Vinca alkaloid skin toxicity: Antidote and drug disposition studies in the mouse

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Abstract

A murine (BALB/c) skin toxicity model was used to evaluate various possible antagonists to vinca alkaloid-induced skin ulceration. Reproducible dose-response relationships were developed for vinblastine (VBL) and vindesine (VDS). With vincristine (VCR) only about 70% of mice developed dose-dependent ulceration. On an equal weight basis, VCR proved to be significantly more toxic than either VBL or VDS (P<.05 by Student's t-test). Effective local intradermal antibodies to VBL, VDS, and VCR included hyaluronidase, normal saline, and calcium leucovorin (P<.05 by the Student's Newman-Keuls multiple range test). Mild, topical skin heating significantly reduced VCR ulceration. In contrast, diphenhydramine and sodium bicarbonate were ineffective as local antibodies. Topical skin cooling, however, significantly increased vinca-induced skin ulcers for VBL, VDS, and VCR (P.05). Hydrocortisone, vitamin A topical cream, and isoproterenol increased skin toxicity. [3H]VBL was given intradermally to follow the drug's pharamacokinetic disposition from the skin and adherent panniculus carnosus muscle. [3H]VBL exhibited two phases of elimination: a rapid early phase [half-life (t( 1/2 ) of ~ 30 min] and a prolonged terminal phase (t( 1/2 ) of ~ 17 hr). The application of heat increased the distributive, early phase of 0.5-2.5 hours and did not enhance the terminal elimination of the drug from skin. Intradermal hyalyronidase significantly reduced the area under the ulceration multiplied by the time curve to one-seventh the control value, the peak [3H]VBL skin concentration to one-half the control value and the terminal [3H]VBL t( 1/2 ) in skin to one-third the control level (P<.05 by Student's t-test). These results show hyaluronidase to be an effective antidote for vinca-induced skin ulceration. Local glucocorticosteroids and topical cooling are definitely contraindicated in the management of inadvertent vinca alkaloid extravasation.

Original languageEnglish (US)
Pages (from-to)113-120
Number of pages8
JournalJournal of the National Cancer Institute
Volume74
Issue number1
StatePublished - 1985

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Vinca Alkaloids
Antidotes
Drug-Related Side Effects and Adverse Reactions
Vinblastine
Skin
Vindesine
Vincristine
Vinca
Hyaluronoglucosaminidase
Students
Skin Ulcer
Diphenhydramine
Sodium Bicarbonate
Leucovorin
Antibodies
Poisons
Vitamin A
Isoproterenol
Pharmaceutical Preparations
Heating

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

@article{18ca1dc3117549678d5e5ddd78214ed0,
title = "Vinca alkaloid skin toxicity: Antidote and drug disposition studies in the mouse",
abstract = "A murine (BALB/c) skin toxicity model was used to evaluate various possible antagonists to vinca alkaloid-induced skin ulceration. Reproducible dose-response relationships were developed for vinblastine (VBL) and vindesine (VDS). With vincristine (VCR) only about 70{\%} of mice developed dose-dependent ulceration. On an equal weight basis, VCR proved to be significantly more toxic than either VBL or VDS (P<.05 by Student's t-test). Effective local intradermal antibodies to VBL, VDS, and VCR included hyaluronidase, normal saline, and calcium leucovorin (P<.05 by the Student's Newman-Keuls multiple range test). Mild, topical skin heating significantly reduced VCR ulceration. In contrast, diphenhydramine and sodium bicarbonate were ineffective as local antibodies. Topical skin cooling, however, significantly increased vinca-induced skin ulcers for VBL, VDS, and VCR (P.05). Hydrocortisone, vitamin A topical cream, and isoproterenol increased skin toxicity. [3H]VBL was given intradermally to follow the drug's pharamacokinetic disposition from the skin and adherent panniculus carnosus muscle. [3H]VBL exhibited two phases of elimination: a rapid early phase [half-life (t( 1/2 ) of ~ 30 min] and a prolonged terminal phase (t( 1/2 ) of ~ 17 hr). The application of heat increased the distributive, early phase of 0.5-2.5 hours and did not enhance the terminal elimination of the drug from skin. Intradermal hyalyronidase significantly reduced the area under the ulceration multiplied by the time curve to one-seventh the control value, the peak [3H]VBL skin concentration to one-half the control value and the terminal [3H]VBL t( 1/2 ) in skin to one-third the control level (P<.05 by Student's t-test). These results show hyaluronidase to be an effective antidote for vinca-induced skin ulceration. Local glucocorticosteroids and topical cooling are definitely contraindicated in the management of inadvertent vinca alkaloid extravasation.",
author = "Dorr, {Robert T} and Alberts, {David S}",
year = "1985",
language = "English (US)",
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journal = "Journal of the National Cancer Institute",
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T1 - Vinca alkaloid skin toxicity

