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(12) Patent Application Publication (10) Pub. No.: US 2010/0204446 A1 Forssmann (43) Pub US 20100204446A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0204446 A1 Forssmann (43) Pub. Date: Aug. 12, 2010 (54) USE OF NATRIURETIC PEPTIDES FOR (30) Foreign Application Priority Data TREATING ANGOEDEMA SYNDROMIES Sep. 11, 2007 (EP) .................................. O711 6 164.O (76) Inventor: Wolf-Georg Forssmann, Jan. 8, 2008 (EP) .................................. O810O2.13.1 Wies-Wambach (DE) Publication Classification Correspondence Address: (51) Int. Cl. UACOBSON HOLMAN PLLC C07K 4/58 (2006.01) 400 SEVENTH STREET N.W., SUITE 600 C07K I4/575 (2006.01) WASHINGTON, DC 20004 (US) (52) U.S. Cl. ......................................... 530/324; 530/326 (21) Appl. No.: 12/733,609 (57) ABSTRACT (22) PCT Filed: Sep. 11, 2008 The present invention relates to the use of a natriuretic pep tide, urodilatin, for treating patients suffering from acute drug (86). PCT No.: PCT/EP2008/062O67 induced angioedema, Such as ACE inhibitor related adverse events. Preferably, a composition comprising an effective S371 (c)(1), amount of urodilatin is intravenously administered to the (2), (4) Date: Mar. 11, 2010 patient continuously for 18 hours to 72 hours. Patent Application Publication Aug. 12, 2010 Sheet 1 of 5 US 2010/020444.6 A1 Prostaglandins NO |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| O is3 CAMP CGMP E52 2 Y K - ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Relaxation Figure 1: Patent Application Publication Aug. 12, 2010 Sheet 2 of 5 US 2010/020444.6 A1 Bar -Urodilatin Sal" NS Š e Patent Application Publication Aug. 12, 2010 Sheet 3 of 5 US 2010/020444.6 A1 NPR-Bi-like NPR-A UrOdilatin Figure 3: Patent Application Publication Aug. 12, 2010 Sheet 4 of 5 US 2010/020444.6 A1 NPR-A UrOdilatin MAPK 8-X- Patent Application Publication Aug. 12, 2010 Sheet 5 of 5 US 2010/020444.6 A1 Endothelial Cell Prostaglandins NPR-A Urodilatin & || || Smooth PDE112 Muscle Cell Relaxation Figure 5: US 2010/0204446 A1 Aug. 12, 2010 USE OF NATRURETC PEPTIDES FOR (Schuster et al., Schweiz. Med. Wochenschr, 1999, 129(9): TREATING ANGOEDEMA SYNDROMIES 362-369). This might be due to the fact that ARB inhibits the VEGF-induced vascular hyperpermeability (Sano et al., Arte rioscl. Thromb. Vasc. Biol., 2006, 26:2673-2680) but increase 0001. The present invention relates to the use of a natri the bradykinin-induced angioedema. uretic peptide for the manufacture of a medicament for the 0005 Besides ACE inhibitors and angiotensin II-receptor treatment of angioedema. antagonists there are also reports on other mechanisms for 0002 Natriuretic peptides are a family of related peptides drug-induced angioedema. Among those are cyclooxygenase that regulate salt and water balance in the body. These pep inhibitors, such as Aspirin (COX-1 inhibitor) and rofecoxib tides are originated in different tissues, have slight variations (COX-2), which are known to induce asthma, urticaria and in their amino acid sequence and in their capability to induce angioedema. The aspirin-induced angioedema is an aspirin natriuresis and diuresis in the kidney. 4 members are known in related hyperSensitivity that is often associated with aspirin the human body: atrial natriuretic peptide (ANP), brain natri intolerant asthma, which causes chronic overproduction of uretic peptide (BNP), C-type natriuretic peptide (CNP), and cysteinyl leukotrienes. Ketoprofen, another non-opiod anal urodilatin (URO, or ularitide). While ANP and BNP are dis getic, inhibits prostaglandins and thus, the production of tributed in the heart and brain, CNP is released from the brain cyclooxygenase, is also known for inducing life-threatening and endothelial cells and urodilatin from the kidney. These asthma, urticaria and angioedema (Kim et al., Curr. Opin. peptides are part of a hormonal system that keeps a fine Allergy Clin. Immunol., 2006, 6(4):266-270; Marshall, Ann. balance of water and blood volume and pressure in the body. Pharmacother, 2005, 39(5):944-908; Grzelewska-RZy Urodilatin, secreted directly by kidney cells, is one of the mowska et al., Allergol. Immunopathol. (Madrid), 1988, hormones responsible for the inhibition of water and Na'- 16(5):305-308; Higashi et al., Allergy Clin. Immunol., 2002, reabsorption in the kidney's collecting duct. Urodilatin is also 110(4):666-667: Asero, Ann. Allergy Asthma Immunol., known for its heart protective abilities and has been studied 2006, 97(2):187-189: Frith et al., Lancet, 1978, 14(2):847 for the use in treatment of renal failure and congestive heart 888). failure (U.S. Pat. No. 5,571,789; U.S. Pat. No. 6,831,064; 0006. Hereditary and acquired angioedemas can also Elsner et al., Am. Heart J. 1995, 129(4):766-773; Forssmann result from a deficiency of the first complement component et al., Clinical Pharmacology and Therapeutics 1998, 64(3): (C1)- or plasma protease inhibitor. The most obvious role of 322-330); Kentsch et al., Eur: J. Clin. Invest. 