Method of improving lower urinary tract symptoms

Abstract

To provide a method for alleviating the symptoms of mammals exhibiting lower urinary tract symptoms (LUTS).SOLUTION: A method comprising: (i) identifying a mammal having LUTS but not having benign prostatic hyperplasia (BPH); and (ii) administering to the mammal having LUTS but not having BPH a therapeutically effective amount of Ile-Asp-Gln-Gln-Val-Leu-Ser-Arg-Ile-Lys-Leu-Glu-Ile-Lys-Arg-Cys-Leu, where the method improves mean obstructive voiding symptoms (MOVS) measured by International Prostate Symptom Score (IPSS) by 30% or more compared with a case in which the peptide is administered.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (Sequence Listing) This application contains a Sequence Listing which has been submitted electronically in ASCII format, the contents of which are incorporated by reference in their entirety. and is incorporated herein by reference.

[0002] This application is a continuation of U.S. Provisional Patent Application No. 16 / 410,685, filed May 13, 2019. No. 60 / 019,493, filed on May 1, 2006, the entire contents of which are incorporated herein by reference. can be.

[0003] An embodiment of the present invention is a method for producing a compound comprising a small peptide-based compound and a pharmaceutically acceptable carrier. and a method for improving lower urinary tract symptoms (LUTS), more specifically LUTS, using a composition comprising the This includes a method for improving obstructive voiding symptoms in a patient with S. [Background technology]

[0004] The European Association of Urology (EAU) and American Urological Association (AUA) guidelines state: LUTS is defined as urinary retention (hypersensitivity) symptoms that affect the lower urinary tract (LUT) (daytime frequency, urgency, etc.) feeling of pressure, frequent urination at night), urinary (obstruction) symptoms (feeling of pressure, weak urine flow, intermittent urine flow, feeling of residual urine), Post-urinary symptoms (leakage after urination) are defined as: Oelke M. et al., European A European Society of Urology (Eur.U) rol. 2013 Jul;64(1):118-40

[0005] Benign prostatic hyperplasia (BPH) is a histological diagnosis of non-malignant cytoplasmic changes of smooth muscle and epithelial cells of the prostate. Lee C et al., "Intrinsic and extrinsic factors controlling benign prostate growth" ”, Prostate, 1997;31:131-138;Auffenberg G. B et al., "Established Medical Therapies for Benign Prostatic Hyperplasia," Urol Clin Nor th Am. 2009;36:443-459. The exact etiology is unknown. Progression of BPH Benign prostatic hyperplasia (BPE), diagnosed by the size of the prostate (pathologically), is Approximately 50% of men with histologically confirmed BPH develop BPE. PE may ultimately lead to bladder outlet obstruction (BOO), which is associated with BPE. When the prostate gland is in a urinary tract infection, it is also called benign prostatic obstruction (BPO). BOO and BPO are Some patients present with BPE without significant LUTS; Some patients may experience LUTS and a significant decline in QoL without BPE. .J. et al., "Urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH)," World J. Mens Health, No. 31(3), 193-207 (2013) .

[0006] Lower urinary tract symptoms (LUTS) are generally classified into two main types: 1) "Urinary retention" "irritability" symptoms, also known as "urinary" symptoms, and 2) "obstruction" symptoms, also known as "urinary" symptoms. Symptoms of irritability and retention include urinary urgency, frequent urination, and nocturia (when you go to bed at night). Symptoms of obstruction and urination include a weak urine stream, difficulty in passing urine, and frequent need to urinate afterward. You have to strain or use force to urinate, you feel like you have urine left in your bladder, or you have to urinate multiple times during urination Symptoms include stopping and restarting.

[0007] Assisting physicians in the treatment of LUTS, BPH, and LUTS / BPH in the US and Europe Guidelines for this purpose have been established. Oelke M, et al., European A European Society of Urology (Eur.U) rol. 2013 July;64(1):118-40. The guidelines include: From observation (WW) for men who are symptomatic but do not require medication or surgical intervention to Various treatment options are discussed, ranging from physical therapy to surgical intervention. The guidelines recommend the use of alpha-blockers (alpha-adrenergic antagonists), 5α-reductase inhibitors (5AR I), antimuscarinics (anticholinergics), PDE5 inhibitors (tadalafil), combination therapy, Also, alpha-blockers, 5ARIs, and antimuscarinics are used. Combination therapy is also recommended.

[0008] Prostate surgery, such as transurethral resection of the prostate, is an absolute indication for LUTS or medical treatment. It is indicated for men with resistant LUTS. Indications for surgery include urinary retention and gross hematuria. The symptoms are severe, such as urinary tract infections and bladder stones. There are urethral microwave therapy and transurethral needle therapy. For men who cannot undergo surgery, catheterization is also available. Prostate stents may be used as an alternative to sterilization. Regardless, it is an effective and safe agent for treating the troublesome symptoms that can result from BPH. These symptoms are associated with chronic urinary tract infections (UTIs), which are a significant unmet medical need. This can lead to more serious problems such as incontinence, acute and chronic urinary retention, and kidney failure.

[0009] Destroys harmful or unwanted cells and tissues, thus facilitating their elimination Some of the drugs known to have the ability to inhibit the growth of bacteria or their further development are: U.S. Patent Nos. 6,924,266, 7,241,738, and 7,317,077 No. 7,408,021, No. 7,745,572, No. 8,067,378, No. 8,2 Nos. 93,703, 8,569,446 and 8,716,247, and , U.S. Patent Application Publication Nos. 2017 / 0360885, 2017 / 0020957, This is disclosed in the specifications of Nos. 2016 / 036138 and 2016 / 0215031. The disclosures of these agents are incorporated herein by reference in their entirety. One known example is fexapotide triflutate.

[0010] It is a treatment for LUTS patients without the risks and side effects of traditional drug therapy or surgical intervention. There is a need for treatments that can improve symptoms in patients with rheumatoid arthritis. It can improve obstructive urinary symptoms in patients with LUTS without side effects or surgical intervention. A cure is needed.

[0011] Throughout this description, including the foregoing description of related art, all publicly available information disclosed herein is incorporated by reference. All available documents (including all U.S. patents and published patent applications) are incorporated by reference in their entirety. The foregoing description of related art is hereby incorporated by reference in its entirety. No admission is made that any of the above documents, including U.S. patent applications therein, are prior art to the present disclosure. Furthermore, there is no disclosure in this document of any drawbacks associated with the products, methods, and / or apparatus described. The statements in the specification are not intended to limit the embodiments in any way. Aspects of the embodiments provide the described products, methods, and and / or device specific features. Summary of the Invention

[0012] The art is currently developing novel therapeutic agents that can improve the quality of life of patients with lower urinary tract symptoms (LUTS). more resistant to toxicity and less frequent (e.g., avoiding the need to take medication daily or weekly) There remains a need for treatments for obstructive voiding in patients with lower urinary tract symptoms. There is also a need for treatments that improve symptoms. Embodiments of the present invention meet these needs. It is something that adds up.

