US20040248989A1 - 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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US20040248989A1
US20040248989A1 US10/454,823 US45482303A US2004248989A1 US 20040248989 A1 US20040248989 A1 US 20040248989A1 US 45482303 A US45482303 A US 45482303A US 2004248989 A1 US2004248989 A1 US 2004248989A1
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bladder
urinary tract
enyl
chloro
phenyl
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Risto Santti
Tomi Streng
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Hormos Medical Ltd
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Priority to US10/454,823 priority Critical patent/US20040248989A1/en
Priority to ES04731197.2T priority patent/ES2524575T3/es
Priority to CA 2527396 priority patent/CA2527396C/en
Priority to EP20100180610 priority patent/EP2258360A3/de
Priority to AU2004245251A priority patent/AU2004245251B2/en
Priority to PCT/FI2004/000270 priority patent/WO2004108645A1/en
Priority to MXPA05013104A priority patent/MXPA05013104A/es
Priority to CNB2004800152437A priority patent/CN100526277C/zh
Priority to KR20057020641A priority patent/KR20060016763A/ko
Priority to EP04731197.2A priority patent/EP1636159B1/de
Priority to RU2005141559/14A priority patent/RU2005141559A/ru
Priority to JP2006508325A priority patent/JP4731470B2/ja
Assigned to HORMOS MEDICAL CORPORATION reassignment HORMOS MEDICAL CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SANTTI, RISTO, STRENG, TOMI
Publication of US20040248989A1 publication Critical patent/US20040248989A1/en
Priority to NO20055187A priority patent/NO337660B1/no
Priority to IS8162A priority patent/IS2958B/is
Assigned to HERCULES TECHNOLOGY GROWTH CAPITAL, INC. reassignment HERCULES TECHNOLOGY GROWTH CAPITAL, INC. SECURITY AGREEMENT Assignors: QUATRX PHARMACEUTICALS COMPANY
Priority to US12/856,738 priority patent/US20100305158A1/en
Priority to AU2010257419A priority patent/AU2010257419B2/en
Assigned to QUATRX PHARMACEUTICALS COMPANY reassignment QUATRX PHARMACEUTICALS COMPANY RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: HERCULES TECHNOLOGY GROWTH CAPITAL INC.
Assigned to HORMOS MEDICAL LTD. reassignment HORMOS MEDICAL LTD. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: HORMOS MEDICAL CORPORATION
Priority to US13/970,026 priority patent/US8962693B2/en
Priority to US14/597,453 priority patent/US9114106B2/en
Priority to US14/832,649 priority patent/US9993442B2/en
Priority to US15/973,783 priority patent/US10780063B2/en
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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
  • 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 micturition. 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 is defined as the inability of the bladder neck to open properly and assume a funnel shape in the presence of a normal detrusor contraction.
  • Video imaging 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.
  • 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.
  • U.S. Pat. No. 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.
  • SERMs 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.
  • 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.
  • FIG. 2 shows the maximal bladder pressure for non-estrogenized rats and for neoDES rats with and without administration of test compounds.
  • FIG. 3 shows the average bladder pressure for non-estrogenized rats and for neoDES rats with and without administration of test compounds.
  • FIG. 4 shows the maximal flow rate for non-estrogenized rats and for neoDES rats with and without administration of test compounds.
  • FIG. 5 shows the average flow rate for non-estrogenized rats and for neoDES rats with and without administration of test compounds.
  • FIG. 6 shows the micturition time for non-estrogenized rats and for neoDES rats with and without administration of test compounds.
  • FIG. 7 shows the amount of residual urine for non-estrogenized rats and for neoDES rats with and without administration of test compounds.
  • FIG. 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.
  • 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 syndromes, trigonitis or orchialgia in a male individual. Furthermore, the term includes interstitial cystitis either in male or female individuals.
  • 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, U.S. Pat. No. 4,996,225, U.S. Pat. No. 4,696,949, U.S. Pat. No. 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, U.S. Pat. No. 4,133,814, U.S. Pat. No. 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 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 be 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 percent 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.
  • 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 subcutaneous 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 urodynamic 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 extracellularly 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.
  • FIG. 1 illustrates one typical micturition cycle showing bladder pressure wave (a) and flow rate wave (b), and the method for calculation of the urodynamic 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.
  • mice were significantly prolonged in neonatally estrogenized rats (Table 5). 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.
  • the micturition time is also shown in FIG. 6.
  • 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).
  • the bladder capacity is also illustrated in FIG. 8.
  • Fispemifene and raloxifene reversed the estrogen-related alterations in flow rates, micturition time, and bladder capacity (fispemifene even in non-estrogenized rats).

