WO2002002118A1 - Traitement des maladies vasculaires peripheriques, des neuropathies du systeme nerveux peripheriques et des neuropathies du systeme nerveux autonome - Google Patents

Traitement des maladies vasculaires peripheriques, des neuropathies du systeme nerveux peripheriques et des neuropathies du systeme nerveux autonome Download PDF

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Publication number
WO2002002118A1
WO2002002118A1 PCT/US2001/041202 US0141202W WO0202118A1 WO 2002002118 A1 WO2002002118 A1 WO 2002002118A1 US 0141202 W US0141202 W US 0141202W WO 0202118 A1 WO0202118 A1 WO 0202118A1
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WO
WIPO (PCT)
Prior art keywords
patient
neuropathies
treating
disease
peripheral
Prior art date
Application number
PCT/US2001/041202
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English (en)
Inventor
Ralph E. Wood
Original Assignee
Wood Ralph E
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 Wood Ralph E filed Critical Wood Ralph E
Priority to IL15342601A priority Critical patent/IL153426A0/xx
Priority to BR0112100-6A priority patent/BR0112100A/pt
Priority to MXPA03000033A priority patent/MXPA03000033A/es
Priority to NZ523108A priority patent/NZ523108A/en
Priority to EP01957540A priority patent/EP1303279A1/fr
Priority to AU2001279275A priority patent/AU2001279275A1/en
Priority to HU0301451A priority patent/HUP0301451A3/hu
Priority to JP2002506740A priority patent/JP2004511433A/ja
Priority to PL01365565A priority patent/PL365565A1/xx
Priority to CA002414352A priority patent/CA2414352A1/fr
Publication of WO2002002118A1 publication Critical patent/WO2002002118A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications

