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(12) Patent Application Publication (10) Pub. No.: US 2010/0261682 A1 Sirén Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2010/0261682 A1 Sirén Et Al US 2010.0261682A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0261682 A1 Sirén et al. (43) Pub. Date: Oct. 14, 2010 (54) METHOD AND MEANS FOR THE (86). PCT No.: PCT/SE2008/OS 1043 TREATMENT OF CACHEXA S371 (c)(1), (2), (4) Date: Jun. 8, 2010 (75) Inventors: Matti Sirén, Helsingfors (FI): Related U.S. Application Data Pontus Gallen-Kallela-Sirén, Helsingfors (FI) (60) Provisional application No. 60/994,061, filed on Sep. 17, 2007, provisional application No. 61/050,778, filed on May 6, 2008. Correspondence Address: (30) Foreign Application Priority Data PORTER WRIGHT MORRIS & ARTHUR, LLP INTELLECTUAL PROPERTY GROUP Sep. 17, 2007 (SE) .................................... O7O2O76-1 41 SOUTH HIGH STREET, 28TH FLOOR Publication Classification COLUMBUS, OH 43215 (51) Int. Cl. A6II 3/665 (2006.01) (73) Assignee: Bioneris AB A6IP3/00 (2006.01) (52) U.S. Cl. ........................................................ 514/144 (21) Appl. No.: 12/676,173 (57) ABSTRACT The present invention relates to the treatment of cachexia in a mammal by the use of a compound comprising a high density (22) PCT Filed: Sep. 17, 2008 negatively charged domain of vicinally oriented radicals. Patent Application Publication Oct. 14, 2010 Sheet 1 of 28 US 2010/0261682 A1 O) O O) S. S. S. - O O. O. O O O O SF d - LD V V : co D CD 9 L CD E CN H O 5 E -- -- 8 c - d \, CN cp N 19 c. s (6) ebueuoubleM s g O s Patent Application Publication Oct. 14, 2010 Sheet 2 of 28 US 2010/0261682 A1 - r N - CYO a Y O D 9. 9 2 L- -r H CN 5 E 3 - E o o O O. O. O. O. O. O. O. O. O. O. O. O. O. 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CN N V vm Duo O %) AA}oe esed seo Patent Application Publication US 2010/0261682 A1 Patent Application Publication Oct. 14, 2010 Sheet 26 of 28 US 2010/0261682 A1 (6) effueuoubleW Patent Application Publication Oct. 14, 2010 Sheet 27 of 28 US 2010/0261682 A1 r N CY) GN D Ce 4. S D CD CD S LL- H CN —-I-T-I-T-I- O O O O O O CN CN re r (6) peun Suoo pool Patent Application Publication Oct. 14, 2010 Sheet 28 of 28 US 2010/0261682 A1 ve CO cy N es 4. 5 O 9 CN US 2010/0261682 A1 Oct. 14, 2010 METHOD AND MEANS FOR THE the risk of sepsis. A significant percentage of cancer and TREATMENT OF CACHEXA AIDS patients suffer from a severe catabolic condition known as cachexia. The mechanism leading to tissue breakdown is FIELD OF THE INVENTION still unclear, but it has been postulated that the effect of the catabolism is to increase the inter- and intracellular Supply of 0001. The present invention relates to the treatment of amino acids. A number of factors appear to be involved in cachexia and a corresponding means. catabolic conditions, such as altered ratios of anabolic/cata bolic hormones, reduced sensitivity of tissues to anabolic BACKGROUND hormones and endogenous cytokines Such as interleukins. 0002 The breakdown of lean body tissue, cachexia, is a 0007 Physiologic and metabolic changes that usually serious problem that occurs in a number of acute and chroni accompany catabolic conditions are for example increased cal clinical conditions. Side effects of various medical treat proteolysis, altered carbohydrate metabolism, increased fat ments can also lead to cachexia. Trauma, Surgery, burn injury, oxidation, increased whole body protein turnover, anorexia, injury, prolonged fasting, sepsis, prolonged bed rest, cancer impaired immune response, decreased wound healing and and AIDS are examples of catabolic states that can lead to a altered drug pharmacokinetics. The clinical treatment of lean significant loss of lean body tissue and skeletal muscle. Pro body wasting in catabolic illness still focuses primarily on the tein catabolism (cachexia) leads to the acceleration of protein provision of specialized enteral and parenteral nutrition. degradation and an elevation of energy expenditure or hyper However, a number of studies have shown that nutritional catabolism. Further, catabolism is often associated with therapy alone is relatively ineffective at reducing net protein elevated urinary nitrogen excretion which leads to a negative breakdown or stimulating protein synthesis during catabolic nitrogen balance. illness. Thus, there is a need for additional agents directed at 0003. Although cachexia causes the depletion of both adi reversing protein losses and restoring the balance of protein pose and muscle tissue, muscle atrophy is the most important metabolism. prognostic factor in determining the Survival of patients who 0008 Cachexia or Wasting Syndrome is frequently asso Suffer from cachexia. The catabolic response in muscles ciated with terminal cancer, but also with AIDS, Congestive results in muscle tissue wasting and increased fatigue and Heart Failure, Chronic Obstructive Pulmonary Disease, Sep severely influences the quality of life of the patients. The sis, Uremia, Acidosis, Diabetes mellitus and other conditions degree of muscle wasting has also been shown to correlate (Hasselgren P O J Biochem & cell Biol 2156-2168, 2005). with a poor response to overall therapy. Specifically, the Cachexia significantly amplifies the impact of the primary response to chemotherapy is impaired in patients with cancer condition and contributes to the morbidity associated with cachexia (van Eys, Annu Rev Nutr 435-461, 1985). these diseases. Cachexia is common in cancer patients, but 0004. The cachexia related catabolic response in skeletal not all types of tumours produce cachexia. Independent of the muscle is primarily caused by Stimulated protein breakdown tumour disease, the reduction of lean body mass in a cachectic and especially by the breakdown of the myofibrillar protein. patient may be life-threatening, in particular due to the This increased protein breakdown is accompanied by impairment of respiratory muscle function. decreased protein synthesis which contributes to the negative 0009 Cachexia results from the imbalance in protein deg proteinbalance in muscle tissue. radation and protein synthesis. In cachexia patients, protein 0005 Intracellular protein breakdown is regulated by sev synthesis is depressed and protein degradation is increased, eral proteolytic pathways including a) lysomal b) Ca-depen leading to an imbalance in the protein metabolism in the dent and c) ubiquitin-proteasome dependent mechanisms.
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