WO2004028440A2 - Utilisation d'antagonistes du recepteur vanilloide pour le traitement de troubles urologiques - Google Patents

Utilisation d'antagonistes du recepteur vanilloide pour le traitement de troubles urologiques Download PDF

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WO2004028440A2
WO2004028440A2 PCT/EP2003/010111 EP0310111W WO2004028440A2 WO 2004028440 A2 WO2004028440 A2 WO 2004028440A2 EP 0310111 W EP0310111 W EP 0310111W WO 2004028440 A2 WO2004028440 A2 WO 2004028440A2
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vrl
chloro
urinary incontinence
hydroxy
phenyl
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PCT/EP2003/010111
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WO2004028440A3 (fr
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Masahiro Shiroo
Takeshi Yura
Noriyuki Yamamoto
Masomi Tajimi
Yasuhiro Tsukimi
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Bayer Healthcare Ag
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Publication of WO2004028440A3 publication Critical patent/WO2004028440A3/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
    • A61K31/16—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
    • 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

  • the present invention relates to methods and pharmaceutical compositions for treating urological disorders. More particularly, this invention concerns the use of a vanilloid receptor (NR1) antagonist for the treatment of urinary incontinence and overactive bladder.
  • NR1 vanilloid receptor
  • capsaicin the main pungent ingredient in "hot” chili peppers desensitizes sensory neurons or C-fiber afferent neurons.
  • Capsaicin and its analogues such as resiniferatoxin(RTX) are shown to be effective in the treatment of urological disorder e.g., urinary incontinence and overactive bladder, through the desensitization of C-fiber afferents [(Chancellor, M. B. and de Groat, W. C, The Journal of Urology, 162, 3-11, 1999) and (Andersson, K-E et al, BJU International, 84, 923-947, 1999)].
  • Vanilloid receptor is a specific neuronal membrane recognition site for capsaicin. It is expressed almost exclusively by primary sensory neurons involved in nociception and neurogenic inflammation. Capsaicin functions as a specific agonist of vanilloid receptors (NR1), which is a functional subtype of vanilloid receptor and predominantly expressed in cell bodies and nerve endings of dorsal root ganglion (DRG) neurons or afferent sensory fibers including C-fiber (Tominaga M. et al, Neuron. 21: 531-543, 1998).
  • NR1 vanilloid receptors
  • DRG dorsal root ganglion
  • the NR1 receptor was recently cloned (Caterina, M.J., et al, Nature, 389 (6653), 816-824 (1997)) and identified as a nonselective cation channel with six transmembrane domains that is structurally related to the TRP (transient receptor potential) channel family. Binding of capsaicin to VR1 opens the ion channel and allows sodium, calcium and possibly potassium ions to flow down their concentration gradients, causing initial depolarization and release of neuro- transmitters from the nerve terminals of C-fiber afferents. That results in incontinence and overactive bladder. Repeated or prolonged exposure of VR1 receptor to capsaicin or RTX, however, rapidly desensitizes them.
  • This acute desensitization of VR1 may be caused by the downregulation and/or internalization of VR1 triggered by the agonists [(Lower Urinary Tract Symptoms. Eds by Kosuke Yasuda et al., Miwa shoten Press, 2000) and (Goso, C; Piovacari, G and Szallasi, A,
  • Another possible mechanism of the long term desensitization may be the decrease of the transport of nerve growth factor (NGF) to the cell body by affecting the axonal signal transmission, that in turn leads to depletion of neuropeptides, thus paralyzing the function of C-fiber (Lower Urinary Tract Symptoms. Eds by Kosuke Yasuda et al, Miwa shoten Press, 2000).
  • NGF nerve growth factor
  • capsaicin and RTX may induce intracellular accumulation of ions leading to osmotic changes and activation of proteolytic enzyme processes to finally deteriorate C-fiber.
  • Capsazepine a capsaicin analog
  • WO02/08221, WO02/090326, WO02/16317, WO02/16318 and WO02/16319 each disclose certain vanilloid receptor antagonists and their use for the treatment of diseases associated with the activity of vanilloid receptor.
  • This invention is to provide a use of a VRl antagonist in the preparation of a medicament for treating or preventing urological disorder.
