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Haematological Adverse Effects of Histamine H2-Receptor Antagonists

Summary

Histamine H2-receptor antagonists are widely used in the treatment of gastrointestinal diseases related to gastric acid hypersecretion. Cimetidine was introduced into medical practice in 1976 and ranitidine, famotidine and nizatidine in 1981, 1985 and 1987, respectively. Haematological adverse effects are relatively uncommon and most have been reported in cases of cimetidine administration.

These adverse effects are reviewed under 4 main headings: (a) blood cytopenias and leucocytosis; (b) coagulation disorders related to drug interactions with oral anticoagulants; (c) reduction of dietary iron absorption; and (d) reduction of dietary cobalamin absorption.

85 reported cases of blood cytopenias attributed to these drugs are reviewed, of which 75 (88%) were associated with cimetidine therapy. In postmarketing surveillance studies, the incidence of cimetidine-associated blood cytopenia has been evaluated at about 2.3 per 100,000 patients. Neutropenia and agranulocytosis are by far the most frequently encountered. Whatever the drug or the type of cytopenia, this adverse effect is almost always rapidly reversible when treatment is stopped. Moreover, in several cases other factors suchas underlying diseases or additional drugs could have been responsible, at least partly, for the cytopenia. The pathophysiological basis of these adverse effects remains poorly explained. Various mechanisms have been proposed, which in some cases are probably associated: (a) direct toxicity for haemopoietic stem cells; (b) drug-induced immune reactions leading to blood or bone marrow cell damage, and (c) drug interactions, with increased and prolonged action of potentially haematotoxic drugs. Mechanisms (a) and (c) appear to be of particular clinical importance in cases of impaired renal elimination of H2-receptor antagonists.

Cimetidine and probably to a lesser extent ranitidine potentiate the action of oral anticoagulants of both coumarin and indanedione structure. This may result in haemorrhagic complications. Such action is a consequence of the reduced hepatic metabolism of oral anticoagulants through a dose-dependent, reversible inhibition of cytochrome P450.

Malabsorption of dietary iron and cobalamin appears to result from inhibition of gastric secretions by the H2-receptor antagonists. This is of no clinical importance in short term treatment, but long term use of H2-receptor antagonists may theoretically contribute to the occurrence of iron or cobalamin deficiency anaemia.

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References

  1. Abraham PA, Opsahl JA, Halstenson CE, Chremos AN, Matzke GR, et al. The effect of famotidine on renal function in patients with renal insufficiency. British Journal of Clinical Pharmacology 24: 385–389, 1987

    PubMed  CAS  Google Scholar 

  2. Aglietta M, Stacchini A, Sanavio F, Piacibello W. H2-receptor antagonists and human granulopoiesis. Experientia 41: 375–376, 1985

    PubMed  CAS  Google Scholar 

  3. Albin H, Couzigou P, Vincon G, Pehourcq F, Fleury B, et al. Pharmacocin/’etique de la cimetidine chez le cirrhotique ascitique. Gastroenterologie Clinique et Biologique 7: 251–255, 1983

    PubMed  CAS  Google Scholar 

  4. Al-Kawas FH, Lenes BA, Sacher RA. Cimetidine and agranulocytosis. Annals of Internal Medicine 90: 992–993, 1979

    PubMed  CAS  Google Scholar 

  5. Allen JI, Syropoulos HJ, Grant B, Eagon JC, Kay NE. Cimetidine modulates natural killer cell function of patients with chronic lymphocytic leukemia. Journal of Laboratory and Clinical Medicine 109: 396–401, 1987

    PubMed  CAS  Google Scholar 

  6. Amos RJ, Kirk B, Amess JAL, Jones AL, Hinds CJ. Bone marrow hypoplasia during intensive care: bone marrow culture studies implicating ranitidine in the suppression of haemopoiesis. Human Toxicology 6: 503–506, 1987

    PubMed  CAS  Google Scholar 

  7. Aymard JP, Balaud A, Netter P, Witz F, Colomb JN, et al. Hypoplasie médullaire avec pancytopénie sanguine associée à la prisé de cimetidine. Thérapie 36: 202–203, 1981

    PubMed  CAS  Google Scholar 

  8. Aymard JP, Herbeuval M, Herbeuval R, Witz, F, Lederlin P, et al. Action de la cimetidine sur les cellules souches de la granulopoièse humaine (CFU-C): étude in vitro sur 31 patients. Pathologie et Biologie 30: 855–857, 1982

    PubMed  CAS  Google Scholar 

  9. Bacigalupo A, Van Lint MT, Peralvo J, Piaggio G, Figari O, et al. Ranitidine and hematologic recovery in aplastic anemia. Haematologica (Pavia) 72: 378–379, 1987

    CAS  Google Scholar 

  10. Bagby GC, Lawrence HJ, Neerhout RC. T-Lymphocyte-mediated granulopoietic failure: in vitro identification of prednisone-responsive patients. New England Journal of Medicine 309: 1073–1078, 1983

    PubMed  Google Scholar 

  11. Belaiche J, Zittoun J, Marquet J, Nurit Y, Yvart J. Effet de la ranitidine sur la sécrétion de facteur intrinsèque gastrique et sur l’absorption de la vitamine B12. Gastroenterologie Clinique et Biologique 7: 381–384, 1983

    PubMed  CAS  Google Scholar 

  12. Bell WR, Anderson KC, Noe DA, Silver BA. Reduction in the plasma clearance rate of warfarin induced by cimetidine. Archives of Internal Medicine 146: 2325–2328, 1986

    PubMed  CAS  Google Scholar 

  13. Bianchi Porro G. Famotidine in the treatment of gastric and duodenal ulceration: overview of clinical experience. Digestion 32 (Suppl.l): 62–69, 1985

    PubMed  Google Scholar 

  14. Binder HJ, Donaldson RM. Effect of cimetidine on intrinsic factor and pepsin secretion in man. Gastroenterology 74: 371–375, 1978

    PubMed  CAS  Google Scholar 

  15. Black JW, Duncan WAM, Durant CJ, Ganellin CR, Parsons EM. Definition and antagonism of histamine H2-receptors. Nature 236: 385–390, 1972

    PubMed  CAS  Google Scholar 

  16. Bodenheimer HC, Thayer WR. Hemochromatosis associated with chronic cimetidine therapy? Journal of Clinical Gastroenterology 3: 83–85, 1981

