CA2560279A1 - Use of a 5-ht3 receptor antagonist for the manufacture of a medicament for the treatment of non-digestive tract derived abdominal disorders associated with pain - Google Patents
Use of a 5-ht3 receptor antagonist for the manufacture of a medicament for the treatment of non-digestive tract derived abdominal disorders associated with pain Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
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- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
The present invention relates to a novel medicinal use of 5-HT3 receptor antagonists, in particular cilansetron, or their pharmacologically compatible derivatives like salts and/or solvates, for the treatment and/or prophylaxis of non-digestive tract derived abdominal disorders associated with pain, in particular Interstitial Cystitis, Chronic Pelvic Pain Syndrome and/or abdominal pain associated with endometriosis.
Description
TREATMENT OF NON-DIGESTIVE TRACT DERIVED ABDOMINAL DISORDERS ASSOCIATED WITH
PAIN
The present invention relates to a novel medicinal use of 5-HT3 receptor antagonists, in particular cilansetron, or their pharmacologically compatible derivatives like salts and/or solvates, f or the treatment and/or prophylaxis of non-digestive tract derived abdominal disorders associated with pain, in particular Interstitial Cystitis, Chronic Pelvic Pain Syndrome and/or abdominal pain associated with endometriosis.
Regarding the therapeutic potential of 5-HT3 receptor antagonists, it is already widely known that those can play a beneficial role in i.a. the treatment of gastrointestinal disorders (see e.g. ~.H. Israili, Curr. Med. Chem. - CNS Agents 1 (2001) 171-199 for a review).
From EP 0 467 365 A2 the use of 5-HT3 receptor antagonists for the treatment of urinary incontinence is already known.
Johansen et al. (see Current Opinion in Urology, 12/1 (2002) 63-67, cited as "Johansen et al." hereinafter) are discussing a relation between the possible aetiological role of mast cells in Interstitial Cystitis and the importance of serotonin as a therapeutic agent in Interstitial Cystitis and Chronic Pelvic Pain Syndrome.
Of non-digestive tract derived abdominal disorders associated with pain, Interstital Cystitis, Chronic Pelvic Pain Syndrome and abdominal pain associated with endometrio-sis may best be cured by administration of 5-HT3 receptor antagonists. Therapy of Inter-stitial Cystitis is preferred. According to the invention, "therapy° is meant to comprise both, prophylaxis and treatment of a disorder.
Interstitial Cystitis is a chronic disorder of the urinary bladder characterised by symptoms of urinary frequency and urgency, suprapubic pain, dyspareunia (anticipation of pain during sexual intercourse), nocturia and chronic pelvic pain (see e.g.
G.
Newsome, Journal of the American Academy of Nurse Practitioners, 15(2) (2003) 64-71).
Interstitial Cystitis occurs primarily in women but also in men. Several pathophysiological mechanisms have been proposed in the past few years including epithelial dysfunction, activation of mast cells, neurogenic inflammation, autoimmunity, occult (viral or bacterial) infection, toxin exposure and pelvic floor dysfunction. Onset of Interstitial Cystitis is pre-dominately in adulthood although it does occur in childhood. The prevalence of Interstitial Cystitis has ranged from about 8 - 60 cases/100,000 female patients depending on the population evaluated. About 10% of patients have severe symptoms that are associated with Hunner's ulcers on bladder biopsy; the rest could be grouped in those with or without bladder inflammation. Interstitial Cystitis in men is probably underdiagnosed and is most commonly misdiagnosed as prostatitis. Symptoms of Interstitial Cystitis are exac-erbated by stress, certain foods and ovulatory hormones. Many patients also experience allergies, irritable bowel syndrome (IBS) and migraines. There have been various reports indicating dysfunction of the bladder glycosaminoglycan (GAG) protective layer and ma-ny publications showing a high number of activated bladder mast cells.
