WO1999002147A1 - Improved methods and compositions for treating male erectile dysfunction - Google Patents
Improved methods and compositions for treating male erectile dysfunction Download PDFInfo
- Publication number
- WO1999002147A1 WO1999002147A1 PCT/US1998/013439 US9813439W WO9902147A1 WO 1999002147 A1 WO1999002147 A1 WO 1999002147A1 US 9813439 W US9813439 W US 9813439W WO 9902147 A1 WO9902147 A1 WO 9902147A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- prostaglandin
- acid
- pharmaceutical composition
- pge
- sulindac
- Prior art date
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- 201000001881 impotence Diseases 0.000 title claims abstract description 61
- 208000010228 Erectile Dysfunction Diseases 0.000 title claims abstract description 50
- 238000000034 method Methods 0.000 title claims description 76
- 239000000203 mixture Substances 0.000 title description 37
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- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 65
- 210000003708 urethra Anatomy 0.000 claims abstract description 57
- 229940122256 15-hydroxyprostaglandin dehydrogenase inhibitor Drugs 0.000 claims abstract description 43
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- 239000000463 material Substances 0.000 claims abstract description 14
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- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 46
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- 239000005642 Oleic acid Substances 0.000 claims description 26
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 claims description 24
- 235000021314 Palmitic acid Nutrition 0.000 claims description 23
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 claims description 23
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- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 claims description 15
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
Definitions
- the present invention relates to methods of treating male erectile dysfunction.
- the present invention further relates to pharmaceutical compositions useful for treating male erectile dysfunction.
- Impotence or lack of a man's ability to have sexual intercourse, is often the subject of jokes. However, millions of men suffer from this condition. Impotence is generally characterized by an inability to maintain a penile erection, and is often referred to as erectile dysfunction. Erectile dysfunction affects men, regardless of age, place of birth, or prior sexual experience.
- the term “erectile dysfunction” refers to certain disorders of the cavernous tissue of the penis and the associated fascia which produce impotence, the inability to attain a sexually functional erection. Impotence is estimated to affect at least 10 million men in the United States alone. Impotence results from disruption of any of numerous physiological or psychological factors which cause the blood flow to and from the penis to remain in balance thereby preventing retention of sufficient blood to cause rigid dilation of the corpus cavernosa and spongiosa. In the context of the present invention, the term “impotence” is used in its broadest sense as the inability to attain a sexually functional erection when desired.
- Treatments for impotence include psychosexual therapy, hormonal therapy, administration of vasodilators such as nitroglycerin and ⁇ -adrenergic blocking agents (hereafter " -blockers”), vascular surgery, implanted penile prostheses. vacuum devices and external aids such as penile splints to support the penis or penile constricting rings to alter the flow of blood through the penis, (see Robert J. Krause, et al., N. Eng. J. Med.. vol. 321, No 24, Dec. 14, 1989). Many patients treat their impotence by self injection of vasoactive drugs directly into the corpora cavernosa (see: Forward 1 st Symposium International Sur L'Erection Pharmactechnik. 17-19 Nov.
- the drugs most commonly used include ⁇ -blockers, such as phenoxybenzamine and phentolamine; smooth muscle relaxants such as papaverine; prostaglandins having a vasoactive function such as prostaglandin E, and combinations of such drugs having different receptor effects to enhance therapy.
- Intercavernous injection doses of papaverine are typically in the range of about 7.5 to 160 mg, while doses of phentolamine are in the range of about 0.1 to 10 mg and doses of prostaglandin E, are in the range of about 2.5 to 50 micrograms (see for example, Kurkle, et al., Urol. Clin. of America, vol. 15, No. 4, pp. 625-629 (1988) and N. Ishii et al., J. of Urol.. vol. 141, pp. 323-325 (1989).
- Vasoactive intestinal peptide has also been reported as producing erection upon intercavernous injection at doses of 10- 100 ⁇ g (see H. bottlesman, Diagnosis and Treatment of Impotence. U.S. Dept. of Health Services, Agency for Health Care Policy and Research, April 1990).
- sildenafil as disclosed in U.S. Patent No 5,270,323 to enhance erections has recently been approved by the FDA and extensively reported in the media. Sildenafil is thought to act by inhibiting the destruction of cyclic GMP in the penis by a specific phosphodiesterase. The limited clinical experience with sildenafil does not allow us to know how effective it may be in general use. It may provide a benefit for 40% of a general population of men with erectile dysfunction. There are widespread concerns about the long-term safety of sildenafil in the general population and recent reports of sudden death in men using it.
- U.S. Patent No 5,731 ,339 discloses the use of oral phentolamine as a possible treatment for male erectile dysfunction.
- U.S. Patent No 5,718,917 discloses the use of a meatal dose of lyophilized PGE-1 for erectile dysfunction. Reports from the previously cited AUA Meeting showed only preliminary reports with no evaluation of possible efficacy (unpublished results from discussion at The International Society on Impotence, AUA 93rd Annual Meeting, May 30, 1998).
- U.S. Patent No 5,708,031 discloses the use of intraurethral PGE-2 in the treatment of erectile dysfunction.
- compositions which comprise:
- compositions are in the form of a urethral suppository, and comprise:
- component (c) a base material that is solid at room temperature and releases components (a) and (b) when inserted in the urethra or meatus.
- component (c) is a base material that is solid at room temperature but melts or dissolves when inserted in the urethra or meatus to release components (a) and (b).
- Figure 1 is a cross-sectional view of the male urethra;
- Figure 2 shows the profile of one embodiment of the present urethral suppository;
- Figure 3 shows the profile of one embodiment of the present urethral suppository
- Figure 4 shows the profile of one embodiment of the present urethral suppository
- Figure 5 shows the profile of one embodiment of the present urethral suppository
- Figure 6 shows the profile of one embodiment of the present urethral suppository
- Figure 7 shows a cross-sectional view of one embodiment of the present urethral suppository
- Figure 8 shows a cross-sectional view of one embodiment of the present urethral suppository
- Figure 9 shows a cross-sectional view of one embodiment of the present urethral suppository
- Figure 10 shows a cross-sectional view of one embodiment of the present urethral suppository
- Figure 11 shows the results of a PGDH inhibition assay for palmitic acid ( ⁇ ) and oleic acid (A);
- Figure 12 graphically illustrates the change in cavernosal artery (CA) peak systolic blood flow as a function of time after the administration of a composition according to the present invention to five men without erectile dysfunction representing a control group ( ⁇ , ⁇ , ⁇ , X, and *);
- CA cavernosal artery
- FIG 13 graphically illustrates the change in cavernosal artery (CA) peak systolic blood flow as a function of time after the administration of a composition according to the present invention for five patients suffering from erectile dysfunction ( ⁇ , ⁇ , A, X, and *);
- CA cavernosal artery
- Figure 14 graphically illustrates the change in cavernosal artery (CA) peak systolic blood flow as a function of time after the administration of a composition according to the present invention for four patients ( ⁇ , ⁇ , ⁇ , and X);
- Figure 15 graphically illustrates the change in cavernosal artery (CA) peak systolic blood flow as a function of time after the administration of a composition containing 125 meg of PGE-2 ( ⁇ ) and a composition containing 125 meg of PGE-2 and 1.25 mg of oleic acid ( ⁇ );
- Figure 16 graphically illustrates the change in cavernosal artery (CA) peak systolic blood flow as a function of time after the administration of a composition containing 500 meg of PGE-2 ( ⁇ ); a composition containing 500 meg of PGE-1 ( ⁇ ); and a composition containing 125 meg of PGE-2 and 1.25 mg of oleic acid (+);
- Figure 17 graphically illustrates the change in cavernosal artery (CA) peak systolic blood flow as a function of time after the administration of a composition containing 25 meg of PGE-2 and 250 meg of palmitic acid ( ⁇ ); a composition containing 100 meg of PGE-2 and 1 mg of palmitic acid ( ⁇ ); and a composition containing 125 meg of PGE-2 and 1.25 mg of palmitic acid (A); and
- CA cavernosal artery
- Figure 18 graphically illustrates the change in cavernosal artery (CA) peak systolic blood flow as a function of time after the administration of a composition containing 125 meg of PGE-2 ( ⁇ ); a composition containing 125 meg of PGE-2 and 1.25 mg of oleic acid ( ⁇ ); and a composition containing 125 meg of PGE-2 and 1.25 mg of palmitic acid (A).
