Use of nitrated lipids for treatment of side effects of toxic medical therapies

a technology of toxic medical therapy and nitrate lipids, which is applied in the direction of anhydride/acid/halide active ingredients, biocide, organic chemistry, etc., can solve the problems of increasing glomerular permeability, limited clinical use of cisplatin, and toxicity in normal tissues of both chemotherapy and radiotherapy, so as to reduce side effects

Inactive Publication Date: 2014-01-23
UNIV OF UTAH RES FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0005]In one aspect, methods and medicaments useful in the treatment of the side effects of toxic medical therapies are disclosed herein. The methods comprise administration of at least one nitrated lipid to a subject in need thereof in amounts effective to treat a side effect of a toxic medical therapy. In some embodiments of the present methods, the side effect is reduced relative to the side effect prior to administration of the nitrated fatty acid or ester thereof. The nitrated lipids may be used to prepare medicaments for treating a side effect of a toxic medical therapy.

Problems solved by technology

However, a drawback of both chemotherapy and radiotherapy is the production of toxicity in normal tissues.
For example, the clinical use of cisplatin is limited by its severe side effects, including neurotoxicity, ototoxicity, nausea and vomiting, hair loss, and nephrotoxicity.
Adriamycin is an anthracycline antibiotic and can cause severe side effects, including podocyte foot process effacement, increase glomerular permeability leading to proteinuria, and inflammation via oxygen free radicals.
Like chemotherapy and radiotherapy, the side effects associated with such treatments may limit the use of the treatment.

Method used

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  • Use of nitrated lipids for treatment of side effects of toxic medical therapies
  • Use of nitrated lipids for treatment of side effects of toxic medical therapies
  • Use of nitrated lipids for treatment of side effects of toxic medical therapies

Examples

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Effect test

example 1

Evaluation of the Therapeutic Potential for Using Nitrated Fatty Acid OA-NO2 in Managing Chemotherapy-Related Toxicity

[0054]A single dose of i.p. injection of cisplatin induced renal dysfunction as indicated by the marked rise in plasma BUN (FIG. 1), accompanied by severe renal histological abnormalities characterized by distortion of the overall renal morphology, dilation of renal tubules, and appearance of protein cast (FIG. 2). In a sharp contrast, posttreatment with OA-NO2 markedly attenuated these functional and pathological changes (FIGS. 1-2). Cisplatin treatment induced increases in plasma level of MPO (marker of neutrophil infiltration) (FIG. 3), kidney expression of NADPH oxidase subunits p47phox and gp91phox (major superoxide generating enzyme) (FIG. 4), kidney thiobarbituric acid-reactive substances (TBARS, index of oxidative stress) (FIG. 5), and activity of caspase (index of apoptosis) (FIG. 6A), all of which were attenuated or completely corrected by OA-NO2. In cultur...

example 2

OA-NO2 Attenuates Albuminuria and Renal Dysfunction in Managing Chemotherapy-Related Toxicity

[0063]BALB / c mice were administered vehicle, ADR, or ADR in combination of OA-NO2; OA-NO2 was delivered via osmotic mini-pump 2 days prior to ADR injection. At day 5 after ADR injection, albuminuria was most evident in ADR group (508.89±48.52 μg / 24 h) as compared with control group (33.39±3.50 μg / 24 h), and was attenuated in ADR+OA-NO2 group (342.40±33.26 μg / 24 h). These changes were observed at day 3 and maintained at day 7. At day 7, plasma albumin was significantly reduced in the ADR group (0.28±0.08 g / dl) as compared with control group (1.01±0.15 g / dl) and was significantly restored in ADR+OA-NO2 group, the decrease of plasma albumin levels were significantly attenuated (0.58±0.13 g / dl), as shown in FIG. 8A. Ninety percent of ADR mice had severe ascites at sacrifice contrasting to only 20% of ADR+OA-NO2 mice having mild ascites, as shown in FIG. 8B.

[0064]ADR mice developed severe hyperli...

example 3

OA-NO2 Attenuates Glomerular Injury and Renal Fibrosis in Managing Chemotherapy-Related Toxicity

[0065]To correlate the reduction of albuminuria to glomerular structure, the effect of drug treatments on glomerulosclerosis was assessed by periodic acid-Schiff (PAS) staining. Being consistent with the data on albuminuria, the ADR mice showed marked glomerulosclerosis as evidenced by mesangial expansion and increased accumulation of extracellular matrix (ECM) in the mesangium, as shown in FIG. 8A. A semiquantitative glomerulosclerotic index of kidney sections confirmed the histological data. The ADR mice showed the highest score, and OA-NO2 treatment led to a marked reduction in the index (P<0.05), as shown in FIG. 8B.

[0066]Because podocyte injury is an early and predominant pathologic feature of ADR model, expression of a number of podocyte markers was examined. WT1 is a pivotal transcription factor that is essential for the maintenance of the differentiated features of adult podocytes...

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Abstract

Methods of treating the side effects of a toxic medical therapy using nitrated lipids are disclosed herein. In particular, the methods comprise the use of nitrated fatty acids or esters thereof to treat side effects, including organ system damage, caused by chemotherapy, radiotherapy, and the administration of other toxic agents.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application claims priority from and is a continuation-in-part from U.S. patent application Ser. No. 12 / 996,848, filed Jun. 18, 2009, which claims priority from PCT Application Serial No. PCT / US2009 / 047825, filed Jun. 18, 2009, which claims priority from U.S. Provisional Application Ser. No. 61 / 073,945, filed Jun. 19, 2008, all of which are herein incorporated by reference in their entireties.STATEMENT OF GOVERNMENT RIGHTS[0002]This invention was made with government support under RO-1 HL079453, RO-1 DK 066592, and DK079162 by the National Institutes of Health. The government has certain rights to this invention.BACKGROUND[0003]The present invention relates to methods of treating the side effects of a toxic medical therapy using nitrated lipids. In particular, the methods comprise the use of nitrated fatty acids or esters thereof to treat side effects, including organ system damage, caused by chemotherapy, radiotherapy, and th...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/201
CPCA61K31/201A61K31/231A61K31/704A61K45/06A61K2300/00
Inventor YANG, TIANXIN
Owner UNIV OF UTAH RES FOUND
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