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WO2006121389A1 - Utilisation d'un antagoniste du recepteur de la neurokinine-2 pour traiter ou prevenir l'hyperactivite du detrusor - Google Patents

Utilisation d'un antagoniste du recepteur de la neurokinine-2 pour traiter ou prevenir l'hyperactivite du detrusor Download PDF

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Publication number
WO2006121389A1
WO2006121389A1 PCT/SE2006/000546 SE2006000546W WO2006121389A1 WO 2006121389 A1 WO2006121389 A1 WO 2006121389A1 SE 2006000546 W SE2006000546 W SE 2006000546W WO 2006121389 A1 WO2006121389 A1 WO 2006121389A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutically
acceptable salt
use according
neurokinin
compound
Prior art date
Application number
PCT/SE2006/000546
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English (en)
Inventor
Russell A. Bialecki
Original Assignee
Astrazeneca Ab
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Publication of WO2006121389A1 publication Critical patent/WO2006121389A1/fr

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder

Definitions

  • Treatment of dysfunction of urinary bladder activities More particularly, treatment of neurogenic detrusor overactivity.
  • Neurogenic detrusor overactivity is a common sequel of suprasacral spinal cord injury.
  • Subpopulations of C-afferent fibers, which are characteristically sensitive to capsaicin, have been implicated in the pathogenesis of this neurogenic detrusor overactivity, de Groat, W.C., et ah: Mechanisms underlying the recovery of urinary bladder function following spinal cord injury, J. Autonom. Nerv. Syst., 30 (Suppl): S71, 1990.
  • Tachykinins are synthesized by C-type afferent neurons.
  • tachykinins substance P, neurokinin A, neurokinin B
  • other peptides from sensory nerves in the bladder wall
  • tachykinins substance P, neurokinin A, neurokinin B
  • CGKP calcitonin gene-related peptide
  • tachykinins The actions of the tachykinins are mediated by activation of three distinct receptor types termed NK-I , NK-2 and NK-3, Maggi, C.A.: The mammalian tachykinin receptors, Gen. Pharmacol., 26: 911, 1995. Specific tachykinin receptors are present in peripheral sensory nerves and smooth muscle of the urinary bladder of several species, including humans.
  • Rat and guinea pig detrusors contain both NK-I and NK-2 receptors, however in humans the NK-2 receptor seems to be the only mediator of contractile response to tachykinins in bladder smooth muscle, Giuliani, S., et ah: Characterization of the tachykinin neurokini-2 receptor in the human urinary bladder by mean of selective receptor antagonists andpeptide inhibitors, J. Pharmacol. Exp.
  • Bladder overactivity and hypersensitivity disorders cause by tachykinins released from sensory nerves are antagonized with drugs selective for NK-2 receptors.
  • NK2RA neurokinin-2 receptor antagonist
  • Neurogenic detrusor overactivity resolved in 50% and 83% of the animals that received the NK2RA for one week at doses of 0.3 mg./kg./day and 0.6 mg./kg./day, respectively.
  • Mean cystometric bladder capacity was 1.2 ⁇ 0.5 versus 1.3 ⁇ 0.4 ml. and mean voiding pressure was 46.1 ⁇ 10.8 versus 40 ⁇ 9.9 cm. H 2 O in animals that received 0.3 versus 0.6 mg./kg./day, respectively.
  • the NK2RA compound produced better urodynamic results when given for 2 weeks rather than 1 week.
  • a NK2RA is effective in the treatment of neurogenic detrusor overactivity after spinal cord injury in the rat and may thus provide an alternative clinical treatment option for neurogenic detrusor overactivity and urgency/frequency syndrome.
  • This NK-2 selective antagonist has both time- and dose- response effects, which further suggests the potential for clinical application.
  • Figure 2 Mean basline (Basal) vesical pressure in animal groups. Asterisk indicates statistical significance (p ⁇ 0.05 vs paraplegics).
  • Figure 3 Mean cystometric bladder capacity in animal groups. Asterisk indicates statistical significance (p ⁇ 0.05 vs paraplegics).
  • Figure 4 Cystometrography in paraplegic rat that received 0.3 mg/kg daily of a NK2RA for two weeks.
  • Figure 5 Mean frequency of detrusor hyperreflexia in animal groups. Asterisk indicates statistical significance (p ⁇ 0.05 vs paraplegics).
  • Figure 6 Mean amplitude of detrusor hyperreflexia (DH) in animal groups. Asterisk indicates statistical significance (p ⁇ 0.05 vs paraplegics).
  • Figure 7 Mean micturition pressure in animal groups. Asterisk indicates statistical significance (p ⁇ 0.05 vs paraplegics).
  • mice served as sham operated control and received 1 ml of saline subcutaneously daily.
  • the 42 remaining animals in this study underwent spinal cord transection at the level of the 10 th thoracic vertebra.
