PROPERTY ORGANIZATION
`PCT WORLD INTELLECTUAL
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`International Burem1
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`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
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`(51)International Patent Classification 6 :
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`(11) International Publication Number: WO 99/40788
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`AOlN 37/18
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`Al
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`1999 ( 19.08.99) (43)International Publication Date:19 August
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`(81)Designated AL. AM, AT, AU, AZ, BA, BB, BG, BR,States:
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`(21)International Application Number: PCT/US99/02554
`BY. CA, CH, CN. CU, CZ, DE, DK, EE, ES, Fl, GB, GD,
`GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP,
`1999 (05.02.99) (22)International Filing Date: 5 February
`KR. KZ, LC, LK, LR, LS, LT, LU, LY, MD, MG, MK,
`MN. MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG,
`SI, SK. SL, TJ, TM, TR, TT, UA, UG, US. UZ, VN, YU,
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`ZW, J\RlPO patent (CH. GM. KE, LS, MW, SD, SZ, UG,
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`ZWJ, Eurasian patent (AM. AZ, BY, KG, KZ, MD, RU, TJ,
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`TM). European patent (AT, BE, CH, CY, DE, DK, ES, Pl,
`FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OAP! patent
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`(for all designated States US): AMYLIN
`cxccJ>I
`(71)Applicant
`(BF. BJ, CF. CG, CI, CM. GA. GN, GW, ML, MR, NE,
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`PHARMACEUTICALS. INC. [USiUS]; 9373 Towne Centre
`SN, TD, TG).
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`Drive, San Diego, CA 92121 (US).
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`(30)Priority Data:
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`60/075,122 13February 1998 (13.02.98) us
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`(72)Inventors; and
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`(.for US only): YOUNG, Andrew. A.
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`Published
`(75)Inventors/Applicant5
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`[US/US]; 9514 Easter Way, San Diego, CA 92121 (US).
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`VINE, Will [US/US]; 14537 Crestline Drive, Poway, CA
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`92064 (US). BEELEY. Nigel. R., A. [US/US]; 227 Loma
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`Corta Drive, Solana Beach, CA 92075 (US). PRICKETT,
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`Kathryn [US/US]; 7612 Trailbrush Terrace, San Diego, CA
`92126 (US).
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`With international search report.
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`MUNSON, Peter, R. et al.; Lyon & Lyon LLP, Suite
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`(74)Agents:
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`4700, 633 West Fifth Street, Los Angeles, CA 90071-2066
`(US).
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`or EXENDIN AND GLP-1(54)Title: INOTROPIC AND DIURETIC EPPECTS
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`(57)Abstract
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`Methods for increasing urine flow are disclosed, comprising administration of an effective amount of GLP-1, an exendin, or an
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`exendin or GLP-1 agonist. Methods for increasing urinary sodium excretion and decreasing urinary potassium concentration are also
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`disclosed. The methods arc useful for treating conditions or disorders associated with toxic hypervolemia, such as renal failure, congestive
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`heart failure, nephrotic syndrome, cirrhosis, pulmonary edema, and hypertension. The present invention also relates to methods for inducing
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`an inotropic response comprising administration of an effective amount of GLP-1. an exendin, or an exendin or GLP-1 agonist. These
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`are useful for treating conditions or disorders that can be alleviated by an increase in cardiac contractility such as congestive heart
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`failure. Pharmaceutical compositions for use in the methods of the invention are also disclosed.
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`Codes used to identify States pai1y to the PCT on the front pages of pamphlets publishing international applications under the PCT.
