WO2004108645A1 - Method for the treatment or prevention of lower urinary tract symptoms - Google Patents

Method for the treatment or prevention of lower urinary tract symptoms Download PDF

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Publication number
WO2004108645A1
WO2004108645A1 PCT/FI2004/000270 FI2004000270W WO2004108645A1 WO 2004108645 A1 WO2004108645 A1 WO 2004108645A1 FI 2004000270 W FI2004000270 W FI 2004000270W WO 2004108645 A1 WO2004108645 A1 WO 2004108645A1
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Prior art keywords
enyl
chloro
urinary tract
lower urinary
bladder
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PCT/FI2004/000270
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French (fr)
Inventor
Risto Santti
Tomi Streng
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Hormos Medical Corporation
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Priority to ES04731197.2T priority Critical patent/ES2524575T3/en
Priority to JP2006508325A priority patent/JP4731470B2/en
Priority to EP04731197.2A priority patent/EP1636159B1/en
Priority to AU2004245251A priority patent/AU2004245251B2/en
Priority to CA 2527396 priority patent/CA2527396C/en
Priority to MXPA05013104A priority patent/MXPA05013104A/en
Publication of WO2004108645A1 publication Critical patent/WO2004108645A1/en
Priority to NO20055187A priority patent/NO337660B1/en
Priority to IS8162A priority patent/IS2958B/en
Priority to AU2010257419A priority patent/AU2010257419B2/en

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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
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    • A61K31/05—Phenols
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    • 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
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
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    • 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
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    • 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
    • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
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    • 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
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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Definitions

  • This invention relates to a method for treatment or prevention of lower urinary tract symptoms with or without pelvic pain in an individual, said method comprising administering to the individual an effective amount of a selective estrogen receptor modulator (SERM).
  • SERM selective estrogen receptor modulator
  • urethral sphincter dysfunction The main functional cause of LUTS is urethral sphincter dysfunction.
  • the urethral sphincter consists of a voluntary (striated) sphincter (rhabdosphincter) and an involuntary (smooth) sphincter.
  • the distal part of the male rhabdosphincter surrounds the membranous part of the urethra and is called external sphincter.
  • the upper or prostatic part of the rhabdosphincter is layered out over the anterior and lateral aspects of the prostate and embedded in the prostatic stroma in men.
  • the urethral smooth muscle is located at the bladder neck and prostatic urethra in men. Lowering of resistance of the smooth and striated sphincter, associated with coordinated detrusor contraction determines complete micturation. In urethral sphincter dysfunction an increased intraluminal bladder pressure is needed to empty the bladder. In the initial stages, there is no reduction in the flow rate because the maximum micturition pressure compensates for the increased outflow resistance. The reduction of the flow rate developing in more advanced clinical stages of urethral dysfunction correlates poorly with the degree of prostatic enlargement.
  • bladder neck dyssynergia 2) external sphincter pseudodyssynergia and 3) Hinman syndrome. They have all been defined as detrusor urethral sphincter dyssynergia.
  • Bladder neck dyssynergia is defined as the inability of the bladder neck to open properly and assume a funneled shape in the presence of a normal detrusor contractionNideoimaging techniques allow the diagnosis of the smooth sphincter dyssynergia.
  • the bladder neck dyssynergia is a life-long condition, and virtually never occurs in the female. The cause of the bladder neck dyssynergia is unknown.
  • Rhabdosphincter dyssynergia is defined as an inappropriate increase in striated urethral muscle (external urethral sphincter) activity during a detrusor contraction and is a well recognized cause of voiding dysfunction in patients with upper neurone lesions.
  • Urodynamic investigations in children with an abnormal voiding pattern have shown dyssynergia between the detrusor and striated urethral sphincter in the absence of neurologic disease (non-neurogenic neurogenic bladder or the Hinman syndrome). This appears to result from unintentional, habitual contractions of the striated urethral sphincter in response to involuntary bladder contraction to prevent urinary incontinence. This dyssynergia probably may at least partly represent a learned habit. The relationship between the Hinman syndrome and the external sphincter pseudodyssynergia is not known.
  • Patients with urethral sphincter dysfunction may develop secondary detrusor instability with irritative symptoms of frequency, urgency and nocturia.
  • LUTS may be associated with chronic pelvic pain.
  • the article written by Oliver W Hakenberg and Manfred P Wirth (Urol Int 2002:68:138-143), concerns chronic pelvic pain syndrome (CPPS) in men. This is defined as a condition of pelvic pain of more than 6 months duration.
  • CPPS chronic pelvic pain syndrome
  • Certain conditions causing CPPS are mentioned, namely abacterial prostatitis, stress prostatitis, prostatodynia, urethral syndrome, trigonitis and orchialgia.
  • Interstitial cystitis in men or women will also typically result in pelvic pain.
  • a primary difficulty noted in patients with CPPS is the inability to voluntarily relax the external sphincter and the pelvic floor muscles. This will result in the emergency of LUTS and dyssynergic voiding.
  • US 5,972,921 describes a method for the treatment of detrusor urethral sphincter dyssynergia in men by administering an aromatase inhibitor to the patient.
  • Said patent gives a summary of the clinical symptoms of male functional detrusor urethral sphincter dyssynergia and its treatments taking into account especially the possible hormonal background of the symptoms.
  • Aromatase inhibitors when studied in men with urinary symptoms (A Radlmaier et al., The Prostate 29:199-208 (1996); J C Gingell et al., The Journal of Urology, vol. 154,399-401, August 1995), increase the concentrations of testosterone.
  • SERMs which act as antiestrogens in the urinary tract, decrease the detrimental effect of natural estrogens without stimulating the prostate size. They can be considered as potentially beneficial compounds in treating the symptoms and functional causes of LUTS.
  • SERM selective estrogen receptor modulators
  • the effects may be tissue-specific as in the case of tamoxifen and toremifene which have estrogen-like effects in the bone, partial estrogen-like effect in the uterus and liver, and pure antiestrogenic effect in breast cancer.