    PubMed  Google Scholar 

  17. Brenner LO. Agranulocytosis and ranitidine. Annals of Internal Medicine 104: 896–897, 1986

    PubMed  CAS  Google Scholar 

  18. Bretagne JF, Reymann JM, Tassou JJ, Alain H, Gosselin A, et al. Pharmacocinétique de la ranitidine par voie intraveineuse et son effet sur la sécrétion acide stimulée par la pentagastrine chez le cirrhotique. Gastroenterologie Clinique et Biologique 7: 355–361, 1983

    PubMed  CAS  Google Scholar 

  19. Burland WL, Mills JG, Sharpe PC, Horton MA, Mollin DL. The effect of cimetidine on intrinsic factor secretion. In Burland WL & Simkins M (Eds) Cimetidine: Proceedings of the 2nd International Symposium on Histamine H2-Receptor Antagonists, pp. 177–183, Excerpta Medica, Amsterdam. 1977

    Google Scholar 

  20. Burland WL, Sharpe PC, Colin-Jones DG, Turnbull PRG, Bowskill P. Reversal of metiamide-induced agranulocytosis during treatment with cimetidine. Lancet 2: 1085, 1975

    PubMed  CAS  Google Scholar 

  21. Byron JW. Bone-marrow toxicity of metiamide. Lancet 2: 1350, 1976

    PubMed  CAS  Google Scholar 

  22. Byron JW. Mechanism for histamine H2-receptor induced cell-cycle changes in the bone marrow stem cell. Agents and Actions 7: 209–213, 1977

    PubMed  CAS  Google Scholar 

  23. Byron JW. Pharmacodynamic basis for the interaction of cimetidine with the bone marrow stem cells (CFU-S). Experimental Hematology 8: 256–263, 1980

    PubMed  CAS  Google Scholar 

  24. Caffee HH, Bingham HG. Leukopenia and silver sulfadiazine. Journal of Trauma 22: 586–587, 1982

    PubMed  CAS  Google Scholar 

  25. Callaghan JT, Bergstrom RF, Rubin, A, Chernish S, Crabtree R, et al. A pharmacokinetic profile of nizatidine in man. Scandinavian Journal of Gastroenterology 22 (Suppl. 136): 9–17, 1987

    Google Scholar 

  26. Calzado MC, Garcia-Castellano JM, Manzanares RM, Martinez F, Prieto B, et al. Effects of cimetidine on haematopoiesis in vitro. British Journal of Pharmacology 75: 301–303, 1982

    PubMed  CAS  Google Scholar 

  27. Campoli-Richards DM, Clissold SP. Famotidine: pharmacodynamic and pharmacokinetic properties and a preliminary review of its therapeutic use in peptic ulcer disease and Zollinger-Ellison syndrome. Drugs 32: 197–221, 1986

    PubMed  CAS  Google Scholar 

  28. Carloss HW, Tavassoli M, McMillan R. Cimetidine-induced granulocytopenia. Annals of Internal Medicine 93: 57–58, 1980

    PubMed  CAS  Google Scholar 

  29. Chandrasekhara KL, Iyer SK, Macchia RJ. Leucopenia and thrombocytopenia with cimetidine. Journal of the National Medical Association 73: 92–98, 1981

    PubMed  CAS  Google Scholar 

  30. Chang HK, Morrison SL. Bone-marrow suppression associated with cimetidine. Annals of Internal Medicine 91: 580, 1979

    PubMed  CAS  Google Scholar 

  31. Ching MS, Mihaly GW, Morgan DJ, Date NM, Hardy KJ, et al. Low clearance of cimetidine across the human placenta. Journal of Pharmacology and Experimental Therapeutics 241: 1006–1009, 1987

    PubMed  CAS  Google Scholar 

  32. Choonara IA, Cholerton S, Haynes BP, Breckenridge AM, Park BK. Interaction between the R enantiomer of warfarin and cimetidine. British Journal of Clinical Pharmacology 21: 85P-86P, 1986

    Google Scholar 

  33. Cloud ML, Safety of nizatidine in clinical trials conducted in the USA and Europe. Scandinavian Journal of Gastroenterology 22 (Suppl. 136): 29–36, 1987

    Google Scholar 

  34. Colin-Jones DG, Langman MJS, Lawson DH, Vessey MP. Postmarketing surveillance of the safety of cimetidine: twelve-month morbidity report. Quarterly Journal of Medicine 54: 253–268, 1985

    PubMed  CAS  Google Scholar 

  35. Collen MJ. Cimetidine-associated thrombocytopenia and leukopenia. Western Journal of Medicine 132: 257–258, 1980

    PubMed  CAS  Google Scholar 

  36. Corbett CL, Holdsworth CD. Fever, abdominal pain, and leucopenia during treatment with cimetidine. British Medical Journal 1: 753–754, 1978

    PubMed  CAS  Google Scholar 

  37. Crapper RM. Fatal agranulocytosis attributable to cimetidine. Medical Journal of Australia 2: 250–251, 1981

    PubMed  CAS  Google Scholar 

  38. Craven ER, Whittington JM. Agranulocytosis four months after cimetidine therapy. Lancet 2: 294–295, 1977

    PubMed  CAS  Google Scholar 

  39. Dammann HG, Dorner M, Greten H. Granulozytopenie bei Behandlung mit Cimetidin. Deutsche Medizinische Wochenschrift 106: 1276, 1981

    Google Scholar 

  40. Danilewitz M, Ou Tim L, Hirschowilz B. Ranitidine suppression of gastric hypersecretion resistant to cimetidine. New England Journal of Medicine 306: 20–22, 1982

    PubMed  CAS  Google Scholar 

  41. Davis TG, Pickett DL, Schlosser JH. Evaluation of a worldwide spontaneous reporting system with cimetidine. Journal of the American Medical Association 243: 1912–1914, 1980

    PubMed  CAS  Google Scholar 

  42. De Galocsy C, Van Ypersele de Strihou C. Pancytopenia with cimetidine. Annals of Internal Medicine 90: 274, 1979

    PubMed  Google Scholar 

  43. Denis J, Thierman-Duffaud D, Opolon P, Levy VG. Thrombopénie induite par la cimétidine. Nouvelle Presse Médicale 10: 2440, 1981