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`FOR THE PURPOSES OF INFORMATION ONLY
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`AL
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`AM
`AT
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`BE
`BF
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`CA
`CF
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`CG
`CH
`CI
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`Albania
`Armenia
`Austria
`Australia
`GA
`AU
`Azerbaijan
`AZ
`GB
`Bosnia and Herzegovina
`BA
`GE
`nn Barbados
`Belgium
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`Burkina Faso
`Bulgaria
`BG
`HJ Benin
`BR Brazil
`Belarus
`BY
`IS
`Canada
`IT
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`Central African Republic
`JP
`Congo
`Switzerland
`Cote d'Ivoire
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`FR
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`GH
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`GN
`GR
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`IL
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`LS
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`LT
`LU
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`LV
`MC
`MD
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`MG
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`MK
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`SI
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`SK
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`TJ
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`VN
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`Spain
`Lesotho
`Slovenia
`ES
`Fl Finland
`Lithuania
`Slovakia
`Luxembourg
`France
`Senega1
`SN
`Gabon
`Latvia
`sz Swaziland
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`United Kingdom
`Monaco
`TD Chad
`Georgia
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`Republic of Moldova
`Togo
`TG
`Ghm1a
`Tajikistan
`fvfadagascar
`Guinea
`The former Yu gos ]av
`Turkmenista
`n
`TM
`Greece
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`Republic of Macedonia
`Turkey
`TR
`Hungary
`Mali
`TT Trinidad and Tobago
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`HU
`ML
`IE Ireland
`M'-1 Mongolia
`Ukraine
`UA
`Israel
`lJG Uganda
`:VIR Mauritania
`Iceland
`MW Malawi
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`United States of America
`us
`Italy
`VIX Mexico
`uz Uzbekistan
`Japan
`'-IE Niger
`Viet Nam
`Kenya
`Netherlands
`Yugoslavia
`NL
`YU
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`Kyrgyzstan
`NO Norway
`zw Zimbabwe
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`Democratic People's i\Z New Zealand
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`Republic of Korea
`Poland
`PL
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`Republic of Korea
`PT Portugal
`Kazakstan
`Romania
`KZ
`RO
`Saint Lucia
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`Russian Federation
`LC
`RL
`LI Liechtenstein
`Sudan
`SD
`Sri Lanka
`SE Sweden
`Liberia
`SG Singapore
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`KE
`KG
`KP
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`Cameroon
`CM
`China
`CN
`cu Cuba
`Czech Republic
`CZ
`Gem1any
`DE
`Denmark
`DK
`EE Estonia
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`KR
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`LK
`LR
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`WO 99/40788
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`PCT /US99/02554
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`DESCRIPTION
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`INOTROPIC AND DIURETIC EFFECTS OF EXENDIN AND GLP-1
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`5 FIELD OF THE INVENTION
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`The present invention relates to methods for increasing urine flow comprising
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`administration of an effective amount of glucagon-like peptide-1 [7-36] amide (abbreviated
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`"GLP-[7-36]NH
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`or GLP-1 agonist. or an exendin 2" or simply "GLP-1 "), an exendin,
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`Methods for increasing urinary sodium excretion and decreasing urinary potassium
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`1 o concentration are also disclosed. The methods are useful for treating conditions or
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`disorders associated with toxic hypervolemia, such as renal failure, congestive heart
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`failure, nephrotic syndrome, cirrhosis, pulmonary edema, and hypertension.
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`Pharmaceutical compositions for use in the methods of the invention are also disclosed.
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`The present invention also relates to methods for inducing an inotropic response
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`15 comprising administration of an effective amount of an exendin, GLP-1, or an exendin or
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`GLP-1 agonist. These methods are useful for treating conditions or disorders that can be
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`alleviated by an increase in cardiac contractility, such as congestive heart failure.
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`The following description summarizes information relevant to the present
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`invention. It is not an admission that any of the information provided herein is prior art to
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`specifically or implicitly nor that any of the publications 2 O the presently claimed invention,
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`referenced are prior art to that invention.
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`GLP-1
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`Glucagon-like peptide-1 [7-36] amide (also referred to as GLP-1[7-36]NH
`2 or
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`25 GLP-1) is a product of the proglucagon gene. It is secreted into plasma mainly from the
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`gut and produces a variety of biological effects related to pancreatic and gastrointestinal
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`function. The parent peptide, proglucagon (PG), has numerous cleavage sites that produce
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`other peptide products dependent on the tissue of origin including glucagon (PG[32-62])
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`and GLP-1[7-36]NH
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`(PG[78-108]) and 2 (PG[72-107]) in the pancreas, and GLP-1[7-37]
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`30 GLP-1[7-36]NH
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`2 (78-
`where GLP-1[7-36]NH2 (PG [78-107]) in the L cells of the intestine
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`107 PG) is the major product.
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`GLP-1 [7-36]NH2, also known as proglucagon [78-107], or commonly, just GLP-
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`1," as used herein, has an insulinotropic effect, stimulating insulin secretion from
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`pancreatic -cells; GLP-1 also inhibits glucagon secretion from pancreatic -cells (Orskov,
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`et al., Diabetes, 42:658-61, 1993; D' Alessio, et al., J. Clin. Invest., 97: 133-38, 1996).