[0013] The present disclosure provides the amino acid sequence Ile-Asp-Gln-Val-Leu-Ser-Arg- It is written as Ile-Lys-Leu-Glu-Ile-Lys-Arg-Cys-Leu Certain peptides, including a specific peptide (fexapotide triflutate or "FT") It has been shown that urinary tract therapy significantly improves lower urinary tract symptoms (LUTS) and obstructive voiding symptoms in LUTS patients. This is based on the discovery that it is possible to

[0014] The present disclosure provides a method for treating unwanted cell proliferation in mammals using FT alone or in combination with other therapeutic agents. When used in combination with additional active agents that can kill LUTS Based in part on the discovery that it provides unexpected relief to patients suffering from obstructive voiding symptoms related to It is.

[0015] The compositions may be administered by aerosol, infusion, bolus injection, implantable device, sustained release system, or the like. Intramuscular, oral, intravenous, intraperitoneal, intraventricular (intravenous tissue), intraventricular, intratumor, intralesion, skin The drug may be administered intravenously, intrathecally, intranasally, intraocularly, intraarterially, topically, or transdermally. The peptide can also be expressed in vivo. administering genes, administering vaccines that induce such production, or genetically modifying By introducing cells, bacteria or viruses that express the peptide in vivo, There are.

[0016] In another embodiment, a composition comprising the FT peptide is administered alone or in combination with other suitable FT peptides in a mammal. At least one attachment capable of treating and / or killing unwanted cell growths. A control composition without FT is administered in combination with an additional active agent. mean obstructive voiding as measured by the International Prostate Symptom Score (IPSS) compared with Improve symptoms (MOVS) by 30% or more.

[0017] In another embodiment, a composition comprising FT can be administered alone or in combination with other steroids to treat undesirable conditions in a mammal. at least one additional activity capable of treating and / or killing the undifferentiated cell growths; When administered in combination with an anti-inflammatory agent, the effect was significantly improved compared to when a control composition not containing FT was administered. In comparison, mean irritative urinary storage symptoms (M) as measured by the International Prostate Symptom Score (IPSS) Improve ISS by more than 20%.

[0018] Both the foregoing general description and the following detailed description are exemplary and explanatory only. , are intended to provide further explanation of the claimed embodiments. Advantages and features will be readily apparent to those skilled in the art from the detailed description of each embodiment below. Deaf. DETAILED DESCRIPTION OF THE INVENTION

[0019] Before describing the embodiments, it is important to note that the present invention is not limited to the specific methodology, protocols, cells, etc. that have been described. It should be understood that the strains, vectors and reagents are not limited thereto. The terminology is intended only to describe particular embodiments and is defined by the appended claims. It should be understood that these are not intended to limit the scope of the embodiments of the present invention, which are limited only by the following: It is.

[0020] Terms and phrases used herein are defined as follows unless otherwise indicated: Throughout this specification, the singular forms "a," "an," and "the" are used unless the context clearly indicates otherwise. Unless otherwise specified, it includes reference to multiple referents. a reference to "a host cell" includes a plurality of host cells, and a reference to "an antibody" includes one or more host cells. The present invention is a reference to a number of antibodies and their equivalents known to those skilled in the art.

[0021] The amino acids and amino acid residues described herein are those commonly accepted as shown in the table below. They may be referenced according to the one-letter or three-letter code assigned to them. [Table 1]

[0022] Fexapotide triflutate ("FT"), as used herein, is a compound having the following amino acid structure: represents a 17-mer peptide having the sequence: Ile-Asp-Gln-Gln-Val-Le u-Ser-Arg-Ile-Lys-Leu-Glu-Ile-Lys-Arg-Cy s-Leu (SEQ ID NO. 1) FT is disclosed in U.S. Patent No. 6,924,266, No. 241,738, No. 7,317,077, No. 7,408,021, No. 7,745, No. 572, No. 8,067,378, No. 8,293,703, No. 8,569,446 and 8,716,247, and U.S. Patent Application Publication No. 2017 / 03608 Nos. 85, 2017 / 0020957, 2016 / 0361380 and 201 The disclosures of these patents and published applications are set forth in US Pat. No. 6 / 0215031. is incorporated herein by reference in its entirety. FT is expressed as follows: SEQ ID NO. 1 (SEQ ID NO. 1): IDQQVLSRIKLEIKRCL or Ile-Asp-Gln-Gln-Val-Leu-Ser-Arg-Ile-Lys- Leu-Glu-Ile-Lys-Arg-Cys-Leu

[0023] The term "fragment" refers to a contiguous portion of the amino acid sequence of a protein or peptide. It consists of subsequences, and naturally occurring fragments such as splice variants and naturally occurring Proteins or polypeptides containing fragments resulting from in vivo protease activity present Such fragments may include amino-terminal, carboxy-terminal, and / or Internally (by natural splicing, etc.) truncated Such fragments may be prepared with or without an amino-terminal methionine. The term "fragment" refers to a covalent bond linked directly or via a linker. derived from the same protein or peptide, having a common or non-common contiguous amino acid sequence. The skilled artisan will be able to easily identify and interpret fragments of the same or different sequences using the guidelines outlined herein. Suitable flags for use in the embodiments can be identified without undue experimentation using methods and procedures. You will be able to select the segment.

[0024] The term "variant" refers to any variant of the amino acid sequence of a protein or peptide described herein. When compared, one or more amino acid substitutions, deletions, and / or insertions are present. The term refers to a protein or polypeptide, including the naturally occurring forms of proteins or peptides. The term "variant" includes allelic variants or alternative splice variants. peptides with similar or homologous amino acid(s) or dissimilar amino acid(s). This includes substitutions of one or more amino acids in the sequence. There are many criteria for what is possible (Gunnar von Heijne, Seq uence Analysis in Molecular Biology, 123- 39 pp. (Academic Press, New York, NY, 1987). Preferred variants include alanine substitutions at one or more amino acid positions. The substitutions that are most likely to have little or no effect on the overall net charge, polarity, or hydrophobicity of the protein. Conservative substitutions that have no effect are included. Conservative substitutions are shown in Table 2 below. [Table 2] Table 3 shows an alternative scheme for amino acid substitution. [Table 3]

[0025] Other variants may consist of less conservative amino acid substitutions, e.g., (a) The structure of the polypeptide backbone of the substituted region, e.g., as a sheet or helical conformation (b) the charge or hydrophobicity of the molecule at the target site, or (c) maintaining the size of the side chains. In general, it is important to select residues that have a more significant difference in their effects on function. Substitutions expected to have a more significant effect are: (a) glycine and / or proline; (b) a parent amino acid in which the parent amino acid is substituted with another amino acid or is deleted or inserted; Aqueous residues, such as seryl or threonyl, are preferred over hydrophobic residues, such as leucyl, isoleucyl, substituted with (or by) aryl, phenylalanyl, valyl, or alanyl (c) a cysteine ​​residue is bonded to (or by) any other residue; (d) residues having electropositive side chains, e.g., lysyl, arginyl, or is that histidyl is preferred to negatively charged residues such as glutamyl or aspartyl. (e) residues with large side chains, e.g. For example, phenylalanine is more soluble than those without such a side chain, e.g., glycine (also Other variants include novel glycosylation sites and and / or designed to create phosphorylation sites or existing glycosyl groups. These include those designed to delete either the cleavage site and / or the phosphorylation site. Mutants may include glycosylation sites, proteolytic cleavage sites and / or cysteine ​​residues. Variants also include at least one amino acid substitution at the linker peptide residue. Add additional amino acid residues before or after the protein or peptide amino acid sequence on the Also included are proteins and peptides, including those containing hydroxyl groups, such as peptides formed by disulfide bond formation. To allow cyclization of the peptide, both the amino and carboxy termini of the FT peptide were It is also possible to add a cysteine ​​residue. The term "variant" also refers to a peptide at least one and up to 25 adjacent to either the 3' or 5' end of the Also included are polypeptides having the amino acid sequence of FT with additional amino acids.

