US00925943OB2 (12) United States Patent (10) Patent No.: US 9.259,430 B2 Rathmacher et al. (45) Date of Patent: *Feb. 16, 2016 (54) NUTRITIONAL INTERVENTION FOR (56) References Cited IMPROVING MUSCULAR FUNCTION AND STRENGTH U.S. PATENT DOCUMENTS 4,992.470 A 2f1991 Nissen (71) Applicant: Metabolic Technologies, Inc., Ames, IA 5,028,440 A 7, 1991 Nissen (US) 5,087.472 A 2f1992 Nissen 5,348,979 A 9, 1994 Nissen et al. 5,360,613 A 11/1994 Nissen (72) Inventors: John Rathmacher, Story City, IA (US); 6,031,000 A 2/2000 Nissen et al. John Fuller, Jr., Zearing, IA (US); 6,103,764 A 8, 2000 Nissen Shawn Baier, Polk City, IA (US); Steve 6,291525 B1 9, 2001 Nissen 8,815,280 B2 * 8/2014 Rathmacher et al. ......... 424/439 Nissen, Ames, IA (US); Naji Abumrad, 2004f0071825 A1 4/2004 Lockwood Nashville, IA (US) 2005/0215640 A1 9, 2005 Baxter et al. 2006, OOO3947 A1 1, 2006 Udell (73) Assignee: Metabolic Technologies, Inc., Ames, IA 2007/0142469 A1 6/2007 Thomas et al. (US) FOREIGN PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 WO 2008024456 A2 2, 2008 U.S.C. 154(b) by 0 days. OTHER PUBLICATIONS This patent is Subject to a terminal dis McCarty et al. (“Toward a Core Nutraceutical Program for Cancer claimer. Management” in Integrative Cancer Therapies 5(2); 2006.* Krebs, H. A. & Lund, P. (1977) Aspects of the regulation of the metabolism of branched-chain amino acids. Advan. Enzyme Regul. (21) Appl. No.: 14/219,522 15:375-394. Harper, A. E., Benevenga, N.J. & Wohlhueter, R. M. (1970) Effects (22) Filed: Mar 19, 2014 of ingestion of disproportionate amounts of amino acids. Physiol. Rev. 53: 428-558. (65) Prior Publication Data Nissen, S. L. & Abumrad, N. N. (1997) Nutritional role of the leucine metabolite beta-hydroxy-beta-methylbutyrate (HMB). J. Nutr. US 2015/OO25047 A1 Jan. 22, 2015 Biochem. 8:300-311. Nissen, S., Sharp, R. Ray, M., Rathmacher, J. A., Rice, J., Fuller, J. C., Jr., Connelly, A. S. & Abumrad, N. N. (1996) The effect of the Related U.S. Application Data leucine metabolite beta-hydroxy beta-methylbutyrate on muscle metabolism during resistance-exercise training. J. Appl. Physiol. (63) Continuation-in-part of application No. 12/634,507, 81(5): 2095-2104. filed on Dec. 9, 2009, now Pat. No. 8,815,280. Nissen, S., Van Koevering, M. & Webb, D. (1990) Analysis of beta hydroxy-beta-methylbutyrate in plasma by gas chromatography and (60) Provisional application No. 61/121,065, filed on Dec. mass spectrometry. Anal. Biochem. 188: 17-19. 9, 2008. Frexes-Steed, M., Warner, M.L., Bulus, N., Flakoll, P. & Abumrad, N. N. (1990) Role of insulin and branched-chain amino acids in regu (51) Int. Cl. lating protein metabolism during fasting. Am. J. Physiol. A 6LX3/59 (2006.01) (Endocrinol. Metab.) 