  • This invention is also to provide a pharmaceutical composition which includes a VRl antagonist for treatment and/or prophylaxis urological disorder. Further this invention is to provide a method for treating urological disorder in a mammal, preferably in a human, which method comprises administering to said mammal a therapeutically effective amount of a VRl antagonist.
  • the VRl antagonist is selected from the group consisting of N- [4-chloro-3 -(trifluoromethyl)phenyl] -N'-(2 ,4-dibromo-7-hydroxy- 1 -naphthyl)urea; N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-(2,4-dichloro-7-hydroxy-l-naphthyl)urea and N-(4-bromo-2-chloro-7-hydroxy- 1 -naphthyl)-N'-[4-chloro-3-(trifluoromethyl)phen- yl]urea,
  • the VRl antagonist is an antibody immunoreactive with
  • the present invention provides a pharmaceutical composition which includes a VRl antagonist for treatment and/or prophylaxis of urological disorder and a use of a VRl antagonist in the preparation of a medicament for treating or preventing urological disorder.
  • a VRl antagonist for treatment and/or prophylaxis of urological disorder and a use of a VRl antagonist in the preparation of a medicament for treating or preventing urological disorder.
  • "Urological disorder” used herein includes all kind of urological diseases and dysfunction. Typical example of the urological disorder is overactive bladder, lower urinary tract symptoms and urinary incontinence, which encompasses detrusor hyper-reflexia, detrusor instability, urgent micturition, micturition of increased frequency, urge urinary incontinence, mix urinary incontinence and the like.
  • VRl antagonists include species that will bind VRl and species that will interfere with the binding of VRl to its ligands, vanilloid and other natural compounds.
  • Antagonists that bind VRl include, without limitation, monoclonal or polyclonal antibodies and fragments thereof, chimeric antibodies and fragment thereof and certain groups of organic small molecules.
  • Antagonists that interfere with VRl binding include, without limitation, monoclonal or polyclonal antibodies and fragments thereof, chimeric antibodies and fragment thereof and certain groups of organic small molecules.
  • VRl antagonists can be produced by methods well known to those skilled in the art.
  • monoclonal VRl antibodies can be produced by generation of antibody-producing hybridomas in accordance with known methods.
  • VRl used in the present invention can be any form of VRl, so long as that form of VRl is capable of binding its ligands.
  • Typical salts of an organic small molecule include salts prepared by reaction of the compounds with a mineral or organic acid, or an organic or inorganic base. Such salts are known as acid addition and base addition salts, respectively.
  • Base addition salts include those derived from inorganic bases, such as, without limitation, ammonium hydroxide, alkaline metal hydroxide, alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, and organic bases, such as, without limitation, ethanolamine, triethylamine, tris(hydroxymethyl)aminomethane, and the like.
  • inorganic bases include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
  • the pharmaceutical composition of the present invention may be administered in oral forms, such as, without limitation normal and enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solution, suspensions, syrups, solid and liquid aerosols and emulsions. They may also be administered in parenteral forms, such as, without limitation, intravenous, intraperitoneal, subcutaneous, intramuscular, and the like forms, well-known to those of ordinary skill in the pharmaceutical arts.
  • the pharmaceutical composition of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal delivery systems well-known to those of ordinary skilled in the art.
  • the dosage regimen with the use of the pharmaceutical compositions of the present invention is selected by one of ordinary skill in the arts, in view of a variety of factors, including, without limitation, age, weight, sex, and medical condition of the recipient, the severity of the condition to be treated, the route of administration, the level of metabolic and excretory function of the recipient, the dosage form employed.
  • compositions of the present invention are preferably formulated prior to administration and include one or more pharmaceutically acceptable excipients.
  • Excipients are inert substances such as, without limitation carriers, diluents, flavoring agents, sweeteners, lubricants, solubilizers, suspending agents, binders, tablet disintegrating agents and encapsulating material.
  • the pharmaceutical formulation of the present invention comprises one or more pharmaceutically-acceptable excipients that are compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the active ingredient may be mixed with a diluent, or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container.
