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The growth capacity of hematopoietic progenitor cells in severe neutropenia induced by famotidine

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Summary

In four cases of severe neutropenia of unknown origin we found a strong inhibition of the growth of granulocyte-macrophage (GM) progenitor cells. The development of GM colonies in culture (GM-CFU-c) was more than 80% reduced in comparison to the control group. In particular, the interleukin 3- (IL-3) and granulocyte macrophage colony-stimulating factor-(GM-CSF) dependent growth was affected; a combination of growth factors (IL-3, GM-CSF, and G-CSF, the granulocyte colony-stimulating factor) resulted in a less reduced growth. The findings were primarily compatible with drug-induced bone marrow failure. Among the medications given to the patients, famotidine, an H2-receptor blocker, was discussed as an agent which possibly triggers off this process. After the withdrawal of famotidine, in three cases a continual increase of the growth of GM precursors was detected, reaching the normal level 7–17 days later. In one case, further investigations of the progenitor cells could not be carried out due to the death of the patient, but the rapid increase of neutrophils in the peripheral blood after withdrawal of famotidine pointed to the recovery of hematopoiesis. In vitro studies showed that famotidine, depending on the dose, inhibits the single growth factor-dependent colony growth (IL-3, GM-CSF, or G-CSF) of bone marrow progenitors from a concentration as low as 10μg/ml. With the combination of all three growth factors only slight inhibitory effects were detectable (up to 150μg/ml famotidine). These results indicate that famotidine, in common with other H2-receptor antagonists, can affect hematopoietic progenitor cells. However, the plasma concentration of famotidine normally used in ulcer therapy does not seem to influence the hematopoiesis. Apparently, the progenitor cells of only a few patients possess a higher sensitivity to the blockade of H2-receptors at this concentration of famotidine. This was demonstrated in one case (patient 3) 2 years after the patient had recovered from famotidine-induced neutropenia. The growth of peripheral myeloid, erythroid, and multilineage progenitor cells of this patient was remarkably reduced even at famotidine concentrations of 0.1–5.0μg/ml whereas in the control group no inhibition was detected at these famotidine concentrations. Again, the IL-3-dependent colony formation was more affected than in the case of the combination of IL-3, GM-CSF, and G-CSF. After the removal of accessory cells the inhibitory effect of famotidine persisted, demonstrating that accessory cells do not play a major role in this process.

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References

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

    Google Scholar 

  2. Beer DJ, Rocklin RE (1984) Histamine-induced suppressor-cell activity. J Allergy Clin Immunol 73: 439–452

    Google Scholar 

  3. Bertaccini G, Coruzzi G, Poli E, Adami M (1986) Pharmacology of the novel H 2 antagonist famotidine: in vitro studies. Agents Actions 19: 180–187

    Google Scholar 

  4. Byron JW (1977) Cimetidine and bone-marrow toxicity. Lancet 2: 555–556

    Google Scholar 

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

    Google Scholar 

  6. Byron JW (1980) Pharmacodynamic basis for the interaction of cimetidine with the bone marrow stem cells (CFUs). Exp Hematol 8: 256–263

    Google Scholar 

  7. Dammann HG (1990) Clinical efficacy of famotidine in the treatment of acid-related diseases: an overview. Hepatogastroenterology 37 (suppl 1): 2–5

    Google Scholar 

  8. Dobrilla G, de Pretis G, Piazzi L, et al (1982) Comparison of once-daily bedtime administration of famotidine and ranitidine in the short-term of duodenal ulcer. Scand J Gastroenterol 22 [Suppl 134]: 21–28

    Google Scholar 

  9. Dobrilla G, de Pretis G, Comberlato M, Amplatz S (1988) Pirenzepine and upper gastrointestinal tract motility in man. Hepatogastroenterology 35: 51–53

    Google Scholar 

  10. Douer D, Kneller A, Ben-Bassat I, Chitaysat SD, Shaked N, Salzberg S, Ramot B (1989) Effect of alpha interferon on growth of leukemic and normal hematopoietic progenitors. Synergism with H2 receptor antagonists. Exp Hematol 17: 443–448

    Google Scholar 

  11. Dy M, Jankovic D, Ploemacher R, Theze J, Schneider E (1991) Concomitant histamine, interleukin 4, and interleukin 6 production by hematopoietic progenitor subsets in response to interleukin 3. Exp Hematol 19: 934–940