[0026] The term "derivative" refers to a compound that has undergone natural processes such as processing and other post-translational modifications. In addition to the above, the polymer may contain, for example, one or more polyethylene glycol molecules, sugars, phosphates, and or other such molecules not naturally attached to the wild-type protein or FT. or by chemical modification techniques, such as by adding such molecules to the Refers to chemically modified proteins or polypeptides. Derivatives include salts. Scientific modifications are found in basic textbooks and in more detailed monographs, as well as in a large research literature. These modifications are well described and well known to those skilled in the art. They may be present in the same or different amounts at several sites on a protein or polypeptide. It will be appreciated that a given protein or polypeptide may be The modifications may occur at any site in the protein or polypeptide. Such sites include the peptide backbone, amino acid side chains, and amino termini. Modifications include, for example, acetylation, acylation, ADP - Ribosylation, amidation, covalent attachment of flavin, covalent attachment of heme moiety, nucleotide or Covalent attachment of nucleotide derivatives, covalent attachment of lipids or lipid derivatives, phosphatidylinositol Covalent bonding, cross-linking, cyclization, disulfide bond formation, demethylation, and covalent cross-linking of inositol formation, cysteine ​​formation, pyroglutamate formation, formylation, gamma-carboxylation, Glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation lysis, oxidation, proteolytic processing, phosphorylation, prenylation, racemization, glycosylation Cosylation, lipid attachment, sulfation, gamma-carboxylation of glutamic acid residues, hydroxyl and transferrinylation, such as ADP-ribosylation, selenoylation, sulfation, and arginylation. These include the RNA-mediated addition of amino acids to proteins, and ubiquitination. For example, Proteins--Structure And Molecular Pro perties, 2nd edition, TECreighton, W.H. Freeman and d Company, New York (1993) and Wold, F., "Postt ranslational Protein Modifications:Persp ectives and prospects”, Posttranslational Covalent Modification Of Proteins,1-12 pp., BC Johnson, Academic Press, New York (19 83); Seifter et al., Meth. Enzymol. 182:626-646 (1 990) and Rattan et al., "Protein Synthesis: Post ranslational Modifications and Aging” Ann See NY Acad Sci 663:48-62 (1992). The term "conductor" includes a conductor that is branched, or branched and cyclic, or unbranched and cyclic. These include chemical modifications that result in proteins or polypeptides that are cyclic, branched, and unbranched. Branched circular proteins or polypeptides may result from post-translational natural processes, It can also be made entirely synthetically.

[0027] The term "homolog" refers to a comparison of the similarity in amino acid positions of two polypeptides. The amino acid sequence of FT and at least Refers to proteins that are at least 60% identical. Similarity or identity between two proteins The degree of issuance is limited to, but not limited to, Computational Molecules. ar Biology, edited by Lesk, AM, Oxford University Press, New York, 1988; Biocomputing:Informat ics and Genome Projects, Smith, DW (ed.), Aca demic Press, New York, 1993;Computer Analyses is of Sequence Data, Part I, Griffin, AM, and Griffin, HG, Humana Press, New Jersey, 1 994;Sequence Analysis in Molecular Biol ogy, von Heinje, G., Academic Press, 1987;S sequence Analysis Primer, Gribskov, M. and D. Edited by Evereux, J., M Stockton Press, New York, 199 1 year; and Carillo H. and Lipman, D., SIAM, J. Ap known methods, including those described in Plied Math., 48:1073 (1988) The preferred method for determining identity is to It is designed to give the largest match between sequences. Methods of determining identity and similarity has been codified in a publicly available computer program.

[0028] Preferred computer programs useful in determining identity and similarity between two sequences are: The ram method includes, but is not limited to, the GCG program package (Devereuil). x, J. et al., Nucleic Acids Research, 12(1):387(1 984), BLASTP, BLASTN, and FASTA, Atschul, S.F. et al., J. Molec. Biol., 215:403-410 (1990). The BLAST X program is available from NCBI and other sources (BLAST Manual, Altschul, S. et al., NCBI NLM NIH Bethesda, Md.20 894;Altschul, S. et al., J.Mol.Biol., 215:403-410 (1990)). For example, GAP (University of Wisconsin Genetics Association) Computer algorithms such as the The percent sequence identity of two proteins or polypeptides is to be determined using the The sequences are aligned so that each amino acid is best matched (determined by the algorithm). (such as "matched span").

[0029] Gap opening penalty (calculated as three times the average diagonal; "average diagonal" is the the average of the diagonals of the comparison matrix; the "diagonal" is the average of the diagonals of the comparison matrix; A score or number assigned to each perfect amino acid match) and a gap extension pair Nulty (usually 1 / 10 of the gap opening penalty), as well as PAM250 Alternatively, a comparison matrix such as BLOSUM62 can be used in conjunction with the algorithm. Standard comparison matrix (see Dayhoff et al. for the PAM250 comparison matrix) :Atlas of Protein Sequence and Structure , vol. 5, supp. 3; for the BLOSUM62 comparison matrix see See Henikoff et al., Proc. Natl. Acad. Sci. USA, 89:1 0915-10919) can also be used in the algorithm. The algorithm calculates the percent identity. Homologues are sometimes Typically one or more amino acid substitutions or deletions when compared to the corresponding protein or peptide , and / or will have insertions.

[0030] The term "fusion protein" refers to a protein in which one or more peptides are fused together, including, but not limited to, Proteins such as antibodies or antibody fragments such as Fab fragments or short chain Fv recombinantly fused or chemically conjugated (including covalent and non-covalent bonds) to the protein The term "fusion protein" refers to a protein conjugated with a fusion protein. Furthermore, peptide multimers (i.e., dimers, trimers, tetramers and higher multimers) are also contemplated. Such multimers include homomeric multimers containing one peptide; multimers containing two or more peptides; and a heteromeric multimer comprising at least one peptide and at least Heteromers containing one or more other proteins. Such multimers are characterized by hydrophobic, parental may be the result of aqueous, ionic and / or covalent associations, bonds or links , may be formed by cross-linking using linker molecules, or indirectly, e.g. They may also be linked by liposome formation.