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`5
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`GLP-1 is reported to inhibit gastric emptying (Williams B, et al., J Clin Endocrinol Metab
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`81 (I): 327-32, 1996; WettergrenA, et al., Dig Dis Sci 38 (4): 665-73, 1993), and gastric
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`acid secretion. (Schjoldager BT, et al., Dig Dis Sci 34 (5): 703-8, 1989; O'Halloran DJ, et
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`al., J Endocrinol 126 (1): 169-73, 1990; Wettergren A, et al., Dig Dis Sci 38 (4): 665-73,
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`1993 ). A diuretic, antidypsogenic effect of intracerebroventricular administration of GLP-
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`1 o
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`1 has been reported, however, this report claims that a peripheral, intraperitoneal injection
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`of GLP-1 did not have this effect. (Tand-Christensen et al., Am. J. Phvsiol., 271 :R848-56,
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`1996). GLP-1 [7-37], which has an additional glycine residue at its carboxy terminus, also
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`stimulates insulin secretion in humans (Orskov, et al., Diabetes, 42:658-61, 1993). A
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`transmembrane G-protein adenylate-cyclase-coupled receptor believed to be responsible
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`15
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`for the insulinotropic effect of GLP-1 has been cloned from a -cell line (Thorens, Proc.
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`Natl. Acad. Sci., USA 89:8641-45, 1992).
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`Glucagon and glucagon-like peptides have been found to have different
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`cardiovascular effects. Glucagon has been reported to have positive inotropic and
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`chronotropic effects, produce a slight increase in arterial blood pressure in normal
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`2 o
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`individuals, and affect regional blood circulation. GLP-1 has been found to produce a
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`moderate increase in both systolic and diastolic blood pressure, while GLP-2 has no effect
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`on those parameters. GLP-1, administered through the jugular vein, has been reported to
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`induce an increase in systolic and diastolic blood pressure and heart rate. (Reviewed in
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`Barragan, J.M., et al., Regul. Peptides, 67:63-68, 1996).
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`EXENDIN
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`Exendins are peptides that are found in the venom of the Gila-monster, a lizard
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`endogenous to Arizona, and the Mexican Beaded Lizard. Exendin-3 is present in the
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`venom of Heloderma horridum, and exendin-4 is present in the venom of Heloderma
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`3 O
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`suspectum (Eng, J., et al., J. Biol. Chem., 265:20259-62, 1990; Eng., J., et al., J. Biol.
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`Chem., 267:7402-05, 1992). The exendins have some sequence similarity to several
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`members of the glucagon-like peptide family, with the highest homology, 53%, being to
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`GLP-1 (Goke, et al., J. Biol. Chem., 268:19650-55, 1993).
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`Exendin-4 is a potent agonist at GLP-1 receptors on insulin-secreting TC 1 cells, at
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`dispersed acinar cells from guinea pig pancreas, and at parietal cells from stomach; the
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`5
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`peptide also stimulates somatostatin release and inhibits gastrin release in isolated
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`stomachs (Goke, et al., J. Biol. Chem. 268:19650-55, 1993; Schepp, et al., Eur. J.
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`Pharmacol., 69: 183-91, 1994; Eissele, et al., Life Sci., 55:629-34, 1994). Exendin-3 and
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`exendin-4 were found to be GLP-1 agonists in stimulating cAMP production in, and
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`amylase release from, pancreatic acinar cells (Malhotra, R., et al., Regulatory Peptides,
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`10
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`41:149-56, 1992; Raufman, et al., J. Biol. Chem. 267:21432-37, 1992; Singh, et al., Regul.
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`Pept. 53:47-59, 1994). The use of the insulinotropic activities of exendin-3 and exendin-4
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`for the treatment of diabetes mellitus and the prevention of hyperglycemia has been
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`proposed (Eng, U.S. Patent No. 5,424,286).
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`Truncated exendin peptides such as exendin[9-39], a carboxyamidated molecule,
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`15
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`and fragments 3-39 through 9-39 have been reported to be potent and selective antagonists
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`of GLP-1 (Goke, et al., J. Biol. Chem., 268:19650-55, 1993; Raufman, J.P., et al., J. Biol.
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`Chem. 266:2897-902, 1991; Schepp, W., et al., Eur. J. Pharm. 269:183-91, 1994;
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`Montrose-Rafizadeh, et al., Diabetes, 45(Suppl. 2): 152A, 1996). Exendin[9-39] blocks
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`endogenous GLP-1 in vivo, resulting in reduced insulin secretion. Wang, et al., J. Clin.
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`20
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`Invest., 95:417-21, 1995; D'Alessio, et al., J. Clin. Invest., 97:133-38, 1996). The receptor
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`apparently responsible for the insulinotropic effect of GLP-1 has been cloned from rat
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`pancreatic islet cells (Thorens, B., Proc. Natl. Acad. Sci. USA 89:8641-8645, 1992).
