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Post-Transplant Events

A prospective, double-blind phase II study evaluating the safety and efficacy of a topical histamine gel for the prophylaxis of oral mucositis in patients post hematopoietic stem cell transplantation

Bone Marrow Transplantation volume 37, pages 757–762 (2006)Cite this article

Abstract

The aim of this study was to evaluate the safety, tolerability and efficacy of a topical gel containing histamine dihydrochloride (HDC) versus a placebo gel in preventing oral mucositis in hematopoietic stem cell transplantation (HSCT) patients. A total of 45 patients post-HSCT were enrolled in a prospective longitudinal, placebo-controlled, double-blind study. Patients were evaluated twice weekly for oral mucositis (OMAS, NCI score), oral pain (VAS), oral function and salivary flow rate. Compliance was assessed using a patient diary. Oral mucositis developed in 85% of the HDC group and 63% of the placebo group. The mean maximal intensity for NCI score was 1.45±1 in the HDC group and 1.21±1.27 in the placebo group (P=0.37). The mean duration of oral mucositis was 4.7±3.6 and 2.33±2.23 days in the HDC and placebo groups, respectively (P=0.06). The same trends were measured with OMAS. Visual analogue scale for oral pain and oral function was not significantly different between the two groups. Histamine dihydrochloride was found to be safe. In the search for topical agents for the prevention of mucositis, we found that HDC neither improves nor worsens oral mucositis in HSCT patients. The balance between the pro- and anti-inflammatory effects of HDC should be investigated further in order to acquire a clinically effective topical medication based on its anti-inflammatory properties.

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References

  1. Scully C, Epstein J, Sonis S . Oral mucositis: a challenging complication of radiotherapy, chemotherapy, and radiochemotherapy: part 1, pathogenesis and prophylaxis of mucositis. Head Neck 2003; 25: 1057–1070.

    Article  Google Scholar 

  2. Lalla RV, Peterson DE . Oral mucositis. Dent Clin N Am 2005; 49: 167–184, ix.

    Article  Google Scholar 

  3. Stiff P . Mucositis associated with stem cell transplantation: current status and innovative approaches to management. Bone Marrow Transplant 2001; 27 (Suppl 2): S3–S11.

    Article  Google Scholar 

  4. Sonis ST, Oster G, Fuchs H, Bellm L, Bradford WZ, Edelsberg J et al. Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantation. J Clin Oncol 2001; 19: 2201–2205.

    Article  CAS  Google Scholar 

  5. Sonis ST, Elting LS, Keefe D, Peterson DE, Schubert M, Hauer-Jensen M et al. Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer 2004; 100 (9 Suppl): 1995–2025.

    Article  Google Scholar 

  6. Agarwala SS, Sabbagh MH . Histamine dihydrochloride: inhibiting oxidants and synergising IL-2-mediated immune activation in the tumour microenvironment. Expert Opin Biol Ther 2001; 1: 869–879.

    Article  CAS  Google Scholar 

  7. Hellstrand K, Hermodsson S, Naredi P, Mellqvist UH, Brune M . Histamine and cytokine therapy. Acta Oncol 1998; 37: 347–353.

    Article  CAS  Google Scholar 

  8. Azuma Y, Shinohara M, Wang PL, Hidaka A, Ohura K . Histamine inhibits chemotaxis, phagocytosis, superoxide anion production, and the production of TNFalpha and IL-12 by macrophages via H2-receptors. Int Immunopharmacol 2001; 1: 1867–1875.

    Article  CAS  Google Scholar 

  9. Treede RD, Meyer RA, Davis KD, Campbell JN . Intradermal injections of bradykinin or histamine cause a flare-like vasodilatation in monkey. Evidence from laser Doppler studies. Neurosci Lett 1990; 115: 201–206.

    Article  CAS  Google Scholar 

  10. Cancer Therapy Evaluation Program forms and templates generic CTC version 2.0. Data collection form. National Cancer Institute, 1999 http://ctep.cancer.gov/forms/CTCv20_4-30-992.pdf.

  11. Sonis ST, Eilers JP, Epstein JB, LeVeque FG, Liggett Jr WH, Mulagha MT et al. Validation of a new scoring system for the assessment of clinical trial research of oral mucositis induced by radiation or chemotherapy. Mucositis Study Group. Cancer 1999; 85: 2103–2113.

    Article  CAS  Google Scholar 

  12. Bellm LA, Epstein JB, Rose-Ped A, Martin P, Fuchs HJ . Patient reports of complications of bone marrow transplantation. Support Care Cancer 2000; 8: 33–39.