- CA cavernosal artery
- the present invention provides novel pharmaceutical compositions which are useful for treating male erectile dysfunction.
- the present pharmaceutical compositions are characterized as comprising (a) a vasodilator; and (b) a 15-hydroxyprostaglandindehydrogenase inhibitor.
- the vasodilator may be any physiologically acceptable vasodilator.
- vasodilators include: (a) nitro vasodilators, including but not limited to nitroglycerin, isosorbide dinitrate, amyl nitrate, isosorbide mononitrate, erythrityl tetranitrate, and sodium nitroprusside; (b) alpha blockers, including but not limited to prazosin, phentolamine, phenoxybenzamine, dibenzamine, doxazosin, terazosin, trimazosin, tolazoline, corynthanine, rauwolscine, and piperoxan; (c) other adrenoreceptor agents, including but not limited to yohimbine, labetalol, carvedilol, terbutaline, and bucindolol; (d) nonspecific vasodilating, substances, such as papaverine; and (e) polypeptide neurotransmitters such as vasoactive intestinal peptide (VIP), calc
- PGE-M PGF-M; PGH-2; PGI-2; 19-hydroxy-PGA-l; 19-hydroxy-PGB-l; PGA-2;
- Cyclodextrin complexes are also included as they may enhance the activity of the solution and stabilize the prostaglandin. Racemic, optically enriched or purified stereoisomers of any of these compounds are also included. Physiologically acceptable salts are also included.
- the prostaglandin is PGE-1, PGE-2, PGD-2, and CL 115,347. Most preferably, the prostaglandin is PGE-2 or PGE-1.
- PGE-1, prostaglandin E is also known as alprostadil or PGE[.
- the formal chemical name of PGE-1 is 3-hydroxy-2-(3-hydroxy-l-octenyl)-5- oxocyclopentaneheptanoic acid, and the structure of PGE-1 is
- Prostaglandin E may be isolated from sheep seminal vesicle tissue as described in Bergstrom et al., Acta. Chem. Scand.. vol. 16, p. 501 (1962) and J. Biol. Chem.. vol. 238, p. 3555 (1963).
- the synthesis of prostaglandin E may be carried out as described in Corey et al., J. Am. Chem. Soc. vol. 91, p. 535 (1969); Corey et al., J. Am. Chem. Soc. vol. 92, p. 2586 (1970); Sih et al, J. Am. Chem. Soc. vol. 94, p.
- PGE-2 prostaglandin E 2 is also known as dinoprostone or PGE 2 .
- the formal chemical name of PGE-2 is 7-[3-hydroxy-2-(3-hydroxy-l-octenyl)-5-oxocyclopentyl]-5- heptenoic acid, and the structure of PGE-2 is:
- Prostaglandin E 2 may be isolated from sheep seminal vesicle tissue as described in Bergstrom et al., Acta. Chem. Scand.. vol. 16, p. 501 (1962). Prostaglandin E 2 may be synthesized as described in Corey et al., J. Am. Chem. Soc. vol 92, p. 397 (1970); Corey et al., J. Am. Chem. Soc. vol. 92, p. 2586 (1970); and Heather et al., Tetrahedron Letters, p. 2313 (1973).
- prostaglandin E, and E 2 are commercially available from Sigma Chemical Company of St. Louis, MO.
- PGE-2 is also commercially available as a PROSTIN E-2 suppository and as PREPIDIL GEL from Pharmacia & UpJohn Company, Kalamazoo, MI, and as Cervidil from Forrest Pharmaceuticals, Inc., St. Louis, MO.
- 15-Deoxy-16-hydroxy-16-methyl-PGE-l methyl ester is also known as misoprostol and has the formal chemical name of ( ⁇ )-methyl-(lR,2R,3R)-3-hydroxy-2- [(E)-(4RS)-4-hydroxy-4-methyl-l-octenyl]-5-oxocyclopentaneheptanoate.
- 15-Deoxy-16- hydroxy-16-methyl-PGE-l methyl ester may be prepared as described in U. S. patent no. 3,965,143, which is incorporated herein by reference.
- Enprostil has the formal chemical name of [l ⁇ ,2 ⁇ (lE,3R * ),3 ⁇ ]-7-[3-hydroxy-2- (3-hydroxy-4-phenoxy-l-butenyl)-5-oxocyclopentyl]-4,5-heptadienoic acid methyl ester.
- Enprostil may be prepared as described in U. S. patent no. 4,178,457, which is incorporated herein by reference.
- PGI-2 is also known as prostacyclin, epoprostenol, prostaglandin I 2 , prostaglandin X, PGI 2 , and PGX.
- Prostacyclin may be prepared as described in U. S. patent no. 4,539,333, which is incorporated herein by reference.
- carbaprostacyclin The structure of carbaprostacyclin is:
- prostaglandin D 2 The structure of prostaglandin D 2 is:
- prostaglandins are described in Alex Gringanz, Introduction to Medicinal Chemistry. Wiley-VCH, Inc., New York, pp. 158-159 and 641-642, 1997, which is incorporated herein by reference.
- Cyclodextrin complexes of the prostaglandin may be used in order to increase the stability and efficacy. Cyclodextrin complexes may be prepared by adding the proper stoichiometric ratio of the prostaglandin to ⁇ , ⁇ , or ⁇ cyclodextrin in an aqueous solvent and then either using as is or lyophilizing to provide a solid clathrate for mixing. These complexes are described in Yamamura et al, J. Chromatogr.. vol. 331, pp. 383-388 (1985); Hirayama et al, Chem. Pharm. Bull., vol. 32 pp. 4237-4240 (1984); Uekama et al, J. Pharm. Sci..