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`Exendins and exendin[9-39] bind to the cloned GLP-1 receptor (rat pancreatic -cell GLP-
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`1 receptor: Fehmann HC, et al., Peptides 15 (3): 453-6, 1994; human GLP-1 receptor:
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`25
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`Thorens B, et al., Diabetes 42 (11): 1678-82, 1993). In cells transfected with the cloned
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`GLP-1 receptor, exendin-4 is an agonist, i.e., it increases cAMP, while exendin[9-39] is an
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`antagonist, i.e., it blocks the stimulatory actions of exendin-4 and GLP-1. Id.
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`Exendin[9-39] also acts as an antagonist of the full length exendins, inhibiting
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`stimulation of pancreatic acinar cells by exendin-3 and exendin-4 (Raufman, et al., J. Biol.
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`3 o Chem. 266:2897-902, 1991; Raufman, et al., J. Biol. Chem., 266:21432-37, 1992).
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`Exendin[9-39] inhibits the stimulation of plasma insulin levels by exendin-4, and inhibits
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`the somatostatin release-stimulating and gastrin release-inhibiting activities of exendin-4
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`and GLP-1 (Kolligs, F., et al., Diabetes, 44:16-19, 1995; Eissele, et al., Life Sciences,
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`55:629-34, 1994). Exendin-4, administered through the jugular vein, has been reported to
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`induce an increase in systolic, diastolic and meanarterial blood pressure, and in heart rate
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`(Barragan,et al., Regul. Pep. 67:63-68, 1996).
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`Exendins have recently been foundto inhibit gastric emptying (U.S. Patent
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`Application Serial No. 08/694,954,filed August 8, 1996, which enjoys common
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`ownership with the present invention and is hereby incorporated by reference).
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`Exendin[9-39] has been usedto investigate the physiological relevance of central GLP-1
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`in control of food intake (Turton, M.D. et al., Nature, 379:69-72, 1996). GLP-1
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`10
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`administered by intracerebroventricular (ICV) injection inhibits food intake in rats. This
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`satiety-inducing effect of GLP-1 delivered by intracerebroventricular injection is reported
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`to be inhibited by ICV injection of exendin[9-39] (Turton, supra). However, it has been
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`reported that GLP-1 does notinhibit food intake in mice when administered byperipheral
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`injection (Turton, M.D., Nature 379:69-72, 1996; Bhavsar, S.P., Soc. Neurosci. Abstr.
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`15
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`21:460 (188.8), 1995). Administration of exendins and exendin agonists hasalso recently
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`been found to reduce food intake (U.S. Provisional Patent Application Serial No.
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`60/034,905, filed January 7, 1997, which enjoys common ownership with the present
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`invention and is hereby incorporated by reference).
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`20
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`DIURETICS
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`Agents that increase urine flow, or diuretics, are useful for treating conditions or
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`disorders that are associated with toxic hypervolemic states. Such conditions or disorders
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`include renalfailure, congestive heart failure, nephrotic syndrome,cirrhosis, pulmonary
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`25
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`edema, and hypertension. Diuretics are also employedto treat conditions in pregnancy,
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`such as pre-eclampsia and eclampsia. Further uses of diuretics include their use to reduce
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`volume before some surgical procedures such as ocular surgery and neurosurgery.
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`Onedifficulty encountered with many diuretics such as thiazides, loop diuretics,
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`carbonic anhydrase inhibitors, and osmotic diuretics, is that although they may be
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`30
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`employed to increase sodium excretion, they also result in an increase of urinary
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`potassium loss. Examplesof the effects of potassium loss include muscular weakness,
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`paralysis (including the paralysis of respiratory muscles), electrocardiographic
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`abnormalities, cardiac dysrhythmia, and cardiacarrest.
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`Anotherdifficulty encountered with somediureticsis their slow rate of action,
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`whichis not conduciveto their use in an emergencysetting.
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`Thus,there is a need for a method of increasing urine flow that does not deplete
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`potassium concentration in the patient and which has a rapid modeofaction. Such
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`methods, and compounds and compositions which are useful therefore, have been invented
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`and are described and claimed herein.
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`Inotropic Compounds
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`Compoundsthat induce inotropic effects (e.g., increase of force of contraction of
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`the heart) have been recognized as being useful for the treatmentof, for example,
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`congestive heart failure. Congestive heart failure, which is one of the most common
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`causes of death and disability in industrialized nations, has a mortality rate of about 50% at
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`five years (Goodman and Gilman s The Pharmacological Basis of Therapeutics, 9th Ed.