  • Raloxifene and droloxifen are similar to tamoxifen and toremifene, except that their antiestrogenic properties dominate. They are known to decrease total and LDL cholesterol, thus deminishing the risk of cardiovascular diseases, and they may prevent osteoporosis and inhibit breast cancer growth in postmenopausal women.
  • the inventors of the present invention have surprisingly found that compounds belonging to the group of selective estrogen receptor modulators have beneficial effects on urodynamic parameters in animal studies. Therefore, the inventors suggest that this class of compounds may be useful for treating or preventing LUTS caused by urethral sphincter dysfunction.
  • this invention concerns a method for treatment or prevention of lower urinary tract symptoms with or without pelvic pain in an individual, said method comprising administering to the individual an effective amount of a selective estrogen receptor modulator, or an isomer, isomer mixture or a pharmaceutically acceptable salt thereof.
  • Figure 2 shows the maximal bladder pressure for non-estrogenized rats and for neoDES rats with and without administration of test compounds.
  • Figure 3 shows the average bladder pressure for non-estrogenized rats and for neoDES rats with and without administration of test compounds.
  • Figure 4 shows the maximal flow rate for non-estrogenized rats and for neoDES rats with and without administration of test compounds.
  • Figure 5 shows the average flow rate for non-estrogenized rats and for neoDES rats with and without administration of test compounds.
  • Figure 6 shows the micturition time for non-estrogenized rats and for neoDES rats with and without administration of test compounds.
  • Figure 7 shows the amount of residual urine for non-estrogenized rats and for neoDES rats with and without administration of test compounds.
  • Figure 8 shows the bladder capacity for non-estrogenized rats and for neoDES rats with and without administration of test compounds.
  • the term "individual” relates particularly to humans, but it shall also be considered to include animals.
  • lower urinary tract symptoms relates to symptoms in male as well as in female individuals.
  • a particularly important class of such symptoms is detrusor urethral sphincter dyssynergia, but the term is not restricted hereto.
  • Any kind of symptoms in the lower urinary tract in male individuals shall be covered by the term.
  • the term “lower urinary tract symptoms” shall also be understood to include abacterial prostatitis, stress prostatitis, trigonitis and orchialgia in male individuals, and interstitial cystitis in male or female individuals. For female individuals, this term further include bladder instability and micturition urgency.
  • pellet pain shall here be understood to include symptoms related to abacterial prostatitis, stress prostatitis, prostatodynia, urethral syndroms, trigonitis or orchialgia in a male individual. Furthermore, the term includes interstitial cystitis either in male or female individuals.
  • selective estrogen receptor modulator and any specific compound belonging to this group shall be understood to cover any geometric isomer, any stereoisomer, racemate or other mixture of isomers of the compound.
  • pharmaceutically acceptable salts and other derivatives such as esters are also included.
  • Suitable selective estrogen receptor modulators (or SERMs) for use in this invention are, for example, the compounds disclosed in V Craig Jordan (2003).
  • SERM compounds for use in the present invention are triphenylalkene or triphenylalkane compounds such as compounds disclosed in WO 01/36360, US 4,996,225, US 4,696,949, US 5,750,576, WO 99/42427 and the toremifene metabolites disclosed in L Kangas, Cancer Chemother Pharmacol (1990)27:8-12.
  • specific drugs disclosed in the aforementioned references can be mentioned toremifene, fispemifene and ospemifene.
  • Tamoxifen and its derivatives such as 4-hydroxytamoxifen, alpha-hydroxytamoxifen, N- desmethyltamoxifen, N,N-didesmethyltamoxifen, deaminotamoxifen, and droloxifene and iodoxifene also examples of suitable SERMs of triphenylalkene structure.
  • SERM compounds are compounds of benzothiophene structure, such as raloxifene and its analogues (described for example in EP 584952, US 4,133,814, US 4,418,068) and arzoxifene.
  • SERMs can be mentioned EM652, EM800, EM776, EM651, EM312, ICI 182780, ERA-923, zindoxifene and deacetylated zindoxifene, ZK119010, TSE-4247, lasoxifene and its analogues, particularly those disclosed in EP 802910, nafoxidine, basedoxifene, GW5638, GW7604, compound no. 32 disclosed in Jordan (2003), ICI 164384, RU 58668, RU 39411 and EM 319.
  • SERMs with no or weak estrogenic effect may suitable for use, particularly in male individuals.
  • a classical method to determine the estrogenic profile of a compound is to evaluate estrogenic effect in immature mouse or rat uterus (Terenius L, Acta Endocrinol 66:431-447, 1971). The animals are exposed for 3 days to the compounds to be investigated at the age of 18 days. On the fourth day the animals are sacrificed and body weight and uterine weight is recorded. Estrogens increase the size and weight of the uterus (uterotropic effect) while antiestrogens inhibit this action.
  • SERMs As specific examples of particularly useful SERMs can be mentioned certain compounds of those disclosed in WO 01/36360, namely
  • the aforementioned six compounds are all classified as weak estrogenic SERMs.
  • the SERM or its isomer, isomer mixture or their pharmaceutically acceptable salts can be administered by various routes.
  • suitable administration forms include, for example, oral formulations; parenteral injections including intravenous, intramuscular, intradermal and subcutanous injections; and transdermal or rectal formulations.
  • Suitable oral formulations include e.g. conventional or slow-release tablets and gelatine capsules.
  • the required dosage of the SERM compounds will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the administration route and the specific compound being employed.
  • fispemifene can be administered perorally preferentially once daily.
  • the daily dose may be 5 - 150 mg, preferably 20-100 mg.
  • Fispemifene can be given as tablets or other formulations like gelatine capsules alone or mixed in any clinically acceptable non-active ingredients which are used in the pharmaceutical industry.
  • mice Male rats were supplied by The Central Animal Laboratory of the University of Turku, Finland. Their mean age was 222 days (SD 48.4). The number of the non- estrogenized rats was 50 and the number of developmentally estrogenized rats was 29. The rats were maintained under standard laboratory conditions at 12:12 light/dark cycle and they got soyfree pelleted food (SDS, Witham, Essex, UK) with free access. They had also free access to tap water.
