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Zone Finhibton Inmillimeters US006191168B1 (12) United States Patent (10) Patent N0.: US 6,191,168 B1 Rubenstein (45) Date of Patent: Feb. 20, 2001 (54) METHODS FOR THE USE OF NONPROTEIN CA 126: 268319, Breton et al, 1997.* AMINO ACIDS AS THERAPEUTIC AGENTS Bell. (1958). “Canavanine and Related Compounds in Legu minosae,” Biochem J. 70:617—619. (75) Inventor: Edward Rubenstein, 5 Waverly Pl., Bisby et al. (1994). Phytochemical Dictionary of the Legu Hillsborough, CA (US) 94010 minose, vol. 1—2. (Title page and table of contents only). Butler et al. (1967). “Uptake and Metabolism of Inorganic (73) Assignee: Edward Rubenstein, Hillsborough, CA Forms of Selenium—75 by Spiroa'ela Oligorrhiza, ” Aust. J. (Us) Biol. Sci. 20:77—86. Conn. (1981). “Secondary Plant Products” The Biochemistry (*) Notice: Under 35 U.S.C. 154(b), the term of this of Plants vol. 7(Title page and table of contents only). patent shall be extended for 0 days. CoWie et al. (1957). “Biosynthesis by Escherichia Coli of Active Altered Proteins Containing Selenium Instead of (21) Appl. No.: 09/324,181 Sulfur,” Biochem et Biophysica Acta. 26:252—261. Gennaro ed. (1995). Remington." The Science and Practice Filed: Jun. 1, 1999 (22) The Science and of Pharmacy (Title page and table of Related US. Application Data contents only). (60) Provisional application No. 60/087,746, ?led on Jun. 2, (List continued on neXt page.) 1998. Primary Examiner—Rebecca Cook (51) Int. Cl.7 ................................................. .. A61K 31/195 (74) Attorney, Agent, or Firm—Morrison & Foerster LLP (52) US. Cl. ........................ .. 514/561; 514/210; 514/274; 514/419; 514/423; 514/315; 514/354; 514/538; (57) ABSTRACT 514/562; 514/563; 514/564; 514/565 Provided are compositions comprising nonprotein amino (58) Field of Search ................................... .. 514/210, 564, 514/561, 565, 562, 419, 274, 423, 315, acids and modi?ed amino acids, as Well as methods for the 354, 563, 538 use of nonprotein amino acids and modi?ed amino acids in inhibiting the groWth of infective agents. In one embodiment (56) References Cited the compounds and compositions may be used for treating an infection in a human or animal. For example, infectious U.S. PATENT DOCUMENTS agents include resistant strains of Acinetobacter, Klebsiella, Serratia, Staphylococcus aureus and Streptococcus 3,950,536 * 4/1976 Barer et al. pneumoniae, vancomyocin-resistant enterococci and multi 4,481,219 11/1984 Watkinson . 5,409,898 4/1995 Darveau et al. drug resistant mycobacteria, and other emerging resistant 5,458,876 10/1995 Monticello . organisms. The compounds and methods are useful for 5,650,320 7/1997 Cau?eld et al. treating infections caused by organisms, including viral pathogens, fungi, yeast, helminths or protoZoans. The non OTHER PUBLICATIONS protein amino acids and modi?ed amino acids may be CA 93: 180253, Al Baldavi, 1978.* administered by any route known in the air, such as CA 96: 173962, Smith et al, 1981.* parenterally, orally, by inhalation or topically, and optionally CA 120: 102294, Hodges et al, 1993.* may be administered in a carrier, such as a polymeric carrier. CA 115: 189747, Yu et al, 1991.* CA 122: 29881, Lai et al, 1994.