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`McGrawHill, New York, pp. 809-838). Inotropic agents currently in clinical use include
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`digitalis, sympathomimetic amines and amrinone (Harrisons Principles of Internal
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`Medicine, 12th Edition, 1991, McGraw Hill, New York, pp. 894-899).
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`Digotoxin, a cardiac glycoside, an ancient but effective therapy for cardiac failure,
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`wasinitially derived from the foxglove leaf, Digitalis purpurea and Digitalis lanata.
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`Cardiac glycosides are potent and highly selective inhibitors of the active transport of
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`sodium and potassium ionsacross cell membranes (Goodman and Gilman, supra).
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`Cardiac glycosides have been reported to increase the velocity of shortening of cardiac
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`muscle, resulting in an improvementin ventricular function; this effect has been reported
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`to be due to an increasein the availability during systole of cytosolic Ca’* to interact with
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`25
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`contractile proteins in increase the velocity and extent of sarcomere shortening (Goodman
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`and Gilman, supra).
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`Digotoxin and related cardiac glycosides (e.g. digitoxin) have useful durations of
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`action becausetheir excretion, mainly via the kidneys, results in plasma t of 1.5-5 days.
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`But the therapeutic index of these drugs is very low with mildly toxic:minimally-effective
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`30
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`dose ratio being 2:1 and lethal:minimally-effective dose ratio being between 5:1 and 10:1.
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`Urinary potassium loss due to use of thiazide and loop diuretics may seriously enhance
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`the dangersofdigitalis intoxication, including susceptibility to cardiac arrhythmia, and
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`potassium-sparing diuretics are often necessary. Slow elimination of cardiac glycosides
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`can prolongthe period ofjeopardy during digitalis intoxication, which has been reported
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`to occur in 20% of hospital patients on these drugs. Absorption and onsetofaction forall
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`cardiac glycosides except ouabain is somewhatprolonged, and this may be a disadvantage
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`in emergency cardiac conditions.
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`Sympathomimetic amines, which generally include epinephrine, isoproterenol,
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`dopamine and dobutamine, can be useful in an acute setting to stimulate myocardial
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`contractility, but they usually require constant intravenous infusion and continuous
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`10
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`intensive monitoring ofthe patient. They typically lose their effectiveness after 8 hours,
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`apparently due to receptor downregulation.
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`Amrinone, a noncatecholamine, non-glycoside agent also requires continuous
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`intravenous administration.
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`This description ofavailable inotropic agentsillustrates the need for, and
`
`15
`
`desirability of, therapies that are (1) inotropic, with (2) rapid onset of action, with (3)
`
`prolonged duration ofaction (includinga persistent effect, with absence of tachyphylaxis),
`
`with (4) low toxicity (a high ratio of toxic to therapeutic dose), with (5) rapid and profound
`
`diuretic effect, with (6) a sparing of urinary potassium loss, and with (7) a convenient
`
`(non-intravenous) route of administration. We have discovered that exendin and GLP-1
`
`20
`
`fulfill these criteria.
`
`SUMMARYOF THE INVENTION
`
`The present invention concernsthe surprising discovery that exendins, GLP-1, and
`
`agonists of these compoundshaverapidinotropic and diuretic effects. Although GLP-1
`
`25
`
`has been reported to not have a diuretic effect when administered peripherally, we have
`
`found, surprisingly, that GLP-1 does in fact have a diuretic effect after peripheral
`
`administration. This diuretic effect of exendins, GLP-1, and exendin and GLP-1 agonists,
`
`is accompanied by an increase in urinary sodium concentration. This diuretic effect is also
`
`accompanied by a decrease in urinary potassium concentration whichis unanticipated as
`
`30
`
`manydiuretics have been found to cause a profound increase in urinary potassium
`
`concentration.
`
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`PCT/US99/02554
`
`7
`
`Thepresent invention is directed to novel methodsfor increasing urine flow
`
`comprising the administration of an exendin, for example, exendin-3 [SEQ ID NO. 1: His
`
`Ser Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe
`[le Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH,], or exendin-4
`
`[SEQ ID NO, 2: His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu
`
`Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro
`
`Ser-NH,], or other compounds whicheffectively bind to the receptor at which exendin
`
`exerts its action on increasing urine flow (exendin agonists). The present invention is also
`
`directed to novel methodsfor increasing urine flow comprising the administration of GLP-
`
`10
`
`1 {SEQ ID NO. 3: His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
`
`Gln Ala Ala Lys Glu Phe Ie Ala Trp Leu Val Lys Gly Arg-NH,], or other compounds
`
`whicheffectively bind to the receptor at which GLP-1 exerts its action on increasing urine
`
`flow (GLP-1 agonists).
