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Sulindac-associated choledocholithiasis
AJG – July, 2001
Letters to the Editor
2283
REFERENCES 1. Basile AS, Jones EA, Skolnick P. The pathogenesis and treatment and hepatic encephalopathy: Evidence for the involvement of benzodiazepine receptor ligands. Pharmacol Rev 1991; 43:27–71. 2. Zieve L, Doizaki WM, Zieve FJ. Synergism between mercaptans and ammonia or fatty acids in the production of coma: A possible role in the pathogenesis of hepatic coma. J Lab Clin Med 1974;83:16 –28. 3. Basile AS, Hughes RD, Harrison PM, et al. Elevated brain concentrations of 1,4-benzodiazepines in fulminant hepatic failure. N Engl Med 1991;325:473– 8. 4. Thornton JR, Losowsky MS. Opoid peptides and primary biliary cirrhosis. BMJ 1988;297:1501– 4. 5. Bergase NV, Jones EA. The pruritus of cholestasis potential pathogenic and therapeutic implications of opoids. Gastroenterology 1995;108:1582– 8.
Reprint requests and correspondence: Ajit Sood, M.D., 6-E, Tagore Nagar, Opp. New DMC&H, Ludhiana-141001, Punjab, India. Received Feb. 20, 2001; accepted Mar. 5, 2001.
Sulindac-Associated Choledocholithiasis TO THE EDITOR: In the August, 1999 issue, Tokumine et al. (1) reported the first case of sulindac-associated cholelithiasis. We add to this literature a report on our patient— the first case of sulindac metabolite–associated choledocholithiasis. A detailed literature search revealed six similar cases, suggesting that sulindac may predispose to stone formation in the biliary tract. An 84-yr-old woman with a 12-yr history of rheumatoid arthritis was admitted to our department because of epigastric pain. She had previously received oxaprozin and diflunisal for 9 yr to control her arthralgia. About 3 yr after starting sulindac (300 mg daily) she developed epigastric pain. On admission, physical examination was unremarkable except for mild epigastric tenderness. Laboratory tests suggested acute biliary tract disease. ERCP revealed multiple stones in the common bile duct (Fig. 1), which were removed by choledocholithotripsy after endoscopic balloon sphincteroplasty on the seventh hospital day. The extracted stones were yellow in color and very fragile. An infrared spectroscopic analysis revealed the stones to be composed of sulindac sulfone, an inactive metabolite of sulindac (Fig. 2) (2, 3). Administration of sulindac was stopped, and there has been no recurrence for 1 yr after cessation of sulindac. Despite an extensive literature search including MEDLINE, we could not find any similar cases of choledocholithiasis composed of sulindac metabolites. However, there
Figure 1. ERCP demonstrated multiple choledocholithiasis.
was only one case report of sulindac-associated stones in the gallbladder and the intrahepatic duct (1). Furthermore, we have noted two isolated reports of associated choledocholithiasis to the Food and Drug Administration since 1989 (4) and case reports of one choledocholithiasis and one intrahepatic debris composed of sulindac in abstracts published in Japanese. However, these four reports were unable to provide detailed information. Altogether, including our case, these sulindac-associated biliary stone cases total six. Furthermore, there have been a few reports of sulindacinduced acute pancreatitis mimicking gallstone pancreatitis (5). These cases may have represented pancreatitis caused by sulindac-associated choledocholithiasis. We wish to alert physicians to this potential complication of sulindac and urge close monitoring for biliary stone formation during long term sulindac therapy. Akashi Eda, M.D. Ichiro Yanaka, M.D. Kiichi Tamada, M.D. Shinichi Wada, M.D. Takeshi Tomiyama, M.D. Kentaro Sugano, M.D. Department of Gastroenterology Jichi Medical School Yakushiji, Japan
2284
Letters to the Editor
AJG – Vol. 96, No. 7, 2001
Figure 2. An infrared spectroscopic analysis of sulindac sulfone (top) and the stones in this case (bottom).
AJG – July, 2001
REFERENCES 1. Tokumine F, Sunagawa T, Shiohira Y, et al. Drug-associated cholelithiasis: A case of sulindac stone formation and the incorporation of sulindac metabolites into the gallstones. Am J Gastroenterol 1999;94:2285– 8. 2. Shen TY, Witzel BE, Jones H, et al. Synthesis of a new antiinflammatory agent, cis-5-fluoro-2-methyl-1-[p-(methylsulfinyl)benzylidenyl]-indene-3-acetic acid. Fed Proc 1972;31: 577. 3. Duggan DE, Hare LE, Ditzler CA, et al. The disposition of sulindac. Clin Pharmacol Ther 1977;21:326 –35. 4. Rare complication with sulindac. FDA Drug Bull 1989;Feb 4. 5. Sugerman HJ. Sulindac-induced acute pancreatitis mimicking gallstone pancreatitis. Am Surg 1989;55:536 – 8. Reprint requests and correspondence: Akashi Eda, M.D., Department of Gastroenterology, Jichi Medical School, Yakushiji, Kawachi, Tochigi 329-0498, Japan. Received Feb. 20, 2001; accepted Mar. 5, 2001.