    PubMed  CAS  Google Scholar 

  44. Desmond PV, Mashford ML, Harman PJ, Morphett BJ, Breen KJ, et al. Decreased oral warfarin clearance after ranitidine and cimetidine. Clinical Pharmacology and Therapeutics 35: 338–341, 1984

    PubMed  CAS  Google Scholar 

  45. Devanesen S. Prolongation of prothrombin time with cimetidine. Medical Journal of Australia 1: 537, 1981

    PubMed  CAS  Google Scholar 

  46. Dölle W, Sewing KF. Agranulocytosis after cimetidine after agranulocytosis induced by carbimazole in a woman with cirrhosis of the liver, hypersplenism and hyperthyroidism. Zeitschrift für Gastroenterologie 18: 81–82, 1980

    PubMed  Google Scholar 

  47. Donn KH, Powell JR, Rogers JF, Plachetka JR. Lack of effect of histamine H2-receptor antagonists on indocyanine green disposition measured by two methods. Journal of Clinical Pharmacology 24: 360–370, 1984

    PubMed  CAS  Google Scholar 

  48. Druart F, Frocrain C, Metois P, Martin J, Matuchansky C. Association of cimetidine and bone-marrow suppression in man. Digestive Diseases and Sciences 24: 730–731, 1979

    PubMed  CAS  Google Scholar 

  49. Dubost JL, Chevallier H, Sultan R, Fallouh H. Neutropenie chez un malade traité par la cimétidine. Médecine et Chirurgie Digestive 9: 523–524, 1980

    CAS  Google Scholar 

  50. Elizaga FV, Jim RTS, Lam CBC, Berman SJ. Hematologic effects of cimetidine. Annals of Internal Medicine 94: 280, 1981

    PubMed  CAS  Google Scholar 

  51. Eridani S, Johnston IDA, Villa S. Cimetidine and granulopoiesis. Annals of Internal Medicine 97: 620, 1982

    PubMed  CAS  Google Scholar 

  52. Esposito R. Cimetidine and iron-deficiency anaemia. Lancet 2: 1132, 1977

    PubMed  CAS  Google Scholar 

  53. Farber BF, Brody JP. Rapid development of aplastic anemia after intravenous chloramphenicol and cimetidine therapy. Southern Medical Journal 74: 1257–1258, 1981

    PubMed  CAS  Google Scholar 

  54. Feely J, Guy E. Ranitidine also reduces liver blood flow. Lancet 1: 169, 1982

    Google Scholar 

  55. Feely J, Wilkinson GR, Wood AJJ. Reduction of liver blood flow and propranolol metabolism by cimetidine. New England Journal of Medicine 304: 692–695, 1981

    PubMed  CAS  Google Scholar 

  56. Feldman EJ. Isenberg JL Effects of metiamide on gastric acid hypersecretion, steatorrhea and bone-marrow function in a patient with systemic mastocytosis. New England Journal of Medicine 295: 1178–1179, 1976

    PubMed  CAS  Google Scholar 

  57. Fernandez-Rodriguez R, Moreno-Sanchez D, De Cuenca Moron B, Martinez-Fernandez R. Leucopenia reversible asociada al uso de cimetidina. Medica Clinica (Barcelona) 88: 123, 1987

    CAS  Google Scholar 

  58. Fielding LP, Chalmers DM, Chanarin I, Levi AJ. Inhibition of intrinsic factor secretion by cimetidine. British Medical Journal 1: 818–819, 1978

    PubMed  CAS  Google Scholar 

  59. Fischer J. Ranitidine and warfarin interaction. Drug Intelligence and Clinical Pharmacy 19: 664–665, 1985

    Google Scholar 

  60. Fitchen JH, Koeffler HP. Cimetidine and granulopoiesis: bone marrow culture studies in normal man and patients with cimetidine-associated neutropenia. British Journal of Haematology 46: 361–366, 1980

    PubMed  CAS  Google Scholar 

  61. Fleischer D, Samloff IM. Cimetidine therapy in a patient with metiamide-induced agranulocytosis. New England Journal of Medicine 296: 342, 1977

    PubMed  CAS  Google Scholar 

  62. Flind AC. Cimetidine and oral anticoagulants. British Medical Journal 2: 1367, 1978

    PubMed  CAS  Google Scholar 

  63. Forrest JAH, Shearman DJC, Spence R, Celestin LR. Neutropenia associated with metiamide. Lancet 1: 392–393, 1975

    PubMed  CAS  Google Scholar 

  64. Gafter U, Komlos L, Weinstein T, Zevin D, Levi J. Thrombocytopenia, eosinophilia and ranitidine. Annals of Internal Medicine 106: 477, 1987

    PubMed  CAS  Google Scholar 

  65. Gamelli RL, Foster RS, Whisnant JK. Hematopoietic toxicity of cimetidine: reexamination using the antimetabolite azathioprine. Transplantation 35: 12–14, 1983

    PubMed  CAS  Google Scholar 

  66. Garg DC, Weidler DJ, Jallad NS, Eshelman FN. The effects of ranitidine and cimetidine on hepatic blood flow. Clinical Pharmacology and Therapeutics 31: 228, 1982

    Google Scholar 

  67. Gelwan JS, Schmitz RL, Pellecchia C. Ranitidine and leukocytosis. American Journal of Gastroenterology 81: 685–687, 1986

    PubMed  CAS  Google Scholar 

  68. Gibson PR, Pidcock ME. Immune-mediated thrombocytopenia associated with ranitidine therapy. Medical Journal of Australia 145: 661–662, 1986

    PubMed  CAS  Google Scholar 

  69. Glotzbach RE. Cimetidine-induced thrombocytopenia. Southern Medical Journal 75: 232–234, 1982

    PubMed  CAS  Google Scholar 

  70. Goldberg A, Lochhead AC, Dagg JH. Histamine-fast achlorhydria and iron absorption. Lancet 1: 848–850, 1963

    PubMed  CAS  Google Scholar 

  71. Gouffier E, Schnurmann D, Durepaire H, Vernant JP. Aplasie médullaire transitoire au cours d’un traitement par la cimétidine. Nouvelle Presse Médicale 7: 2660, 1978

    PubMed  CAS  Google Scholar 

  72. Grasela DM, Rocci ML, Rotmensch HH, Vlasses PH. Multiple dose cimetidine does not affect indocyanine green clearance. Drug Intelligence and Clinical Pharmacy 17: 454, 1983

