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(12) Patent Application Publication (10) Pub. No.: US 2006/0020035 A1 Neu Welt Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2006/0020035 A1 Neu Welt Et Al US 20060020035A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0020035 A1 Neu Welt et al. (43) Pub. Date: Jan. 26, 2006 (54) BONE MARROW PROTECTION WITH Related U.S. Application Data N-ACETYL-L-CYSTEINE (60) Provisional application No. 60/552,425, filed on Mar. (75) Inventors: Edward A. Neuwelt, Portland, OR 11, 2004. (US); Leslie L. Muldoon, Tigard, OR (US) Publication Classification Correspondence Address: (51) Int. Cl. SEED INTELLECTUAL PROPERTY LAW A61K 31/198 (2006.01) GROUP PLLC (52) U.S. Cl. .............................................................. 514/562 701 FIFTHAVE SUTE 6300 (57) ABSTRACT The present invention provides methods for preventing or SEATTLE, WA 98104-7092 (US) ameliorating chemotherapeutic agent-induced bone marrow (73) Assignee: Oregon Health & Science University, toxicity. These methods comprise administering an effective Portland, OR amount of N-acetyl-L-cysteine (L-NAC), alone or in com bination with other agents, to a Subject in need thereof. The (21) Appl. No.: 11/078,013 present invention also provides compositions for preventing or ameliorating chemotherapeutic agent-induced bone mar (22) Filed: Mar. 11, 2005 row toxicity that comprises L-NAC. Patent Application Publication Jan. 26, 2006 Sheet 1 of 7 US 2006/0020035 A1 6 N-Acetylcysteine dose -A-NAC 1200 i.a. (n=3) -O-NAC 1000 i.a. (n=3) 2 -W-NAC 400 i.V. (n=4) -HNAC 140 i.a. (n=2) 6 to 20 30 40 50 60 to 80 go Time (minutes after infusion) FIG. I. Patent Application Publication Jan. 26, 2006 Sheet 3 of 7 US 2006/0020035 A1 g . esses on as so M none STS NAC I's Chemoprotective Agent FIG. 2B Patent Application Publication Jan. 26, 2006 Sheet 4 of 7 US 2006/0020035 A1 120 0.O 6 O 4. O t . 2 O it . t | s . t AA . YYYYY NAC Oe STS NAC + STS Chemoprotective Agent FIG. 2C Patent Application Publication Jan. 26, 2006 Sheet 5 of 7 US 2006/0020035 A1 Patent Application Publication Jan. 26, 2006 Sheet 6 of 7 US 2006/0020035 A1 N 1. Tri-drug 3 O 93.-- NAC- alia +. Tri-drug. XK. K. um 4. NAC+Tri-drugi-STS .X . transa Aasai 4-Yee x 5. Untreated Control e. se 20 as Mean+l.. - s.d., n=8- a per group m m e.g. a a -- . ( : - 0. N nown 23.3: 3 N : , .338 areasual: 2 3 4 5 Treatment Group FIG. 3D Patent Application Publication Jan. 26, 2006 Sheet 7 of 7 US 2006/0020035 A1 Effect of L-NAC and D-NAC On rat blood Counts after chemo pilot data 01-20-04 KXL-NAC $$3$2 ~~~~~~~~~~); -ºººººººººººººººººººººº! HØA HIIII] white cells granulocytes |×××××××××××××××!3 HØ4'platelets FIG. 4 US 2006/0020035 A1 Jan. 26, 2006 BONE MARROW PROTECTION WITH 0010. According to the present invention, L-NAC may be N-ACETYL-L-CYSTEINE administered intravenously, intra-arterially, intra-perito neally, orally, intradermally, Subcutaneously, or transder CROSS-REFERENCE TO RELATED mally. In certain embodiments, the L-NAC is administered APPLICATION intra-arterially, Such as via the descending aorta. 0001) This application claims the benefit under 35 U.S.C. 0011. In certain embodiments, L-NAC is administered S 119(e) of U.S. Provisional Patent Application No. 60/552, prior to the administration of the chemotherapeutic agent or 425, filed Mar. 11, 2004, which this provisional application at least one of the chemotherapeutic agents. In other embodi is incorporated herein by reference in its entirety. ments, L-NAC is administered concurrently with the admin istration of the chemotherapeutic agent or at least one of the STATEMENT OF GOVERNMENT INTEREST chemotherapeutic agents. In certain embodiments, L-NAC is administered following the administration of the chemo 0002 This invention was made with government support therapeutic agent or at least one of the chemotherapeutic under Contract No. NS34608 awarded by National Institutes agents. For instance, L-NAC may be administered at least of Health. The government has certain rights in this inven about 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, tion. 2 hours, 3 hours or 4 hours prior to the administration of the chemotherapeutic agent(s). BACKGROUND OF THE INVENTION 0012. In certain embodiments, L-NAC may be adminis 0003) 1. Field of the Invention tered in conjunction with one or more other thiol-based compounds. In certain embodiments, the thiol-based com 0004. The present invention is directed to a method for pounds have a free radical Scavenging activity. The thiol preventing or ameliorating chemotherapeutic agent-induced based compounds may be Selected from a group consisting bone marrow toxicity. In particular, the invention is directed of Sodium thiosulfate, glutathione ethyl ester, D-methionine, to administering N-acetyl-L-cysteine (L-NAC), alone or in S-adenosyl-methionine, cysteine, N,N'-diacetyl-cysterine, combination with other agents, to prevent or ameliorate Such cyStathione, glutathione, glutathione ethyl ester, glutathione a side effect. diethyl ester, S-(1,2-dicarboxyethyl) glutathione triester, 0005 2. Description of the Related Art cySteamine, cysteine isopropylester, thiol amifostine and