WO2000035431A2 - Treatment of erectile dysfunction in diabetes patients - Google Patents
Treatment of erectile dysfunction in diabetes patients Download PDFInfo
- Publication number
- WO2000035431A2 WO2000035431A2 PCT/GB1999/004095 GB9904095W WO0035431A2 WO 2000035431 A2 WO2000035431 A2 WO 2000035431A2 GB 9904095 W GB9904095 W GB 9904095W WO 0035431 A2 WO0035431 A2 WO 0035431A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- diabetic
- nitrergic
- synthase
- inhibitor
- rats
- Prior art date
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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
-
- 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
-
- 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
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
- A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Definitions
- the present invention relates to the prevention or reduction of nitrergic nerve degeneration in diabetic mammals and in particular to the prevention of erectile dysfunction in male diabetic mammals.
- Erectile dysfunction is a common problem among diabetic men, particularly those suffering from diabetes mellitus. The likelihood of erectile dysfunction developing and the severity of the dysfunction both increase with the duration of diabetes.
- penile prostheses are available to assist such patients in achievement of an erection and the short term success rate is good. However, such treatment often leads to problems with infection and ischaemia and alternative treatments are therefore required.
- nitric oxide NO
- Andersson et al Phyisol. Rev. 75, 191-235 (1995).
- NOS nitric oxide synthase
- both NO itself and activators of NOS may be suitable candidates for therapeutic treatment of erectile dysfunction.
- erectile dysfunction in diabetics is due to selective degeneration in the nitrergic nerves innervating the penis.
- NO itself is responsible for the degeneration of the relevant nitrergic nerves in diabetic men.
- the present invention provides the use of a pharmaceutically acceptable inhibitor of NO synthase in the manufacture of a medicament for use in preventing or reducing degeneration of nitrergic nerves in a preventing or reducing degeneration of nitrergic nerves in a diabetic mammal.
- Also provided is a method of preventing or reducing degeneration of nitrergic nerves in a diabetic mammal which method comprises the administration to the said mammal of an effective amount of a pharmaceutically acceptable inhibitor of NO synthase. Typically, a safe and effective amount is administered.
- an agent for the prevention or reduction of degeneration of nitrergic nerves in a diabetic mammal comprising a pharmaceutically acceptable inhibitor of NO synthase.
- the mammal is suffering from diabetes mellitus.
- the present invention is particularly suitable for preventing or reducing degeneration of nitrergic nerves containing neuronal NO synthase.
- the cytotoxic effect of NO on nitrergic nerves in diabetics may be due to overproduction of NO, leading to overstimulation and thus degeneration of nitrergic nerves. It may also be due to an alteration in endogenous anti-oxidant mechanisms which could render nitrergic nerves prone to the cytotoxic effects of NO.
- the said diabetic mammal is preferably a human.
- the said medicament or said agent is for use, or the said method is effective, in preventing erectile dysfunction in a male mammal.
- Erectile dysfunction may be defined as an inability to obtain or sustain an erection adequate for intercourse.
- a reduction of nitrergic nerve degeneration is achieved by application of an NO synthase inhibitor if subsequent degeneration occurs to a lesser extent than if the NO synthase inhibitor had not been applied.
- substantially no degeneration takes place during treatment with the NO synthase inhibitor.
- degeneration of nitrergic nerves includes any morphological or functional impairment.
- nitrergic nerves is intended to include any nerves whose transmitter function depends on the release of NO.
- the said medicament or said agent is for use, or the said method is effective, in preventing or reducing degeneration of the nitrergic nerves innervating the genitals of a male or female mammal.
- Any pharmaceutically acceptable inhibitor of NO synthase can be used in the present invention.
- Competitive, non-competitive, reversible and irreversible inhibitors are suitable.
- the inhibitor may inhibit iNOS, eNOS and/or nNOS. Preferably, it inhibits eNOS and/or nNOS.
- Suitable inhibitors include L-arginine analogues, thiocitrullines, indazole derivatives, imidazole derivatives, hydrazine derivatives, thioureas, thiazoles, biotin derivatives and phenyl-substituted thiopene amidines.
