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Intrahepatic cholestasis and pure red cell aplasia associated with ticlopidine
European Journal of Internal Medicine 14 (2003) 192–195 www.elsevier.com / locate / ejim
Brief report
Intrahepatic cholestasis and pure red cell aplasia associated with ticlopidine Nobuo Waguri b
a,b ,
*, Masaru Yamamoto a
a Department of Internal Medicine, Sannocho Hospital, 2 -30 Honcho 5, Sanjo City, Niigata 955 -0071, Japan The Third Department of Internal Medicine, Niigata University, School of Medicine, 1 -757 Asahimachi-Dori, Niigata City, Niigata 951 -8122, Japan
Received 12 September 2002; accepted 14 January 2003
Abstract A 77-year-old woman developed jaundice and anemia 3 and 8 weeks, respectively, after starting ticlopidine (100 mg daily) for cerebral infarction. From the laboratory findings, including histological study of the liver and bone marrow specimen, ticlopidine-induced intrahepatic cholestasis and pure red cell aplasia were highly suspected. Jaundice slowly improved after the withdrawal of ticlopidine. Anemia immediately improved with steroid therapy. These are very rare adverse effects of ticlopidine; nevertheless, periodic laboratory examinations are recommended. 2003 Elsevier Science B.V. All rights reserved. Keywords: Ticlopidine; Intrahepatic cholestasis; Jaundice; Pure red cell aplasia; Prednisolone
1. Introduction Ticlopidine is an antiplatelet agent that inhibits ADPinduced platelet aggregation [1] and that is widely used for the prevention of vascular thrombosis. Frequently reported toxicities of ticlopidine include diarrhea, rash, and neutropenia [2,3]. Other hematologic toxicities include bleeding, thrombocytopenia, thrombotic thrombocytopenic purpura, and aplastic anemia [2]. Aplastic anemia is an uncommon condition that has been reported in some cases [4–7]. However, to our knowledge, there are only a few published reports of pure red cell aplasia (PRCA) associated with ticlopidine [8,9]. Here we described a case with severe intrahepatic cholestasis and PRCA following ticlopidine use.
*Corresponding author. The Third Department of Internal Medicine, Niigata University, School of Medicine, 1-757 Asahimachi-Dori, Niigata 951-8122, Japan. Tel.: 181-25-227-2207; fax: 181-25-227-0776. E-mail address: [email protected] (N. Waguri).
2. Case report A 77-year-old woman was admitted to our hospital in March 19, 2000 with sudden onset of right hemiparesis. She had a past history of hypertension and cerebral infarction, and her medications included nitrendipine, alphacalcidol, and aspirin (81 mg daily). All laboratory findings on admission, including routine hematological study and hepatobiliary enzymes, were within the normal ranges (Table 1). Magnetic resonance imaging of the brain revealed an acute infarction of the left middle cerebral arterial territory, as well as some other small old infarctions. Ozagrel sodium (80 mg daily) was administered for 2 weeks and the patient’s symptoms improved slightly. Consequently, oral ticlopidine hydrochloride (100 mg daily) was started. Three weeks after the start of ticlopidine, the patient developed liver dysfunction and jaundice (Table 1). However, ultrasonography, computed tomography, and magnetic resonance cholangiography showed no abnormal findings in the hepatobiliary systems. Serological tests for hepatitis A, B, and C were negative. Antinuclear and antimitochondrial antibodies were also
0953-6205 / 03 / $ – see front matter 2003 Elsevier Science B.V. All rights reserved. doi:10.1016 / S0953-6205(03)00037-2
N. Waguri, M. Yamamoto / European Journal of Internal Medicine 14 (2003) 192–195
193
Table 1 Laboratory findings Date
March 21, 2000
April 25, 2000
June 5, 2000
July 17, 2000
White cell count (/ ml) Red cell count (310 4 / ml) Hemoglobin (g / dl) Hematocrit (%) Platelet count (310 4 / ml) Reticulocyte count (%) Aspartate aminotransferase (IU / l) Alanine aminotransferase (IU / l) Lactate dehydrogenase (IU / l) Alkaline phosphatase (IU / l) g-Glutamyl transpeptidase (IU / l) Total bilirubin (mg / dl) Direct bilirubin (mg / dl)
6200 374 11.6 35.6 20.4 1.2 22 12 324 207 13 1.2 0.2
3600 364 11.7 35.0 20.0
3300 172 5.7 16.7 23.8 0.4 44 68 624 1402 384 15.3 10.3
3100 337 10.9 33.3 15.6 33.0 29 88 377 1067 886 2.6 1.4
negative. Sixty milliliters daily of Stronger NeoMinophagen C (SNMC; Minophagen Pharmaceutical Co., Tokyo, Japan), an aqueous solution containing 40 mg glycyrrhiza supplemented with glycine and cystein in a 20-ml ampoule, were given intravenously. In May 8, 2000, all of the drugs were stopped except SNMC (Fig. 1). A liver biopsy specimen showed intrahepatic cholestasis, especially in the centrilobular region, and a small amount of inflammatory infiltration in the periportal area. Disappearance of the bile duct component was seen in three of eight portal tracts. From the patient’s clinical course and histological findings, druginduced intrahepatic cholestasis was highly suspected.
