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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Acceleration of tuberculosis treatment by adjunctive therapy with verapamil as an efflux inhibitor
American Journal of Respiratory and Critical Care Medicine, Volume 188, No. 5, Year 2013
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Description
Rationale: A major priority in tuberculosis (TB) is to reduce effective treatment timesandemergenceof resistance. Recent studies in macrophages and zebrafish show that inhibition of mycobacterial efflux pumps with verapamil reduces the bacterial drug tolerance and may enhance drug efficacy. Objectives: Using mice, a mammalian model known to predicthuman treatment responses, and selecting conservative human bioequivalent doses, we tested verapamil as an adjunctive drug together with standard TB chemotherapy. As verapamil is a substrate for CYP3A4, which is induced by rifampin, we evaluated the pharmacokinetic/ pharmacodynamic relationships of verapamil and rifampin coadministration in mice. Methods: Using doses that achieve human bioequivalent levels matched to those of standard verapamil, but lower than those of extended release verapamil, we evaluated the activity of verapamil addedto standardchemotherapy in bothC3HeB/FeJ(whichproduce necrotic granulomas)andthe wild-type backgroundC3H/HeJmouse strains. Relapse rates were assessed after 16, 20, and 24 weeks of treatment in mice. Measurements and Main Results: We determined that a dose adjustment of verapamil by 1.5-fold is required to compensate for concurrent use of rifampin during TB treatment. We found that standard TB chemotherapy plus verapamil accelerates bacterial clearance in C3HeB/FeJ mice with near sterilization, and significantly lowers relapse rates in just 4 months of treatment when compared with mice receiving standard therapy alone. Conclusions: These data demonstrate treatment shortening by verapamil adjunctive therapy in mice, and strongly support further study of verapamil and other efflux pump inhibitors in human TB. Copyright © 2013 by the American Thoracic Society.
Authors & Co-Authors
Gupta, Shashank
United States, Baltimore
Johns Hopkins University
United States, Chevy Chase
Howard Hughes Medical Institute
Tyagi, Sandeep K.
United States, Baltimore
Johns Hopkins University
Almeida, Deepak V.G.
United States, Baltimore
Johns Hopkins University
South Africa, Durban
Africa Health Research Institute
Maiga, Mariama C.
United States, Baltimore
Johns Hopkins University
United States, Chevy Chase
Howard Hughes Medical Institute
Ammerman, Nicole C.
United States, Baltimore
Johns Hopkins University
South Africa, Durban
Africa Health Research Institute
Bishai, William R.
United States, Baltimore
Johns Hopkins University
United States, Chevy Chase
Howard Hughes Medical Institute
South Africa, Durban
Africa Health Research Institute
Statistics
Citations: 153
Authors: 6
Affiliations: 3
Identifiers
Doi:
10.1164/rccm.201304-0650OC
ISSN:
1073449X
Research Areas
Cancer
Infectious Diseases