[go: up one dir, main page]

WO1999002161A1 - Utilisation d'inhibiteurs de la phosphordiesterase dans le traitement de maladies de la prostate - Google Patents

Utilisation d'inhibiteurs de la phosphordiesterase dans le traitement de maladies de la prostate Download PDF

Info

Publication number
WO1999002161A1
WO1999002161A1 PCT/EP1997/003617 EP9703617W WO9902161A1 WO 1999002161 A1 WO1999002161 A1 WO 1999002161A1 EP 9703617 W EP9703617 W EP 9703617W WO 9902161 A1 WO9902161 A1 WO 9902161A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydroxy
benzyl
methylendioxy
quinazoline
pyrimidin
Prior art date
Application number
PCT/EP1997/003617
Other languages
English (en)
Inventor
Wolf-Georg Forssmann
Christian Georg Stief
Michael Carsten Truss
Stefan Ückert
Udo Jonas
Original Assignee
Forssmann Wolf Georg
Christian Georg Stief
Michael Carsten Truss
Ueckert Stefan
Udo Jonas
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Forssmann Wolf Georg, Christian Georg Stief, Michael Carsten Truss, Ueckert Stefan, Udo Jonas filed Critical Forssmann Wolf Georg
Priority to CA002295616A priority Critical patent/CA2295616C/fr
Priority to PCT/EP1997/003617 priority patent/WO1999002161A1/fr
Priority to AU36210/97A priority patent/AU3621097A/en
Priority to US09/462,090 priority patent/US20020025969A1/en
Publication of WO1999002161A1 publication Critical patent/WO1999002161A1/fr
Priority to US10/443,870 priority patent/US8106061B2/en
Priority to US13/339,561 priority patent/US8791124B2/en

