RU2780890C2 - Method for treatment of benign prostatic hyperplasia, using antibiotics - Google Patents

Abstract

FIELD: medicine; urology; therapy.

SUBSTANCE: invention relates to the field of medicine, namely to urology and therapy; it is intended for the treatment of benign prostatic hyperplasia (hereinafter – BPH). A method for improvement of symptoms in mammals suffering from BPH includes the administration of at least three different compositions, each of which contains one or several antibiotics. Moreover, the first composition contains a fluoroquinolone antibiotic, the second one – metronidazole, and the third one – an antibiotic selected from imipenem, gentamicin, and cephalothin. The third composition is administrated by an intramuscular injection.

EFFECT: use of the invention provides for effective treatment of benign prostatic hyperplasia.

11 cl, 13 tbl, 10 ex

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This PCT application claims priority under U.S. Patent Application No. 15/938,920, filed March 28, 2018, which is expressly incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. SEQUENCE LIST

[0002] This application contains a sequence listing that has been submitted electronically in ASCII format and is hereby incorporated herein by reference in its entirety. The specified ASCII copy, created on May 15, 2018, is named 063307-0458312_SL.txt and is 749 bytes in size.

2. Field of invention

[0003] Embodiments include methods for treating benign prostatic hyperplasia using compositions that contain at least one antibiotic. Other embodiments include methods for treating benign prostatic hyperplasia using compositions that contain at least one antibiotic, one or more small peptide compounds, and a pharmaceutically acceptable carrier.

3. Description of the prior art

[0004] Benign prostatic hyperplasia (BPH) is a histological diagnosis that refers to non-malignant proliferation of smooth muscle and epithelial cells of the prostate. Lee C, et al ., "Intrinsic and extrinsic factors controlling benign prostatic growth", Prostate, 1997;31:131-138; Auffenberg GB, et al ., "Established medical therapy for benign prostatic hyperplasia", Urol Clin North Am,. 2009;36:443-459. The exact etiology is unknown. The progression of BPH can lead to benign prostate enlargement (BPE), which is defined by the size of the prostate (pathological). Approximately 50% of men with histologic BPH develop BPE. BPE is capable of eventually causing bladder outlet obstruction (BOO), which is also called benign prostatic obstruction (BPO) when associated with BPE. BOO and BPO are determined by urodynamic measurements.

[0005] The development of BPH is a phenomenon of male aging. The prostate weighs a few grams at birth and undergoes androgen-induced growth at puberty, leading to an increase in adult size up to 20 g by the second decade of life. The prostate gland typically maintains stable weight and histological characteristics for approximately 25 years. In the fifth decade, the second growth spurt begins in most men. This second growth phase begins in the periurethral zone of the gland as localized cell proliferation. Growth and enlargement may progress to compression of the remaining normal gland, leading to a significant increase in the size of the gland and causing obstruction of the urinary tract and/or rectum.

[0006] Benign prostatic hyperplasia (BPH) is associated with difficulty in the function of the lower urinary tract. Such symptoms include problems such as a feeling of incomplete emptying of the bladder after urination; the need to urinate frequently; interruption and resumption several times during urination; difficulty in delaying urination; weak urinary stream; the need to make an effort and press during urination; and the need to urinate during the night after going to bed. Diagnosis of prostate conditions involves consideration of all possible conditions in the differential diagnosis, e.g. cancer, infection, benign enlargement, etc. and this assessment requires tests and assessments performed by qualified clinicians using techniques and data from history, physical examination, imaging , laboratory tests, and specialized testing such as urinary flow rate and other functional tests, endoscopy, biopsies, and clinical responses to interventions and drugs.

[0007] Diagnosis of prostatitis includes a thorough history and physical examination, tests and cultures of urine and prostate secretions, and often therapeutic responses to courses of antibiotics. The spectrum of prostatitis symptoms can include non-specific symptoms as well as more typical symptoms of pain and signs of inflammation. Non-specific symptoms may include urinary urgency, urinary frequency, nocturia, and urinary disturbances, which also occur in BPH. Antibiotics and anti-infectives are not considered accepted treatment for BPH.

[0008] BPH is believed to arise from an internal set of ducts and glands that are within or near the wall of the urethra. The initial lesions usually consist of a small stromal overgrowth of loose connective tissue containing no glandular components. However, as the nodule grows and develops, glandular tissue predominates. After the onset of the hyperplastic process, all elements of the normal prostate gland (stromal, muscular and glandular) are involved in progressive growth to varying degrees. Determinations of the relative amounts of these tissues in patients with BPH have demonstrated that the amount of fibromuscular tissue significantly exceeds the amount of glandular or epithelial tissue. The fibromuscular stroma makes up approximately 45% of the volume of a normal prostate, as opposed to approximately 60% in a hyperplastic gland.

[0009] Hypertrophy of the stromal and glandular (epithelial) components may occur separately or together. The variable response is confirmed by the nature of the nodules and their developmental phases. Glands in hyperplastic nodules appear to have the ability to develop and form new ducts and acini. Stromal nodules are rarely large, while clinically significant neoplasms usually have large glandular components. Prostate enlargement is often described in terms of glandular enlargement; however, smooth muscle is also an important component. The prostate capsule contains an even greater proportion of muscle tissue.

[0010] The primary symptom of benign prostate enlargement is urinary tract obstruction. Urethral obstruction occurs as a result of compression or lengthening of the urethra. Benign nodular hyperplasia itself can cause urinary tract obstruction through physical obstruction of the urethra or dysfunction of the muscle or nerves supplying the urinary tract sphincter. The exact location of nodular hyperplasia will be determined by the speed and intensity of obstruction symptoms. A small, strategically located nodule may cause more obstruction than larger, more lateral hypertrophies that remain within the prostate capsule. Hematuria is a common symptom of BPH because prostatic hypertrophy is the growth of vessels with dilated veins on the surface of the urethra. Other irritating symptoms include increased frequency of urination and a strong urge to urinate, forcing the passage of urine with a minimal warning symptom. The most serious complication of prostatic hypertrophy is an effect in which obstruction occurs in the upper urinary tract. Obstruction can lead to hydronephrosis, severe kidney damage, and potentially fatal uremia.

[0011] There are a number of treatments for BPH currently available, see chapter 1 of the American Urological Association for Education and Research, Inc., (2001) guideline for the treatment of benign prostatic hyperplasia (BPH); Oelke M, et al ., European Association of Urology, Eur. Urol . 2013 Jun; 64(1):118-40. The guideline discusses treatment options ranging from watchful waiting (WW), for men who are symptomatic but not worried enough to require medication or surgery, to drug and surgical options. If medical treatment is needed, drugs such as α-blockers or alpha-adrenergic antagonists (eg, alfuzosin, doxazosin, tamsulosin, terazosin, silodosin), 5-α-reductase inhibitors 5ARIs (dutasteride, finasteride), antimuscarinics ( anticholinergics), a PDE5 inhibitor (tadalafil), and combinations thereof. Minimally invasive therapies include transurethral needle ablation (TUNA) and transurethral microwave thermotherapy (TUMT). Invasive surgical procedures include open prostatectomy, transurethral holmium laser ablation (HoLAP) or laser enucleation (HoLEP), holmium laser resection (HoLRP), photoselective vaporization (PVP), transurethral incision of the prostate (TUIP), transurethral vaporization of the prostate (TUVP), and transurethral resection of the prostate (TURP).

[0012] Prostatectomy is a currently accepted procedure for alleviating bladder neck obstruction due to BPH. The goals of surgical treatment are aimed at reversing and eliminating the effects of urinary tract obstruction, such as renal failure, urinary stone formation, and infection. In addition, it is desirable to improve the patient's quality of life by allowing him to empty at normal intervals with good control and to provide normal sexual function. Indications for surgical prostatectomy include: a man in his 70s; normal kidneys; a fairly healthy bladder; noticeable enlargement of the prostate gland during rectal examination; certain obstruction of the urethra; more than four ounces of residual urine; and symptoms of frequent urination, pain, tenesmus, burning, attacks of urethral fever, epididymitis, and hematuria. If patients have sufficient bladder neck obstruction to cause severe symptoms and have a good surgical prognosis, removal of obstructive prostate tissue is usually recommended by the suprapubic, retropubic, perineal, or transurethral route.

[0013] Mortality rates for open surgical prostatectomy are virtually comparable across techniques, with the risk of mortality fluctuating around 1%. The risk of death is less in patients undergoing TURP. Patients with documented renal failure are considered to have a poor prognosis for prostatectomy. Men over the age of 80 are at greater risk as the death rate for TURP increases.

[0014] Castration is widely known to be effective in preventing BPH. The prostate gland, enlarged or normal, atrophies after orchiectomy and changes to a small, dense fibrous growth, in which only remnants of the glandular tubules and ducts are present. Although this procedure was used at the turn of the century, it was abandoned in favor of excising the tissue causing the obstruction. Most attempts to control prostate enlargement have focused on the administration of hormonal steroids and are based on the concept that castration results in symptomatic improvement and reduction in prostate size due to the removal of the main source of androgen stimulation. Specific antiandrogenic therapeutic agents have been directed to inhibition of prostate growth by preventing the onset of symptoms of urinary tract obstruction or by inducing regression and involution of the prostate, thereby alleviating the symptoms of obstruction.

[0015] Efforts to deprive the prostate of androgen stimulation have been based on various approaches, including estrogen-based luteinizing hormone (LH) suppression and antiandrogen therapy. Estrogen therapy for BPH is based on the fact that estrogens at appropriate doses reduce circulating testosterone levels. Medical forms of therapy aimed at controlling BPH include the use of antiandrogens, which inhibit prostate growth but do not cause harmful side effects. Antiandrogens have been shown to competitively inhibit the binding of dihydrotestosterone to cellular receptors and reduce testosterone concentrations in men to castration levels. However, when antiandrogens are discontinued, hyperplasia returns. Therefore, patients undergoing this type of therapy expect lifelong drug treatment with the associated unwanted side effects of antiandrogen therapy. Commonly reported side effects of this therapy include breast enlargement, nipple tenderness, loss of sex drive, impotence, and acne.

