bleeding peptic ulcer. Gastrointest Endosc 2003;57:160 –4. 3. Green FW Jr, Kaplan MM, Curtis LE, et al. Effect of acid and pepsin on blood coagulation and platelet aggregation: A possible contributor prolonged gastroduodenal mucosal hemorrhage. Gastroenterology 1978;74:38 –43. 4. Scho¨ neka¨ s H, Ahrens H, Pannewick U, et al. Comparison of two doses of intravenous pantoprazole in peptic ulcer bleeding [abstract P0121]. Gastroenterology 1999;116(suppl V pt 2): A104. 5. Brunner G, Luna P, Hartmann M, et al. Optimizing the intragastric pH as a supportive therapy in upper GI bleeding. Yale J Biol Med 1996;69:225–31. 6. Schaffalitzky de Muckadell OB, Havelund T, Harling H, et al. Effect of omeprazole on the outcome of endoscopically treated bleeding peptic ulcers. Randomized double-blind placebo-controlled multicentre study. Scand J Gastroenterol 1997;32: 320 –7. 7. Wolfe MM, Welage LS, Sachs G. Proton pump inhibitors and gastric acid secretion. Am J Gastroenterol 2001;96:3467–8. 8. Katashima M, Yamamoto K, Tokuma Y, et al. Comparative pharmacokinetic/pharmacodynamic analysis of proton pump inhibitors omeprazole, lansoprazole and pantoprazole, in humans. Eur J Drug Metab Pharmacokinet 1998;23:19 –26. 9. Shin JM, Sachs G. Restoration of acid secretion following treatment with proton pump inhibitors. Gastroenterology 2002; 123:1588 –97.

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Reprint requests and correspondence: Charles Maltz, M.D., Weill Cornell Medical School, Division of Gastroenterology and Hepatic Diseases, New York Presbyterian Hospital, 520 East 70th Street, New York, NY 10021. Received July 8, 2003; accepted July 15, 2003.

Re: A Look Back TO THE EDITOR: I appreciated the column by Dr. Robert Kravetz, “A Look Back” (Am J Gastroenterol 2003;98:924), regarding the treatment regimens for stomach disorders and his list of the “giants” of medicine who paved the way for current therapy. This history of our profession certainly teaches us the foundation of these problems as well as the evolution of the therapeutic processes. In addition, it recognizes the leaders who were responsible for “setting the pace.” I thank the Editorial Board of The American Journal of Gastroenterology for having the insight to include this column in the Journal. Jamie S. Barkin, M.D., F.A.C.P., M.A.C.G. University of Miami, School of Medicine Division of Gastroenterology Mt. Sinai Medical Center Miami, Florida Reprint requests and correspondence: Jamie S. Barkin, M.D., Mount Sinai Medical Center, Division of Gastroenterology, 4300 Alton Road, Miami, FL 33140. Received July 9, 2003; accepted July 15, 2003.

Colon Lavage–Induced Ileocecal Valve Ulceration TO THE EDITOR: Recently, we cared for a 55-yr-old woman who was otherwise healthy and in whom colonoscopy was performed on a screening basis. She tolerated her preprocedural sodium phosphate preparation well. Colonoscopy was performed to the cecum uneventfully and without difficulty. Upon reaching the cecum, a shallow, clean-based ulceration that was nonbleeding and encircled the ileocecal valve (ICV) was noted (Fig. 1). The surrounding mucosa in the cecum and ascending colon were unremarkable, and the ileal mucosa was similarly decidedly normal. Biopsies of the ICV ulceration showed only nonspecific change and no granulomata. The patient had normal bowel habits, there were no recent changes, and she remained asymptomatic. Her screening colonoscopy was otherwise normal, save small internal hemorrhoids. Over the past 14 yr, I (JCY) have infrequently noted such ulcerations as an isolated finding, ordinarily in patients in whom the finding seems to be incidental and of no clinical significance. I have noted these lesions in one in perhaps every 300 – 400 colonoscopic examinations. I would hy-

Figure 1. Colonoscopic photograph of an isolated ulceration surrounding the ileocecal valve.

pothesize that these lesions are related to relative, mild ischemia of the ICV region, which occurs in association with vigorous activity of the ICV during colon evacuation induced by laxative lavage preparations. Anecdotally, I have been impressed that none of the patients in whom I have observed such lesions have had overt symptoms related to the colonoscopic findings or obvious difficulty with tolerating their laxative preparations. I do not believe the finding of these lesions is specifically related to any particular laxative preparation, because they have been noted after magnesium citrate, PEG, and sodium phosphate-based regimens. The findings are certainly not reminiscent of the aphthoid-like lesions that are well-known to be induced by sodium phosphate (1–3). Finding of these lesions is seemingly uncommon but not rare. Recognizing that these asymptomatic, isolated, and ordinarily incidental lesions are preparation-induced will be beneficial in that it might avoid unnecessary evaluation and angst. Joseph C. Yarze, M.D., F.A.C.P., F.A.C.G. Kevin J. Herlihy, M.D. Gastroenterology Associates of Northern New York Elaine C. Winchell, R.N., C.G.R.N. Northern GI Endoscopy Glens Falls, New York

REFERENCES 1. Hixson LJ. Colorectal ulcers associated with sodium phosphate catharsis. Gastrointest Endosc 1995;42:101–2. 2. Zwas FR, Cirillo NW, El-Serag HB, Eisen RN. Colon mucosal abnormalities associated with oral sodium phosphate solution. Gastrointest Endosc 1996;43:463–6. 3. Watts DA, Lessells AM, Penman ID, Ghosh S. Endoscopic and histologic features of sodium phosphate bowel preparationinduced colonic ulceration: Case report and review. Gastrointest Endosc 2002;55:584 –7.