    CAS  Google Scholar 

  13. Rubenstein EB, Peterson DE, Schubert M, Keefe D, McGuire D, Epstein J et al. Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer 2004; 100 (9 Suppl): 2026–2046.

    Article  Google Scholar 

  14. Spielberger R, Stiff P, Bensinger W, Gentile T, Weisdorf D, Kewalramani T et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med 2004; 351: 2590–2598.

    Article  CAS  Google Scholar 

  15. Chaushu G, Itzkovitz-Chaushu S, Yefenof E, Slavin S, Or R, Garfunkel AA . A longitudinal follow-up of salivary secretion in bone marrow transplant patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995; 79: 164–169.

    Article  CAS  Google Scholar 

  16. Epstein JB, Tsang AH, Warkentin D, Ship JA . The role of salivary function in modulating chemotherapy-induced oropharyngeal mucositis: a review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002; 94: 39–44.

    Article  Google Scholar 

  17. Epstein JB, Schubert MM . Managing pain in mucositis. Semin Oncol Nurs 2004; 20: 30–37.

    Article  Google Scholar 

  18. McGuire DB, Yeager KA, Dudley WN, Peterson DE, Owen DC, Lin LS et al. Acute oral pain and mucositis in bone marrow transplant and leukemia patients: data from a pilot study. Cancer Nurs 1998; 21: 385–393.

    Article  CAS  Google Scholar 

  19. Demarosi F, Lodi G, Soligo D, Sardella A, Volpe AD, Carrassi A et al. Transdermal fentanyl in HSCT patients: an open trial using transdermal fentanyl for the treatment of oral mucositis pain. Bone Marrow Transplant 2004; 33: 1247–1251.

    Article  CAS  Google Scholar 

  20. Ferretti GA, Ash RC, Brown AT, Largent BM, Kaplan A, Lillich TT . Chlorhexidine for prophylaxis against oral infections and associated complications in patients receiving bone marrow transplants. J Am Dent Assoc 1987; 114: 461–467.

    Article  CAS  Google Scholar 

  21. Epstein JB, Truelove EL, Hanson-Huggins K, Mancl LA, Chen A, Press OW et al. Topical polyene antifungals in hematopoietic cell transplant patients: tolerability and efficacy. Support Care Cancer 2004; 12: 517–525.

    Article  Google Scholar 

  22. Sirois J, Menard G, Moses AS, Bissonnette EY . Importance of histamine in the cytokine network in the lung through H2 and H3 receptors: stimulation of IL-10 production. J Immunol 2000; 164: 2964–2970.

    Article  CAS  Google Scholar 

  23. Roitt I . Immunology, 4th edn. Mosby: London, 1996, pp 14.8–14.9.

    Google Scholar 

  24. Jutel M, Blaser K, Akdis CA . Histamine in allergic inflammation and immune modulation. Int Arch Allergy Immunol 2005; 137: 82–92.

    Article  CAS  Google Scholar 

  25. Meropol NJ, Somer RA, Gutheil J, Pelley RJ, Modiano MR, Rowinsky EK et al. Randomized phase I trial of recombinant human keratinocyte growth factor plus chemotherapy: potential role as mucosal protectant. J Clin Oncol 2003; 21: 1452–1458.

    Article  CAS  Google Scholar 

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Acknowledgements

The early stage of the study was supported by Maxim Ltd (San Diago, CA, USA). We thank Dr SDM Robinson for her editorial assistance and Dr M Baras for the statistical analysis.

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Authors and Affiliations

  1. Department of Oral Medicine, The Hebrew University-Hadassah School of Dental Medicine, Jerusalem, Israel

    S Elad, Y Cohen & O Diss

  2. Department of Bone Marrow Transplantation, Hadassah University Medical Center, Jerusalem, Israel

    A Ackerstein, M Bitan, M Y Shapira, I Resnick, B Gesundheit, D Barak, L Dray & R Or

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  1. S Elad
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  2. A Ackerstein
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  4. M Y Shapira
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  6. B Gesundheit
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  7. Y Cohen
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  8. O Diss
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Correspondence to S Elad.

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Elad, S., Ackerstein, A., Bitan, M. et al. A prospective, double-blind phase II study evaluating the safety and efficacy of a topical histamine gel for the prophylaxis of oral mucositis in patients post hematopoietic stem cell transplantation. Bone Marrow Transplant 37, 757–762 (2006). https://doi.org/10.1038/sj.bmt.1705331

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