Conception Soon After Discontinuing Interferon/Ribavirin Therapy: A Successful Outcome TO THE EDITOR: Interferon alfa-2b and ribavirin combination therapy is now widely recommended for the treatment of chronic hepatitis C (1). Based on the teratogenic effects in animal models and the persistence of ribavirin in gonadal tissue, it is recommended that women of childbearing age should not become pregnant while on ribavirin and for at least 6 months after therapy. Ribavirin is listed as a category X and interferon as a category C drug by the Food and Drug Administration with regards to pregnancy risk. We report on a patient who became pregnant 3.5 months after stopping treatment, with a successful outcome. The patient was a 29-yr-old woman diagnosed with chronic hepatitis C. She had briefly experimented with i.v. drugs 12 years prior. She was treated with interferon alfa-2b (3 mU three times a week) and ribavirin (1000 mg daily). Treatment was stopped prematurely, after 7 wk, because of severe hemolysis. She became pregnant 3.5 months after discontinuing treatment and, despite medical recommendations, opted to continue the pregnancy. Fetal ultrasounds were normal at the 13th and 19th wk of gestation. A normal baby boy weighing 9 lb 4 oz was born at 41 wk gestation. The child is being observed closely by a pediatrician and is developing normally. At 3 months he is in the 90th percentile for both height and weight. Our treatment options in hepatitis C disease are currently improving; however, there is little known about the safety of the medications used with regards to pregnancy, and as a result there is a tendency to err on the side of caution. As far as interferon is concerned, there are reports of successful pregnancy outcomes in patients with various hematological malignancies, particularly chronic myelogenous leukemia, treated with interferon ␣ during pregnancy (2). There are
Letters to the Editor
2285
two proposed mechanisms for this apparent lack of teratogenicity. Interferon inhibits cell proliferation by effects on protein synthesis and RNA degradation, rather than by inhibition of DNA synthesis. Secondly, because of the size of interferon ␣ (19,300 d), it does not appear to cross the placental barrier to any great extent. With regards to ribavirin, limb abnormalities are reported in hamsters (3), whereas craniofacial defects were more predominant in rats (4). Both defects were seen in mice, in addition to neurological (i.e., exencephaly, encephalocele) and ocular (i.e., anophthalmia, microphthalmia) abnormalities. In the mouse model, a dose of 10 mg/kg, injected i.p., was found to have no measurable effect at any stage of embryonic development (5). However, with incremental dosages, higher rates of malformations were observed. The method of administration also appears to be important because oral administration led to more teratogenic effects than i.v. or i.p. routes. This suggests that the metabolite of ribavirin generated in the maternal GI tract and/or liver is potentially a greater teratogen. No data are yet available for humans. We believe that this is the first report of ribavirin use in proximity to conception. Patients should indeed avoid becoming pregnant while on oral or aerosolized ribavirin. For ethical reasons, a controlled study on this issue is not possible. Individual case reports, such as this, are therefore essential to evaluate the safety of ribavirin in pregnancy. Daniel Mishkin, M.D. Marc Descheˆnes, M.D. Department of Internal Medicine Jewish General Hospital Division of Gastroenterology Department of Medicine Royal Victoria Hospital Center McGill University Health Center Montre´al, Canada
REFERENCES 1. Poynard T, Marcellin P, Lee SS, et al. Randomized trial of interferon ␣2b plus ribavirin for 48 weeks or for 24 weeks versus interferon ␣2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 1998;352: 1426 –32. 2. Haggstrom J, Adriansson M, Hybbinette T, et al. Two cases of CML treated with alpha interferon during second and third trimester of pregnancy with analysis of the drug in the new-born immediately postpartum. Eur J Haematol 1996;57:101–2. 3. Kilham L, Ferm VH. Congenital anomalies induced in hamster embryos with ribavirin. Science 1977;195:413– 4. 4. Ferm VH, Willhite C, Kilham L. Teratogenic effects of ribavirin on hamster and rat embryos. Teratology 1978;17:93–102. 5. Kochnar DM, Penner JD, Knudsen TB. Embryotoxic, teratogenic and metabolic effects of ribavirin in mice. Toxicol Appl Pharmacol 1980;52:99 –112.