[0031] The term "peptidomimetic" or "mimetic" refers to a peptide or mimics the biological activity of proteins but is no longer peptidic in chemical nature, i.e. that is, biomolecules that no longer contain peptide bonds (i.e., amide bonds between amino acids). As used herein, the term peptidomimetic has a broader meaning. Molecules used in flavourings that are no longer completely peptidic in nature, e.g. pseudopeptides, semi-peptides Examples of peptide mimetics in this broader sense include peptides and peptoids. The following structures are examples of peptides (where some of the peptides are replaced with structures lacking peptide bonds): The peptidomimetics according to the embodiments, whether entirely non-peptide or partially non-peptide, A peptidomimetic closely mimics the three-dimensional arrangement of the active groups of the peptide on which it is based. This similarity in the geometry of the active site provides a spatial arrangement of reactive chemical moieties. As a result, peptidomimetics have effects on biological systems that mimic the biological activity of peptides. Has.

[0032] Peptidomimetics of embodiments of the present invention preferably possess both three-dimensional shape and biological activity. In this respect, peptides known in the art are substantially similar to the peptides described herein. Examples of methods for structurally modifying peptides to generate peptidomimetics include the use of D-amino acid residue structures. The structure involves inversion of the main chain chiral center, leading to the undesired D-amino acid residue structure, especially at the N-terminus. Enhanced stability against proteolytic degradation without adverse activity This example is based on the paper "Tritriated D-ala1-Peptide TB inding” Smith CS et al., Drug Development Res. , 15, pp. 371-379 (1988). The second method is to Modification of cyclic structures for stability, such as imides and lactams (Ede et al., Smith th and Rivier (eds.) "Peptides: Chemistry and d Biology,” in Escom, Leiden (1991), pp. 268-270. ) An example of this is U.S. Patent No. 4,457,489 (1985), Goldstein Conformationally restricted thymopentin-like proteins, such as those disclosed in G. et al. No. 6,239,999, the disclosure of which is incorporated herein by reference in its entirety. The third method involves converting the peptide bonds within the peptide into pseudopeptides that make them resistant to proteolysis. The substitution is by a thiol bond.

[0033] Some pseudopeptide bonds generally do not affect peptide structure and biological activity One example of this approach is retro-inverso ) pseudopeptide bonds ("Biologically active "retroinverso analogues of thymopentin", S isto A. et al., Rivier, JE and Marshall, GR (supervisors) M.) “Peptides, Chemistry, Structure and Biol ogy,” Escom, Leiden (1990), pp. 722-773, and Da lpozzo et al. (1993), Int. J. Peptide Protein Res ., 41:561-566, incorporated herein by reference). Following this modification, The amino acid sequence is such that one or more peptide bonds are replaced with reversed pseudopeptide bonds. The sequence may be identical to that of the peptides described above, except for the N-terminal end. The peptide bond is replaced because such a substitution allows for the exopeptidyl transferase to act on the N-terminus. This is because it would provide resistance to proteolysis by enzymes. They can also be further modified by substituting other chemical groups of similar structure. Increased stability against enzymatic cleavage with little or no loss of activity Another suitable pseudopeptide bond known to promote is the reduced isostere pseudopeptide bond. (Couder et al. (1993), Int. J. Peptide Protein Res., 41:181-184, incorporated herein by reference in its entirety).

[0034] Therefore, the amino acid sequences of these peptides are such that one or more peptide bonds form an isostere. It may be identical to the sequence of FT except that it is replaced by a pseudopeptide bond. Preferably, the most N-terminal peptide bond is substituted, since such substitution is It may confer resistance to proteolysis by terminally acting exopeptidases. The synthesis of peptides with one or more reduced isostere pseudopeptide bonds is It is known in the art (Couder et al. (1993), cited above). Examples include the replacement of peptide bonds by the introduction of ketomethylene or methylsulfide bonds. do.

[0035] Peptoid derivatives of the peptides described herein contain structural determinants important for biological activity. retains its original structure but removes peptide bonds, thereby conferring resistance to proteolysis These represent another class of peptidomimetics (Simon et al., 1992, Proc Natl. Acad. Sci. USA, 89:9367-9371, the entire contents of which are incorporated herein by reference. Peptoids are oligomers of N-substituted glycines. -alkyl groups have been described, each corresponding to the side chain of a natural amino acid (Simon et al. 1992), cited above). Some or all of the amino acids of the peptide may be replaced with the amino acids to be replaced. The acid can be replaced with the corresponding N-substituted glycine.

[0036] The term "peptidomimetic" or "mimetic" also refers to an inverse peptide, as defined below. D-peptides and enantiomers are also included.

[0037] The term "reverse D peptide" refers to a peptide with amino acids in reverse order as compared to the L-amino acid sequence of the peptide. It refers to biologically active proteins or peptides consisting of D-amino acids arranged in a cyclic or cyclic fashion. Therefore, the carboxy-terminal residue of an L-amino acid peptide is the amino-terminal residue of a D-amino acid peptide. For example, the peptide ETESH is d S d E d T d E d where, E d , H d , S d , and T dcorrespond to L-amino acids, E, H, S, and T, respectively. It is a D-amino acid.

[0038] The term "enantiomer" refers to one or more L-amino acids in the amino acid sequence of a peptide. Biologically active proteins in which acid residues are replaced by the corresponding D-amino acid residues or a peptide.

[0039] As used herein, the term "composition" refers to a compound containing FT and, optionally, an additional active ingredient. The term "composition" broadly refers to any composition containing a therapeutic agent. The composition may be a dry blend, an aqueous solution, or a mixture thereof. The composition containing the FT may comprise a sterile composition. These probes can be stored in lyophilized form. It can also be associated with stabilizers such as carbohydrates. In this case, the probe may contain salts, e.g., NaCl; detergents, e.g., sodium dodecyl sulfate; sodium dodecyl sulfate (SDS); and other components, such as Denhardt's solution, skim milk, salmon sperm DNA, etc. The composition can be placed in an aqueous solution containing

[0040] In one embodiment where an additional active agent is used with FT, the term "active agent" refers to an To refer to any agent capable of removing unwanted cell and / or tissue growths Suitable active agents include (i) anti-cancer active agents (alkylating agents, topoisomerase I inhibitors, topoisomerase II inhibitors, RNA / DNA antimetabolites, and antimitotics (ii) active agents for treating benign growths, e.g., anti-acne and anti-wart agents; (iii) an antiandrogen compound (cyproterone acetate (1α,2β-methylene- 6-chloro-17α-acetoxy-6-dehydroprogesterone) tamoxifen, allo (iv) alpha 1-adrenergic receptor blockers (tamsulosin, Lazosin, doxazosin, prazosin, bunazosin, indoramin, alfuzosin, cilonin dosin), (v) 5α-reductase inhibitors (finasteride, dutasteride), (v i) Phosphodiesterase type 5 (PDE5) inhibitors (tadalafil) and their combinations These may include, but are not limited to, combinations.

