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Possible cardiac side effects of granisetron, an antiemetic agent, in patients with bone and soft-tissue sarcomas receiving cytotoxic chemotherapy

  • Original Article
  • Antiemetics, Granisetron, Chemotherapy, Arrhythmia, Vagus Nerve
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Abstract

The cardiac effect of granisetron, a selective 5-hydroxytryptamine3 receptor antagonist, on 12 patients with bone and soft-tissue sarcomas treated by cytotoxic chemotherapy consisting of multiple courses was examined. Of the 12 patients, 4 showed significant electrocardiographical changes, including sinus bradycardia, integral change of P-waves, junctional escape beat, and atrioventricular (AV) block with Wenckebach phenomenon, indicating stimulatory regulation of the vagus nerve. These changes were observed in each patient after several courses of chemotherapy but not in the first course. There was no correlation between the electrocardiographical changes and the chemotherapeutic agents used or the type of tumor present. A patient with osteosarcoma showed persistent bradycardia in three courses, all protocols of which contained high-dose methotrexate. From these findings we conclude that the cardiac responses may be due to stimulated activity of the vagal efferent nerve, which is regulated reflexly by afferent nerve activity suppressed by granisetron. On the other hand, the antiemetic efficacy of granisetron was satisfactory. These results suggest that careful observation of the heart is necessary when granisetron is used, especially for chemotherapy consisting of repeated multiple courses.

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References

  1. Addelman M, Erlichman C, Fine S, Warr D, Murray C (1990) Phase I/II trial of granisetron: a novel 5-hydroxytryptamine antagonist for the prevention of chemotherapy-induced nausea and vomiting. J Clin Oncol 8:337–341

    CAS  PubMed  Google Scholar 

  2. Andrews PLR, Davis CJ, Grahame-Smith DG, and Leslie RA (1986) Increase in3H-2-deoxyglucose uptake in the ferret area postrema produced by apomorphine administration or electrical stimulation of the abdominal vagus. J Physiol., (Lond) 382: 187

    Google Scholar 

  3. Andrews PLR, Rapeport WG, Sanger GJ (1988) Neuropharmacology of emesis induced by anti-cancer therapy. Trends Pharmacol Sci 9: 334–341

    Article  CAS  PubMed  Google Scholar 

  4. Andrews PLR, Bhandari P, Davey PT, Bingham S, Marr HE, Blower PR (1992) Are all 5-HT3 receptor antagonists the same? Eur J Cancer 28A [Suppl 1]: S2-S6.

    Article  CAS  PubMed  Google Scholar 

  5. Bacci G, Picci P, Ruggieri P, Mercuri M, Avella M, Capanna R, Brach Del Prever A, Mancini A, Gherlinzoni F, Padovani G, Leonessa C, Biagini R, Ferraro A, Ferruzzi A, Cazzola A, Manfrini M, Campanacci M (1990) Primary chemotherapy and delayed surgery (neoadjuvant chemotherapy) for osteosarcoma of the extremities. Cancer 65: 2539–2553

    Article  CAS  PubMed  Google Scholar 

  6. Coates A, Abraham S, Kaye SB, Sowerbutts T, Frewin C, Fox RM Tattersall MHN (1983) On the receiving end—patient perception of the side-effects of cancer chemotherapy. Eur J Cancer Clin Oncol, 19: 203–208

    Article  CAS  PubMed  Google Scholar 

  7. Elliott P, Seemungal BM, Wallis DI (1990) Antagonism of the effects of 5-hydroxytryptamine on the rabbit isolated vagus nerve by BRL 43694 and metoclopramide. Naunyn-Schmiedeberg's Arch Pharmacol 341: 503–509

    CAS  Google Scholar 

  8. Fake CS, King FD, Sanger GJ (1987) BRL 43694: a potent and novel 5-HT3 receptor antagonist. Br J Pharmacol 91: 335

    Google Scholar 

  9. Frytak S, Moertel CG (1981) Management of nausea and vomiting in the cancer patient. JAMA 245: 393–396

    Article  CAS  PubMed  Google Scholar 

  10. Goldman MJ (1976) Normal cardiac rhythm and the atrial arrhythrias. In: Maruzen Asian (ed) Principles of clinical electrocardiography. 8th edn. Lange Medical Publications/Maruzen, Tokyo, Japan, pp 200–226

    Google Scholar 

  11. Hawthorn J, Osler KJ, Andrews PLR (1988) The role of the abdominal visceral innervation and 5-hydroxytryptamine M-receptors in vomiting induced by the cytotoxic drugs cyclophosphamide and cisplatin in the ferret. Q J Exp Physiol 73: 7–21

    Article  CAS  PubMed  Google Scholar 

  12. Joss RA, Brand BC, Buser KS, Cerny T (1990) The symptomatic control of cytostatic drug-induced emesis. A recent history and review. Eur J Cancer 26 [Suppl 1]: S2-S8