Definitions

  • This invention relates to the use of cyclic guanosine 3', 5'-monophosphate type five (cGMP PDE5) inhibitors, including the compound sildenafil, for the treatment of disease related to peripheral vascular diseases, peripheral neuropathies, autonomic neuropathies, particularly the diseases which are related to diabetes.
  • cGMP PDE5 cyclic guanosine 3', 5'-monophosphate type five
  • Diabetes mellitus is a serious and widespread chronic disease. Studies predict that the 1996 global diabetes prevalence of 120 million should more than double to 250 million by the year 2025, primarily due to increasing age, obesity, sedentary lifestyles, and changing dietary patterns. Many serious and costly complications affect individuals suffering from diabetes mellitus, including heart disease, kidney failure, and blindness. Nevertheless, foot complications by far take the greatest toll. It is believed that 40-70% of all lower extremity amputations are related to diabetes mellitus. Additionally, approximately 85% of all diabetes-related lower extremity amputations are preceded by a foot ulcer.
  • diabetes mellitus Patients with diabetes mellitus are at increased risk of developing one or more foot ulcers as a result of established long-term complications of the disease, which include impaired nerve function (neuropathy) and/or ischemia.
  • impaired nerve function neuroopathy
  • ischemia ischemia
  • Neuropathy is yet another major complication of diabetes mellitus. No well- established treatments exist for either its symptomatic treatment or for prevention of progressive decline in nerve function. Estimates of the prevalence of neuropathy in diabetes vary widely, from a low of 5% to a high of 80%, largely due to the numerous definitions and clinical descriptions of neuropathy. Nevertheless, the additive effects of neuropathy in the suffering diabetic patient are well known and documented
  • the effect of the neuropathy is complex.
  • the loss of sensory information from the foot is related to abnormal and prolonged pressure on the areas of the foot (sensory neuropathy).
  • Motor neuropathy leads to deformity, further increasing pressure loading on the foot.
  • autonomic neuropathy loss of innervation of the sweat glands results in dry skin which cracks creating an environment amenable to infection.
  • Autonomic dysfunction contributes further by altering the distribution of micro-circulatory blood flow, directing the blood flow through shunts and away from the nutritive skin capillaries.
  • NO nitric oxide
  • cGMP cyclic guanosine monophosphate
  • cGMP PDE5 inhibitors such as sildenafil citrate
  • PDE5 competitive, potent, and selective inhibitors of cGMP-specific phosphodiesterase
  • Such inhibitor compounds therefore, increase intracellular concentrations of nitric-oxide derived cGMP, thereby enhancing the effect of NO, which is responsible for the efficacy of sildenafil in the treatment of male erectile dysfunction.
  • cGMP PDE5 inhibitor or a pharmaceutical composition thereof, also may be used in combination with other therapeutic agents or treatments that are now or may later be useful in the treatment of the above-mentioned disease states.
  • the present invention also provides for the use of a cGMP PDE5 inhibitor for the manufacture of a composition for the treatment of diabetic ulcers. It is also within the concept of this invention to treat peripheral vascular diseases such as Raynaud's Phenomenon, including CREST syndrome, autoimmune diseases such as systemic lupus erythematosis, rheumatoid diseases and diabetic retinopathies.
  • peripheral vascular diseases such as Raynaud's Phenomenon, including CREST syndrome, autoimmune diseases such as systemic lupus erythematosis, rheumatoid diseases and diabetic retinopathies.
  • the present invention would also be beneficial in peripheral and autonomic neuropathies or any other disease entity, that results from small vessel disease and directly large vessel disease.
  • Another object of this invention is the treatment of onychiomycosis (fungal) infection of the nailbed).
  • cGMP PDE5 inhibitors A number of potent and selective cGMP PDE5 inhibitors are now known and their activity can be determined readily by in- vitro screening against cGMP PDE enzymes from a number of sources, in accordance with published procedures.
  • a number of pyrazolopyrimidinone compounds are described as cGMP PDE5 inhibitors in EPO 0463756, EPO 0526004, WO 93/12095, WO 94/05661, WO 94/00453, WO 95/19978 and WO 98/49166, the complete disclosures of which are fully incorporated herein by reference.
  • Some cGMP-PDE5 inhibitors which can be used in the present invention include, for example, 5-(2-ethoxy-5-mo holinoacetylphenyl)-l-methyl-3-n-propyl-l- 6-dihydro-7H-20 pyrazolo[4, 3-d]pyrimidin-7-one; 5-(5-morpholinoacetyl-2-n- propoxyphenyl)-l-methyl-3-n-propyl-l-,6-dihydro-7H pyrazolo[4,3-d]pyrimidin- 7-one; 5-[2-ethoxy-5-(4-methyl- 1 -piperazin- 1 -yl-sulphonyl)-phenyl]- 1 ,6- dihydro-l-methyl-3 propylpyrazolo[4, 3-d]pyrimidin-7-one; 5-[2-allyloxy-5- (4-methyl-l-piperazinlysulphonyl)-phenyl]-l-methyl-3-n