- the present composition will contain prostaglandin E, or prostaglandin E 2 in an amount of 0.1 ⁇ g to 10 mg, preferably 1 to 500 ⁇ g (for transurethral administration), preferably 2 ⁇ g to 200 ⁇ g (for meatal administration) per unit dosage.
- prostaglandin E or prostaglandin E 2 in an amount of 0.1 ⁇ g to 10 mg, preferably 1 to 500 ⁇ g (for transurethral administration), preferably 2 ⁇ g to 200 ⁇ g (for meatal administration) per unit dosage.
- a different vasodilator it will be present in an amount which produces the same effect as the above-specified amounts of prostaglandin E, and prostaglandin E 2 .
- 15-hydroxyprostaglandindehydrogenase inhibitor any compound which exhibits a significant inhibition of prostaglandin degrading enzyme, or 15-hydroxyprostaglandindehydrogenase (PGDH).
- PGDH 15-hydroxyprostaglandindehydrogenase
- Type I which is NAD + dependent
- Type II which is NADP + dependent
- Type I operates at a Km one order of magnitude lower than Type II and is thus more significant physiologically.
- Type I PGDH is described in Mak et al, Biochimica et Biophysica Acta. vol. 1035, pp. 190- 196 (1990) ; Ensor et al, J.
- Type II PGDH is described in Chang, et al, Biochem. Biophys. Res. Commun.. vol. 99, pp. 745-751 (1981); Jarabak, et al, Prostaglandins. vol. 18, pp. 241-246 (1979), and Lin, et al, Biochem. Biophvs. Res. Commun.. vol. 81, pp. 1227-1234 (1978), all of which are incorporated herein by reference.
- suitable 15-hydroxyprostaglandindehydrogenase inhibitors include but are not limited to glycyrrhizic acid, licorice, glycyrrhetinic acid, various glycosides of glycrrhetinic acid, carboxenolone, DHEA, spironolactone, sofalcone, indomethacin, sulindac, etodolac, oleic acid, palmitic acid, sulphasalazine and analogues thereof, and ethacrynic acid, furosemide,chlorothiazide, hydrochlorothiazide, papaverine, cis-sulindac sulfide, trans-sulindac sulfide, cis-sulindac, trans-sulindac, glutathione thiosulfonate, divalent copper cations, divalent zinc cations, selenium,
- Glycyrrhizic acid is also known as glycyrrhizin, glycyrrhizinic acid, and glycyrrhetinic acid glycoside.
- the formal chemical name is 20 ⁇ -carboxy-l l-oxo-30- norolean-12-en-3 ⁇ -yl-2-O- ⁇ -D-glucopyranuronosyl- ⁇ -D-glucopyranosiduronic acid, and the structure is:
- Glycyrrhizic acid is commercially available from Sigma Chemical Company of St. Louis, MO.
- Glycyrrhetinic acid is unglycosylated glycyrrhizic acid, and its structure is:
- Glycyrrhetinic acid may be obtained from licorice extract.
- Carbenoxolone is also known as 3 ⁇ -hydroxy-l l-oxo-20 ⁇ -olean-12-en-29-oic acid hydrogen butanedioate and has the following structure:
- Carbenoxolone may be synthesized as described in U.S. Patent No. 3,070,623, which is incorporated herein by reference.
- Licorice is also known as sweet root liquorice and glycyrrhiza and is described in the Merck Index, 10 th edition, citation 4368 as "glycyrrhiza, Licorice, liquorice; sweet root. Dried rhizome and root of Glycyrrhiza glabra L., var. typica Regel & Herder (Spanish licorice), or of G. Glabra L., var. glandulifera (Waldst. & Kit.) Regel & Herder (Russian licorice), or of other varieties of G.
- Licorice is a crude preparation prepared from dried rhizomes or roots and as such contains large numbers of compounds many of which are not identified.
- a simple aqueous extract of a commercially available dried licorice root preparation may be prepared as follows. Two grams of this dried licorice root was mixed with 10 mis of distilled water, stirred until thoroughly mixed at room temperature and filtered to remove particulate matter. This simple aqueous extract of licorice is effective in inhibiting PGDH and may be used as is in the present invention.
- Spironolactone is also known as Aldactone A or Verospiron.
- the formal chemical name of spironolactone is 17-hydroxy-7-mercapto-3-oxo-17 ⁇ -pregn-4-ene-21- carboxylic and ⁇ -lactone, 7-acetate, and the structure is:
- Spironolactone is commercially available from Sigma Chemical Company of St. Louis, Mo.
- Sofalcone may be prepared as described in U.S. Patent No. 4,085,135, which is incorporated herein by reference.
- DHEA is formally known as 3-hydroxyandrost-5-en-17-one or dehydroepiandrosterone or prasterone.
- the structure of DHEA is:
- DHEA may be prepared as described in H. Hosoda et al, J. Org. Chem.. vol. 38, p. 4209 ( 1973), which is incorporated herein by reference.
- Sulfasalazine is also known as 2-hydroxy-5[[4-[(2- pyridinylamino)sulfonyl]phneyl]azo]benzoic acid and has the structure:
- sulfasalazine analogs have been shown to be inhibitors of PGDH by Berry et al, Biochemical Pharmacology, vol. 32, pp. 2863-2871 (1983).
- sulfasalazine analogs which may be used as the PGDH inhibitor in the present compositions include:
- Etodolac is also known as l,8-diethyl-l,3,4,9-tetrahydropyrano-[3,4-b]indole-l- acetic acid.
- Etodolac may be prepared as described U.S. Patent No. 3,843,681, which is incorporated herein by reference.
- Indomethacin is also known as l-(4-chlorobenzoyl)-5-methoxy-2-methyl-lH- indole-3-acetic acid. Indomethacin may be prepared as described in U.S. Patent No. 3,161,654, which is incorporated herein by reference.
- Sulindac is also known as 5-fluoro-2-methyl-l-[[4- (methylsulfinyl)phenyl]methylene]-lH-indene-3-acetic acid.
- Sulindac may be prepared as described in U.S. Patent Nos. 3,654,349 and 3,647,858, which are incorporated herein by reference.
- 15-hydroxyprostaglandindehydrogenase inhibitors include aliphatic and aromatic carboxylic acids.
- Suitable carboxylic acids particularly include any straight chain or branched, saturated, monounsaturated, or polyunsaturated aliphatic C 8 -C 31 carboxylic acid.
- Particularly preferred for use as component (b) in the present suppositories are free fatty acids including, but not limited to, palmitic acid, oleic acid, elaidic acid, stearic acid, capric acid, lauric acid, myristic acid, linoleic acid, arachidic acid and arachadonic acid, all of which are commercially available from Sigma Chemical Co., St. Louis, MO.