- L-arginine analogues examples include methyl-L-arginine, N G - nitro-L-arginine methyl esther (L-NAME), N G -monomethyl-L-arginine (L-NMMA), N G -amino-L-arginine (L-NAA), N w ,N w -dimethyl-L-arginine ( ADMA), N W ,N* 2 - dimethyl-L-arginine (SDMA), N ⁇ efhyl-L-arginine (L-NEA), N w -methyl-L- homoarginine (L-NMHA), N -nitro-L-arginine (L-NOARG), N ⁇ -iminoethyl-L- ornithine (L-NIO), N ⁇ -iminoethyl-L-lysine (L-homo-NIO) and L-canavanine (L- CAN).
- suitable thiocit examples
- SMTC L-thiocitrulline
- Et-TC L-S-ethyl-thiocitrulline
- suitable indazole derivatives include indazole and 7-substituted indazoles such as 7-nitroindazole and 3-bromo-7-nitroindazole.
- hydrazine derivatives examples include aminoguanidine.
- suitable imidazole derivatives include phenyl substituted imidazoles such as 1-phenyl-imidazole.
- thioureas examples include S-methylisothiourea sulphate, ⁇ -(S- methylisothioureido)-L-norvaline (L-MLN), S-ethylisothiourea (SETU) and S- isopropylisothiourea (SIPT).
- suitable thiazoles include 2-amino-thiazole and 2-amino-4,5- dimethyl thiazole.
- biotin derivatives examples include 2-iminobiotin.
- Preferred NOS inhibitors are selective inhibitors of neuronal NOS.
- Such selective inhibitors include N -nitro-L-arginine (L-NOARG), N w -nitro-L-arginine methyl ester (L-NAME), N ⁇ -iminoethyl-L-ornithine (L-NIO), L-thiocitrulline (L-
- TC S-methyl-L-thiocitrulline
- Et-TC L-S-ethyl-thiocitrulline
- 2-amino- thiazole 2-amino-4,5-dimethyl thiazole, 7-nitroindazole (7-NI) and phenyl- substituted thiopene amidines.
- the above NOS inhibitors are commercially available, or may be made by analogy with known methods.
- the inhibitor may be a pharmaceutically acceptable salt of one the above compounds.
- Suitable salts include salts with pharmaceutically acceptable acids, both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succininc, tartaric, benzoic, acetic, methanesulphonic, efhanesulphonic, benzenesulphonic or p-toluenesulphonic acid.
- Salts may also be formed with pharmaceutically acceptable bases such as alkali metal (eg sodium or potassium) and alkali earth metal (eg calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines or heterocyclic amines.
- Inhibitors of NOS can be identified by: (a) contacting a candidate compound with NOS and a substrate and co- factor therefor, under conditions under which NOS activity, in the absence of an inhibitor, would be expected to occur; and
- a suitable such assay for identifying inhibitors of NOS is a microtiter plate assay in which NOS activity is measured by determining the change in absorbance as
- This assay comprises:
- the buffer is a HEPES buffer capable of maintaining a pH of about 7, preferably about 7.4.
- the cofactors comprise oxyhemoglobin, NADPH and BH 4 . They may also comprise CaCl 2 , MgCl 2 , FMN, FAD and/or CaM.
- the NOS may be a naturally occurring form of eNOS, iNOS, or nNOS or may be a variant which retains NOS activity, for example variants produced by mutagenesis techniques.
- NOS used in the assay is preferably of mammalian origin, for example rodent (including rat and mouse) or primate (such as human).
- the NOS is of human origin.
- the NOS may be obtained from mammal cellular extracts or produced recombinantly from, for example, bacteria, yeast or higher eukaryotic cells including mammalian cell lines and insect cell lines.
- NOS used in the assay is recombinant. More preferably, it is obtained by expression in S/21 cells according to the methodology in Charles et al, Methods in Molecular Biology (edited by M.A.
- Step (c) of the assay may be carried out by reading the difference in absorbance between 420 and 405 nm. Typically, this is done by a spectrometer.
- NOS inhibitors used in the present invention typically achieve at least 50% NOS inhibition, more preferably at least 80% NOS inhibition. Ideally, they achieve substantially complete NOS inhibition.