  • the animals were anesthetized by intramuscular injection of ketamine (50 mg./kg. body weight) and xylazine (5 mg./kg. body weight).
  • Body temperature was maintained between 37 0 C and 38 0 C during the surgery and for the first postoperative 48 hours using a controlled heating pad connected to an electronic rectal thermometer. After sufficient depth of anesthesia, the last rib was identified and the level of the corresponding vertebra was localized.
  • a midline dorsal incision was made about 2-cm over the subcutaneous trunci to expose the vertebral spine and the paraspinous muscle. These muscles were split from their attachment to the spinal processes and retracted laterally.
  • Laminectomy of TlO vertebra was done using a curved scissor. Using a sharp iris scissor, the spinal cord was completely transected under direct visual control aided by microscopic magnification. To ensure complete transection of the spinal cord, a 5 mm gap between the proximal and distal ends was created and a piece of Gel-foam (Upjohn Company of Canada, Don Mills, Ontario, Canada) was placed between the severed ends of the spinal cord.
  • Gel-foam Upjohn Company of Canada, Don Mills, Ontario, Canada
  • the overlying muscles were then approximated and the skin closed using 4-zero catgut sutures.
  • Six animals served as normal controls, while 32 underwent spinal cord transection at the 10 th thoracic vertebra. Two weeks after spinal cord injury, 6 animals underwent filling cystometrography to confirm neurogenic detrusor overactivity, while another 12 served as control paraplegics. The remaining 24 paraplegic animals were used to test the drug and were divided into 2 equal groups of 12. Group 1 received the drug in a dose of 0.3 mg./kg. daily, while group 2 received a dose of 0.6 mg./kg. daily. Each control paraplegic and treatment group was further subdivided into 2 subgroups of 6 rats. In subgroup 1, filling cystometrography was done 3 weeks after spinal cord injury, while in subgroup 2 it was done 4 weeks after spinal cord injury. Animal grouping and drug administration.
  • Group 1 received the drug at a dose of 0.3 mg./kg. daily, while group 2 received a dose of 0.6 mg./kg. daily.
  • Each control paraplegic and treatment group was further subdivided into 2 subgroups of 6 rats. In subgroup 1, filling cystometrography was done 3 weeks after spinal cord injury, while in subgroup 2 it was done 4 weeks after spinal cord injury.
  • the compound competitively antagonized the contractile responses evoked by neurokinin A (NKA) on human bronchus as well as responses evoked by [ ⁇ -Ala s ]-NKA(4-10) on guinea-pig trachea (GPT) or rabbit pulmonary artery (RPA), with similar potency (-logK ⁇ -9.5 and 9.0, respectively).
  • M274773 was inactive in binding studies against 110 additional ion channels, enzymes, transporters and receptors including adrenergic, serotonergic, nicotinic, muscarinic, dopaminergic, gabaergic and histaminergic varities. Animal care.
  • Each rat was housed in a separate cage containing special bedding materials to prevent decubitus ulcer formation.
  • the position of the animals was changed at least twice daily for the first week.
  • the animals were given trimethoprim (2.2 mg./kg. body weight) subcutaneously twice daily for the first three days after spinal cord injury.
  • trimethoprim 2.2 mg./kg. body weight
  • the bladder was emptied manually every 8 hours after surgery until reflex voiding was recovered (first two weeks), after which the bladder was emptied twice daily.
  • AU animals were weighed twice weekly. Animals in which ulcers, self- mutilation or significant weight loss developed were sacrificed.
  • Cystometrography was done in awake animals to study the detrusor response to filling after supraspinal transection and to evaluate the effect of different doses and intervals of M274773 on urinary bladder function after spinal cord injury.
  • a PE-90 polyethylene catheter (Clay- Adam, Parsippany, New Jersey) was implanted into the bladder through the dome as previously described, Yaksh, TX. , et al.,: Micturition in rats: a chronic model for study of bladder function and effect of anesthetics, Am. J. Physiol., 251: Rl 177, 1986.
  • the catheter was tunneled subcutaneously and exteriorized at the nape of the neck. Cystometrography was done 48 hours after tube implantation into the bladder.
  • the bladder catheter was connected via a t-tube to a pressure transducer (Stetham Instruments, Inc., Oxnard, California) and a Flo-Gard 6200 volumetric infusion pump (Travenol Laboratories, Inc., Deerfield, Illinois).
  • the conscious rat was placed without any restraint in a metabolic cage. After the bladder had been emptied, room temperature saline was infused into the bladder at a rate of 100 ⁇ l. per minute. Intravesical pressure was recorded continuously using a Mac Lab/2e computer (AD Instruments, Castle Hill, Australia).