  • the inventor has determined that the preferred compound, 5-[2-ethoxy-5-(4-methylpiperazin 1-yl sulphonyl)-phenyl]-l, 6-dihydro-l -methyl-3 -propylpyrazolo [4,3-d] pyrimidine-7-one (sildenafil), and pharmaceutically acceptable salts thereof; including the citrate salt, has been very effective in the treatment of foot ulcers related to diabetes.
  • cycli guanosine 3', 5'-monophosphate type five (cGMP PDE5) inhibitors including the compound sildenafil, for which we have shown is effective in the treatment of diabetic foot ulcers
  • cGMP PDE5 inhibitors including the compound sildenafil
  • the treatment of the present invention would also be beneficial in peripheral and autonomic neuropathies or any other disease entity that results from small vessel disease and directly large vessel disease.
  • onychiomycosis (fungal infection of the nailbed) particularly of the lower extremity has resolved completely without the use of antifungal medication when treated exclusively with sildenafil.
  • the patient in this case was requesting treatment for erectile dysfunction and again the inventor discovered this unexpected beneficial result.
  • the inventor has observed such results in varied diseases which have the common element of peripheral vascular disease or peripheral neuropathy.
  • the beneficial effect of the method is believed to be due to increase vascular flow of the small vessels which aided the body in healing itself.
  • Patient #1 is an insulin dependent diabetic who had been suffering from erectile dysfunction and who subsequently had a diabetic foot ulcer.
  • the foot ulcer was healing.
  • This foot ulcer began approximately two years prior and the patient had been through vascular studies, had seen vascular surgeons, podiatrists, and had been in wound care clinics with minimal results at best. He had also been hospitalized for approximately a month on IV antibiotics, etc. and the threat was very real that the patient was going to require a below the knee amputation.
  • the ulcer would appear to be healing at times only to reoccur to its pretreatment size and depth.
  • sildenafil treatment had began for his erectile dysfunction, it was noted that the ulcer was decreasing in the size and the patient was instructed to begin taking 50 mg of sildenafil once a day. This resulted in complete resolution of the diabetic food ulcer in one month and the patient has continued on this same treatment for the past two years without reoccurrence.
  • Patient #2 was suffering from chronic changes of both lower extremities secondary to peripheral vascular disease and diabetes mellitus. He was being followed for his diabetes mellitus and stated he was having trouble with erectile dysfunction and once sildenafil treatment was instituted, not only did his erectile dysfunction significantly improve but the chronic changes of both lower extremities secondary to the peripheral vascular disease also significantly improved or resolved completely.
  • Patient #3 suffers from severe peripheral vascular disease secondary to arteriosclerosic. Conventional treatments such as femoral popliteal bypass surgery, surgical insertion of (Greenfield filter) thrombotic preventive umbrella, administration of heparin and administration of coumadin have all failed to alleviate the condition.
  • Sildenafil has been prescribed for erectile dysfunction and the patient is being closely followed to monitor improvements in the arteriosclerosic condition.
  • Patient #4 suffered from erectile dysfunction. He also suffered from onychiomycosis (fungal infection of the nailbed). He was placed on sildenafil treatment taking one 50 mg pill on an as-needed basis. On that treatment schedule his erectile dysfimction improved and surprisingly his fungal infection was cured.
  • the cGMP PDE5 inhibitor is preferably administered as a pharmaceutical composition.
  • the compound can be administered in any conventional oral, parenteral, rectal, or transdermal dosage form, usually with a pharmaceutically acceptable carrier or diluent.
  • a pharmaceutically acceptable carrier or diluent usually with a pharmaceutically acceptable carrier or diluent.
  • Oral administration of a pharmaceutical composition may be in the form of a solution, suspension, tablet, pill, capsule, powder or the like.
  • Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate are used in conjunction with various disintegrants, such as potato or tapioca starch, and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin, and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate, and talc are often used for tabletting purposes.
  • Solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules; preferred materials in this connection also include lactose or milk sugar, as well as high molecular weight polyethylene glycols.
  • the compounds can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and/or suspending agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various similar combinations thereof. It is also within the concept of the present invention to administer the effective compound in admixture with a foodstuff or drink.