  • the estrogenized rats were developed as follows: Male Noble rats were treated neonatally with estrogen (10 ⁇ g of diethylstilbestrol (DES)) in rap seed oil (10 ⁇ g/40 ⁇ l) s.c. on days 1-5 of postnatal life. After the treatment with diethylstilbestrol, the neoDES rats were left to grow for 4-5 months before treatment with study drugs.
  • DES diethylstilbestrol
  • the dosing volume was 0.2 ml solutions/50 g body weight and the dose level of fispemifene or raloxifene 1 and/or 10 mg/kg body weight.
  • the dose was given once a day for six weeks.
  • the rats were weighed for the first time on the same day, as the treatments began. Afterwards the animals were weighed once a week. This was carried out to ensure the right dosing to rats.
  • the anaesthetized rats (non-estrogenized or neonatally estrogenized) were treated orally with fispemifene or raloxifene using doses of 1 and/or 10 mg/kg body weight.
  • the rats were anesthetized with chloral hydrate (0.9 g/kg, Sigma Chemical Co. St. Luis. MO 63178, USA) for a basic anaesthetic, and i.v. injection of urethane (0.32 g/kg, Sigma Chemical Co. St. Luis. MO 63178, USA) was used to maintain anesthesia for urodynamical measurements.
  • the body temperature was kept constant at +36- 38°C by a thermostatically controlled animal blanket and if needed, with a heating lamp.
  • the bladder and the distal part of urethra were exposed with a midline incision of the lower abdomen.
  • transvesical cystometry a 20G i.v. cannula was inserted through the bladder apex into the lumen.
  • the cannula was connected to an infusion pump and to a pressure transducer.
  • the whole system was filled with saline. Measurements were made at the infusion rate of 0.23 ml/min.
  • An ultrasonic flow probe was used for measurement of the flow rate from the distal part of urethra.
  • the flow probe was connected to a flow meter, with sampling rate of 100 Hz.
  • the electrical activity of the striated urethral sphincter was measured extracellularily with suction electrode.
  • the electrode was attached on anterior surface of the muscle by suction (provided by a flow of tap water).
  • the suction electrode and pressure transducer were connected to an amplifier.
  • Low frequency AC coupling (0.8 Hz) was used in electrical activity measurement.
  • the reference and ground electrodes were placed on the edge of the wound so that ECG signal was not observable.
  • the tissues were kept moist during measurements with warm (+37°C) saline.
  • the pressure and flow meter signals were transferred to the Biopac-system.
  • the Biopac-system was connected to a personal computer. Continuous recording was made with Acq Knowledge 3.5.3 program with sample rate of 400 Hz.
  • Intraluminal pressure high frequency oscillations (IPHFOs) of bladder pressure are characteristic in male rodent micturition during the second phase, during which also the urine flow occurs.
  • the maximum and mean bladder pressures were calculated from the pressure oscillations seen in pressure wave. The maximum value was measured from the highest peak and the mean value from all IPHFOs during the second phase of micturition.
  • the maximum flow rate value was measured from the highest flow rate peak and the mean flow rate value from all flow peaks during the second phase of micturition. The duration of the micturition and the volume of the residual urine were measured.
  • Figure 1 illustrates one typical micturition cycle showing bladder pressure wave (a) and flow rate wave (b), and the method for calculation of the urodynamical parameters.
  • the measurement of the maximal bladder pressure, flow rate, and micturition time are shown in the figure.
  • Parameters of mean bladder pressure and - flow rate are measured as average from all the bladder pressure and flow rate peaks, respectively.
  • NeoDES treatment decreased the flow rate and SERMs normalized it indicating a positive effect on urodynamics.
  • Treatment with fispemifene or raloxifene increased both the maximal (Table 3) and mean (Table 4) flow rate in non- and neonatally estrogenized rats with dose of 10 mg/kg. No differences were seen with dose of 1 mg/kg in non- estrogenized rats.
  • Neonatally estrogenized rats received only 10 mg/kg of drug treatment. Neonatally estrogenized rats showed lower flow rates than non- estrogenized rats.
  • miceturition time was significantly prolonged in neonatally estrogenized rats. This is well understandable, because the urine flow rate was decreased. Treatments with HM-101 or raloxifene did not shorten the micturition time in non-estrogenized rats. In neonatally estrogenized rats the treatments shortened the micturition time. Although the effect did not quite reach the statistical significance, the effect can be considered beneficial.
  • the micturition time is also shown in Figure 6.
  • the amount of residual urine was increased significantly in neonatally estrogenized rats indicating that the bladder was not completely empty after urination. Residual urine leads to increased urination frequency and is also a risk factor of lower urinary tract infections.
  • the treatment with fispemifene (10 mg/kg) did reduce the amount of residual urine both in non- and neonatally estrogenized rats. This result is very promising and indicates improved functional activity of the bladder.
  • Raloxifene (10 mg/kg) reduced the amount of residual urine almost significantly in non- estrogenized, and significantly in neonatally estrogenized rats (Table 6).
  • the residual urine is also shown in Figure 7.
  • the bladder capacity is also illustrated in Figure 8.
  • the rhabdosphincter function was improved in both non- and neonatally estrogenized rats, but the EMG changes were not statistically significant. Fispemifene and raloxifene reversed the estrogen-related alterations in flow rates, micturition time, and bladder capacity (fispemifene even in non-estrogenized rats).

Abstract

This invention concerns a method for treatment or prevention of lower urinary tract symptoms with or without pelvic pain in an individual, said method comprising administering to the individual an effective amount of a selective estrogen receptor modulator, or an isomer, isomer mixture or a pharmaceutically acceptable salt thereof.

Description

METHOD FOR THE TREATMENT OR PREVENTION OF LOWER URINARY TRACT SYMPTOMS
FIELD OF THE INVENTION
This invention relates to a method for treatment or prevention of lower urinary tract symptoms with or without pelvic pain in an individual, said method comprising administering to the individual an effective amount of a selective estrogen receptor modulator (SERM).
BACKGROUND OF THE INVENTION
The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference.