[0016] Testosterone is a prohormone that is converted to dihydrotestosterone in the prostate by the action of 5-α-reductase. As a result, the enzyme 5-α-reductase has been proposed as a target for suicide inhibitors to reduce dihydrotestosterone levels. This has been shown to mediate benign prostate enlargement. Steroidal diazoketones have been shown to be unique analogs of natural substrates for the 5-α-reductase enzyme and inhibit the catalytic activity of the enzyme through the formation of covalent bonds at or near the active site of the enzyme via diazonium alkylation.

[0017] Ketoconazole is an imidazole derivative that has been shown to be a strong inhibitor of testosterone formation in the gonads and adrenals. Ketoconazole does not appear to affect pituitary LH secretion; however, it inhibits cholesterol synthesis, resulting in a clinical decrease in gonadal and adrenal androgen levels, and has low toxicity. The hormonal changes that occur with the administration of ketoconazole are dose-dependent and completely reversible. The drug has been shown to be useful in clinical conditions where inhibition of steroid production in the gonads or adrenal glands may be beneficial. Ketoconazole has been shown to be a strong inhibitor of testosterone synthesis and may have a therapeutic benefit in BPH therapy. Possible side effects of ketoconazole therapy include decreased sex drive, impotence, gynecomastia, and hypogonadism.

[0018] Ornithine decarboxylase is an enzyme that is involved in the biosynthesis of the polyamines putrescine, spermidine and spermine. These polyamines are believed to be involved in enhancing cell growth and replication. Elevated levels of these polyamines are found in the prostate and other glands that are rapidly proliferating. In the synthesis of potent suicidal ornithine decarboxylase inhibitors such as DL-α-difluoromethylornithine (DFMO), prostate levels of ornithine decarboxylase have been shown to markedly decrease, followed by a decrease in putrescine and spermidine levels. In animals, administration of the suicide inhibitor of ornithine decarboxylase, DFMO, resulted in inhibition of prostate growth. In addition, in tissue culture, DFMO inhibits DNA synthesis and slows down the proliferation of human prostate adenoma cells. This compound may find application in the treatment of prostate adenoma.

[0019] Additional attempts at medical control of BPH as an alternative to surgical methods of therapy have included the use of potent LHRH (luteinizing hormone releasing hormone) agonists that block testicular testosterone production by inhibiting pituitary release of gonadotropins. The primary effect of LHRH agonists in humans is to lower serum testosterone levels. Leuprolide and nafarelin acetate have been shown to reduce circulating androgen and estrogen levels in men to castration levels within three weeks. Such compounds, at continuous and therapeutic doses, desensitize the pituitary gland and block the release of sex steroid hormones. The degree of testosterone suppression achieved with potent LHRH agonists has been shown to be effective in the treatment of obstructive benign prostatic hypertrophy. Disadvantages of this form of therapy include the need to maintain drug treatment indefinitely, as androgen suppression is reversible, followed by regrowth of hyperplastic tissue. In addition, side effects include impotence, decreased libido, hot flashes, and may include an initial increase in symptoms of obstruction.

[0020] Other efforts to prevent or treat BPH by non-surgical means include the use of neuropharmacological agents such as α-1-adrenergic blocking agents. Prazosin, chytrin, phentolamine and ketanserin are antiadrenergic drugs aimed at relaxing the urinary sphincter mechanism. Pharmacological treatment of BPH with α-adrenergic blockers provides a means of helping a large number of patients with prostate enlargement in whom surgery is not considered necessary or should be deferred. Various α-adrenergic blocking agents that have been used to treat BPH include the compounds phenoxybenzamine (potential mutagen), prazosin (minipres), phentolamine (regitin), nicergoline (sermion), terazosin (chytrin), and thymoxamine. Side effects are present in approximately 30% of patients taking phenoxybenzamine for the treatment of BPH and include hypotension, dizziness, unconsciousness, tachycardia, weakness, and retrograde ejaculation or no retrograde ejaculation. In approximately 10% of all treatments, side effects are not tolerated and therapy must be discontinued. Prazosin and chytrin appear to cause less side effects. The possibility of cerebral hypotension or ischemia is a contraindication for these agents. Rapidly acting intravenous blockers such as phentolamine should be used with caution, especially in older age groups. However, it is believed that nicergoline has a beneficial effect on cerebral circulation.

[0021] Pharmacological data have demonstrated that the size of the prostate gland in animals can be reduced after lowering serum cholesterol levels. Polyene macrolides have been shown to be effective and potent hypocholesterolemic agents. Polyene macrolides as a group are characterized by a specific physicochemical affinity for sterols and sterol-containing cell membranes. Based on animal toxicity studies, polyene macrolides have been shown to reduce serum testosterone levels, inhibit testicular function, and induce changes in prostate histology. The polyene macrolide antifungal agents candicidin and amphotericin B have been shown to shrink the prostate, but human clinical trials have not shown a reduction in the number of patients requiring surgery for symptoms of obstruction due to BPH. US Patent No. 6296847, the disclosure of which is incorporated herein by reference in its entirety.

[0022] Over the past 40 years, many attempts have been made to medically control this disease. Interpretation of the results of these attempts has been complicated by the fact that patients with BPH-related symptoms often experience temporary improvement or remission of voiding symptoms after using diagnostic equipment alone. The effectiveness of pharmaceutical treatments for BPH is often measured in terms of mean improvement on the International Prostate Symptom Score (IPSS) from baseline. Most published studies show that at best, the average improvement in IPSS from the use of pharmaceutical agents (alone or in combination) ranges from approximately 2 to at best 6 points over 12 months or longer. Roehrborn, et al ., “Influence of baseline variables on changes in . . . , GJUI Int , Vol. 113, pp. 623-635 (2014); Hutchison, et al ., "The Efficacy of Drugs for the Treatment of LUTS/BPH, A Study in 6 European Countries", European Urology , Vol. 51, pp. 207-216 (2007). It is generally accepted that mean IPSS mean improvement values for FDA-approved conventional oral BPH drugs range from about 3 to about 5.

[0023] Certain peptide-based agents are known to have the ability to destroy and therefore either promote the removal or inhibit further growth of harmful or unwanted cells and tissue, such as benign hyperplastic cells and prostate tissue. These funds are disclosed in US patent No. 6924266; 7241738; 7317077; 7408021; 7745572; 8067378; 8293703; 8569446; and 8716247; and publications of US Patent Applications No. 2017/0360885; 2017/0020957; 2016/0361380; and 2016/0215031, the disclosures of which are herein incorporated by reference in their entirety. One such agent is known as fexapotide triflutate.

[0024] There is a need for treatments that can improve the symptoms of BPH without the risks and side effects associated with conventional drug therapies or surgery.

[0025] Throughout this specification, including the foregoing description of the prior art, any and all public documents described herein, including any and all published U.S. patent applications, are expressly incorporated herein by reference in their entirety. The foregoing description of the prior art is in no way intended to be an admission that any of the documents described therein, including pending US patent applications, are prior art to the present invention. Moreover, the description in this document of any disadvantages associated with the described products, methods and/or apparatus is not intended to limit the embodiments. Indeed, aspects of the embodiments may include certain features of the products, methods, and/or devices described without suffering from their described disadvantages.

SUMMARY OF IMPLEMENTATION OPTIONS

[0026] There remains a need for new, less toxic, and less frequently used (eg, avoiding the need to take daily or weekly medications) methods of treating BPH and improving the quality of life of patients suffering from BPH.

[0027] The present invention is based in part on the discovery that antibiotics, when administered alone or in combination with certain peptides, including the specific peptide described by the amino acid sequence Ile-Asp-Gln-Gln-Val-Leu-Ser-Arg-Ile-Lys-Leu -Glu-Ile-Lys-Arg-Cys-Leu (SEQ ID NO: 1) (fexapotide triflutate or "FT"), capable of treating BPH as evidenced by a mean IPSS improvement ranging from about 4.0 to about 8 .0 points during the first year.

[0028] The present invention is also based in part on the discovery that antibiotics, either alone or in combination with FT, are effective in improving peak urinary flow rate (Qmax) in men suffering from BPH. The average improvement in Qmax may range from about 1.0 to about 4.0.

[0029] Antibiotics and optional FT can be administered together or separately and can be administered orally, intramuscularly, orally, intravenously, intraperitoneally, intracerebral (intraparenchymal), intracerebroventricular, intratumoral, intralesional, intradermal, intrathecal, intranasal, intraocular, intraarterial, topical, transdermally, by aerosol, infusion, bolus injection, implant device, sustained release system, etc.

[0030] Both the foregoing general description and the following detailed description are illustrative and explanatory and are intended to provide further explanation of the embodiments as stated. Other objects, advantages, and features will be apparent to those skilled in the art from the following detailed description of the embodiments.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] Before describing the embodiments, it should be understood that the present invention is not limited to the specific methodology, protocols, cell lines, vectors, and reagents described, as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of embodiments of the present invention, which will be limited only by the appended claims.

[0032] The terms and phrases used in this document are defined below, unless otherwise indicated. Throughout this specification, singular noun forms include reference to plural forms unless the context clearly specifies otherwise. Thus, for example, reference to "host cell" includes a plurality of such host cells, and reference to "antibody" is a reference to one or more antibodies and their equivalents known to those skilled in the art, etc.