T2 - Antidote and drug disposition studies in the mouse

AU - Dorr, Robert T

AU - Alberts, David S

PY - 1985

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N2 - A murine (BALB/c) skin toxicity model was used to evaluate various possible antagonists to vinca alkaloid-induced skin ulceration. Reproducible dose-response relationships were developed for vinblastine (VBL) and vindesine (VDS). With vincristine (VCR) only about 70% of mice developed dose-dependent ulceration. On an equal weight basis, VCR proved to be significantly more toxic than either VBL or VDS (P<.05 by Student's t-test). Effective local intradermal antibodies to VBL, VDS, and VCR included hyaluronidase, normal saline, and calcium leucovorin (P<.05 by the Student's Newman-Keuls multiple range test). Mild, topical skin heating significantly reduced VCR ulceration. In contrast, diphenhydramine and sodium bicarbonate were ineffective as local antibodies. Topical skin cooling, however, significantly increased vinca-induced skin ulcers for VBL, VDS, and VCR (P.05). Hydrocortisone, vitamin A topical cream, and isoproterenol increased skin toxicity. [3H]VBL was given intradermally to follow the drug's pharamacokinetic disposition from the skin and adherent panniculus carnosus muscle. [3H]VBL exhibited two phases of elimination: a rapid early phase [half-life (t( 1/2 ) of ~ 30 min] and a prolonged terminal phase (t( 1/2 ) of ~ 17 hr). The application of heat increased the distributive, early phase of 0.5-2.5 hours and did not enhance the terminal elimination of the drug from skin. Intradermal hyalyronidase significantly reduced the area under the ulceration multiplied by the time curve to one-seventh the control value, the peak [3H]VBL skin concentration to one-half the control value and the terminal [3H]VBL t( 1/2 ) in skin to one-third the control level (P<.05 by Student's t-test). These results show hyaluronidase to be an effective antidote for vinca-induced skin ulceration. Local glucocorticosteroids and topical cooling are definitely contraindicated in the management of inadvertent vinca alkaloid extravasation.

AB - A murine (BALB/c) skin toxicity model was used to evaluate various possible antagonists to vinca alkaloid-induced skin ulceration. Reproducible dose-response relationships were developed for vinblastine (VBL) and vindesine (VDS). With vincristine (VCR) only about 70% of mice developed dose-dependent ulceration. On an equal weight basis, VCR proved to be significantly more toxic than either VBL or VDS (P<.05 by Student's t-test). Effective local intradermal antibodies to VBL, VDS, and VCR included hyaluronidase, normal saline, and calcium leucovorin (P<.05 by the Student's Newman-Keuls multiple range test). Mild, topical skin heating significantly reduced VCR ulceration. In contrast, diphenhydramine and sodium bicarbonate were ineffective as local antibodies. Topical skin cooling, however, significantly increased vinca-induced skin ulcers for VBL, VDS, and VCR (P.05). Hydrocortisone, vitamin A topical cream, and isoproterenol increased skin toxicity. [3H]VBL was given intradermally to follow the drug's pharamacokinetic disposition from the skin and adherent panniculus carnosus muscle. [3H]VBL exhibited two phases of elimination: a rapid early phase [half-life (t( 1/2 ) of ~ 30 min] and a prolonged terminal phase (t( 1/2 ) of ~ 17 hr). The application of heat increased the distributive, early phase of 0.5-2.5 hours and did not enhance the terminal elimination of the drug from skin. Intradermal hyalyronidase significantly reduced the area under the ulceration multiplied by the time curve to one-seventh the control value, the peak [3H]VBL skin concentration to one-half the control value and the terminal [3H]VBL t( 1/2 ) in skin to one-third the control level (P<.05 by Student's t-test). These results show hyaluronidase to be an effective antidote for vinca-induced skin ulceration. Local glucocorticosteroids and topical cooling are definitely contraindicated in the management of inadvertent vinca alkaloid extravasation.

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