204 371 571 1280 379 6.0 4.3
Since there are no reports of severe cholestasis associated with any of the other drugs that were administered except ticlopidine, ticlopidine was considered to be the causative drug. The level of total bilirubin reached a maximum (28.8 mg / dl) and then slowly decreased. Oral ursodeoxycolic acid (300 mg daily) was added, and the level of serum bilirubin returned to normal 3 months after the onset of jaundice. Following the peak of jaundice, normocytic normochromic anemia suddenly developed (Fig. 1). Leukopenia and thrombocytopenia were not observed (Table 1). No gastrointestinal bleeding was revealed by fecal examinations, upper gastrointestinal endoscopy, or total colonos-
Fig. 1. Clinical course of the patient. Hb, hemoglobin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; T-Bil, total bilirubin; UDCA, ursodeoxycholic acid; SNMC, Stronger Neo-Minophagen C; PSL, prednisolone; RBC, packed red blood cell transfusion.
194
N. Waguri, M. Yamamoto / European Journal of Internal Medicine 14 (2003) 192–195
copy. Laboratory examinations revealed a reticulocyte count of 0.4%, serum Fe level of 216 mg / dl (40–162), UIBC level of 13 mg / dl (182–304), and serum ferritin level of 1700 ng / ml (6–167). IgG and IgM antibodies to human parvovirus B19 were negative. Bone marrow examination in June 12 demonstrated slightly hypocellular marrow with a marked decrease only in the erythroid element. A diagnosis of PRCA was made and oral prednisolone therapy (30 mg daily) was started. The reticulocyte count immediately increased to 5.8%, and the anemia subsequently diminished. The dose of prednisolone was gradually tapered to 5 mg daily with no recurrence of anemia. The patient was discharged in September.
registrations of 12 PRCA patients who received ticlopidine (unpublished data provided by Daiichi Pharmaceutical Co. Ltd., Tokyo, Japan). It is also unclear why only erythroid components of bone marrow are involved. The PRCA in our case followed intrahepatic cholestasis and improved with steroid therapy. Given the fact that steroid therapy was highly effective, an immunological mechanism for PRCA might be suspected. In conclusion, we report a case of severe intrahepatic cholestasis and PRCA associated with ticlopidine. Although these adverse effects are rare, periodic hematological and liver function tests in the first 3 months following the start of ticlopidine are recommended.
3. Discussion
Acknowledgements
Adverse effects have occasionally been noted in some ticlopidine trials. The Canadian American Ticlopidine Study reported a 4.4% incidence of abnormal liver function tests in patients receiving ticlopidine [10]. However, the Ticlopidine Aspirin Stroke Study reported no hepatotoxicity among recipients of ticlopidine [3]. The mechanisms of liver injury have not yet been established. Recent reports have suggested direct injury by ticlopidine metabolites inhibiting cytochrome P450 2C19 and 2D6 [11,12]. In general, cholestatic type liver injury predominates in ticlopidine-induced liver injuries. However, there are only a few reports of severe cholestasis with jaundice [13–15]. According to one review [15], liver dysfunction appears 1 week to 3 months after starting ticlopidine. In our case, the onset of jaundice was 3 weeks after starting ticlopidine. Other causative factors, such as hepatitis viruses, were excluded and the histological findings of the liver were compatible with drug-induced intrahepatic cholestasis. In our case, anemia developed 3 weeks after the withdrawal of ticlopidine. Bone marrow examination revealed a marked decrease only in the erythroid element, and the diagnosis of PRCA was made. The patient’s clinical status showed no signs of viral infection. In addition, she was seronegative for antibodies to human parvovirus B19, which is considered to be one of the most common causes of PRCA. No other cause of PRCA, including autoimmune diseases, was discovered except for ticlopidine. The onset of PRCA was 3 weeks after withdrawal of ticlopidine, i.e. 8 weeks after the start of ticlopidine. This time lag was considered to be an acceptable duration for ticlopidine-induced PRCA [4,6]. Hematological toxicity is one of the most dangerous side effects of ticlopidine with neutropenia being the most frequent condition. The mechanisms of ticlopidine-induced neutropenia and aplastic anemia are not fully understood, although a direct injury mechanism and an immunological mechanism have been proposed [16,17]. PRCA associated with ticlopidine is a very rare condition and there are only a few published reports [8,9]. In Japan, there have been the
The authors thank Minoru Nomoto, MD, and Yoshiaki Moriyama, MD, for performing the histological diagnosis of the liver and bone marrow specimens, respectively.