  • At least three reproducible voiding cycles were recorded per animal.
  • the variables recorded during cystometrography were resting bladder pressure, uninhibited contractions, frequency of uninhibited detrusor contractions per minute, amplitude of the uninhibited detrusor contractions in cm. H 2 O, bladder capacity and spontaneous voiding pressure.
  • a contraction of 15 cm. H 2 O and more was considered unstable.
  • the presence of unstable bladder contractions in this model of neurogenic bladder was considered neurogenic detrusor overactivity.
  • Data analysis was done using 1-way analysis of variance. AU data were shown as the mean plus or minus standard deviation, with p ⁇ 0.05 considered statistically significant. Results Sham operated controls.
  • mean baseline vesical pressure in control paraplegic animals 3 weeks after spinalization was 9 ⁇ 1.7 cm.H 2 0, mean cystometric capacity was 0.7 ⁇ 0.2 ml. and mean micturition pressure was 59 ⁇ 14.2 cm.H 2 0. These control paraplegic animals showed neurogenic detrusor overactivity with a mean frequency of 3.6 ⁇ 0.7 contractions per minute and a mean amplitude of 29 ⁇ 4 cm. H 2 O.
  • mean baseline vesical pressure in control paraplegic animals was 12 ⁇ 2.1 cm. H 2 O with a mean cystometric capacity of 0.56 ⁇ 0.1 ml. and a mean micturition pressure of 64.6 ⁇ 12 cm. H 2 O.
  • Neurogenic detrusor overactivity also disappeared in 50 % and 66 % of the animals that received a dose of 0.3 mg./kg. M274773 daily for 1 and 2 weeks, respectively (Fig. 4). Although neurogenic detrusor overactivity did not disappear in 50 % and 33% of the animals, there was a significant decrease in the mean frequency of these hyperreflexic contractions to 2,1 ⁇ 0.7 and 1.1 ⁇ 0.1 contractions per minute when M274773 was given at 0.3 mg./kg. daily for 1 and 2 weeks, respectively (Fig. 5). The significant decrease in the frequency of the hyperreflexic contractions was associated with a decrease in the mean amplitude of these contractions to 27 ⁇ 3 and 20 ⁇ 2.8 cm.
  • detrusor overactivity in a subject may be treated by administration of a therapeutically-effective amount of a neurokinin-2 receptor antagonist or a pharmaceutically-acceptable salt thereof to a subject. More particularly, it is contemplated that detrusor overactivity in a subject may be treated by administration of a therapeutically-effective amount of (5)-iV-[2-(3 ) 4- dicb.lorophenyl)-4-[4-(2-oxo-piperidin-l-yl)piperidino]butyl]-iV-metb.yl-2-fluorobenzamide or pharmaceutically-acceptable salt thereof to said subject. It is further contemplated that such treatment may be effective wherein said subject is a human.
  • said pharmaceutically-acceptable salt is selected from a chloride, a sulfate, a tosylate, a mesylate, a napsylate, a besylate, a phosphate, a salicylate, a tartrate, a lactate, a citrate, a benzoate, a succinate, an acetate or a maleate.
  • such treatment may be effective when additionally comprising co-administering one or more other medically-compatible therapeutic agents.
  • Such treatment may be effective wherein said other therapeutic agents are selected from, an estrogenic agent, a progestational substance, an alpha-adrenergic agonist, a beta-adrenergic receptor blocking agent, a cholinergic-receptor blocking compound or a cholinergic-receptor-stimulating drug.
  • said other therapeutic agents are selected from, an estrogenic agent, a progestational substance, an alpha-adrenergic agonist, a beta-adrenergic receptor blocking agent, a cholinergic-receptor blocking compound or a cholinergic-receptor-stimulating drug.
  • Such treatment may be effective wherein said compound or pharmaceutically-acceptable salt thereof is administered in a physiologically- acceptable manner, selected from topical application, ingestion, inhalation, insufflation or injection.
  • Such treatment may be effective wherein said compound or pharmaceutically-acceptable salt thereof is administered topically.
  • such treatment may be achieved by administering by capsule, tablet, aqueous solution, aqueous suspension, non-aqueous suspension, suppository, aerosol or powder a daily dose range of 5 to 100 mg of said compound or said pharmaceutically-acceptable salt thereof, in a single dose or divided into two, three or four daily doses.
  • Such treatment may be achieved with a pharmaceutical composition for treating or preventing detrusor overactivity comprising (5)-iV-[2-(3,4- dichlorophenyl)-4-[4-(2-oxo-piperidin-l-yl)piperidino]butyl]-iV-methyl-2-fluorobenzamide or pharmaceutically-acceptable salt thereof and at least one pharmaceutically-acceptable excipient or diluent.
  • (5)-iV-[2-(3,4-dichlorophenyl)-4-[4-(2- oxoperhydro ⁇ yrimidin-l-yl)piperidino]butyl]-iV-methylbenzamide or a pharmaceutically- acceptable salt thereof may be used in the preparation of a medicament for treating or preventing detrusor overactivity.