[0041] The present disclosure provides a method for treating unwanted cell proliferation in mammals using FT alone or in combination with other therapeutic agents. When used in combination with additional active agents that can kill LUTS Based in part on the discovery that it provides unexpected relief to patients suffering from obstructive voiding symptoms related to While the inventors do not intend to be limited to any particular theory or procedure, the present inventors believe that FT When administered to mammals, it has been shown to produce unexpectedly excellent improvement effects in patients with LUTS. The present inventors discovered that FT is a steroid hormone that acts as a steroid hormone in the body. When administered alone or in combination with other active agents, it can improve the symptoms of LUTS patients (irritability, "We unexpectedly discovered that the symptoms of urinary tract infection (including both urinary and obstructive voiding symptoms) improved dramatically," said Dr.

[0042] Patients treated with the compositions described herein were administered a control composition that did not contain FT. Compared with the control group, the mean obstructive voiding symptoms (M VS) dramatically improved by over 30%. Reduce obstructive voiding symptoms (MVS) by approximately 30% to approximately 150%, approximately 35% to approximately 125%, or approximately 45%. Patients treated with the compositions described herein may experience improvement in the range of F Mean stimulated urine collection as measured by IPSS compared to administration of a control composition without T Symptoms (MISS) improved dramatically by 20% or more. MISS is about 20% to about 50%, about 25% to about 40%, or about 30%. The improvement can be in the range of 0% to approximately 35%.

[0043] The present inventors have demonstrated that administering conventional oral BPH medications to patients with LUTS is more effective than placebo alone. Mean obstructive voiding symptoms (MOVS) measured by IPSS compared with patients receiving Furthermore, the mean irritative urinary storage symptom (MISS) measured by IPSS was dramatically reduced. The inventors found that the reduction rate of MOVS was about 50% and the reduction rate of MISS was about Conventional BPH treatments cannot be expected to improve symptoms in LUTS patients. The dramatic improvement achieved by the present invention, which involves the administration of FT, was therefore unexpected.

[0044]

[0010] Embodiments of the present invention include a method of treating a mammal having LTUS, the method comprising: FT may be administered alone or in combination with an additional active agent in one or more doses to a mammal. This method includes administering a composition containing FT intramuscularly, orally, intravenously, orally. In the abdominal cavity, in the cerebral (soft tissue), in the ventricles, in lesions, in the eyes, in arteries, in the cerebrospinal cavity intratumorally, intranasally, topically, transdermally, subcutaneously, intradermally, alone or with a carrier These include, but are not limited to, administration in a complex with

[0045] Any mammal can benefit from the use of the present invention. Mammals include humans. , mice, rabbits, dogs, sheep and other livestock, as well as veterinarians, zookeepers, and field This includes any mammal that has been or can be treated by animal care workers. Preferred mammals are humans, sheep, and dogs. The words "patient" and "patient" are used interchangeably.

[0046] Other smaller fragments of FT may be used if these peptides have the same or similar biological activity. It will be apparent to those skilled in the art that the NTP peptide may be selected to have the same structure. Other fragments may also be used so that these peptides have the same or similar biological activity. The peptides of each embodiment encompass these other fragments. Generally, the peptides of each embodiment contain at least four amino acids, preferably at least five. amino acids, more preferably at least six amino acids.

[0047] In addition, an embodiment of the present invention provides a composition comprising an FT comprising two or more FT sequences linked together. and administering to a mammal (or patient) suffering from LUTS, including administering to the mammal (or patient) with an additional active agent. The present invention encompasses methods of treating a cancer cell line comprising two or more FT sequences, as long as the FT has the desired biological activity. would also have the desired biological activity.

[0048] FT and its fragments, variants, derivatives and homologues encompassed in embodiments of the present invention Fusion proteins and mimetics can be produced using methods known to those skilled in the art. DNA technology, protein synthesis, and the synthesis of natural peptides, proteins, mutants, and derivatives Methods such as the isolation of mutants and homologues can be used. Variants, derivatives, homologues, fusion proteins and mimetics may be synthesized using methods known to those skilled in the art. peptides, proteins and their fragments, variants, derivatives and homologues Such methods involve cleaving peptides or proteins to produce FT fragments. These include, but are not limited to, the use of proteases to No. 4,266, No. 7,241,738, No. 7,317,077, No. 7,408,021 No. 7,745,572, No. 8,067,378, No. 8,293,703, No. 8 Nos. 5,569,446 and 8,716,247, and U.S. Patent Application Publication No. 2 No. 017 / 0360885, No. 2017 / 0020957, No. 2016 / 036138 0 and any of the methods disclosed in Patent Application No. 2016 / 0215031. The FT peptides described herein can be prepared using the methods described above.

[0049] The present embodiment relates to a method of treating a mammal with LUTS, the treatment resulting in an IPS. Improved obstructive and / or irritative symptoms associated with LUTS as measured using S Such methods include administering a therapeutically effective amount of FT, alone or in combination with FT-1, to a mammal in need thereof. The mammal in need of treatment is a mammal, such as a prostate mammals with LUTS, whether or not they also suffer from benign prostatic hyperplasia (BPH), or The mammal in need of treatment may be a mammal with both BPH and LUTS. Additionally, a mammal in need of treatment is any mammal for which improvement of symptoms associated with LUTS would be beneficial. The animal may be any mammal.

[0050] If an additional active agent is used, the additional active agent may be selected from the following: One or more active agents can be used: (i) anti-cancer active agents (alkylating agents, topoisomerase I inhibitors, topoisomerase II inhibitors, RNA / DNA antimetabolites, and mitotic inhibitors (ii) active agents for treating benign growths, such as anti-acne and anti-wart active agents; (iii) antiandrogen compounds (cyproterone acetate (1α, 2β) -Methylene-6-chloro-17α-acetoxy-6-dehydroprogesterone) tamoxifen (iv) α1-adrenergic receptor blockers (tamsulosin) terazosin, doxazosin, prazosin, bunazosin, indoramin, alfuzosin , silodosin), (v) 5α-reductase inhibitors (finasteride, dutasteride) , (vi) phosphodiesterase type 5 (PDE5) inhibitors (tadalafil) and their Preferably, the additional active agent is tamsulosin, finasteride, terrazon Syn, doxazosin, prazosin, tadalafil, alfuzosin, silodosin, Dutasteride dutasteride, a combination of dutasteride and tamsulosin, and mixtures and combinations thereof combinations thereof.

