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MXPA99001975A - Method of inhibiting fibrosis with a somatostatin agonist - Google Patents

Method of inhibiting fibrosis with a somatostatin agonist

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Publication number
MXPA99001975A
MXPA99001975A MXPA/A/1999/001975A MX9901975A MXPA99001975A MX PA99001975 A MXPA99001975 A MX PA99001975A MX 9901975 A MX9901975 A MX 9901975A MX PA99001975 A MXPA99001975 A MX PA99001975A
Authority
MX
Mexico
Prior art keywords
phe
thr
trp
lys
cys
Prior art date
Application number
MXPA/A/1999/001975A
Other languages
Spanish (es)
Inventor
D Culler Michael
G Kasprzyk Phillip
Original Assignee
Biomeasure Incorporated
D Culler Michael
Kasprzyk Philip G
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biomeasure Incorporated, D Culler Michael, Kasprzyk Philip G filed Critical Biomeasure Incorporated
Publication of MXPA99001975A publication Critical patent/MXPA99001975A/en

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Abstract

The present invention relates to a method of inhibiting fibrosis in a patient. The method comprises administering a therapeutically effective amount of a somatostatin, a somatostatin agonist or apharmaceutically acceptable salt thereof to said patient.

Description

METHOD FOR INHIBITING FIBROSIS WITH A SOMATOSTATINE AGONIST BACKGROUND OF INVENTION The tissue comprises organized, cellular groups which bind to an extracellular matrix and are surrounded by a network of blood vessels. Fibrosis is an abnormal accumulation of a collagen matrix after injury or inflammation that alters the structure and function of various tissues. Despite the location, the main pathology of fibrosis involves an excessive deposition of a collagen matrix that replaces normal tissue at that site. Progressive fibrosis in the kidney, liver, lung, heart, bone or bone marrow and skin is a leading cause of death and suffering. See, for example, Border et al., New Engl. J. Med. 331: 1286 (1994). The development of fibrosis has been correlated to overexpression and overproduction of TGF-β in numerous tissues and fibrotic disease states (see Border et al., New Engl J Med 1994, pp. 1286-92).
SUMMARY OF THE INVENTION The present invention relates to a method of treating fibrosis in a patient (e.g., a mammal, such as a human). The method includes the step of administering to the patient a therapeutically effective amount of somatostatin or a somatostatin agonist. Somatostatin or somatostatin agonist can be administered orally, topically or parenterally, for example, administered intravenously, subcutaneously or by implantation of a sustained release formulation. Fibrosis is the abnormal accumulation of an extracellular matrix (eg, collagen) in the tissue. For example, fibrosis can be localized: in the kidney, for example, fibrosis as seen in glomerulonephritis, diabetic nephropathy, allograft rejection and HIV nephropathy; in the liver, for example, cirrhosis and veno-occlusive disease; in the lung, for example, idiopathic fibrosis, in the skin, for example, systemic sclerosis, keloids, scars and eosinophilia-myalgia syndrome; in the central nervous system, for example, infra-ocular fibrosis; in the cardiovascular system, for example, vascular restenosis; in the nose, for example, nasal polyposis, in bone or bone marrow; in an endocrine organ and in the gastrointestinal system. A fibrotic disorder can be induced by a number of causes including: chemotherapy, for example, pulmonary fibrosis resulting from treatment with bleomycin, chlorambucil, cyclophosphamide, methotrexate, mustine or procarbazine; exposure to radiation, either accidental or intentional, such as radiation therapy, for example, interstitial lung disease (ILD) resulting from radiation; environmental or industrial factors or pollutants such as chemicals, fumes, metals, vapors, gases, etc. (for example, ILD resulting from asbestos, or coal dust); a drug or combination of drugs, for example, antibiotics (eg, penicillins, sulfonamides, etc.), cardiovascular drugs (eg, hydralazine, beta-blockers, etc.), CNS drugs (phenytoin, chlorpromazine, etc.), anti-inflammatory drugs (for example, gold salts, phenylbutazone, etc.), etc. they can cause ILD; an immune reaction disorder, (e.g., chronic host disease against graft with dermal fibrosis), disease states (e.g., aspiration pneumonia that is a known cause of ILD) that includes parasite-induced fibrosis; and injuries, for example, numb trauma, surgical splits, battlefield injuries, etc. as penetrating injuries of the CNS. In one aspect, this invention provides a method for inhibiting fibrosis in a patient, the method comprising administering to the patient a therapeutically effective amount of somatostatin or a somatostatin agonist; a preferred method of the above method is wherein the method comprises administering to the patient a therapeutically effective amount of a somatostatin agonist. In another aspect, this invention provides a method for inhibiting fibrosis in a patient, which comprises administering to the patient a therapeutically effective amount of a somatostatin agonist, wherein the fibrosis that is inhibited is in the: kidney where the fibrotic disorder inhibited in the kidney is preferably glomerulonephritis, diabetic nephropathy, graft rejection or HIV nephropathy, lung, wherein the inhibited fibrotic disorder in the lung is preferably idiopathic fibrosis or autoimmune fibrosis, liver where the fibrotic disorder inhibited in the liver is preferably cirrhosis or disease veno-occlusive, skin, wherein the inhibited fibrotic disorder in the skin is preferably systemic sclerosis, keloids, scars or eosinophilia-myalgia syndrome, central nervous system, wherein the inhibited fibrotic disorder in the central nervous system is preferably infra-ocular fibrosis, bone or bone marrow system cardiovascular, an endocrine organ or gastrointestinal system. Each of the immediately preceding methods is preferred. In yet another aspect, this invention provides a method for inhibiting fibrosis in a patient, the method comprising administering to the patient a therapeutically effective amount of a somatostatin agonist, wherein the fibrosis is induced by chemotherapy and preferably the inhibited fibrosis is in the kidney, lung, liver, skin, central nervous system, bone or bone marrow, cardiovascular system, an endocrine organ or gastrointestinal system. Each of the immediately preceding methods is preferred. In yet another aspect, this invention provides a method for inhibiting fibrosis in a patient, which comprises administering to the patient a therapeutically effective amount of a somatostatin agonist, wherein the fibrosis is induced by radiation and preferably the inhibited fibrosis is in the kidney, lung, liver, skin, central nervous system, bone or bone marrow, cardiovascular system, an endocrine organ or gastrointestinal system. Each of the immediately preceding methods is preferred. In yet another aspect, this invention provides a method for inhibiting fibrosis in a patient, comprising administering to the patient a therapeutically effective amount of a somatostatin agonist, wherein the fibrosis is induced by a drug or combination of drugs and preferably fibrosis. inhibited is in the kidney, lung, liver, skin, central nervous system, bone or bone marrow, cardiovascular system, an endocrine organ or gastrointestinal system. Each of the immediately preceding methods is preferred. In yet another aspect, this invention provides a method for inhibiting fibrosis in a patient, which comprises administering to the patient a therapeutically effective amount of a somatostatin agonist, wherein the fibrosis is induced by a disease state and preferably inhibited fibrosis. it is in the kidney, lung, liver, skin, central nervous system, bone or bone marrow, cardiovascular system, an endocrine organ or gastrointestinal system. Each of the immediately preceding methods is preferred. In still another aspect, this invention provides a method for inhibiting fibrosis in a patient, which comprises administering to the patient a therapeutically effective amount of a somatostatin agonist, wherein the fibrosis is induced by an environmental or industrial factor, and preferably the Inhibited fibrosis is in the kidney, lung, liver, skin, central nervous system, bone or bone marrow, cardiovascular system, an endocrine organ or gastrointestinal system. Each of the immediately preceding methods is preferred. In still another aspect, this invention provides a method for inhibiting fibrosis in a patient, which comprises administering to the patient a therapeutically effective amount of a somatostatin agonist, wherein the fibrosis is induced by an immune response by the patient and preferably the patient. inhibited fibrosis is in the kidney, lung, liver, skin, central nervous system, bone, or bone marrow cardiovascular system, an endocrine organ or gastrointestinal system. Each of the immediately preceding methods is preferred. In still another aspect, this invention provides a method for inhibiting fibrosis in a patient, which comprises administering to the patient a therapeutically effective amount of a somatostatin agonist, wherein the fibrosis is induced by a wound and preferably the inhibited fibrosis is the kidney, lung, liver, skin, central nervous system, bone or bone marrow, cardiovascular system, an endocrine organ or gastrointestinal system. Each of the immediately preceding methods is preferred. In yet another aspect, this invention provides a method for inhibiting fibrosis in a patient, which comprises administering to the patient a therapeutically effective amount of a somatostatin agonist, wherein the somatostatin agonist has a superior binding affinity for the subtype receptor. 1 of somatostatin, human with respect to the other human somatostatin subtype receptors, for the human somatostatin subtype 2 receptor relative to the other human somatostatin subtype receptors, for the human somatostatin subtype 3 receptor relative to the other human somatostatin subtype receptors , for the human somatostatin subtype 4 receptor relative to the other human somatostatin subtype receptors, or for the human somatostatin subtype 5 receptor relative to the other human somatostatin subtype receptors; or wherein the somatostatin agonist has a higher binding affinity for two or more of the human somatostatin receptor subtypes, for example, 1, 2, 3, 4 and / or 5. Each of the immediately preceding methods is preferred. . In yet another aspect, this invention provides a method for inhibiting fibrosis in a patient, which comprises administering to the patient a therapeutically effective amount of a somatostatin agonist, wherein the somatostatin agonist is: R A 1? -A? 2'-A3-D-Trp-Lys-A 6c-_A? 7 '_- A? S °.