- binding agents e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone
- disaggregating agents e.g. starch, alginic acid, alginates or sodium starch glycolate
- dyestuffs effervescing mixtures
- dyestuffs e
- an erection may be achieved by reducing the amount of NOS inhibitor, or ceasing administration of NOS inhibitor, in good time before an erection is required.
- the dosage is reduced or the treatment suspended no more than 3 days before an erection is required. In some cases, dosage reduction or suspension of treatment up to 1 day before an erection is required will suffice.
- FIG 1 shows sections stained using the polyclonal antibody against nNOS.
- (a) shows a stained section from a Group III (saline) control rat
- (b) shows a stained section from a 4 week diabetic rat (note the varicosity formation and breakage in the nerve fibres)
- (c) shows a stained section from an 8 week diabetic rat (note that the nitrergic nerves became very sparse)
- (d) shows a stained section from an 8 week diabetic rat treated with L-NAME (note that the structure and number of the nitrergic nerve fibres are preserved during diabetes).
- the parameters of the electrical field stimulation were 50 V, 0.3 ms pulse duration, 1-25 Hz, for 5 s, every 2 minutes.
- EFS electrical field stimulation
- Rats prepared in Reference Example 1 were sacrificed at 1 week, 2 weeks, 3 weeks, 4 weeks and 8 weeks for the purpose of an NO synthase activity assay.
- the protective effect of L-NAME on the erectile function of the rats prepared in Reference Example 1 was investigated by studying the effects of in vivo electrical stimulation of the cavernous nerve. Anaesthesia was induced in the rats with sodium thiopentone (120 mg kg "1 , i.p.) and was maintained by a subsequent injection of sodium pent ⁇ barbital (5 mg kg' 1 , i.p.) as required. The right external jugular vein and left carotid artery were cannulated for saline infusion (50 ⁇ l min '1 ) and for blood pressure monitoring, respectively. The penile shaft and cavernous nerve were exposed as described in Rehman et al, Am. J. Physiol. 272, H1960-H1971 (1997).
- rabbits prepared in Reference Example 2 were sacrificed after 30 weeks.
- the corpus cavernosum of the rabbits were frozen in liquid nitrogen and pulverised in a stainless steel pestle and mortar.
- NO synthase was assayed in the supernatant by the formation of [U- 14 C]-citrulline from L-[U- 14 C]- arginine as described in Knowles et al, In Methods in Molecular Biology, (ed. Titheradge, MA) (Humana Press, Totowa, 1997). The results showed a significant decrease in the activity of the enzyme at the
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP99959520A EP1137460A2 (en) | 1998-12-11 | 1999-12-06 | Treatment of erectile dysfunction in diabetes patients |
AU16664/00A AU1666400A (en) | 1998-12-11 | 1999-12-06 | Treatment of erectile dysfunction in diabetes patients |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9827393.1 | 1998-12-11 | ||
GBGB9827393.1A GB9827393D0 (en) | 1998-12-11 | 1998-12-11 | Treatment of erectile dysfunction in diabetes patients |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2000035431A2 true WO2000035431A2 (en) | 2000-06-22 |
WO2000035431A3 WO2000035431A3 (en) | 2000-11-09 |
Family
ID=10844117
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1999/004095 WO2000035431A2 (en) | 1998-12-11 | 1999-12-06 | Treatment of erectile dysfunction in diabetes patients |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1137460A2 (en) |
AU (1) | AU1666400A (en) |
GB (1) | GB9827393D0 (en) |
WO (1) | WO2000035431A2 (en) |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5439938A (en) * | 1993-04-07 | 1995-08-08 | The Johns Hopkins University | Treatments for male sexual dysfunction |
FR2753098A1 (en) * | 1996-09-06 | 1998-03-13 | Sod Conseils Rech Applic | PHARMACEUTICAL COMPOSITION COMPRISING AT LEAST ONE NO SYNTHASE INHIBITOR AND AT LEAST ONE TRAP FOR REACTIVE OXYGEN FORMS |