`
`Inafirst aspect, the invention features a method ofincreasing urine flow in an
`
`15
`
`individual comprising administering to the individual a therapeutically effective amount of
`
`an exendin or an exendin agonist. In one preferred aspect, said exendin is exendin-3.
`
`Morepreferably, said exendin is exendin-4. By an exendin agonist is meant a compound
`
`that mimics the effects of exendin on increasing urine flow, increasing sodium excretion,
`
`and/or decreasing urinary potassium concentration, (the potassium concentration in
`
`20
`
`excreted urine) by binding to the receptor or receptors where exendin causesthiseffect.
`
`Certain novel exendin agonist compoundsare described in U.S. Provisional Patent
`
`Application Serial No. 60/055,404,filed August 8, 1997, which enjoys common
`
`ownership with the present invention and is hereby incorporated by this reference. Certain
`
`other novel exendin agonist compoundsare described in U.S. Provisional Patent
`
`25
`
`Application Serial Nos. 60/066,029 and 60/065,442, both filed November 14, 1997 which
`
`enjoy common ownership with the present invention and are hereby incorporated bythis
`
`reference. Preferred exendin agonist compoundsincludethose described in U.S.
`
`Provisional Patent Application Serial Nos. 60/055,404 and 60/065,442.
`
`In one preferred aspect the exendin or exendin agonist used in the methodsofthe
`
`30
`
`present invention is exendin-4. In another preferred aspect, the exendin is exendin-3. In
`
`other preferred aspects, the exendin or exendin agonist is a compoundofthe formula (1)
`
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`[SEQ ID NO. 4]:
`
`Xaa, Xaa, Xaa, Gly Kaa, Xaa, Xaa, Xaa, Xaa, Xaaj,
`
`Xaa,, Xaa,, Xaa,, Xaa,, Xaa,, Xaa,, Xaa,, Ala Xaa,. Xaayq
`
`Xaa,, Xaa,, Xaa,, Xaa,, Xaa,; Xaa,, Xaa,, Xaa,_-Z,; wherein
`
`PCT/US99/02554
`
`Xaa, is His, Arg or Tyr;
`
`Xaa, is Ser, Gly, Ala or Thr;
`
`Xaa, is Asp or Glu;
`
`Xaa, is Ala or Thr;
`
`Xaa, is Ala, Phe, Tyr or naphthylalanine;
`
`10
`
`Xaa, is Thr or Ser;
`
`Xaa, is Ala, Ser or Thr;
`
`Xaay is Asp or Glu;
`
`Xaajy is Ala, Leu, Ile, Val, pentylglycine or Met;
`
`Xaa,, is Ala or Ser;
`
`15
`
`Xaa,, is Ala or Lys;
`
`Xaa,, is Ala or Gln;
`
`Xaa,, is Ala, Leu,Ile, pentylglycine, Val or Met;
`
`Xaa,,; is Ala or Glu;
`
`Xaaj;, is Ala or Glu;
`
`20
`
`Xaa,, is Ala or Glu;
`
`aaj, is Ala or Val;
`
`Xaa,, is Ala or Arg;
`
`Xaa,, is Ala or Leu;
`
`Xaa,, is Phe, Tyr or naphthylalanine;
`
`25
`
`Xaa,, is Ile, Val, Leu, pentylglycine,tert-butylglycine
`
`or Met;
`
`Xaa,, is Ala, Glu or Asp;
`
`Xaa,,; is Ala, Trp, Phe, Tyr or naphthylalanine;
`
`Xaa,, is Ala or Leu;
`
`30
`
`Xaa,, is Ala or Lys;
`
`Xaa,, is Ala or Asn;
`
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`WO 99/40788
`
`Z, is-OH,
`
`-NH,,
`
`Gly-Z,,
`
`Gly Gly-Z,,
`
`Gly Gly Xaa;,-Z,,
`
`Gly Gly Xaa,, Ser-Z,,
`
`Gly Gly Xaa,, Ser Ser-Z,,
`
`Gly Gly Xaa,, Ser Ser Gly-Z,,
`
`Gly Gly Xaa,, Ser Ser Gly Ala-Z,,
`
`10
`
`Gly Gly Xaa,, Ser Ser Gly Ala Xaa,,-Z,,,
`
`Gly Gly Xaa,, Ser Ser Gly Ala Xaa,, Xaa,,-Z,,
`
`Gly Gly Xaa,, Ser Ser Gly Ala Xaa,, Xaa,, Xaaj-Z,, or
`
`Gly Gly Xaa31 Ser Ser Gly Ala Xaa,, Xaa,, Xaajg Xaaqo-Z,;
`
`wherein Kaa,,, Xaa,,, Xaa,, and Kaa,, are independently
`
`15
`
`selected from the group consisting of Pro,
`
`homoproline, 3Hyp, 4Hyp, thioproline,
`
`N-alkylglycine, N-alkylpentylglycine and
`
`N-alkylalanine; Xaa,, is Ser, Thr or Tyr; and
`
`Z, is -OH or -NH,; and pharmaceutically acceptable salts thereof;
`
`20
`
`provided that no more than three of Xaa,, Xaa;, Xaa,, Xaag, Xaajo, Xaaj,,, Nady, Xaayz,
`