    Google Scholar 

  12. Echizen H, Shoda R, Umeda N, Ishizaki T (1988) Plasma famotidine concentration versus intragastric pH in patients with upper gastrointestinal bleeding and in healthy subjects. Clin Pharmacol Ther 44: 690–698

    Google Scholar 

  13. Feldman M, Burton ME (1990) Histamine 2-receptor antagonists. Standard therapy for acid-peptic diseases. N Engl J Med 323: 1749–1755

    Google Scholar 

  14. Fitchen JH, Koeffler HP (1980) Cimetidine and granulopoiesis: bone marrow culture studies in normal man and patients with cimitidine-associated neutropenia. Br J Haematol 46: 361–366

    Google Scholar 

  15. Garovoy MR, Reddish RE, Rocklin RE (1983) Histamineinduced suppressor factor (HSF): inhibition of helper T-cell generation and function. J Immunol 130: 357–361

    Google Scholar 

  16. Gespach C, Saal F, Cost H, Abita J-P (1982) Identification and characterization of surface receptors for histamine in the human promyelocytic leukemia cell line HL-60. Comparison with human peripheral neutrophils. Mol Pharmacol 22: 547–553

    Google Scholar 

  17. Gespach C, Marrec N, Balitrand N (1985) Relationship between3H-histamine uptake and H2-receptors in the human promyelocytic leukemia cell line HL-60. Agents Actions 16: 279–283

    Google Scholar 

  18. Gitlin N, McCullough AJ, Smith L, et al (1987) A multicenter, double-blind, randomized, placebo-controlled comparison of nocturnal and twice-a-day famotidine in the treatment of active duodenal ulcer disease. Gastroenterology 92: 48–53

    Google Scholar 

  19. Heit W, Heimpel H, Fischer A, Frickhofen N (1985) Drug-induced agranulocytosis: evidence for the commitment of bone marrow haematopoiesis. Scand J Haematol 35: 459–468

    Google Scholar 

  20. Hellstrand K, Hermodsson S (1986) Histamine H2-receptormediated regulation of human natural killer cell activity. J Immunol 137: 656–660

    Google Scholar 

  21. Hellstrand K, Hermodsson S (1987) Differential effects of histamine receptor antagonists on human natural killer cell activity. Int Arch Allergy Appl Immunol 84: 247–255

    Google Scholar 

  22. Howard JM, Chremos AM, Collen MJ, et al. (1985) Famotidine, a new, potent, long-acting histamine H2-receptor antagonist: comparison with cimetidine and ranitidine in the treatment of Zollinger-Ellison syndrome. Gastroenterology 88: 1026–1033

    Google Scholar 

  23. Humphries TJ (1987) Famotidine: a notable lack of drug interactions. Scand J Gastroenterol 134 [Suppl]: 55–60

    Google Scholar 

  24. Klotz U, Arvela P, Rosenkranz B (1985) Famotidine, a new H2-receptor antagonist, does not affect hepatic elimination of diazepam or tubular secretion of procainamide. Eur J Clin Pharmacol 28: 671–675

    Google Scholar 

  25. Lebel B, Schneider E, Piquet-Pellorce C, Machavoine F, Kindler V, Luffau G, Dy M (1990) Antigenic challenge of immunized mice induces endogenous production of IL-3 that increases histamine synthesis in hemopoietic organs. J Immunol 145: 1222–1226

    Google Scholar 

  26. Lipsy RJ, Fennerty B, Fagan TC (1990) Clinical review of histamine-2-receptor antagonists. Arch Intern Med 150: 745–751

    Google Scholar 

  27. List AF, Beaird DH, Kummet T (1988) Ranitidine-induced granulocytopenia: recurrence with cimitidine administration. Ann Intern Med 108: 566–567

    Google Scholar 

  28. McGuigan JE (1981) A consideration of the adverse effects of cimetidine. Gastroenterology 80: 181–192

    Google Scholar 

  29. Mayer P, Valent P, Schmidt G, Liehl E, Bettelheim P (1989) The in vivo effects of recombinant human interleukin-3: demonstration of basophil differentiation factor, histamine-producing activity, and priming of GM-CSF-responsive progenitors in nonhuman primates. Blood 74: 613–621