WO1998013037A1 (en) * | 1996-09-25 | 1998-04-02 | The Regents Of The University Of California | Methods of using agmatine to reduce intracellular polyamine levels and to inhibit inducible nitric oxide synthase |
US5814650A (en) * | 1992-09-28 | 1998-09-29 | Lifegroup S.P.A. | Biotin amides able to control glucidic metabolisms under dysmetabolic conditions and relative therapeutical compositions |
WO1998042361A1 (en) * | 1997-03-26 | 1998-10-01 | Spencer E Martin | Human erectile dysfunction and methods of treatment |
WO1998051260A2 (en) * | 1997-05-14 | 1998-11-19 | Redox, Inc. | Use of d-arginine and/or l-arginine to protect the amino groups of biological substances from damage, inactivation, or modification by toxic carbonyls and/or dicarbonyls |
WO1999057114A1 (en) * | 1998-05-04 | 1999-11-11 | Fujisawa Pharmaceutical Co., Ltd. | Heterocyclic carboxamide derivatives as inhibitors of nitric oxide production |
-
1998
- 1998-12-11 GB GBGB9827393.1A patent/GB9827393D0/en not_active Ceased
-
1999
- 1999-12-06 EP EP99959520A patent/EP1137460A2/en not_active Withdrawn
- 1999-12-06 AU AU16664/00A patent/AU1666400A/en not_active Abandoned
- 1999-12-06 WO PCT/GB1999/004095 patent/WO2000035431A2/en not_active Application Discontinuation
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5814650A (en) * | 1992-09-28 | 1998-09-29 | Lifegroup S.P.A. | Biotin amides able to control glucidic metabolisms under dysmetabolic conditions and relative therapeutical compositions |
US5439938A (en) * | 1993-04-07 | 1995-08-08 | The Johns Hopkins University | Treatments for male sexual dysfunction |
FR2753098A1 (en) * | 1996-09-06 | 1998-03-13 | Sod Conseils Rech Applic | PHARMACEUTICAL COMPOSITION COMPRISING AT LEAST ONE NO SYNTHASE INHIBITOR AND AT LEAST ONE TRAP FOR REACTIVE OXYGEN FORMS |
WO1998013037A1 (en) * | 1996-09-25 | 1998-04-02 | The Regents Of The University Of California | Methods of using agmatine to reduce intracellular polyamine levels and to inhibit inducible nitric oxide synthase |
WO1998042361A1 (en) * | 1997-03-26 | 1998-10-01 | Spencer E Martin | Human erectile dysfunction and methods of treatment |
WO1998051260A2 (en) * | 1997-05-14 | 1998-11-19 | Redox, Inc. | Use of d-arginine and/or l-arginine to protect the amino groups of biological substances from damage, inactivation, or modification by toxic carbonyls and/or dicarbonyls |
WO1999057114A1 (en) * | 1998-05-04 | 1999-11-11 | Fujisawa Pharmaceutical Co., Ltd. | Heterocyclic carboxamide derivatives as inhibitors of nitric oxide production |
Non-Patent Citations (6)
Title |
---|
CELLEK S; RODRIGO J; LOBOS E; FERNANDEZ P; SERRANO J AND MONCADA S: "Selective nitrergic neurodegeneration in diabetes mellitus - a nitric oxide-dependent phenomenon" BRITISH JOURNAL OF PHARMACOLOGY, vol. 128, no. 8, December 1999 (1999-12), pages 1804-1812, XP002141458 * |
FRATI-MUNARI A C ET AL: "ÄTreatment of diabetic neuropathyÜ. Tratamiento de la neuropatia diabetica." GACETA MEDICA DE MEXICO, (1998 JAN-FEB) 134 (1) 85-92. REF: 51 , XP000920623 * |
KOUR NAM-WEE; YAJIMA MICHITAKA; LEE SHANG-SEN; LUE TOM F; TANAGHO EMIL A: "Aminoguanidine reverses the impairment of cavernous nerve induced intracavernosal pressure response in streptozotocin diabetic rats." JOURNAL OF UROLOGY, vol. 151, no. 5 SUPPL., 1994, page 429A XP000920621 * |
R. BERKOW: "The Merck Manual of Diagnosis and Therapy, Fifteenth Edition" , MERCK SHARP & DOHME RESEARCH LABORATORIES , NEW YORK XP002141459 page 1655, paragraph 4 - paragraph 5 * |
SEFTEL, A.D.; VAZIRI, N.D.; NI, Z.; RAZMJOUEI, K.; FOGARTY J. ET AL.: "Advanced glycation end products in human penis: elevation in diabetic tissue, site of deposition, and possible effect through iNOS or eNOS. " UROLOGY, vol. 50, no. 6, December 1997 (1997-12), pages 1016-1026, XP000920679 * |