    CAS  PubMed  Google Scholar 

  13. Kunze DL (1972) Reflex discharge patterns of cardiac vagal efferent fibres. J Physiol (Lond) 222: 1–15

    Article  CAS  Google Scholar 

  14. Lemerle J, Amaral D, Southall DP, Upward J, Murdoch RD (1991) Efficacy and safety of granisetron in the prevention of chemotherapy-induced emesis in paediatric patients. Eur J Cancer 27: 1081–1083

    Article  CAS  PubMed  Google Scholar 

  15. Leslie RA, Reynolds DJM, Andrews PLR, Grahame-Smith DG, Davis CJ Harvey JM (1990) Evidence for presynaptic 5-hydroxytryptamine3 recognition sites on vagal afferent terminals in the brainstem of the ferret. Neuroscience 38: 667–673

    Article  CAS  PubMed  Google Scholar 

  16. Marty M, on behalf of the Granisetron Study Group (1990) A comparative study of the use of granisetron, a selective 5-HT3 antagonist, versus a standard anti-emetic regimen of chlorpromazine plus dexamethasone in the treatment of cytostatic-induced emesis. Eur J Cancer 26 [Suppl 1] S28-S32

    PubMed  Google Scholar 

  17. Marty M, on behalf on the Granisetron Study Group (1992) A comparison of granisetron as a single agent with conventional combination antiemetic therapies in the treatment of cytostatic-induced emesis. Eur J Cancer 28A [Suppl 1]: S12-S16

    Article  PubMed  Google Scholar 

  18. Mendeloff AI (1974) Constipation, diarrhea, and disturbances of anorectal function. In: Wintrobe MM, Thorn GW, Adams RD, Braunwald E, Isselbacher KJ Petersdorf RG. (eds) Harrison's principles of internal medicine, 7th edn. McGraw-Hill, New York, pp 213–218

    Google Scholar 

  19. Milano S, Grelot L, Chen Z, Bianchi AL (1990) Vagal-induced vomiting in decerebrate cat is not suppressed by specific 5-HT3 receptor antagonists. J Auton Nerve Syst 31: 109–118

    Article  CAS  Google Scholar 

  20. Nelson DR, Thomas DR (1989) [3H]-BRL 43694 (graniseton), a specific ligand for 5-HT3 binding sites in rat brain cortical membranes. Biochem Pharmacol 38: 1693–1695

    Article  CAS  PubMed  Google Scholar 

  21. Plosker GL, Goa KL (1991) Granisetron: a review of its pharmacological properties and therapeutic use as an antiemetic. Drugs 42: 805–824

    Article  CAS  PubMed  Google Scholar 

  22. Rosen G, Caparros B, Nirenberg A, Marcove RC, Huvos AG, Kosloff C, Lane J, Murphy L (1981) Ewing's sarcoma: ten-year experience with adjuvant chemotherapy. Cancer 47: 2204–2213

    Article  CAS  PubMed  Google Scholar 

  23. Rosen G, Caparros B, Huvos AG, Kosloff C, Nirenberg A, Cacavio A, Marcove RC, Lane JM, Mehta B, and Urban C (1982) Preoperative chemotherapy for osteogenic sarcoma: selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer 49: 1221–1230

    Article  CAS  PubMed  Google Scholar 

  24. Spear JF, Kronhaus KD, Moore EN, Kline KP (1979) The effect of brief vagal stimulation on isolated rabbit sinus node. Circ Res 44: 75–88

    Article  CAS  PubMed  Google Scholar 

  25. Upward JW, Arnold BDC, Link C, Pierce DM, Allen A, Tasker TCG (1990) The clinical pharmacology of granisetron (BRL 43694), a novel specific 5-HT3 antagonist. Eur J Cancer 26 [Suppl 1]: S12-S15.

    CAS  PubMed  Google Scholar 

  26. Wallick DW, Martin PJ (1989) Brief vagal bursts can induce Wenckebach arrhythmia. Am J Physiol 257: H935-H941

    CAS  PubMed  Google Scholar 

  27. Wallick DW, Martin PJ, Masuda Y, Levy MN (1982) Effects of autonomic activity and changes in heart rate on atrioventricular conduction. Am J Physiol 243: H523-H527

    CAS  PubMed  Google Scholar 

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Watanabe, H., Hasegawa, A., Shinozaki, T. et al. Possible cardiac side effects of granisetron, an antiemetic agent, in patients with bone and soft-tissue sarcomas receiving cytotoxic chemotherapy. Cancer Chemother. Pharmacol. 35, 278–282 (1995). https://doi.org/10.1007/BF00689445

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  • DOI: https://doi.org/10.1007/BF00689445

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