* 16 Claims, 1 Drawing Sheet DOSE/RESPONSE CURVE L-PYROGLUTAMIC ACID/STAPHYLOCOCCUS aureus ZONEOFINHIBITIONINMILLIMETERS . I I I 1 2 3 4 CONCENTRATION IN MOLES US 6,191,168 B1 Page 2 OTHER PUBLICATIONS Rosenthal. (1977). “The Biological Effects and Mode of Action of L—cavanine, AStructural Analogue of L—arginine,” Green et al. (1983). “Enhancement of Human Tumor Cell Killing by L—Canavanine in Combination With y—Radia The Quarterly Review of Biology 52:155—178. tion,” Cancer Res. 43:4180—4182. Rubin. (1997). Scienti?c American Medicine. Scienti?c Hakoda et al. (1992). “Production and Biological Activities American, Inc., NeW York pp. 1—20. of a NeW Antifungal Antibiotic, Tan—950 A,” J. Antibiotics 45 :854—860. Schenk et al. (1991). “[3—(3—IsolaXaZolin— Kruse et al. (1958). “The Competitive Effect of Canavanine 5—On—2—YL)—Alanine From Pisum: Allelopathic Properties on UtiliZation of Arginine in GroWth of Walker Carcinosa and Antimycotic Bioassay,” Phytochemistry 30(2):467—470. rcoma 256 Cells in Vitro,” Cancer Res. 18:279—282. Kydonieus ed. (1992). Treatise on Controlled DrugDelivery Simberkoff. (1994). “Drug—Resistant Pneumococcal Infec Princeton, NeW Jersey. (Title page and table of contents tions in the United States,” JAMA 271:1875—1876. only). Simon. (1997). Scienti?c American Medicine. Scienti?c Lee. (1992). Treatise on Controlled Drug Delivery. Kydo American, Inc., NeW York pp. 7—26. nieus ed., Marcel Dekker, Inc.: NeW York., pp. 155—197. Levy. (1998). “Multidrug Resistance—A Sign of the SWaffar et al. (1994). “Inhibition of the GroWth of Human Times,” NewEng. J. Med. 338:1376—1378. Pancreatic Cancer Cells by the Arginine Antimetabolite March ed. (1985). Advanced Organic Chemistry Wiley—In L—Cavanine,” Cancer Res. 54:6045—6048. sterscience Publication (Title page and table of contents only). Thomas et al. (1986) “GroWth Inhibition of a Rat Colon O’Hanley. (1996) Scienti?c American Medicine. Dale et al. Tumor by L—Canavanine,” Cancer Res. 46:2898—2903. ed., Scienti?c American, Inc., NeW York pp. 4—8. Wallsgrove ed. (1995) AminoAcids and Their Derivatives In Osborne et al. (1994). “The Magical and Medicinal Usage of Higher Plants Cambridge University Press (Title page and Stangeria eriopus in South Africa,” J. Ethno. 43:67—72. table of contents only). Paris et al. (1995). “Unusual Transformation of the 3—HydroXyl—Picolinoyl Residue of Pristinamycin IA,” J. of WeitZman et al. (1996). “Dermatophytes Gross and Micro Antibiotics 48:676—682. scopic,” Dermatol. Clin. 14(1):9—22. Phung—Ba et al. (1995). “Interaction of Pristinamycin IA With P—Glycoprotein in Human Intestinal Epithelial Cells,” Weller. (1998). Scienti?c American Medicine. Scienti?c European J. Pharm. 288:187—192. American, Inc., NeW York pp. 1—18. Robinson ed. (1980). The Organic Constituents of Higher Wink (1997) “Special Nitrogen Metabolism” Plant Bio Plants Amherst, Mass: Corus Press, 1980. (Title page and chemistry Dey et al. ed. Academic Press, pp. 439—486, 1997. table of contents only). Ron et al. (1992). Treatise on Controlled Drug Delivery Woods “Antibacterial Susceptibility Tests, Detection and Kydonieus ed. Marcel Dekker, Inc.: NeW York, pp. 199—224. Disc Diffusion Methods” Manual of Clinical Microbiology Rosenthal et al. ed. (1979). “Naturally Occurring, Toxic 6th Edition Murray et al ed. ASM Press: Washington DC, Nonprotein Amino Acids” Herbivores: Their Interaction pp. 1327—1341, 1995. with Secondary Plant Metabolites Academic Press, pp. 361—363. * cited by examiner U.S. Patent Feb. 20, 2001 US 6,191,168 B1 DOSE/RESPONSE CURVE L-PYROGLUTAMIC AClD/STAPHYLOCOCCUS aureus CONCENTRATION IN MOLES US 6,191,168 B1 1 2 METHODS FOR THE USE OF NONPROTEIN 1991, v. 30(2), pp. 467—470. 