-R3 / R2 or a pharmaceutically acceptable salt thereof, wherein A1 is a D- or L- isomer of Ala, Leu, Lie, Val, NIe, Thr, Ser, β-Nal, β-Pal, Trp, Phe, 2, 4- dichloro-Phe, pentafluoro-Phe, pX-Phe, or oX-Phe; A2 is Ala, Leu, Lie, Val, Nle, Phe, β-Nal, pyridyl-Ala, Trp, 2,4-dichloro-Phe, pentafluoro-Phe, o-X-Phe, or p-X-Phe; A3 is pyridyl-Ala, Trp, Phe, β-Nal, 2,4-dichloro-Phe, pentafluoro-Phe, o-X-Phe, or p-X-Phe; A6 is Val, Ala, Leu, Lie, Nle, Thr, Abu, or Ser; A7 is Ala, Leu, Lie, Val, NIe, Phe, β-Nal, pyridyl-Ala, Trp, 2,4-dichloro-Phe, pentafluoro-Phe, o-X-Phe, or p-X-Phe; A8 is a D- or L-isomer of Ala, Leu, Lie, Val, Nle, Thr, Ser, Phe,, β-Nal, pyridyl-Ala, Trp, 2,4-dichloro-Phe, pentafluoro-Phe, pX -Phe, or oX-Phe; wherein X for each occurrence is independently selected from the group consisting of CH3, Cl, Br, F, OH, OCH3 and N02; each R-L and R2 independently, is H, lower acyl or lower alkyl; and R3 is OH or NH2; with the proviso that at least one of A1 and A8 and one of A2 and A7 must be an aromatic amino acid; and with the additional condition that A1, A2, A7 and A8 can not all be aromatic amino acids. In yet another aspect, a method for inhibiting fibrosis in a patient is provided, which comprises administering to the patient a therapeutically effective amount of a somatostatin agonist, wherein the somatostatin agonist is: HD-Phe-p-chloro-Phe -Tyr-D-Trp-Lys-Thr-Phe-Thr-NH2; H-D-Phe-p-N02-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2; H-D-Nal-p-chloro-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2; H-D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH2; H-D-Phe-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2; H-D-Phe-p-chloro-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2; or H-D-Phe-Ala-Tyr-D-Trp-Lys-Val-Ala-β-D-Nal-NH 2 or a pharmaceutically acceptable salt thereof. In yet another aspect, a method for inhibiting fibrosis in a patient is provided, which comprises administering to the patient a therapeutically effective amount of a somatostatin agonist, wherein the somatostatin agonist is: D-Phe-Cys-Phe-D -Trp-Lys-Thr-Cys-ß-Nal-NH2; D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-β-Nal-NH 2; D-ß-Nal-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2; D-Phe-Cys-Phe-D-Trp-Lys-Thr- in-Thr-NH2; D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-OH; D-Phe-Cys-Phe-D-Trp-Lys-Thr-Pen-Thr-OH; Gly-Pen-Phe-D-Trp-Lys-Thr-Cys-Thr-OH; Phe-Pen-Tyr-D-Trp-Lys-Thr-Cys-Thr-OH; Phe-Pen-Phe-D-Trp-Lys-Thr-Pen-Thr-OH; H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol; H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; H-D-Trp-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2; H-D-Trp-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2, • H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH 2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2; Ac-D-Phe-Lys * -Tyr-D-Trp-Lys-Val-Asp-Thr-NH2, wherein an amide bridge is between Lys * and Asp; Ac-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (Et) 2-Gly-cys-phe-D-Trp-Lys-Thr-cys-Thr-NH2; Ac-D-hArg (Bu) -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (Et) 2-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2, • Ac-L-hArg (Et) 2-Cys-Phe-D-Trp-Lys-Thr -Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH2; Ac-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NHEt; Ac-L-hArg (CH2-CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys (Me) -Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys (Me) -Thr-Cys-Thr-NHEt; Ac-hArg (CH3, hexyl) -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; H-hArg (hexyl) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NHEt; Ac-D-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH2; Propionyl-D-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys (iPr) -Thr-Cys-Thr-NH2; Ac-D-ß-Nal-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Gly-hArg (Et) ¡. -N? L ,; As-D-Lys (iPr) -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Tpr-Lys-Thr-Cys-Phe-NH2; Ac-D-hArg (Et) 2-D-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-Cys-Lys-Asn-4-Cl-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Ser-D-Cys-NH2; Bmp-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2; Bmp-Tyr-D-Trp-Lys-Val-Cys-Phe-NH2; Bmp-Tyr-D-Trp-Lys-Val-Cys-p-Cl-Phe-NH2; Bmp-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH 2; H-D-ß-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2; HD-Phe-cys-Tyr-D-Trp-Lys-Abu-cys-Thr-NH2, • HD-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-β-Nal-NH2, • H- pentafluoro-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2; Ac-D-β-Nal-Cys-pentafluoro-Phe-D-Trp-Lys-Val-Cys-Thr-NH 2; H-D-β-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH 2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH 2; H-D-β-Nal-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH 2; H-D-p-Cl-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2; Ac-D-p-Cl-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2; H-D-Phe-Cys-β-Nal-D-Trp-Lys-Val-Cys-Thr-NH 2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH2; cycle (Pro-Phe-D-Trp-N-Me-Lys-Thr-Phe) cycle (Pro-Phe-D-Trp-N-Me-Lys-Thr-Phe) cycle (Pro-Phe-D-Trp- Lys-Thr-N-Me-Phe) cycle (N-Me-Ala-Tyr-D-Trp-Lys-Thr-Phe) cycle (Pro-Tyr-D-Trp-Lys-Thr-Phe) cycle (Pro- Phe-D-Trp-Lys-Thr-Phe) cycle (Pro-Phe-L-Trp-Lys-Thr-Phe) cycle (Pro-Phe-D-Trp (F) -Lys-Thr-Phe); Cyclo (Pro-Phe-Tr (F) -Lys-Thr-Phe); cycle (Pro-Phe-D-Trp-Lys-Ser-Phe); Cyclo (Pro-Phe-D-Trp-Lys-Thr-p-Cl-Phe); Cyclo (D-Ala-N-Me-D-Phe-D-Thr-D-Lys-Trp-D-Phe) Cyclo (D-Ala-N-Me-D-Phe-D-Val-Lys-D-) Trp-D-Phe) Cyclo (D-Ala-N-Me-D-Phe-D-Thr-Lys-D-Trp-D-Phe) Cyclo (D-Abu-N-Me-D-Phe-D- Val-Lys-D-Trp-D-Tyr), cycle (Pro-Tyr-D-Trp-t-4-AchxAla-Thr-Phe); Cyclo (Pro-Phe-D-Trp-t-4-AchxAla-Thr-Phe); Cyclo (N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe); Cyclo (N-Me-Ala-Tyr-D-Trp-t-4-AchxAla-Thr-Phe); Cyclo (Pro-Tyr-D-Trp-4-Amphe-Thr-Phe); Cyclo (Pro-Phe-D-Trp-4-Amphe-Thr-Phe); Cyclo (N-Me-Ala-Tyr-D-Trp-4-Amphe-Thr-Phe); Cycle (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba); Cycle (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba-Gaba); cycle (Asn-Phe-D-Trp-Lys-Thr-Phe); Cyclo (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-NH (CH 2) 4 CO) cyclo (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-β-Ala); Cyclo (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-D-Glu) -OH; Cyclo (Phe-Phe-D-Trp-Lys-Thr-Phe); Cyclo (Phe-Phe-D-Trp-Lys-Thr-Phe-Gly); cycle (Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba); Cyclo (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gly); cycle (Asn-Phe-Phe-D-Trp (F) -Lys-Thr-Phe-Gaba); cycle (Asn-Phe-Phe-D-Trp (N02) -Lys-Thr-Phe-Gaba); cycle (Asn-Phe-Phe-Trp (Br) -Lys-Thr-Phe-Gaba); cycle (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe (I) -Gaba); Cycle (Asn-Phe-Phe-D-Trp-Lys-Thr-Tyr (But) -Gaba); cycle (Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Pro-Cys) OH; Cyclo (Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Pro-Cys) - OH; Cyclo (Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Tpo-Cys) - OH; Cyclo (Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-MeLeu- Cys) -OH; Cyclo (Phe-Phe-D-Trp-Lys-Thr-Phe-Phe-Gaba); Cyclo (Phe-Phe-D-Trp-Lys-Thr-Phe-D-Phe-Gaba); Cyclo (Phe-Phe-D-Trp (5F) -Lys-Thr-Phe-Phe-Gaba); Cyclo (Asn-Phe-Phe-D-Trp-Lys (Ac) -Thr-Phe-NH- (CH2) 3-CO); cycle (Lys-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba); cycle (Lys-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba); or cycle (Orn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba) or a pharmaceutically acceptable salt thereof.
In yet another aspect, there is provided a method for inhibiting fibrosis in a patient which comprises administering to the patient a therapeutically effective amount of a somatostatin agonist, wherein the somatostatin agonist is D-β-Nal-Cys-Typ-D -Trp-Lys-Thr- Cys-Thr-NH2, H-Cys-Phe-Phe-D-Trp-Lys-Thr-Phe-Cys-NH2, HO. { CH2) 2 - N r ~ x N - CH2-CO-D-Phe-Cys-Tyr-0-T-Lys-Abu-Cys-Thr-NHa / \ HO (CH2) 3 - N? N - (CH2) 2-SO! Í-D-P ß-Cys-Tyr-D-Trp-Lys.Abu-Cys «Thr-NH2, or D-Phe-cyclo (Cys-Phe-D-Trp-Lys-Thr-Cys) -Thr-ol or a pharmaceutically acceptable salt thereof. Each of the immediately preceding methods is preferred. In a further aspect, this invention provides a method for inhibiting overexpression of TGF-β, which comprises administering to a subject an effective amount of somatostatin, somatostatin agonist or a pharmaceutically acceptable salt thereof; preferred of this method is where a somatostatin agonist is administered; a preferred method of the immediately preceding method wherein the somatostatin agonist has a higher binding affinity for the human somatostatin subtype 1 receptor relative to the other human somatostatin subtype receptors, for the human somatostatin subtype 2 receptor relative to the other receptors subtype of human somatostatin, for the human somatostatin subtype 3 receptor relative to the other human somatostatin subtype receptors, for the human somatostatin subtype 4 receptor relative to the other human somatostatin subtype receptors, or for the somatostatin subtype 5 receptor human with respect to the other human somatostatin subtype receptors; or wherein the somatostatin agonist has a higher binding affinity for two or more of the receptor subtypes, for example, 1, 2, 3, 4 and / or 5 of human somatostatin. Each of the above methods is preferred. In still another aspect, this invention provides a method for inhibiting the overexpression of TGF-β, which comprises administering to a subject an effective amount of a somatostatin agonist, wherein the somatostatin agonist is: or a pharmaceutically acceptable salt thereof, wherein A1 is a D- or L- isomer of Ala, Leu, Lie, Val, NIe, Thr, Ser, β-Nal, β-Pal, Trp, Phe, 2, 4- dichloro-Phe, pentafluoro-Phe, pX-Phe, or oX-Phe; A2 is Ala, Leu, Lie, Val, Nle, Phe, β-Nal, pyridyl-Ala, Trp, 2,4-dichloro-Phe, pentafluoro-Phe, o-X-Phe, or p-X-Phe; A3 is pyridyl-Ala, Trp, Phe, β-Nal, 2,4-dichloro-Phe, pentafluoro-Phe, o-X-Phe, or p-X-Phe; A6 is Val, Ala, Leu, Lie, Nle, Thr, Abu, or Ser; A7 is Ala, Leu, Lie, Val, Nle, Phe, β-Nal, pyridyl-Ala, Trp, 2,4-dichloro-Phe, pentafluoro-Phe, o-X-Phe, or p-X-Phe; A8 is a D- or L-isomer of Ala, Leu, Lie, Val, NIe, Thr, Ser, Phe,, β-Nal, pyridyl-Ala, Trp, 2,4-dichloro-Phe, pentafluoro-Phe, pX -Phe, or oX-Phe; wherein X for each occurrence is independently selected from the group consisting of CH3, Cl, Br, F, OH, OCH3 and N02; each Rx and R2 independently, is H, lower acyl or lower alkyl; and R3 is OH or NH2; with the proviso that at least one of A1 and A8 and one of A2 and A7 must be an aromatic amino acid; and with the additional condition that A1, A2, A7 and A8 can not all be aromatic amino acids. Also, this invention provides a method for inhibiting overexpression of TGF-β, which comprises administering to a subject an effective amount of a somatostatin agonist, wherein the somatostatin agonist is: HD-Phe-p-chloro-Phe- Tyr-D-Trp-Lys-Thr-Phe-Thr-NH2; H-D-Phe-p-N02-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2; H-D-Nal-p-chloro-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2; H-D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH2; H-D-Phe-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2; H-D-Phe-p-chloro-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2; or H-D-Phe-Ala-Tyr-D-Trp-Lys-Val-Ala-β-D-Nal-NH 2 or a pharmaceutically acceptable salt thereof. Also, this invention provides a method for inhibiting overexpression of TGF-β, which comprises administering to a subject an effective amount of somatostatin agonist, wherein the somatostatin agonist is: D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-β-Nal-NH 2; D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-β-Nal-NH 2; D-ß-Nal-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2, • D-Phe-Cys-Phe-D-Trp-Lys-Thr-Pen-Thr-NH2; D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-OH; D-Phe-Cys-Phe-D-Trp-Lys-Thr-Pen-Thr-OH; Gly-Pen-Phe-D-Trp-Lys-Thr-Cys-Thr-OH; Phe-Pen-Tyr-D-Trp-Lys-Thr-Cys-Thr-OH; Phe-Pen-Phe-D-Trp-Lys-Thr-Pen-Thr-OH, • H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol; H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; H-D-Trp-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2; H-D-Trp-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH 2, - H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH 2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2; Ac-D-Phe-Lys * -Tyr-D-Trp-Lys-Val-Asp-Thr-NH2, wherein an amide bridge is between Lys * and Asp; Ac-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (Et) 2-Gly-cys-phe-D-Trp-Lys-Thr-cys-Thr-NH2; Ac-D-hArg (Bu) -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (Et) 2-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-L-hArg (Et) 2-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH2; Ac-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NHEt; Ac-LthArg (CH2-CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys (Me) -Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys (Me) -Thr-Cys-Thr-NHEt; Ac-hArg (CH3, hexyl) -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; H-hArg (hexyl) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NHEt; Ac-D-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH2; Propionyl-D-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys (iPr) -Thr-Cys-Thr-NH2; Ac-D-β-Nal-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Gly-hArg (Et) 2-NH 2; Ac-D-Lys (iPr) -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Tpr-Lys-Thr-Cys-Phe-NH2; Ac-D-hArg (Et) 2-D-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-Cys-Lys-Asn-4-Cl-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Ser-D-Cys-NH2; Bmp-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2; Bmp-Tyr-D-Trp-Lys-Val-Cys-Phe-NH2; Bmp-Tyr-D-Trp-Lys-Val-Cys-p-Cl-Phe-NH2; Bmp-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH 2; H-D-β-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH 2, • H-D-Phe-cys Tyr-D-Trp-Lys-Abu-cys-Thr-NH 2; HD-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-ß-Nal-NH2, • H-pentafluoro-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2; Ac-D-β-Nal-Cys-pentafluoro-Phe-D-Trp-Lys-Val-Cys-Thr-NH 2; H-D-β-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH 2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH 2; HD-ß-Nal-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2, • HDp-Cl-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2, • Ac-Dp-Cl-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2; H-D-Phe-Cys-β-Nal-D-Trp-Lys-Val-Cys-Thr-NH 2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH2; cycle (Pro-Phe-D-Trp-N-Me-Lys-Thr-Phe) cycle (Pro-Phe-D-Trp-N-Me-Lys-Thr-Phe) cycle (Pro-Phe-D-Trp- Lys-Thr-N-Me-Phe) cycle (N-Me-Ala-Tyr-D-Trp-Lys-Thr-Phe) cycle (Pro-Tyr-D-Trp-Lys-Thr-Phe) cycle (Pro- Phe-D-Trp-Lys-Thr-Phe) cycle (Pro-Phe-L-Trp-Lys-Thr-Phe) cycle (Pro-Phe-D-Trp (F) -Lys-Thr-Phe); cycle (Pro-Phe-Trp (F) -Lys-Thr-Phe); cycle (Pro-Phe-D-Trp-Lys-Ser-Phe); Cyclo (Pro-Phe-D-Trp-Lys-Thr-p-Cl-Phe); Cyclo (D-Ala-N-Me-D-Phe-D-Thr-D-Lys-Trp-D-Phe) Cyclo (D-Ala-N-Me-D-Phe-D-Val-Lys-D-) Trp-D-Phe) Cyclo (D-Ala-N-Me-D-Phe-D-Thr-Lys-D-Trp-D-Phe) Cyclo (D-Abu-N-Me-D-Phe- -Val -Lys-D-Trp--Tyr), cycle (Pro-Tyr-D-Trp-t-4-AchxAla-Thr-Phe); Cyclo (Pro-Phe-D-Trp-t-4-AchxAla-Thr-Phe); Cyclo (N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe); Cyclo (N-Me-Ala-Tyr-D-Trp-t-4-AchxAla-Thr-Phe); Cyclo (Pro-Tyr-D-Trp-4-Amphe-Thr-Phe); Cyclo (Pro-Phe-D-Trp-4-Amphe-Thr-Phe); Cyclo (N-Me-Ala-Tyr-D-Trp-4-Amphe-Thr-Phe), -cycle (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba); Cycle (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba-Gaba); cycle (Asn-Phe-D-Trp-Lys-Thr-Phe); Cyclo (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-NH (CH 2) 4 CO) cyclo (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-β-Ala); Cyclo (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-D-Glu) -OH; Cyclo (Phe-Phe-D-Trp-Lys-Thr-Phe); Cyclo (Phe-Phe-D-Trp-Lys-Thr-Phe-Gly); cycle (Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba); Cyclo (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gly); cycle (Asn-Phe-Phe-D-Trp (F) -Lys-Thr-Phe-Gaba); cycle (Asn-Phe-Phe-D-Trp (N02) -Lys-Thr-Phe-Gaba); cycle (Asn-Phe-Phe-Trp (Br) -Lys-Thr-Phe-Gaba); cycle (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe (I) -Gaba); Cycle (Asn-Phe-Phe-D-Trp-Lys-Thr-Tyr (But) -Gaba); cycle (Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Pro-Cys) OH; Cyclo (Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Pro-Cys) - OH; Cyclo (Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Tpo-Cys) - OH; Cyclo (Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-MeLeu- Cys) -OH; Cyclo (Phe-Phe-D-Trp-Lys-Thr-Phe-Phe-Gaba); Cyclo (Phe-Phe-D-Trp-Lys-Thr-Phe-D-Phe-Gaba); Cyclo (Phe-Phe-D-Trp (5F) -Lys-Thr-Phe-Phe-Gaba); Cyclo (Asn-Phe-Phe-D-Trp-Lys (Ac) -Thr-Phe-NH- (CH2) 3-CO); cycle (Lys-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba); cycle (Lys-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba); or cycle (Orn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba) or a pharmaceutically acceptable salt thereof. Also, this invention provides a method for inhibiting overexpression of TGF-β, which comprises administering to a subject an effective amount of somatostatin agonist, or a pharmaceutically salt thereof wherein the somatostatin agonist or a pharmaceutically salt thereof is D-ß-Nal-Cys-Typ-D-Trp-Lys-Thr-Cys-Thr-NH2, H-Cys-Phe-Phe-D-Trp-Lys-Thr-Phe-Cys-NH2, HO (CH2) 2- N-CH2-CO-D-Phß-Cys-Tyr.D-Tf.Lys-Abu-Cys-Thr-NH2 / - \ HO (CH2) 2- N N- (CH2) 2-SOrD-Pß-Cys-Tyr-D-Trp-Lys.Abu-Cys.Tr-NH2, or D-Phe-cyclo (Cys-Phe-D-Trp-Lys-Thr-Cys) -Thr-ol or a pharmaceutically acceptable salt thereof. Each of the above methods is preferred. In yet another aspect, this invention provides a method wherein it is preferred that from each of the methods described above that the somatostatin agonist be administered parenterally more preferably than the parenterally administered somatostatin agonist is administered in a sustained release formulation. . It is also preferred that from each of the methods described above that the somatostatin agonist, or the pharmaceutically acceptable salt thereof, be administered orally or topically. Each of the above methods is preferred. Yet another aspect of the present invention provides a pharmaceutical composition useful for inhibiting fibrosis in a patient, which comprises a pharmaceutically acceptable carrier and an effective amount of somatostatin, somatostatin agonist, or a pharmaceutically acceptable salt thereof, preferred from the immediately preceding pharmaceutical composition is a pharmaceutical composition comprising a somatostatin agonist or a pharmaceutically acceptable salt of the same. Yet another aspect of the present invention provides a pharmaceutical composition useful for inhibiting the overexpression of TGF-β, which comprises a pharmaceutically acceptable carrier and an effective amount of somatostatin, somatostatin agonist or a pharmaceutically acceptable salt thereof, preferred from the The immediately preceding pharmaceutical composition is a pharmaceutical composition comprising a somatostatin agonist or a pharmaceutically acceptable salt thereof. The definition of "somatostatin agonist" will be defined later. A therapeutically effective amount depends on the condition being treated, the treatment regimen, the route of administration chosen, and the specific activity of the compound used and will ultimately be defined by the attending physician or veterinarian. In one embodiment, the somatostatin agonist is administered to the patient until it stops and / or reverses the fibrotic process. In another embodiment, the somatostatin agonist is administered during the lifetime of the patient. In yet another embodiment, the somatostatin agonist is administered prior to the event initiating the fibrotic process (eg, prior to chemotherapy or exposure to radiation such as radiation therapy). Somatostatin or a somatostatin agonist has been injected parenterally, for example, intravenously, into the bloodstream of the subject being treated. However, it will be readily appreciated by those skilled in the art that the route, such as subcutaneous, intramuscular, intraperitoneal, enterally, transdermally, transmucosally, sustained release polymer compositions (e.g., a polymer of lactic or micro-acid) particle or implant of lactic-glycolic acid copolymer), profusion, nasal, oral, topical, vaginal, rectal, nasal, sublingual, etc., will vary with the condition being treated and the activity and bioavailability of the somatostatin agonist that is use The dose of the active ingredient administered in a method of this invention can be varied, however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The dose selected will depend on the desired therapeutic effect, the route of administration, and the duration of the treatment. In general, dose levels of 0.000001 to 100 mg / kg of body weight are daily administered to humans and other animals, e.g., mammals. A preferred dose range is 0.01 to 5.0 mg / kg of body weight daily that can be administered as a single dose or divided into multiple doses. While it is possible that the somatostatin agonist is administered as the pure or substantially pure compound, too, it can be presented as a pharmaceutical formulation or preparation. The formulations to be used in the present invention, both for humans and animals, comprise any of the somatostatin agonists to be described below, together with one or more pharmaceutically acceptable carriers thereof, and optionally other therapeutic ingredients. - The carrier must be "acceptable" in the sense that it is compatible with the active ingredient (s) of the formulation (eg, capable of stabilizing peptides) and not harmful to the subject being treated. Desirably, the formulation should not include oxidizing agents or other substances with which the peptides are known to be incompatible. For example, somatostatin agonists in the cyclized form (eg, internal cysteine disulfide bond) are oxidized; in this way, the presence of reducing agents as excipient can lead to an opening of the cysteine disulfide bridge. On the other hand, highly oxidative conditions can lead to the formation of cysteine sulfoxide and to the oxidation of tryptophan. Consequently, it is important to carefully select the excipient. PH is another key factor, and it may be necessary to buffer the product under mildly acidic conditions (pH 5 to 6). The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the pharmacy art. All methods include the step of placing the active ingredient (s) in association with the carrier which constitutes one or more additional ingredients. In general, formulations for tablets or powders are prepared by uniformly and intimately mixing the active ingredient with finely divided solid carriers, and then, if necessary, in the case of tablets, forming the product in the desired shape and size. Formulations suitable for parenteral (e.g., intravenous) administration, on the other hand, conveniently comprise sterile aqueous solutions of the active ingredient (s). Preferably, the salts solutions are isotonic, with the blood of the subject being treated. These formulations can be conveniently prepared by dissolving the active ingredient (s) in a solvent comprising water to produce an aqueous solution, and returning to the sterile solution. The formulation may be presented in unit or multi-dose containers, for example, closed vials or vials. Formulations suitable for parenteral sustained release administrations (eg, biodegradable polymer formulations) are also known in the art. See, for example, U.S. Patent Nos. 3,773,919 and 4,767,628, the teachings of which are incorporated herein by reference, and PCT publication number WO 94/15587. Compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as cocoa butter or a suppository wax. Compositions for nasal or sublingual administration are also prepared with normal excipients well known in the art. For topical administration, they are best used in the form of solutions, creams, balms, lotions, ointments and the like. Somatostatin or somatostatin agonist can also be administered with known (eg, chemotherapeutic) initiators of the fibrotic process to improve fibrosis or to prevent the initiation of fibrosis. Other features and advantages of the invention will be apparent from the following description of preferred embodiments and claims.