References [1] Harker LA, Bruno JJ. Ticlopidine’s mechanism of action on human platelets. In: Hass WK, Easton JD, editors, Ticlopidine, platelets and vascular disease, New York: Springer-Verlag, 1993, pp. 41–59. [2] Molony BA. An analysis of the side-effects of ticlopidine. In: Hass WK, Easton JD, editors, Ticlopidine, platelets and vascular disease, New York: Springer-Verlag, 1993, pp. 117–39. [3] Hass WK, Easton JD, Adams Jr. HP, Pryse-Phillips W, Molony BA, Anderson S et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. Ticlopidine Aspirin Stroke Study Group. N Engl J Med 1989;321:501–7. [4] Yeh SP, Hsueh EJ, Wu H, Wang YC. Ticlopidine-associated aplastic anemia. A case report and review of literature. Ann Hematol 1998;76:87–90. [5] Ceylan C, Kirimli O, Akarsu M, Undar B, Guneri S. Early ticlopidine-induced hepatic dysfunction, dermatitis and irreversible aplastic anemia after coronary artery stenting (letter). Am J Hematol 1998;59:260. [6] Taher A, Ammash Z, Dabajah B, Nasrallah A, Mourad FH. Ticlopidine-induced aplastic anemia and quick recovery with GCSF: case report and literature review. Am J Hematol 2000;63:90– 3. [7] Pullarkat VA, Rho H, Murata-Collins JL, Liebman HA. Ticlopidineinduced aplastic anemia: development of chromosomal abnormalities and response to immunosuppressive therapy. Am J Hematol 2000;63:141–4. [8] Pascual S, Sarrion JV, Jarque I, Arguello L, Berenguer J. Cholestatic hepatitis and anemia induced by ticlopidine. Gastroenterol Hepatol (Spanish) 1996;19:208–9. [9] Finsterer J. Severe normochrome and normocytic anemia after 19 months on ticlopidine. J Neuropsychiatry Clin Neurosci 1999;11:118–9. [10] Gent M, Blakely JA, Easton JD, Ellis DJ, Hachinski VC, Harbison JW et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989;1:1215–20. [11] Ha-Duong NT, Dijols S, Macherey AC, Goldstein JA, Dansette PM, Mansuy D. Ticlopidine as a selective mechanism-based inhibitoe of human cytochrome P450 2C19. Biochemistry 2001;40:1211–22.
N. Waguri, M. Yamamoto / European Journal of Internal Medicine 14 (2003) 192–195 [12] Ko JW, Desta Z, Soukhova NV, Tracy T, Flockhart DA. In vitro inhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine: potent effect on CYP2C19 and CYP2D6. Br J Clin Pharmacol 2000;49:343–51. [13] Grimm IS, Litynski JJ. Severe cholestasis associated with ticlopidine. Am J Gastroenterol 1994;89:279–80. [14] Hirota WK, Moses F, Blouch D, Sjogren M. Ticlopidine associated intrahepatic cholestasis. Am J Gastroenterol 1996;91:2019. [15] Iqbal M, Goenka P, Young MF, Thomas E, Borthwick TR. Ti-
195
clopidine-induced cholestatic hepatitis: report of three cases and review of the literature. Dig Dis Sci 1999;43:2223–6. [16] Ono K, Kurohara K, Yoshihara M, Shimamoto Y, Yamaguchi M. Agranulocytosis caused by ticlopidine and its mechanism. Am J Hematol 1991;37:239–42. [17] Liu ZC, Urtrecht JP. Metabolism of ticlopidine by activated neutrophils: implications for ticlopidine-induced agranulocytosis. Drug Metab Dispos 2000;28:726–30.