- the 15-hydroxyprostaglandindehydrogenase inhibitor will typically be present in an amount of 25 to 100, preferably 50 to 100, units of PGDH inhibition activity, per unit dosage.
- the amount of inhibitor which corresponds to a unit of PGDH inhibition activity may be determined using either the pig penile PGDH assay or human placental PGDH assay with any of the specific assays (spectrophotometric or radio-chemical or Anggard and Samuelsson) described in the Examples. For inhibitors which exhibit a significant absorption at 340 nm, it may be preferred to use the radio-chemical assay.
- the appropriate amount of 15-hydroxyprostaglandindehydrogenase inhibitor may be determined using the cavernosal artery blood flow assay described in the Examples.
- the present pharmaceutical compositions may take any form which is suitable for administration to the penis either via injection into the corpora cavernosa or transurethral administration, or topically applied to the urethral meatus or the skin of the glans.
- the pharmaceutical composition is suitably in the form of an isotonic saline solution.
- the pharmaceutical composition is in a form suitable for transurethral or meatal administration, and in this case the composition is typically in the form of a solution, an ointment, or a suppository.
- the pharmaceutical composition is in the form of a suppository.
- the suppository will contain sufficient amounts of (a) and (b) such that administration of a single suppository is sufficient to provide the desired result.
- a suppository would typically contain: (a) 0.1 ⁇ g to 10 mg, preferably 1 to 500 ⁇ g (for transurethral administration), preferably 2 to 200 ⁇ g (for meatal administration), of prostaglandin E, or 0.1 ⁇ g to 10 mg, preferably 1 to 500 ⁇ g (for transurethral administration), preferably 2 to 200 ⁇ g (for meatal administration), of prostaglandin E 2 ; and (b) 25 to 100 units, preferably 50 to 100 units, of the 15- hydroxyprostaglandindehydrogenase inhibitor.
- the present pharmaceutical compositions may further comprise a coagent.
- suitable co-agents include: 1. ACE inhibitors, including but not limited to captopril, enalapril, enalaprilat, quinapril, lisinopril, and ramipril, may enhance the efficacy of the present method and decrease long term complications, such as inflammatory and fibrotic responses;
- Nitro vasodilators including but not limited to nitroglycerin, isosorbide dinitrate, amyl nitrate, isosorbide mononitrate, erythrityl tetranitrate, and sodium nitroprusside, may enhance the efficacy of the present method;
- Alpha blockers including but not limited to prazosin, phentolamine, phenoxybenzamine, dibenzamine, doxazosin, terazosin, trimazosin, tolazoline, corynthanine, rauwolscine, and piperoxan, are especially desirable for increasing the efficacy and prolonging the action of the present method;
- adrenoreceptor agents including but not limited to yohimbine, labetalol, carvedilol, and bucindolol, may also enhance the activity and prolong the action of the present method;
- Phosphodiesterase (PDE) inhibitors including but not limited to caffeine, aminophylline, theophylline, amrinone, milrinone, vesnarinone, vinpocetine, pemobendan, cilostamide, enoximone, peroximone, rolipram, R020-1724, zaniprast, dipyridamole, and sildenafil, may also be effective in enhancing the efficacy of the present method and for prolonging the effect;
- Muscarinic agents such as pilocarpine, edrophonium, and bethanacol
- Dopaminergic agonists such as apomorphine and bromocriptine
- Ergot alkaloids such as ergotamine and ergotamine analogs, including acetergamine, bravergoline, bromerguride, clanegollone, ergonovine, ergotamine tartrate, and pergolide;
- Opiate antagonists such as naloxone, naltrexone, nalmefene, nalorphine, methyl naltrexone, CTOP, diprenorphine, ⁇ -funaltrexamine, naloxonazine, nor- binaltorphimine, natrindole, BNTX, and other analogs, which exhibit opioid antagonistic properties;
- Polypeptide neurotransmitters such as VIP, calcitonin, calcitonin gene related product, VIP analogs, and cholecystokinin and all its analogs such as CCK8; 11.
- Mast cell stabilizers such as chromolyn, nedochromolyn, zileuton, piripost,
- MK-886, MK-0591, ICI-D2318, docebenone, and leukotriene receptor antagonists and 12.
- Agents such as forskolin and and water soluble analogues that directly stimulate adenylate cyclase; dibutyryl-cyclic AMP, dibutyryl-cyclic GMP and guanylin may enhance the relaxation of cavernosal tissues by increasing the amounts of cyclic AMP and cyclic GMP.
- the present invention provides a method for treating male erectile dysfunction, by administering a pharmaceutical composition which comprises (a) prostaglandin E Albany prostaglandin E 2 , or a mixture thereof; and (b) a 15- hydroxyprostaglandindehydrogenase inhibitor.
- a pharmaceutical composition which comprises (a) prostaglandin E Albany prostaglandin E 2 , or a mixture thereof; and (b) a 15- hydroxyprostaglandindehydrogenase inhibitor.
- the present method may be advantageously carried out using any of the present pharmaceutical compositions described above.
- the pharmaceutical composition may be administered either by topical administration to the urethral meatus or the skin of the glans or by injection into the corpora cavernosa or via transurethral administration. Injection into the corpora cavernosa may be carried out as described in Botto I. Linet and Frances G. Ogrinc, New England Journal of Medicine, vol. 334, pp. 873-877 (April 4, 1996), which is incorporated herein by reference.
- the present method involves topical or transurethral administration. Topical administration may be carried out by dripping a solution of the composition directly on the urethral meatus. Alternatively, a suppository may be placed directly into the urethral meatus.
- Transurethral administration may be carried out by application of a solution, ointment, emulsion, suppository, or any liquid form via a catheter as described in Herin Padam-Nathan et al., New England Journal of Medicine, vol. 336, pp. 1-7 (January 2, 1997); and Wolfson V., et al., Urology, vol. 42, pp. 73-75 (1993), which are incorporated herein by reference.
- the present method is carried out by topical administration of a suppository.
- Suppositories may be administered transurethrally using a device such as those described in Herin Padam- Nathan et al., New England Journal of Medicine, vol. 336, pp. 1-7 (January 2, 1997), which is incorporated herein by reference.
- the pharmaceutical composition is administered 1 to 50 minutes, preferably 10 to 20 minutes, prior to the time of commencing sexual intercourse.
- the present method is carried out by administering one of the present pharmaceutical compositions described above.
- the present method is carried out by either intraurethral administration of the present suppository or topical application of the present solution, cream, or ointment to the urethral meatus.
- the prostaglandin E, or prostaglandin E 2 need not be administered simultaneously with the 15- hydroxyprostaglandindehydrogenase inhibitor. Rather, the 15- hydroxyprostaglandindehydrogenase inhibitor may be preadministered. Pre-treatment or simultaneous treatment with a 15-hydroxyprostaglandindehydrogenase inhibitor also decreases the burning sensation associated with the administration of the prostaglandin. In addition, blocking the PGDH tremendously enhances the absorption and effectiveness of the prostaglandin leading to a remarkably lower dose requirement.