Lower urinary tract symptoms (LUTS)
Typical clinical symptoms included in this group are hesitance, poor urinary stream, terminal drippling and incomplete bladder emptying. The main functional cause of LUTS is urethral sphincter dysfunction. The urethral sphincter consists of a voluntary (striated) sphincter (rhabdosphincter) and an involuntary (smooth) sphincter. The distal part of the male rhabdosphincter surrounds the membranous part of the urethra and is called external sphincter. The upper or prostatic part of the rhabdosphincter is layered out over the anterior and lateral aspects of the prostate and embedded in the prostatic stroma in men. The urethral smooth muscle is located at the bladder neck and prostatic urethra in men. Lowering of resistance of the smooth and striated sphincter, associated with coordinated detrusor contraction determines complete micturation. In urethral sphincter dysfunction an increased intraluminal bladder pressure is needed to empty the bladder. In the initial stages, there is no reduction in the flow rate because the maximum micturition pressure compensates for the increased outflow resistance. The reduction of the flow rate developing in more advanced clinical stages of urethral dysfunction correlates poorly with the degree of prostatic enlargement.
Three different clinical outcomes have been described: 1) bladder neck dyssynergia, 2) external sphincter pseudodyssynergia and 3) Hinman syndrome. They have all been defined as detrusor urethral sphincter dyssynergia.
Bladder neck dyssynergia is defined as the inability of the bladder neck to open properly and assume a funneled shape in the presence of a normal detrusor contractionNideoimaging techniques allow the diagnosis of the smooth sphincter dyssynergia. The bladder neck dyssynergia is a life-long condition, and virtually never occurs in the female. The cause of the bladder neck dyssynergia is unknown.
During the normal micturition cycle, an increase in external sphincter electromyographic activity accompanies bladder filling (continence reflex). This is followed by relaxation of rhabdosphincter and the pelvic floor muscles, which begins before or at the beginning of the detrusor contraction and persists throughout the contraction. Rhabdosphincter dyssynergia is defined as an inappropriate increase in striated urethral muscle (external urethral sphincter) activity during a detrusor contraction and is a well recognized cause of voiding dysfunction in patients with upper neurone lesions. This overcompensation owing to the loss of supraspinal influences is done to counteract the elevated bladder pressure caused by uninhibited detrusor contraction (an exaggerated continence reflex). In external sphincter pseudodyssynergia, incoordination between the bladder and urethral sphincter is not due to a neurological lesion but is secondary to a dysfunction resulting in an increased tone of the external sphincter and the pelvic floor muscles. Pseudodyssynergia is determined by intermittent increase in sphincter EMG and/or intermittent narroeing of the urethra at this site.
Urodynamic investigations in children with an abnormal voiding pattern have shown dyssynergia between the detrusor and striated urethral sphincter in the absence of neurologic disease (non-neurogenic neurogenic bladder or the Hinman syndrome). This appears to result from unintentional, habitual contractions of the striated urethral sphincter in response to involuntary bladder contraction to prevent urinary incontinence. This dyssynergia probably may at least partly represent a learned habit. The relationship between the Hinman syndrome and the external sphincter pseudodyssynergia is not known.
Patients with urethral sphincter dysfunction may develop secondary detrusor instability with irritative symptoms of frequency, urgency and nocturia.
LUTS may be associated with chronic pelvic pain. The article written by Oliver W Hakenberg and Manfred P Wirth (Urol Int 2002:68:138-143), concerns chronic pelvic pain syndrome (CPPS) in men. This is defined as a condition of pelvic pain of more than 6 months duration. Certain conditions causing CPPS are mentioned, namely abacterial prostatitis, stress prostatitis, prostatodynia, urethral syndrome, trigonitis and orchialgia. Interstitial cystitis in men or women will also typically result in pelvic pain. A primary difficulty noted in patients with CPPS is the inability to voluntarily relax the external sphincter and the pelvic floor muscles. This will result in the emergency of LUTS and dyssynergic voiding.
On the basis of the findings in experimental animals (Streng: Hormone-related reversible urinary rhabdosphincter disorder in male laboratory rodents - possible clinical implications. Academic dissertation, University of Turku, 2002), we suggest that the increased ratio of estrogen to androgen concentration (relative overaromatization of androgens) in the organism plays a role in the development of the urethral sphincter dysfunction in men. In male animals chronically treated with estrogen bladder outlet obstruction develops with complete urinary retention and hypertrophy of the bladder wall. Neonatally estrogenized animals have a lower voided urine volume and decreased ratio of urinary flow rate - to - bladder pressure, which are consistent with infravesical obstruction. These urodynamic changes of the neonatally estrogenized animals are reversed after the treatment of aromatase inhibitor in adulthood. The urethral smooth and striated sphincters and neurones innervating them show androgen and estrogen receptors suggesting that they are the potential target of androgens and estrogen actions. The prostate of these animals have reduced size and show signs of inflammation.
US 5,972,921 describes a method for the treatment of detrusor urethral sphincter dyssynergia in men by administering an aromatase inhibitor to the patient. Said patent gives a summary of the clinical symptoms of male functional detrusor urethral sphincter dyssynergia and its treatments taking into account especially the possible hormonal background of the symptoms. Aromatase inhibitors, when studied in men with urinary symptoms (A Radlmaier et al., The Prostate 29:199-208 (1996); J C Gingell et al., The Journal of Urology, vol. 154,399-401, August 1995), increase the concentrations of testosterone. This causes an increase in the size of prostate and on the other hand may worsen the static obstruction caused ny the enlarged prostate and consequently the symptoms. Therefore, other mechanisms of action are desirable. SERMs, which act as antiestrogens in the urinary tract, decrease the detrimental effect of natural estrogens without stimulating the prostate size. They can be considered as potentially beneficial compounds in treating the symptoms and functional causes of LUTS.
