Administration of a thiol-based chemoprotectant compound

a thiol-based chemoprotectant and compound technology, applied in the direction of antinoxious agents, drug compositions, peptide/protein ingredients, etc., can solve the problem of dose limitation of cytotoxic agents

Inactive Publication Date: 2006-08-10
OREGON HEALTH & SCI UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0022] The present invention provides a method and compound for locally administering a thiol based chemoprotectant to treat or mitigate the side effects of cytotoxic cancer therapy for brain tumors located in the head or neck. Further, the present invention provides a method and compound for locally administering a thiol-based chemoprotectant to an organ or tissue to protect against injury from diagnostic or therapeutic intra-arterial procedures. The method includes administering a thiol-based chemoprotectant agent intra-arterially in conjunction with, before, or after administration of a cytotoxic agent.
[0032] Further, one advantage of NAC is that it is protective against multiple intra-arterial procedure toxicities, including but not limited to those caused by radiographic contrast agents.

Problems solved by technology

The cytotoxic agent is dose-limited due to myelosuppressive effects systemically.

Method used

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  • Administration of a thiol-based chemoprotectant compound
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  • Administration of a thiol-based chemoprotectant compound

Examples

Experimental program
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Effect test

example 1

[0064] This example shows the results of an in vivo experiment in rats having a catheter implanted in the descending aorta for NAC administration. The rats were set up for drug administration by pushing a catheter forward past the junction of the external and internal carotid arteries (toward the aorta), and temporarily sealing off the internal carotid for good measure so nothing goes to the brain (left carotid aortic infusion method). In patients where entry is via the femoral artery and the catheter is threaded through the aorta to get to the brain in the first place, one would just pull the catheter back to the aorta to do the NAC infusion.

[0065] Rats were treated with carboplatin (200 mg / m2), melphalan (10 mg / m2 ) and etoposide phosphate (100 mg / m2). In the NAC animals, NAC was infused with the left carotid aortic infusion method immediately after the chemotherapeutic agents, at concentrations ranging from 400-1200 mg / m2. White blood cells (wbc) and platelets (plt) were counted...

example 2

[0069] This example shows the results of NAC delivery by different means of catheter-based administration. In this experiment, radiolabeled NAC was administered to rats by three different routes. Liver and kidney tissue, in addition to the ipsilateral and contralateral hemispheres of the brain, were analyzed for radioactivity. Results are shown as the percent of the injected radioactive dose per gram of tissue. Route indicates intravenous (i.v.), intra-arterial into the right carotid artery (i.a.), or left carotid with internal artery occlusion and aortic infusion (left carotid aortic infusion). The left carotid aortic infusion intra-arterial method uses descending aorta placement of the catheter tip and NAC administration.

routeleft hemright hemliverkidneynumberi.v.0.020.030.590.722i.a.0.030.410.570.703Left carotid0.040.040.291.422aortic infusion

[0070] These data show that i.a. delivery provided much brain delivery in the infused hemisphere. When the NAC was administered i.v., neg...

example 3

[0071] This example tested whether the inventive method for intra-arterial infusion (via the left carotid artery, with left internal artery occlusion) could reduce brain delivery of NAC and increase systemic delivery. Brain delivery was 0.04 % of the injected dose with the inventive method (n=2).

[0072] In conjunction with other pharmacological and physiological data, these results show that NAC is protective when N-acetylcysteine is administered prior to, (preferably 30 minutes prior to), the cytotoxic agent at a dose which provides a serum concentration of NAC of between 0.5 mM to 15.0 mM, preferably 5 mM to 12.5 mM. Generally, a dose of between 40.0 mg / kg to 1000 mg / Kg of N-acetylcysteine will provide an appropriate serum concentration in humans and other mammals.

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Abstract

A method of administration of a thiol-based chemoprotectant agent including NAC (N-acetylcysteine) and STS (sodium thiosulfate) that markedly affects biodistribution and protects against injury from diagnostic or therapeutic intra-arterial procedures. A method for treating or mitigating the side effects of cytotoxic cancer therapy for tumors located in the head or neck and brain tumors. The thiol-based chemoprotectant agent is administered intra-arterially with rapid and first pass uptake in organs and tissues other than the liver.

Description

RELATED APPLICATIONS [0001] The present application is a continuation of U.S. patent application Ser. No. 10 / 257,879 filed on May 16, 2003, which claims priority to PCT / USO1 / 040624 having an international filing date of Apr. 26, 2001, which claims the benefit of the filing dates under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 60 / 199,936 filed on Apr. 26, 2000 and U.S. Provisional Application No. 60 / 229,870 filed on Aug. 30, 2000, which are hereby incorporated by reference.FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT [0002] The present invention was partially supported under NIH grant No. NS 33618 and by The Department of Veterans Affairs merit review grant. The United States Government may have certain rights in this invention.BACKGROUND OF THE INVENTION [0003] The present invention is based, in part, upon the discovery that a method of administration of N-acetylcysteine (NAC) markedly affects its effective biodistribution. The present invention provides a method for tre...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/05A61K31/198A61K33/04A61K9/08A61K31/095A61K31/195A61K31/337A61K31/661A61K33/243A61K38/06A61K45/00A61K47/06A61P35/00A61P43/00
CPCA61K9/08A61K31/195A61K31/198A61K31/661A61K38/063A61K2300/00Y10S514/922A61K33/04A61K31/282A61P35/00A61P39/00A61P43/00A61K33/243A61K31/095A61K9/0019
Inventor NEUWELT, EDWARD A.MULDOON, LESLIEPAGEL, MICHAEL A.
Owner OREGON HEALTH & SCI UNIV
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