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(11) EP 2 185 183 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 38/22 (2006.01) C07K 14/47 (2006.01) 16.03.2016 Bulletin 2016/11 A61F 13/00 (2006.01) A61P 43/00 (2006.01)

(21) Application number: 08804032.4 (86) International application number: PCT/EP2008/062067 (22) Date of filing: 11.09.2008 (87) International publication number: WO 2009/034134 (19.03.2009 Gazette 2009/12)

(54) USE OF NATRIURETIC FOR TREATING ANGIOEDEMA SYNDROMES VERWENDUNG VON NATRIURETISCHEN PEPTIDEN ZUR BEHANDLUNG VON ANGIOÖDEMEN UTILISATION DE PEPTIDES NATRIURÉTIQUES POUR LE TRAITEMENT DES SYNDROMES DE L’OEDÈME DE QUINCKE

(84) Designated Contracting States: (74) Representative: von Kreisler Selting Werner - AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Partnerschaft HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT von Patentanwälten und Rechtsanwälten mbB RO SE SI SK TR Deichmannhaus am Dom Bahnhofsvorplatz 1 (30) Priority: 11.09.2007 EP 07116164 50667 Köln (DE) 08.01.2008 EP 08100213 (56) References cited: (43) Date of publication of application: EP-A- 0 369 474 WO-A-2004/022579 19.05.2010 Bulletin 2010/20 WO-A-2006/110743 WO-A1-88/06596

(73) Proprietor: CardioPep Pharma GmbH Remarks: 30625 Hannover (DE) Thefile contains technical information submitted after the application was filed and not included in this (72) Inventor: FORSSMANN, Wolf-Georg specification 79697 Wies-Wambach (DE)