Links

Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine

Definitions

  • the prostate gland is an organ of about chest-nut size which in males surrounds the cervix of the vesical outlet. In 50% of the males in the age of above 50 years, a benign growth of the prostate gland occurs which may result in severe difficulties in the miction up to anuria and which is subject to treatment obligation. Most of the affected patients must be treated with surgical methods .
  • BPH benign prostatic hyperplasia
  • the glandular portions of the prostate gland increase by double their volume, and the muscular and fibrous portions increase by four times their volume (Christmas and Kirby, .J. Urol . 9: 36-40, 1991) . Since these muscle cells account for a large portion of the total prostatic tissue (at least 35%) , a distinct improvement of miction can be achieved by means of a pharmacologically induced relaxation of these muscle cells (Hedlund and Andersson, J. Urol. 130: 275-278, 1983) .
  • the substances used to date mostly belong to the group of alpha-receptor blockers (Lepor et al . , J. Urol.
  • the physiological transmission of information for the relaxation of smooth muscle cells is effected by messengers of the blood (hormones) or the nerves (neurotransmitters) . These messengers and neurotransmitters cause an increase in the levels of the cyclic nucleotides "cyclic adenosine monophosphate” (cAMP) and "cyclic guanosine monophosphate” (cGMP) in the smooth muscle cell, resulting in relaxation.
  • cAMP and cGMP themselves are hydrolized by phosphodiesterases (PDEs) . Inhibitors of the PDEs in turn reduce the digestion of cTAMP and cGMP, resulting in an increase of these molecules within the cell and thus in a relaxation of the smooth muscle cell .
  • PDEs phosphodiesterases
  • sPDE I, sPDE IV and sPDE V are of particular importance in human prostatic muscles : After performing Q-sepharose chromatography, there has been found a typical pattern of the human prostatic tissue showing the presence of the PDE isoforms I, IV and V (figure 1) . A well-aimed inhibition of these isoenzymes will result in relaxation of the prostatic muscles even when minute doses of a specific inhibitor are administered, with no appreciable effects in other organ strips, in particular vessels, being observed. Therefore, they have an excellent efficiency in the treatment of prostatic diseases .
  • the subject matter of the invention is the use of specific inhibitors of sPDE I, sPDE IV and sPDE V in the prophylaxis and treatment of prostatic diseases, in particular benign prostatic hyperplasia, the so-called urge symptoms, pollacuria (frequent micturition) , nycturia (nocturnal micturition) , weakened urine jet, urge incontinence (involuntary discharge of urine) , prostatism, instabilities of the bladder muscles, impotence, and the use of the inhibitors for the preparation of medicaments useful for this purpose as well as medicaments containing sPDE I, IV and V inhibitors for the objects mentioned.
  • Preferred selective inhibitors of PDE I, IV and V are: - (2-propoxyphenyl) -8-azapurin-6-one (zaprinast)
  • the pharmacologically compatible salts are obtained in a similar manner by neutralizing the bases with inorganic or organic acids.
  • inorganic acids there may be used, for example, hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid
  • organic acids for example, carboxylic, sulfo or sulfonic acids, such as acetic acid, tartaric acid, lactic acid, propionic acid, glycolic acid, malonic acid, maleinic acid, fumaric acid, tannic acid, succinic acid, alginic acid, benzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, cinnamic acid, mandelic acid, citric acid, malic acid, salicylic acid, 3-aminosalicylic acid, ascorbic acid, embonic acid, nicotinic acid, isonicotinic acid, oxalic acid, amino acids, methane- sulfonic acid, ethanesulf
  • an effective amount of the inhibitors of sPDE I, IV or V or of the salts thereof is used in addition to the usual excipients, vehicles and additives.
  • the dosage depends on the species, body weight, age, individual condition, and kind of administration .
  • Possible dosage forms are oral, intravenous, transdermal, subcutaneous and intravesicular formulations.
  • the latter are, in particular, those solutions and formulations which are also used for parenteral administration.
  • Formulations for parenteral administration will contain from 0.15 ⁇ g to 1 mg, preferably from 5 to 500 ⁇ g, of the compounds mentioned per unit dose and may be present in separate unit dose forms, such as ampoules or vials.
  • solutions of the active ingredient are used, more preferably aqueous solutions, and mainly isotonic solutions, but also suspensions.
  • injection forms may be provided as a ready preparation, or they may be formulated only immediately before use by admixing the active compound, for example, the lyophilizate, optionally together with other solid carriers, with the solvent or suspension medium desired.
  • galenic preparations such as tablets, coated tablets, capsules, dis- persible powders, granules, aqueous or oily suspensions, syrups, liquors or drops.
  • Solid preparations may contain inert excipients and vehicles, such as calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates, gelatin, guar gum, magnesium or aluminium stearate, methylcellulose, talcum, highly dispersed silicic acids, silicone oil, higher-molecular fatty acids (such as stearic acid) , agar-agar, or vegetable or animal fats and oils, solid high-molecular polymers (such as polyethylene glycol) ; formulations useful for oral administration may optionally contain additional flavoring and/or sweetening agents.