Selective estrogen receptor modulators
"SERM"s (selective estrogen receptor modulators) have both estrogen-like and antiestrogenic properties (Kauffman & Bryant, Drug News Perspect 8:531-539, 1995). The effects may be tissue-specific as in the case of tamoxifen and toremifene which have estrogen-like effects in the bone, partial estrogen-like effect in the uterus and liver, and pure antiestrogenic effect in breast cancer. Raloxifene and droloxifen are similar to tamoxifen and toremifene, except that their antiestrogenic properties dominate. They are known to decrease total and LDL cholesterol, thus deminishing the risk of cardiovascular diseases, and they may prevent osteoporosis and inhibit breast cancer growth in postmenopausal women. There are also almost pure antiestrogens under development. They are mainly aimed at the treatment of breast cancer (Wakeling & Bowler, J Steroid Biochem 30:1-6, 1988). A review of investigated and/or marketed SERM compounds is published in N Craig Jordan, J Medicinal Chemistry (2003):46, Νo.7.
SUMMARY OF THE INVENTION
The inventors of the present invention have surprisingly found that compounds belonging to the group of selective estrogen receptor modulators have beneficial effects on urodynamic parameters in animal studies. Therefore, the inventors suggest that this class of compounds may be useful for treating or preventing LUTS caused by urethral sphincter dysfunction.
Thus, this invention concerns a method for treatment or prevention of lower urinary tract symptoms with or without pelvic pain in an individual, said method comprising administering to the individual an effective amount of a selective estrogen receptor modulator, or an isomer, isomer mixture or a pharmaceutically acceptable salt thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows a typical micturition cycle (a = bladder pressure; b = flow rate).
Figure 2 shows the maximal bladder pressure for non-estrogenized rats and for neoDES rats with and without administration of test compounds.
Figure 3 shows the average bladder pressure for non-estrogenized rats and for neoDES rats with and without administration of test compounds.
Figure 4 shows the maximal flow rate for non-estrogenized rats and for neoDES rats with and without administration of test compounds.
Figure 5 shows the average flow rate for non-estrogenized rats and for neoDES rats with and without administration of test compounds. Figure 6 shows the micturition time for non-estrogenized rats and for neoDES rats with and without administration of test compounds.
Figure 7 shows the amount of residual urine for non-estrogenized rats and for neoDES rats with and without administration of test compounds.
Figure 8 shows the bladder capacity for non-estrogenized rats and for neoDES rats with and without administration of test compounds.
DETAILED DESCRIPTION OF THE INVENTION
Definitions:
The term "individual" relates particularly to humans, but it shall also be considered to include animals.
The term "lower urinary tract symptoms" relates to symptoms in male as well as in female individuals. For male individuals, a particularly important class of such symptoms is detrusor urethral sphincter dyssynergia, but the term is not restricted hereto. Any kind of symptoms in the lower urinary tract in male individuals shall be covered by the term. Thus, in this invention the term "lower urinary tract symptoms" shall also be understood to include abacterial prostatitis, stress prostatitis, trigonitis and orchialgia in male individuals, and interstitial cystitis in male or female individuals. For female individuals, this term further include bladder instability and micturition urgency.
The term "pelvic pain" shall here be understood to include symptoms related to abacterial prostatitis, stress prostatitis, prostatodynia, urethral syndroms, trigonitis or orchialgia in a male individual. Furthermore, the term includes interstitial cystitis either in male or female individuals. The wording "selective estrogen receptor modulator" and any specific compound belonging to this group shall be understood to cover any geometric isomer, any stereoisomer, racemate or other mixture of isomers of the compound. Furthermore, pharmaceutically acceptable salts and other derivatives such as esters are also included.
Suitable selective estrogen receptor modulators (or SERMs) for use in this invention are, for example, the compounds disclosed in V Craig Jordan (2003).
Thus, examples of suitable SERM compounds for use in the present invention are triphenylalkene or triphenylalkane compounds such as compounds disclosed in WO 01/36360, US 4,996,225, US 4,696,949, US 5,750,576, WO 99/42427 and the toremifene metabolites disclosed in L Kangas, Cancer Chemother Pharmacol (1990)27:8-12. As examples of specific drugs disclosed in the aforementioned references can be mentioned toremifene, fispemifene and ospemifene. Tamoxifen and its derivatives such as 4-hydroxytamoxifen, alpha-hydroxytamoxifen, N- desmethyltamoxifen, N,N-didesmethyltamoxifen, deaminotamoxifen, and droloxifene and iodoxifene also examples of suitable SERMs of triphenylalkene structure.
Other preferable examples of SERM compounds are compounds of benzothiophene structure, such as raloxifene and its analogues (described for example in EP 584952, US 4,133,814, US 4,418,068) and arzoxifene.
As further examples of suitable SERMs can be mentioned EM652, EM800, EM776, EM651, EM312, ICI 182780, ERA-923, zindoxifene and deacetylated zindoxifene, ZK119010, TSE-4247, lasoxifene and its analogues, particularly those disclosed in EP 802910, nafoxidine, basedoxifene, GW5638, GW7604, compound no. 32 disclosed in Jordan (2003), ICI 164384, RU 58668, RU 39411 and EM 319.
The aforementioned specific SERMs or classes of SERMs are examples only, and other SERMs may be suitable for use in this invention as well. SERMs with no or weak estrogenic effect may suitable for use, particularly in male individuals. A classical method to determine the estrogenic profile of a compound is to evaluate estrogenic effect in immature mouse or rat uterus (Terenius L, Acta Endocrinol 66:431-447, 1971). The animals are exposed for 3 days to the compounds to be investigated at the age of 18 days. On the fourth day the animals are sacrificed and body weight and uterine weight is recorded. Estrogens increase the size and weight of the uterus (uterotropic effect) while antiestrogens inhibit this action. The results are given as per cent of estrogen stimulation (100 % with estradiol). In our tests, we used a high dose level, i.e. 10-50 mg/kg. Compounds causing an uterotropic effect < 40 % are for this purpose classified as weak estrogenic compounds, compounds causing an uterotropic effect > 70 % are classified as strong estrogenic compounds and compounds in-between, an uterotropic effect of 41-69 % are classified as moderate estrogenic agents.