Abbreviations ß-Nal = ß-naphthylalanine ß-Nal = ß-pyridylalanine hArg (Bu) = N-guanidino- (butyl) -homoarginine hArg (Et) 2 = N, N '-guanidino- (diethyl) - homoarginine hArg (CH2CF3 ) 2 = N, N'-guanidino-bis- (2, 2, 2-trifluoroethyl) homoarginine hArg (CH3, hexyl) = N, N'-guanidino- (methyl, hexyl) homoarginine Lys (Me) = Ne-methylisine Lys (iPr) = Neopropyllysine AmPhe = aminomethylfine lalanin AchxAla = aminociclohexylalanine Abu = a-aminobutyric acid Tpo = 4-thiaproline MeLeu = N -methyleucine Orn = ornithine Nle = norleucine Nva = norvaline Trp (br) = 5-bromo- tryptophan Trp (F) = 5 fluoro-tryptophan Trp (N02) = 5-nitro-tryptophan Gaba =? -aminobutyric acid Bmp = ß-mercaptopropionyl Ac = acetyl Pen = pencylamine.
DETAILED DESCRIPTION OF THE INVENTION It is believed that one skilled in the art can use the present invention to its fullest extent, based on the following description. The following specific modalities, therefore, should be interpreted as illustrative only and are not limiting of the rest of the description in any way. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are commonly given to them by one skilled in the art to which this invention pertains. Also, all publications, patent applications, patents, and other references mentioned herein are incorporated by reference. The fibrosis that is inhibited can be located in several parts of the body and can be of a particular kind, for example, the fibrosis can be localized: in the kidney, for example, the. fibrosis observed in glomerulonephritis (see Yoshioka et al, Lab Invest 1993; 68: 154-63), diabetic nephropathy (see Yamamoto et al, Proc.
Nati Acad Sci USA 1993; 90: 1814-8), rejection of the graft (see Shihab et al, J Am Soc Nephrol 1993; 4: 671, abstract), and HIV nephropathy (see Border et al., J Am Soc Nephrol 1993; 4: 675, abstract); in the liver, for example, cirrhosis, (see Castilla et al, N Engl J Med 1991; 324: 933-940 and Nagy et al, Hepatology 1991; 14: 269-73), and veno-occlusive disease (see Anscher et al, N Engl J Med 1993; 328: 1592-8); in the lung, for example, idiopathic fibrosis, (see, Anscher et al, N Engl J Med 1993; 328: 1592-8 and Brockelmann et al, Proc Nati Acad Sci USA 1991; 88: 6642-6) and autoimmune fibrosis ( see Deguchi, Ann Rheum Dis 1992; 51: 362-5); in the skin, for example, systemic sclerosis (see Kulozik et al, J Clin Invest 1990; 86: 917-22), keloids (see Peltonen et al, J Invest Dermatol 1991; 97: 240-8), scars (see Ghahary et al, J Lab Clin Med 1993; 122: 465-73), and eosinophilia-myalgia syndrome (see Varga et al, Ann Intern Med 1992; 116: 140-7; in the central nervous system, for example, infra-ocular fibrosis (see Conner et al, J Clin Invest. 1989; 83: 1661-6), in the cardiovascular system, for example, vascular restenosis (see Nikol et al, J Clin Invest 1992; 90: 1582-92); in the nose, for example, nasal polyposis (see Ohno et al, J Clin Invest 1992; 89: 1662-8); in bone or bone marrow (see Harrison Principies of, Infernal Medicine, Thirteenth Edition, Volume 2, Chapter 362, pp. 2197-2199; Najean, Y et al, Leuk Lymphoma, 1996, 22 Suppl 1: 111-119; and Reith, J.D. et al, Am J Srg Pathol, 1996 20 (11): 1368-1377); in an endocrine organ (see Endocrinology, Third Edition, Edited by Leslie J. Degroot, Vol. 1, pp. 165-177 and pp. 747-751); and in the gastrointestinal system (see Mizoi, T. Et al, Cancer Res, 1993 53 (1): 183-190; and Tahara, E, J. Cancer Res. Clin Oncol, 1990, 116 (2), 121- 131). A fibrotic disorder can be induced by a number of causes including: chemotherapy, for example, pulmonary fibrosis that results from treatment with bleomycin, chlorambucil, cyclophosphamide, methotrexate,, mustine, or procarbazine (see Key Facts in Oncology by Lilly, Drug Therapy, p.11, 1994); exposure to radiation either accidental or intentional as in radiation therapy, for example, interstitial lung disease (ILD) resulting from radiation (see Cecil Textbook of Medicine, 19th Edition, edited by James B. Wyngaarden, Lloyd H. Smith, Jr. and J. Claude Bennet, Chapter 60, Table 60-5, page 399, 1992); environmental or industrial factors or pollutants such as chemicals, fumes, metals, vapors, gases, etc., for example, ILD resulting from asbestos or coal dust (see Cecil Textbook pf Medicine, 19th Edition, edited by James B. Wyngaarden , Lloyd H. Smith, Jr. and J. Claude Bennet, Chapter 60, Table 60-2, pp. 398, 1992); a drug or combination of drugs, for example, antibiotics (eg, penicillins, sulfonamides), cardiovascular drugs (eg, hydralazine, beta blockers, etc.), CNS drugs (Phenytoin, chlorpromazine, etc.) Anti-inflammatory drugs (eg, gold salts, phenylbutazone, etc.) etc can cause ILD (see Cecil Texbook of Medicine, 19th Edition, edited by James B. Wyngaarden, Lloyd H. Smith , Jr. and J. Claude Bennet, Chapter 60, Table 60-4, pp. 398, 1992); an immune reaction disorder, eg, chronic host disease against the graft with dermal fibrosis, (see Fibrotic Skin Diseases, Editorial, J. Uitto and S. Jimenez, Arch, Dermol, Vol. 126, May 1990, p. .662), disease states such as aspiration pneumonia which is a known thing of ILD, (see Harrison 's Principies of Infernal Medicine, Twelfth Edition, Chapter 211, Table 211-1, P 1083) and parasite-induced fibrosis (see Wahl, S.M., Kidney Int, 1997, 51 (5): 1370-1375); and wounds, for example, numb trauma, surgical incisions, battlefield wounds, etc., as well as penetrating lesions of the CNS (see Ann Logan, et al, Brain Research, 587 (1992), 216-225).
Somatostatin and its agonists Somatostatin (somatotropin inhibition release factor or SRIF) has both an isoform of 14 amino acids (somatostatin-14) and an isoform of 28 amino acids (somatostatin-28). See Wilson, J & Foster, D, Williams Textbook of endocrinology, p. 510 (7th ed., 1985). The compound is an inhibitor of growth hormone secretion and was originally isolated from the hypothalamus. Brazeau et al., Science 179: 77 (1973). Native somatostatin has a very short rate of effect in vivo since it is rapidly inactivated by endo- and exopeptidase. Many new analogs have been prepared in order to improve the duration of the effect, biological activity and selectivity (for example, for the particular somatostatin receptor) of this hormone. These analogues will be referred to as "somatostatin agonist" herein. Additionally, compounds that are short peptides modified by organic and non-peptide portions, such as organic molecules that do not have an amino acid recognized in the art as part of their structure, that bind to the somatostatin receptor (s) are also within the meaning of "somatostatin agonist". Several somatostatin receptors (SSTR) have been isolated, for example, SSTR-1, SSTR-2, SSTR-3, SSTR-4, and SSTR-5. In this manner, the somatostatin agonist can be an SSTR-1 agonist, SSTR-2 agonist, SSTR-3 agonist, SSTR-4 agonist, of an SSTR-5 agonist. In one embodiment, the somatostatin agonist is an SSTR-2 agonist or an SSTR-5 agonist. What is meant by an "SSTR-2 agonist" or an "SSTR-5 agonist" is a compound that (1) has a high affinity (eg, Ki of less than 1 M or, preferably, less than 10 nM) for the SSTR-2 or SSTR-5, respectively (as defined by the receptor binding assay described below), and (2) inhibits the formation of fibrosis (eg, as defined by the biological assay described later). The somatostatin agonist may also be selective for a particular somatostatin receptor, for example, it has a higher binding affinity for a particular somatostatin receptor subtype. In one embodiment, the somatostatin receptor is a selective agonist of SSTR-2 or SSTR-5. Somatostatin agonists that can be used to practice the therapeutic method of the present invention include but are not limited to those covered by the formulas, or those specifically cited in the publications set forth below, all of which are thus incorporated by reference. Application number EP. P5 164 EU (inventor G. Keri); Van Binst, G. And collaborators. Peptide Research 5: 8 (1992); Horvath, A. et al. Abstract, "Conformations of Somatostatin Analogs Having Antitumor Activity", 22nd European peptide Symposium, September 13-19, 1992, Interlaken, Switzerland; PCT Application WO 91/09056 (1991); Application EP 0 363 589 A2 (1990); American Patent Number. 4,904,642 (1990); American Patent Number. 4,871,717 (1989); American Patent Number. 4,853,371 1987) North American Patent Number. 4, 725, 577 1988) North American Patent Number. 4,684,620 1987) North American Patent Number. 4,650,787 1987) North American Patent Number. 4,603,120 1986) North American Patent Number. 4,585,755 1986) Application EP 0 203 031 A2 (1986); American Patent Number. 4,522,813 1985) United States Patent Number. 4,486,415 1984) North American Patent Number. 4,486,101 1984) North American Patent Number. 4,435,385 1984) North American Patent Number. 4,395,403 1983) North American Patent Number. 4,369,179 1983) North American Patent Number. 4,360,516 1982) North American Patent Number. 4,358,439 1982) North American Patent Number. 4,328,214 1982) North American Patent Number. 4,316,890 1982) North American Patent Number. 4,310,518 1982) North American Patent Number. 4,291,022 1981) North American Patent Number. 4,238,481 1980) North American Patent Number. 4,235,886 1980) North American Patent Number. 4,224,190 1980) North American Patent Number. 4,211,693 1980) North American Patent Number. 4,190,648 1980) North American Patent Number. 4,146,612 (1979); American Patent Number. 