  • inert excipients and vehicles such as calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates,
  • Liquid preparations may be sterilized and/or may optionally contain additives, such as preservatives, stabilizers, wetting agents, penetration agents, emulsifiers, spreading agents, solubilizers, salts for adjusting the osmotic pressure or for buffering, and/or viscosity modifiers.
  • additives such as preservatives, stabilizers, wetting agents, penetration agents, emulsifiers, spreading agents, solubilizers, salts for adjusting the osmotic pressure or for buffering, and/or viscosity modifiers.
  • Such additives are, for instance, tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts) .
  • complexing agents such as ethylenediaminetetraacetic acid and its non-toxic salts
  • high-molecular polymers such as, for example, liquid polyethylene oxide, carboxymethylcelluloses, polyvinylpyrroli- dones, dextranes, or gelatin.
  • Solid vehicles are, for instance, starch, lactose, mannitol, methylcellulose, talcum, highly dispersed silicic acids, higher-molecular fatty acids (such as stearic acid) , gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high-molecular polymers (such as polyethylene glycol) .
  • Oily suspensions for parenteral or topical (in this case intra- vesicular) administrations may contain vegetable, synthetic or semisynthetic oils, such as, for instance, liquid fatty acid esters having from 8 to 22 carbon atoms in the fatty acid chains, for example, palmitic, lauric, tridecylic, margaric, stearic, arachic, myristic, behenic, pentadecylic, linolic, elaidic, brassidic, erucic or oleic acids, which may be esterified with monohydric to trihydric alcohols having from 1 to 6 carbon atoms, such as, for instance, methanol , ethanol, propanol , butanol, pentanol, or isomers thereof, glycol, or glycerol.
  • vegetable, synthetic or semisynthetic oils such as, for instance, liquid fatty acid esters having from 8 to 22 carbon atoms in the fatty acid chains, for
  • Such fatty acid esters are, for instance, commercially available miglyols, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG 6-caprylic acid, caprylates/caprates of saturated fatty alcohols, polyoxyethyleneglycerol trioleates, ethyl oleate, waxy fatty acid esters, such as synthetic duck uropygial fat, coconut oil fatty acid isopropyl ester, oleic acid oleyl ester, oleic acid decyl ester, lactic acid ethyl ester, dibutyl phthalate, adipic acid diisopropyl ester, polyol fatty acid ester, etc.
  • silicone oils of various viscosities or fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol or oleyl alcohol, fatty acids, such as oleic acid.
  • vegetable oils such as castor oil, almond oil, olive oil, sesame oil, cottonseed oil, peanut oil or soybean oil, may be used.
  • the materials mentioned have the additional property of a spreading agent, i.e. there will be a particularly good spreading on the skin.
  • solvents such as ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, polyethyleneglycols, phthalates, adipates, propylene glycol, glycerol, dipropylene or tripropylene glycol, waxes, methylcellosolve, cellosolve, esters, morpholines, dioxane, dimethylsulfoxide, dimethylformamide, tetrahydrofurane, cyclohexanone, etc.
  • alcohols for example, such as ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, polyethyleneglycols, phthalates, adipates, propylene glycol, glycerol, dipropylene or tripropylene glycol, waxes, methylcellosolve, cellosolve, esters, morpholines, dioxane, dimethylsulfoxide, dimethylformamide
  • cellulose ethers which can dissolve or swell both in water and in organic solvents and will form a kind of film after drying, such as hydroxypropyl - cellulose, methylcellulose, ethylcellulose, or soluble starches.
  • Mixed gelling and film-forming agents are also possible by all means.
  • ionic macromolecules such as sodium carboxymethylcellulose, polyacrylic acid, poly- methacrylic acid, and salts thereof, sodium amylopectine semi- glycolate, alginic acid or propylene glycol alginate as the sodium salt, gum arabic, xanthan gum, guar gum or carrageen.
  • glycerol paraffins having different viscosities
  • triethanolamine triethanolamine
  • collagen allantoin
  • novantisolic acid perfume oils
  • surfactants such as, for example, sodium lauryl sulfate, fatty alcohol ether sulfates, disodium N-lauryl ⁇ -iminodipropionate, polyoxyethylated castor oil, or sorbitan monooleate, sorbitan monostearate, cetyl alcohol, lecithin, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ether, cetyltrimethylammonium chloride, or monoalkyl/ dialkyl polyglycol ether ortho-phosphoric acid monoethanolamine salts .
  • surfactants such as, for example, sodium lauryl sulfate, fatty alcohol ether sulfates, disodium N-lauryl ⁇ -iminodipropionate, polyoxyethylated castor oil, or sorbitan monooleate, sorbitan monostearate, cetyl alcohol, lecithin, glycerol
  • Stabilizers such as montmorillonites or colloidal silicic acids, for the stabilization of emulsions or for preventing decomposition of active substances, such as antioxidants, for example, tocopherols or butylhydroxyanisol , or preservatives, such as p- hydroxybenzoic acid ester, may also be required for the preparation of the formulations desired.
  • active substances such as antioxidants, for example, tocopherols or butylhydroxyanisol
  • preservatives such as p- hydroxybenzoic acid ester