[0033] As used herein, the term antibiotic means antibiotics, antiseptics, and disinfectants. Примеры антибиотиков включают этилсукцинат эритромицина, этилкарбонат эритромицина, глюкогептаноат эритромицина, стеарат эритромицина, пропионат лаурилсульфата эритромицина, лактобионат эритромицина, триацетилолеандомицин, фосфат олеандомицина, сульфат амикацина, сульфат беканамицина, аминодезоксиканамицин, моносульфат канамицина, тобрамицин, ацетилкитазамицин, китазамицин, сукцинат китазамицина, тартрат китазамицина, хлорамфеникол, альгининсукцинат хлорамфеникола , сукцинат натрия хлорамфеникола, стеарат хлорамфеникола, морфолинoацетат хлорамфеникола, пальмитат хлорамфеникола, стеароилгликолят хлорамфеникола, морфолинoацетат сульфата хлорамфеникола, гидрохлорид колистина, колистин, метансульфонат натрия колистина, сульфат колистина, джозамицин, пропионат джозамицина, гидрохлорид дигидрострептомицина, сульфат дигидрострептомицина, соединение стрептомицина , streptomycin hydrochloride, streptomycin calcium chloride hydrochloride, streptomycin sulfate, streptomycin isoniazone sulfate, cephalo cetril sodium, cefazolin sodium, cefapirin sodium, cephalexin, cefaglycin, cephalothin sodium, cephaloridine, sodium ceftezol, cephradine, oxytetracycline hydrochloride, oxytetracycline, calcium oxytetracycline, chlortetracycline hydrochloride, chlortetracycline, tetracycline hydrochloride, roletetracycline nitrate, L-methylenelysine tetracycline, tetracycline metaphosphate, rolitetracycline, dimethylchlorotetracycline hydrochloride, dimethylchlorotetracycline, doxycycline hydrochloride, minocycline hydrochloride, metacycline hydrochloride, actinomycin D, azalomycin F, enbiomycin sulfate, enramycin hydrochloride, aureothricin, capreomycin sulfate, carcinophyllin, carbomycin, gramicidin, gramicidin S hydrochloride, griseofulvin sulphate, chromomycin , cycloserine, sarcomycin, sikkanin, dibekacin sulfate, acetylspiramycin, spiramycin, spectinomycin hydrochloride, daunorubicin hydrochloride, doxorubicin hydrochloride, trichomycin, nystatin, neocarzinostatin, calcium novobiocin, sodium novobiocin, viomycin sulfate, bacitracin, variotin, paromomycin sulfate, pimaricin, pyrrolnitrine, sodium fusidate, fradiomycin palmitate, fradiomycin sulfate, bleomycin hydrochloride, bleomycin sulfate, ampicillin, ampicillin sodium, imipenem, metronidazole, talampicillin hydrochloride, sodium carbenicillin, carbenicillin indanyl phenyloxymethyl, methylpenycyllin sodium, methylpenicillin sodium, Potassium Penicillin, Calcium Phenoxymethylpenicillin, Benzathine Phenoxymethylpenicillin, Potassium Penicillin, Sodium Penicillin, Procaine Penicillin, Potassium Benzylpenicillin, Sodium Benzylpenicillin, Procaine Benzylpenicillin, Benzathine Benzylpenicillin, Potassium Penicillin Compound, Potassium Benzylpenicillin Compound, Benzylpenicillin Sodium Compound, Hydrochloride Hydrochloride Benzylpenicillin Compound, Hydrochloride Dam Chloride clindamycin, lincomycin hydrochloride, amoxicillin, sodium oxacillin, sodium cloxacillin, cyclacillin, sodium dicloxacillin, sodium sulbenicillin, pivmecillinam hydrochloride, pheneticill potassium in, flucloxacillin sodium, potassium propicillin, potassium hetacillin, sodium methicillin, pentamycin, polymyxin B sulfate, mitomycin C, maridomycin propionate, mikamycin, midecamycin, rifampicin, ribostamycin sulfate, pyrrolnitrin, actinomycin, bleomycin, daunorubicin, doxorubicin, and neocarzinostatin. Other antibiotics include fluoroquinolone antibiotics such as ciprofloxacin (Cipro), gemifloxacin (Faktiv), levofloxacin (Levaquin), moxifloxacin (Avelox), norfloxacin (Noroxin), and ofloxacin (Floxin). As antiseptics and disinfectants, it is preferable to use dye-based medicines such as acrinol or acriflavin, etc., furan-based medicines such as nitrofurazone, etc., cationic soap-based medicines such as chloride benzalkonium or benzethonium chloride, etc., cyclohexidine and povidone-iodine. As a rule, it is preferable to use a combination of two or more antibiotics.

[0034] The amino acids and amino acid residues described herein may be referred to in accordance with the accepted one- or three-letter code provided in the table below.

Table 1

Three-letter amino acid designation Single letter designation Designation Alanine A Ala Arginine R Arg Asparagine N Asn Aspartic acid D asp Cysteine C Cys Glutamine Q Gln Glutamic acid E Glu Glycine G gly Histidine H His Isoleucine I ile Leucine L Leu Lysine K Lys Methionine M Met Phenylalanine F Phe Proline P Pro Serene S Ser Threonine T Thr tryptophan W trp Tyrosine Y Tyr Valine V Val

[0035] As used herein, fexapotide triflutate ("FT") means a 17-mer peptide having the amino acid sequence: Ile-Asp-Gln-Gln-Val-Leu-Ser-Arg-Ile-Lys-Leu-Glu-Ile- Lys-Arg-Cys-Leu (SEQ ID NO. 1). FT is disclosed in US Pat. Nos. 6,924,266; 7241738; 7317077; 7408021; 7745572; 8067378; 8293703; 8569446; and 8716247, as well as in the publications of applications for US patent No. 2017/0360885; 2017/0020957; 2016/0361380; and 2016/0215031. The disclosures of these patents and published applications are incorporated herein by reference in their entirety.

FT is represented by:

SEQ ID NO.1 : IDQQVLSRIKLEIKRCL or Ile-Asp-Gln-Gln-Val-Leu-Ser-Arg-Ile-Lys-Leu-Glu-Ile-Lys-Arg-Cys-Leu.

[0036] The term "fragment" refers to a protein or polypeptide that consists of a continuous subsequence of the amino acid sequence of a protein or peptide and includes naturally occurring fragments such as splice variants and fragments generated by naturally occurring in vivo protease activity. Such a fragment may be truncated at the amino-terminus, carboxy-terminus and/or internally (eg, by natural splicing). Such fragments may be prepared with or without the amino-terminal methionine. The term "fragment" includes fragments that are the same or different from the same protein or peptide, with or without a common contiguous amino acid sequence, joined together, either directly or through a linker. One skilled in the art will be able to select the appropriate fragment for use in the embodiments without undue experimentation using the guidelines and procedures set forth herein.

[0037] The term "variant" refers to a protein or polypeptide in which there are one or more amino acid substitutions, deletions, and/or insertions compared to the amino acid sequence of the protein or peptide, and includes naturally occurring allelic variants or alternative splice variants of the protein. or a peptide. The term "variant" includes the replacement of one or more amino acids in a peptide sequence with a similar or homologous amino acid(s) or different amino acid(s). There are many scales according to which amino acids can be classified as similar or homologous. (Gunnar von Heijne, Sequence Analysis in Molecular Biology, p. 123-39 (Academic Press, New York, N.Y. 1987). Preferred options include alanine substitutions at one or more amino acid positions. Other preferred substitutions include conservative substitutions that have little effect or do not affect the overall net charge, polarity, or hydrophobicity of the protein Conservative substitutions are set out in Table 2 below.

table 2

Conservative amino acid substitutions

Main Arginine
Lysine
Histidine Sour Glutamic acid
Aspartic acid Uncharged polar Glutamine
Asparagine
Serene
Threonine
Tyrosine non-polar Phenylalanine
tryptophan
Cysteine
Glycine
Alanine
Valine
Proline
Methionine
Leucine
Isoleucine

Table 3 shows another scheme of amino acid substitutions.

Table 3

original balance Substitutions Ala gly; ser Arg lys Asn gln; his asp glu Cys ser Gln asn Glu asp gly ala; pro His asn; gln ile eu; val Leu ile; val Lys arg; gln; glu Met leu; tyr; ile Phe met; leu; tyr Ser thr Thr ser trp tyr Tyr trp; phe Val ile; leu

[0038] Other variants may consist of less conservative amino acid substitutions, such as selected residues, that differ more significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the region of the substitution, for example, in a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site; or (c) the bulk of the side chain. Substitutions that are generally expected to have a more significant effect on function are those in which (a) glycine and/or proline are substituted with another amino acid or removed or inserted; (b) a hydrophilic moiety, eg seryl or threonyl, is substituted (or replaced) with a hydrophobic moiety, eg leucyl, isoleucyl, phenylalanyl, valyl or alanyl; (c) the cysteine residue is substituted (or replaced) by any other residue; (d) a residue having an electropositive side chain, eg lysyl, arginyl or histidyl, is substituted (or replaced) by a residue having an electronegative charge, eg glutamyl or aspartyl; or (e) a residue having a bulky side chain, eg phenylalanine, is substituted (or replaced) with a residue not having such a side chain, eg glycine. Other options include options designed to either create a new site(s) of glycosylation and/or phosphorylation, or options designed to remove existing site(s) of glycosylation and/or phosphorylation. Variants include at least one amino acid substitution at a glycosylation site, a proteolytic cleavage site, and/or a cysteine residue. Variants also include proteins and peptides with additional amino acid residues before or after the amino acid sequence of the protein or peptide on the linker peptides. For example, a cysteine residue may be added to both the amino and carboxy termini of the FT to allow the peptide to be cyclized via disulfide bond formation. The term "variant" also encompasses polypeptides that have the amino acid sequence FT with at least one and no more than 25 or more additional amino acids flanking either the 3' or 5' end of the peptide.