combinations thereof. In certain embodiments, the thiol 0006 Chemotherapy causes numerous toxic side effects, based compound or composition is Sodium thiosulfate. including bone marrow toxicity, mucositis, liver and kidney toxicity, and ototoxicity. Bone marrow toxicity can force a 0013 In certain embodiments, the methods of the present dose reduction, reducing chemotherapy efficacy and can also invention further comprise administering an effective cause major morbidity, even death in patients. amount of sodium thiosulfate (STS). STS may be adminis tered intravenously or intra-arterially. It may be adminis 0007 Current treatments to reduce bone marrow side tered prior to, concurrent with, or Subsequent to, the admin effects include recombinant growth factors that are lineage istration of chemotherapeutic agent(s). The dosage of specific. Such growth factors include EPO (erythropoietin) administrating STS may be at least about 1, 2, 3, 4, 5, 6, 7, for red cells and G-CSF (granulocyte colony Stimulating 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 g/m° in factor) or GM-CSF (granulocyte macrophage colony Stimu humans. In addition, multiple doses (e.g., 1, 2, 3, 4, 5, 6, 8, lating factor) for various lineages of white cells. However, or 10) may be used. Such growth factors act to Stimulate lineage specific precur Sor cells to divide and mature down lineage-Specific paths. 0014. The chemotherapeutic agent may be any com Thus, the use of growth factorS results in a more rapid pound that is administered to a mammalian Subject to recovery from bone marrow toxicity but does not generally destroy, or otherwise adversely affect, cancer cells. Such reduce the nadir of toxicity. Such growth factors have been agents may be platinum derivatives, taxanes, Steroid deriva able to allow a patient to tolerate a greater number of tives, anti-metabolites, plant alkaloids, antibiotics, arsenic cytotoxic treatments, but generally not higher doses of the derivatives, intercalating agents, alkylating agents, enzymes, cytotoxic agent administered. biological response modifiers and combinations thereof. In certain embodiments, the chemotherapeutic agents are alky 0008. The present invention meets the need for develop lating agents, Such as platinum-containing alkylating agents. ing more effective bone marrow protection against chemo Exemplary platinum-containing alkylating agents include therapy and further provides other related advantages. cisplatin, carboplatin, oxyplatin, or combinations thereof. In certain embodiments, the chemotherapeutic agents comprise BRIEF SUMMARY OF THE INVENTION melphalan, carboplatin and etoposide phosphate. 0009. The present invention provides methods for pre 0015. A patient in need of prevention or amelioration of venting or ameliorating chemotherapeutic agent-induced chemotherapeutic agent-induced bone marrow toxicity may toxicity, Such as bone marrow toxicity. Such methods com be a human, a non-human primate, or another mammal that prise administering to a patient in need thereof an effective will undergo (or is undergoing) chemotherapy and is at high amount of L-NAC. It was discovered by the present inven risk for (or is Suffering from) chemotherapeutic agent tors that only the L-form, not the D-form of N-acetylcys induced bone marrow toxicity. In certain embodiments, the teine, is effective in ameliorating chemotherapeutic agent patient may Suffer from a tumor in the head or neck (e.g., induced bone marrow toxicity. In certain embodiments, the brain tumor or cancer). In other embodiments, the patient methods of the present invention do not adversely affect the may Suffer from a tumor or cancer located other than head efficacy of the chemotherapeutic agents. or neck. In certain embodiments, the patient receives a blood US 2006/0020035 A1 Jan. 26, 2006 brain barrier disruption procedure. In other embodiments, magnification, 4x. FIG. 3D shows tumor volumes. All the patient does not receive a blood brain barrier disruption treatment groups were significantly different from the procedure. untreated controls; ***, P<0.0001. No significant differ 0016. The dosage of L-NAC useful in preventing or ences were found comparing treatment groups with or ameliorating bone marrow toxicity may be about 200, 300, without chemoprotection. Data are indicated as 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, or meanistandard deviation (n=8/group). 1400 mg/kg in humans. In addition, multiple doses (e.g., 1, 0022 FIG. 4 shows effect of L-NAC and D-NAC on rat 2, 3, 4, 5, 16, 8, 9, 10, etc.) may be used. blood counts after chemotherapy. 0.017. In one embodiments, the methods of the present DETAILED DESCRIPTION OF THE invention comprises (i) administering to a patient in need INVENTION thereof about 1,000 mg/kg to about 1,400 mg/kg of L-NAC about 30 minutes or about 60 minutes prior to the admin 0023 The present invention provides methods for pre istration of chemotherapeutic agent(s) and (ii) administering venting or ameliorating chemotherapeutic agent-induced about 8 to about 20 g/m of STS about 4 hours and/or about bone marrow toxicity (including thrombocytopenia).
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