[0051] The therapeutic compositions described herein comprise a therapeutically active agent in admixture with a pharmaceutically acceptable carrier. In some alternative embodiments, the additional active agent may be present in the same composition as FT. In other embodiments, the composition containing FT can be administered in a It is administered as an injection, while the additional active agent is administered as an oral medication (gel, capsule, tablet, liquid The carrier material is water for injection, preferably a solution for administration to a mammal. It may be water supplemented with other materials normally found in fluids. Typically, FT is a physiologically tolerable The purified FT peptide is combined with one or more carriers, excipients, or diluents that are It is administered in the form of a composition containing neutral buffered saline or serum albumin. Physiological saline is an example of a suitable carrier. Preferably, the product is prepared by dissolving in a suitable excipient (e.g., saline). The drug is formulated as a lyophilizate using a soluble sugar. If desired, other standard carriers, diluents, and The composition of each embodiment may contain an appropriate pH value within a range known to those skilled in the art. a buffer solution having a pH of about 7.0 to 8.5, such as a Tris buffer solution having a pH of about 4.0 to The solution may also contain acetate buffer at 5.5, which may further contain sorbitol or a suitable substitute. It is also possible.

[0052] Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, pills, powders, and granules. In such solid dosage forms, the additional active agent and / or FT may be, but is not limited to: (a) sodium citrate or dicalcium phosphate. (b) one or more inert excipients (or carriers) such as starch, lactose, sucrose, buprenorphine, (c) fillers or extenders such as sugar, mannitol, and silicic acid; Cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia (d) humectants such as glycerol; (e) agar, calcium carbonate, dipotassium iodide, etc. Potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate (f) solution coagulation retarders such as paraffin; (g) quaternary ammonia (h) absorption enhancers such as acetyl alcohol and glycol monostearate; (i) wetting agents such as glycerol; (ii) adsorbents such as kaolin and bentonite; and (j) Talc, calcium stearate, magnesium stearate, solid polyethylene Lubricants such as glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0053] Liquid dosage forms for oral administration may be pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or the like. Liquid dosage forms include, in addition to the active compound, Inert diluents, such as water or other solvents, solubilizers, and emulsifiers, may be included. Examples of emulsifiers include ethyl alcohol, isopropyl alcohol, ethyl carbonate, and ethyl acetate. , benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol Recall, dimethylformamide, oils, such as cottonseed oil, peanut oil, and corn germ Oils, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol polyethylene glycols, fatty acid esters of sorbitan, or these substances and mixtures thereof.

[0054] Besides such inert diluents, the composition can also contain wetting agents, emulsifying and suspending agents, sweetening agents, Adjuvants such as flavors and fragrances may also be included.

[0055] Actual dosage levels of the active ingredients in the compositions of this invention will vary depending on the particular composition and method of administration. Varying amounts of FT and additional active agent(s) may be used to obtain an effective amount to obtain the desired therapeutic response. The selected dosage level therefore depends on the desired therapeutic effect, the route of administration, the desired duration of treatment, and other factors.

[0056] For mammals, including humans, effective amounts can be administered based on body surface area. Dose correlations for different species of animals and humans (mg / M 2 (based on body surface area) is E. J. Freireich et al., Cancer Chemother. Rep., 5 0(4):219 (1966). Body surface area is calculated based on the height and weight of the individual. can be approximately determined from (e.g., Scientific Tables, Geigy P harmaceuticals, Ardsley, New York, pp. 537-538 (197 (0 years) reference).

[0057] The total daily dose of FT peptide and additional active agent administered to the host may be administered in a single dose or in divided doses. Dosage unit compositions may be divided into submultiples thereof that may be used to make up the daily dose. However, the specific dose level for any particular patient may vary. , body weight, general health, sex, diet, time and route of administration, potency, absorption and The efficacy and safety of the drug depend on various factors, such as its dosage and excretion rate, its combination with other drugs, and the severity of the particular disease being treated. It will be understood that the dosage may vary depending on the cause. In another preferred embodiment, the composition is administered in two doses. In this embodiment, the interval between administrations of the composition is from 2 months to 10 years, or Varying from 8 months to 4 years or over a range of about 1 year (e.g., between 1 and 2 years) Ugh.

[0058] The method of administering a composition comprising FT according to an embodiment of the present invention comprises administering the composition to an aerosol. It can be administered intramuscularly, orally, by sol, injection, bolus injection, implantable device, or sustained release system. Intravenous, intraperitoneal, intraventricular (intravenous tissue), intraventricular, intratumor, intralesion, intradermal, intrathecal, intranasal This includes, but is not limited to, intraocular, intra-arterial, topical, rectal, intraperitoneal, and transdermal administration. See, for example, U.S. Patent Nos. 6,924,266, 7,241,738, and 7,317 ,077, No. 7,408,021, No. 7,745,572, No. 8,067,378 Nos. 8,293,703, 8,569,446 and 8,716,247 and U.S. Patent Application Publication Nos. 2017 / 0360885 and 2017 / 00209 57, 2016 / 0361380, and 2016 / 0215031 Any of the disclosed methods of administration can be used.

[0059] In one embodiment, the present invention provides a method for treating LUTS, including in mammals that also optionally have BPH. The present invention relates to a method for improving symptoms in a mammal suffering from BPH, particularly a mammal that also has LUTS. determining a therapeutically effective amount of FT (SEQ ID NO. 1: (Ile-Asp-G ln-Gln-Val-Leu-Ser-Arg-Ile-Lys-Leu-Glu-I administering to the mammal at least once In one embodiment, the method comprises: At least one active agent administered in combination is selected from the group consisting of: (1) to (40) (1) 5α-reductase inhibitors and / or antiestrogens, (2) 5α- reductase inhibitors and / or aromatase inhibitors, (3) 5α-reductase inhibitors (4) 5α-reductase inhibitors, anti-estrogen gens, and aromatase inhibitors, (5) 5α-reductase inhibitors, antiestrogens, and 17β-HSD inhibitors, (6) 5α-reductase inhibitors, aromatase inhibitors, Antiestrogens and 17β-HSD inhibitors, (7) 5α-reductase inhibitors, anti- androgens and antiestrogens, (8) 5α-reductase inhibitors, antiandrogens , and aromatase inhibitors, (9) 5α-reductase inhibitors, antiandrogens, and and 17β-HSD inhibitors, (10) 5α-reductase inhibitors, antiandrogens, anti-esophageal tronogens, and aromatase inhibitors, (11) 5α-reductase inhibitors, antiandrogen Gen, aromatase inhibitor, and 17β-HSD inhibitor, (12) 5α-reductase inhibitors, antiandrogens, aromatase inhibitors, antiestrogens, and 17β-HSD inhibitors, (13) 17β-HSD inhibitors, and antiestrogens, (14) 17β-HS D inhibitors, and aromatase inhibitors, (15) 17β-HSD inhibitors, aromatase inhibitors (16) 17β-HSD inhibitors, antiandrogens, and Antiestrogens, (17)17β-HSD inhibitors, antiandrogens, and aromatase inhibitors, (18) 17β-HSD inhibitors, antiandrogens, antiestrogens, and allo (19) Antiestrogens, and aromatase inhibitors, (20) Antiestrogens androgens, aromatase inhibitors, and antiandrogens, (21) LHRH agonists or or antagonist, 5α-reductase inhibitor, and anti-estrogen, (22)LH RH agonists or antagonists, 5α-reductase inhibitors, and aromatase inhibitors, (23) LHRH agonists or antagonists, 5α-reductase inhibitors , and 17β-HSD inhibitors, (24) LHRH agonists or antagonists, 5 α-reductase inhibitors, antiestrogens, and aromatase inhibitors, (25)LHR H agonists or antagonists, 5α-reductase inhibitors, antiestrogens, and and 17β-HSD inhibitors, (26) LHRH agonists or antagonists, 5α-reductase inhibitors, ductase inhibitors, aromatase inhibitors, antiestrogens, and 17β-HSD inhibitors , (27) LHRH agonists or antagonists, 5α-reductase inhibitors, anti- androgens, and antiestrogens, (28) LHRH agonists or antagonists , 5α-reductase inhibitor, antiandrogen, and aromatase inhibitor, (29)L HRH agonists or antagonists, 5α-reductase inhibitors, antiandrogens, and 17β-HSD inhibitors, (30) LHRH agonists or antagonists, 5α -reductase inhibitors, antiandrogens, antiestrogens, and aromatase inhibitors, (31) LHRH agonists or antagonists, 5α-reductase inhibitors, anti- drogens, aromatase inhibitors, and 17β-HSD inhibitors, (32) LHRH agonists inhibitors or antagonists, 5α-reductase inhibitors, antiandrogens, aromatase inhibitors, antiestrogens, and 17β-HSD inhibitors, (33) LHRH agonists or or antagonist, 17β-HSD inhibitor, and anti-estrogen, (34)LHRH agonists or antagonists, 17β-HSD inhibitors, and aromatase inhibitors, (35) LHRH agonists or antagonists, 17β-HSD inhibitors, aromatizers enzyme inhibitors, and antiestrogens, (36) LHRH agonists or antagonists, 17β-HSD inhibitor, antiandrogen, and antiestrogen, (37)LHRH androgen inhibitors or antagonists, 17β-HSD inhibitors, antiandrogens, and aromatase inhibitors. enzyme inhibitors, (38) LHRH agonists or antagonists, 17β-HSD inhibitors , antiandrogen, antiestrogen, and aromatase inhibitor, (39) LHRH ists or antagonists, antiestrogens, and aromatase inhibitors, and (4 0) LHRH agonists or antagonists, antiestrogens, aromatase inhibitors, and antiandrogens.