    Google Scholar 

  73. Grillot-Courvalin C, Vinci G, Tsapis A, Dokhelar MC, Vainchenker W, et al. The syndrome of T8 hyperlymphocytosis: variation in phenotype and cytotoxic activities of granular cells and evaluation of their role in associated neutropenia. Blood 69: 1204–1210, 1986

    Google Scholar 

  74. Gross S, Worthington-White DA. Cimetidine suppression of CFU-C in males. American Journal of Hematology 17: 279–286, 1984

    PubMed  CAS  Google Scholar 

  75. Hamborg B, Kittang E, Schjonsby H. The effect of ranitidine on the absorption of food cobalamins. Scandinavian Journal of Gastroenterology 20: 756–758, 1985

    PubMed  CAS  Google Scholar 

  76. Harenberg J, Staiger C, De Vries JX, Walter E, Weber E, et al. Cimetidine does not increase the anticoagulant effect of phenprocoumon. British Journal of Clinical Pharmacology 14: 292–293, 1982

    PubMed  CAS  Google Scholar 

  77. Harmon DC, Shuman R. Ranitidine. New England Journal of Medicine 310: 1604, 1984

    Google Scholar 

  78. Hast R, Bernell P, Befrits R, Dowding C, Sjögren AM. Decrease in helper (T4+) lymphocytes following cimetidine treatment for duodenal ulcer. Clinical and Experimental Immunology 64: 114–118, 1986

    PubMed  CAS  Google Scholar 

  79. Herrera A, Solal-Celigny P, Dresch C, Vallin J, Bernades P. Ranitidine. New England Journal of Medicine 310: 1604–1605, 1984

    Google Scholar 

  80. Hess WA, Kornblith PL. Combination of lomustine and cimetidine in the treatment of a patient with malignant glioblastoma: a case report. Cancer Treatment Reports 69: 733, 1985

    PubMed  CAS  Google Scholar 

  81. Hetzel D, Birkett D, Miners J. Cimetidine interaction with warfarin. Lancet 2: 639, 1979

    PubMed  CAS  Google Scholar 

  82. Hetzel DJ, Bochner F, Hallpike JF, Shearman DJC, Hann CS. Cimetidine interaction with phenytoin. British Medical Journal 282: 1512, 1981

    PubMed  CAS  Google Scholar 

  83. Hummer-Sigiel M, Girard A, Mandoria JY, Colson T, Jacquier A. Thrombopénie sous ranitidine et thiophenicol: responsabilité du thiophenicol. Cahiers d’Anesthésiologie 33: 363–365, 1985

    PubMed  CAS  Google Scholar 

  84. Humphries TJ. Famotidine: a notable lack of drug interaction. Scandinavian Journal of Gastroenterology 22 (Suppl. 134): 55–60, 1987

    Google Scholar 

  85. Idvall J. Cimetidine-associated thrombocytopenia. Lancet 2: 159, 1979

    PubMed  CAS  Google Scholar 

  86. Imai Y, Inada M, Tamura S, Kawata S, Minami Y, et al. Comparative effects of famotidine and cimetidine on 7-ethoxycoumarin O-deethylase activity in human livers. British Journal of Clinical Pharmacology 22: 495–496, 1986

    PubMed  CAS  Google Scholar 

  87. Isaacs AJ. Cimetidine and thrombocytopenia. British Medical Journal 280: 294, 1980

    PubMed  CAS  Google Scholar 

  88. Iyer SK, Chandrasekhara KL. Leukopenia with cimetidine. Journal of the National Medical Association 72: 805–806, 1980

    PubMed  CAS  Google Scholar 

  89. Jacobs A, Owen GM. Effect of gastric juice on iron absorption in patients with gastric atrophy. Gut 10: 488–490, 1969

    PubMed  CAS  Google Scholar 

  90. Jacobs A, Rhodes J, Peters DK, Campbell H, Eakins JD. Gastric acidity and iron absorption. British Journal of Haematology 12: 728–736, 1966

    PubMed  CAS  Google Scholar 

  91. James C, Prout BJ. Marrow suppression and intravenous cimetidine. Lancet 1: 987, 1978

    PubMed  CAS  Google Scholar 

  92. Johnson NM, Black AE, Hughes ASB, Clarke SW. Leucopenia with cimetidine. Lancet 2: 1226–1227, 1977

    Google Scholar 

  93. Jorizzo JL, Sams WM, Jegasothy BV, Olansky J. Cimetidine as an immunomodulator: chronic mucocutaneous candidiasis as a model. Annals of Internal Medicine 92: 192–195, 1980

    PubMed  CAS  Google Scholar 

  94. Keller HJ, Kirste G, Wilms H. Cimetidin-induzierte Leukopenie nach Nierentransplantation. Deutsche Medizinische Wochenschrift 108: 1128–1129, 1983

    PubMed  CAS  Google Scholar 

  95. Khokhar N, Akavaram NR. Cimetidine-induced leukopenia: case reports. Military Medicine 145: 853–855, 1980

    PubMed  CAS  Google Scholar 

  96. Kirch W, Hoensch H, Janisch HD. Interactions and non-interactions with ranitidine. Clinical Pharmacokinetics 9: 493–510, 1984

    PubMed  CAS  Google Scholar 

  97. Kitchens CS. Lack of antiplatelet effect of cimetidine in hemophiliacs. Southern Medical Journal 73: 391–392, 1980

    PubMed  CAS  Google Scholar 

  98. Klotz SA, Kay BF. Cimetidine and agranulocytosis. Annals of Internal Medicine 88: 579–580, 1978

    PubMed  CAS  Google Scholar 

  99. Klotz U. Lack of effect of nizatidine on drug metabolism. Scandinavian Journal of Gastroenterology 22 (Suppl. 136): 18–23,1987

    Google Scholar 

  100. Knodell RG, Holtzman JL, Crankshaw DL, Steele NM, Stanley LN. Drug metabolism by rat and human hepatic microsomes in response to interaction with H2-receptor antagonists. Gastroenterology 82: 84–88, 1982