As specific examples of particularly useful SERMs can be mentioned certain compounds of those disclosed in WO 01/36360, namely
(Z)-2-[3-(4-Chloro- 1 ,2-diphenyl-but- 1 -enyl)phenoxy]ethanol (Z)-2-{2-[4-(4-Chloro-l ,2-diphenylbut-l -enyl)phenoxy]ethoxy}ethanol (also known under the generic name fispemifene)
(Z)- { 2- [3 -(4-Chloro- 1 ,2-diphenylbut- 1 -enyl)phenoxy] ethyl } dimethylamine
(E)-3 - {4-Chloro- 1 - [4-(2-hydroxyethoxy)phenyl] -2-phenyl-but- 1 -enyl } -phenol
(E)-3 - {4-Chloro- 1 -[4-(2-imidazol- 1 -yl-ethoxy)phenyl] -2-phenyl-but- 1 -enyl} -phenol, and
(Z)-3- {4-Chloro- 1 - [4-(2-imidazol- 1 -yl-ethoxy)phenyl]-2-phenyl-but- 1 -enyl} -phenol.
The aforementioned six compounds are all classified as weak estrogenic SERMs.
For the purpose of this invention, the SERM or its isomer, isomer mixture or their pharmaceutically acceptable salts can be administered by various routes. The suitable administration forms include, for example, oral formulations; parenteral injections including intravenous, intramuscular, intradermal and subcutanous injections; and transdermal or rectal formulations. Suitable oral formulations include e.g. conventional or slow-release tablets and gelatine capsules.
The required dosage of the SERM compounds will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the administration route and the specific compound being employed. For example, fispemifene can be administered perorally preferentially once daily. The daily dose may be 5 - 150 mg, preferably 20-100 mg. Fispemifene can be given as tablets or other formulations like gelatine capsules alone or mixed in any clinically acceptable non-active ingredients which are used in the pharmaceutical industry.
The invention will be illuminated by the following non-restrictive Experimental Section.
EXPERIMENTAL SECTION
Methods and materials
Tested drugs:
We studied the effects of two SERMs, namely fispemifene, which also is known under the code HM-101, and raloxifene on voiding in control as well as in developmentally estrogenized male rats. As vehicle was used polyethylene glycol (PEG).
Animals:
Male rats were supplied by The Central Animal Laboratory of the University of Turku, Finland. Their mean age was 222 days (SD 48.4). The number of the non- estrogenized rats was 50 and the number of developmentally estrogenized rats was 29. The rats were maintained under standard laboratory conditions at 12:12 light/dark cycle and they got soyfree pelleted food (SDS, Witham, Essex, UK) with free access. They had also free access to tap water.
The estrogenized rats (neoDES) were developed as follows: Male Noble rats were treated neonatally with estrogen (10 μg of diethylstilbestrol (DES)) in rap seed oil (10 μg/40μl) s.c. on days 1-5 of postnatal life. After the treatment with diethylstilbestrol, the neoDES rats were left to grow for 4-5 months before treatment with study drugs.
Dosing and weighing:
The dosing volume was 0.2 ml solutions/50 g body weight and the dose level of fispemifene or raloxifene 1 and/or 10 mg/kg body weight. The dose was given once a day for six weeks. The rats were weighed for the first time on the same day, as the treatments began. Afterwards the animals were weighed once a week. This was carried out to ensure the right dosing to rats.
Study design for urodynamical studies:
There were eight groups of adult male rats. The anaesthetized rats (non-estrogenized or neonatally estrogenized) were treated orally with fispemifene or raloxifene using doses of 1 and/or 10 mg/kg body weight.
The following animal codes are used in the study:
Treatment of non-estrogenized rats:
- Control rats (only with vehicle treatment) Co
- Rats treated with fispemifene, 1 mg/kg dose HMCol
- Rats treated with fispemifene, 10 mg/kg dose HMColO - Rats treated with raloxifene, 1 mg/kg dose RalCol
- Rats treated with raloxifene, 10 mg/kg dose RalCo 10 Treatment of neonatally estrogenized rats:
- Control rats (neoDES) (only with vehicle treatment) neoDES
- Rats treated with fispemifene, 10 mg/kg dose HMDES 10
- Rats treated with raloxifene, 10 mg/kg dose RalDES 10
The above codes are used in the tables and figures.
Measurements and apparatus:
The rats were anesthetized with chloral hydrate (0.9 g/kg, Sigma Chemical Co. St. Luis. MO 63178, USA) for a basic anaesthetic, and i.v. injection of urethane (0.32 g/kg, Sigma Chemical Co. St. Luis. MO 63178, USA) was used to maintain anesthesia for urodynamical measurements. The body temperature was kept constant at +36- 38°C by a thermostatically controlled animal blanket and if needed, with a heating lamp. The bladder and the distal part of urethra were exposed with a midline incision of the lower abdomen. In transvesical cystometry a 20G i.v. cannula was inserted through the bladder apex into the lumen. The cannula was connected to an infusion pump and to a pressure transducer. The whole system was filled with saline. Measurements were made at the infusion rate of 0.23 ml/min. An ultrasonic flow probe was used for measurement of the flow rate from the distal part of urethra. The flow probe was connected to a flow meter, with sampling rate of 100 Hz. At the same time with the measurements of transvesical cystometry and flow rate, the electrical activity of the striated urethral sphincter (rhabdosphincter) was measured extracellularily with suction electrode. The electrode was attached on anterior surface of the muscle by suction (provided by a flow of tap water). The suction electrode and pressure transducer were connected to an amplifier. Low frequency AC coupling (0.8 Hz) was used in electrical activity measurement. The reference and ground electrodes were placed on the edge of the wound so that ECG signal was not observable. The tissues were kept moist during measurements with warm (+37°C) saline. The pressure and flow meter signals were transferred to the Biopac-system. The Biopac-system was connected to a personal computer. Continuous recording was made with Acq Knowledge 3.5.3 program with sample rate of 400 Hz.
The setup of the apparatus for use in this method is disclosed in US 5,972,921 (column 9-10, Figure 3).
Three representative voidings were chosen for further analysis from each rat. Intraluminal pressure high frequency oscillations (IPHFOs) of bladder pressure are characteristic in male rodent micturition during the second phase, during which also the urine flow occurs. The maximum and mean bladder pressures were calculated from the pressure oscillations seen in pressure wave. The maximum value was measured from the highest peak and the mean value from all IPHFOs during the second phase of micturition. The maximum flow rate value was measured from the highest flow rate peak and the mean flow rate value from all flow peaks during the second phase of micturition. The duration of the micturition and the volume of the residual urine were measured.