[0060] The following examples are provided to illustrate various embodiments of the present invention. The invention is not limited to the specific conditions or details set forth in these examples. It should be understood that throughout this specification, references to publicly available patents, including U.S. patents, are not intended to be limiting. Any and all references to such documents are specifically incorporated herein by reference. In particular, embodiments of the present invention are directed to U.S. Pat. Nos. 6,924,266, 7,241,738, No. 7,317,077, No. 7,408,021, No. 7,745,572, No. 8,0 Nos. 67,378, 8,293,703, 8,569,446 and 8,716 ,247 , and U.S. Patent Application Publication No. 2017 / 0360885, 2017 Nos. / 0020957, 2016 / 0361380, and 2016 / 021503 The examples contained in the patent application Ser. No. 10 / 1999, filed on Oct. 1, 2002, are expressly incorporated by reference. Each of these documents is incorporated herein by reference. The specific peptides identified were isolated from normal rodent muscle tissue, subcutaneous connective tissue, dermis, etc. demonstrated that it is an effective agent for inducing cell death in vivo in various tissues. It makes it clear. [Example]

[0061] Under double-blind conditions, ultrasound-guided by a urologist in a clinical setting, patients with BPH were randomly assigned to receive a urinary tract exam. In some cases, patients with LTUS are treated with a) FT (SEQ ID NO: 1 (Ile- Asp-Gln-Gln-Val-Leu-Ser-Arg-Ile-Lys-Leu- Glu-Ile-Lys-Arg-Cys-Leu) (2.5 mg), pH 7. b) intraprostatic injection of either phosphate buffered saline ("PBS") or c) PBS alone Patients were followed for 1 to 6 years by regular physical examinations, laboratory tests, and symptom management. Symptom assessment was performed to assess improvement or worsening of prostate symptoms. The International Prostate Symptom Score (IPSS) is a quantitative scale used to measure prostate function. The SS quantifies the following: 1) the feeling of incomplete urination, 2) frequent urination, 3) intermittent urinary stream, and 4) the feeling of urgency to urinate. 5) Weak urinary flow. 6) Straining. 7) The need to urinate after going to bed at night (nocturia).

[0062] IPSS items 1, 3, 5, and 6 are measures of obstructive voiding, and IPSS item 2 , 4, and 7 are scales indicating irritative urination. The difference between the line's irritable urine collection score and the follow-up score, and the baseline obstructive The difference between the voiding score and the follow-up score was calculated. Surprisingly, only one FT injection was administered. The improvement in obstructive voiding symptoms in subjects receiving the injection was more significant than the change in irritative voiding symptoms. The results of these tests are summarized in Table 4. [Table 4]

[0063] As shown in Table 4, patients treated with the compositions described herein had significantly higher FT scores than those without the FT. The mean International Prostate Symptom Score (IPSS) was 0.1% compared to the control group. Obstructive voiding symptoms (MVS) improved by 46% or more. Patients treated with the described compositions showed significantly improved FT-free survival compared to patients treated with a control composition that did not contain FT. As a result, mean irritative urinary storage symptoms (MISS) measured by IPSS improved by more than 34%. Therefore, administration of FT significantly improved MOVS and MISS in BPH patients. Since BPH patients may or may not have LUTS, For patients with both PH and LUTS, the improvement effect is even greater. It seems so. [Example]

[0064] In the second analysis group, ultrasound-guided urology was performed by a urologist in the clinic under double-blind conditions. Therefore, patients with BPH were given intraprostatic injections of PBS vehicle alone at pH 7.2. Participants were followed for one to three years with regular physical examinations, laboratory tests, and symptom evaluations. The subjects received only PBS vehicle injections and then received tamsulosin, terazosin, and doxazosin. Alpha-blockers such as phenytoin, 5α-reductase inhibitors such as finasteride and dutasteride, or For the treatment of BPH with phosphodiesterase type 5 inhibitors (PDE5 inhibitors) such as tadalafil Patients who were given conventional oral medications in addition to The IPSS quantifies: 1) Sensation of residual urine. 2) Frequent urination. 3) Intermittent urinary stream. 4) Urgency to urinate. 5) Weakened urinary stream. 6) 7) The need to urinate after going to bed at night (nocturia). Items 1 and 6 are measures of obstructive voiding, and items 2, 4, and 7 of the IPSS are measures of irritative voiding. Blinded placebo-treated patients and those receiving conventional oral BPH treatment were included. In subsequently blinded placebo-treated patients, baseline stimulatory urine scores were significantly higher than those in placebo-treated patients. Differences from baseline to follow-up scores, and from baseline obstructive voiding scores to follow-up scores The difference between the two groups was calculated. The amount of improvement in urinary voiding and irritable urination results was comparable to the change seen in subjects after the first placebo injection. The results of these trials were not significantly better than those of the control group, and in fact were worse. Shown in 5. [Table 5]