  • solutions in oil or in aqueous propylene glycol can be employed, as well as sterile aqueous solutions of the corresponding water-soluble salts.
  • aqueous solutions may be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes.
  • the sterile aqueous media employed are all readily obtainable by standard techniques, which are well-known to those skilled in the art.
  • transdermal e.g., topical
  • dilute sterile, aqueous or partially aqueous solutions are prepared.
  • Transdermal administration of compounds for therapeutic purposes is increasingly becoming a common practice, as in the case of nicotine patches or motion sickness preventatives.
  • the transdermal application of relatively large molecules, such as those contained in compositions of antigens and adjuvants has been shown to be effective as described in U.S. Patent 5,910,306 and U.S. Patent 5,980,898, the complete disclosures of which are fully incorporated herein by reference.
  • Transdermal application can be accomplished by direct application to the skin, in admixture with a carrier, such as for example a salve or cream, or as covered by or applied to a patch, which is placed on the skin of the patient.
  • cGMP PDE5 inhibitor administered in a range of from 0.5 to 400 mg per day, as disclosed in disclosed in U.S. Patent nos.
  • an effective dose is 5 to 125 mg per day, more preferably 10-110 mg per day and most preferably 25-100 mg per day, which can be administered as a tablet or capsule up to three times a day.
  • the precise dosage will be as determined by the prescribing physician and will depend on the age and weight of the patient and severity of the symptoms, as described above.
  • an effective dosage of the compound of the present invention can also provide a prophylactic to assist in the prevention of foot ulcers in a patient suffering from the disease diabetes.
  • the skilled practitioner can prescribe an effective dosage of the compound using the dosages disclosed above and tailored to the specific needs of the patient being treated.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Cardiology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Ophthalmology & Optometry (AREA)
  • Oncology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Communicable Diseases (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne une méthode de traitement destinée à un patient souffrant d'une maladie vasculaire périphérique, de neuropathies du système nerveux périphérique ou de neuropathies du système nerveux autonome, comprenant l'administration d'un inhibiteur de cGMP PDE5 tel que le sildenafil. Cette méthode convient particulièrement pour les patients souffrant d'un ulcère diabétique du pied, d'un syndrome de Raynaud, d'un syndrome Crest, d'une érythromatose, de maladies rhumatoïdes, de rétinopathies diabétiques et d'onychomycoses. L'invention concerne également l'administration d'un inhibiteur de cGMP PDE5 en tant qu'agent de prévention à des patients présentant une prédisposition à une maladie vasculaire périphérique, une neuropathie périphérique ou une neuropathie du système nerveux autonome.
PCT/US2001/041202 2000-06-30 2001-06-29 Traitement des maladies vasculaires peripheriques, des neuropathies du systeme nerveux peripheriques et des neuropathies du systeme nerveux autonome WO2002002118A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
IL15342601A IL153426A0 (en) 2000-06-30 2001-06-29 Method of treating peripheral vascular diseases, peripheral neuropathies, and autonomic neuropathies
BR0112100-6A BR0112100A (pt) 2000-06-30 2001-06-29 Método de tratamento de doenças vasculares periféricas, neuropatias periféricas e neuropatias autonÈmicas
MXPA03000033A MXPA03000033A (es) 2000-06-30 2001-06-29 Procedimiento de tratamiento de enfermedades vasculares perifericas, neuropatias perifericas y neuropatias autonomicas.
NZ523108A NZ523108A (en) 2000-06-30 2001-06-29 Method of treating diabetic complications i.e. peripheral vascular diseases, peripheral neuropathies, and autonomic neuropathies with cGMP PDE5 inhibitors such as sildenafil
EP01957540A EP1303279A1 (fr) 2000-06-30 2001-06-29 Traitement des maladies vasculaires peripheriques, des neuropathies du systeme nerveux peripheriques et des neuropathies du systeme nerveux autonome
AU2001279275A AU2001279275A1 (en) 2000-06-30 2001-06-29 Method of treating peripheral vascular diseases, peripheral neuropathies, and autonomic neuropathies
HU0301451A HUP0301451A3 (en) 2000-06-30 2001-06-29 Use of cgmp pde5 inhibitors for the preparation of pharmaceutical compositions treating peripheral vascular diseases, peripheral neuropathies and autonomic neuropathies
JP2002506740A JP2004511433A (ja) 2000-06-30 2001-06-29 末梢血管疾患、末梢ニューロパシー、及び自律性ニューロパシーの処置方法
PL01365565A PL365565A1 (en) 2000-06-30 2001-06-29 Method of treating peripheral vascular diseases, peripheral neuropathies, and autonomic neuropathies
CA002414352A CA2414352A1 (fr) 2000-06-30 2001-06-29 Traitement des maladies vasculaires peripheriques, des neuropathies du systeme nerveux peripheriques et des neuropathies du systeme nerveux autonome