  • the carrier may serve as a diluent, which may be solid, semi-solid, or liquid material which acts as a vehicle, or can be in the form of tablets, pills powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, containing, for example, up to 10% by weight of the active pharmaceutical composition, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
  • a diluent which may be solid, semi-solid, or liquid material which acts as a vehicle, or can be in the form of tablets, pills powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, containing, for example, up to 10% by weight of the active pharmaceutical composition, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
  • the active ingredient may be combined with an oral, and non-toxic, pharmaceutically-acceptable carrier, such as, without limitation, lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate, methyl cellulose, and the like; together with, optionally, disintegrating agents, such as, without limitation, maize, starch, methyl cellulose, agar bentonite, xanthan gum, alginic acid, and the like; and optionally, binding agents, for example, without limitation, gelatin, natural sugars, beta-lactose, corn sweeteners, natural and synthetic gums, acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like; and, optionally, lubricating agents, for example, without limitation, magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium benzoate,
  • the carrier may be a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient may be mixed with a carrier having binding properties in suitable proportions and compacted in the shape and size desired to produce tablets.
  • the powders and tablets preferably contain from about 1 to about 99 weight percent of the active ingredient which is the novel composition of the present invention.
  • Suitable solid carriers are magnesium carboxy- methyl cellulose, low melting waxes, and cocoa butter.
  • Sterile liquid formulations include suspensions, emulsions, syrups and elixirs.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable carriers, such as sterile water, sterile organic solvent, or a mixture of both sterile water and sterile organic solvent.
  • a pharmaceutically acceptable carriers such as sterile water, sterile organic solvent, or a mixture of both sterile water and sterile organic solvent.
  • the active ingredient can also be dissolved in a suitable organic solvent, for example, aqueous propylene glycol.
  • Other compositions can be made by dispersing the finely divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil.
  • the formulation may be in unit dosage form, which is a physically discrete unit containing a unit dose, suitable for administration in human or other mammals.
  • a unit dosage form can be a capsule or tablets, or a number of capsules or tablets.
  • a "unit dose" is a predetermined quantity of the active pharmaceutical composition of the present invention, calculated to produce the desired therapeutic effect, in association with one or more excipients.
  • the quantity of active ingredient in a unit dose may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved.
  • Typical oral dosages of the present invention when used for the indicated effects, will range from about O.Olmg /kg/day to about 100 mg/kg/day, preferably from 0.1 mg/kg/day to 30 mg/kg/day, and most preferably from about 0.5 mg/kg/day to about 10 mg/kg/day.
  • parenteral administration it has generally proven advantageous to administer quantities of about 0.001 to lOOmg /kg/day, preferably from 0.01 mg/kg/day to 1 mg/kg/day.
  • the pharmaceutical compositions of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses, two, three, or more times per day. Where delivery is via transdermal forms, of course, administration is continuous.
  • the transfectants were cloned by limiting dilution in selection medium (DMEM F12 medium (Gibco BRL) supplemented with 10% fetal calf serum (FCS), 1.4 mM Sodium pyruvate, 20 mM HEPES, 0.15% Sodium bicarbonate, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin, 2 mM glutamine, non-essential amino acids and 2 mg/ml G418). Ca influx was examined in the capsaicin-stimulated clones. A high responder clone was selected and used for further experiments.
  • selection medium DMEM F12 medium (Gibco BRL) supplemented with 10% fetal calf serum (FCS), 1.4 mM Sodium pyruvate, 20 mM HEPES, 0.15% Sodium bicarbonate, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin, 2 mM glutamine, non-essential amino
  • the human VRl-CHOluc9aeq cells were maintained in the selection medium in 5% CO 2 - air humidified atmosphere at 37 °C and passaged every 3-4 days at l-2.5xl0 5 cells/flask (75 mm 2 ).
  • Human VRl-CHOluc9aeq cells were suspended in a culture medium which is the same as the selection medium except for G418 and seeded at a density of 1,000 cells per well into 384-well plates (black walled clear-base / Nalge
  • the fluorescence changes indicating mobilization of cytoplasmic Ca 2+ was measured by FDSS-3000 (Excitation wave-length at 488 nm, Emission wave-length at 540 nm / Hamamatsu Photonics) for 60 sec after the stimulation with 10 nM capsaicin. Integral R of the fluorescence changes was calculated in the samples treated with a test compound and vehicle respectively. Inhibitory effect of the compound was calculated by a comparison of the integral R values.
  • Rat vanilloid receptor (rVRl) cDNA was cloned from libraries of axotomized dorsal root ganglia (Caterina, M.J., et al, Nature, 389 (6653), 816-824 (1997)). The cloned rVRl cDNA were constructed with pcDNA3 vector and transfected into the CHOluc9aeq cell line, which contains aequorin and CRE- luciferase reporter genes as read-out signals.