258: E907-E917. A6 IK3I/9 (2006.01) Robinson, W. G. Bachhawat, B.K. & Coon, M.J. (1954) Enzymatic A2.3L I/302 (2006.01) carbon dioxide fixation by senecioyl coenzyme A. Fed. Proc. 13:281. A2.3L I/303 (2006.01) (Continued) A2.3L I/305 (2006.01) Primary Examiner — Blessing MFubara A2.3L I/30 (2006.01) (74) Attorney, Agent, or Firm — Davis Brown Law Firm; A23K L/I6 (2006.01) Emily Harris (52) U.S. Cl. CPC. A61 K3I/59 (2013.01); A23K 1/16 (2013.01); (57) ABSTRACT A23K 1/1603 (2013.01); A23L 1/30 (2013.01); The present invention provides a composition comprising A23L I/302 (2013.01); A23L I/303 (2013.01); HMB and Vitamin D. Methods of administering HMB and A23L I/3051 (2013.01); A61K 31/19 (2013.01); Vitamin D to an animal are also described. Vitamin D and A23 V 2002/00 (2013.01) HMB are administered to increase muscle mass, strength, and (58) Field of Classification Search functionality. The combination of Vitamin D and HMB CPC ........ A61K 3 1/59; A61K 31/19: A23L 1/302: together has a synergistic effect, which results in a Surprising A23L 1/303: A23L 1/3051, A23L 1/30; and unexpected level of improvement in muscle mass, A23K 1/16: A23K 1/1603 strength and functionality. See application file for complete search history. 20 Claims, 8 Drawing Sheets US 9.259,430 B2 Page 2 (56) References Cited Eley, H. L. Russell, S.T., Baxter, J. H. Mukherji, P. & Tisdale, M. J. (2007) Signaling pathways initiated by beta-hydroxy-beta OTHER PUBLICATIONS methylbutyrate to attenuate the depression of protein synthesis in skeletal muscle in response to cachectic stimuli. Am. J. Physiol Rudney, H. & Farkas, T. G. (1955) Biosynthesis of branched chain Endocrinol. Metab 293: E923-E931. acids. Fed. Proc. Sep. 757-759. Smith, H. J., Mukerji, P. & Tisdale, M. J. (2005) Attenuation of Rabinowitz, J. L., Dituri, F. Cobey, F. & Gurin, S. (1955) Branched proteasome-induced proteolysis in skeletal muscle by beta-hydroxy chain acids in the biosynthesis of squalene and cholesterol. Fed. Proc. beta-methylbutyrate in cancer-induced muscle loss. Cancer Res.65: 14: 760-761. 277-283. Coon, M.J. (1955) Enzymatic synthesis ofbranched chain acids from amino acids. Fed. Proc. 14: 762-764. Smith, H. J. Wyke, S. M. & Tisdale, M.J. (2004) Mechanism of the Gey, K. F. Pletsher, A., Isler, O. Ruegg, R. & Wursch, J. (1957) The attenuation of proteolysis-inducing factor stimulated protein degra influence of isoperenic C5 and C6 compounds upon the acetate dation in muscle by beta-hydroxy-beta-methylbutyrate. Cancer Res. incorporation into cholesterol. Helvetica Chim. Acta 40: 2354-2368. 64: 8731-8735. Gey, K. F., Pletsher, A., Isler, O. Ruegg, R. & Wursch, J. (1957) Eley, H. L. Russell, S. T. & Tisdale, M. J. (2008) Mechanism of Influence ofiosoprenoid C5 and C6 compounds on the incorporation Attenuation of Muscle Protein Degradation Induced by Tumor of acetate in cholesterol. Helvetica Chim. Acta 40: 2354-2368. Necrosis Factor Alpha and Angiotensin II by beta-Hydroxy-beta Isler, O. Ruegg, R., Wursch, J., Gey, K. F. & Pletsher, A. (1957) methylbutyrate. Am. J. Physiol Endocrinol. Metab 295: E 1417 Biosynthesis of cholesterol from beta, t-dihydroxy-beta E1426. methylvaleric acid. Helvetica Chim. Acta 40: 2369-2373. Eley, H. L. Russell, S. T. & Tisdale, M. J. (2008) Attenuation of Zabin, I. & Bloch, K. (1951) The utilization of butyric acid for the depression of muscle protein synthesis induced by lipopolysac synthesis of cholesterol and fatty acids. J. Biol. Chem. 192:261-266. charide, tumor necrosis factor and angiotensin II by beta-hydroxy