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 185 183 B1

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Description intubation was required. The occurrence of angioedema varied from a few days to several months. In one case a [0001] The present invention relates to the use of latency of 8 years was recorded, demonstrating that this urodilatin for the manufacture of a medicament for the kind of adverse drug reaction is actually hard to be de- treatment of angioedema. 5 tected. During the administration of ACE-inhibitors ede- [0002] Natriuretic peptides are a family of related pep- ma could recur for up to 20 times. Angiotensin II receptor tides that regulate salt and water balance in the body. antagonists (ARB) are also capable of introducing an- These peptides are originated in different tissues, have gioedema, but the course is usually milder (Schuster et slight variations in their sequence and in their al., Schweiz. Med. Wochenschr., 1999, 129(9):362-369). capability to induce natriuresis and diuresis in the . 10 This might be due to the fact that ARB inhibits the VEGF- 4 members are known in the human body: atrial natriu- induced vascular hyperpermeability (Sano et al., Arteri- retic (ANP), brain (BNP), C- oscl. Thromb. Vasc. Biol., 2006, 26:2673-2680) but in- type natriuretic peptide (CNP), and urodilatin (URO, or crease the -induced angioedema. ularitide). While ANP and BNP are distributed in the heart [0005] Besides ACE inhibitors and angiotensin II-re- and brain, CNP is released from the brain and endothelial 15 ceptor antagonists there are also reports on other mech- cells and urodilatin from the kidney. These peptides are anisms for drug-induced angioedema. Among those are part of a hormonal system that keeps a fine balance of cyclooxygenase inhibitors, such as Aspirin (COX-1 in- water and blood volume and pressure in the body. Urodil- hibitor) and rofecoxib (COX-2), which are known to in- atin, secreted directly by kidney cells, is one of the hor- duce asthma, urticaria and angioedema. The aspirin-in- mones responsible for the inhibition of water and Na +-re- 20 duced angioedema is an aspirin-related hypersensitivity absorption in the kidney’s collecting duct. Urodilatin is that is often associated with aspirin-intolerant asthma, also known for its heart protective abilities and has been which causes chronic overproduction of cysteinyl leuko- studied for the use in treatment of renal failure and con- trienes. Ketoprofen,another non-opiodanalgetic, inhibits gestive heart failure (US 5,571,789; US 6,831,064; Elsn- prostaglandins and thus, the production of cyclooxyge- er et al., Am. Heart J. 1995, 129(4):766-773; Forssmann 25 nase, is also known for inducing life-threatening asthma, et al., Clinical Pharmacology and Therapeutics 1998, urticaria and angioedema (Kim et al., Curr. Opin. Allergy 64(3):322-330); Kentsch et al., Eur. J. Clin. Invest. 1992, Clin. Immunol., 2006, 6(4):266-270; Marshall, Ann. Phar- 22(10):662-669; Kentsch et al., Eur. J. Clin. Invest. 1995, macother., 2005,39(5):944-908; Grzelewska-Rzymows- 25(4):281-283). ka et al., Allergol. Immunopathol. (Madrid), 1988, [0003] Besides natriuretic peptides ACE inhibitors and 30 16(5):305-308; Higashi et al., Allergy Clin. Immunol., angiotensin II-receptor blockers are used as therapeutic 2002, 110(4):666-667; Asero, Ann. Allergy Asthma Im- drugs in patients with hypertension and congestive heart munol., 2006, 37(2):187-189; Frith et al., Lancet, 1978, failure. But an often under-recognized side effect of ACE 14(2):847-888). inhibitors as well as angiotensin II receptor antagonists [0006] Hereditary and acquired angioedemas can also is the development of angioedema. This is a particularly 35 result from a deficiency of the first complement compo- important side effect to realize since it can be life threat- nent (C1)- or plasma inhibitor. The most obvi- ening if not treated properly. The term angioedema is ous role of the C1-Inhibitor is the prevention of excessive used to describe an abrupt and short lived swelling of the vascular permeability where bradykinin is a key player. skin, mucuos membranes including upper respiratory The lack of this leads to recurrent subcutaneous and oropharyngeal areas. Although it can occur in any 40 and submucosal angioedema. Acquired C1-esterase in- part of the body, it most frequently involves the head, hibitor deficiency has been observed in association with neck, lips, mouth, tongue, larynx, pharynx, and subglottal lymphoproliferative, disorders, malignancy, autoimmune areas and rarely accompanied with urticaria. It has been diseases and infections (Davis, Immunol. Allergy Clin. demonstrated that bradykinin levels were 12-fold in- North Am., 2006, 26(4):633-651; Agostoni and Cicardi, creased during acute angioedema attacks (heredetary 45 Medicine (Baltimore), 1992, 71(4):206-215; Longhurst et or acquired). ACE-Inhibitors extend the vasodilating ef- al., Clin. Exp. Immunol., 2006, 147:11-17). fect of bradykinin due to the inhibition of its breakdown [0007] WO8806596 A1 discloses the use of a fragment (Flattery and Sica, Prog. Cardiovasc. Nurs. 2007, of the natriuretic peptide urodilatin for the preparation of 22(1):47-51; Sica, J. Clin. Hypertens. 2004,medicaments for treating generalised edema, lung ede- 6(7):410-416; Campbell, Hypertension, 50 2003,ma, brain edema, primary and secondary lymphinter alia 41:383-389; Hedner et al., Br. Med. J., 1992,generalised edema, lung edema, brain edema, primary 304:941-946; Cupido and Rayner, S. Afr. Med. J, 2007, and secondary lymph edema. 97(4):244-245). [0008] Angioedema is an underestimated clinical prob- [0004] The Swiss Drug Monitoring Center (SANZ) re- lem, since many cases are nonallergic reactions such as ported on 98 cases of drug-induced angioedema, 94 cas- 55 bradykinin-induced angioedema caused either by genet- es of ACE inhibitor-induced and 4 cases of angiotension ic defects or by ACE-inhibitors. Some angioedema which II-receptor antagonist-induced angioedema. 28 of these manifest in the larynx are life threatening. The vast ma- cases were classified severe and in three patients even jority of angioedema are caused by ACE-inhibitors block-