4,133,782 (1979) Examples of somatostatin agonists include, but are not limited to, the following somatostatin analogues and the pharmaceutically acceptable salt thereof which are described in the references cited above: D-β-Nal-Cys-Tyr-D-Trp- Lys-Thr-Cys-Thr-NH2 (BIM-23014); D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-β-Nal-NH 2; D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-β-Nal-NH 2; D-ß-Nal-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2, • D-Phe-Cys-Phe-D-Trp-Lys-Thr-Pen-Thr-NH2; D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-OH; D-Phe-Cys-Phe-D-Trp-Lys-Thr-Pen-Thr-OH, • Gly-Pen-Phe-D-Trp-Lys-Thr-Cys-Thr-OH; Phe-Pen-Tyr-D-Trp-Lys-Thr-Cys-Thr-OH, • Phe-Pen-Phe-D-Trp-Lys-Thr-Pen-Thr-OH; H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol; H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; H-D-Trp-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2, • H-D-Trp-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2; Ac-D-Phe-Lys * -Tyr-D-Trp-Lys-Val-Asp-Thr-NH2, wherein an amide bridge is between Lys * and Asp; Ac-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (Et) 2-Gly-cys-phe-D-Trp-Lys-Thr-cys-Thr-NH2; Ac-D-hArg (Bu) -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (Et) 2-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-L-hArg (Et) 2-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-Gl? -Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH2; Ac-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NHEt; Ac-L-hArg (CH2-CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys (Me) -Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys (Me) -Thr-Cys-Thr-NHEt; Ac-hArg (CH3, hexyl) -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; H-hArg (hexyl) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NHEt; Ac-D-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH2; Propionyl-D-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys (iPr) -Thr-Cys-Thr-NH2; Ac-D-β-Nal-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Gly-hArg (Et) 2-NH 2; Ac-D-Lys (iPr) -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Tpr-Lys-Thr-Cys-Phe-NH2; Ac-D-hArg (Et) 2-D-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-Cys-Lys-Asn-4-Cl-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Ser-D-Cys-NH2; Bmp-Tyr-D-Trp-Lys-Val-Cys-Thr-NH 2, • Bmp-Tyr-D-Trp-Lys-Val-Cys-Phe-NH 2; Bmp-Tyr-D-Trp-Lys-Val-Cys-p-Cl-Phe-NH2; , Bmp-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH 2; < H-D-ß-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2; H-D-Phe-cys-Tyr-D-Trp-Lys-Abu-cys-Thr-NH2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-β-Nal-NH 2; H-pentafluoro-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2; Ac-D-β-Nal-Cys-pentafluoro-Phe-D-Trp-Lys-Val-Cys-Thr-NH 2; H-D-β-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH 2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH 2; H-D-β-Nal-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH 2; H-D-p-Cl-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2; Ac-D-p-Cl-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2; H-D-Phe-Cys-β-Nal-D-Trp-Lys-Val-Cys-Thr-NH 2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH2; Cyclo (Pro-Phe-D-Trp-N-Me-Lys-Thr-Phe); Cyclo (Pro-Phe-D-Trp-N-Me-Lys-Thr-Phe); Cyclo (Pro-Phe-D-Trp-Lys-Thr-N-Me-Phe); Cyclo (N-Me-Ala-Tyr-D-Trp-Lys-Thr-Phe); Cyclo (Pro-Tyr-D-Trp-Lys-Thr-Phe); Cyclo (Pro-Phe-D-Trp-Lys-Thr-Phe); Cyclo (Pro-Phe-L-Trp-Lys-Thr-Phe); Cyclo (Pro-Phe-D-Tr (F) -Lys-Thr-Phe); cycle (Pro-Phe-Trp (F) -Lys-Thr-Phe); cycle (Pro-Phe-D-Trp-Lys-Ser-Phe); Cyclo (Pro-Phe-D-Trp-Lys-Thr-p-Cl-Phe); Cyclo (D-Ala-N-Me-D-Phe-D-Thr-D-Lys-Trp-D-Phe) Cyclo (D-Ala-N-Me-D-Phe-D-Val-Lys-D-) Trp-D-Phe) Cyclo (D-Ala-N-Me-D-Phe-D-Thr-Lys-D-Trp-D-Phe) Cyclo (D-Abu-N-Me-D-Phe-D- Val-Lys-D-Trp-D-Tyr), cycle (Pro-Tyr-D-Trp-t-4-AchxAla-Thr-Phe); Cyclo (Pro-Phe-D-Trp-t-4-AchxAla-Thr-Phe); Cyclo (N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe); Cyclo (N-Me-Ala-Tyr-D-Trp-t-4-AchxAla-Thr-Phe); Cyclo (Pro-Tyr-D-Trp-4-Amphe-Thr-Phe); Cyclo (Pro-Phe-D-Trp-4-Amphe-Thr-Phe); Cyclo (N-Me-Ala-Tyr-D-Trp-4-Amphe-Thr-Phe); Cycle (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba); Cycle (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba-Gaba); cycle (Asn-Phe-D-Trp-Lys-Thr-Phe); Cyclo (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-NH (CH2) 4C0) Cyclo (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-β-Ala); Cycle Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-D-Glu) -OH; Phe-Phe-D-Trp-Lys-Thr-Phe cycle); Phe-Phe-D-Trp-Lys-Thr-Phe-Gly cycle); Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba cycle); Cycle Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gly); Cycle Asn-Phe-Phe-D-Tr (F) -Lys-Thr-Phe-Gaba); Cycle Asn-Phe-Phe-D-Trp (N02) -Lys-Thr-Phe-Gaba); Cycle Asn-Phe-Phe-Trp (Br) -Lys-Thr-Phe-Gaba); Cycle Asn-Phe-Phe-D-Trp-Lys-Thr-Phe (I) -Gaba); Cycle Asn-Phe-Phe-D-Trp-Lys-Thr-Tyr (But) -Gaba); cycle (Bmp Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Pro-Cys) - OH; Cyclo (Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Pro-Cys) - OH; Cyclo (Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Tpo-Cys) - OH; Cyclo (Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-MeLeu- Cys) -OH; Cyclo (Phe-Phe-D-Trp-Lys-Thr-Phe-Phe-Gaba); Cyclo (Phe-Phe-D-Trp-Lys-Thr-Phe-D-Phe-Gaba); Cyclo (Phe-Phe-D-Trp (5F) -Lys-Thr-Phe-Phe-Gaba); Cyclo (Asn-Phe-Phe-D-Trp-Lys (Ac) -Thr-Phe-NH- (CH2) 3-CO); cycle (Lys-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba); cycle (Lys-Ph.e-Phe-D-Trp-Lys-Thr-Phe-Gaba); cycle (Orn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba); and H-Cys-Phe-Phe-D-Trp-Lys-Thr-Phe-Cys-NH2 (BIM-23268). It is noted that for all somatostatin agonists described herein, each amino acid residue represents the structure of -NH-C (R) H-CO-, in which R is the side chain (e.g., CH3 for Ala) except for Thr-ol which means -NH-CH (CH (CH3) OH) -CH2-0H and Pro which means prolinyl. The lines between amino acid residues represent peptide bonds that bind amino acids. Also, where the amino acid residue is optically active, it is the proposed L-shape configuration unless form D is expressly designated. A disulfide bridge is formed between two Cys residues; however, it is not shown. The use of linear somatostatin agonists of the following formula is also within the invention: R \ A1-A2-A3-D-Trp-Lys-A € -A-A8-R3 / R2 or a pharmaceutically acceptable salt thereof, wherein A1 is a D- or L- isomer of Ala, Leu, Lie, Val, NIe, Thr, Ser, β-Nal, β-Pal, Trp, Phe, 2, 4- dichloro-Phe, pentafluoro-Phe, pX-Phe, or oX-Phe; A2 is Ala, Leu, Lie, Val, NIe, Phe, β-Nal, pyridyl-Ala, Trp, 2,4-dichloro-Phe, pentafluoro-Phe, o-X-Phe, or p-X-Phe; A3 is pyridyl-Ala, Trp, Phe, β-Nal, 2,4-dichloro-Phe, pentafluoro-Phe, o-X-Phe, or p-X-Phe; A6 is Val, Ala, Leu, Lie, Nle, Thr, Abu, or Ser; A7 is Ala, Leu, Lie, Val, Nle, Phe, β-Nal, pyridyl-Ala, Trp, 2,4-dichloro-Phe, pentafluoro-Phe, o-X-Phe, or p-X-Phe; A8 is a D- or L-isomer of Ala, Leu, lie. Val, NIe, Thr, Ser, Phe,, ß-Nal, pyridyl-Ala, Trp, 2,4-dichloro-.Phe, .. pentafluoro-Phe, p-X-Phe, o or X-Ph <; ^; each Rj, and R2 independently, is H, lower acyl or lower alkyl; and R3 is OH or NH2; with the proviso that at least one of A1 and A8 and one of A2 and A7 must be an aromatic amino acid; and with the additional condition that A1, A2, A7 and A8 can not all be aromatic amino acids. Examples of linear agonists to be used in the method of this invention include: H-D-Phe-p-chloro-Phe-Tyr-D-Trp-Lys-Thr-Phe-Thr-NH2; H-D-Phe-p-N02-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2; H-D-Nal-p-chloro-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2; H-D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH2; H-D-Phe-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2; H-D-Phe-p-chloro-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2; and H-D-Phe-Ala-Tyr-D-Trp-Lys-Val-Ala-β-D-Nal-NH 2 or a pharmaceutically acceptable salt thereof. If desired, one or more chemical moieties may be attached, for example, sugar derivative, mono- or poly-hydroxy-C2.12 alkyl, mono- or poly-hydroxy-C2.12 acyl groups, or piperazine derivatives, to the somatostatin agonist, for example, to the N-terminal amino acid. See, PCT Application WO 88/02756, European Application 0 329 295, and PCT Application Number WO 94/044752. An example of a somatostatin agonist containing N-terminal chemical substitutions are: / \ HO (CH2) 2-N N- (CH2) -CO-D-Ph6-Phe-P e-D-Trp- and 3-Thr-Ph? -Thr-NH2 H0 (CH2) 2-N N- (CK2) 2-S02"D-Phe-Phe-Phe-D-Trp-Lya-Thr-Phe-Thr-NH HO. { CH2) 2-N N- < CH2) -CO-D-P e-Cys-Tyr-D-Trp ~ Ly3-Abu-Cy3-Thr-NH2 (BIM-23190); Y HO (CH2 | 2-N N- <CH2) 2-S02-D-Phe-Cys-Tyr-D-Trp-Lys-A u-Cy5-Thr-NH2 ÍBIM-23197) or a pharmaceutically acceptable salt thereof Synthesis of Somatostatin Agonists The methods for synthesizing somatostatin agonists are well documented and are within the ability of the person skilled in the art, for example, as illustrated in the North American patents and other references cited hereinabove. The synthesis of short sequences of amino acids is well established in the technique of peptides. For example, the synthesis of D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2, described above, can be synthesized by following the protocol set forth in U.S. Patent No. 4, 8.53, .371 and the synthesis of HD-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH2 can be achieved by following the protocol set forth in example i in European patent application 0 395 417 Al. Synthesis of somatostatin agonists with a substituted N-terminal can be achieved, for example, by following the protocol set forth in WO 88/02756, European Patent Application No. 0 329 295, and PCT Publication No. WO 94/04752.