Letters to the Editor
2283
REFERENCES 1. Basile AS, Jones EA, Skolnick P. The pathogenesis and treatment and hepatic encephalopathy: Evidence for the involvement of benzodiazepine receptor ligands. Pharmacol Rev 1991; 43:27–71. 2. Zieve L, Doizaki WM, Zieve FJ. Synergism between mercaptans and ammonia or fatty acids in the production of coma: A possible role in the pathogenesis of hepatic coma. J Lab Clin Med 1974;83:16 –28. 3. Basile AS, Hughes RD, Harrison PM, et al. Elevated brain concentrations of 1,4-benzodiazepines in fulminant hepatic failure. N Engl Med 1991;325:473– 8. 4. Thornton JR, Losowsky MS. Opoid peptides and primary biliary cirrhosis. BMJ 1988;297:1501– 4. 5. Bergase NV, Jones EA. The pruritus of cholestasis potential pathogenic and therapeutic implications of opoids. Gastroenterology 1995;108:1582– 8.
Reprint requests and correspondence: Ajit Sood, M.D., 6-E, Tagore Nagar, Opp. New DMC&H, Ludhiana-141001, Punjab, India. Received Feb. 20, 2001; accepted Mar. 5, 2001.
Sulindac-Associated Choledocholithiasis TO THE EDITOR: In the August, 1999 issue, Tokumine et al. (1) reported the first case of sulindac-associated cholelithiasis. We add to this literature a report on our patient— the first case of sulindac metabolite–associated choledocholithiasis. A detailed literature search revealed six similar cases, suggesting that sulindac may predispose to stone formation in the biliary tract. An 84-yr-old woman with a 12-yr history of rheumatoid arthritis was admitted to our department because of epigastric pain. She had previously received oxaprozin and diflunisal for 9 yr to control her arthralgia. About 3 yr after starting sulindac (300 mg daily) she developed epigastric pain. On admission, physical examination was unremarkable except for mild epigastric tenderness. Laboratory tests suggested acute biliary tract disease. ERCP revealed multiple stones in the common bile duct (Fig. 1), which were removed by choledocholithotripsy after endoscopic balloon sphincteroplasty on the seventh hospital day. The extracted stones were yellow in color and very fragile. An infrared spectroscopic analysis revealed the stones to be composed of sulindac sulfone, an inactive metabolite of sulindac (Fig. 2) (2, 3). Administration of sulindac was stopped, and there has been no recurrence for 1 yr after cessation of sulindac. Despite an extensive literature search including MEDLINE, we could not find any similar cases of choledocholithiasis composed of sulindac metabolites. However, there
Figure 1. ERCP demonstrated multiple choledocholithiasis.
was only one case report of sulindac-associated stones in the gallbladder and the intrahepatic duct (1). Furthermore, we have noted two isolated reports of associated choledocholithiasis to the Food and Drug Administration since 1989 (4) and case reports of one choledocholithiasis and one intrahepatic debris composed of sulindac in abstracts published in Japanese. However, these four reports were unable to provide detailed information. Altogether, including our case, these sulindac-associated biliary stone cases total six. Furthermore, there have been a few reports of sulindacinduced acute pancreatitis mimicking gallstone pancreatitis (5). These cases may have represented pancreatitis caused by sulindac-associated choledocholithiasis. We wish to alert physicians to this potential complication of sulindac and urge close monitoring for biliary stone formation during long term sulindac therapy. Akashi Eda, M.D. Ichiro Yanaka, M.D. Kiichi Tamada, M.D. Shinichi Wada, M.D. Takeshi Tomiyama, M.D. Kentaro Sugano, M.D. Department of Gastroenterology Jichi Medical School Yakushiji, Japan
2284
Letters to the Editor
AJG – Vol. 96, No. 7, 2001
Figure 2. An infrared spectroscopic analysis of sulindac sulfone (top) and the stones in this case (bottom).
AJG – July, 2001
REFERENCES 1. Tokumine F, Sunagawa T, Shiohira Y, et al. Drug-associated cholelithiasis: A case of sulindac stone formation and the incorporation of sulindac metabolites into the gallstones. Am J Gastroenterol 1999;94:2285– 8. 2. Shen TY, Witzel BE, Jones H, et al. Synthesis of a new antiinflammatory agent, cis-5-fluoro-2-methyl-1-[p-(methylsulfinyl)benzylidenyl]-indene-3-acetic acid. Fed Proc 1972;31: 577. 3. Duggan DE, Hare LE, Ditzler CA, et al. The disposition of sulindac. Clin Pharmacol Ther 1977;21:326 –35. 4. Rare complication with sulindac. FDA Drug Bull 1989;Feb 4. 5. Sugerman HJ. Sulindac-induced acute pancreatitis mimicking gallstone pancreatitis. Am Surg 1989;55:536 – 8. Reprint requests and correspondence: Akashi Eda, M.D., Department of Gastroenterology, Jichi Medical School, Yakushiji, Kawachi, Tochigi 329-0498, Japan. Received Feb. 20, 2001; accepted Mar. 5, 2001.