    PubMed  CAS  Google Scholar 

  101. Lambie DG, Johnson RH. Drugs and folate metabolism. Drugs 30: 145–155, 1985

    PubMed  CAS  Google Scholar 

  102. Lavarenne J, Maradeix B. Atteintes de la lignée blanche et cimetidine. Thérapie 37: 385–388, 1982

    PubMed  CAS  Google Scholar 

  103. Lavarenne J, Moreau C. Les effets indésirables de la cimétidine: travail coopératif des centres de pharmacovigilance hospitalière, bilan des observations et confrontation aux données de la littérature. Thérapie 35: 83–112, 1980

    PubMed  CAS  Google Scholar 

  104. Lebert PA, McLeod SM, Mahon WA, Soldin SJ, Vandenberghe HM. Ranitidine kinetics and dynamics, I: oral dose studies. Clinical Pharmacology and Therapeutics 30: 539–544, 1981

    PubMed  CAS  Google Scholar 

  105. Lederlin P, Witz F, Colomb JN, Rumilly F, Eisenmann JC, et al. Aspects cliniques, étiologiques et évolutifs des agranulocytoses aigues médicamenteuses: à propos de 42 observations. Thérapie 37: 389–393, 1982

    PubMed  CAS  Google Scholar 

  106. Legendre C, Canaud B, Beraud JJ, Brunin JL, Balmes JL, et al. Neutropenie sévère, récidivante et reversible induite par la cimétidine. Presse Médicale 13: 44, 1984

    CAS  Google Scholar 

  107. Lewis DS, Beck ER. Reversible agranulocytosis in association with cimetidine and hepatic failure. Postgraduate Medical Journal 58: 443–444, 1982

    PubMed  CAS  Google Scholar 

  108. Lin JH, Cocchetto DM, Yeh KC, Dugan DE. Comparative effects of H2-receptor antagonists on drug interaction in rats. Drug Metabolism and Disposition 14: 649–653, 1986

    PubMed  CAS  Google Scholar 

  109. Linhardt GE, Gadacz TR. Prolonged WBC depression after cimetidine in a patient with chronic myelogenous leukemia. Southern Medical Journal 74: 353–355, 1981

    PubMed  Google Scholar 

  110. List AF, Beaird DH, Kummet T. Ranitidine-induced granulocytopenia: recurrence with cimetidine administration. Annals of Internal Medicine 108: 566–567, 1988

    PubMed  CAS  Google Scholar 

  111. Littlejohn GO, Urowitz MB. Cimetidine, lupus erythematosus, and granulocytopenia. Annals of Internal Medicine 91: 317–318, 1979

    PubMed  CAS  Google Scholar 

  112. Lopez-Luque A, Rodriguez-Cuartero A, Perez-Galvez N, Pomares-Mora J, Pena-Yanez A. Cimetidine and bone-marrow toxicity. Lancet 1: 444, 1978

    PubMed  CAS  Google Scholar 

  113. Ma KW, Brown DC, Masler DS, Silvis SE. Effects of renal failure on blood levels of cimetidine. Gastroenterology 74: 473–477, 1978

    PubMed  CAS  Google Scholar 

  114. Mann HJ, Schneider JR, Miller JB, Delaney JP. Cimetidine-associated thrombocytopenia. Drug Intelligence and Clinical Pharmacy 17: 126–128, 1983

    PubMed  CAS  Google Scholar 

  115. Mar DD, Brandstetter RD, Miskovitz PF, Fotino M. Cimetidine-induced, immune-mediated leukopenia and thrombocytopenia. Southern Medical Journal 75: 1283–1285, 1982

    PubMed  CAS  Google Scholar 

  116. Mashford ML, Harman PJ, Morphett BJ, Breen KJ, Desmond PV. Ranitidine does not affect chlormethiazole or indocyanine green disposition. Clinical Pharmacology and Therapeutics 34: 231–233, 1983

    PubMed  CAS  Google Scholar 

  117. McDaniel JL, Stein JJ. Thrombocytopenia with cimetidine therapy. New England Journal of Medicine 300: 864, 1979

    PubMed  CAS  Google Scholar 

  118. McGowan WAW. Safety of cimetidine in obstetric patients. Journal of the Royal Society of Medicine 72: 902–907, 1979

    PubMed  CAS  Google Scholar 

  119. McGregor CGA, Cochran AJ, Ogg LJ, Gray GR, Smith IS, et al. Immunological and other laboratory studies of patients receiving short-term cimetidine therapy. Lancet 1: 122–123, 1977

    PubMed  CAS  Google Scholar 

  120. Mikhailidis DP, Mikhailidis AM, Dandona P. Prevention or cure for stress-induced gastrointestinal bleeding. British Medical Journal 281: 1005–1006, 1980

    PubMed  CAS  Google Scholar 

  121. Mohammed R, Clark JS, Adams JF, Hearns JB, Crean GP. The effect of ranitidine hydrochloride, a new histamine H2-receptor antagonist, on intrinsic factor secretion. Clinical Therapeutics 4: 118–120, 1981

    PubMed  CAS  Google Scholar 

  122. Morichau-Beauchant M, Houin, G, Mavier P, Alexandre C, Dhumeaux D. Pharmacokinetics and bioavailability of ranitidine in normal subjects and cirrhotic patients. Digestive Diseases and Sciences 31: 113–118, 1986

    PubMed  CAS  Google Scholar 

  123. Mountford R, Preece AW, Jones R, Grove E, Cottrell J. Effect of treatment with famotidine on T-lymphocyte populations and activity in duodenal ulcer patients. Gut 28: A1338–A1339, 1987

    Google Scholar 

  124. Nagler A, Rozenbaum H, Enat R, Tatarsky I, Katz R, et al. Immune basis for cimetidine-induced pancytopenia. American Journal of Gastroenterology 82: 359–361, 1987

    PubMed  CAS  Google Scholar 

  125. Nakatani T. Granulocytopenia associated with ranitidine in a patient with renal transplant. British Medical Journal 295: 333, 1987

    Google Scholar 

  126. Nouel O, Pariente EA, Slaoui H, Renoux M. Agranulocytose à la cimétidine: un accident immuno-allergique? Gastroenterologie Clinique et Biologique 3: 481, 1979

    PubMed  CAS  Google Scholar 

  127. Ohnishi K, Saito M, Nomura F, Okuda K, Suzuki N, et al. Effect of famotidine on hepatic hemodynamics and peptic ulcer. American Journal of Gastroenterology 82: 415–418, 1987