Somatostatin Receptor Binding Assays SSTR-1 cDNA clones, SSTR-2, SSTR-3, SSTR-4 and human SSTR-5, have been described (SSTR-1, and SSTR-2 in Yamada, and, et al, Proc. Nati. Acad. Sci. USA., 89: 251-255 (1992); -3 in Yamada, et al., Mol.Endocrinol., 6: 2136-2142 (1993); and SSTR-4 and SSTR-5 in Yamada, et al., Biochem. Biophys., Res. Commun. 195: 844-852. (1993)) and are also available from the American Type Culture Collection (ATCC, Rockville, MD) (ATCC numbers 79044 (SSTR-1), 79046 (SSTR-2), and 79048 (SSTR-3)). Based on the restriction endonuclease maps, the entire coding region of each SSTR cDNA can be cleaved by digestion with suitable restriction endonuclease (Maniatis, T., et al., Molecular Cloning - A Laboratory Manual, CSHL, 1982). . Restriction endonucleases are available from New England Biolabs (Beverly, MA). This cDNA fragment was inserted into the mammalian expression vector, pCMV (Russell, D., et al., J. Biol. Chem., 264: 8222-8229 (1989)), using normal molecular biology techniques (see for example, Maniantis T., et al., Molecular Cloning - A Laboratory Manual, Cold Spring Harbor Laboratory, 1982) to produce the expression plasmid, pCMV-human in SSTR-1 up to pMCV-human SSTR-5. Other mammalian expression vectors include pcDNA / Amp (Invitrogen, Sandlesy, CA). The expression plasmids were introduced into the appropriate bacterial host, E. coli HB101 (Stratagene, La Jolla, CA) and the plasmid DNAs, for transfection, were prepared in cesium chloride gradients. CHO-K1 cells (Chinese hamster ovary) were obtained from the ATCC (ATCC number CCL 61). The cells were cultured and maintained in Ham's F12 medium (Gibco BRL, Grand Island, Ny) supplemented with 10% fetal bovine serum under culture conditions for normal tissues. For transfection, the cells were seeded at a density of 1 x 106/60 cm plate (Baxter Scientific Products, McGaw Park, IL). DNA-mediated transfection was carried out using the calcium phosphate coprecipitation method (Ausubel, F.M., et al., Current Protocols in Molecular Biology, John Wiley &Sons, 1987). Plasmid pRSV-neo (ATCC, ATCC number 37198) was included as a selectable marker at 1/10 of the concentration of the expression plasmid. Clonal CHO-Kl cell lines that have stably inherited the transfected DNA were selected for culture in Ham's F12 medium containing 10% fetal bovine serum and 0.5 mg / ml G418 (Sigma). The cells were cloned into rings and expanded in the same medium for analysis. Expression of Human SSTR-1 receptors up to SSTR-5 in CHO-Kl cells was detected by Northern blot analysis of the total RNA prepared from the cells (Sambrook, JE, et al., Molecular Cloning -A Laboratory, Manual, ed. 2, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 1989) and by receptor binding using [125I-Tyr1: L] somatostatin-14, as a ligand The transfected cell lines expressing the human SSTR receptors were expanded per clone in culture and used in the following SSTR binding protocol. Crude membranes were prepared by homogenizing the transfected cells in 20 ml of 50 mM Tris-HCl, in ice-cold serum with a tissue homogenizer (setting 6, 15 seconds). A buffer was added to obtain an additional volume of 40 ml, and the homogenate was centrifuged, in a Sorval® SS-34 rotor (Sorval, Newtown, Connecticut) at 39,000 g for 10 minutes at 0-4 ° C. The supernatant The result was decanted and discarded. The pellet was homogenized in an ice-cooled buffer, diluted and centrifuged as before. The final pellet was redispersed in 10 mM Tris HCl and kept on ice for the assay in receptor binding. Aliquots of the membrane preparation were incubated for 30 minutes at 30 ° C with [125I-Tyr11] 0.05 mM somatostatin-14 (2000 Ci / mmol; Amersham Corp., Arlintong Heights, IL) in 50 M HEPES (pH 7.4) containing a test somatostatin agonist of various concentrations (eg, 10"11 to 10 ~ s), 10 mg / ml serum albumin bovine (fraction V) (Sigma Chemical Co, St. Louis, MO), MgCl2 (5 mM), Trasilol (also known as aprotin) (Sigma Chemical Co) (200 KIU ml), bacitracin (Sigma Chemical Co). (0.02) mg / ml), and phenylmethylsulfonyl fluoride (Sigma Chemical Co) (0.02 mg / ml) The final assay volume was 0.3 ml The incubations were terminated by rapid filtration through GF / C filter (pre-moistened) or 0.3% polyethyleneimine washes for 3 minutes) using a Brandel filtration manifold (Brandel Research and Development Co., Gaithersburg, Mariland) Each tube and filter was then washed three times with 5 ml aliquots of ice-cooled buffer. defined the specific binding as the [125I-Tyr11] total somatostatin-14 bound minus the binding in the presence of 1000 mM of somatostatin-14. The ki values for the somatostatin agonists tested were calculated using the following formula: ki = IC50 / [1+ (LC / LEC)] where ICS0 is the test somatostatin agonist combination required to inhibit 50 percent of the specific binding of radioligand [125I-Tyr11] somatostatin-14, LC is the radioligand concentration (0.05 nM) and LEC is the constant dissociation of the radioligand equilibrium (0.16 nM). The ki values (nM) for the somatostatin agonists tested are shown in Table I. TABLE I Inhibition of Fibrosis Somatostatin agonists can be tested for their ability to inhibit fibrosis. (a) Demonstration of In Vitro Anti-Fibrotic Activity Rats were injected either with anti-thymocyte (ATS) serum "(see S- .. Okuda-, J. Clin. Invest., Vol. 86, 1990, pp. 453-462) to induce glomerulonephritis or with phosphate buffered saline (PBS) to serve as controls. Six days later, the kidneys were removed, and the glomeruli were isolated and placed in culture for 72 hours. Culture conditions consisted of 2000 glomeruli / well in a 1 ml volume of serum-free RPMI 1640 (with insulin supplementation) (Gibco, Gaithersburg, Maryland). The somatostatin or somatostatin agonist test was added to the culture time. The culture supernatant was collected and stored at -70 ° C until it was assessed to determine the concentration of the transforming growth factor of collagen I, β-1 (TGF-β), fibronectin containing an extra A domain ( fibronectin EDA +), and plasminogen activator inhibitor I (PAI-I) as markers of fibrotic activity. In addition, the individual glomeruli were examined by immunofluorescent staining and labeled for the relevant matrix proteins. The values were compared between fibrotic control glomeruli, negative, treated with PSB; fibrotic control glomeruli, positive, not treated with drug; and fibrotic glomeruli, treated with drug, treated with ATS, to determine the degree to which the fibrotic process is inhibited by somatostatin or somatostatin agonists. (b) Demonstration of the In Vivo Anti-Fibrotic Activity. Rats were injected either with anti-thymocyte serum (ATS) to induce glomerulonephritis or with phosphate buffered saline (PBS) as a control. One hour later, treatment was initiated with somatostatin or a somatostatin agonist. Somatostatin or somatostatin agonist were administered subcutaneously twice a day for 5 days. On day 5, the rats were placed in metabolic cages, and the urine was collected for 24 hrs to determine the protein content. On day 6, the kidneys were removed, and the tissue samples were placed either in formalin or frozen for histological evaluation. The glomeruli were isolated from the remaining tissue and placed in culture for 72 hours. Culture conditions consisted of 2000 glomeruli / well at a volume of 1 ml serum-free RPMI 1640 (with insulin supplementation). The culture supernatant was collected and stored at -10 ° C until it was assessed to determine the concentration of the transforming growth factor of collagen I, β-1 (TGF-β), fibronectin containing an extra A domain ( fibronectin EDA +), and plasminogen activator inhibitor I (PAI1) _ as markers of fibrotic activity. The presence of the matrix proteins is measured via immunofluorescent staining of the frozen sections of the kidney with antibodies to the matrix proteins induced by TGFβ-1, such as fibronectin EDA +, collagen I, PAI1, and tenasin. From direct measurements of cultured isolated glomeruli of TGFß-1, PAI1, and secreted fibronectin in culture supernatant can be determined via ELISA. The glomeruli from the samples in each group can be used to extract mRNA and message levels for TGFß-1, GADPH, collagen I, collagen II; fibronectin, and PAI1 determined by Northern analysis. As an indicator of the histological, ordinary changes, paraffin sections stained with PAS (Periodic acid-Schiff) were staggered based on their pathological matrix markings. The values are compared between the negative fibrotic control animals treated with PBS; the fibrotic control animals, positive, treated with drug, treated with ATS; and animals treated with ATS-treated drugs to determine the degree to which the fibrotic process is inhibited by somatostatin or the somatostatin agonist.
OTHER MODALITIES The foregoing description has been limited to specific embodiments of this invention. However, it will be evident that they can make variations and modifications to the invention, with the achievement of some or all of the advantages of the invention. These modalities are also within the scope of the following claims.

Claims (31)

  1. CLAIMS: 1. A method for inhibiting fibrosis in a patient, the method comprising administering to the patient a therapeutically effective amount of somatostatin or a somatostatin agonist.
  2. 2. A method according to claim 1, wherein the method comprises administering to the patient a therapeutically effective amount of a somatostatin agonist.
  3. A method according to claim 2, wherein the fibrosis is in the kidney, lung, liver, skin, central nervous system, bone or bone marrow, cardiovascular system, organ endocrine and / or in the gastrointestinal system.
  4. The method according to claim 2, wherein the fibrosis is induced by chemotherapy, radiation, by a drug or a combination of drugs, by a disease state, by an environmental or industrial factor, by an immune reaction or by a wound .
  5. The method according to claim 2, wherein the somatostatin agonist is administered parenterally.
  6. 6. The method according to claim 5, wherein the somatostatin agonist is administered in a sustained release formulation.
  7. 7. A method according to claim 3, wherein the somatostatin agonist is administered parenterally.
  8. 8. A method according to claim 7, wherein the somatostatin agonist is administered in a sustained release formulation.
  9. 9. A method according to claim 2, wherein the somatostatin agonist is administered topically or orally.
  10. 10. A method according to claim 3, wherein the disorder. fibrotic in. he . Kidney is glomerulonephritis, diabetic nephropathy, allograft rejection or HIV nephropathy; fibrotic disorder of the lung is idiopathic fibrosis or autoimmune fibrosis; The fibrotic disorder in the liver is cirrhosis or veno-occlusive disease, the fibrotic disorder in the skin is systemic sclerosis, keloids, scars by burn or eosinophilia-myalgia syndrome and the fibrotic disorder in the central nervous system is infra-ocular fibrosis.
  11. 11. A method according to claim 4, wherein the fibrosis induced by chemotherapy is in the kidney, lung, liver, skin, central nervous system, bone or bone marrow, cardiovascular system, in an endocrine organ or in the gastrointestinal system.
  12. 12. A method according to claim 4, wherein the radiation-induced fibrosis is in the kidney, lung, liver, skin, central nervous system, bone or bone marrow, cardiovascular system, in an endocrine organ or in the gastrointestinal system.
  13. 13. A method for inhibiting TGF-β overexpression comprising administering to a subject an effective amount of somatostatin or a somatostatin agonist, or a pharmaceutically acceptable salt thereof.