- the inhibition of PGDH may be used in combination with any prostaglandin or prostaglandin analogue which is suitable for inclusion in the present compositions by nature of its vasodilating activity.
- the present invention provides novel pharmaceutical compositions which are characterized as being in the form of a urethral suppository and comprising:
- the prostaglandin and the 15-hydroxyprostaglandindehydrogenase inhibitor may be the same as described above.
- the present composition will contain prostaglandin E, or prostaglandin E 2 in an amount of 0.1 ⁇ g to 10 mg, preferably 1 to 500 ⁇ g (for transurethral administration), preferably 2 to 200 ⁇ g (for meatal administration), per unit dosage.
- the 15-hydroxyprostaglandindehydrogenase inhibitor will typically be present in an amount of 25 to 100, preferably 50 to 100, units of PGDH inhibition activity, per unit dosage. The amount of inhibitor which corresponds to a unit of PGDH inhibition activity is determined using the methods described above.
- the 15-hydroxyprostaglandindehydrogenase inhibitor is a fatty acid, such as palmitic acid, oleic acid, elaidic acid, stearic acid, capric acid, lauric acid, myristic acid, linoleic acid, arachidic acid and arachadonic acid
- the fatty acid will suitably be present in the suppository in an amount of from about 0.1 ⁇ g to about 20 mg, preferably from about 100 ⁇ g to about 10 mg.
- the suppository will suitably contain the 15- hydroxyprostaglandindehydrogenase inhibitor in an amount of 01. Mg to 20 mg, preferably 0.5 mg to 10 mg, per unit dosage of prostaglandin.
- Component (c), the base or carrier material may be composed of any material or mixture of materials that is compatible with component (a), the prostaglandin vasodilator, and component (b), the 15-hydroxyprostaglandindehydrogenase inhibitor, and which releases components (a) and (b) upon insertion into the meatus or urethra.
- materials suitable for use as component (c) which releases components (a) and (b) upon insertion of the suppository into the urethra include materials such as hydrogels which contain or are saturated with components (a) and (b).
- suitable gels include triacetin, hydroxycellulose, gels composed of water, propylene glycol, hydroxypropyl methylcellulose and any other gels which are compatible with the prostaglandin.
- a particularly preferred gel is lecithin organogel prepared according to H. Willimann et al, "Lecithin organolgel as matrix for transdermal transport of drugs," J. Pharm. Sci.. vol. 81(9), pp. 871-874 (1992), which is incorporated herein by reference. This particular preparation exhibits a dramatically enhanced potency.
- components (a) and (b) can be formulated into a cross- linked polyethylene oxide/urethane polymer which is well tolerated by living tissues and releases components (a) and (b) in a controlled release manner.
- Controlled release compositions are disclosed in D. H. Lewis, Controlled Release of Pesticides and Pharmaceuticals. Plenum Press, New York, 1981 ; and A. F. Kydonieus, Controlled Release Technologies: Methods. Theory, and Applications. CRC Press, Boca Raton, 1980, which are incorporated herein by reference.
- component (c) is a material or mixture of materials which is compatible with component (a), the prostaglandin vasodilator, and component (b), the 15-hydroxyprostaglandindehydrogenase inhibitor, and which results in the final composition having a melting point ranging from about 70° to about 100°F, preferably from about 70° to about 90°F.
- Suitable materials for use as component (c) include but are not limited to fatty acid esters, such as ethyl stearate, methyl stearate, isopropyl stearate, butyl stearate, and cetyl lactate; fatty acid ethers, such as laureth 9; cholesterol esters, such as cholesteryl oleate and cholesteryl palmitate ; cholesterol ethers; fatty acid diglycerides; fatty acid triglycerides; fatty acids; phospholipids; glycolipids; and sphingolipids.
- Ethyl stearate is a particularly preferred compound for use as component (c).
- Other materials suitable for use as component (c) include polyethylene glycol
- PEG poly(ethylene glycol)
- the PEG is chosen so that the suppository is a solid or semisolid at room temperature but melts/dissolves rapidly in the urethra. Good results have been achieved using PEG with an average molecular weight of about 1450.
- the suppositories of this embodiment may further comprise one or more of the same co-agents described above.
- compositions include alpha-blockers and/or PDE inhibitors. Any combinations of the single above-listed compounds or multiple combinations of different compounds or different groups may also be used. In some instances, it may be advantageous to pretreat with one or more of the co-agents. For example, pretreatment with a PGDH inhibitor followed by treatment with PGE will enhance the efficacy of the present method.
- the present urethral suppositories will typically be oblong in shape with a length to width aspect ratio of from about 1 :1 to about 75:1, preferably from about 5:1 to about 20:1.
- the length of the suppository may vary from about 1 mm to about 100 mm, preferably from about 2 mm to about 75 mm.
- the length of the suppository may be tailored to direct the dosage of the prostaglandin to either the urethral meatus or the penile urethra.
- the length of the suppository is preferably from about 2 mm to about 60 mm, more preferably from about 5 mm to about 50 mm, and most preferably from about 10 mm to about 40 mm.
- the length of the suppository is preferably from about 50 mm to about 100 mm, more preferably from about 60 mm to about 100 mm, and most preferably from about 60 mm to about 80 mm.
- Figures 2-6 show the profile or side view of some embodiments of the present suppository, while Figures 7-10 show the cross-sectional view of some embodiments of the present suppository.
- Figure 2 shows the side view of a suppository with a straight shaft 1 and a rounded tip 2.
- Figure 3 shows the side view of a suppository with a straight shaft 1 and a pointed tip 2.
- Figure 4 shows the side view of a suppository with a straight shaft 1, a rounded tip 2, and flat base or stop 3 attached to the end of the shaft 1 distal to the tip 2.
- Figure 5 shows the side view of a suppository with a straight shaft 1, a pointed tip 2, and flared base or stop 3 attached to the end of the shaft 1 distal to the tip 2.
- Figure 6 shows the side view of a suppository which is tapered along the entire length of the shaft 1 and has a pointed tip 2.
- the present suppository is not limited to any particular cross-sectional shape. As shown in Figures 7-10, the present suppositories may be either circular, elliptical, oblong, or football-shaped in cross-section. Circular and elliptical cross-sectional shapes are preferred.
- Figure 7 shows the cross-sectional view of a suppository which does not have a base or stop 3 and in which the shaft 1 is substantially circular in cross-section.
- Figure 8 shows the cross-sectional view of a suppository which does not have a base or stop 3 and in which the shaft 1 is substantially oblong in cross-section.
- Figure 9 shows the cross-sectional view of a suppository which has a base or stop 3 which is substantially circular and in which the shaft 1 is substantially circular in cross-section.
- Figure 10 shows the cross-sectional view of a suppository which has a base or stop 3 which is substantially circular and in which the shaft 1 is substantially oblong in cross- section.
- the suppository has a round or pointed tip to facilitate entry into the urethra (see Figures 2-5).