  • intravesicular formulations preferably contain highly compatible organic solvents, such as ethanol, methylpyrrolidone, polyethylene glycol, oleyl alcohol, octanol, linolic acid, triacetin, propylene glycol, glycerol, solketal, or dimethylsulfoxide .
  • highly compatible organic solvents such as ethanol, methylpyrrolidone, polyethylene glycol, oleyl alcohol, octanol, linolic acid, triacetin, propylene glycol, glycerol, solketal, or dimethylsulfoxide .
  • preparations filling and sealing of the preparations is done under the usual antimicrobial and aseptic conditions.
  • preparations are preferably packed in separate unit doses for easy handling, and if required for stability reasons, as with parenteral forms, also by separately packing the active ingredients or their combinations as lyophilizates, optionally with solid carriers, and the solvents required etc.
  • sildenafil Fifty milligrams of sildenafil is dissolved in distilled water together with 750 mg of NaCl, the pH is adjusted to 3.7 with 1 N HCl, distilled water is added to give a total of 100 ml, and the solution is packed in 0.5 ml ampoules.
  • sildenafil From 500 mg of sildenafil, 2 ml of isopropyl myristate and 10 ml of ethanol, a solution for topical administration is prepared and packed in unit doses of 2 ml each.
  • Human prostatic tissue freshly collected in the course of an operation is cut into small strips (about 3 x 3 x 6 mm) .
  • the latter are then installed in a bath containing a nutrient solution ensuring survival of the organic strips.
  • a measuring element By coupling the organic strips to a measuring element, length and force changes of the organic strip can be recorded, and thus actions of medicaments added to the organ bath nutrient solution can be examined through the length and force changes (increase or decrease) of the organic strip.
  • the organic strips are contracted with an appropriate standard medicament (e.g., carbachol) .
  • an inhibitor of a specific phosphodiesterase is now added in incremental dosage (10 ⁇ 8 , 10 "7 , 10 "6 etc.
  • Fresh tissue obtained during an operation is homogenized and then ultracentrifuged. Next, the supernatant is filtered, pipetted off and chromatographed.
  • the determination of sPDE is performed as described in M. Truss et al . : Urology 45(5): 893-901, 1995.
  • the determination of the amount of radioactivity permits to calculate the enzyme activity in pmol/ml x min.
  • a plot of the activity curve allows to identify fractions in which the phosphodiesterase activity is particularly high.
  • the phosphodiesterase activity of each peak exhibits a different composition with respect to the activity of the different substrates. This special composition of the phosphodiesterase activity allows for the assignment to a specific phosphodiesterase (sPDE) .
  • a substance is considered an inhibitor of an sPDE if the concentration thereof which is necessary for inhibiting 50% of the substrate hydrolysis (IC 50 ) is at least 20 times lower in the respective peak fraction containing the specific phosphodiesterase than in other peak fractions.
  • enzyme preparations are again prepared, as described above. Now, however, the compound to be tested is added prior to the incubation of the enzyme mixtures according to peak fractions. Then, renewed determination and plotting of the enzyme activity allows to identify a substance as being an inhibitor of the specific phosphodiesterase according to the above-mentioned definition.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation d'inhibiteurs de la phosphordiestérase I, IV et V pour la prévention et le traitement de maladies de la prostate, plus particulièrement l'utilisation de a) 2- (2-propoxy-phényl)-8-azapurin-6-one (zaprinast); b) dipyridamole; c) 1-(3-chlorophénylamino)-4-phénylphtalazine (M5445); d) 2-(N-(4-carboxypipéridine-6-chloro-4-(3,4-(méthylène-dioxy)benzyl)amino)qinazoline (E 4021, ER 21355); e) 2,3-dihydro-8- hydroxy-7-nitro-1, 4-benzodioxine-2-méthanol, alpha-nitrate (E 4701); f) 4-((3,4-(méthylènedioxy) benzyl)amino)-6, 7,8-triméthoxy-quinazoline; g) 1-méthyl-3-propyl-6- (5-(N-(4-méthylmorpholino) sulfonyl)-2-éthoxyphényl)pyrazole [4,5]pyrimidine-4(5H)one (sildenafil); i) 1-cyclopentyl-3-méthyl-6- (4-pyridinyl)pyrazolo (3, 4-d)pyrimidine-4(5H)one (WIN 58237); j) 7-(3-(4-acétyl-3- hydroxy-2-propyl-phénoxy) -2-hydroxy-propoxy)-2-carboxy-2, 3-didéhydro-chromane-4-one (FPL-557212); k) quinazolines et leur dérivés triméthoxy; l) pyrazolopyrimidones; ainsi que leurs sels pharmaceutiquement compatibles, des quinazolines et leur dérivés triméthoxy, des pyrazolopyrimidones ou leurs sels compatibles pour une administration locale et par voie générale.
PCT/EP1997/003617 1997-07-09 1997-07-09 Utilisation d'inhibiteurs de la phosphordiesterase dans le traitement de maladies de la prostate WO1999002161A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
CA002295616A CA2295616C (fr) 1997-07-09 1997-07-09 Utilisation d'inhibiteurs de la phosphodiesterase dans le traitement de maladies de la prostate
PCT/EP1997/003617 WO1999002161A1 (fr) 1997-07-09 1997-07-09 Utilisation d'inhibiteurs de la phosphordiesterase dans le traitement de maladies de la prostate
AU36210/97A AU3621097A (en) 1997-07-09 1997-07-09 Use of phosphordiesterase inhibitors in the treatment of prostatic diseases
US09/462,090 US20020025969A1 (en) 1997-07-09 1997-07-09 Use of phosphordiesterase inhibitors in the treatment of prostatic diseases
US10/443,870 US8106061B2 (en) 1997-07-09 2003-05-23 Use of phosphodiesterase inhibitors in the treatment of prostatic diseases
US13/339,561 US8791124B2 (en) 1997-07-09 2011-12-29 Use of phosphordiesterase inhibitors in the treatment of prostatic diseases