2 3 EP 2 185 183 B1 4 ing the renin-arigiotensin-aldosterone system (RAAS). induced angioedema. So far ACE inhibitors and angiotensin II antagonists are [0013] Natriuretic peptides, such as Urodilatin, are fur- the drugs of choice for patients associated with cardio- ther effective in treating heart failure patients. A new vascular diseases, which constitute the leading cause of method for administering urodilatin that is surprisingly death in the United States regardless of gender or eth- 5 effective for the purpose of treating angioedema is one nicity. Among these diseases, congestive heart failure further embodiment of the present invention. (CHF) is of particularly high prevalence. This life-threat- [0014] As used herein, the term "angioedema" encom- ening condition is accompanied by great financial impact. passes all types of cardiovascular conditions that, re- So far, ACE inhibitors and angiotensin II-antagonists gardless of their cause, are generally recognized by a have been used to counteract this threat more or less 10 physician as angioedema, which includes but are not lim- successfully. Both groups of inhibitors are known to in- ited to hereditary angioedema, acquired angioedema, duce yet another threat, angioedema, ACE inhibitors and particularly drug-induced angioedema. These con- more than AII-antagonists. Angioedema can lead to rapid ditions typically involve weakened heart function com- swelling of the skin, mucosa and submucosal tissue and bined with a build-up of body fluid resulting in abrupt and becomes life-threatening whenever airway obstruction 15 short lived swelling of the skin, mucuos membranes in- and suffocation occurs. cluding upper respiratory and oropharyngeal areas. Al- [0009] Thus, there is a new strong need for providing though it can occur in any part of the body, it most fre- new and more effective methods for treating heart failure quently involves the head, neck, lips, mouth, tongue, lar- without the negative side effects of angioedema. ynx, pharynx, and subglottal areas and rarely accompa- [0010] This problem is solved by the urodilatin of this 20 nied with urticaria. invention. [0015] The natriuretic peptide of the invention is urodil- [0011] Therefore, it is one object of this invention to atin. provide, Urodilatin for the manufacture of a medicament [0016] In one particular embodiment of the invention for the treatment of angioedema. The present invention urodilatin is further used for the manufacture of a medi- represents a novel inventive procedure for treating an- 25 cament for the simultaneous treatment of heart failure gioedema in patients suffering from this syndrome of dif- and angioedema. ferent etiologies. This method is substantiated by intra- [0017] In one additional aspect, said medicament is venously applying an adequately effective concentration administered intravenously at the rate of at least 7.5 of urodilatin (ularitide) to acutely appearing oedema. The ng/kg/min and up to a maximal rate of 60 ng/kg/min. infusion may be continous for at least 24 hours. The treat- 30 [0018] In another aspect of the invention, said medi- ment method also implies that an initial bolus infusion of cament further comprises mannitol, in particular 3 to 10% urodilatin may be used in special cases, when the risk of or 4 to 8 % of mannitol respective to the final infusion potential impairment of kidney function is relatively low solution. compared to the expected benefit. [0019] In one embodiment of the invention said medi- [0012] Thus Urodilatin may exceptionally been given 35 cament further comprises NaCl, in particular 0.9 % of to angioedema patients by a high dose intravenous bolus NaCl respective to the final infusion solution. Further, the application or a short-lasting high dose infusion for one final infusion solution can be reconstituted with other hour then followed by an intravenous dose infusion of aqueous inactive ingredients used in standard medical moderate concentration only in deleterious cases of syn- praxis. drome. Urodilatin application induces strong and 40 [0020] In another embodiment, the medicament is ad- natriuretic effects in acute renal failure models and dis- ministered for a time period of at least 24 hours, or of 18 plays beneficial hemodynamic effects resulting in a vol- to 24 hours, or 24 to 72 hours, or for more than 72 hours. ume redistribution favorable in angioedema whereby a [0021] In a particular aspect, urodilatin is further used withdrawal of fluid from interstitial tissues is observed. for the manufacture of a medicament for the treatment As a vasodilator that relaxes both arterial and venous 45 of drug-induced angioedema provoked by inhibitors of blood vessels it reduces the pre- and after load of the angiotensin converting enzyme. Toxic substances in- heart. Together with its diuretic capability it counteracts gested in nutrition and others can also induce the drug- existing edema as well as the regeneration of edema. induced angioedema. Furthermore, as a bronchodilator it also improves bron- [0022] In order to understand the possible mechanism chial asthma and other obstructive pulmonary diseases 50 by which urodilatin prevents and reduces angioedema, often accompanied with angioedema. Responsible for one has to understand the various signal pathways of the drug-induced angioedema are the up regulation of bradykinin, which is the main responsible factor for he- B1- and B2-receptors and thus, the prolonged bradykinin reditary and acquired angioedema. Bradykinin acts response. The bradykinin effect responsible for the gen- through two different forms of receptors, B1R and B2R, eration of edema is tyrosine kinase mediated. Urodilatin 55 which both coupleto similar signal transduction pathways shows counter-regulatory effects towards bradykinin in but differ in terms of variation of Ca 2+ concentration. B1R bronchi and inhibits the tyrosine kinase activated path- is mainly associated with PLC activation and the phos- way by bradykinin explaining its positive effect on ACE- phoinositol pathway but can also act through PLA2 and