- the suppository may be tapered along all of or at least a substantial part of its length (see Figure 6).
- the base of the suppository may be distended or flared to provide a built-in stop, so that the depth of the insertion may be determined by the length from the tip of the suppository to the beginning of the flare (see Figures 4 and 5).
- the base of the suppository may be attached to a piece of foil, plastic, or paper or attached to the inside of the tip of a condom in order to set the depth of insertion.
- the present suppositories will typically have a cross-section having a maximum dimension of from about 0.1 mm to about 25 mm, preferably from about 1 mm to about 10 mm, particularly from about 2 mm to about 6 mm, along the portion of the suppository intended to be inserted into the urethra.
- the suppository should be thick enough to retain sufficient structural integrity to permit insertion of the suppository into the urethra without breaking or significantly bending the suppository.
- the present suppository may have a shape in which the base of the suppository is distended or flared.
- the distended or flared portion of the suppository will typically have a minimum dimension of at least about 5 mm, preferably at least about 10 mm.
- there is in principal no upper limit on the maximum cross- sectional dimension of the distended or flared portion of the suppository practically speaking, it is not necessary to make the distended or flared portion any larger than what is required to prevent insertion of the suppository into the urethra beyond the point at which the distended or flared portion begins.
- the suppository will contain sufficient amounts of (a) and (b) such that administration of a single suppository is sufficient to provide the desired result.
- a suppository would typically contain: (a) 0.1 ⁇ g to 1.0 mg, preferably 1 ⁇ g to 500 ⁇ g (for transurethral administration), preferably 2 ⁇ g to 200 ⁇ g (for meatal administration), of prostaglandin E, or 0.1 ⁇ g to 1.0 mg, preferably 1 ⁇ g to 500 ⁇ g (for transurethral administration), preferably 2 ⁇ g to 200 ⁇ g (for meatal administration), of prostaglandin E 2 ; and (b) 25 to 100 units, preferably 50 to 100 units, of the 15- hydroxyprostaglandindehydrogenase inhibitor.
- the present suppository contains 1 to 20 mg of oleic acid per each mg of prostaglandin E 2 (i.e., a 1:1 to 20:1 weight ratio of oleic acid:prostaglandin E 2 ).
- the present suppository contains prostaglandin E 2 and palmitic acid in a palmitic acid:prostaglandin E 2 weight ratio of 1 : 1 to 20: 1.
- the present suppositories are characterized as having a pH of 3 to 7, preferably 4 to 6.
- Such suppositories may be prepared by simply adding a sufficient amount of a pharmaceutically acceptable acid or base, e.g., HC1 or NaOH to adjust the pH to the desired value.
- a pharmaceutically acceptable acid or base e.g., HC1 or NaOH
- a pharmaceutically acceptable citrate salt e.g., sodium citrate
- 0.5 ml of 0.01 Molar sodium citrate at pH 4.5 is lyophilized, and the powdered residue is added to a unit dose of prostaglandin E 2 in ethyl stearate.
- the lyophilized citrate will dissolve and buffer the pH of the urethra to about pH 4.5 and thereby enhance the activity of the prostaglandin E 2 as the ethyl stearate pellet dissolves.
- the present invention provides a method for treating male erectile dysfunction, by administering the present suppository to a patient in need thereof.
- the present method may be carried out by either transurethral administration or meatal administration of the present suppository.
- the male penile urethra consists of three segments: the bulbar urethra, the pendulous urethra, and the navicular fossa.
- transurethral administration refers to the administration of agents to the bulbar and pendulous urethra which are covered by pseudostratified or stratified columnar epithelium.
- meanatal administration refers to the administration of agents to the urethra of the navicular fossa and/or to the penile meatus (as shown in Figure 1) that are covered by stratified squamous epithelium.
- Meatal administration is thus essentially the same as topical administration with respect to the difficulty of administering an effective transdermal dose.
- a meatal dose of a vasoactive prostaglandin would typically be expected to be 10 to 20 (or more) times greater than a transurethral dose due to the difficulty of traversing the denser epithelium.
- the present suppositories exhibit the improvement of making meatal administration feasible and effective even when using the same dosage as effective in transurethral administration.
- Meatal administration may be preferred over transurethral administration for a number of reasons. Meatal administration is generally easier to carry out than transurethral administration and may be the only possible means of administration in patients with narrowing or scarring of the urethra.
- the depth of insertion of the suppository in meatal administration is, as measured from the external opening of the penis, generally between 2 mm and 60 mm depending on individual differences and the degree of penile tumescence at the time of administration.
- the depth of insertion of the suppository in transurthral administration is, as measured from the external opening of the penis, generally greater than 50 mm depending on individual differences and the degree of penile tumescence at the time of administration.
- Meatal or transurethral administration may be easily effected by selection of a suppository with a shaft of the appropriate length and a distended or flared base and insertion of the suppositories to the depth of the distended or flared base.
- compositions may be applied directly to the external skin of the glans penis to produce an erection.
- Such a method of use may require increasing the dose of the prostaglandin E-l or E-2 to 250 meg - 2.5 mg with the corresponding amount of inhibitor.
- the suppository is inserted into the urethra 1 to 50 minutes, preferably 10 to 20 minutes, prior to the time of commencing sexual intercourse. Meatal administration may result in a slower onset of the effect of the active agent and, thus, may preferably be carried out earlier than transurethral administration. Those suppositories in which component (c) dissolves or melts in the urethra are simply inserted into the urethra.
- suppositories in which component (c) releases components (a) and (b) in the urethra but does not itself dissolve or melt in the urethra are preferably inserted into the urethra to a depth which leaves a portion of the suppository protruding from the urethra, left in the urethra until the desired effect is achieved, and then removed from the urethra by means of the protruding portion.
- the prostaglandin E, or prostaglandin E 2 need not be administered simultaneously with the 15- hydroxyprostaglandindehydrogenase inhibitor.
- the 15- hydroxyprostaglandindehydrogenase inhibitor may be preadministered in a first suppository followed by treatment with the prostaglandin in a second suppository.
- Pre- treatment or simultaneous treatment with a 15-hydroxyprostaglandindehydrogenase inhibitor decreases the burning sensation associated with the administration of the prostaglandin.
- blocking the PGDH tremendously enhances the absorption and effectiveness of the prostaglandin leading to a remarkably lower dose requirement.
- the present suppositories may be manufactured by any standard method known to the art, including but not limited to extrusion, casting, and injection molding.
- the present suppositories may be prepared by forming, under sterile conditions, an intimate mixture containing the appropriate relative amounts of components (a), (b), and (c) at a temperature above the melting point of component (c) and then forming the suppository of the desired shape by extrusion, casting, or injection molding.
- the present suppositories and methods offer a number of advantages as compared with conventional compositions and methods for treating male erectile dysfunction.
- the present suppositories and methods offer a number of advantages as compared with conventional compositions and methods for treating male erectile dysfunction.