  14. 14. A method according to claim 13, wherein a somatostatin agonist or a pharmaceutically acceptable salt thereof is administered.
  15. A method according to claim 14, wherein the somatostatin agonist has a higher binding affinity for the human somatostatin subtype 1 receptor, has a higher binding affinity for the human somatostatin subtype 2 receptor, has a higher affinity for binding to the human somatostatin subtype 3 receptor, has a higher binding affinity for the human somatostatin subtype 4 receptor, or has a higher binding affinity for the human somatostatin subtype 5 receptor.
  16. 16. A method according to claim 14, wherein the somatostatin agonist has a higher binding affinity for two or more of the following: human somatostatin subtype 1 receptor, human somatostatin subtype 2 receptor, human somatostatin subtype 3 receptor, subtype 4 of human somatostatin or subtype 5 of human somatostatin.
  17. 17. A method according to claim 14, wherein the somatostatin agonist is: AL-A2-A-D-trp- ys-A6-A-Aβ-R3 / R2 or a pharmaceutically acceptable salt thereof, wherein A1 is a D- or L-isomer of Ala, Leu, lie. Val, NIe, Thr, Ser, ß-Nal, ß-Pal, Trp, Phe, 2, 4-dichloro-Phe, pentafluoro-Phe, pX-Phe, or oX-Phe, where X is CH3, Cl, Br , F, OH, OCH3 O N02; A2 is Ala, Leu, Lie, Val, Nle, Phe, β-Nal, pyridyl-Ala, Trp, 2,4-dichloro-Phe, pentafluoro-Phe, oX-Phe, or pX-Phe, where X is CH 3 , Cl, Br, F, OH, 0CH3 or N02; A3 is pyridyl-Ala, Trp, Phe, β-Nal, 2,4-dichloro-Phe, pentafluoro-Phe, oX-Phe, or pX-Phe, where X is CH3, Cl, Br, F, OH, 0CH3 or N02; A6 is Val, Ala, Leu, Lie, Nle, Thr, Abu, or Ser; A7 is Ala, Leu, Lie, Val, NIe, Phe, β-Nal, pyridyl-Ala, Trp, 2,4-dichloro-Phe, pentafluoro-Phe, oX-Phe, or pX-Phe, where X is CH3 , Cl, Br, F, OH, 0CH3 or N02; A8 is a D- or L-isomer of Ala, Leu, Lie, Val, NIe, Thr, Ser, Phe, ß-Nal, pyridyl-Ala, Trp, 2,4-dichloro-Phe, pentafluoro-Phe, pX-Phe, or oX-Phe, where X is CH3, Cl, Br, F , OH, 0CH3 or N02; each Rx and R2 independently, is H, lower acyl or lower alkyl; and R3 is OH or NH2; with the proviso that at least one of A1 and A8 and one of A2 and A7 must be an aromatic amino acid; and with the additional proviso that A1, A2, A7 and A8 can not all be aromatic amino acids.
  18. 18. A method according to claim 14, wherein the somatostatin agonist is H-D-Phe-p-chloro-Phe-Tyr-D-Trp-Lys-Thr-Phe-Thr-NH2; H-D-Phe-p-N02-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2; H-D-Nal-p-chloro-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2; H-D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH2; H-D-Phe-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2; H-D-Phe-p-chloro-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2; H-D-Phe-Ala-Tyr-D-Trp-Lys-Val-Ala-β-D-Nal-NH 2 D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-b-Nal-NH 2; D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-b-Nal-NH2; Db-Nal-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2, • D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2, • D-Phe- Cys-Phe-D-Trp-Lys-Thr-Pen-Thr-NH2; D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-OH; D-Phe-Cys-Phe-D-Trp-Lys-Thr-Pen-Thr-OH; Gly-Pen-Phe-D-Trp-Lys-Thr-Cys-Thr-OHj Phe-Pen-Tyr-D-Trp-Lys-Thr-Cys-Thr-OHj Phe-Pen-Phe-D-Trp-Lys- Thr-Pen-Thr-OH; H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol; HD-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2j HD-Trp-Cys-yr-D-Trp-Lys-Val-Cys-Thr-NH2 HD-Trp-Cys-Phe- D-Trp-Lys-Thr-Cys-Thr-NH2 / HD-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2J HD-Phe-Cys-Tyr-D-Trp-Lys-Val -Cys-Trp-NH2J HD-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH21 Ac-D-Phe-Lys * -Tyr-D-Trp-Lys-Val-Asp-Thr- NH2, where an amide bridge is between Lys * and Asp; Ac-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-cys-Thr-NH2; Ac-D-hArg (Bu) -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (Et) 2-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-L-hArg (Et) 2-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH2; Ac-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NHEt; Ac-L-hArg (CH2-CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys (Me) -Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys (Me) -Thr-Cys-Thr-NHEt; Ac-hArg (CH3, hexyl) -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; H-hArg (hexyl) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NHEt; Ac-D-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH2; Propionyl-D-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys (iPr) -Thr-Cys-Thr-NH2; Ac-D-β-Nal-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Gly-hArg (Et) 2-NH 2; Ac-D-Lys (iPr) -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Tpr-Lys-Thr-Cys-Phe-NH2; Ac-D-hArg (Et) 2-D-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-Cys-Lys-Asn-4-Cl-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Ser-D-Cys-NH2; Bmp-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2; Bmp-Tyr-D-Trp-Lys-Val-Cys-Phe-NH2; Bmp-Tyr-D-Trp-Lys-Val-Cys-p-Cl-Phe-NH2; Bmp-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH 2; H-D-b-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2; H-D-Phe-cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-b-Nal-NH2; H-pentafluoro-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2; Ac-D-b-Nal-Cys-pentafluoro-Phe-D-Trp-Lys-Val-Cys-Thr-NH2; H-D-b-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-b-Nal-NH2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-b-Nal-NH 2, • H-D-b-Nal-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH 2; H-D-p-Cl-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2; Ac-D-p-Cl-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2; H-D-Phe-Cys-b-Nal-D-Trp-Lys-Val-Cys-Thr-NH2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH2; Cyclo (Pro-Phe-D-Trp-N-Me-Lys-Thr-Phe); Cyclo (Pro-Phe-D-Trp-N-Me-Lys-Thr-Phe); Cyclo (Pro-Phe-D-Trp-Lys-Thr-N-Me-Phe); Cyclo (N-Me-Ala-Tyr-D-Trp-Lys-Thr-Phe); cycle (Pro-Tyr-D-Trp-Lys-Thr-Phe) cycle (Pro-Phe-D-Trp-Lys-Thr-Phe) cycle (Pro-Phe-L-Trp-Lys-Thr-Phe) cycle ( Pro-Phe-D-Trp (F) -Lys-Thr-Phe); cycle (Pro-Phe-Trp (F) -Lys-Thr-Phe); cycle (Pro-Phe-D-Trp-Lys-Ser-Phe); Cyclo (Pro-Phe-D-Trp-Lys-Thr-p-Cl-Phe); Cyclo (D-Ala-N-Me-D-Phe-D-Thr-D-Lys-Trp-D-Phe); Cyclo (D-Ala-N-Me-D-Phe-D-Val-Lys-D-Trp-D-Phe); Cyclo (D-Ala-N-Me-D-Phe-D-Thr-Lys-D-Trp-D-Phe); Cyclo (D-Abu-N-Me-D-Phe-D-Val-Lys-D-Trp-D-Tyr), Cyclo (Pro-Tyr-D-Trp-t-4-AchxAla-Thr-Phe); Cyclo (Pro-Phe-D-Trp-t-4-AchxAla-Thr-Phe), -cycle (N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe); Cyclo (N-Me-Ala-Tyr-D-Trp-t-4-AchxAla-Thr-Phe); Cyclo (Pro-Tyr-D-Trp-4-Amphe-Thr-Phe); Cyclo (Pro-Phe-D-Trp-4-Amphe-Thr-Phe); Cyclo (N-Me-Ala-Tyr-D-Trp-4-Amphe-Thr-Phe); Cycle (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba); Cycle (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba-Gaba); cycle (Asn-Phe-D-Trp-Lys-Thr-Phe); Cyclo (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-NH (CH2) 4CO) Cyclo (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-b-Ala); Cyclo (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-D-Glu) -OH; Cyclo (Phe-Phe-D-Trp-Lys-Thr-Phe); Cyclo (Phe-Phe-D-Trp-Lys-Thr-Phe-Gly); cycle (Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba); Cyclo (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gly); cycle (Asn-Phe-Phe-D-Trp (F) -Lys-Thr-Phe-Gaba); cycle (Asn-Phe-Phe-D-Trp (N02) -Lys-Thr-Phe-Gaba); cycle (Asn-Phe-Phe-Trp (Br) -Lys-Thr-Phe-Gaba); cycle (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe (I) -Gaba); Cycle (Asn-Phe-Phe-D-Trp-Lys-Thr-Tyr (But) -Gaba); cycle (Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Pro-Cys) OH; Cyclo (Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Pro-Cys) - OH; Cyclo (Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Tpo-Cys) - OH; Cyclo (Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-MeLeu- Cys) -OH; Cyclo (Phe-Phe-D-Trp-Lys-Thr-Phe-Phe-Gaba); Cyclo (Phe-Phe-D-Trp-Lys-Thr-Phe-D-Phe-Gaba); Cyclo (Phe-Phe-D-Trp (5F) -Lys-Thr-Phe-Phe-Gaba); Cyclo (Asn-Phe-Phe-D-Trp-Lys (Ac) -Thr-Phe-NH- (CH2) 3-CO); cycle (Lys-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba) cycle (Lys-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba) cycle (Orn-Phe-Phe-D-) Trp-Lys-Thr-Phe-Gaba) Db-Nal-Cys-Typ-D-Trp-Lys-Thr-Cys-Thr-NH2, H-Cys-Phe-Phe-D-Trp-Lys-Thr-Phe- Cys-NH2, HOÍCHJJJ- N N- CH2-CO-D-Phe-Cys-Tyr-D «Tf-Lys-Abu-Cys-Thr-NH2 / - \ HO (CH2) a- N N - (CH2) 2-SO D-Phß-Cys-Tyr-D-Tf-Lys.Abu-Cys-Thr.NH2 or D-Phe-cyclo (Cys-Phe-D-Trp-Lys-Thr-Cys) -Thr-ol or a pharmaceutically acceptable salt thereof.
  19. 19. A method according to claim 2, wherein the somatostatin agonist has a higher binding affinity for the human somatostatin subtype 1 receptor, has a higher binding affinity for the human somatostatin subtype 2 receptor, has a higher affinity for binding to the human somatostatin subtype 3 receptor, has a higher binding affinity for the human somatostatin subtype 4 receptor or has a higher binding affinity for the human somatostatin subtype 5 receptor.
  20. 20. A method according to claim 2, wherein the somatostatin agonist has a higher binding affinity for two or more of the following: human somatostatin subtype 1 receptor, human somatostatin subtype 2 receptor, human somatostatin subtype 3 receptor, subtype 4 of human somatostatin or subtype 5 of human somatostatin.
