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PROTECTIVE EFFICACY OF MG-SUPPLEMENTATION AGAINST NRTI-INDUCED CARDIAC TOXICITY

Award Number: R21AT003993
ORGANIZATION: CENTER FOR DRUG EVALUATION AND RESEARCH, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2006
PERIOD OF PERFORMANCE END DATE: 09/29/2008

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PROTECTIVE EFFICACY OF MG-SUPPLEMENTATION AGAINST NRTI-INDUCED CARDIAC TOXICITY - DESCRIPTION (provided by applicant): Zidovudine (AZT) cardiotoxicity in HIV patients has been well documented, but the potential beneficial effect of magnesium (Mg)-supplementation has never be explored. AZT toxicity is linked to increased oxidative stress which may be mediated by abnormal iron status. Since other clinically used nucleoside reverse transcriptase inhibitor (NRTI) drugs are structurally similar to AZT, their potential interaction with endogenous iron may represent a common mechanism of oxidative toxicity. Our in vitro studies suggest that AZT synergizes with iron in causing endothelial cytotoxicity and that supra levels of extracellular magnesium are cytoprotective. This proposal will explore whether dietary supplementation of either Mg oxide (inorganic) or Mg gluconate (an organic salt) will attenuate chronic NRTI-induced systemic inflammation and cardiac injury n vivo, and if the protective mechanism(s) associated with the Mg supplements can be revealed using NRTI- treated in vitro models. The specific aims are: (1) Determine the differential protective effects of upplemental inorganic and organic Mg-salts against AZT (and other NRTIs)-mediated membrane and endothelial cell oxidative injury; (2) Assess if dietary supplementation of Mg-salts (Mg oxide and Mg- gluconate: 3 and 6- fold higher than normal) in the rat attenuates chronic AZT-induced cardiovascular inflammation, oxidative stress, and neutrophil activation; and (3) Determine if Mg-supplementation attenuates AZT-enhanced myocardial susceptibility to imposed ischemia/reperfusion (I/R) stress ex vivo. We will employ immunohistochemical and pathology techniques to localize inflammatory cyokines and white blood cell infiltrates. Oxidative stress in vivo will be determined biochemically by changes in tissue/blood glutathione status, iron status, and lipid peroxidation products (F2-isoprostanes, conjugated dienes). Changes in tolerance to perfused heart l/R-stress will be determined by free radical production (ESR spin trapping), and alterations in oxidative tissue injury markers and functional recovery. This proposed exploratory effort may reveal a potential usefulness of Mg-supplements as an effective, yet relatively inexpensive adjunct therapy to lessen NRTI-related cardiovascular toxicity.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2007 ( Subtotal = $185,704 )
2007	2007	GEORGE WASHINGTON UNIVERSITY	2100 M STREET, NW, SUITE 310	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Research and Training in Complementary and Integrative Health	000	2	8/27/2007	NON-COMPETING CONTINUATION	$185,704
														Subtotal = $185,704

Issue Date FY: 2006 ( Subtotal = $229,500 )
2006	2006	GEORGE WASHINGTON UNIVERSITY	2100 M STREET, NW, SUITE 310	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Research and Training in Complementary and Integrative Health	000	1	9/29/2006	NEW	$229,500
														Subtotal = $229,500

Grand Total All Awards = $415,204

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PROTECTIVE EFFICACY OF MG-SUPPLEMENTATION AGAINST NRTI-INDUCED CARDIAC TOXICITY

Award Number: R21AT003993

ORGANIZATION: CENTER FOR DRUG EVALUATION AND RESEARCH, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/30/2006

PERIOD OF PERFORMANCE END DATE: 09/29/2008

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