    Google Scholar 

  30. Merck Sharp & Dohme (1986) Pepcid product information. West Point, PA, USA

  31. Metcalf D (1984) The hemopoietic colony-stimulating factors. Elsevier, Amsterdam, pp 96–150

    Google Scholar 

  32. Minkowski M, Lebel B, Arnould A, Dy M (1990) Interleukin 3 induces histamine synthesis in the human hemopoietic system. Exp Hematol 18: 1158–1163

    Google Scholar 

  33. Nagler A, Rozenbaum H, Ernat R, Tatarsky I, Katz R, Pollack S (1987) Immune basis for cimetidine-induced pancytopenia. Am J Gastroenterol 82: 359–361

    Google Scholar 

  34. Nakaya N, Tasaka K (1988) The influence of histamine on precursors of granulocytic leukocytes in murine bone marrow. Life Sci 42: 999–1010

    Google Scholar 

  35. Onishi K (1991) Pharmacokinetics of famotidine after intravenous administration in liver disease. Am J Gastroenterol 86: 41–45

    Google Scholar 

  36. Sawutz DG, Kalinyak K, Whitsett JA, Johnson CC (1984) Histamine H 2 receptor desensitization in HL-60 human promyelocytic leukemia cells. J Pharmacol Exp Ther 231: 1–7

    Google Scholar 

  37. Schneider E, Piquet-Pellorce C, Dy M (1990) New role of histamine in interleukin-3-induced proliferation of hematopoietic stem cells. J Cell Physiol 143: 337–343

    Google Scholar 

  38. Shounan Y, You-Heng X (1988) The influence of histamine at various concentrations on the cell-cycle state of hematopoietic stem cells (CFU-s). Int J Cell Cloning 6: 290–295

    Google Scholar 

  39. Socinski MA, Cannistra SA, Elias A, Antman KH, Schnipper L, Griffin JD (1988) Granulocyte-macrophage colonystimulating factor expands the circulating haemopoietic progenitor cell compartment in man. Lancet 28 (1): 1194–1198

    Google Scholar 

  40. Spector SA, Tyndall M, Kelley E (1982) Effects of acyclovir combined with other antiviral agents on human cytomegalovirus. Am J Med 73: 1A, 36–39

    Google Scholar 

  41. Takano K, Sugiyama S, Goto H, Nakazawa S, Ozawa T (1988) Effect of the H2-blocker famotidine on gastric mucosal prostaglandin levels in water immersion stress in rats. Arzneimittelforsch Drug Res 38: 364–365

    Google Scholar 

  42. Takaue Y, Kawano Y, Reading CL, et al (1990) Effects of recombinant human G-CSF, GM-CSF, IL-3, and IL-1α on the growth of purified human peripheral blood progenitors. Blood 76: 330–335

    Google Scholar 

  43. Tang ZC, Xu YH (1987) Comparison of the effects of 4-methylhistamine on the cell-cycle response between CFU-s and its subpopulation. Int J Cell Cloning 5: 511–517

    Google Scholar 

  44. Tasaka K, Nakaya N, Nonaka T (1990) Effects of histamine, granulocyte colony-stimulating factor and db-cAMP on the differentiation of HL-60 cells. Agents Actions 30: 240–242

    Google Scholar 

  45. Uyttenbroeck W, Korthout M, De Bock R, Van Boecksdaele DR, Peetermans ME (1990) Cimetidine-induced pancytopenia. Effect on human CFU-MIX colony formation. Blut 60: 323–327

    Google Scholar 

  46. Vincent PC (1986) Drug-induced aplastic anaemia and agranulocytosis incidence and mechanisms. Drugs 31: 52–63

    Google Scholar 

  47. Wang RW, Miwa GT, Argenbright LS, Lu AYH (1988) In vitro studies on the interaction of famotidine with liver microsomal cytochrome P-450. Biochem Pharmacol 37: 3049–3053

    Google Scholar 

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  1. Abteilung Hämatologie/Onkologie, Medizinische Universitätsklinik, Robert-Koch-Strasse 40, W-3400, Göttingen, Federal Republic of Germany

    T. Liersch, J. -H. Beyer, G. Krieger & K. Vehmeyer

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  1. T. Liersch
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  2. J. -H. Beyer
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  3. G. Krieger
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  4. K. Vehmeyer
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Liersch, T., Beyer, J.H., Krieger, G. et al. The growth capacity of hematopoietic progenitor cells in severe neutropenia induced by famotidine. Ann Hematol 64, 231–239 (1992). https://doi.org/10.1007/BF01738302

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