  • a pharmaceutically-acceptable salt may be selected from a chloride, a sulfate, a tosylate, a mesylate, a napsylate, a besylate, a phosphate, a salicylate, a tartrate, a lactate, a citrate, a benzoate, a succinate, an acetate or a maleate.
  • (,y)-iV-[2-(3,4-dichloro ⁇ henyl)-4-[4-(2- oxo ⁇ erhydropyrimidin-l-yl)piperidino]butyl]-iV-methylbenzamide or a pharmaceutically- acceptable salt thereof may be used in the preparation of a medicament suitable for coadministration with one or more other medically-compatible therapeutic agents.
  • said other medically-compatible therapeutic agents may be selected from, an estrogenic agent, a progestational substance, an alpha-adrenergic agonist, a beta-adrenergic receptor blocking agent, a cholinergic-receptor blocking compound or a cholinergic-receptor-stimulating drug.
  • (,S)-iV-[2-(3,4-dichlorophenyl)-4-[4-(2- oxoperhydropyrimidin-l-yl)piperidino]butyl]-iV-methylbenzamide or a pharmaceutically- acceptable salt thereof may be used in a medicament suitable for administration orally, parenterally, rectally, by inhalation or by insufflation. It is further contemplated that such a medicament may comprise a tablet or capsule containing about 0.1 mg up to about 250 mg of said compound or pharmaceutically- acceptable salt thereof.
  • a medicament may comprise about 0.1 mg to about 250 mg of said compound suitable for administration by inhalation as a single dose or divided into two, three or four daily doses. It is further contemplated that a medicament comprising about 5 mg to about 100 mg of said compound may be suitable for administration by inhalation as a single dose or divided into two, three or four daily doses.
  • a medicament comprising about 5 mg to about 100 mg may be suitable for administration as a capsule, a tablet, an aqueous solution, an aqueous suspension, a non-aqueous suspension, a suppository, an aerosol or a powder.
  • (5)-7V-[2-(3,4-dichlorophenyl)-4-[4-(2- oxoperhydropyrimidin-l-yl)piperidino]butyl]-N-methylbenzamide or a pharmaceutically- acceptable salt thereof may be used for treating or preventing detrusor overactivity.
  • (5)-iV-[2-(3,4-dichlorophenyl)-4-[4-(2- oxoperhydropyrimidm-l-yl)piperidino]butyl]- ⁇ r -methylbenzamide may be used for treating or preventing detrusor overactivity in the form of a pharmaceutically-acceptable salt selected from a chloride, a sulfate, a tosylate, a mesylate, a napsylate, a besylate, a phosphate, a salicylate, a tartrate, a lactate, a citrate, a benzoate, a succinate, an acetate or a maleate.
  • a pharmaceutically-acceptable salt selected from a chloride, a sulfate, a tosylate, a mesylate, a napsylate, a besylate, a phosphate, a salicylate, a tartrate, a lactate,
  • (.S)-iV-[2-(3,4-dichlorophenyl)-4-[4-(2- oxoperhydropyrimidin-l-yl)piperidino]butyl]-iV-methylbenzamide or a pharmaceutically- acceptable salt thereof for treating or preventing detrusor overactivity may be used by coadministration with one or more other medically-compatible therapeutic agents.
  • ( ⁇ S)-_V-[2-(3 ,4-dichlorophenyl)-4-[4-(2- oxoperhydropyrimidin-l-yl)piperidino]butyl]-iV-methylbenzamide or a pharmaceutically- acceptable salt thereof for treating or preventing detrusor overactivity may be used with other medically-compatible therapeutic agents selected from, an estrogenic agent, a progestational substance, an alpha-adrenergic agonist, a beta-adrenergic receptor blocking agent, a cholinergic-receptor blocking compound or a cholinergic-receptor-stimulating drug.
  • (,S)-iV-[2-(3,4-dichlorophenyl)-4-[4-(2- oxoperhydropyrimidin-l-yl)piperidino]butyl]-7V-methylbenzamide or a pharmaceutically- acceptable salt thereof for treating or preventing detrusor overactivity may be used by administrating orally, parenterally, rectally, by inhalation or by insufflation.
  • (5)-iV-[2-(3,4-dichlorophenyl)-4-[4-(2- oxoperhydropyrimidin-l-yl)piperidino]butyl]-iV-methylbenzamide or a pharmaceutically- acceptable salt thereof for treating or preventing detrusor overactivity may be used by administering as a capsule, a tablet, an aqueous solution, an aqueous suspension, a nonaqueous suspension, a suppository, an aerosol or a powder.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Le traitement de l'hyperactivité du détrusor chez un sujet consiste à administrer une quantité thérapeutiquement efficace d'un antagoniste du récepteur de la neurokinine-2 ou un sel pharmaceutiquement acceptable de ce dernier. Cette invention porte également sur des compositions pharmaceutiques contenant un tel composé.
PCT/SE2006/000546 2005-05-10 2006-05-08 Utilisation d'un antagoniste du recepteur de la neurokinine-2 pour traiter ou prevenir l'hyperactivite du detrusor WO2006121389A1 (fr)