- the present suppositories and methods offer a number of advantages as compared with conventional compositions and methods for treating male erectile dysfunction.
- the present suppositories and methods offer a number of advantages as compared with conventional compositions and methods for treating male erectile dysfunction.
- the present suppositories and methods offer a number of advantages as compared with conventional compositions and methods for treating male erectile dysfunction.
- the present suppositories and methods offer a number of advantages as compared with conventional compositions and methods for treating male erectile dysfunction.
- the present suppositories and methods offer a number of advantages as compared with conventional compositions and methods for treating male erectile dysfunction.
- A. Pig Penile Urethral Mucosa Preparation Fresh hog penises from sexually mature animals are obtained from a local slaughter house. They are immediately washed in tap water and then in ice-cold normal saline. The urethra corresponding to the section extending from the fossa navicularis and extending to the membraneous region of the urethra is separated from the corpus spongiosum. This region is called the penile urethra, and the corresponding length of the urethra is measured in millimeters and recorded. The weight of the urethra is also recorded.
- the mucosa is homogenized with four volumes of an ice-cold 100 mM potassium phosphate buffer (pH 7.4) containing 1 mM EDTA and 1 mM dithiothreitol. Following centrifugation at 15,000 g for 15 minutes, the resultant supernatant fraction is used as the enzyme source of the penile mucosa.
- prostaglandin E As a substrate, prostaglandin E, is incubated with the pig penile urethral mucosa prepared above.
- the reaction mixture is contained in a total volume of 2.0 ml of the same buffer used above for the preparation of the pig penile urethral mucosa preparation.
- Prostaglandin E, (50 microM) and NAD (300 microM) are used as substrates.
- the reaction is initiated by the addition of the prostaglandin E,. Incubation is done at 37 °C and is terminated by the addition of 0.5 mL of 2NaOH.
- the oxidation of the prostaglandin is assayed by monitoring the reduction of NAD+ at 340 nanometers in a spectrophotometer. Reaction times are adjusted so that the initial quantity of prostaglandin is oxidized by 50 to 80%.
- Radiochemical determination The same reactions conditions listed for spectrophotometric analysis are used except that (5, 6, 8, 11, 12, 14, 15(n)- 3 H)- prostaglandin E 2 (specific activity, 171 Ci, mmol) from Dupont de Nemours is used as a typical substrate. Any other tritiated prostaglandin substrate can be utilized in this assay.
- methanol precipitation 75% volume/volume)
- water is added to dilute the methanol to 10 volume percent. Soluble phase extractions are performed using octadecyl 18-C silica cartridges (J.T. Baker, Deventer, Holland).
- the prostaglandin is then eluted from the cartridge with 4 ml of absolute methanol and dried with a stream of dry argon. Dried extracts are run on 20 X 20, 60 A silica plates using the organic phase of ethyl acetate/acetic acid/isooctane/water (11 :2:5:10:). Authentic prostaglandin E 2 , 15-keto-prostaglandin E 2 , and 13, 14-dihydro- 15-keto-prostaglandin E 2 are comigrated on separate lanes.
- a mU is defined as that amount of enzyme which oxidizes 1 nanomole of prostaglandin E 2 or E, per min at 37°C, pH 7.4.
- the number of mU PGDH per mm of pig penile urethra is then calculated by dividing the total number of mU by the mm of urethra used to prepare the enzyme.
- one unit of PGDH inhibition activity is defined as the quantity of inhibitor that prevents one percent of the quantity of prostaglandin present from being oxidized using one of the assays described below.
- the PGDH may be pig penile PGDH as described above or human placental PGDH as described below.
- the enzyme activity and percent inhibition are preferably measured as described immediately below.
- human placental PGDH the enzyme activity and percent inhibition are preferably measured as described in Anggard, E. And Samuelsson, B. (1966) Ark. Kem. 25, 293- 340.
- Radiochemical Determination The assay for inhibition is run with and without inhibitor added as listed above in the determination of PGDH activity radiochemically. A given inhibitor is added to the reaction mixture just prior to the addition of the prostaglandin E 2 being analyzed and the analysis performed as listed. The quantity of prostaglandin oxidized is calculated and interpreted as listed above for spectrophotometric analysis of inhibitor activity.
- Placenta is one of the richest sources of PGDH containing large quantities of both Type I and II. Placental PGDH can thus be readily utilized as an enzyme source to be used for determining PGDH enzyme inhibitor activity and in deciding upon the relative amounts of prostaglandin and PGDH inhibitor to be incorporated into a unit dose for this invention.
- Placenta from a healthy mother with a normal vaginal delivery was placed immediately after delivery on ice. Within 1 hour of delivery, a portion of the placenta ( ⁇ l ⁇ ) was obtained and rinsed repeatedly with aliquots of ice cold (1-5 °C) homogenate buffer containing lOmM potassium phosphate ( pH 7.4 ), 20% glycerol, 1 mM EDTA, 1 mM dithiothreitol and 100 units heparin per liter until all visible blood and mucous were removed; then the membranes were dissected away and the tissue cut into small pieces. The placenta is extremely rich in blood vessels so the rinsing with buffer was repeated in order to remove as much hemoglobin as practical.
- PGDH activity was assayed according to Anggard and Samuelsson (see Anggard, E. And Samuelsson, B. (1966) Ark. Kem. 25, 293-340). However, any other compatible method of measuring PGDH activity including the 2 methods already listed in this report are acceptable.
- the absorbance may be used directly or the specific activity of the enzyme calculated. Typical values of PGDH activity obtained were in the range of 4.85 - 6.25 picomoles of 15-ketoprostaglandin E2/ min-ml for homogenate. This assay exhibits roughly the amount of PGDH activity expected to be found in the human penis (Roy, A.C., Adaikan, P.G., Sen, D.K. and
- Inhibitor activity may be determined by dissolving the chemical to be tested in the assay buffer and pre-incubating the homogenate with the inhibitor for 15 minutes prior to starting the assay listed above by addition of the PGE2.
- Figure 11 shows examples of the data derived. Fatty acids are not very water soluble so they were dissolved in 95% ethanol and added in aliquots of -25 microliters. The presence of this amount of alcohol has no effect on enzyme activity. Some sodium salts of fatty acids will precipitate on addition of NaOH. This visible precipitate should be removed by filtration through a 0.22 micron filter prior to measurement of absorbance to ensure accurate results.
- delicate enzyme systems may exhibit a great deal of interassay variability.
- unit doses of palmitic acid should have - twice or more of the molar quantity of PGE2 used in order to have >50% inhibition of PGDH.
- Unit doses should have -2 x or more the molar ratio of oleic acid to PGE2.
- One can easily use this method to determine the approximate quantities of inhibitor needed per unit dose by simply substituting the inhibitor being tested into this assay in an appropriate solvent and checking to make sure that the chosen solvent does not inhibit the enzyme.
- a different prostaglandin it should be substituted for PGE2 in the above assay.