[0039] The term "derivative" refers to a chemically modified protein or polypeptide that has been chemically modified either through natural processes such as processing and other post-translational modifications, but also through chemical modification techniques, for example, by adding one or more polyethylene glycol molecules, sugars, phosphates and/or other such molecules, where the molecule or molecules are not naturally attached to wild-type or FT proteins. Derivatives include salts. Such chemical modifications are well described in the main texts and in more detailed monographs, as well as in numerous research literature, and are well known to those skilled in the art. It is understood that the same type of modification may be present to the same or different extent at multiple data sites on a protein or polypeptide. Also, a given protein or polypeptide may contain many types of modifications. Modifications can occur anywhere on a protein or polypeptide, including the peptide backbone, amino acid side chains, and amino or carboxy termini. Modifications include, for example, acetylation, acylation, ADP-ribosylation, amidation, flavin covalent attachment, heme moiety covalent attachment, nucleotide or nucleotide derivative covalent attachment, lipid or lipid derivative covalent attachment, phosphotidylinositol covalent attachment, crosslinking, cyclization, disulfide bond formation , demethylation, covalent crosslinking, cysteine formation, pyroglutamate formation, formylation, gamma-carboxylation, glycosylation, GPI-anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemization, glycosylation, lipid addition , sulfation, gamma-carboxylation of glutamic acid residues, hydroxylation and ADP-ribosylation, selenoylation, sulfation, amino acid addition, transport-mediated RNA to proteins, such as arginylation and ubiquitination. See, for example, Proteins--Structure And Molecular Properties, 2nd Ed., T. E. Creighton, W. H. Freeman and Company, New York (1993) and Wold, F., "Posttranslational Protein Modifications: Perspectives and Prospects", pgs. 1-12 in Posttranslational Covalent Modification Of Proteins, B. C. Johnson, Ed., Academic Press, New York (1983); Seifter et al., Meth. Enzymol. 182:626-646 (1990) and Rattan et al., "Protein Synthesis: Posttranslational Modifications and Aging", Ann. N.Y. Acad. sci. 663:48-62 (1992). The term "derivatives" includes chemical modifications that make a protein or polypeptide branched or cyclic, with or without branching. Cyclic, branched and branched circular proteins or polypeptides can be produced by natural post-translational processes and can also be produced by fully synthetic methods.

[0040] The term "homolog" refers to a protein that is at least 60 percent identical in its FT amino acid sequence, as determined by standard methods that are commonly used to compare the similarity in amino acid position of two polypeptides. The degree of similarity or identity between two proteins can be easily calculated by known methods, including, without limitation, those described in Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part I, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991; and Carillo H. and Lipman, D., SIAM, J. Applied Math., 48:1073 (1988). Preferred methods for determining identity are designed to provide the greatest match between the tested sequences. Methods for determining identity and similarity are codified in publicly available computer programs.

[0041] Preferred computer program methods useful for determining identity and similarity between two sequences include, without limitation, the GCG software package (Devereux, J., et al., Nucleic Acids Research, 12(1): 387 (1984)) , BLASTP, BLASTN, and FASTA, Atschul, S. F. et al., J. Molec. Biol., 215: 403-410 (1990). The BLAST X program is publicly available from NCBI and other sources (BLAST Manual, Altschul, S., et al., NCBI NLM NIH Bethesda, Md. 20894; Altschul, S., et al., J. Mol. Biol., 215: 403 -410 (1990) For example, using a computer algorithm such as GAP (Genetic Computer Group, University of Wisconsin, Madison, Wisconsin), two proteins or polypeptides for which percent sequence identity is to be determined are aligned to optimally match their respective amino acids ( "match length" as determined by the algorithm).

[0042] The gap opening penalty (which is calculated as 3 times the average diagonal; "average diagonal" is the average of the diagonal of the applied comparison matrix; "diagonal" is the score or number assigned to each perfect match of amino acids on a particular comparison matrix) and the gap continuation penalty (which is typically {share(1/10)} times the gap opening penalty), as well as a comparison matrix such as PAM 250 or BLOSUM 62, are used in conjunction with the algorithm. Standard comparison matrix (see Dayhoff et al. in Atlas of Protein Sequence and Structure, vol. 5, supp. 3 for the PAM250 comparison matrix; see Henikoff et al., Proc. Natl. Acad. Sci USA, 89:10915- 10919 for the comparison matrix BLOSUM 62) can also be applied by the algorithm. The percent identity is then calculated by the algorithm. Homologues typically have one or more amino acid substitutions, deletions and/or insertions compared to the reference protein or peptide, as the case may be.

[0043] The term "fusion protein" refers to a protein in which one or more peptides are recombinantly fused or chemically conjugated (including covalently and non-covalently) to a protein, such as (but not limited to) an antibody or antibody fragment, such as a Fab fragment or Fv short chain. The term "fusion protein" also refers to multimers (ie, dimers, trimers, tetramers and higher multimers) of peptides. Such multimers include homomeric multimers containing one peptide, heteromeric multimers containing more than one peptide, and heteromeric multimers containing at least one peptide and at least one other protein. Such multimers may result from hydrophobic, hydrophilic, ionic and/or covalent compounds, bonds or cross-links, may be formed by cross-links using linker molecules, or may be linked indirectly, through, for example, the formation of liposomes.

[0044] The term "peptidomimetic" or "mimetic" refers to biologically active compounds that mimic the biological activity of a peptide or protein, but are no longer peptide in chemical nature, that is, they no longer contain peptide bonds (i.e., amide bonds between amino acids) . As used herein, the term peptidomimetic is used more broadly to include molecules that are no longer fully peptide in nature, such as pseudopeptides, partial peptides, and peptoids. Examples of peptidomimetics in this broader sense (where part of the peptide is replaced by a structure that lacks peptide bonds) are described below. Regardless of whether they are wholly or partially non-peptidic, peptidomimetics according to embodiments provide a spatial arrangement of reactive chemical moieties that is very similar to the three-dimensional arrangement of active groups in the peptide on which the peptidomimetic is based. As a result of this similar active site geometry, the peptidomimetic has an effect on biological systems that is similar to the biological activity of the peptide.

[0045] The peptidomimetics of the embodiments are preferably substantially similar in both three-dimensional form and biological activity to the peptides described herein. Examples of methods of structural modification of a peptide known in the art to create a peptidomimetic include inversion of the chiral centers of the backbone resulting in structuring of the D-amino acid residue, which can, especially at the N-terminus, lead to increased stability for proteolytic degradation without adversely affecting activity. An example is given in "Tritriated D-ala.sup.1-Peptide T Binding", Smith C. S. et al., Drug Development Res., 15, pp. 371-379 (1988). The second way is to change the ring structure for stability, such as N to C interchain imides and lactams (Ede et al. in Smith and Rivier (Eds.) "Peptides: Chemistry and Biology", Escom, Leiden (1991), pp. 268-270). An example of this is given in conformationally constrained thymopentin-like compounds such as those disclosed in US Patent No. 4,457,489 (1985) to Goldstein, G. et al., the disclosure of which is incorporated by reference herein in its entirety. The third way is to replace the peptide bonds in the peptide with pseudopeptide bonds, which confers resistance to proteolysis.

[0046] A number of pseudopeptide bonds have been described that generally do not affect the structure and biological activity of the peptide. One example of this approach is the replacement of retroinverso-pseudopeptide bonds (“Biologically active retroinverso analogues of thymopentin”, Sisto A. et al in Rivier, J. E. and Marshall, G. R. (eds) “Peptides, Chemistry, Structure and Biology”, Escom, Leiden (1990), pp. 722-773) and Dalpozzo, et al. (1993), Int. J. Peptide Protein Res., 41:561-566, incorporated herein by reference). According to this modification, the amino acid sequences of the peptides may be identical to those of the peptide described above, except that one or more peptide bonds are replaced by a retro-inverse-pseudo-peptide bond. Preferably, most of the N-terminal peptide bond is substituted, since such a substitution confers resistance to proteolysis by exopeptidases acting at the N-terminus. Additional modifications can also be made by replacing the chemical groups of amino acids with other chemical groups with a similar structure. Another suitable pseudopeptide bond known to increase resistance to enzymatic degradation with little or no loss of biological activity is a reduced isosteric pseudopeptide bond (Couder, et al. (1993), Int. J. Peptide Protein Res., 41: 181-184, incorporated herein by reference in its entirety).

[0047] Thus, the amino acid sequences of these peptides may otherwise be identical to the FT sequence, except that one or more peptide bonds are replaced by an isosteric pseudopeptide bond. Preferably, most of the N-terminal peptide bond is substituted, since such a substitution would confer resistance to proteolysis by exopeptidases acting at the N-terminus. The synthesis of peptides with one or more reduced isosteric pseudopeptide bonds is known in the art (Couder et al. (1993), cited above). Other examples include the introduction of ketomethylene or methyl sulfide bonds to replace peptide bonds.

[0048] Peptoid peptide derivatives are another class of peptidomimetics that retain important structural determinants for biological activity but eliminate peptide bonds, thereby conferring resistance to proteolysis (Simon, et al., 1992, Proc. Natl. Acad. Sci. USA , 89:9367-9371, incorporated herein by reference in its entirety). Peptoids are oligomers of N-substituted glycines. A number of N-alkyl groups have been described, each corresponding to a naturally occurring amino acid side chain (Simon, et al. (1992), cited above). Some or all of the amino acids of the peptides may be replaced with an N-substituted glycine corresponding to the substituted amino acid.

[0049] The term "peptidomimetic" or "mimetic" also includes reverse D-peptides and enantiomers as defined below.

[0050] The term "reverse D-peptide" refers to a biologically active protein or peptide consisting of D-amino acids arranged in reverse order compared to the L-amino acid sequence of the peptide. Thus, the carboxy-terminal residue of an L-amino acid peptide becomes the amino-terminal residue of a D-amino acid peptide, and so on. For example, the ETESH peptide (SEQ ID NO: 2) becomes H _d S _d E _d T _d E _d , where E _d , H _d , S _d and T _d are D-amino acids corresponding to the L-amino acids E, H, S and T, respectively.

[0051] The term "enantiomer" refers to a biologically active protein or peptide in which one or more L-amino acid residues in the amino acid sequence of the peptide are replaced by the corresponding D-amino acid(s) residue(s).