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US67962405P 2005-05-10 2005-05-10
US60/679,624 2005-05-10

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WO2006121389A1 true WO2006121389A1 (fr) 2006-11-16

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10086034B2 (en) 2013-08-01 2018-10-02 Dignify Therapeutics, Llc Compositions and methods for inducing urinary voiding and defecation

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000025766A2 (fr) * 1998-10-30 2000-05-11 Astrazeneca Ab Traitement de l'asthme gastrique
WO2001097811A1 (fr) * 2000-06-22 2001-12-27 Astrazeneca Ab Methode de traitement d'une suractivite de la vessie
WO2003037889A1 (fr) * 2001-11-02 2003-05-08 Astrazeneca Ab Composes et methode de traitement de la vessie hyperactive
WO2003037341A1 (fr) * 2001-11-02 2003-05-08 Astrazeneca Ab Methode de traitement d'une suractivite de la vessie

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000025766A2 (fr) * 1998-10-30 2000-05-11 Astrazeneca Ab Traitement de l'asthme gastrique
WO2001097811A1 (fr) * 2000-06-22 2001-12-27 Astrazeneca Ab Methode de traitement d'une suractivite de la vessie
WO2003037889A1 (fr) * 2001-11-02 2003-05-08 Astrazeneca Ab Composes et methode de traitement de la vessie hyperactive
WO2003037341A1 (fr) * 2001-11-02 2003-05-08 Astrazeneca Ab Methode de traitement d'une suractivite de la vessie

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ABDEL-KARIM A.M. ET AL.: "Effects of M274773, A neurokinin-2 receptor antagonist, on bladder function in chronically spinalized rats", THE JOURNAL OF UROLOGY, vol. 174, October 2005 (2005-10-01), pages 1488 - 1492, XP005377677 *
RUMSEY W. ET AL.: "Pharmacology of ZM274773: A Selective and Orally-Active Non-Peptide Neurokinin-A(NK-2) Receptor Antagonist", FASEB JOURNAL, vol. 13, no. 4, 1999, pages A365, XP003000358 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10086034B2 (en) 2013-08-01 2018-10-02 Dignify Therapeutics, Llc Compositions and methods for inducing urinary voiding and defecation

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