Diagnosis is by history, physical examination, laboratory tests, and cystoscopic ex-amination; it thus largely remains a diagnosis of exclusion. Approved treatments so far include intravesical administration of dimethylsulphoxide (DMSO) or oral pentosanpoly-sulphate (PPS) but today's management of Interstitial Cystitis also may include dietary changes, antihistamines, tricyclic antidepressants, oral and intravesicle glucosaminogly-cans, hydrodistention, pain management and emotional support. Criteria for diagnosis of Interstitial Cystitis have been established by the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases (Gillenwater et al. J. Urol 140 (1988) 203-208).
These include glomerulations or Hunner's Ulcer on cystoscopic examination and pain associ-ated with bladder or urinary urgency. Recently, Interstitial Cystitis is often divided into two subtypes: classical and nonulcer disease (Peeker and Fall J. Urol. 167 (2002) 2472).
Chronic Pelvic Pain Syndrome is a syndrome often related to Interstitial Cystitis.
According to the classification of the US National Institiute of Health as "Type III Prostati-tis" (see J.N. Krieger et al., JAMA 282 (1999) 236-237) it is to be regarded as a chronic, abacterial prostatitis. Patients with non-inflammatory Chronic Pelvic Pain Syndrome are the largest group of prostatitis patients according to the US National Institute of of Diabe-tes and Digestive and Kidney Diseases classification and are characterized by the ab-sence of objective findings. Interestingly, for the majority of patients, no objective find-ings link the symptoms of prostatitis to the prostate gland or to the male genital tract and thus, no findings seem to link the symptoms of Chronic Pelvic Pain Syndrome to the male in particular. Mounting evidence instead suggests, that a significant overlap may exist between Interstitial Cystitis and Chronic Pelvic Pain Syndrome in epidemiology, pathophysiology and even therapy. In fact, both conditions might represent different manifestations of the same disease process. For example, very similar theories of pathogenesis exist for both conditions: occult infections, epithelial dysfunction, neuro-genic inflammation mast cell activation and autoimmunity are features that seem to play a role in the formation of Interstital Cystitis as well as in the formation of Chronic Pelvic Pain Syndrome (see e.g: Johansen et al.; R.M. Moldwin, Current Urology Reports (2002) 313-318). Similar medications for both conditions will therefore seem promising.
For a review on Chronic Pelvic Pain Syndrome see for example M. McNaughton-Collins et al., Ann. Intern. Med. 133 (2000) 367-381.
Endometriosis is a well-known gynaecological disorder that affects 10 to 15%
of women in the reproductive age. It is a benign disease defined as the presence of viable uterine tissue, e.g. endometrial gland and stroma cells outside the uterine cavity. It is most frequently found in the pelvic area, in particular in the ovaries. In women developing endometriosis, the endometrial cells entering the peritoneal cavity by retrograde me n-struation (the most likely mechanism) have the capacity to adhere to and invade the peri-toneal lining, and are then able to implant and grow. The implants respond to steroid hormones of the menstrual cycle in a similar way as the endometrium in the uterus. The infiltrating lesions and the blood from these lesions which are unable to leave the body cause inflammation of the surrounding tissue. The most common symptoms of endome-triosis are dysmenorrhoea, dyspareunia and (chronic) abdominal pain. The occurrence of these symptoms is not related to the extent of the lesions. Some women with severe endometriosis are asymptomatic, while women with mild endometri osis may have severe pain. Up to now, no reliable and easy to use non-invasive test is available to diagnose endometriosis. Laparoscopy has to be performed to diagnose the disease.
Endometrio-sis is classified according to the 4 stages set up by the American Fertility Society (AFS).
Stage I corresponds to minimal disease while stage IV is severe, depending on the loca-tion and the extent of the endometriosis. Endometriosis is found in up to 50%
of the women with infertility. However, currently no causal relation has been proven between mild endometriosis and infertility. Moderate to severe endometriosis can cause tubal damage and adhesions leading to infertility. Despite extensive research, the cause of endometriosis is still largely unknown. Several theories for the origin of endometriosis have been proposed, although no single hypothesis explains all cases of the disease completely. However, the key event in all these theories seems to be the occurrence of retrograde menstruation. The aims of treatment of endometriosis are currently pain relief, resolution of the endometriotic tissue and restoration of fertility (if desired). The two com-mon treatments are surgery or anti-inflammatory and/or hormonal therapy or a combina-tion thereof.