`Xaa,4, Xaa,;, Xaaj,,, Xaa,,, Kaa, XAa», Xaa,,, Xaa,4, Xaa;, Xaa,,, Xaa,,, and Kaa,, are
`
`Ala; and provided also that the compoundis not exendin-3 [SEQ ID NO. 1] or exendin-4
`
`[SEQ ID NO.2]. In other aspects of the invention, the increase in urine flow is
`
`accompanied by an increase in sodium excretion in said individual. In most preferred
`
`25
`
`aspects, the increase in urine flow doesnot increase urinary potassium concentration in
`
`said individual.
`
`In other embodiments of the invention, a method is provided for decreasing the
`
`concentration of potassium in the urine of an individual comprising administering to said
`
`individual a therapeutically effective amount of an exendin or an exendin agonist.
`
`30
`
`In yet another aspect of the invention, a method is provided for preventing or
`
`alleviating a condition or disorder associated with toxic hypervolemia in an individual,
`
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`WO 99/40788
`
`PCT/US99/02554
`
`10
`
`comprising administering to said individual a therapeutically effective amount of an
`
`exendin or an exendin agonist.
`
`By condition or disorder associated with toxic hypervolemia is meant any
`
`condition or disorder in a subject that is either caused by, complicated by, or aggravated by
`
`a relatively high extracellular volume. Such conditions or disorders include, but are not
`
`limited to, renal failure, congestive heart failure, nephrotic syndrome, pulmonary edema,
`
`cirrhosis, and hypertension.
`
`The present invention also provides a method of inducing rapid diuresis in an
`
`individual comprising administering to said individual a therapeutically effective amount
`
`10
`
`of an exendin or an exendin agonist. One preferred use of this methodis in preparation of
`
`a patient for a surgical procedure where a reduction in extracellular volumeis desired,
`
`such as in some ocular surgical procedures or in some neurosurgical procedures. Thus, the
`
`present invention provides a method of preparing an individual for a surgical procedure
`
`comprising administering to said individual a therapeutically effective amount of an
`
`15
`
`exendin or an exendin agonist. Preferably, said exendin or exendin agonist is administered
`
`to said individual before said surgical procedure.
`
`In other preferred aspects, a method is provided for increasing renal plasma flow
`
`and glomerularfiltration rate in an individual comprising administering to said individual
`
`a therapeutically effective amount of an exendin or an exendin agonist.
`
`20
`
`In yet other preferred aspects, a method is provided for treating pre-eclampsia or
`
`eclampsia of pregnancy in an individual comprising administering to said individual a
`
`therapeutically effective amount of an exendin or an exendin agonist.
`
`The preferred mode of administration of said exendin or exendin agonist is by
`
`peripheral (subcutaneousor intravenous) administration. Preferably, said exendin or
`
`25
`
`exendin agonist is administered subcutaneously. Preferably, about 1 g - 30 g to about 10-
`
`20 mg of the exendin or exendin agonist is administered per dose. More preferably, about
`
`30 gto about 10 mg,or about 300 g to about S5mg of the exendin or exendin agonistis
`
`administered per dose. Most preferably, about 30 g to about 1 mgofthe exendin or
`
`exendin agonist is administered per dose.
`
`30
`
`In other preferred aspects, said peripheral administration is selected from the group
`
`consisting of buccal, nasal, pulmonary,oral, intraocular, rectal, and transdermal
`
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`
`administration.