  • the transfectants were cloned by limiting dilution in selection medium (DMEM/F12 medium (Gibco BRL) supplemented with 10% fetal calf serum (FCS), 1.4 mM Sodium pyruvate, 20 mM HEPES, 0.15% Sodium bicarbonate, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin, 2 mM glutamine, non-essential amino acids and 2 mg/ml G418). Ca 2+ influx was examined in the capsaicin-stimulated clones. A high responder clone was selected and used for further experiments.
  • the rat VR1-DMEM/F12 medium Gibco BRL
  • FCS fetal calf serum
  • FCS fetal calf serum
  • FCS fetal calf serum
  • FCS fetal calf serum
  • FCS fetal calf serum
  • FCS fetal calf serum
  • FCS fetal cal
  • CHOluc9aeq cells were maintained in the selection medium in 5% CO 2 - air humidified atmosphere at 37 °C and passaged every 3-4 days at 1-2.5x10 5 cells/flask (75 mm 2 ).
  • Rat VRl-CHOluc9aeq cells were suspended in a culture medium which is the same as the selection medium except for G418 and seeded at a density of 1,000 cells per well into 384- well plates (black walled clear-base / Nalge Nunc International). Following the culture for 48 hrs the medium was changed to 2 ⁇ M Fluo-3 AM (Molecular Probes) and 0.02% Puronic F-127 in assay buffer (Hank's balanced salt solution (HBSS), 17 mM HEPES (pH7.4), 1 mM Probenecid, 0.1% bovine serum albumin (BSA)) and the cells were incubated for 60 min at 25°C.
  • assay buffer Hort's balanced salt solution (HBSS), 17 mM HEPES (pH7.4), 1 mM Probenecid, 0.1% bovine serum albumin (BSA)
  • DRG dorsal root ganglia
  • PBS phosphate balanced solution
  • FCS fetal calf serum
  • the DRG neuron cells were resuspended in Ham F12/5% FCS/5% horse serum (Gibco BRL) and dispersed by repeated pipetting and passing through 70 ⁇ m mesh (Falcon) and seeded into a 96-well culture plate. The culture plate was incubated for 3 hours at 37°C to remove contaminating
  • Non-adherent cells were recovered and further cultured in laminin-coated 384 well plates (Nunc) at a density of lxlO 4 cells/50 ⁇ l/well for 2 days in the presence of 50 ng/ml recombinant rat NGF (Sigma) and 50 ⁇ M 5-fluorodeoxyuridine (Sigma).
  • DRG neuron cells were washed twice with assay buffer (HBSS supplemented with 17 mM HEPES (pH 7.4) and 0.1% BSA). After incubating with 2 ⁇ M fluo-3AM (Molecular Probe), 0.02% PF127 (Gibco BRL) and 1 mM probenecid (Sigma) for 40 min at 37°C, and cells were washed with assay buffer 3 times. The cells were incubated with VRl antagonists or vehicle (dimethylsulphoxide) and then with 1 ⁇ M capsaicin in FDSS-6000 (Excitation wave-length at 480nm, Emission wave-length at 520nm / Hamamatsu Photonics). The fluorescence changes at 520nm were monitored for 2.5 min. Integral R of the fluorescence change was calculated in the samples treated with a compound and vehicle, respectively. Inhibitory effect of the compound was calculated by comparison of the integral R values. EXAMPLE 4
  • Isometric tension was recorded under a load of 1 g using longitudinal strips of rat detrusor muscle. Bladder strips were equilibrated for 60 min before each stimulation. Contractile response to 80 mM KC1 was determined at 15 min intervals until reproducible responses were obtained. The response to KC1 was used as an internal standard to evaluate the maximal response to capsaicin. The effects of the compounds were investigated by incubating the strips with compounds for 30 min prior to the stimulation with l . ⁇ M capsaicin (vehicle: 80% saline, 10% EtOH, and 10% Tween 80). One of the preparations made from the same animal was served as a control while the others were used for evaluating compounds. Ratio of each capsaicin-induced contraction to the internal standard (i.e. KCl-induced contraction) was calculated and the effects of the test compounds on the capsaicin-induced contraction were evaluated.
  • KCl-induced contraction i.e. KCl-induced contraction
  • Rats were anesthetized by intraperitoneal administration of urethane (Sigma) at 1.25 g/kg.