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP1997/003617 WO1999002161A1 (fr) 1997-07-09 1997-07-09 Utilisation d'inhibiteurs de la phosphordiesterase dans le traitement de maladies de la prostate

Related Child Applications (3)

Application Number Title Priority Date Filing Date
US09462090 A-371-Of-International 1997-07-09
US09/462,090 A-371-Of-International US20020025969A1 (en) 1997-07-09 1997-07-09 Use of phosphordiesterase inhibitors in the treatment of prostatic diseases
US10/443,870 Continuation US8106061B2 (en) 1997-07-09 2003-05-23 Use of phosphodiesterase inhibitors in the treatment of prostatic diseases

Publications (1)

Publication Number Publication Date
WO1999002161A1 true WO1999002161A1 (fr) 1999-01-21

Family

ID=8166680

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1997/003617 WO1999002161A1 (fr) 1997-07-09 1997-07-09 Utilisation d'inhibiteurs de la phosphordiesterase dans le traitement de maladies de la prostate

Country Status (3)

Country Link
AU (1) AU3621097A (fr)
CA (1) CA2295616C (fr)
WO (1) WO1999002161A1 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999066933A1 (fr) * 1998-06-25 1999-12-29 New Millennium Pharmaceutical Research, Inc. Traitement de la dyserection par administration de sildenafil par voie nasale
WO2000007597A1 (fr) * 1998-07-31 2000-02-17 Hexal Ag Systeme de traitement transmuqueux pour l'utilisation de sildenafil
EP1020190A3 (fr) * 1998-10-21 2000-10-25 Pfizer Products Inc. Traitement de l' hyperplasie prostatique benigne avec des élévateurs du cGMP
WO2001005386A3 (fr) * 1999-07-15 2001-07-19 Shmuel Simon Composition pharmaceutique utile dans le traitement de bourdonnement d'oreilles et de surdite
WO2003051346A3 (fr) * 2001-12-17 2004-02-12 Altana Pharma Ag Nouvelle utilisation d'inhibiteurs de pde5
FR2845993A1 (fr) * 2002-10-16 2004-04-23 Univ Pasteur Composes pharmaceutiques inhibiteurs specifiques de la pde5 du muscle lisse, compositions pharmaceutiques les contenant et utilisations therapeutiques
US6828473B2 (en) 2000-11-01 2004-12-07 Pfizer Inc. Modulation of PDE11A activity
WO2005077374A1 (fr) * 2004-02-06 2005-08-25 Becton, Dickinson And Company Formulations d'inhibiteurs de la phosphodiesterase 5 et procedes d'utilisation
WO2007047282A1 (fr) * 2005-10-12 2007-04-26 Lilly Icos Llc Traitement d'une hypertrophie benigne de la prostate et de symptomes dans les voies urinaires inferieures
WO2007072169A3 (fr) * 2005-12-20 2007-11-01 Pfizer Prod Inc Combinaison pharmaceutique utilisee pour traiter des troubles urinaires du bas appareil (tuba)
WO2013057205A1 (fr) 2011-10-20 2013-04-25 Technische Universitaet Wien Dérivés de diazabicycloalcane et de diazaspiroalcane comme inhibiteurs de la phosphodiestérase-5

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19540642A1 (de) * 1995-11-01 1997-05-07 Stief Christian Georg Priv Doz Verwendung von Inhibitoren der Phosphodiesterase bei der Behandlung von Prostataerkrankungen

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19540642A1 (de) * 1995-11-01 1997-05-07 Stief Christian Georg Priv Doz Verwendung von Inhibitoren der Phosphodiesterase bei der Behandlung von Prostataerkrankungen