`
`Li
`
`PCT/US99/02554
`
`The present invention also provides pharmaceutical compositionsfor use in the
`
`treatment of conditions or disorders associated with hypervolemia comprising a
`
`therapeutically effective amountof an exendin or exendin agonist in association with a
`
`pharmaceutically acceptablecarrier.
`
`In yet other aspects, the invention provides pharmaceutical compositions for use in
`
`increasing urine flow in an individual comprising a therapeutically effective amount of an
`
`exendin or exendin agonistin association with a pharmaceutically acceptable carrier.
`
`In further aspects, the invention provides pharmaceutical compositions for use in
`
`10
`
`treating pre-eclampsia or eclampsia of pregnancyin an individual comprising a
`
`therapeutically effective amount of an exendin or exendin agonist in association with a
`
`pharmaceutically acceptable carrier.
`
`Preferably, these pharmaceutical compositions comprise exendin-3. More
`
`preferably. these pharmaceutical compositions comprise exendin-4.
`
`15
`
`Preferably, these pharmaceutical compositions comprise an exendin agonist of
`
`formula I [SEQ ID NO.4].
`
`The present invention is also directed to novel methodsforincreasing urine flow
`
`comprising the administration of GLP-1.
`
`In one embodimentthe invention features a method ofincreasing urine flow in an
`
`20
`
`individual comprising administering to the individual a therapeutically effective amount of
`
`GLP-1 or GLP-1 agonist. By GLP-1 agonist is meant a compoundthat mimicsthe
`
`effects of GLP-1 onincreasing urine flow, increasing sodium excretion, and/or decreasing
`
`urinary potassium concentration, by binding to the receptor or receptors where GLP-1
`
`causes this effect. Certain GLP-1 agonists are described in Chenet al., U.S. Patent No.
`
`25
`
`5,512,549, issued April 30, 1996,entitled Glucagon-Like Insulinotropic Peptide Analogs,
`
`Compositions and Methods of Use. Other GLP-1 agonists are described in Johnsonet al.,
`
`U.S. Patent No. 5,574,008, issued November 12, 1996,entitled, Biologically Active
`
`Fragments of Glucagon-Like Insulinotropic Peptide. Still other GLP-1 agonists are
`
`described in Buckleyet al., U.S. Patent No. 5,545,618, issued August 13, 1996, entitled
`
`30
`
`GLP-1 Analogs Useful for Diabetes Treatment. All three referenced U.S. patents are
`
`incorporated herein bythis reference.
`
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`WO 99/40788
`
`:
`
`12
`
`PCT/US99/02554
`
`In other aspects of the invention, the increase in urine flow is accompanied by an
`
`increase in sodium excretion in said individual. In most preferred aspects, the increase in
`
`urine flow does not increase urinary potassium concentration in said individual.
`
`In other embodiments of the invention, a method is provided for decreasing the
`
`concentration of potassium in the urine of an individual comprising administering to said
`
`individual a therapeutically effective amount of GLP-1 or a GLP-1 agonist.
`
`In yet another aspect ofthe invention, a methodis provided for preventing or
`
`alleviating a condition or disorder associated with toxic hypervolemia in an individual,
`
`comprising administering to said individual a therapeutically effective amount of GLP-1
`
`10
`
`or a GLP-1 agonist.
`
`The present invention also provides a method ofinducing rapid diuresis in an
`
`individual comprising administering to said individual a therapeutically effective amount
`
`of GLP-1 or a GLP-1 agonist. One preferred use of this methodis in preparation ofpatient
`
`for surgical procedures where a reduction in extracellular volumeis desired, such as in
`
`15
`
`some ocular surgical procedures and some neurosurgical procedures. Thus, the present
`
`invention provides a methodof preparing an individual for a surgical procedure
`
`comprising administering to said individual a therapeutically effective amount of GLP-1
`
`or a GLP-1 agonist. Preferably, said GLP-1 or GLP-1 agonist is administered to said
`
`individual before said surgical procedure.
`
`20
`
`In other preferred aspects, a methodis provided for increasing renal plasma flow
`
`and glomerular filtration rate in an individual comprising administering to said individual
`
`a therapeutically effective amount of GLP-1 or GLP-1 agonist.
`
`In yet other preferred aspects, a method is provided for treating pre-eclampsia or
`
`eclampsia of pregnancy in an individual comprising administering to said individual a
`
`25
`
`therapeutically effective amount of GLP-1 or GLP-1 agonist.
`
`The preferred mode of administration of said GLP-1 or GLP-1 agoni