TESFAYE S.: "Diabetic neuropathy: Current treatment and potential therapeutic approaches." DIABETES, NUTRITION AND METABOLISM - CLINICAL AND EXPERIMENTAL, (1994) 7/ (375-379). , XP000920809 * |
Also Published As
Publication number | Publication date |
---|---|
AU1666400A (en) | 2000-07-03 |
GB9827393D0 (en) | 1999-02-03 |
EP1137460A2 (en) | 2001-10-04 |
WO2000035431A3 (en) | 2000-11-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
LOCATELLI et al. | Dual y-aminobutyric acid control of prolactin secretion in the rat | |
Petersen et al. | Suppression of spontaneous LH surges in estrogen-treated ovariectomized rats by microimplants of antiestrogens into the preoptic brain | |
Toda et al. | Nitric oxide and penile erectile function | |
Roky et al. | Prolactin and rapid eye movement sleep regulation | |
Lambrecht et al. | Role of calcitonin gene-related peptide and nitric oxide in the gastroprotective effect of capsaicin in the rat | |
US5929061A (en) | Method for treating vascular headaches | |
US5439938A (en) | Treatments for male sexual dysfunction | |
Thiéry et al. | Role of hypothalamic catecholamines in the regulation of luteinizing hormone and prolactin secretion in the ewe during seasonal anestrus | |
Sahu et al. | Insulin and insulin-like growth factor II suppress neuropeptide Y release from the nerve terminals in the paraventricular nucleus: a putative hypothalamic site for energy homeostasis | |
US6855707B2 (en) | Method for the treatment of lipid and glucose metabolism disorders | |
US5712265A (en) | Administration of pirenzepine, methyl scopolamine and other muscarinin receptor antagonists for treatment of glucose metabolism disorders | |
US20080003209A1 (en) | Method for treatment of neurodegenerative diseases and the effects of aging | |
CA2254116C (en) | Method and composition for the treatment of lipid and glucose metabolism disorders | |
Terry et al. | Cysteamine effects on monoamines, dopamine-β-hydroxylase and the hypothalamic-pituitary axis | |
WO1997041873A9 (en) | Method and composition for the treatment of lipid and glucose metabolism disorders | |
Hellstrom et al. | Penile erection in the primate: induction with nitric-oxide donors | |
Lin et al. | KMUP‐1 relaxes rabbit corpus cavernosum smooth muscle in vitro and in vivo: involvement of cyclic GMP and K+ channels | |
Giuliano et al. | Central noradrenergic control of penile erection | |
Apud et al. | Biochemical and functional aspects on the control of prolactin release by the hypothalamo-pituitary GABAergic system | |
MANDAHL et al. | Hypertonic KCI, NaCI and capsaicin intracamerally causes release of substance P‐like immunoreactive material into the aqueous humor in rabbits | |
Bertrand et al. | Implication of D2-like dopaminergic receptors in the median eminence during the establishment of long-day inhibition of LH secretion in the ewe | |
US6465465B1 (en) | Process for the treatment of erectile dysfunction and product therefor | |
EP1137460A2 (en) | Treatment of erectile dysfunction in diabetes patients | |
Fiók et al. | Site of γ-aminobutyric acid (GABA)-mediated inhibition of growth hormone secretion in the rat | |
Bybee et al. | Inhibitory feedback effects of prolactin on its secretion involve central nervous system dopaminergic mediation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
ENP | Entry into the national phase in: |
Ref country code: AU Ref document number: 2000 16664 Kind code of ref document: A Format of ref document f/p: F |
|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
AK | Designated states |
Kind code of ref document: A3 Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A3 Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1999959520 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 09857601 Country of ref document: US |
|
WWP | Wipo information: published in national office |
Ref document number: 1999959520 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1999959520 Country of ref document: EP |