[0065] From the results of Table 5, BPH patients who received conventional oral BPH medications had a significantly higher risk of developing rheumatoid arthritis compared with placebo-controlled drugs. There was no improvement in MOVE or MISS compared with patients who received only In this study, patients who received conventional oral BPH medications showed a slight worsening of LUTS symptoms. Therefore, drugs known to be effective in treating BPH appear to be effective in preventing LU. Patients with TS cannot expect any improvement in their symptoms, let alone any dramatic improvement in patients treated with FT. I didn't expect any improvement. [Example]

[0066] In the third analysis group, ultrasound-guided urology was performed by a clinic urologist under double-blind conditions. Therefore, patients with BPH were given intraprostatic injections of PBS vehicle alone at pH 7.2. Participants were followed for one to three years with regular physical examinations, laboratory tests, and symptom evaluations. 131 patients who received PBS vehicle alone were followed up 1-3 years later with phosphate buffered saline (PBS) FT (SEQ ID NO. 1) dissolved in physiological saline pH 7.2 (hereinafter referred to as "PBS") Ile-Asp-Gln-Val-Leu-Ser-Arg-Ile-Lys-Leu- A crossover injection of 2.5 mg of Ile-Lys-Arg-Cys-Leu) was administered. Patients who received blinded placebo treatment (group 1), blinded placebo treatment Patients who subsequently received conventional oral BPH medication (group 2), blinded Patients who received placebo and subsequently received FT treatment (Group 3) The difference between baseline obstructive voiding scores and follow-up scores was calculated. The amount of improvement in obstructive voiding symptom outcomes in subjects who received a prior placebo injection followed by an FT injection was: This was significantly better than the changes seen in subjects after the first placebo injection and was consistent with the blinded process. The improvement was significantly better than that seen in patients who received placebo followed by oral conventional BPH medication. These results are shown in Table 6 below. [Table 6]

[0067] As shown in Table 6, patients treated with the compositions described herein had a higher incidence of HIV infection than those treated with the International Prostate Symptom Scale (IPSS). Mean obstructive voiding symptoms (MVS) measured by core (IPSS) were significantly higher than those of the control composition without FT. 104% or more after administration of placebo compared with conventional oral BPH FT was shown to be effective in treating BPH, showing an improvement of over 320% compared to when medication was administered. It has been reported that there are known BPH treatments (e.g., conventional oral medications - see the examples above) 2) have been shown to be ineffective for both irritative and obstructive symptoms. Therefore, there is no reason to expect that administration of FT will improve obstructive voiding symptoms in patients with LUTS. Do not expect a 300% or greater improvement compared to other known BPH medications. It was. [Example]

[0068] In the fourth analysis group, ultrasound-guided urology was performed by a clinic urologist under double-blind conditions. Therefore, patients with BPH were given either PBS vehicle at pH 7.2 or one containing FT. Patients were followed for 1 to 3 years by regular physical examinations, laboratory tests, and Symptoms were assessed and followed up. 217 patients received placebo alone in a double-blind study. (Group 1). 287 patients received FT monotherapy in a double-blind study (Group 2). Loop 2). After 1-3 years, 131 patients who received PBS vehicle alone had a clotting time of 1-3 days. In the last group, 189 patients received FT injections at the suction cup (group 3). received blinded FT followed by a second FT injection 1-3 years later (fourth group) In blinded placebo-treated patients (n=217), baseline The difference between the obstructive voiding score and the follow-up score was calculated, and the difference between the FT-treated group and the FT-treated group was calculated. FT injections were compared with 4 (n = 607) in the same study. These improvements were significantly better than those seen in subjects who received only placebo injections. The test results are summarized in Table 7. [Table 7]

[0069] As shown in Table 7, patients treated with the compositions described herein had significantly higher FT scores than those without the FT. The mean International Prostate Symptom Score (IPSS) was 0.1% compared to the control group. Obstructive voiding symptoms (MVS) improved by more than 105%.

[0070] The results of the above examples demonstrate the unexpected benefit of FT peptide in improving the symptoms of LUTS patients. Those skilled in the art will appreciate that the methods and compositions of the present invention can be used in conjunction with the methods and compositions of the present invention. It will be apparent that various modifications and variations may be made without departing from the spirit or scope of the present invention. .

Claims

1. 1. A method for improving symptoms in a mammal having lower urinary tract symptoms (LUTS), comprising: (i) identifying a mammal that has LUTS but does not have benign prostatic hyperplasia (BPH); and, (ii) administering to a mammal having the LUTS but not having BPH a therapeutically effective amount of SEQ ID NO. 1(Ile-Asp-Gln-Gln-Val-Leu-Ser-Arg- Ile-Lys-Leu-Glu-Ile-Lys-Arg-Cys-Leu) and a step of: The method provides a reduction in the number of inflammatory cytokines in the blood compared to administration of a control composition not containing SEQ ID NO.

1. , mean obstructive voiding symptoms (MOVS) as measured by the International Prostate Symptom Score (IPSS) ) by 30% or more.

2. The method comprises administering a therapeutically effective amount of SEQ ID NO. 1 of claim 1 and a carrier. The method of claim 1 .

3. 10. The method of claim 1, comprising administering SEQ ID NO. 1 two or more times.

4. SEQ ID NO. 1 is administered orally, subcutaneously, intradermally, intranasally, or intravenously. , consisting of intramuscular, intrathecal, intranasal, intratumoral, topical and transdermal administration.

10. The method of claim 1, wherein the administration is by a method selected from the group:

5. The method provides a method for determining the mean obstructive voiding symptoms (MOVS) measured by the IPSS.

10. The method of claim 1, wherein the improvement ranges from about 30% to about 150%.

6. The method allows the mean obstructive voiding symptoms (MOVS) measured by the IPSS to be 6. The method of claim 5, wherein the improvement in the luminance of the luminance is in the range of about 35% to about 125%.

7. The method allows the mean obstructive voiding symptoms (MOVS) measured by the IPSS to be 7. The method of claim 6, wherein the improvement in the luminance of the luminance is in the range of about 45% to about 105%.

8. The results of IPSS measurements in patients receiving oral medications effective in treating benign prostatic hyperplasia and the method reduces the mean obstructive voiding symptoms (MOVS) by 300% compared to the mean MOVS obtained by the method. % or more improvement.

9. The method was compared to the administration of a control composition not containing SEQ ID NO.

1. and mean obstructive voiding symptoms (MO) as measured by the International Prostate Symptom Score (IPSS). VS) is improved by 20% or more.

10. The method provides a method for determining the mean irritative urinary storage symptom (MISS) measured by the IPSS.

10. The method of claim 9, wherein the improvement ranges from about 20% to about 50%.

11. The method determines the mean irritative urinary storage symptom (MISS) measured by the IPSS.

11. The method of claim 10, wherein the improvement in the range of about 25% to about 40% is achieved.

12. The method determines the mean irritative urinary storage symptom (MISS) measured by the IPSS.

12. The method of claim 11, wherein the improvement in the range of about 30% to about 35% is achieved.

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