[0052] As used herein, the term "composition" broadly refers to any composition containing an antibiotic and optionally an FT. The composition may contain a dry composition, an aqueous solution or a sterile composition. Compositions that optionally include FT can be used as hybridization probes. The probes may be stored in lyophilized form and may be associated with a stabilizing agent such as carbohydrate. In hybridization, the probe can be placed in an aqueous solution containing salts such as NaCl, detergents such as sodium dodecyl sulfate (SDS), and other components such as Denhardt's solution, milk powder, DNA from salmon milt, etc.

[0053] The present invention is also based in part on the discovery that the use of antibiotics, either alone or in combination with FT, is capable of treating and/or ameliorating the symptoms of BPH and provides an improvement in mean IPSS scores that is comparable to and better than current FDA-approved drugs. for oral use in BPH. Without being limited by any particular theory or operation, the inventor of the present invention found that administration of antibiotics alone or in combination with FT significantly improved symptoms in patients suffering from BPH and significantly improved peak urinary flow rate.

[0054] Any antibiotic or combinations thereof can be used in embodiments. Preferably, the composition contains a suitable antibiotic to prevent or reduce the occurrence of a bacterial infection that may be associated with urinary tract infections. Antibiotics used should provide sufficient protection against commonly encountered bacterial strains of uropathogens, including: Escherichia coli, Streptococcus faecalis, Proteus/Pseudomonas spp. and coagulase-positive Staphylococcus. In one embodiment, the method comprises administering one, two, three or more antibiotics of the same or different composition and via the same or different route of administration. Antibiotics used in embodiments can be selected from one or more of erythromycin, kitazamycin, streptomycin, cephalothin, cefazolin, tetracycline, gramicidin, griseofulvin, gentamicin, novobiocin, ampicillin, imipenem, metronidazole, ceftriaxone, cephalexin, ciprofloxacin, gemifloxacin, levofloxacin, , moxifloxacin, norfloxacin, nitrofurantoin, ofloxacin, trimethoprim/sulfamethoxaxol, and derivatives and salts of any of the above. The antibiotics may also be selected from one or more of ampicillin, gentamicin, imipenem, cephalothin, metronidazole, ciprofloxacin, gemifloxacin, fosfomycin, levofloxacin, moxifloxacin, norfloxacin, nitrofurantoin, and ofloxacin. Antibiotics can be administered in two or three different courses, including a course of a fluoroquinolone antibiotic, a course of metronidazole, and an intramuscular injection of an antibiotic selected from imepenem, gentamicin, and cephalothin.

[0055] Patients treated with the compositions described herein show significant improvement in the International Prostate Symptom Score (IPSS) compared to control administration and compared to a mean IPSS improvement of 3-5 for currently available timing of FDA-approved oral drugs for BPH (see, for example, McConnell, JD et al ., "The effect of finasteride on the risk of acute urinary retention. . . ", NEJM , Vol. 338, pp. 557-63 (1998); Roehrborn, CG et al ., "The effects of combination therapy with dutasteride and tumsulosin on . . . ," Eur Urol ., Nov.; 58(5):801 (2010)). Embodiments may result in an average improvement in IPSS during the first year in the range of about 4 to about 8 points, or about 5 to about 7 points, or about 6 to about 7 points. When compared with the mean improvement in IPSS for currently available FDA-approved drugs for use in BPH, administration of antibiotics resulted in a greater improvement in mean IPSS of about 20% to about 300%, or about 25% to about 200%, or approximately 30% to approximately 150% during the first year. When compared with placebo-only mean improvement in IPSS (scored in the range of about 1.5 to 3 points after 90 days and about 1 to 1.5 points at 1 year), antibiotics resulted in a greater improvement in mean IPSS score of about 50% to about 600%, or about 75% to about 500%, or about 90% to about 350% during the first year.

[0056] Embodiments can result in a mean improvement in IPSS at 42 months ranging from about 2 to about 6 points, or from about 3 to about 5 points, or from about 4 to about 5 points. When compared with the mean improvement in IPSS for currently available FDA-approved drugs for use in BPH (scored in the range of approximately 2-4), administration of antibiotics resulted in a greater improvement in mean IPSS of approximately 0% to approximately 200%, or approximately 0% to about 150%, or from about 0% to about 100% after 42 months. These results are indeed unexpected, especially since the use of antibiotics has never been previously described as useful or effective in the treatment of BPH. The fact that the use of antibiotics is effective and in many cases much more effective than traditional oral drugs is an unexpected finding. When compared with placebo-only mean improvement in IPSS (scored in the range of about 1 to 2 points at 42 months), antibiotic administration resulted in a greater improvement in mean IPSS score of about 50% to about 400%, or about 75% to about 350 %, or from about 100% to about 300% after 42 months.

[0057] Patients treated with the compositions described herein also showed an improvement in peak urinary flow rate (Qmax) in males suffering from BPH. Embodiments may result in an average improvement in Qmax during the first year ranging from about 1 to about 4, or from about 1.3 to about 3.0, or from about 1.5 to about 2.5, or from about 1.75 up to about 2.0. When compared with improvement in Qmax for currently available FDA-approved drugs for use in BPH (reported to range from about 0.8 to 2.2 at 90 days and from about 1.5 to 2.2 at 1 year), administration of antibiotics provided in all cases from a slight decrease of about 15% to an improvement of about 150%, or an improvement of about 130%, or an improvement of about 50% during the first year. When compared with mean improvement in Qmax for placebo alone (marked from about 0.5 to 0.8), administration of antibiotics provided a greater improvement in Qmax of about 75% to about 350%, or about 100% to about 325%, or about 125% to approximately 300% during the first year.

[0058] Embodiments include a method of treating a mammal suffering from BPH, comprising administering at least one antibiotic once or more than once to the mammal, either alone or in combination with FT. The method includes, without limitation, administering a composition containing an antibiotic orally, intramuscularly, intravenously, intraperitoneally, intracerebral (intraparenchymal), intracerebroventricularly, intralesionally, intraocularly, intraarterially, intrathecally, intratumorally, intranasally, topically, transdermally, subcutaneously or intradermally, either alone or in carrier-conjugated form. In one embodiment, the mammal may be given a course of a broad spectrum antibiotic (typically 7 days) such as a fluoroquinolone antibiotic, a course (typically 7 days) of an antibiotic such as metronidazole, and receive an intramuscular injection of a third broad spectrum antibiotic such as imipenene. , gentamicin or cephalothin.

[0059] In some embodiments, administration of fluoroquinolones such as ciprofloxacin or levofloxacin (etc.) may include oral administration of about 300 mg to about 600 mg, or about 400 mg to about 550 mg, or 500 mg twice a day. day for from about 5 days to about 10 days or more. Administration of metronidazole or secnidazole or tinidazole may include oral administration of about 300 mg to about 600 mg, or about 400 mg to about 550 mg, or 500 mg three times a day for about 5 days to about 10 days or more. Administration of gentamicin and the like may include administration by intramuscular injection of about 50 mg to about 200 mg, or about 75 mg to about 150 mg, or 100 mg once a day for two or more days. Administration of primaxin (imipenem) or invanz (ertapenem) and the like may include administration by intramuscular injection of about 0.1 g to about 5 g, or about 0.5 g to about 1.5 g, or 1 g once per day for one or more days. Those skilled in the art will be able to determine the appropriate amount of antibiotic depending on the type of antibiotic and using the guidance provided herein.

[0060] Co-administration of FT with antibiotics may result in an additional mean IPSS improvement of from about 1.0 points to about 5.0 points, or from about 1.2 points to about 3.5 points, or from about 1.5 points to approximately 3.0 points. Accordingly, if the mean improvement in IPSS from antibiotics was about 6.2, then the mean improvement in IPSS from the combination of antibiotic and FT would be from about 7.2 points to about 11.2 points. The mean improvement in IPSS from administration of a combination of antibiotic and FT may be from about 5.0 points to about 13.0 points, or from about 6.0 points to about 11.0 points, or from about 7.5 points to about 9.0 points. points, or from about 8.0 points to about 9.0 points.

[0061] Any mammal can benefit from the use of the present invention, including humans, mice, rabbits, dogs, sheep and other livestock, any mammal treated or treated by a veterinarian, zookeeper or conservationist. Preferred mammals are humans, sheep and dogs. Throughout this description, mammals and patients are used interchangeably.

[0062] One of skill in the art will appreciate that other smaller FT fragments can be chosen such that these peptides will have the same or similar biological activity. The person skilled in the art can choose other fragments so that these peptides have the same or similar biological activity. The peptides of the embodiments encompass these other moieties. In general, the peptides of the embodiments have at least 4 amino acids, preferably at least 5 amino acids, and more preferably at least 6 amino acids.

[0063] FT and its fragments, variants, derivatives, homologues, fusion proteins, and mimetics covered by this embodiment can be obtained using methods known to those skilled in the art, such as recombinant DNA technology, protein synthesis, and isolation of naturally occurring peptides, proteins, variants, their derivatives and homologues. FT and its fragments, variants, derivatives, homologues, fusion proteins and mimetics can be obtained from other peptides, proteins and fragments, variants, derivatives and homologues using methods known to those skilled in the art. Such methods include, but are not limited to, the use of proteases to cleave a peptide or protein to an FT. Any method disclosed, for example, in US patent No. 6924266; 7241738; 7317077; 7408021; 7745572; 8067378; 8293703; 8569446; and 8,716,247 and U.S. Patent Publication Nos. 2017/0360885; 2017/0020957; 2016/0361380; and 2016/0215031 can be used to produce the FT peptide described herein.

[0064] An additional embodiment includes administering a composition comprising one or more antibiotics, optionally an FT, and optionally an additional active agent. The additional active agent, if used, may be one or more active agents selected from (i) anticancer active agents (such as alkylating agents, topoisomerase I inhibitors, topoisomerase II inhibitors, RNA/DNA antimetabolites, and antimitotic agents); (ii) active agents for the treatment of benign neoplasms, such as active agents for acne and skin growths (salicylic acid); (iii) antiandrogen compounds (cyproterone acetate (1α,2ß-methylene-6-chloro-17-α-acetoxy-6-dehydroprogesterone)), tamoxifen, aromatase inhibitors); (iv) alpha-1 adrenergic receptor blockers (tamsulosin, terazosin, doxazosin, prazosin, bunazosin, indoramin, alfulzosin, silodosin); (v) 5-α-reductase inhibitors (finasteride, dutasteride); (vi) phosphodiesterase type 5 (PDE5) inhibitors (tadalafil) and combinations thereof. Preferably, the additional active agent is selected from the group consisting of tamsulosin, finasteride, terazosin, doxazosin, prazosin, tadalafil, alfulzosin, silodosin, dutasteride, a combination of dutasteride and tamsulosin, and mixtures and combinations thereof.