    PubMed  CAS  Google Scholar 

  128. O’Reilly RA. Comparative interaction of cimetidine and ranitidine with racemic warfarin in man. Archives of Internal Medicine 144: 989–991, 1984

    PubMed  Google Scholar 

  129. Patwardhan RV, Yarborough GW, Desmond PV, Johnson RF, Schenker S, et al. Cimetidine spares the glucuronidation of lorazepam and oxazepam. Gastroenterology 79: 912–916, 1980

    PubMed  CAS  Google Scholar 

  130. Peden NR, Boyds EJS, Brown RA, Gibbs JH, Potts RC, et al. Cimetidine, the immune system, and cancer. Lancet 1: 900–901, 1981

    Google Scholar 

  131. Peden NR, Robertson AJ, Boyd EJS, Brown RA, Gibbs JH, et al. Mitogen stimulation of peripheral blood lymphocytes of duodenal ulcer patients during treatment with cimetidine or ranitidine. Gut 23: 398–403, 1982

    PubMed  CAS  Google Scholar 

  132. Petz LD, Gitlin N, Grant K, Rodvien R, Brotman M. Cimetidine-induced hemolytic anemia: the fallacy of clinical associations. Journal of Clinical Gastroenterology 5: 405–409, 1983

    PubMed  CAS  Google Scholar 

  133. Posnett DN, Stein RS, Graber SE, Krantz SB. Cimetidine-induced neutropenia: a possible dose-related phenomenon. Archives of Internal Medicine 139: 584–586, 1979

    PubMed  CAS  Google Scholar 

  134. Powell JR, Donn KH. Histamine H2-antagonist drug interactions in perspective: mechanistic concepts and clinical implications. American Journal of Medicine 77 (Suppl. 5B): 57–84, 1984

    PubMed  CAS  Google Scholar 

  135. Puurunen J, Sotaniemi E, Pelkonen O. Effect of cimetidine on microsomal drug metabolism in man. European Journal of Clinical Pharmacology 18: 185–187, 1980

    PubMed  CAS  Google Scholar 

  136. Rate R, Bonnell M, Chervenak C, Pavinich G. Cimetidine and hematologic effects. Annals of Internal Medicine 91: 795, 1979

    PubMed  CAS  Google Scholar 

  137. Reddy J, Bailey RR. Cimetidine and thrombocytopenia. New Zealand Medical Journal 91: 232, 1980

    PubMed  CAS  Google Scholar 

  138. Reiffers J, Piquet Y, Roussy P, Boisseau C, Couzigou P, et al. Thrombopenie après traitement par cimétidine. Nouvelle Presse Médicale 10: 2586–2587, 1981

    PubMed  CAS  Google Scholar 

  139. Reilly PEB, Carrington LE, Winzor DJ. The interaction of cimetidine with rat liver microsomes. Biochemical Pharmacology 32: 831–835, 1983

    PubMed  CAS  Google Scholar 

  140. Rendic S, Alebic-Kolbah T, Kajfez F, Ruf HH. Interaction of ranitidine with liver microsomes. Xenobiotica 12: 9–17, 1982

    PubMed  CAS  Google Scholar 

  141. Rendic S, Kajfez F, Ruf HH. Characterization of cimetidine, ranitidine and related structures’ interaction with cytochrome P-450. Drug Metabolism and Disposition 11: 137–142, 1983

    PubMed  CAS  Google Scholar 

  142. Rendic S, Sunjic V, Toso R, Kajfez F, Ruf HH. Interaction of cimetidine with liver microsomes. Xenobiotica 9: 555–564, 1979

    PubMed  CAS  Google Scholar 

  143. Richter JE, Gerhardt DC, Pasquale DN, Castell DO. Cimetidine and hematologic suppression: things are not always as they appear. Digestive Diseases and Sciences 25: 960–963, 1980

    PubMed  CAS  Google Scholar 

  144. Rotoli B, Formisano S, Alfinito F. Autoimmune haemolytic anaemia associated with cimetidine. Lancet 2: 583, 1979

    PubMed  CAS  Google Scholar 

  145. Rowley-Jones D, Flind AC. Continuing evaluation of the safety of cimetidine. In Baron (Ed.) Cimetidine in the 80s, pp. 261–269, Churchill Livingstone, Edinburgh, 1981

    Google Scholar 

  146. Sahasrabudhe DM, McCune CS, O’Donnell RW, Henshaw EC. Inhibition of suppressor T lymphocytes (Ts) by cimetidine. Journal of Immunology 138: 2760–2763, 1987

    CAS  Google Scholar 

  147. Saigenji K, Fukutomi H, Nakazawa S. Famotidine: postmarketing clinical experience. Scandinavian Journal of Gastroenterology 22 (Suppl. 134): 34–40, 1987

    Google Scholar 

  148. Salom IL, Silvis SE, Doscherholmen A. Effect of cimetidine on the absorption of vitamin B12. Scandinavian Journal of Gastroenterology 17: 129–131, 1982

    PubMed  CAS  Google Scholar 

  149. Sasaki Y, Hayashi N, Kasahara A, Matsuda Y, Furusawa S, et al. Influence of ranitidine on hepatic blood flow assessed by organ-reflectance spectrophotometer and pulse-doppler ultrasonic flowmeter. Digestive Diseases and Sciences 30: 1043–1048, 1985

    PubMed  CAS  Google Scholar 

  150. Sazie E, Jaffe JP. Severe granulocytopenia with cimetidine and phenytoin. Annals of Internal Medicine 93: 151–152, 1980

    PubMed  CAS  Google Scholar 

  151. Schentag JJ, Cerra FB, Calleri GM, Leising ME, French MA, et al. Age, disease, and cimetidine disposition in healthy subjects and chronically ill patients. Clinical Pharmacology and Therapeutics 29: 737–743, 1981

    PubMed  CAS  Google Scholar 

  152. Schmitt J, Jacquier A, Huttin B, Lambert H, Baille N, et al. Pancytopenie aigue avec atteinte médullaire au cours d’un traitement par la cimétidine. Nouvelle Presse Médicale 8: 2982, 1979