Brief report
Intrahepatic cholestasis and pure red cell aplasia associated with ticlopidine Nobuo Waguri b
a,b ,
*, Masaru Yamamoto a
a Department of Internal Medicine, Sannocho Hospital, 2 -30 Honcho 5, Sanjo City, Niigata 955 -0071, Japan The Third Department of Internal Medicine, Niigata University, School of Medicine, 1 -757 Asahimachi-Dori, Niigata City, Niigata 951 -8122, Japan
Received 12 September 2002; accepted 14 January 2003
Abstract A 77-year-old woman developed jaundice and anemia 3 and 8 weeks, respectively, after starting ticlopidine (100 mg daily) for cerebral infarction. From the laboratory findings, including histological study of the liver and bone marrow specimen, ticlopidine-induced intrahepatic cholestasis and pure red cell aplasia were highly suspected. Jaundice slowly improved after the withdrawal of ticlopidine. Anemia immediately improved with steroid therapy. These are very rare adverse effects of ticlopidine; nevertheless, periodic laboratory examinations are recommended. 2003 Elsevier Science B.V. All rights reserved. Keywords: Ticlopidine; Intrahepatic cholestasis; Jaundice; Pure red cell aplasia; Prednisolone
1. Introduction Ticlopidine is an antiplatelet agent that inhibits ADPinduced platelet aggregation [1] and that is widely used for the prevention of vascular thrombosis. Frequently reported toxicities of ticlopidine include diarrhea, rash, and neutropenia [2,3]. Other hematologic toxicities include bleeding, thrombocytopenia, thrombotic thrombocytopenic purpura, and aplastic anemia [2]. Aplastic anemia is an uncommon condition that has been reported in some cases [4–7]. However, to our knowledge, there are only a few published reports of pure red cell aplasia (PRCA) associated with ticlopidine [8,9]. Here we described a case with severe intrahepatic cholestasis and PRCA following ticlopidine use.
*Corresponding author. The Third Department of Internal Medicine, Niigata University, School of Medicine, 1-757 Asahimachi-Dori, Niigata 951-8122, Japan. Tel.: 181-25-227-2207; fax: 181-25-227-0776. E-mail address: [email protected] (N. Waguri).
2. Case report A 77-year-old woman was admitted to our hospital in March 19, 2000 with sudden onset of right hemiparesis. She had a past history of hypertension and cerebral infarction, and her medications included nitrendipine, alphacalcidol, and aspirin (81 mg daily). All laboratory findings on admission, including routine hematological study and hepatobiliary enzymes, were within the normal ranges (Table 1). Magnetic resonance imaging of the brain revealed an acute infarction of the left middle cerebral arterial territory, as well as some other small old infarctions. Ozagrel sodium (80 mg daily) was administered for 2 weeks and the patient’s symptoms improved slightly. Consequently, oral ticlopidine hydrochloride (100 mg daily) was started. Three weeks after the start of ticlopidine, the patient developed liver dysfunction and jaundice (Table 1). However, ultrasonography, computed tomography, and magnetic resonance cholangiography showed no abnormal findings in the hepatobiliary systems. Serological tests for hepatitis A, B, and C were negative. Antinuclear and antimitochondrial antibodies were also
0953-6205 / 03 / $ – see front matter 2003 Elsevier Science B.V. All rights reserved. doi:10.1016 / S0953-6205(03)00037-2
N. Waguri, M. Yamamoto / European Journal of Internal Medicine 14 (2003) 192–195
193
Table 1 Laboratory findings Date
March 21, 2000
April 25, 2000
June 5, 2000
July 17, 2000
White cell count (/ ml) Red cell count (310 4 / ml) Hemoglobin (g / dl) Hematocrit (%) Platelet count (310 4 / ml) Reticulocyte count (%) Aspartate aminotransferase (IU / l) Alanine aminotransferase (IU / l) Lactate dehydrogenase (IU / l) Alkaline phosphatase (IU / l) g-Glutamyl transpeptidase (IU / l) Total bilirubin (mg / dl) Direct bilirubin (mg / dl)
6200 374 11.6 35.6 20.4 1.2 22 12 324 207 13 1.2 0.2
3600 364 11.7 35.0 20.0
3300 172 5.7 16.7 23.8 0.4 44 68 624 1402 384 15.3 10.3
3100 337 10.9 33.3 15.6 33.0 29 88 377 1067 886 2.6 1.4
negative. Sixty milliliters daily of Stronger NeoMinophagen C (SNMC; Minophagen Pharmaceutical Co., Tokyo, Japan), an aqueous solution containing 40 mg glycyrrhiza supplemented with glycine and cystein in a 20-ml ampoule, were given intravenously. In May 8, 2000, all of the drugs were stopped except SNMC (Fig. 1). A liver biopsy specimen showed intrahepatic cholestasis, especially in the centrilobular region, and a small amount of inflammatory infiltration in the periportal area. Disappearance of the bile duct component was seen in three of eight portal tracts. From the patient’s clinical course and histological findings, druginduced intrahepatic cholestasis was highly suspected.
