Skip to main content
SpringerLink
Log in

The inhibitory effects of a positive inotropic quinolinone derivative, 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone (OPC-8212), on bone-marrow progenitor cells and peripheral lymphocytes

  • Originals
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Summary

3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone (OPC-8212) is a quinolinone derivative with positive inotropic properties.

In order to elucidate the effect of OPC-8212 on the haemopoietic system we studied its in vitro effect on bone-marrow progenitor cells (granulocyte/monocyte colonyforming units [CFU-GM] and erythroid burst-forming units [BFU-E]), on the proliferation and secretion of granulocyte/monocyte colony-stimulating factor (GM-CSF) and interferon-γ (IFN-γ) by peripheral lymphocytes, and on GM-CSF secretion by fibroblasts from healthy individuals. The dose-effect relations of OPC-8212 on CFU-GM proliferation and on lymphocytic GM-CSF secretion showed no effect at very low drug concentrations, with a threshold at the lower end of the therapeutic range and highly significant dose-dependent inhibition at concentrations above that threshold. BFU-E, peripheral lymphocyte proliferation and lymphocytic IFN-γ secretion were depressed, although to a lesser extent, in a linear dose-dependent fashion. OPC-8212 did not affect GM-CSF secretion by one strain of fibroblasts but reduced it at higher concentrations in assays with another strain of cells. We conclude that direct toxic effects on bone-marrow progenitor cells, in combination with the inhibition of cytokines involved in the regulation of haemopoiesis in certain susceptible individuals, may be responsible for idiosyncratic reactions to OPC-8212.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Tominaga M, Yo E, Ogawa H, Yamashita S, Yabuuchi Y, Nakagawa K (1984) Studies on positive inotropic agents. I. Synthesis of 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone and related compounds. Chem Pharma Bull 32: 2100–2110

    Google Scholar 

  2. Yamashita S, Hosokawa T, Kojima M, Mori T, Yabuuchi Y (1984) In vitro and in vivo studies of 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone (OPC-8212), a novel positive inotropic drug, in various animals. Arzneimittelforschung/Drug Research 34: 342–346

    Google Scholar 

  3. Inoue M, Hori M, Nakajima S, Kitakaze M, Fukunami M, Ishida Y, Abe H (1984) Effects of 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone (OPC-8212), a new inotropic agent, on cardiotonic activity and coronary hemodynamics. Arzneimittelforschung/Drug Research 34: 355–359

    Google Scholar 

  4. Lathrop DA, Schwartz A (1984) Electro-mechanical effects of 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone (OPC-8212), a new positive inotropic agent. Isolated adult Purkinje strands and ventricular trabeculae. Arzneimittelforschung/Drug Research 34: 371–375

    Google Scholar 

  5. Lathrop DA, Varro A, Schwartz A (1989) Rate-dependent electrophysiological effects of OPC-8212: comparison to sotalol. Eur J Pharmacol 164: 487–496

    Google Scholar 

  6. Feldman AM, Becker LC, Llewellyn MP, Baughman KL (1988) Evaluation of a new inotropic agent, OPC-8212, in patients with dilated cardiomyopathy and heart failure. Am Heart J 116: 771–777

    Google Scholar 

  7. Yatani A, Imoto Y, Schwartz A, Brown AM (1989) New positive inotropic agent OPC-8212 modulates single Ca+2 channels in ventricular myocytes of guinea pig. J Cardiovasc Pharmacol 13: 812–819

    Google Scholar 

  8. Ijima T, Taira N (1987) Membrane current changes responsible for the positive inotropic effect of OPC-8212, a new positive inotropic agent, in single ventricular cells of the guinea pig heart. J Pharmacol Exp Ther 240: 657–662

    Google Scholar 

  9. Endoh M, Yanagisawa T, Taira N, Blinks JR (1986) Effects of new inotropic agents on cyclic nucleotide metabolism and calcium transients in canine ventricular muscle. Circulation 733: III 117–133

    Google Scholar 

  10. Rapundalo ST, Lathrop DA, Harrison SA, Beavo JA, Schwartz A (1988) Cyclic AMD-dependent and cyclic AMP-independent actions of a novel cardiotonic agent, OPC-8212. Arch Pharmacol 338: 692–698

    Google Scholar 

  11. Taira N, Endoh M, Iijima T, Satoh K, Yanagisawa T, Yamashita S, Maruyama M, Kawada M, Morita T, Wada Y (1984) Mode and mechanism of action of 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone (OPC-8212), a novel positive inotropic drug, on the dog heart. Arzneimittelforschung/Drug Research 34: 347–355

    Google Scholar 

  12. Metcalf D, Merchav S, Wagemaker G (1982) Commitment by GM-CSF of M-CSF of bipotential GM progenitor cells to granulocyte or macrophage formation. In: Baum, Ledney and Thierfelder (eds) Experimental haematology today. Karger, Basel, pp 3–9

    Google Scholar 

  13. Burgess AW, Wison EMA, Metcalf D (1977) Stimulation by human placental conditioned medium of hemopoietic colony formation by human bone-marrow cells. Blood 49: 573–583

    Google Scholar 

  14. Brattig NW, Diao GJ, Berg PA (1988) The specificity of the lymphocyte transformation test in a patient with hypersensitivity reactions to pyrazolone compounds. A 10-week follow-up study before and after rechallenge. Eur J Clin Pharmacol 35: 39–45