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MAP kinase pathways. The activated Ca2+ pathways in [0025] While the B2R pathway is responsible for the endothelial cells lead to activation of prostaglandins and antihypertensive, antihypertrophic and antiproliferative to a rise in cAMP levels in smooth muscle cells. Further- effects of ACE-inhibitors and the formation of hereditary more, eNOS is activated and releases NO which increas- angioedema, the B1R signaling pathway seems to be es cGMP levels in smooth muscle cells. Both processes 5 mainly responsible for inflammatory reactions, asthma are responsible for the relaxation of smooth muscle cells and allergy, sepsis, brain edema and drug-induced an- (see figure 1). While B2R can be desensitized by phos- gioedema. phorylation of specific serine and tyrosine residues in the C-terminal domain, B1R lacks any of these residues and Figure 1: Schematic representation of the signaling cannot be down regulated except for endocytosis proc- 10 pathways of bradykinin through the receptor types esses. In the hereditary angioedema (HAE) the C1-In- B1R and B2R. ER: endothelial reticulum; PLC: phos- hibitor is either not functional or not present at all leading pholipase C; DAG: diacylglycerol; IP 3: inositol 1,4,5- to a continuous release of bradykinin and an increased triphosphate; PLA2: phospholipase A 2; NO: nitric ox- vascular permeability. Inhibition of B2R by specific an- ide; eNOS: endothelial NO synthase. tagonists such as HOE-140, reveres the increased per- 15 meability. In the acquired form of angioedema the natural Figure 2: Urodilatin acts as a receptor antagonist breakdown of bradykinin is prevented, e.g. by ACE-in- for B1R and blocks downstream signaling. hibitors since the angiotensin 1 converting enzyme among other things inactivates bradykinin. While a B2R Figure 3: Urodilatin desensitizes the B2R bradykinin antagonist is effective in the HAE, it is less effective in 20 receptor and blocks downstream signaling through the acquired form of angioedema and other bradykinin- a) the NPR-A receptor and activation of a cGMP- related forms of edema. In vivo studies demonstrated dependent protein kinase (PKG) and subsequent that the up regulation of B1R led to the release of cy- phosphorylation of a serine residue of the B2R; b) a tokines, activation of PKC and tyrosine kinase pathways NPR-Bi-like receptor which acts as a tyrosine kinase including MAP kinase and NFκB, and subsequently to 25 and phosphorylates a tyrosine residue on the B2R. the formation of edema. Quite recently it could be shown In both cases the receptor is inactive for further that bradykinin and substance P-induced edema in the bradykinin binding. hamster cheek pouch is tyrosine kinase dependent and the bradykinin-mediated effect could be attenuated using Figure 4: Urodilatin blocks downstream signaling of the unspecific tyrosine kinase inhibitors genistein and tyr- 30 the B1R bradykinin receptor through binding to the phostin 25. NPR-A receptor and activation of a cGMP-depend- [0023] CNP, amember of the natriuretic peptidefamily, ent protein kinase (PKG) which activates a MAPK does not only use the familiar cGMP signaling pathway phosphatase (MAPKP) and subsequently inhibits but can also bind to a receptor that lacks guanylate cy- the MAPK signaling pathway. clase activity but acts as a tyrosine kinase, named NPR- 35 Bi. The human embryonic kidney cell line HEK-293 dis- Figure 5: Urodilatin blocks downstream signaling of plays many features of the late tubule of the kidney and bradykinin through binding to the NPR-A receptor have the ability of releasing urodilatin. In these cells it and activation of cGMP-dependent protein phos- was shown that ANP/urodilatin is able to counteract ty- phatases (PDE1/2) which deactivate cAMP and pre- rosine phosphorylation via activation of a cGMP-depend- 40 vent smooth muscle relaxation. ent pathway. [0024] This leaves several possibilities how urodilatin can interact with the bradykinin signaling pathway in an Claims inhibitory fashion: 1) Urodilatin could be a direct B1R re- ceptor antagonist. 2) Urodilatin can desensitize B2R45 1. Use of urodilatin for the manufacture of a medica- through phosphorylation by a cGMP-dependent protein ment for the treatment of angioedema. kinase (PKG) at the specific serine residue or through tyrosine phosphorylation at the according tyrosine resi- 2. The use according to claim 1, wherein urodilatin is due using an NPRi-like receptor pathway. 3) Urodilatin used for the manufacture of a medicament for the can interfere with the B1R pathway by activating MAP 50 simultaneous treatment of heart failure. kinase-directed phosphatases and thus, inactivating specific MAP-kinases through phosphorylation process- 3. The use according to claim 1 or 2, wherein said med- es by PKG. 4) Urodilatin can activate cAMP-specific icament is administered intravenously at the rate of phosphodiesterases through PKG activation and thus, at least 7.5 ng/kg/min and up to a maximal rate of 55 limiting the bradykinin-activated PLA 2-response (see fig- 60 ng/kg/min. ure 2-5). 5) PKG phosphorylation can counter regulate the target ion channel in smooth muscle cells that is ty- 4. The use according to any one of claims 1-3, wherein rosine phosphorylated. said medicament further comprises mannitol, in par-