Figure 1 illustrates one typical micturition cycle showing bladder pressure wave (a) and flow rate wave (b), and the method for calculation of the urodynamical parameters. The measurement of the maximal bladder pressure, flow rate, and micturition time are shown in the figure. Parameters of mean bladder pressure and - flow rate are measured as average from all the bladder pressure and flow rate peaks, respectively.
Statistics
Continuous recording was made by Acq Knowledge 3.5.3 program (MP100 Manager Ver. 3.5.3, Copyright © 1992-95 BIOPAC Systems Inc.). Further numerical data were carried out with Excel 2000 (Microsoft Corporation, Redmond, WA, USA), and the statistical analysis with Statistica for Windows 5.1 (Stat Soft, Inc., Tulsa, OK, USA). Statistical analysis was carried out with ANOVA and the post hoc tests with HSD test. If Levene's test for variances shows significant differences (p<0.05) between the treatment groups, Kruskall-Wallis test was be used, and Mann- Whitney U test was used as a post hoc test.
Results
Bladder pressure
There were no significant differences in the bladder pressures (maximal and mean) between the groups (Table 1 and 2). Because neoDES treatment did not influence on the bladder pressure, it is not expected that SERMs would influence on it either.
Table 1. Maximal bladder pressure (MBP) (measured from highest bladder pressure oscillation). M= Mann- Whitney U test.
Figure imgf000015_0001
Table 2. Mean bladder pressure (MeBP) (measured from all bladder pressure oscillations). A=One Way ANOVA and Tukey HSD test; M= Mann- Whitney U test.
Figure imgf000016_0001
The maximal and average bladder pressures are also shown in Figures 2 and 3.
Flow rate
Decreased urine flow rate is a definite sign of urination problems. NeoDES treatment decreased the flow rate and SERMs normalized it indicating a positive effect on urodynamics. Treatment with fispemifene or raloxifene increased both the maximal (Table 3) and mean (Table 4) flow rate in non- and neonatally estrogenized rats with dose of 10 mg/kg. No differences were seen with dose of 1 mg/kg in non- estrogenized rats. Neonatally estrogenized rats received only 10 mg/kg of drug treatment. Neonatally estrogenized rats showed lower flow rates than non- estrogenized rats. Table 3. Maximal flow rate (MFR) (measured from highest flow rate peak). A=One Way ANOVA and Tukey HSD test; M= Mann-Whitney U test.
Figure imgf000017_0001
Table 4. Mean flow rate (MeFR) (measured from all flow rate peaks). M= Mann- Whitney U test.
Figure imgf000017_0002
The maximal and mean flow rates are also shown in Figures 4 and 5. Micturition time
Micturition time was significantly prolonged in neonatally estrogenized rats. This is well understandable, because the urine flow rate was decreased. Treatments with HM-101 or raloxifene did not shorten the micturition time in non-estrogenized rats. In neonatally estrogenized rats the treatments shortened the micturition time. Although the effect did not quite reach the statistical significance, the effect can be considered beneficial.
Table 5. Micturition time (MT; the time from the first flow peak to last one). M= Mann- Whitney U test.
Figure imgf000018_0001
The micturition time is also shown in Figure 6.
Residual urine
The amount of residual urine was increased significantly in neonatally estrogenized rats indicating that the bladder was not completely empty after urination. Residual urine leads to increased urination frequency and is also a risk factor of lower urinary tract infections. The treatment with fispemifene (10 mg/kg) did reduce the amount of residual urine both in non- and neonatally estrogenized rats. This result is very promising and indicates improved functional activity of the bladder. Raloxifene (10 mg/kg) reduced the amount of residual urine almost significantly in non- estrogenized, and significantly in neonatally estrogenized rats (Table 6).
Table 6. Residual urine (RU). M= Mann- Whitney U test.
Figure imgf000019_0001
The residual urine is also shown in Figure 7.
Bladder capacity
Bladder capacity was increased significantly in neonatally estrogenized rats. Although the increased bladder capacity can be considered beneficial as such, the increase in neoDES rats indicates abnormal relaxation of bladder wall muscles and thus damage of the bladder (due to residual urine and slow urine flow). The bladder tries to compensate the increased need of bladder volume. However, in such conditions the bladder wall looses its strength. Treatment with fispemifene (10 mg/kg) reduced significantly the bladder capacity in neonatally estrogenized rats, and raloxifene almost significantly indicating that the bladder wall has retained its normal strength and function. This effect can be considered very beneficial. No effects were seen in non-estrogenized rats (Table 7). This is expected, as the bladder in these animals is not damaged. Table 7. Bladder capacity (BC). M= Mann-Whitney U test.
Figure imgf000020_0001
The bladder capacity is also illustrated in Figure 8.
Discussion and conclusions
Treatments with SERMs (fispemifene or raloxifene) had similar effects in non- and neonatally estrogenized rats. They had increased maximum and mean flow rates. Duration of micturition consisting of multiple voidings in neonatally estrogenized rats was shortened, while no differences were seen in bladder pressures between the groups. Amount of residual urine was reduced both in non- and neonatally estrogenized rats, which indicates improvement of bladder function even in the non- estrogenized rats as well as the increase in flow rates does. It is known that estrogenization of the rodents increases the bladder capacity. This was evident also in present study. The treatments with these SERMs decreased the bladder capacity in neonatally estrogenized rats. Thus the studied SERMs had antiestrogen function on bladder capacity. The rhabdosphincter function was improved in both non- and neonatally estrogenized rats, but the EMG changes were not statistically significant. Fispemifene and raloxifene reversed the estrogen-related alterations in flow rates, micturition time, and bladder capacity (fispemifene even in non-estrogenized rats).
It will be appreciated that the methods of the present invention can be incorporated in the form of a variety of embodiments, only a few of which are disclosed herein. It will be apparent for the expert skilled in the field that other embodiments exist and do not depart from the spirit of the invention. Thus, the described embodiments are illustrative and should not be construed as restrictive.