Plaut, G. W. E. & Lardy, H. A. (1951) Enzymatic incorporation of beta-methylbutyrate. Am. J. Physiol Endocrinol. Metab 295: E1409 C14-bicarbonate into acetoacetate in the presence of various Sub E1416. Strates. J. Biol. Chem. 192: 435-445. Nissen, S. L. & Sharp, R. L. (2003) Effect of dietary Supplements on Bloch, K., Clark, L. C. & Haray, I. (1954) Utilization of branched lean mass and strength gains with resistance exercise: a meta-analy chain acids in cholesterol synthesis. J. Biol. Chem. 211: 687-699. sis. J Appl. Physiol 94: 651-659. Rudney, H. (1954) The synthesis of beta-hydroxy-beta Kreider, R., Ferreira, M., Wilson, M. & Almada, A. (1999) Effects of methylglutaric acid in rat liver homogenates. J. Am. Chem. Soc. 76: calcium beta-hydroxy-beta-methylbutyrate (HMB) supplementation 2595. during resistance-training on markers of catabolism, body composi Bachhawat, B. K. Robinson, W. G. & Coon, M. J. (1955) The tion and strength. IntJ Sports Med 20: 503-509. enzymatic cleavage of beta-hydroxy-beta-methylglutaryl coenzyme Gallagher, P. M., Carrithers, J. A., Godard, M. P. Schutze, K. E. & a to aceto-acetate and acetyl coenzyme A. J. Biol. Chem. 216: 727 Trappe, S. W. (2000) beta-Hydroxy-beta-methylbutyrate ingestion, T36. Part II: Effects on hematology, hepatic, and renal function. MedSci McAllan, A. B. & Smith, R. H. (1984) The efficiency of microbial Sports Exerc 32(12): 2116-2119. protein synthesis in the rumen and the degradability offeed nitrogen Nissen, S. Panton, L., Sharp, R. L., Vukovich, M., Trappe, S.W. & between the mouth and abomasum in steers given different diets. Br. Fuller, J. C., Jr. (2000) beta-Hydroxy-beta-methylbutyrate (HMB) J. Nutr. 51: 77-83. Supplementation in humans is safe and may decrease cardiovascular Adamson, L. F. & Greenberg, D. M. (1957) The significance of risk factors. J Nutr 130: 1937-1945. certain carboxylic acids as intermediates in the biosynthesis of cho Rathmacher, J. A., Nissen, S., Panton, L., Clark, R. H., Eubanks, M. lesterol. Biochim. Biophys. Acta 23: 472-479. P. Barber, A. E., D'Olimpio, J. & Abumrad, N. N. (2004) Supple Jowko, E. et al. (2001) Creatine and beta hydroxy-beta mentation with a combination of beta-hydroxy-beta-methylbutyrate methylbutyrate (HMB) additively increases lean body mass and (HMB), arginine, and glutamine is safe and could improve muscle strength during a weight training program. Nutr. 17:558-566. hematological parameters. JPENJ Parenter Enteral Nutr 28: 65-75. Knitter, A. E. et al. (2000) Effects of beta-hyroxy-methylbutyrate on Eubanks May, P. Barber, A., Hourihane, A., D'Olimpio, J. T. & muscle damage following a prolonged run. J. Appl. Physiol. 89(4): Abumrad, N. N. (2002) Reversal of cancer-related wasting using oral 1340-1344. Supplementation with a combination of beta-hydroxy-beta Gallagher, P. M., Carrithers, J. A., Godard, M. P. Schulze, K. E. & methylbutyrate, arginine, and glutamine. Am. J. Surg. 183: 471-479. Trappe, S. W. (2000) beta-Hydroxy-betamethylbutyrate ingestion, Clark, R. H., Feleke, G., Din, M.Yasmin, T. Singh, G. Khan, F. & Part I: Effects on strength and fat free mass. MedSci Sports Exerc Rathmacher, J.