[0065] The therapeutic compositions described herein may contain a therapeutically effective amount of one or more antibiotics in admixture with a pharmaceutically acceptable carrier. In some alternative embodiments, the FT and/or additional active agent(s) may be administered in the same composition with the antibiotic, and in other embodiments, the composition containing one or more antibiotics is administered orally (as a gel, capsules, tablets, liquids, etc.), and a separate composition containing one or more antibiotics, is administered as an injection. Optionally, the FT is administered in the form of a composition containing the purified FT peptide in combination with one or more physiologically acceptable carriers, excipients, or diluents. Neutral buffered saline or saline mixed with serum albumin are exemplary appropriate carriers. Preferably the product is formulated as a lyophilisate using appropriate excipients (eg sucrose). Other standard carriers, solvents and excipients may be included as desired. Optionally, additional(additional) active(active) agent(s) can be administered orally (in the form of a gel, capsule, tablet, liquid, etc.). Compositions according to embodiments may also contain buffers known to those skilled in the art with a suitable pH range, including tris buffer pH approximately 7.0-8.5 or acetate buffer pH approximately 4.0-5.5, which may further include sorbitol or a suitable substitute thereof.

[0066] Solid dosage forms for oral administration include, without limitation, capsules, tablets, pills, powders, and granules. In such solid dosage forms, the antibiotic and optionally the FT and/or additional active agent may be admixed with at least one of the following: (a) one or more inert excipients (or carrier) such as sodium citrate or dicalcium phosphate; (b) fillers or dry diluents such as starches, lactose, sucrose, glucose, mannitol and silicic acid; (c) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (d) moisturizers such as glycerin; (e) disintegrants such as agar-agar, calcium carbonate, potato and tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (f) dissolution retarders such as paraffin; (g) absorption accelerators such as quaternary ammonium compounds; (h) wetting agents such as acetyl alcohol and glycerol monostearate; (i) adsorbents such as kaolin and bentonite; and (j) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. For capsules, tablets and pills, dosage forms may also contain buffering agents.

[0067] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and tinctures. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers. Examples of emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil. oil, glycerin, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters with sorbitan or mixtures of these substances, and the like.

[0068] In addition to such inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavors, and perfumes.

[0069] Actual dosage levels of active ingredients in compositions according to embodiments may vary to obtain an amount of antibiotic, optional FT, and optional additional active agent that is effective to produce the desired therapeutic response for a particular composition and route of administration. Therefore, the selected dosage level depends on the desired therapeutic effect, the route of administration, the desired duration of treatment and other factors.

[0070] In the case of mammals, including humans, effective amounts can be administered based on body surface area. The relationship of dosages for animals of various sizes, species and humans (in terms of mg/m ² body surface) is described in EJ Freireich et al., Cancer Chemother. Rep. 50(4):219 (1966). Body surface area can be roughly determined from the height and weight of an individual (see, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, NY pp. 537-538 (1970)).

[0071] The total daily dose of antibiotic, optional FT peptide, and optional and additional active agent administered to the host may be in single or divided doses. A dosage unit of the composition may contain as many such submultiples as may be used to constitute a daily dose. However, it should be understood that the specific dosage level for any particular patient will depend on a variety of factors including body weight, general health, sex, diet, time and route of administration, efficacy of the drug administered, rate of absorption. and excretion, combination with other drugs, and the severity of the particular disease being treated.

[0072] In some embodiments, at least one optional active agent may be selected from the group consisting of (1) a 5α-reductase inhibitor and/or antiestrogen, (2) a 5α-reductase inhibitor and/or an aromatase inhibitor, (3) 5α-reductase inhibitor and/or 17β-HSD inhibitor, (4) 5α-reductase inhibitor, antiestrogen and aromatase inhibitor, (5) 5α-reductase inhibitor, antiestrogen and 17β-HSD inhibitor, (6) 5α-reductase inhibitor, aromatase inhibitor , antiestrogen and 17β-HSD inhibitor, (7) 5α-reductase inhibitor, antiandrogen and antiestrogen, (8) 5α-reductase inhibitor, antiandrogen and aromatase inhibitor, (9) 5α-reductase inhibitor, antiandrogen and 17β-HSD inhibitor, ( 10) 5α-reductase inhibitor, antiandrogen, antiestrogen and aromatase inhibitor, (11) 5α-reductase inhibitor, antiandrogen, aromatase inhibitor and 17β-HSD inhibitor, (12) 5α-reductase inhibitor, antiandrogen, aromatase inhibitor, antiestrogen and 17β- HSD, (13) inhibitor 17β-HSD and antiestrogen, (14) 17β-HSD inhibitor and aromatase inhibitor, (15) 17β-HSD inhibitor, aromatase inhibitor and antiestrogen, (16) 17β-HSD inhibitor, antiandrogen and antiestrogen, (17) 17β-HSD inhibitor, antiandrogen and aromatase inhibitor, (18) 17β-HSD inhibitor, antiandrogen, antiestrogen and aromatase inhibitor, (19) antiestrogen and aromatase inhibitor and (20) antiestrogen, aromatase inhibitor and antiandrogen, (21) LHRH agonist or antagonist, 5α-reductase inhibitor and an antiestrogen, (22) LHRH agonist or antagonist, 5α-reductase inhibitor and aromatase inhibitor, (23) LHRH agonist or antagonist, 5α-reductase inhibitor and 17β-HSD inhibitor, (24) LHRH agonist or antagonist, 5α-reductase inhibitor, antiestrogen and aromatase inhibitor, (25) LHRH agonist or antagonist, 5α-reductase inhibitor, antiestrogen and 17β-HSD inhibitor, (26) LHRH agonist or antagonist, 5α-reductase inhibitor, aromatase inhibitor, antiestrogen and 17β-HSD inhibitor, (27 ) a LHRH gonist or antagonist, 5α-reductase inhibitor, antiandrogen and antiestrogen, (28), LHRH agonist or antagonist, 5α-reductase inhibitor, antiandrogen and aromatase inhibitor, (29) LHRH agonist or antagonist, 5α-reductase inhibitor, antiandrogen and 17β inhibitor -HSD, (30) LHRH agonist or antagonist, 5α-reductase inhibitor, antiandrogen, antiestrogen and aromatase inhibitor, (31) LHRH agonist or antagonist, 5α-reductase inhibitor, antiandrogen, aromatase inhibitor and 17β-HSD inhibitor, (32) agonist or LHRH antagonist, 5α-reductase inhibitor, antiandrogen, aromatase inhibitor, antiestrogen and 17β-HSD inhibitor, (33) LHRH agonist or antagonist, 17β-HSD inhibitor and antiestrogen, (34) LHRH agonist or antagonist, 17β-HSD inhibitor and inhibitor aromatase, (35) LHRH agonist or antagonist, 17β-HSD inhibitor, aromatase inhibitor and antiestrogen, (36) LHRH agonist or antagonist, 17β-HSD inhibitor, antiandrogen and antiestrogen, (37) agonist or LHRH antagonist, 17β-HSD inhibitor, antiandrogen and aromatase inhibitor, (38) LHRH agonist or antagonist, 17β-HSD inhibitor, antiandrogen, antiestrogen and aromatase inhibitor, (39) LHRH agonist or antagonist, antiestrogen and aromatase inhibitor and (40) agonist or an LHRH antagonist, an antiestrogen, an aromatase inhibitor, and an antiandrogen.

[0073] The following examples are provided to illustrate embodiments of the present invention. However, it should be understood that the embodiments should not be limited to the specific conditions or details described in these examples. Throughout the description, any and all references to the public document, including the US patent, are expressly incorporated by reference. In particular, embodiments explicitly include by reference the examples contained in US Patent Nos. 6,924,266; 7241738; 7317077; 7408021; 7745572; 8067378; 8293703; 8569446; and 8,716,247 and U.S. Patent Publication Nos. 2017/0360885; 2017/0020957; 2016/0361380; and 2016/0215031.

Example One [0074] In a study of 977 male patients with BPH, intraprostatic injection of either a) NX-1207 in phosphate buffered sodium chloride solution, pH 7.2 ("PBS") or b) PBS alone in double-blind conditions with the help of a urologist in the office under ultrasonic control. Prior to receiving drug or placebo, each patient began a course of broad-spectrum antibiotics that included 7 days of a fluoroquinolone antibiotic, 7 days of metronidazole, and an intramuscular injection of a third broad-spectrum antibiotic such as imipenem or gentamicin or cephalothin. Each patient was followed up for one year or longer with regular physical examinations, laboratory tests, and symptom assessments. Symptomatic evaluation was performed according to the International Prostate Symptom Score (IPSS), which is a quantitative scale used to assess symptomatic improvement or deterioration of the prostate. IPSS scores were as follows: 1) incomplete emptying of the bladder after voiding; 2) frequent urination; 3) interruption and resumption during urination; 4) an urgent need to urinate; 5) weakness of the urinary stream; 6) the need to press and make efforts during urination; 7) the need to urinate after going to bed at night (nocturia). The difference from baseline in IPSS was compared between patients who received NX-1207 versus those who received PBS alone. After 90 days, it was found that patients who received antibiotics plus placebo alone had improvements in their BPH symptom scores that were superior to those typically found with conventional BPH medications. The results are summarized in Table 4.