Claims

1. Use of a selective estrogen receptor modulator, or an isomer, isomer mixture or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition useful for treatment or prevention of lower urinary tract symptoms with or without pelvic pain in an individual.
2. The use according to claim 1 wherein the lower urinary tract symptoms are bladder/urethra dyssynergia, bladder neck dyssynergia or Hinman syndrome in male individuals.
3. The use according to claim 1 wherein the lower urinary tract symptoms are micturition urgency in female individuals.
4. The use according to claim 1 wherein the lower urinary tract symptoms are abacterial prostatitis, stress prostatitis, trigonitis or orchialgia in male individuals.
5. The use according to claim 1 wherein the lower urinary tract symptoms are bladder instability or interstitial cystitis in male or female individuals.
6. The use according to claim 1 wherein the pelvic pain is related to abacterial prostatitis, stress prostatitis, prostatodynia, urethral syndroms, trigonitis, or orchialgia in male individuals.
7. The use according to claim 1 wherein the pelvic pain is interstitial cystitis in male or female individuals.
8. The use according to claim 1 wherein the selective estrogen receptor modulator is a triphenylalkene compound, a triphenylalkane compound, a benzothiophene compound, EM652, EM800, EM776, EM651, EM312, ICI 182780, ERA-923, zindoxifene, deacetylated zindoxifene, ZK119010, TSE-4247, lasoxifene, a lasoxifene analogue, nafoxidine, basedoxifene, GW5638, GW7604, ICI 164384, RU 58668, RU 39411 or EM 319.
9. The use according to claim 1 wherein the selective estrogen receptor modulator is a compound with low or no estrogenic activity.
10. The use according to claim 9 wherein the selective estrogen receptor modulator is selected from a group consisting of:
(Z)-2-[3-(4-Chloro-l ,2-diphenyl-but-l -enyl)phenoxy]ethanol, (Z)-2- {2- [4-(4-Chloro- 1 ,2-diphenylbut- 1 -enyl)phenoxy]ethoxy } ethanol (fispemifene),
(Z)-{2-[3-(4-Chloro-l,2-diphenylbut-l-enyl)phenoxy]ethyl}dimethylamine,
(E)-3 - {4-Chloro- 1 - [4-(2-hydroxyethoxy)phenyl] -2-phenyl-but- 1 -enyl } -phenol,
(E)-3 - {4-Chloro- 1 -[4-(2-imidazol- 1 -yl-ethoxy)phenyl] -2-phenyl-but- 1 -enyl} - phenol,
(Z)-3 - {4-Chloro- 1 - [4-(2-imidazol- 1 -yl-ethoxy)ρhenyl] -2-phenyl-but- 1 -enyl } - phenol, or raloxifene, or any isomer, isomer mixture or pharmaceutically acceptable salt thereof.
11. The use according to claim 9 wherein the selective estrogen receptor is fispemifene.
12. Method for treatment or prevention of lower urinary tract symptoms with or without pelvic pain in an individual, said method comprising administering to the individual an effective amount of a selective estrogen receptor modulator, or an isomer, isomer mixture or a pharmaceutically acceptable salt thereof.
13. The method according to claim 12 wherein the lower urinary tract symptoms are bladder/urethra dyssynergia, bladder neck dyssynergia or Hinman syndrome in male individuals.
14. The method according to claim 12 wherein the lower urinary tract symptoms are micturition urgency in female individuals.
15. The method according to claim 12 wherein the lower urinary tract symptoms are abacterial prostatitis, stress prostatitis, trigonitis or orchialgia in male individuals.
16. The method according to claim 12 wherein the lower urinary tract symptoms are bladder instability or interstitial cystitis in male or female individuals.
17. The method according to claim 12 wherein the pelvic pain is related to abacterial prostatitis, stress prostatitis, prostatodynia, urethral syndroms, trigonitis, or orchialgia in male individuals.
18. The method according to claim 12 wherein the pelvic pain is interstitial cystitis in male or female individuals.
19. The method according to claim 12 wherein the selective estrogen receptor modulator is a triphenylalkene compound, a triphenylalkane compound, a benzothiophene compound, EM652, EM800, EM776, EM651, EM312, ICI 182780, ERA-923, zindoxifene, deacetylated zindoxifene, ZK119010, TSE-4247, lasoxifene, a lasoxifene analogue, nafoxidine, basedoxifene, GW5638, GW7604, ICI 164384, RU 58668, RU 39411 or EM 319.
20. The method according to claim 12 wherein the selective estrogen receptor modulator is a compound with low or no estrogenic activity.
21. The method according to claim 20 wherein the selective estrogen receptor modulator is selected from a group consisting of: (Z)-2-[3-(4-Chloro-l,2-diphenyl-but-l-enyl)ρhenoxy]ethanol,
(Z)-2-{2-[4-(4-Chloro-l,2-diρhenylbut-l-enyl)phenoxy]ethoxy}ethanol (fispemifene),
(Z)-{2-[3-(4-Chloro-l,2-diphenylbut-l-enyl)phenoxy]ethyl}dimethylamine, (E)-3- {4-Chloro- 1 - [4-(2-hydroxyethoxy)phenyl] -2-phenyl-but- 1 -enyl} -phenol,
(E)-3 - {4-Chloro- 1 - [4-(2-imidazol- 1 -yl-ethoxy)ρhenyl] -2-phenyl-but- 1 -enyl } - phenol,
(Z)-3 - {4-Chloro- 1 - [4-(2-imidazol- 1 -yl-ethoxy)phenyl] -2-phenyl-but- 1 -enyl} - phenol, or raloxifene, or any isomer, isomer mixture or pharmaceutically acceptable salt thereof.
22. The method according to claim 20 wherein the selective estrogen receptor is fispemifene.
PCT/FI2004/000270 2003-06-05 2004-05-05 Method for the treatment or prevention of lower urinary tract symptoms WO2004108645A1 (en)

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NO20055187A NO337660B1 (en) 2003-06-05 2005-11-04 Use of a selective estrogen receptor modulator for the preparation of a pharmaceutical composition suitable for treating or preventing symptoms in the lower urinary tract.
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