  • the abdomen was opened through a midline incision, and a polyethylene catheter (BECTON DICKINSON, PE50) was implanted into the bladder through the dome.
  • a polyethylene catheter BECTON DICKINSON, PE50
  • saline Otsuka
  • the bladder catheter was connected via T-tube to a pressure transducer (Viggo-Spectramed Pte Ltd, DT-XXAD) and a microinjection pump (TERUMO). Saline was infused at room temperature into the bladder at a rate of 3.6 ml/hr. Intravesical pressure was recorded continuously on a chart pen recorder (Yokogawa). At least three reproducible micturition cycles, corresponding to a 20-minute period, were recorded before a capsaicin infusion and used as baseline values.
  • a testing compound dissolved in the mixture of ethanol, Tween 80 (ICN Biomedicals Inc.) and saline (1 : 1 : 8, v/v/v) was administered intravenously at 3 mg/kg or 10 mg/kg. 2min after the administration of the compound, saline including 30 ⁇ M of capsaicin (Nacalai Tesque) was infused at room temperature into the bladder at a rate of 3.6 ml/hr.
  • Cyclophosphamide (CYP) dissolved in saline was administered intra- peritoneally at 150 mg/kg 48 hours before experiment.
  • Rats were anesthetized by intraperitoneal administration of urethane (Sigma) at 1.25 g/kg. The abdomen was opened through, a midline incision, and a polyethylene catheter (BECTON DICKINSON, PE50) was implanted into the bladder through the dome. In parallel, the inguinal region was incised, and a polyethylene catheter (BECTON DICKINSON, PE50) filled with saline (Otsuka) was inserted into a femoral vein. After the bladder was emptied, the rats were left for 1 hour for recovery from the operation.
  • urethane Sigma
  • a testing compound dissolved in the mixture of ethanol, Tween 80 (ICN Biomedicals Inc.) and saline (1 : 1 : 8, v/v/v) was administered intravenously at 0.05 mg/kg, 0.5 mg/kg or 5 mg/kg. 3min after the administration of the compound, saline (Nacalai Tesque) was infused at room temperature into the bladder at a rate of 3.6 ml hr.
  • the cystometry parameters were analyzed as described previously [ Lecci A et al, Eur. J. Pharmacol. 259: 129-135, 1994].
  • the micturition frequency calculated from micturition interval and the bladder capacity calculated from a volume of infused saline until the first micturition were analyzed from the cystometry data.
  • the testing compounds-mediated inhibition of the frequency and the testing compounds-mediated increase of bladder capacity were evaluated using unpaired Student's t-test. A probability levels less than 5% was accepted as significant difference. Data were analyzed as the mean + SEM from 4 - 7 rats.
  • Human P2X1 -transfected CHOluc9aeq cell line was established and maintained in Dulbecco's modified Eagle's medium (DMEM/F12) supplemented with 7.5% FCS, 20 mM HEPES-KOH (pH 7.4), 1.4 mM sodium pyruvate, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin, 2 mM glutamine (Gibco BRL) and 0.5 Units/ml apyrase (grade I, Sigma).
  • the suspended cells were seeded in each well of 384-well optical bottom black plates (Nalge Nunc International) at 3 x 10 3 / 50 ⁇ l / well. The cells were cultured for following 48 hrs to adhere to the plates.
  • P2X1 receptor agonist-mediated increases in cytosolic Ca 2+ levels were measured using a fluorescent Ca 2+ chelating dye, Fluo-3 AM (Molecular Probes).
  • the plate-attached cells were washed twice with washing buffer (HBSS, 17 mM HEPES-KOH (pH 7.4), 0.1% BSA and 0.5 units/ml apyrase), and incubated in 40 ⁇ l of loading buffer (1 ⁇ M Fluo-3 AM, 1 mM probenecid, 1 ⁇ M cyclosporin A, 0.01% pluronic (Molecular Probes)in washing buffer) for 1 hour in a dark place.
  • the plates were washed twice with 40 ⁇ l washing buffer and 35 ⁇ l of washing buffer were added in each well with 5 ⁇ l of test compounds or 2 ',3 '-o-(2,4,6-trinitrophenyl) adenosine 5'- triphpsphate (Molecular Probes) as a reference. After further incubation for
  • the tested compounds inhibited the capsaicin-induced increase of intracellular calcium levels (Ca 2+ flux) in the cell line expressing human and rat VRl in a concentration dependent manner with ICso values at nanomolar range.
