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A phase I study of monohydroxyethylrutoside in healthy volunteers

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Abstract

The flavonol monohydroxyethylrutoside (monoHER) has demonstrated protection against doxorubicin-induced cardiotoxicity in in vitro and in vivo studies without affecting the antitumor effect. In the present phase I study, the possible side effects and the pharmacokinetics of monoHER were evaluated in healthy volunteers with the aim to develop a safe and feasible dose to be evaluated in cancer patients treated with doxorubicin. The study was performed as a single blind, randomized trial in healthy volunteers (age between 19 and 56 years). At each dose level, six subjects received monoHER and three placebo. MonoHER was solubilized in 100 ml dextrose 5% and administered as an i.v. infusion in 10 min. The placebo consisted of 100 ml dextrose 5%. The starting dose of monoHER was 100 mg/m2. Dose escalation by 100% of the preceding dose took place after finishing each dose level until the protecting pharmacokinetic values for C max and AUC∞ (as observed in mice after 500 mg/kg monoHER i.p.) were reached and/or serious side effects were observed. The dose was escalated up to 1,500 mg/m2. The mean values of C max and AUC∞ were 360±69.3 μM and 6.8±2.1 μmol min/ml, respectively. These values were comparable to the C max and AUC∞ observed under the protecting conditions in mice. No serious side effects occurred during the entire study. Thus, 1,500 mg/m2 is a feasible and safe dose to be evaluated in a phase II study to investigate the protective properties of monoHER against doxorubicin-induced cardiotoxicity in cancer patients.

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Acknowledgments

We wish to thank the staff of the Department of Hospital Pharmacy, Vrije Universiteit Medical Center, Amsterdam, The Netherlands, for their assistance. This work was supported by a grant-in-aid from the Koningin Wilhelmina Foundation, Amsterdam, The Netherlands.

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Authors and Affiliations

  1. Department of Medical Oncology, Vrije Universiteit Medical Center, De Boelelaan 1117, BR 232, 1081 HV, Amsterdam, The Netherlands

    Anja M. Willems, Anne M. Bruynzeel, Marc A. Kedde, Cees J. van Groeningen & Wim J. van der Vijgh

  2. Department of Pharmacology and Toxicology, University Maastricht, Maastricht, The Netherlands

    Aalt Bast

Authors
  1. Anja M. Willems
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  2. Anne M. Bruynzeel
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  3. Marc A. Kedde
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  4. Cees J. van Groeningen
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  5. Aalt Bast
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  6. Wim J. van der Vijgh
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Additional information

Preliminary results of this study have been presented as a poster at AACR (Proc. AACR 43 (2002) 2751).

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Willems, A.M., Bruynzeel, A.M., Kedde, M.A. et al. A phase I study of monohydroxyethylrutoside in healthy volunteers. Cancer Chemother Pharmacol 57, 678–684 (2006). https://doi.org/10.1007/s00280-005-0083-7

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  • DOI: https://doi.org/10.1007/s00280-005-0083-7

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