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999066933A1 (fr) * 1998-06-25 1999-12-29 New Millennium Pharmaceutical Research, Inc. Traitement de la dyserection par administration de sildenafil par voie nasale
US6200591B1 (en) 1998-06-25 2001-03-13 Anwar A. Hussain Method of administration of sildenafil to produce instantaneous response for the treatment of erectile dysfunction
WO2000007597A1 (fr) * 1998-07-31 2000-02-17 Hexal Ag Systeme de traitement transmuqueux pour l'utilisation de sildenafil
EP1020190A3 (fr) * 1998-10-21 2000-10-25 Pfizer Products Inc. Traitement de l' hyperplasie prostatique benigne avec des élévateurs du cGMP
US6693107B1 (en) 1999-07-15 2004-02-17 Shmuel Simon Pharmaceutical composition useful for the treatment of tinnitus and hearing loss
WO2001005386A3 (fr) * 1999-07-15 2001-07-19 Shmuel Simon Composition pharmaceutique utile dans le traitement de bourdonnement d'oreilles et de surdite
US6828473B2 (en) 2000-11-01 2004-12-07 Pfizer Inc. Modulation of PDE11A activity
WO2003051346A3 (fr) * 2001-12-17 2004-02-12 Altana Pharma Ag Nouvelle utilisation d'inhibiteurs de pde5
FR2845993A1 (fr) * 2002-10-16 2004-04-23 Univ Pasteur Composes pharmaceutiques inhibiteurs specifiques de la pde5 du muscle lisse, compositions pharmaceutiques les contenant et utilisations therapeutiques
WO2004035584A1 (fr) * 2002-10-16 2004-04-29 Universite Louis Pasteur Composes pharmaceutiques inhibiteurs specifiques de la pde5 du muscle lisse, compositions pharmaceutiques les contenant et utilisations therapeutiques
WO2005077374A1 (fr) * 2004-02-06 2005-08-25 Becton, Dickinson And Company Formulations d'inhibiteurs de la phosphodiesterase 5 et procedes d'utilisation
WO2007047282A1 (fr) * 2005-10-12 2007-04-26 Lilly Icos Llc Traitement d'une hypertrophie benigne de la prostate et de symptomes dans les voies urinaires inferieures
WO2007072169A3 (fr) * 2005-12-20 2007-11-01 Pfizer Prod Inc Combinaison pharmaceutique utilisee pour traiter des troubles urinaires du bas appareil (tuba)
WO2013057205A1 (fr) 2011-10-20 2013-04-25 Technische Universitaet Wien Dérivés de diazabicycloalcane et de diazaspiroalcane comme inhibiteurs de la phosphodiestérase-5

Also Published As

Publication number Publication date
AU3621097A (en) 1999-02-08
CA2295616C (fr) 2009-05-12
CA2295616A1 (fr) 1999-01-21

Similar Documents

Publication Publication Date Title
US6395736B1 (en) Compositions and methods for the treatment of anorectal disorders
US6083483A (en) Inhibitors of phosphodiesterase IV for x-ray imaging
US8791124B2 (en) Use of phosphordiesterase inhibitors in the treatment of prostatic diseases
US6423719B1 (en) Method for treating benign prostate hyperplasia
CA2295616C (fr) Utilisation d'inhibiteurs de la phosphodiesterase dans le traitement de maladies de la prostate
TW200401650A (en) Pharmaceutical composition for the treatment of radiation-induced skin damage
US5891904A (en) Use of inhibitors of phosphodiesterase IV
PT2035006E (pt) Utilização de alopurinol para o tratamento da eritrodisestesia palmo-plantar
ES2312588T3 (es) Regulacion de la secrecion del jugo pancreatico que comprende un agente de regulacion del receptor del lpa.
JPH11279080A (ja) 傷痕を少なくするための組成物
DE19540642A1 (de) Verwendung von Inhibitoren der Phosphodiesterase bei der Behandlung von Prostataerkrankungen
WO1997005876A9 (fr) Utilisation d'inhibiteurs de la phosphodiesterase dans la fabrication de medicaments pour le traitement des maladies de la vessie
EP0843553A1 (fr) Utilisation d'inhibiteurs de la phosphodiesterase dans la fabrication de medicaments pour le traitement des maladies de la vessie
CN101460172B (zh) 别嘌醇在制备治疗手足综合征的药物中的用途
KR100863758B1 (ko) 항문직장 장애의 치료 조성물 및 방법
AU774064B2 (en) Compositions and methods for the treatment of anorectal disorders
CN1205634A (zh) 磷酸二酯酶抑制剂在制备用于治疗膀胱疾病的药物中的应用
EP4232002A1 (fr) Traitement transdermique pour le dysfonctionnement érectile
CA2009402A1 (fr) Utilisation de la benzydamine et de ses sels pour le soulagement de la douleur associee aux infections herpetiques et vaporisation au laser des condylomes
CN116490187A (zh) 用于癌症治疗的激酶抑制剂组合
Terranova et al. Local anesthesia
MXPA01005733A (en) Compositions and methods for the treatment of anorectal disorders
ZA200104778B (en) Compositions and methods for the treatment of anorectal disorders.

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA US

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
ENP Entry into the national phase

Ref document number: 2295616

Country of ref document: CA

Ref country code: CA

Ref document number: 2295616

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 09462090

Country of ref document: US

DPE2 Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101)