1992, 22(10): the C1-Inhibitor is the prevention of excessive vascular per 662-669; Kentschet al., Eur: J. Clin. Invest. 1995, 25(4):281 meability where bradykinin is a key player. The lack of this 283). enzyme leads to recurrent Subcutaneous and Submucosal 0003 Besides natriuretic peptides ACE inhibitors and angioedema. Acquired C1-esterase inhibitor deficiency has angiotensin II-receptor blockers are used as therapeutic drugs been observed in association with lymphoproliferative disor in patients with hypertension and congestive heart failure. But ders, malignancy, autoimmune diseases and infections an often under-recognized side effect of ACE inhibitors as (Davis, Immunol. Allergy Clin. North Am..., 2006, 26(4):633 well as angiotensin II receptor antagonists is the development 651; Agostoni and Cicardi, Medicine (Baltimore), 1992, of angioedema. This is a particularly important side effect to 71(4):206-215; Longhurst et al., Clin. Exp. Immunol., 2006, realize since it can be life threatening if not treated properly. 147:11-17). The term angioedema is used to describe an abrupt and short 0007 Angioedema is an underestimated clinical problem, lived Swelling of the skin, mucuoS membranes including since many cases are nonallergic reactions such as bradyki upper respiratory and oropharyngeal areas. Although it can nin-induced angioedema caused either by genetic defects or occur in any part of the body, it most frequently involves the by ACE-inhibitors. Some angioedema which manifest in the head, neck, lips, mouth, tongue, larynx, pharynx, and Sub larynx are life threatening. The vast majority of angioedema glottal areas and rarely accompanied with urticaria. It has are caused by ACE-inhibitors blocking the renin-angiotensin been demonstrated that bradykinin levels were 12-fold aldosterone system (RAAS). So far ACE inhibitors and increased during acute angioedema attacks (heredetary or angiotensin II antagonists are the drugs of choice for patients acquired). ACE-Inhibitors extend the vasodilating effect of associated with cardiovascular diseases, which constitute the bradykinin due to the inhibition of its breakdown (Flattery leading cause of death in the United States regardless of and Sica, Prog. Cardiovasc. Nurs. 2007. 22(1):47-51; Sica, J. gender or ethnicity. Among these diseases, congestive heart Clin. Hypertens. 2004, 6(7):410-416: Campbell, Hyperten failure (CHF) is of particularly high prevalence. This life Sion, 2003, 41:383-389; Hedner et al., Br: Med. J., 1992, threatening condition is accompanied by great financial 304:941-946; Cupido and Rayner, S. Aft: Med. J. 2007,97(4): impact. So far, ACE inhibitors and angiotensin II-antagonists 244-245). have been used to counteract this threat more or less Success 0004. The Swiss Drug Monitoring Center (SANZ) fully. Both groups of inhibitors are known to induce yet reported on 98 cases of drug-induced angioedema, 94 cases of another threat, angioedema, ACE inhibitors more than AII ACE inhibitor-induced and 4 cases of angiotension II-recep antagonists. Angioedema can lead to rapid Swelling of the tor antagonist-induced angioedema. 28 of these cases were skin, mucosa and Submucosal tissue and becomes life-threat classified severe and in three patients even intubation was ening whenever airway obstruction and Suffocation occurs. required. The occurrence of angioedema varied from a few 0008 Thus, there is a new strong need for providing new days to several months. In one case a latency of 8 years was and more effective methods for treating heart failure without recorded, demonstrating that this kind of adverse drug reac the negative side effects of angioedema. tion is actually hard to be detected. During the administration 0009. This problem is solved by the natriuretic peptides of of ACE-inhibitors edema could recur for up to 20 times. this invention. Angiotensin II receptorantagonists (ARB) are also capable of 0010. Therefore, it is one object of this invention to pro introducing angioedema, but the course is usually milder vide a natriuretic peptide, in particular Urodilatin, for the US 2010/0204446 A1 Aug. 12, 2010 manufacture of a medicament for the treatment of 0017. In another aspect of the invention, said medicament angioedema. The present invention represents a novel inven further comprises mannitol, in particular 3 to 10% or 4 to 8% tive procedure for treating angioedema in patients suffering of mannitol respective to the final infusion solution. from this syndrome of different etiologies. This method is 0018. In one embodiment of the invention said medica Substantiated by intravenously
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