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ticular 3 to 10% mannitol respective to the final infu- 8. Verwendung gemäß einem der Ansprüche 1 bis 7, sion solution. wobei das natriuretische Peptid zur Herstellung ei- nes Medikaments zur Behandlung eines wirkstoffin- 5. The use according to any one of claims 1-4, wherein duzierten Angioödems, das durch Inhibitoren des said medicament further comprises NaCl, in partic- 5 Angiotensin-konvertierenden Enzyms hervorgeru- ular 0.9 % of NaCl respective to the final infusion fen wird, verwendet wird. solution.

6. The use according to any one of claims 1-5, wherein Revendications said medicament is administered for a time period 10 of at least 24 hours. 1. Utilisation d’urodilatine pour la fabrication d’un mé- dicament destiné au traitement de l’oedème de 7. The use according to any one of claims 1-5, wherein Quincke. said medicament is administered for a time period of 18 to 24 hours, or 24 to 72 hours, or for more than 15 2. Utilisation selon la revendication 1, dans laquelle 72 hours. l’urodilatine est utilisée pour la fabrication d’un mé- dicament destiné au traitement simultané d’une in- 8. The use according to any one of claims 1-7, wherein suffisance cardiaque. the natriuretic peptide is used for the manufacture of a medicament for the treatment of drug induced 20 3. Utilisation selon la revendication 1 ou 2, dans laquel- angioedema provoked by inhibitors of angiotensin le ledit médicament est administré par voie intravei- converting enzyme. neuse au débit d’au moins 7,5 ng/kg/min et jusqu’à un débit maximal de 60 ng/kg/min.

Patentansprüche 25 4. Utilisation selon l’une quelconque des revendica- tions1 à 3, dans laquelleledit médicament comprend 1. Verwendung von Uroditatin zur Herstellung eines en outre le mannitol, en particulier 3 à 10 % de man- Medikaments zur Behandlung eines Angioödems. nitol par rapport à la solution d’infusion finale.

2. Verwendung gemäß Anspruch 1, wobei Urodilatin, 30 5. Utilisation selon l’une quelconque des revendica- zur Herstellung eines Medikaments zur gleichzeiti- tions1 à 4, dans laquelleledit médicament comprend gen Behandlung von Herzinsuffizienz verwendet en outre du NaCl, en particulier 0,9 % de NaCl par wird. rapport à la solution d’infusion finale.