    PubMed  CAS  Google Scholar 

  153. Sedman AJ. Cimetidine-drug interactions. American Journal of Medicine 76: 109–114, 1984

    PubMed  CAS  Google Scholar 

  154. Selker HP, Rosenbloom BE, Weinstein IM. Cimetidine and cytopenia. Western Journal of Medicine 135: 330–336, 1981

    PubMed  CAS  Google Scholar 

  155. Serlin MJ, Sibeon RG, Breckenridge AM. Lack of effect of ranitidine on warfarin action. British Journal of Clinical Pharmacology 12: 791–794, 1981

    PubMed  CAS  Google Scholar 

  156. Serlin MJ, Sibeon RG, Mossman S, Breckenridge AM, Williams JRB, et al. Cimetidine: interaction with oral anticoagulants in man. Lancet 2: 317–319, 1979

    PubMed  CAS  Google Scholar 

  157. Shields LI, Files JA, Doll DC, Greenberg BR. Ranitidine and agranulocytosis. Annals of Internal Medicine 104: 128, 1986

    PubMed  CAS  Google Scholar 

  158. Sica DA, Comstock T, Harford A, Eshelman F. Ranitidine pharmacokinetics in continuous ambulatory peritoneal dialysis. European Journal of Clinical Pharmacology 32: 587–591, 1987

    PubMed  CAS  Google Scholar 

  159. Silver BA, Bell WR, Cimetidine potentiation of the hypoprothrombinemic effect of warfarin. Annals of Internal Medicine 90: 348–349, 1979

    PubMed  CAS  Google Scholar 

  160. Sinco A, Conte G, Ambriz R, Aviles A, Morales MR, et al. Cimetidina y neutropenia transitoria en un paciente con hemophilia. Revista de Investigacion Clinica (Mexico) 33: 289–291, 1981

    CAS  Google Scholar 

  161. Skikne BS, Lynch SR, Cook JD. Role of gastric acid in iron food absorption. Gastroenterology 81: 1068–1071, 1981

    PubMed  CAS  Google Scholar 

  162. Smith SR, Kendall MJ. Ranitidine versus cimetidine: a comparison of their potential to cause clinically important drug interactions. Clinical Pharmacokinetics 15: 44–56, 1988

    PubMed  CAS  Google Scholar 

  163. Smout AJPM, Bakker B. Agranulocytose door cimetidine. Nederlands Tijdschrift voor Geneeskunde (Amsterdam) 125: 2152–2154, 1981

    CAS  Google Scholar 

  164. Somogyi A, Gugler R. Cimetidine excretion into breast milk. British Journal of Clinical Pharmacology 7: 627–629, 1979

    PubMed  CAS  Google Scholar 

  165. Somogyi A, Gugler R. Drug interactions with cimetidine. Clinical Pharmacokinetics 7: 23–41, 1982

    PubMed  CAS  Google Scholar 

  166. Somogyi A, Muirhead M. Pharmacokinetic interactions of cimetidine 1987. Clinical Pharmacokinetics 12: 321–366, 1987

    PubMed  CAS  Google Scholar 

  167. Sonne J, Poulsen HE, Dossing M, Larsen NE, Andreasen PB. Cimetidine clearance and bioavailability in hepatic cirrhosis. Clinical Pharmacology and Therapeutics 29: 191–197, 1981

    PubMed  CAS  Google Scholar 

  168. Sorkin EM, Darvey DL. Review of cimetidine drug interactions. Drug Intelligence and Clinical Pharmacy 17: 110–120, 1983

    PubMed  CAS  Google Scholar 

  169. Speeg KV, Patwardhan RV, Avant GR, Mitchell MC, Schenker S. Inhibition of microsomal drug metabolism by histamine H2-receptor antagonists studied in vivo and in vitro in rodents. Gastroenterology 82: 89–96, 1982

    PubMed  CAS  Google Scholar 

  170. Spinka R, Honetz N. Akute granulozytopenie unter cimetidin. Wiener Medizinische Wochenschrift 134: 141–145, 1984

    PubMed  CAS  Google Scholar 

  171. Spychal RT, Wickham NWR. Thrombocytopenia associated with ranitidine. British Medical Journal 291: 1687, 1985

    PubMed  CAS  Google Scholar 

  172. Stein RS, Howard CA. Clinical assessment of cimetidine myelotoxicity. Southern Medical Journal 73: 293–294, 1981

    Google Scholar 

  173. Steinberg WM, King CE, Toskes PP. Malabsorption of protein-bound cobalamin but not unbound cobalamin during cimetidine administration. Digestive Diseases and Sciences 25: 188–192, 1980

    PubMed  CAS  Google Scholar 

  174. Streeter AM, Duraiappah B, Boyle R, O’Neill BJ, Pheils MT. Malabsorption of vitamin B12 after vagotomy. American Journal of Surgery 128: 340–343, 1974

    PubMed  CAS  Google Scholar 

  175. Streeter AM, Goulston KJ, Bathur FA, Hilmer RS, Crane GG, et al. Cimetidine and malabsorption of cobalamin. Digestive Diseases and Sciences 27: 13–16, 1982

    PubMed  CAS  Google Scholar 

  176. Takabatake T, Ohta H, Maekawa M, Yamamoto Y, Ishida Y, et al. Pharmacokinetics of famotidine, a new H2-receptor antagonist, in relation to renal function. European Journal of Clinical Pharmacology 28: 327–331, 1985

    PubMed  CAS  Google Scholar 

  177. Tan-Ngamtrong D, Hitanant S, Vanasin B. Auto-immune hemolytic anemia during treatment with cimetidine. Journal of the Medical Association of Thailand 70: 156–159, 1987

    PubMed  CAS  Google Scholar 

  178. Teichmann RK, Zumtobel V, Heberer G. Agranulozytose durch cimetidin. Chirurg 49: 397–398, 1978

    PubMed  CAS  Google Scholar 

  179. Testa R, Grasso A, Dagnino F, Ibba R, Varagona G, et al. Famotidine does not affect indocyanine green disposition and serum bile acid levels in healthy subjects. British Journal of Clinical Pharmacology 23: 779–780, 1987

    PubMed  CAS  Google Scholar 

  180. Texereau P, Ancelin P, Briaud M, Moussie D. Un cas d’agranulocytose aigue chez un malade traité par ranitidine. Gastroenterologie Clinique et Biologique 11: 829–830, 1987

