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Phase I and pharmacokinetic study of D-verapamil and doxorubicin.

The calcium antagonist verapamil (a mixture of D- and L-racemers) is a potent modulator of the multi-drug resistance phenotype in vitro at a concentration of 6 microM. Clinical studies have shown dose-limiting toxicity of hypotension and heart block when plasma levels approach the concentrations act...

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Autores principales: Bissett, D., Kerr, D. J., Cassidy, J., Meredith, P., Traugott, U., Kaye, S. B.
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 1991
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1977847/
https://www.ncbi.nlm.nih.gov/pubmed/1684909
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author Bissett, D.
Kerr, D. J.
Cassidy, J.
Meredith, P.
Traugott, U.
Kaye, S. B.
author_facet Bissett, D.
Kerr, D. J.
Cassidy, J.
Meredith, P.
Traugott, U.
Kaye, S. B.
author_sort Bissett, D.
collection PubMed
description The calcium antagonist verapamil (a mixture of D- and L-racemers) is a potent modulator of the multi-drug resistance phenotype in vitro at a concentration of 6 microM. Clinical studies have shown dose-limiting toxicity of hypotension and heart block when plasma levels approach the concentrations active in vitro. Previous data indicate that the D-isomer is less cardioactive than the L-isomer but they appear to be equipotent in reversing drug resistance in vitro. In an attempt to increase plasma verapamil concentrations, we have treated ten patients (total of 27 courses) with oral D-verapamil (DVPM), 150-300 mg 6 h, and doxorubicin i.v. 70 mg m2 q 3 weeks. Hypotension (supine systolic BP less than 100 mmHg or a fall in systolic BP of greater than 30 mmHg) occurred in 5/6 patients at 1200 mg day DVPM, in 1/5 at 800 mg day, and in 1/5 at 600 mg day. PQ prolongation (greater than 0.23 s) was demonstrated in 2/5 patients at 800 mg day DVPM. Plasma levels of DVPM and its active metabolite norverapamil were measured and, combining these, levels of 3-4 microM were achieved at 1200 mg day DVPM; however this dose is likely to lead to unacceptable toxicity in the outpatient setting. Using an oral outpatient schedule of administration, an appropriate dose of DVPM is 800 mg day. This provides a combined plasma level (for VPM and DVPM) of 2-3 microM. If DVPM is to prove useful as a resistance modulator, it may require to be administered intravenously with careful inpatient monitoring and support.
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spelling pubmed-19778472009-09-10 Phase I and pharmacokinetic study of D-verapamil and doxorubicin. Bissett, D. Kerr, D. J. Cassidy, J. Meredith, P. Traugott, U. Kaye, S. B. Br J Cancer Research Article The calcium antagonist verapamil (a mixture of D- and L-racemers) is a potent modulator of the multi-drug resistance phenotype in vitro at a concentration of 6 microM. Clinical studies have shown dose-limiting toxicity of hypotension and heart block when plasma levels approach the concentrations active in vitro. Previous data indicate that the D-isomer is less cardioactive than the L-isomer but they appear to be equipotent in reversing drug resistance in vitro. In an attempt to increase plasma verapamil concentrations, we have treated ten patients (total of 27 courses) with oral D-verapamil (DVPM), 150-300 mg 6 h, and doxorubicin i.v. 70 mg m2 q 3 weeks. Hypotension (supine systolic BP less than 100 mmHg or a fall in systolic BP of greater than 30 mmHg) occurred in 5/6 patients at 1200 mg day DVPM, in 1/5 at 800 mg day, and in 1/5 at 600 mg day. PQ prolongation (greater than 0.23 s) was demonstrated in 2/5 patients at 800 mg day DVPM. Plasma levels of DVPM and its active metabolite norverapamil were measured and, combining these, levels of 3-4 microM were achieved at 1200 mg day DVPM; however this dose is likely to lead to unacceptable toxicity in the outpatient setting. Using an oral outpatient schedule of administration, an appropriate dose of DVPM is 800 mg day. This provides a combined plasma level (for VPM and DVPM) of 2-3 microM. If DVPM is to prove useful as a resistance modulator, it may require to be administered intravenously with careful inpatient monitoring and support. Nature Publishing Group 1991-12 /pmc/articles/PMC1977847/ /pubmed/1684909 Text en https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.
spellingShingle Research Article
Bissett, D.
Kerr, D. J.
Cassidy, J.
Meredith, P.
Traugott, U.
Kaye, S. B.
Phase I and pharmacokinetic study of D-verapamil and doxorubicin.
title Phase I and pharmacokinetic study of D-verapamil and doxorubicin.
title_full Phase I and pharmacokinetic study of D-verapamil and doxorubicin.
title_fullStr Phase I and pharmacokinetic study of D-verapamil and doxorubicin.
title_full_unstemmed Phase I and pharmacokinetic study of D-verapamil and doxorubicin.
title_short Phase I and pharmacokinetic study of D-verapamil and doxorubicin.
title_sort phase i and pharmacokinetic study of d-verapamil and doxorubicin.
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1977847/
https://www.ncbi.nlm.nih.gov/pubmed/1684909
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