  21. 21. A method according to claim 2, wherein the somatostatin agonist is: R \ A1-A2-A3-D-Trp-Lys-A6-A7-A8-R3 / R2 or a pharmtically acceptable salt thereof, wherein A1 is a D- or L- isomer of Ala, Leu, Lie, Val, Nle, Thr, Ser, b-Nal, b-Pal, Trp, Phe, 2, 4- dichloro-Phe, pentaf luoro-Phe, pX-Phe, or oX-Phe, wherein X is CH3, Cl, Br, F, OH, OCH3 or N02; A2 is Ala, Leu, Lie, Val, Nle, Phe, b-Nal, pyridyl-Ala, Trp, 2,4-dichloro-Phe, pentaf luoro-Phe, oX-Phe, or pX-Phe, where X is CH3, Cl, Br, F, OH, OCH3 or N02; A3 is pyridyl-Ala, Trp, Phe, b-Nal, 2,4-dichloro-Phe, pentaf luoro-Phe, oX-Phe, or pX-Phe, wherein X is CH3, Cl, Br, F, OH, OCH3 or N02; Aß is Val, Ala, Leu, Lie, Nle, Thr, Abu, or Ser; A7 is Ala, Leu, Lie, Val, Nle, Phe, b-Nal, pyridyl-Ala, Trp, 2,4-dichloro-Phe, pentafluoro-Phe, oX-Phe, or pX-Phe, where X is CH3 , Cl, Br, F, OH, OCH3 or N02; A8 is a D- or L-isomer of Ala, Leu, Lie, Val, Nle, Thr, Ser, Phe, b-Nal, pyridyl-Ala, Trp, 2,4-dichloro-Phe, pentafluoro-Phe, pX-Phe, or oX-Phe, where X is CH3, Cl, Br, F , OH, OCH3 OR N02; each R and R2 independently, is H, lower acyl or lower alkyl; and R3 is OH or NH2; with the proviso that at least one of A1 and A8 and one of A2 and A7 must be an aromatic amino acid; and with the additional condition that A1, A2, A7 and A8 can not all be aromatic amino acids.
  22. 22. A method according to claim 2, wherein the somatostatin agonist is: H-D-Phe-p-chloro-Phe-Tyr-D-Trp-Lys-Thr-Phe-Thr-NH2; H-D-Phe-p-N02-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2; H-D-Nal-p-chloro-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2; H-D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH2; H-D-Phe-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2; HD-he-p-chloro-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2, • HD-Phe-Ala-Tyr-D-Trp-Lys-Val-Ala-β-D-Nal -NH2 D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-b-Nal-NH2; D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-b-Nal-NH2, • D-b-Nal-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2; D-Phe-Cys-Phe-D-Trp-Lys-Thr-Pen-Thr-NH2; D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-OH; D-Phe-Cys-Phe-D-Trp-Lys-Thr-Pen-Thr-OH; Gly-Pen-Phe-D-Trp-Lys-Thr-Cys-Thr-OH, • Phe-Pen-Tyr-D-Trp-Lys-Thr-Cys-Thr-OH, • Phe-Pen-Phe-D- Trp-Lys-Thr-Pen-Thr-OH, • HD-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol; H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2, • H-D-Trp-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2; H-D-Trp-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2, • H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2; Ac-D-Phe-Lys * -Tyr-D-Trp-Lys-Val-Asp-Thr-NH2, wherein an amide bridge is between Lys * and Asp; Ac-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-cys-Thr-NH2; Ac-D-hArg (Bu) -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (Et) 2-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-L-hArg (Et) 2-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH2; Ac-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NHEt; Ac-L-hArg (CH2-CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys (Me) -Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys (Me) -Thr-Cys-Thr-NHEt; Ac-hArg (CH3, hexyl) -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; H-hArg (hexyl) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NHEt; Ac-D-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH2; Propionyl-D-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys (iPr) -Thr-Cys-Thr-NH2; Ac-D-β-Nal-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Gly-hArg (Et) 2-NH 2; Ac-D-Lys (iPr) -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Tpr-Lys-Thr-Cys-Phe-NH2; Ac-D-hArg (Et) 2-D-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-Cys-Lys-Asn-4-Cl-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Ser-D-Cys-NH2; Bmp-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2; Bmp-Tyr-D-Trp-Lys-Val-Cys-Phe-NH2; Bmp-Tyr-D-Trp-Lys-Val-Cys-p-Cl-Phe-NH2; Bmp-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH 2; H-D-b-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2; H-D-Phe-cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2; HD-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-b-Nal-NH2, - H-pentafluoro-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2; Ac-D-b-Nal-Cys-pentafluoro-Phe-D-Trp-Lys-Val-Cys-Thr-NH2; H-D-b-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-b-Nal-NH 2, • H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-b-Nal-NH 2; H-D-b-Nal-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2; H-D-p-Cl-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2; Ac-D-p-Cl-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2; H-D-Phe-Cys-b-Nal-D-Trp-Lys-Val-Cys-Thr-NH2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH2; cycle (Pro-Phe-D-Trp-N-Me-Lys-Thr-Phe) cycle (Pro-Phe-D-Trp-N-Me-Lys-Thr-Phe) cycle (Pro-Phe-D-Trp- Lys-Thr-N-Me-Phe) Cyclo (N-Me-Ala-Tyr-D-Trp-Lys-Thr-Phe); Cyclo (Pro-Tyr-D-Trp-Lys-Thr-Phe); Cyclo (Pro-Phe-D-Trp-Lys-Thr-Phe); Cyclo (Pro-Phe-L-Trp-Lys-Thr-Phe); cycle (Pro-Phe-D-Trp (F) -Lys-Thr-Phe); cycle (Pro-Phe-Trp (F) -Lys-Thr-Phe); cycle (Pro-Phe-D-Trp-Lys-Ser-Phe); Cyclo (Pro-Phe-D-Trp-Lys-Thr-p-Cl-Phe); Cyclo (D-Ala-N-Me-D-Phe-D-Thr-D-Lys-Trp-D-Phe); Cyclo (D-Ala-N-Me-D-Phe-D-Val-Lys-D-Trp-D-Phe); Cyclo (D-Ala-N-Me-D-Phe-D-Thr-Lys-D-Trp-D-Phe); Cyclo (D-Abu-N-Me-D-Phe-D-Val-Lys-D-Trp-D-Tyr), Cyclo (Pro-Tyr-D-Trp-t-4-AchxAla-Thr-Phe); Cyclo (Pro-Phe-D-Trp-t-4-AchxAla-Thr-Phe); Cyclo (N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe); Cyclo (N-Me-Ala-Tyr-D-Trp-t-4-AchxAla-Thr-Phe); Cyclo (Pro-Tyr-D-Trp-4-Amphe-Thr-Phe); Cyclo (Pro-Phe-D-Trp-4-Amphe-Thr-Phe); Cyclo (N-Me-Ala-Tyr-D-Trp-4-Amphe-Thr-Phe); Cycle (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba); Cycle (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba-Gaba); cycle (Asn-Phe-D-Trp-Lys-Thr-Phe); cycle (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-NH (CH2) 4C0) cycle (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-b-Ala); Cyclo (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-D-Glu) -OH; Cyclo (Phe-Phe-D-Trp-Lys-Thr-Phe); Cyclo (Phe-Phe-D-Trp-Lys-Thr-Phe-Gly); cycle (Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba); Cyclo (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gly); cycle (Asn-Phe-Phe-D-Trp (F) -Lys-Thr-Phe-Gaba); cycle (Asn-Phe-Phe-D-Trp (N02) -Lys-Thr-Phe-Gaba); cycle (Asn-Phe-Phe-Trp (Br) -Lys-Thr-Phe-Gaba); cycle (Asn-Phe-Phe-D-Trp-Lys-Thr-Phe (I) -Gaba); Cycle (Asn-Phe-Phe-D-Trp-Lys-Thr-Tyr (But) -Gaba); cycle (Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Pro-Cys) OH; cycle (Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Pro-Cys) OH; cycle (Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Tpo-Cys) OH; cycle (Bmp-Lys-Asn-Phe-Phe-D-Tr-Lys-Thr-Phe-Thr-MeLeu- Cys) -OH; Cyclo (Phe-Phe-D-Trp-Lys-Thr-Phe-Phe-Gaba); Cyclo (Phe-Phe-D-Trp-Lys-Thr-Phe-D-Phe-Gaba); Cyclo (Phe-Phe-D-Trp (5F) -Lys-Thr-Phe-Phe-Gaba); Cyclo (Asn-Phe-Phe-D-Trp-Lys (Ac) -Thr-Phe-NH- (CH2) 3-C0); cycle (Lys-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba) cycle (Lys-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba) cycle (Orn-Phe-Phe-D-) Trp-Lys-Thr-Phe-Gaba) Db-Nal-Cys-Typ-D-Trp-Lys-Thr-Cys-Thr-NH2, H-Cys-Phe-Phe-D-Trp-Lys-Thr-Phe- Cys-NH2, HO (CH2) 2-N-CH2-CO-D-Phß-Cys-Tyr-D-Tf.Lys-Abu-Cys-Thr-NH2 HO (CH2) 2- N XXN- (CH2) 2-SO2-D-Pß.Cys-Tyr-D-Trp-Lys.Abu-Cys-tr-NH2, or D-Phe-cyclo (Cys-Phe-D-Trp-Lys-Thr-Cys) -Thr-ol or a pharmaceutically acceptable salt thereof.
  23. 23. A method according to claim 4, wherein the fibrosis induced by a drug or a combination of drugs is in the kidney, in the lung, in the liver, in the skin, of the central nervous system, in bone or bone marrow. , in the cardiovascular system, in an endocrine organ or in the gastrointestinal system.
  24. 24. A method according to claim 4, wherein the fibrosis induced by a disease state is in the kidney, in the lung, in the liver, in the skin, of the central nervous system, in the bone or bone marrow, in the cardiovascular system, in an endocrine organ or in the gastrointestinal system.
  25. 25. A method according to claim 4, wherein the fibrosis induced by an environmental or industrial factor is in the kidney, in the lung, in the liver, in the skin, of the central nervous system, in the bone or bone marrow, in cardiovascular system, in an endocrine organ or in the gastrointestinal system.
  26. 26. A method according to claim 4, wherein the fibrosis induced by an immune reaction is in the kidney, in the lung, in the liver, in the skin, of the central nervous system, in the bone or bone marrow, in the system. cardiovascular, in an endocrine organ or in the gastrointestinal system.
  27. 27. A method according to claim 4, wherein the fibrosis induced by a wound is in the kidney, in the lung, in the liver, in the skin, of the central nervous system, in the bone or bone marrow, in the cardiovascular system , in an endocrine organ or in a gastrointestinal system.
  28. 28. A pharmaceutical composition useful for inhibiting fibrosis in a patient, which comprises a pharmaceutically acceptable carrier and an effective amount of somatostatin or a somatostatin agonist, or a pharmaceutically acceptable salt thereof.
  29. 29. A pharmaceutical composition according to claim 28, wherein the composition comprises a somatostatin agonist or a pharmaceutically acceptable salt thereof.
  30. 30. A pharmaceutical composition useful for inhibiting overexpression of TGF-β, which comprises a pharmaceutically acceptable carrier and an effective amount of somatostatin or a somatostatin agonist, or a pharmaceutically acceptable salt thereof.
  31. 31. A pharmaceutical composition according to claim 30, wherein the composition comprises a somatostatin agonist or a pharmaceutically acceptable salt thereof.
MXPA/A/1999/001975A 1996-08-30 1999-02-26 Method of inhibiting fibrosis with a somatostatin agonist MXPA99001975A (en)

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