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US10/454,823 US20040248989A1 (en) 2003-06-05 2003-06-05 Method for the treatment or prevention of lower urinary tract symptoms
RU2005141559/14A RU2005141559A (ru) 2003-06-05 2004-05-05 Способ лечения и предотвращения симптомов нижнего отдела мочевых путей
AU2004245251A AU2004245251B2 (en) 2003-06-05 2004-05-05 Method for the treatment or prevention of lower urinary tract symptoms
CA 2527396 CA2527396C (en) 2003-06-05 2004-05-05 Method for the treatment or prevention of lower urinary tract symptoms
EP20100180610 EP2258360A3 (de) 2003-06-05 2004-05-05 Verfahren zur Behandlung bzw. Prävention von Symptomen in den ableitenden Harnwegen
JP2006508325A JP4731470B2 (ja) 2003-06-05 2004-05-05 下部尿路症の治療または予防方法
PCT/FI2004/000270 WO2004108645A1 (en) 2003-06-05 2004-05-05 Method for the treatment or prevention of lower urinary tract symptoms
MXPA05013104A MXPA05013104A (es) 2003-06-05 2004-05-05 Metodo para el tratamiento o prevencion de sintomas del tracto urinario inferior.
CNB2004800152437A CN100526277C (zh) 2003-06-05 2004-05-05 治疗或预防下泌尿道症状的方法
KR20057020641A KR20060016763A (ko) 2003-06-05 2004-05-05 하위 비뇨관 증상들의 치료 또는 예방 방법
EP04731197.2A EP1636159B1 (de) 2003-06-05 2004-05-05 Verfahren zur behandlung bzw. prävention von symptomen in den ableitenden harnwegen
ES04731197.2T ES2524575T3 (es) 2003-06-05 2004-05-05 Método para el tratamiento o la prevención de síntomas del tracto urinario inferior
NO20055187A NO337660B1 (no) 2003-06-05 2005-11-04 Anvendelse av en selektiv østrogenreseptor-modulator for fremstilling av en farmasøytisk blanding egnet til behandling eller forebyggelse av symptomer i nedre urinveier.
IS8162A IS2958B (is) 2003-06-05 2005-12-01 Aðferð til þess að meðhöndla eða fyrirbyggja einkenni í neðri þvagvegum
US12/856,738 US20100305158A1 (en) 2003-06-05 2010-08-16 Method for the treatment or prevention of lower urinary tract symptoms
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US13/970,026 US8962693B2 (en) 2003-06-05 2013-08-19 Method for the treatment or prevention of lower urinary tract symptoms
US14/597,453 US9114106B2 (en) 2003-06-05 2015-01-15 Method for the treatment or prevention of lower urinary tract symptoms
US14/832,649 US9993442B2 (en) 2003-06-05 2015-08-21 Method for the treatment or prevention of lower urinary tract symptoms
US15/973,783 US10780063B2 (en) 2003-06-05 2018-05-08 Method for the treatment or prevention of lower urinary tract symptoms

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US9321712B2 (en) 2012-10-19 2016-04-26 Fermion Oy Process for the preparation of ospemifene

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JP6697467B2 (ja) 2014-12-29 2020-05-20 オロン エス．ピー．エー． オスペミフェン及びフィスペミフェンを調製するためのプロセス

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US8962693B2 (en) 2015-02-24
EP2258360A3 (de) 2011-03-23
IS8162A (is) 2005-12-01
NO20055187L (no) 2005-12-19
EP2258360A2 (de) 2010-12-08
CN1798723A (zh) 2006-07-05
NO337660B1 (no) 2016-05-30
AU2004245251B2 (en) 2010-10-07
US20130345313A1 (en) 2013-12-26
US20150126613A1 (en) 2015-05-07

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