    PubMed  CAS  Google Scholar 

  181. Thijssen HHW, Janssen GMJ, Baars LGM. Lack of effect of cimetidine on pharmacodynamics and kinetics of single oral doses of R- and S-acenocoumarol. European Journal of Clinical Pharmacology 30: 619–623, 1986

    PubMed  CAS  Google Scholar 

  182. Tishler M, Abramov AL. Cimetidine-induced eosinophilia. Drug Intelligence and Clinical Pharmacy 19: 377–378, 1985

    PubMed  CAS  Google Scholar 

  183. Tomioka K, Yamada T, Tachikawa S. Effects of famotidine (YM-11170), an H2-receptor antagonist on in vivo immediate and delayed type hypersensitivity reactions and antibody formation. Drugs under Experimental and Clinical Research 9: 881–889, 1983

    CAS  Google Scholar 

  184. Tong GL, Lien EJ. Biotransformation of drugs: quantitative structure-activity relationships for barbiturates, tertiary amines and substituted imidazoles. Journal of Pharmaceutical Science 65: 1651–1654, 1976

    CAS  Google Scholar 

  185. Tonkonow B, Hoffman R. Aplastic anemia and cimetidine. Archives of Internal Medicine 140: 1123–1124, 1980

    PubMed  CAS  Google Scholar 

  186. Toon S, Hopkins KJ. Garstang FM, Rowland M. Comparative effects of ranitidine and cimetidine on the pharmacokinetics and pharmacodynamics of warfarin in man. European Journal of Clinical Pharmacology 32: 165–172, 1987

    PubMed  CAS  Google Scholar 

  187. Truong TK, Grand’Maison F, Longpré B. Myelotoxicose due à la cimétidine. Union Médicale du Canada 115: 834–836, 1986

    PubMed  CAS  Google Scholar 

  188. Tyden G, Thulin L, Nyberg B. The effect of cimetidine on liver blood flow in anaesthetized man. Acta Chirurgica Scandinavica 149: 303–305, 1983

    PubMed  CAS  Google Scholar 

  189. Ufberg MH, Brooks CM, Bosanac PR, Kintzel JE. Transient neutropenia in a patient receiving cimetidine. Gastroenterology 73: 635–638, 1977

    PubMed  CAS  Google Scholar 

  190. Valente P, Axelrod JL. Acute leukopenia associated with silver sulfadiazine therapy. Journal of Trauma 18: 146–147, 1978

    PubMed  CAS  Google Scholar 

  191. Verma DS, Johnston DA, McCredie KB. Identification of T lymphocyte subpopulations that regulate elaboration of granulocyte-macrophage colony stimulating factor. British Journal of Haematology 57: 505–520, 1984

    PubMed  CAS  Google Scholar 

  192. Vickers MR, Milliner KJ, Fallowfield C, Dracott BN. The effects of histamine H2-receptor antagonists on PHA induced lymphocyte proliferation. Agents and Actions 15: 242–248, 1984

    CAS  Google Scholar 

  193. Villeneuve JP, Fortunet-Fouin H, Arsène D. Cimetidine kinetics and dynamics in patients with severe liver disease. Hepatology 3: 923–927, 1983

    PubMed  CAS  Google Scholar 

  194. Volkin RL, Shadduck RK, Winkelstein A, Zeigler ZR, Selker R. Alternative mechanisms for severe neutropenia. Archives of Internal Medicine 142: 1971, 1982

    Google Scholar 

  195. Wallin BA, Jacknowitz A, Raich PC. Cimetidine and effect of warfarin. Annals of Internal Medicine 90: 993, 1979

    PubMed  CAS  Google Scholar 

  196. Wehr M, Schäfer K, Bode JC. Granulozytopenie unter Cimetidintherapie. Deutsche Medizinische Wochenschrift 105: 1571–1573, 1980

    PubMed  CAS  Google Scholar 

  197. Wilkinson CF, Hetnarski K, Cantwell GP, Di Carlo FJ. Structure-activity relationships in the effects of 1-alkylimidazoles on microsomal oxidation in vitro and in vivo. Biochemical Pharmacology 23: 2377–2386, 1974

    PubMed  CAS  Google Scholar 

  198. Wong YY, Lichtor T, Brown FD. Severe thrombocytopenia associated with phenytoin and cimetidine therapy. Surgical Neurology 23: 169–172, 1985

    PubMed  CAS  Google Scholar 

  199. Yao E, Tsukasaki K, Kamei T, Kuriyama K, Ichimaru M. Effect of bolus methylprednisolone therapy on a case of cimetidine-associated aplastic anemia (in Japanese). Rinsho Ketsueki 28: 100–105, 1987

    PubMed  CAS  Google Scholar 

  200. Yates VM, Kerr REI. Cimetidine and thrombocytopenia. British Medical Journal 280: 1453, 1980

    PubMed  CAS  Google Scholar 

  201. Yeomans ND, Hanson RG, Smallwood RA, Mihaly GW, Louis WJ. Effect of chronic ranitidine treatment on secretion of intrinsic factor. British Medical Journal 285: 264, 1982

    PubMed  CAS  Google Scholar 

  202. Yue CP, Mann KS, Chan KH. Severe thrombocytopenia due to combined cimetidine and phenytoin therapy. Neurosurgery 20: 963–965, 1987

    PubMed  CAS  Google Scholar 

  203. Zeldis JB, Friedman LS, Isselbacher KJ. Ranitidine: a new H2-receptor antagonist. New England Journal of Medicine 309: 1368–1373, 1983

    PubMed  CAS  Google Scholar 

  204. Zoumbos NC, Gascon P, Djeu JY, Trost SR, Young NS. Circulating activated suppressor T lymphocytes in aplastic anemia. New England Journal of Medicine 312: 257–265, 1985

    PubMed  CAS  Google Scholar 

  205. Zulli P, Di Nisio Q. Cimetidine treatment during pregnancy. Lancet 2: 945–946, 1978

    PubMed  CAS  Google Scholar 

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Correspondence to Jean-Pierre Aymard.

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Aymard, JP., Aymard, B., Netter, P. et al. Haematological Adverse Effects of Histamine H2-Receptor Antagonists. Med Toxicol Adverse Drug Exp 3, 430–448 (1988). https://doi.org/10.1007/BF03259895

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Keywords

  • Cimetidine
  • Ranitidine
  • Oral Anticoagulant
  • Famotidine
  • Agranulocytosis