  • Functional activity (Ca 2+ flux) in the capsaicin-stimulated rat DRG cells was inhibited by the tested compounds.
  • Significant inhibition of the capsaicin-induced rat bladder detrusor contraction was observed for the tested compounds.
  • VRl antagonist on the capsaicin-induced overactive bladder in vivo in anesthetized rats was investigated.
  • the overactive bladder was induced by intra- vesical infusion of capsaicin solution.
  • the frequency of the micturition was compared.
  • Fig. 1 presents charts showing bladder capacity and voiding frequency in normal rats (Normal), cyclophosphamide treated rats (CYP-rats), CYP-rats treated with VRl antagonist, (N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-(2,4-dichloro-7-hydroxy- 1 - naphthyl)urea) (CYP-VRl) and CYP-rats treated with capsaicin to desensitize sensory nerve (CYP-capsaicin).
  • Fig. 2 presents graphs which show the bladder capacity in normal rats (Normal), cyclophosphamide treated rats (CYP-rats) and CYP-rats treated with VRl antagonist (N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-(2,4-dichloro-7-hydroxy-l- naphthyl)urea) (CYP-VRl).
  • VRl antagonist N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-(2,4-dichloro-7-hydroxy-l- naphthyl)urea
  • Fig. 3 presents graphs which show the micturition frequency in normal rats (Normal), cyclophosphamide treated rats(CYP-rats) and CYP-rats treated with VRl antagonist (N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-(2,4-dichloro-7-hydroxy- 1 -naph- thyl)urea) (CYP-VRl).
  • Avelino, A. and Cruz, F Peptide immunoreactivity and ultrastructure of rat urinary bladder nerve fibers after topical desensitization by capsaicin or resiniferatoxin., Auton. Neurosci; 86 (1-2): 37-46, 2000

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Abstract

L'invention concerne des procédés de traitement de troubles urologiques. Plus particulièrement, l'invention concerne l'utilisation d'un antagoniste d'un récepteur vanilloïde (VR1) pour la prophylaxie et le traitement de l'incontinence urinaire et de l'hyperactivité de la vessie.
PCT/EP2003/010111 2002-09-24 2003-09-11 Utilisation d'antagonistes du recepteur vanilloide pour le traitement de troubles urologiques WO2004028440A2 (fr)

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AU2003273856A AU2003273856A1 (en) 2002-09-24 2003-09-11 Vr1 antagonists for the treatment of urological disorders

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EP02021367.4 2002-09-24
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US7432275B2 (en) 2002-12-13 2008-10-07 Neurogen Corporation Carboxylic acid, phosphate or phosphonate substituted quinazolin-4-ylamine analogues as capsaicin receptor modulators
US7566712B2 (en) 2003-07-16 2009-07-28 Neurogen Corporation Biaryl piperazinyl-pyridine analogues
US7728005B2 (en) 2003-10-14 2010-06-01 Ajinomoto Co., Inc. Ether derivative
US8128591B2 (en) 2008-11-10 2012-03-06 Warsaw Orthopedic, Inc. Multiple component mixing and delivery system
US8759361B2 (en) 2006-08-23 2014-06-24 Neurogen Corporation 2-phenoxy pyrimidinone analogues
DE102022104759A1 (de) 2022-02-28 2023-08-31 SCi Kontor GmbH Co-Kristall-Screening Verfahren, insbesondere zur Herstellung von Co-Kristallen

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US7566712B2 (en) 2003-07-16 2009-07-28 Neurogen Corporation Biaryl piperazinyl-pyridine analogues
US7728005B2 (en) 2003-10-14 2010-06-01 Ajinomoto Co., Inc. Ether derivative
US8759361B2 (en) 2006-08-23 2014-06-24 Neurogen Corporation 2-phenoxy pyrimidinone analogues
US8128591B2 (en) 2008-11-10 2012-03-06 Warsaw Orthopedic, Inc. Multiple component mixing and delivery system
DE102022104759A1 (de) 2022-02-28 2023-08-31 SCi Kontor GmbH Co-Kristall-Screening Verfahren, insbesondere zur Herstellung von Co-Kristallen

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