- a vasodilator other than a prostaglandin one should incorporate the actual weight of the inhibitor as derived from using PGE2 and oleic acid in the above assay into a unit dose.
- Another method of determining the optimum amount of an inhibitor to be used in a unit dose is to make up the inhibitor in various amounts per unit dose in a suppository form. One may then administer these varying doses of inhibitor to a patient and measure the peak systolic blood flow as well as assess the degree of erection induced. One may easily deduce an appropriate dose for any inhibitor using this technique.
- a 46-year-old white male with multiple etiologies of erectile dysfunction including atherosclerosis, tobacco use, antidepressant use, and a 30-year history of phimosis and resulting obliteration of the glans penis by scarring was evaluated. Due to urethral strictures (from scar tissue), the urethra was narrowed to about 2 mm near the tip of the penis making insertion of a catheter impossible. A suppository (as described in Example 1 ) was easily and painlessly inserted into the urethra occluding it at the stricture. After 20 minutes, the patient experienced a firm erection, which lasted 60 minutes.
- the urethra of a 42 year old male with a history of erectile dysfunction was pretreated with 1 ml of 0.9 percent (w/v) DHEA in water. After 15 minutes, an aqueous solution containing 250 ⁇ g of PGE 2 and 150 ⁇ g of phentolamine hydrochloride was applied directly to the urethra. An absence of burning was noted and an enhanced effectiveness was seen.
- Example 6 The urethra of a 42 year old male with a history of erectile dysfunction was pretreated with 1 ml of 0.9 percent (w/v) DHEA in water. After 15 minutes, an aqueous solution containing 250 ⁇ g of PGE 2 and 150 ⁇ g of phentolamine hydrochloride was applied directly to the urethra. An absence of burning was noted and an enhanced effectiveness was seen. Example 6.
- aqueous solution containing: 0.1 ml of 10% w/v carbenoxolone was applied topically to the urethral meatus of a 42 year old male with a history of erectile dysfunction for 5 minutes before application of 500 ⁇ g of PGE2 and 500 ⁇ g of phentolamine, in liposomes. An erection was produced in 15 minutes and lasted for 90 minutes.
- a 47-year-old white male without history of erectile dysfunction was evaluated for cavernosal arterial blood flow using a KNOLL/MIDUS system by Urometrics, Inc. ultrasonic doppler flow analyzer.
- the baseline for unstimulated blood flow in the penile cavernosal arteries was .025 meters/second (see Figure 14).
- a #12 French catheter was inserted into the urethra 4 centimeters and 150 nanomoles of carbenoxolone (PGDH inhibitor) was infused as a pretreatment 15 minutes prior to infusion of 150 nanomoles of PGE 2 and phentolamine hydrochloride (a 1 :1 molar ratio of enzyme inhibitor to prostaglandin).
- PGDH inhibitor carbenoxolone
- a 42-year-old white male with a history of erectile dysfunction was assessed using the KNOLL/MIDUS system; baseline blood flow (flaccid) was 0.03 meters per second.
- baseline blood flow (flaccid) was 0.03 meters per second.
- 3.0 micromoles of carbenoxolone were used as a pretreatment to inhibit prostaglandin degradation.
- 0.75 micromoles of PGE 2 and phentolamine hydrochloride were administered intraurethrally (which is a 4 to 1 molar ratio of inhibitor to PGE 2 ).
- cavernosal blood flow had increased to 0.49 meters per second which is a 16.3-fold increase in cavernosal arterial blood flow (see Figure 14).
- the basal (flaccid) cavernosal arterial blood flow on a 42-year-old white male with erectile dysfunction was found to be 0.03 meters/second.
- 6.6 micromoles of carbenoxolone in a suppository of polyethyleneglycol MW 1450 was placed on the urethral meatus and allowed to dissolve for 15 minutes prior to administration of 0.83 micromoles of PGE 2 and phentolamine (an 8 to 1 molar ratio of inhibitor to PGE 2 ).
- Cavernosal arterial blood flow increased over the next 15 minutes 0.43 meters per second which is a 14-fold increase in blood flow (see Figure 14).
- a 47 year old male with erectile disorder was given a meatal suppository of 16 mm length and 2 mm diameter containing 125 meg PGE-2 and his response followed by measuring peak cavernosal artery blood flow over time. On a different day, he was given a meatal suppository containing 125 meg PGE-2 + 1.25 mg oleic acid as a PGDH inhibitor. The results as shown in Fig. 15 illustrate the dramatic increase in peak response and length of response brought on by this invention.
- Example 13 A 43 year old male with erectile disorder was given meatal suppositories with ethyl stearate and a 10:1 ratio by weight of palmitic acid as a PGDH inhibitor with varying amounts of PGE-2 from 25 meg - 125 meg (See Figure 17). Note that the 25 meg dose gave a peak flow response that equalled the 125 meg PGE-2 dose. This meatal dose of 25 meg gave a response equivalent to the response that one would see with an intercavernosal injection demonstrating the remarkable efficacy of this method.
Abstract
Description
Claims
Priority Applications (6)
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EP98935499A EP1005336A4 (en) | 1997-07-09 | 1998-07-09 | Improved methods and compositions for treating male erectile dysfunction |
KR1020007000183A KR20010021625A (en) | 1997-07-09 | 1998-07-09 | Improved Methods and Compositions for Treating Male Erectile Dysfunction |
JP2000501742A JP2001509480A (en) | 1997-07-09 | 1998-07-09 | Improved methods and compositions for treating male erectile dysfunction |
CA002295595A CA2295595A1 (en) | 1997-07-09 | 1998-07-09 | Improved methods and compositions for treating male erectile dysfunction |
AU84734/98A AU742787B2 (en) | 1997-07-09 | 1998-07-09 | Improved methods and compositions for treating male erectile dysfunction |
NO20000085A NO20000085L (en) | 1997-07-09 | 2000-01-07 | Improved methods and preparations for the treatment of erectile dysfunction in men |
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US08/890,445 US6103765A (en) | 1997-07-09 | 1997-07-09 | Methods for treating male erectile dysfunction |
US08/890,445 | 1997-07-09 | ||
US6829497P | 1997-12-19 | 1997-12-19 | |
US60/068,294 | 1997-12-19 |
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AU (1) | AU742787B2 (en) |
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Also Published As
Publication number | Publication date |
---|---|
AU742787B2 (en) | 2002-01-10 |
JP2001509480A (en) | 2001-07-24 |
US20020128314A1 (en) | 2002-09-12 |
NO20000085D0 (en) | 2000-01-07 |
AU8473498A (en) | 1999-02-08 |
KR20010021625A (en) | 2001-03-15 |
US6414027B1 (en) | 2002-07-02 |
EP1005336A4 (en) | 2001-01-17 |
US6559184B2 (en) | 2003-05-06 |
NO20000085L (en) | 2000-03-01 |
CA2295595A1 (en) | 1999-01-21 |
EP1005336A1 (en) | 2000-06-07 |
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