204 371 571 1280 379 6.0 4.3
Since there are no reports of severe cholestasis associated with any of the other drugs that were administered except ticlopidine, ticlopidine was considered to be the causative drug. The level of total bilirubin reached a maximum (28.8 mg / dl) and then slowly decreased. Oral ursodeoxycolic acid (300 mg daily) was added, and the level of serum bilirubin returned to normal 3 months after the onset of jaundice. Following the peak of jaundice, normocytic normochromic anemia suddenly developed (Fig. 1). Leukopenia and thrombocytopenia were not observed (Table 1). No gastrointestinal bleeding was revealed by fecal examinations, upper gastrointestinal endoscopy, or total colonos-
Fig. 1. Clinical course of the patient. Hb, hemoglobin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; T-Bil, total bilirubin; UDCA, ursodeoxycholic acid; SNMC, Stronger Neo-Minophagen C; PSL, prednisolone; RBC, packed red blood cell transfusion.
194
N. Waguri, M. Yamamoto / European Journal of Internal Medicine 14 (2003) 192–195
copy. Laboratory examinations revealed a reticulocyte count of 0.4%, serum Fe level of 216 mg / dl (40–162), UIBC level of 13 mg / dl (182–304), and serum ferritin level of 1700 ng / ml (6–167). IgG and IgM antibodies to human parvovirus B19 were negative. Bone marrow examination in June 12 demonstrated slightly hypocellular marrow with a marked decrease only in the erythroid element. A diagnosis of PRCA was made and oral prednisolone therapy (30 mg daily) was started. The reticulocyte count immediately increased to 5.8%, and the anemia subsequently diminished. The dose of prednisolone was gradually tapered to 5 mg daily with no recurrence of anemia. The patient was discharged in September.
registrations of 12 PRCA patients who received ticlopidine (unpublished data provided by Daiichi Pharmaceutical Co. Ltd., Tokyo, Japan). It is also unclear why only erythroid components of bone marrow are involved. The PRCA in our case followed intrahepatic cholestasis and improved with steroid therapy. Given the fact that steroid therapy was highly effective, an immunological mechanism for PRCA might be suspected. In conclusion, we report a case of severe intrahepatic cholestasis and PRCA associated with ticlopidine. Although these adverse effects are rare, periodic hematological and liver function tests in the first 3 months following the start of ticlopidine are recommended.
3. Discussion
Acknowledgements
Adverse effects have occasionally been noted in some ticlopidine trials. The Canadian American Ticlopidine Study reported a 4.4% incidence of abnormal liver function tests in patients receiving ticlopidine [10]. However, the Ticlopidine Aspirin Stroke Study reported no hepatotoxicity among recipients of ticlopidine [3]. The mechanisms of liver injury have not yet been established. Recent reports have suggested direct injury by ticlopidine metabolites inhibiting cytochrome P450 2C19 and 2D6 [11,12]. In general, cholestatic type liver injury predominates in ticlopidine-induced liver injuries. However, there are only a few reports of severe cholestasis with jaundice [13–15]. According to one review [15], liver dysfunction appears 1 week to 3 months after starting ticlopidine. In our case, the onset of jaundice was 3 weeks after starting ticlopidine. Other causative factors, such as hepatitis viruses, were excluded and the histological findings of the liver were compatible with drug-induced intrahepatic cholestasis. In our case, anemia developed 3 weeks after the withdrawal of ticlopidine. Bone marrow examination revealed a marked decrease only in the erythroid element, and the diagnosis of PRCA was made. The patient’s clinical status showed no signs of viral infection. In addition, she was seronegative for antibodies to human parvovirus B19, which is considered to be one of the most common causes of PRCA. No other cause of PRCA, including autoimmune diseases, was discovered except for ticlopidine. The onset of PRCA was 3 weeks after withdrawal of ticlopidine, i.e. 8 weeks after the start of ticlopidine. This time lag was considered to be an acceptable duration for ticlopidine-induced PRCA [4,6]. Hematological toxicity is one of the most dangerous side effects of ticlopidine with neutropenia being the most frequent condition. The mechanisms of ticlopidine-induced neutropenia and aplastic anemia are not fully understood, although a direct injury mechanism and an immunological mechanism have been proposed [16,17]. PRCA associated with ticlopidine is a very rare condition and there are only a few published reports [8,9]. In Japan, there have been the
The authors thank Minoru Nomoto, MD, and Yoshiaki Moriyama, MD, for performing the histological diagnosis of the liver and bone marrow specimens, respectively.