Table 4

Treatment Number of patients Duration after treatment Average improvement (points) placebo plus antibiotics 391 90 days 6.7 [7.02] Commonly used oral drug for the treatment of BPH 90 days 3-5*

*based on published reports. [x] indicates standard deviation [0075] As shown in Table 4, patients treated with one or more antibiotics experienced a mean improvement in IPSS ranging from about 34% to about 123% compared to conventional drugs for oral use for the treatment of BPH when measured 90 days after treatment. Therefore, the administration of one or more antibiotics provides a greater mean improvement in IPSS in BPH patients than FDA-approved oral drugs for the treatment of BPH. This improvement is unexpected in light of the fact that antibiotics were previously unknown to have any effect or any significant effect in the treatment of BPH.

Example Two [0076] In a study of 977 male patients with BPH, intraprostatic injection of either a) NX-1207 in phosphate buffered sodium chloride solution, pH 7.2 ("PBS") or b) PBS alone in double-blind conditions with the help of a urologist in the office under ultrasonic control. Prior to receiving drug or placebo, each patient began a course of broad-spectrum antibiotics that included 7 days of a fluoroquinolone antibiotic, 7 days of metronidazole, and an intramuscular injection of a third broad-spectrum antibiotic such as imipenem or gentamicin or cephalothin. Each patient was followed up for one year or longer with regular physical examinations, laboratory tests, and symptom assessments. Symptomatic evaluation was performed according to the International Prostate Symptom Score (IPSS), which is a quantitative scale used to assess symptomatic improvement or deterioration of the prostate. IPSS scores were as follows: 1) incomplete emptying of the bladder after voiding; 2) frequent urination; 3) interruption and resumption during urination; 4) an urgent need to urinate; 5) weakness of the urinary stream; 6) the need to press and make efforts during urination; 7) the need to urinate after going to bed at night (nocturia). The difference from baseline in IPSS was compared between patients who received NX-1207 versus those who received PBS alone. After 12 months, it was found that patients who received antibiotics plus placebo alone experienced an improvement in their BPH symptom scores that was superior to those typically found with conventional BPH medications. The results are summarized in Table 5.

Table 5

Treatment Number of patients Duration after treatment Average improvement (points) placebo plus antibiotics 391 1 year 6.2 [7.09] Commonly used oral drug for the treatment of BPH 1 year 2-4*

*based on published reports. [x] indicates the standard deviation

[0077] The results presented in Table 5 demonstrate that patients treated with one or more antibiotics experienced a mean improvement in IPSS ranging from about 55% to about 210% compared to conventional oral medications for BPH treatment when measured 1 year after treatment. Therefore, the administration of one or more antibiotics provides a greater mean improvement in IPSS in BPH patients than FDA-approved oral drugs for the treatment of BPH. This improvement is unexpected.

Example three

[0078] In a study of 977 male patients with BPH, intraprostatic injection of either a) NX-1207 in phosphate buffered sodium chloride solution, pH 7.2 ("PBS") or b) PBS alone in double-blind conditions with the help of an office urologist room under ultrasonic control. Prior to receiving drug or placebo, each patient began a course of broad-spectrum antibiotics that included 7 days of a fluoroquinolone antibiotic, 7 days of metronidazole, and an intramuscular injection of a third broad-spectrum antibiotic such as imipenem or gentamicin or cephalothin. Each patient was followed up for one year or longer with regular physical examinations, laboratory tests, and symptom assessments. The Peak Urinary Flow Rate (Qmax) is a measurement made in a flowmeter that outputs the maximum urinary flow rate recorded electronically in ml/second. Qmax was compared in patients who received NX-1207, when compared with patients who received only PBS. After 3 months, patients treated with antibiotics alone plus placebo were found to have improved peak urinary flow rates that were comparable to or better than those typically found with conventional BPH medications. The results are summarized in Table 6.

Table 6

Treatment Number of patients Duration after treatment Average improvement placebo + antibiotics 391 3 months +1.9 [4.65] Common oral medications for the treatment of BPH 3 months +0.8-2.2*

*Based on values reported in the literature, unadjusted for dropouts considered to be failures. [x] stands for standard deviation.

[0079] The results presented in Table 6 demonstrate that patients treated with one or more antibiotics experienced a mean improvement in Qmax comparable to or better than the improvement typically found with conventional drugs. After 3 months, administration of one or more antibiotics provided a mean improvement in Qmax over conventional oral BPH drugs ranging from about -13% to about 137%.

Example four

[0080] In a study of 977 male patients with BPH, intraprostatic injection of either a) NX-1207 in phosphate buffered sodium chloride solution, pH 7.2 ("PBS") or b) PBS alone in double-blind conditions with the help of an office urologist room under ultrasonic control. Prior to receiving drug or placebo, each patient began a course of broad-spectrum antibiotics that included 7 days of a fluoroquinolone antibiotic, 7 days of metronidazole, and an intramuscular injection of a third broad-spectrum antibiotic such as imipenem or gentamicin or cephalothin. Each patient was followed up for one year or longer with regular physical examinations, laboratory tests, and symptom assessments. Peak urinary flow rate (Qmax) is a measurement made in a flowmeter that outputs the maximum urinary flow rate recorded electronically. Qmax was compared in patients who received NX-1207, when compared with patients who received only PBS. After 12 months, patients treated with antibiotics plus placebo alone were found to have improved peak urinary flow rates that were comparable to those typically found with conventional BPH medications. The results are summarized in Table 7.

Table 7

Treatment Number of patients Duration after treatment Average improvement placebo + antibiotics 391 1 year +1.9 [4.64] Common oral medications for the treatment of BPH 1 year +1.5-2.2*

*Based on values reported in the literature, unadjusted for dropouts considered to be failures. [x] stands for standard deviation.

[0081] The results presented in Table 7 demonstrate that patients treated with one or more antibiotics experienced a mean improvement in Qmax comparable to or better than the improvement typically found with conventional drugs. After 1 year, administration of one or more antibiotics provided a mean improvement in Qmax over conventional oral BPH drugs ranging from about −13% to about 27%.

Example Five [0082] In a study of 977 male patients with BPH, intraprostatic injection of either a) NX-1207 in phosphate buffered sodium chloride solution, pH 7.2 ("PBS") or b) PBS alone in double-blind conditions with the help of a urologist in the office under ultrasonic control. Prior to receiving drug or placebo, each patient began a course of broad-spectrum antibiotics that included 7 days of a fluoroquinolone antibiotic, 7 days of metronidazole, and an intramuscular injection of a third broad-spectrum antibiotic such as imipenem or gentamicin or cephalothin. Each patient was followed up for one year or longer with regular physical examinations, laboratory tests, and symptom assessments. Symptomatic evaluation was performed according to the International Prostate Symptom Score (IPSS), which is a quantitative scale used to assess symptomatic improvement or deterioration of the prostate. IPSS scores were as follows: 1) incomplete emptying of the bladder after voiding; 2) frequent urination; 3) interruption and resumption during urination; 4) an urgent need to urinate; 5) weakness of the urinary stream; 6) the need to press and make efforts during urination; 7) the need to urinate after going to bed at night (nocturia). The difference from baseline in IPSS was compared between patients who received NX-1207 versus those who received PBS alone. After 90 days, it was found that patients who received antibiotics plus placebo alone had improvements in their BPH symptom scores that were superior to those typically found in oral placebo-only BPH trials. The results are summarized in Table 8.

Table 8

Treatment Number of patients Duration after treatment Average improvement (points) placebo plus antibiotics 391 90 days 6.7 [7.02] Placebo only 90 days 1.5-3*

*based on published reports. [x] indicates standard deviation [0083] As shown in Table 8, patients treated with one or more antibiotics experienced a mean improvement in IPSS ranging from about 123% to about 350% compared to placebo alone when measured 90 days after treatment. Therefore, the administration of one or more antibiotics provides a greater mean improvement in IPSS in BPH patients than FDA-approved oral drugs for the treatment of BPH. This improvement is unexpected.

Example Six [0084] In a study of 977 male patients with BPH, intraprostatic injection of either a) NX-1207 in phosphate buffered sodium chloride solution, pH 7.2 ("PBS") or b) PBS alone in double-blind conditions with the help of a urologist in the office under ultrasonic control. Prior to receiving drug or placebo, each patient began a course of broad-spectrum antibiotics that included 7 days of a fluoroquinolone antibiotic, 7 days of metronidazole, and an intramuscular injection of a third broad-spectrum antibiotic such as imipenem or gentamicin or cephalothin. Each patient was followed up for one year or longer with regular physical examinations, laboratory tests, and symptom assessments. Symptomatic evaluation was performed according to the International Prostate Symptom Score (IPSS), which is a quantitative scale used to assess symptomatic improvement or deterioration of the prostate. IPSS scores were as follows: 1) incomplete emptying of the bladder after voiding; 2) frequent urination; 3) interruption and resumption during urination; 4) an urgent need to urinate; 5) weakness of the urinary stream; 6) the need to press and make efforts during urination; 7) the need to urinate after going to bed at night (nocturia). The difference from baseline in IPSS was compared between patients who received NX-1207 versus those who received PBS alone. After 12 months, patients treated with antibiotics plus placebo alone were found to have improved their BPH symptom scores that were superior to those typically found in oral placebo-only BPH trials. The results are summarized in Table 9.

Table 9

Treatment Number of patients Duration after treatment Average improvement (points) placebo plus antibiotics 391 1 year 6.2 [7.09] Placebo only 1 year 1-1.5*

*based on published reports. [x] indicates the standard deviation

[0085] The results presented in Table 9 demonstrate that patients treated with one or more antibiotics experienced a mean improvement in IPSS ranging from about 313% to about 520% compared to placebo alone when measured at 1 year. after treatment. Therefore, the administration of one or more antibiotics provides a greater mean improvement in IPSS in BPH patients than FDA-approved oral drugs for the treatment of BPH. This improvement is unexpected.