    Google Scholar 

  15. Schultze JL, Stettin A, Berg PA (1991) Demonstration of specifically sensitized lymphocytes in patients treated with an aqueous mistletoe extract (Viscum album L.). Klin Wochenschr 69: 397–403

    Google Scholar 

  16. Heimpel H (1988) Drug-induced agranulocytosis. Med Toxicol Adverse Drug Exp 3: 449–462

    Google Scholar 

  17. Young GAR, Vincent PC (1980) Drug-induced agranulocytosis. Clin Haematol 9: 483–504

    Google Scholar 

  18. Dexter TM, Spooncer E (1987) Growth and differentiation in the hemopoietic system. Ann Rev Cell Biol 3: 423–441

    Google Scholar 

  19. Zoumbos NC, Djeu JY, Young NS (1984) Interferon is the suppressor of hematopoiesis generated by stimulated lymphocytes in vitro. J Immunol 133: 769–774

    Google Scholar 

  20. Brockbank KGM, DeJong JP (1987) Hemopoiesis on skin-derived fibroblasts in vitro. Leukemia 1: 609–612

    Google Scholar 

  21. Eliason JF, Thorens B, Kindler V, Vassalli P (1988) The roles of granulocyte-macrophage-stimulating factor and IL-3 in stromal cell-mediated hemopoiesis in vivo. Exp Hematol 16: 307–312

    Google Scholar 

  22. Kulessa W, Becker EW, Berg PA (1992) Wiederholte Agranulozytose nach Einnahme von Calciumdobesilat. Dtsch Wochenschr 10: 372–374

    Google Scholar 

  23. Pisciotta AV (1973) Immune and toxic mechanisms in drug-induced agranulocytosis. Sem Hematol 10: 279–310

    Google Scholar 

  24. Idänpään HJ, Alhava E, Olkinuora M, Palva IP (1977) Agranulocytosis during treatment with clozapine. Eur J Clin Pharmacol 11: 193–198

    Google Scholar 

  25. Young GAR, Vincent PC (1980) Drug-induced agranulocytosis. Clin Haematol 9: 483–503

    Google Scholar 

  26. Somekh E, Douer D, Shaked N, Rubinstein E (1988) In vitro effects of ciprofloxacin and pefloxacin on growth of normal human hematopoietic progenitor cells and on leukemic cell lines. J Pharmacol Exp Ther 248: 415–418

    Google Scholar 

  27. Wiberg JJ, Nuttall FQ (1972) Methimazole toxicity from high doses. Ann Intern Med 77: 414–416

    Google Scholar 

  28. Gallicchio VS, Hulette BC (1989) In vitro effect of lithium on carbamazepine-induced inhibition of murine and human bone-marrow-derived granulocyte-macrophage, erythroid, and megakaryocyte progenitor stem cells (42837). Proc Soc Exp Med Biol 190: 109–116

    Google Scholar 

  29. Matsuzaki M, Tokioka T, Suga K, Sueoka E, Ono K, Sano M, Shimamoto Y, Yamaguchi M (1990) [Phenytoin induced agranulocytosis: direct and T cell-mediated mechanisms]. Rinsho-Ketsueki 31: 474–478

    Google Scholar 

  30. Boogaerts MA, Peters M, Peerman C, Kesteloot H, Verwilghen RL (1984) Mechanism of aprindine induced agranulocytosis: direct toxicity on CFU-C and CFU-GEMM. Scand J Haematol 32: 175–178

    Google Scholar 

  31. Kelton JG, Huang AT, Mold N, Logue GL, Rosse WF (1979) The use of in vitro techniques to study drug induced pancytopenia. New Engl J Med 301: 621–624

    Google Scholar 

  32. Sommadossi J-P, Carlisle R (1986) Toxicity of 3′-azido-3′-deoxythymidine and 9-(1,3-dihydroxy-2-propoxymethyl)guanine for normal human hematopoietic progenitor cells in vitro. Antimicrob Agents Chemother 31: 452–454

    Google Scholar 

  33. Huhn D (1980) Medikamentös induzierte Störungen der Hämatopoese. Dtsch Med Wochenschr 105: 1576–1581

    Google Scholar 

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

    Google Scholar 

  35. Mathews KP (1984) Clinical spectrum of allergic and pseudoallergic drug reactions. J Allerg Clin Immunol 74: 558–566

    Google Scholar 

  36. Kallos P, West GB (1983) Pseudo-allergic reactions in man. In Turner P, Shand DG (eds) Recent Advances in Clinical Pharmacology 3, Churchill Livingstone, Edinburgh, pp 235–252

    Google Scholar 

  37. Ohnishi A, Ishizaki T (1988) Pharmacokinetic profile of OPC-8212 in humans: a new, nonglycosidic, inotropic agent. J Clin Pharmacol 28: 719–726

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine, University of Tübingen, Tübingen, FRG

    F. W. Busch, A. Tillmann, E. W. Becker, M. Owsianowski & P. A. Berg

Authors
  1. F. W. Busch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Tillmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E. W. Becker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Owsianowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P. A. Berg
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Busch, F.W., Tillmann, A., Becker, E.W. et al. The inhibitory effects of a positive inotropic quinolinone derivative, 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone (OPC-8212), on bone-marrow progenitor cells and peripheral lymphocytes. Eur J Clin Pharmacol 42, 629–633 (1992). https://doi.org/10.1007/BF00265927

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00265927

Key words

Search

Navigation