Conception Soon After Discontinuing Interferon/Ribavirin Therapy: A Successful Outcome TO THE EDITOR: Interferon alfa-2b and ribavirin combination therapy is now widely recommended for the treatment of chronic hepatitis C (1). Based on the teratogenic effects in animal models and the persistence of ribavirin in gonadal tissue, it is recommended that women of childbearing age should not become pregnant while on ribavirin and for at least 6 months after therapy. Ribavirin is listed as a category X and interferon as a category C drug by the Food and Drug Administration with regards to pregnancy risk. We report on a patient who became pregnant 3.5 months after stopping treatment, with a successful outcome. The patient was a 29-yr-old woman diagnosed with chronic hepatitis C. She had briefly experimented with i.v. drugs 12 years prior. She was treated with interferon alfa-2b (3 mU three times a week) and ribavirin (1000 mg daily). Treatment was stopped prematurely, after 7 wk, because of severe hemolysis. She became pregnant 3.5 months after discontinuing treatment and, despite medical recommendations, opted to continue the pregnancy. Fetal ultrasounds were normal at the 13th and 19th wk of gestation. A normal baby boy weighing 9 lb 4 oz was born at 41 wk gestation. The child is being observed closely by a pediatrician and is developing normally. At 3 months he is in the 90th percentile for both height and weight. Our treatment options in hepatitis C disease are currently improving; however, there is little known about the safety of the medications used with regards to pregnancy, and as a result there is a tendency to err on the side of caution. As far as interferon is concerned, there are reports of successful pregnancy outcomes in patients with various hematological malignancies, particularly chronic myelogenous leukemia, treated with interferon ␣ during pregnancy (2). There are
Letters to the Editor
2285
two proposed mechanisms for this apparent lack of teratogenicity. Interferon inhibits cell proliferation by effects on protein synthesis and RNA degradation, rather than by inhibition of DNA synthesis. Secondly, because of the size of interferon ␣ (19,300 d), it does not appear to cross the placental barrier to any great extent. With regards to ribavirin, limb abnormalities are reported in hamsters (3), whereas craniofacial defects were more predominant in rats (4). Both defects were seen in mice, in addition to neurological (i.e., exencephaly, encephalocele) and ocular (i.e., anophthalmia, microphthalmia) abnormalities. In the mouse model, a dose of 10 mg/kg, injected i.p., was found to have no measurable effect at any stage of embryonic development (5). However, with incremental dosages, higher rates of malformations were observed. The method of administration also appears to be important because oral administration led to more teratogenic effects than i.v. or i.p. routes. This suggests that the metabolite of ribavirin generated in the maternal GI tract and/or liver is potentially a greater teratogen. No data are yet available for humans. We believe that this is the first report of ribavirin use in proximity to conception. Patients should indeed avoid becoming pregnant while on oral or aerosolized ribavirin. For ethical reasons, a controlled study on this issue is not possible. Individual case reports, such as this, are therefore essential to evaluate the safety of ribavirin in pregnancy. Daniel Mishkin, M.D. Marc Descheˆnes, M.D. Department of Internal Medicine Jewish General Hospital Division of Gastroenterology Department of Medicine Royal Victoria Hospital Center McGill University Health Center Montre´al, Canada
REFERENCES 1. Poynard T, Marcellin P, Lee SS, et al. Randomized trial of interferon ␣2b plus ribavirin for 48 weeks or for 24 weeks versus interferon ␣2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 1998;352: 1426 –32. 2. Haggstrom J, Adriansson M, Hybbinette T, et al. Two cases of CML treated with alpha interferon during second and third trimester of pregnancy with analysis of the drug in the new-born immediately postpartum. Eur J Haematol 1996;57:101–2. 3. Kilham L, Ferm VH. Congenital anomalies induced in hamster embryos with ribavirin. Science 1977;195:413– 4. 4. Ferm VH, Willhite C, Kilham L. Teratogenic effects of ribavirin on hamster and rat embryos. Teratology 1978;17:93–102. 5. Kochnar DM, Penner JD, Knudsen TB. Embryotoxic, teratogenic and metabolic effects of ribavirin in mice. Toxicol Appl Pharmacol 1980;52:99 –112.