Example seven

[0086] In a study of 977 male patients with BPH, intraprostatic injection of either a) NX-1207 in phosphate buffered sodium chloride solution, pH 7.2 ("PBS"), or b) PBS alone under double-blind conditions with the help of an office urologist room under ultrasonic control. Prior to receiving drug or placebo, each patient began a course of broad-spectrum antibiotics that included 7 days of a fluoroquinolone antibiotic, 7 days of metronidazole, and an intramuscular injection of a third broad-spectrum antibiotic such as imipenem or gentamicin or cephalothin. Each patient was followed up for one year or longer with regular physical examinations, laboratory tests, and symptom assessments. Peak urinary flow rate (Qmax) is a measurement made in a flowmeter that outputs the maximum urinary flow rate recorded electronically. Qmax was compared in patients who received NX-1207, when compared with patients who received only PBS. After 3 months, patients treated with antibiotics alone plus placebo were found to have improvements in their peak urinary flow rates that were superior to those typically found in oral placebo-only BPH trials. The results are summarized in Table 10.

Table 10

Treatment Number of patients Duration after treatment Average improvement Placebo+
antibiotics 391 3 months +1.9 [4.65] Placebo only 3 months +0.5-0.8*

*Based on values reported in the literature, unadjusted for dropouts considered to be failures. [x] stands for standard deviation.

[0087] The results presented in Table 10 demonstrate that patients treated with one or more antibiotics experienced a mean improvement in Qmax comparable to or better than the improvement typically found with conventional drugs. After 3 months, administration of one or more antibiotics provided a mean improvement in Qmax compared to placebo control alone, ranging from about 138% to about 280%.

Example eight

[0088] In a study of 977 male patients with BPH, intraprostatic injection of either a) NX-1207 in phosphate buffered sodium chloride solution, pH 7.2 ("PBS") or b) PBS alone under double-blind conditions with the help of an office urologist room under ultrasonic control. Prior to receiving drug or placebo, each patient began a course of broad-spectrum antibiotics that included 7 days of a fluoroquinolone antibiotic, 7 days of metronidazole, and an intramuscular injection of a third broad-spectrum antibiotic such as imipenem or gentamicin or cephalothin. Each patient was followed up for one year or longer with regular physical examinations, laboratory tests, and symptom assessments. Peak urinary flow rate (Qmax) is a measurement made in a flowmeter that outputs the maximum urinary flow rate recorded electronically. Qmax was compared in patients who received NX-1207, when compared with patients who received only PBS. After 12 months, patients treated with antibiotics alone plus placebo were found to have improvements in their peak urinary flow rates that were superior to those typically found in oral placebo-only BPH trials. The results are summarized in Table 11.

Table 11

Treatment Number of patients Duration after treatment Average improvement Placebo+
antibiotics 391 1 year +1.9 [4.64] Placebo only 1 year +0.5-0.8*

*Based on values reported in the literature, unadjusted for dropouts considered to be failures. [x] stands for standard deviation.

[0089] The results presented in Table 11 demonstrate that patients treated with one or more antibiotics experienced a mean improvement in Qmax that was superior to that typically found in BPH trials using oral placebo alone. After 1 year, administration of one or more antibiotics provided a mean improvement in Qmax compared to placebo control alone, ranging from about 138% to about 280%.

Example Nine [0090] In a study of 977 male patients with BPH, intraprostatic injection of either a) NX-1207 in phosphate buffered sodium chloride solution, pH 7.2 ("PBS") or b) PBS alone under double-blind conditions with the help of a urologist in the office under ultrasonic control. Prior to receiving drug or placebo, each patient began a course of broad-spectrum antibiotics that included 7 days of a fluoroquinolone antibiotic, 7 days of metronidazole, and an intramuscular injection of a third broad-spectrum antibiotic such as imipenem or gentamicin or cephalothin. Each patient was followed up for one year or longer with regular physical examinations, laboratory tests, and symptom assessments. Symptomatic evaluation was performed according to the International Prostate Symptom Score (IPSS), which is a quantitative scale used to assess symptomatic improvement or deterioration of the prostate. IPSS scores were as follows: 1) incomplete emptying of the bladder after voiding; 2) frequent urination; 3) interruption and resumption during urination; 4) an urgent need to urinate; 5) weakness of the urinary stream; 6) the need to press and make efforts during urination; 7) the need to urinate after going to bed at night (nocturia). The difference from baseline in IPSS was compared between patients who received NX-1207 versus those who received PBS alone. After a long period of time (average 42 months), it was found that patients treated with antibiotics plus placebo alone had improvements in their BPH symptom scores that were comparable to or better than those typically found with conventional BPH medications. The results are summarized in Table 12.

Table 12

Treatment Number of patients Duration after treatment Average improvement (points) placebo plus antibiotics 391 42 months 4.0 [6.03] Commonly used oral drug for the treatment of BPH 1 year 2-4*

*based on published reports. [x] indicates the standard deviation

[0091] The results presented in Table 12 demonstrate that patients treated with one or more antibiotics experienced a mean improvement in IPSS ranging from about 0% to about 100% compared to conventional oral drugs for BPH treatment when measured 42 months after treatment. Therefore, administration of one or more antibiotics provides a mean IPSS improvement in BPH patients that is comparable to or superior to the improvement typically found with conventional BPH medications. This result is unexpected.

Example Ten [0092] In a study of 977 male patients with BPH, intraprostatic injection of either a) NX-1207 in phosphate buffered sodium chloride solution, pH 7.2 ("PBS") or b) PBS alone in double-blind conditions with the help of a urologist in the office under ultrasonic control. Prior to receiving drug or placebo, each patient began a course of broad-spectrum antibiotics that included 7 days of a fluoroquinolone antibiotic, 7 days of metronidazole, and an intramuscular injection of a third broad-spectrum antibiotic such as imipenem or gentamicin or cephalothin. Each patient was followed up for one year or longer with regular physical examinations, laboratory tests, and symptom assessments. Symptomatic evaluation was performed according to the International Prostate Symptom Score (IPSS), which is a quantitative scale used to assess symptomatic improvement or deterioration of the prostate. IPSS scores were as follows: 1) incomplete emptying of the bladder after voiding; 2) frequent urination; 3) interruption and resumption during urination; 4) an urgent need to urinate; 5) weakness of the urinary stream; 6) the need to press and make efforts during urination; 7) the need to urinate after going to bed at night (nocturia). The difference from baseline in IPSS was compared between patients who received NX-1207 versus those who received PBS alone. After a long period of time (mean 42 months), it was found that patients treated with antibiotics plus placebo alone experienced an improvement in their BPH symptom scores that was superior to those normally found with oral placebo alone. The results are summarized in Table 13.

Table 13

Treatment Number of patients Duration after treatment Average improvement (points) placebo plus antibiotics 391 42 months 4.0 [6.03] Placebo only 42 months 1-2*

*based on published reports. [x] indicates the standard deviation

[0093] The results presented in Table 13 demonstrate that patients treated with one or more antibiotics experienced a mean improvement in IPSS ranging from about 100% to about 300% compared to placebo alone when measured at 42 months. after treatment. Therefore, the administration of one or more antibiotics provided a greater mean improvement in IPSS in BPH patients that was superior to the improvement normally found with oral placebo alone.

[0094] Published reports shown in the tables above include one or more of the following: McConnell, JD et al ., "The effect of finasteride on the risk of acute urinary retention. . . ", NEJM , Vol. 338, pp. 557-63 (1998); Roehrborn, CG et al ., "The effects of combination therapy with dutasteride and tumsulosin on . . . ," Eur Urol ., Nov.; 58(5):801 (2010); Lukacs, B et al ., “Management of Lower Urinary Tract Symptoms Related to . . . " Eur Urol ., Feb.; 64; pp 493-501 (2013); and Cindolo, L et al ., “Drug Adherence and Clinical Outcomes for Patients Under Pharmacological Therapy for . . . " Eur Urol ., Feb.; 68; pp 418-425 (2015).

[0095] The results from the above examples illustrate the excellent effect of using antibiotics to improve IPSS and Qmax in patients suffering from BPH. Those skilled in the art will appreciate that various modifications and changes can be made to the methods and compositions according to the embodiments of the present invention without departing from the spirit or scope of the embodiments.

Claims (14)

1. A method for improving symptoms in a mammal suffering from BPH, comprising administering to the mammal at least three separate compositions, each containing one or more antibiotics, the method comprising: 1) administering a first composition containing a fluoroquinolone antibiotic; 2) introducing a second composition containing metronidazole; 3) administering an intramuscular injection of a third composition containing an antibiotic selected from imipenem, gentamicin and cephalothin. 2. The method of claim 1 wherein the fluoroquinolone antibiotic is selected from the group consisting of ciprofloxacin, gemifloxacin, fosfomycin, levofloxacin, moxifloxacin, norfloxacin, ofloxacin, and derivatives and salts of any of the above. 3. The method of claim 2 wherein the fluoroquinolone antibiotic is selected from ciprofloxacin and levofloxacin. 4. The method of claim 1, further comprising improving the International Prostate Symptom Score (IPSS) by reducing the mean IPSS score from baseline by 5-7 points within one year. 5. The method of claim 1, further comprising improving the mean IPSS score over the mean IPSS mean improvement with oral BPH drugs by between about 30% and about 150% during the first year. 6. The method of claim 1, further comprising improving the mean IPSS score over the placebo control by between about 75% and about 500% during the first year. 7. The method of claim 1, further comprising improving the International Prostate Symptom Score (IPSS) by reducing the mean IPSS score from baseline by 4-5 points over 42 months. 8. The method of claim 1, further comprising improving mean IPSS score over mean improvement in mean IPSS score with oral BPH drugs by between about 0% and about 200% over 42 months. 9. The method of claim 1, further comprising improving the mean IPSS score over a placebo control by between about 75% and about 350% over 42 months. 10. The method of claim 1, further comprising improving the peak urinary flow rate (Qmax) by increasing the maximum urinary flow rate by about 1.3 ml/s to about 3.0 ml/s during the first year . 11. The method of claim 1, further comprising improving mean Qmax over placebo control by between about 100% and about 325% during the first year.