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US21506500P 2000-06-30 2000-06-30
US60/215,065 2000-06-30
US21902900P 2000-07-18 2000-07-18
US60/219,029 2000-07-18

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US10/311,907 A-371-Of-International US20030105108A1 (en) 2000-06-30 2001-06-29 Method of treating peripheral vascular diseases, peripheral neuropathies, and autonomic neuropathies
US10/798,135 Continuation US20040176387A1 (en) 2000-06-30 2004-03-10 Method of treating peripheral vascular diseases, peripheral neuropathies, and autonomic neuropathies

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WO2002002118A1 true WO2002002118A1 (fr) 2002-01-10

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PCT/US2001/041202 WO2002002118A1 (fr) 2000-06-30 2001-06-29 Traitement des maladies vasculaires peripheriques, des neuropathies du systeme nerveux peripheriques et des neuropathies du systeme nerveux autonome

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EP (1) EP1303279A1 (fr)
JP (1) JP2004511433A (fr)
KR (1) KR20030047907A (fr)
CN (1) CN1440287A (fr)
AU (1) AU2001279275A1 (fr)
BR (1) BR0112100A (fr)
CA (1) CA2414352A1 (fr)
HU (1) HUP0301451A3 (fr)
IL (1) IL153426A0 (fr)
MX (1) MXPA03000033A (fr)
NZ (1) NZ523108A (fr)
PL (1) PL365565A1 (fr)
WO (1) WO2002002118A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002015893A2 (fr) * 2000-08-21 2002-02-28 Pfizer Limited Traitement de blessures
WO2004082667A1 (fr) * 2003-03-17 2004-09-30 Pfizer Products Inc. Traitement du diabete insulino-dependant a l'aide d'inhibiteurs de pde5
EP1838319A2 (fr) * 2005-01-07 2007-10-03 The Johns Hopkins University Compositions d'inhibiteur des pde5 et procedes pour l'immunotherapie
US8133903B2 (en) 2003-10-21 2012-03-13 Los Angeles Biomedical Research Institute at Harbor—UCLA Medical Center Methods of use of inhibitors of phosphodiesterases and modulators of nitric oxide, reactive oxygen species, and metalloproteinases in the treatment of peyronie's disease, arteriosclerosis and other fibrotic diseases
EP3727366A4 (fr) * 2017-12-19 2021-04-21 Malesil Research & Technology Llc Méthode pour le traitement des ulceres du pied diabétique

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2877013A1 (fr) * 2004-10-27 2006-04-28 Assist Publ Hopitaux De Paris Indentification d'une mutation de jak2 impliquee dans la polyglobulie de vaquez

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6043252A (en) * 1997-05-05 2000-03-28 Icos Corporation Carboline derivatives
US6075028A (en) * 1999-09-23 2000-06-13 Graham; Richard Method of treating Tourette's syndrome and related CNS disorders

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6043252A (en) * 1997-05-05 2000-03-28 Icos Corporation Carboline derivatives
US6075028A (en) * 1999-09-23 2000-06-13 Graham; Richard Method of treating Tourette's syndrome and related CNS disorders

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002015893A2 (fr) * 2000-08-21 2002-02-28 Pfizer Limited Traitement de blessures
WO2002015893A3 (fr) * 2000-08-21 2003-03-13 Pfizer Ltd Traitement de blessures
WO2004082667A1 (fr) * 2003-03-17 2004-09-30 Pfizer Products Inc. Traitement du diabete insulino-dependant a l'aide d'inhibiteurs de pde5
US8133903B2 (en) 2003-10-21 2012-03-13 Los Angeles Biomedical Research Institute at Harbor—UCLA Medical Center Methods of use of inhibitors of phosphodiesterases and modulators of nitric oxide, reactive oxygen species, and metalloproteinases in the treatment of peyronie's disease, arteriosclerosis and other fibrotic diseases
EP1838319A2 (fr) * 2005-01-07 2007-10-03 The Johns Hopkins University Compositions d'inhibiteur des pde5 et procedes pour l'immunotherapie
EP1838319A4 (fr) * 2005-01-07 2009-12-09 Univ Johns Hopkins Compositions d'inhibiteur des pde5 et procedes pour l'immunotherapie
EP3727366A4 (fr) * 2017-12-19 2021-04-21 Malesil Research & Technology Llc Méthode pour le traitement des ulceres du pied diabétique

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Publication number Publication date
HUP0301451A3 (en) 2004-10-28
NZ523108A (en) 2005-04-29
IL153426A0 (en) 2003-07-06
CA2414352A1 (fr) 2002-01-10
BR0112100A (pt) 2003-05-20
AU2001279275A1 (en) 2002-01-14
KR20030047907A (ko) 2003-06-18
MXPA03000033A (es) 2003-09-25
JP2004511433A (ja) 2004-04-15
PL365565A1 (en) 2005-01-10
HUP0301451A2 (hu) 2003-09-29
CN1440287A (zh) 2003-09-03
EP1303279A1 (fr) 2003-04-23

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