3. Verwendung gemäß Anspruch 1 oder 2, wobei das 35 6. Utilisation selon l’une quelconque des revendica- Medikament intravenös mit einer Geschwindigkeit tions 1 à 5, dans laquelle ledit médicament est ad- von wenigstens 7,5 ng/kg/min und bis zu einer ma- ministré pendant une période d’au moins 24 heures. ximalen Geschwindigkeit von 60 ng/kg/min verab- reicht wird. 7. Utilisation selon l’une quelconque des revendica- 40 tions 1 à 5, dans laquelle ledit médicament est ad- 4. Verwendung gemäß einem der Ansprüche 1 bis 3, ministré pendant une période de 18 à 24 heures, ou wobei das Medikament weiterhin Mannit umfasst, de 24 à 72 heures, ou pendant plus de 72 heures. insbesondere 3 bis 10% Mannit in Bezug auf die fer- tige Infusionslösung. 8. Utilisation selon l’une quelconque des revendica- 45 tions 1 à 7, dans laquelle le peptide natriurétique est 5. Verwendung gemäß einem der Ansprüche 1 bis 4, utilisé dans la fabrication d’un médicament destiné wobei das Medikament weiterhin NaCl umfasst, ins- au traitement d’un oedème de Quincke d’origine mé- besondere 0,9% NaCl in Bezug auf die fertige Infu- dicamenteuse provoqué par des inhibiteurs de l’en- sionslösung. zyme de conversion de l’angiotensine. 50 6. Verwendung gemäß einem der Ansprüche 1 bis 5, wobei das Medikament während einer Zeitspanne von wenigstens 24 Stunden verabreicht wird.

7. Verwendung gemäß einem der Ansprüche 1 bis 5, 55 wobei das Medikament während einer Zeitspanne von 18 bis 24 Stunden oder 24 bis 72 Stunden oder mehr als 72 Stunden verabreicht wird.

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REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 5571789 A [0002] • WO 8806596 A1 [0007] • US 6831064 B [0002]

Non-patent literature cited in the description

• ELSNER et al. Am. Heart J., 1995, vol. 129 (4), • SANO et al. Arterioscl. Thromb. Vasc. Biol., 2006, 766-773 [0002] vol. 26, 2673-2680 [0004] • FORSSMANN et al. Clinical Pharmacology and • KIM et al. Curr. Opin. Allergy Clin. Immunol., 2006, Therapeutics, 1998, vol. 64 (3), 322-330 [0002] vol. 6 (4), 266-270 [0005] • KENTSCH et al. Eur. J. Clin. Invest., 1992, vol. 22 • MARSHALL. Ann. Pharmacother., 2005, vol. 39 (5), (10), 662-669 [0002] 944-908 [0005] • KENTSCH et al. Eur. J. Clin. Invest., 1995, vol. 25 • GRZELEWSKA-RZYMOWSKA et al. Allergol. Im- (4), 281-283 [0002] munopathol. (Madrid), 1988, vol. 16 (5), 305-308 • FLATTERY ; SICA. Prog. Cardiovasc. Nurs., 2007, [0005] vol. 22 (1), 47-51 [0003] • HIGASHI et al. Allergy Clin. Immunol., 2002, vol. 110 • SICA. J. Clin. Hypertens., 2004, vol. 6 (7), 410-416 (4), 666-667 [0005] [0003] • ASERO. Ann. Allergy Asthma Immunol., 2006, vol. • CAMPBELL. Hypertension, 2003, vol. 41, 383-389 37 (2), 187-189 [0005] [0003] • FRITH et al. Lancet, 1978, vol. 14 (2), 847-888 [0005] • HEDNER et al. Br. Med. J., 1992, vol. 304, 941-946 • DAVIS. Immunol. Allergy Clin. North Am., 2006, vol. [0003] 26 (4), 633-651 [0006] • CUPIDO ; RAYNER. S. Afr. Med. J, 2007, vol. 97 (4), • AGOSTONI ; CICARDI. Medicine (Baltimore), 1992, 244-245 [0003] vol. 71 (4), 206-215 [0006] • SCHUSTER et al. Schweiz. Med. Wochenschr., • LONGHURST et al. Clin. Exp. Immunol., 2006, vol. 1999, vol. 129 (9), 362-369 [0004] 147, 11-17 [0006]

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