2-Amino-3-(2,5-dihydro-5 AMINO ACIDS AS THERAPEUTIC AGENTS oxo-4-isoxaZolyl) propanoic acid has been reported to have antifungal activity against yeast including Candida albicans CROSS REFERENCE TO RELATED in vitro and in vivo in mice, and to have a loW toxicity in APPLICATIONS mice. Hakoda et al., J. Antibiotics, 45:854—860 (1992). While there have been a feW isolated studies of certain This application claims the bene?t of US. Provisional activities of nonprotein amino acids, as Well as studies Patent Application Ser. No. 60/087,746, ?led Jun. 2, 1998, identifying numerous different kinds of nonprotein amino the disclosure of Which is incorporated herein by reference acids in plants, for the most part, nonprotein amino acids, in its entirety. 10 and in particular, methods for treating humans or animals therapeutically With nonprotein amino acids, have remained TECHNICAL FIELD largely unexplored. This invention relates to compositions comprising non The emergence of resistant bacterial organisms poses a protein amino acids, and methods for the use of nonprotein serious problem in infectious diseases, despite the availabil amino acids as anti-infective agents. 15 ity of a large number of agents used for the prevention or treatment of bacterial infections. This is especially true in BACKGROUND ART the hospital environment, in Which outbreaks of highly resistant strains of Acinetobacter, Klebsiella, Serratia, and Plant and animal proteins generally include tWenty “pro Staphylococcus aureus, among many others, pose a constant tein” amino acids: glycine, alanine, valine, leucine, threat. H. Simon, “Antimicrobial chemotherapy,” in Scien isoleucine, lysine, phenylalanine, tryptophan, tyrosine, ti?cAmerican Medicine, Scienti?c American, Inc., Dale and serine, threonine, cysteine, methionine, arginine, asparagine, Federman, Eds., NeW York, 7:XIV:11, June, 1997; and Levy, aspartic acid, glutamine, glutamic acid, histidine, and pro N. Engl. J. Med., 338:1376—1378 (1998). The problem of line. Hundreds of other “nonprotein” amino acids exist in resistance to antimicrobial agents extends to the larger nature. Most of the naturally occurring nonprotein amino 25 community. Penicillin-resistant Streptococcus pneumoniae acids are produced in plants, especially in seeds, in Which are an example. Simberkoff,JA]\/[A, 271:1875—1876 (1994). their concentration may reach very high levels. Wink, M. The inevitability of resistance oWing to microbial mutations “Special Nitrogen Metabolism,” in Plant Biochemistry, Dey, results in the ongoing need for the development of anti P. M. and Harborne, J. B., Eds., Academic Press, San Diego, bacterial therapeutic agents. pp. 439—486, 1997; Bell, Biochem. J., 70:617—619 (1958); 30 Fungal infections remain a serious problem in the man and Rosenthal and Bell, “Naturally Occurring, Toxic Non agement of normal as Well as immunologically impaired protein Amino Acids,” in Herbivores: Their Interaction with hosts. In the United States the principal systemic mycotic Secondary Plant Metabolites, Rosenthal and J anZen, Eds., infections in immunologically competent individuals are Academic Press, NeW York, pp. 361—363, 1979. histoplasmosis, coccidioimycosis and blastomycosis.
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