References [1] Harker LA, Bruno JJ. Ticlopidine’s mechanism of action on human platelets. In: Hass WK, Easton JD, editors, Ticlopidine, platelets and vascular disease, New York: Springer-Verlag, 1993, pp. 41–59. [2] Molony BA. An analysis of the side-effects of ticlopidine. In: Hass WK, Easton JD, editors, Ticlopidine, platelets and vascular disease, New York: Springer-Verlag, 1993, pp. 117–39. [3] Hass WK, Easton JD, Adams Jr. HP, Pryse-Phillips W, Molony BA, Anderson S et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. Ticlopidine Aspirin Stroke Study Group. N Engl J Med 1989;321:501–7. [4] Yeh SP, Hsueh EJ, Wu H, Wang YC. Ticlopidine-associated aplastic anemia. A case report and review of literature. Ann Hematol 1998;76:87–90. [5] Ceylan C, Kirimli O, Akarsu M, Undar B, Guneri S. Early ticlopidine-induced hepatic dysfunction, dermatitis and irreversible aplastic anemia after coronary artery stenting (letter). Am J Hematol 1998;59:260. [6] Taher A, Ammash Z, Dabajah B, Nasrallah A, Mourad FH. Ticlopidine-induced aplastic anemia and quick recovery with GCSF: case report and literature review. Am J Hematol 2000;63:90– 3. [7] Pullarkat VA, Rho H, Murata-Collins JL, Liebman HA. Ticlopidineinduced aplastic anemia: development of chromosomal abnormalities and response to immunosuppressive therapy. Am J Hematol 2000;63:141–4. [8] Pascual S, Sarrion JV, Jarque I, Arguello L, Berenguer J. Cholestatic hepatitis and anemia induced by ticlopidine. Gastroenterol Hepatol (Spanish) 1996;19:208–9. [9] Finsterer J. Severe normochrome and normocytic anemia after 19 months on ticlopidine. J Neuropsychiatry Clin Neurosci 1999;11:118–9. [10] Gent M, Blakely JA, Easton JD, Ellis DJ, Hachinski VC, Harbison JW et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989;1:1215–20. [11] Ha-Duong NT, Dijols S, Macherey AC, Goldstein JA, Dansette PM, Mansuy D. Ticlopidine as a selective mechanism-based inhibitoe of human cytochrome P450 2C19. Biochemistry 2001;40:1211–22.
N. Waguri, M. Yamamoto / European Journal of Internal Medicine 14 (2003) 192–195 [12] Ko JW, Desta Z, Soukhova NV, Tracy T, Flockhart DA. In vitro inhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine: potent effect on CYP2C19 and CYP2D6. Br J Clin Pharmacol 2000;49:343–51. [13] Grimm IS, Litynski JJ. Severe cholestasis associated with ticlopidine. Am J Gastroenterol 1994;89:279–80. [14] Hirota WK, Moses F, Blouch D, Sjogren M. Ticlopidine associated intrahepatic cholestasis. Am J Gastroenterol 1996;91:2019. [15] Iqbal M, Goenka P, Young MF, Thomas E, Borthwick TR. Ti-
195
clopidine-induced cholestatic hepatitis: report of three cases and review of the literature. Dig Dis Sci 1999;43:2223–6. [16] Ono K, Kurohara K, Yoshihara M, Shimamoto Y, Yamaguchi M. Agranulocytosis caused by ticlopidine and its mechanism. Am J Hematol 1991;37:239–42. [17] Liu ZC, Urtrecht JP. Metabolism of ticlopidine by activated neutrophils: implications for ticlopidine-induced agranulocytosis. Drug Metab Dispos 2000;28:726–30.