It has now surprisingly been discovered that 5-HT3 receptor antagonists can serve as treatment and/or prophylaxis for non-digestive tract derived abdominal disorders associated with pain, in particular Interstitial Cystitis, Chronic Pelvic Pain Syndrome and/or abdominal pain associated with endometriosis.
The object of the invention is thus the novel use of a 5-HT3 receptor antagonist or a pharmacologically compatible dernrative thereof like a salt and/or a solvate, for the treatment and/or prophylaxis of non-digestive tract derived abdominal disorders associated with pain, in particular Interstitial Cystitis, Chronic Pelvic Pain Syndrom and/or abdominal pain associated with endometriosis, in larger mammals and humans.
Suitable 5-HT3 receptor antagonists according to the invention are in particular selected from the group consisting of alosetron, azasetron, bemesetron, cilansetron, dolasetron, fabesetron, galdansetron, granisetron, indisetron, itasetron, lerisetron, lurosetron, ondansetron, palonosetron, ramosetron, ricasetron, tropisetron, zacopride and zatosetron.
Cilansetron is the preferred 5-HT3 receptor antagonist. Cilansetron comes within the scope of European Patent EP 0 297 651 B1 and has the chemical name (R)-(-)-4,5,6,8,9,10-hexahydro-10-[(2-methyl-1H-imidazol-1-yl)methyl]-11H-pyrido-[3,2,1 jk]-carbazol-11-one. Cilansetron may preferably be used in the form of its hydrochloride.
Usually, cilansetron hydrochloride monohydrate is used. Further pharmacologically compatible acid addition salts of cilansetron are known from e.g. EP 0 297 651 B1.
The beneficial influence of 5-HT3 receptor antagonists according to the invention can be demonstrated e.g. by an in vivo animal test model predictive for the therapeutic potential of test compounds in non-digestive tract derived abdominal disorders associated with pain, in particular of Interstitial Cystitis. In this test model, the effect of 5-HT3 receptor antagonists on rats with cyclophosphamide-induced cystitis was investigated.
Inflammation of the bladder responsible for bladder overactivity was induced by an intraperitoneal (i.p.) cyclophosphamide injection (150 mg/kg, i.p.) 48h before testing (Maggi et al., J Auton New Syst 38 (1992) 201 ) using male Wistar rats weighing 300-350 g. Rats were anesthetized with urethane delivered subcutaneously in saline (1.2 glkg) and their temperature was maintained at 37°C. Following a midline abdominal incision a catheter was inserted through the bladder dome and sealed with a tie. The catheter was connected via a T-tube to a pressure transducer and a syringe pump, to allow filling of the bladder with warm (37°C) saline at 50 NUmin simultaneously with recording of i n-travesical pressure. This catheter was later used for cystometry.
For each voiding and non-voiding contraction, the threshold pressure (ThP, corre-sponding to the bladder pressure at the onset of the voiding contraction (mm Hg), the maximal voiding pressure (MP, defined by the maximal bladder pressure reached during voiding contraction {mm Hg)) the basal pressure (BaP, defined by the lowest bladder pressure reached after the voiding contraction (mm Hg) and the area under the curve of the bladder pressure {AUP) during voiding (mm Hg x s) was calculated for each rat and averaged for each condition. In addition, the frequency of contractions was determined.
Test groups consisting of 10 rats each were used. Drug treatments were performed as described in the following table 1.
Table 1: Group design for test model of 5-HT3 receptor antagonists on rats with cyclo-phosphamide-induced cystitis Group Pretreatment 48 Acute treatment h be-fore acute treatment 1 (control) vehicle vehicle 2 (cystitis control) Cyclophosphamide vehicle 150 mg/kg i.p.
3 (cystitis + reference Cyclophosphamide HOE140 130 Ng/kg compound) i.v 150 mg/kg i.p.
4 (cystitis + cilansetronCyclophosphamide Cilansetron 0.01 0.01 mg/kg mglkg i.v.
i.v.) 150 mg/kg i.p.
PAIN
The present invention relates to a novel medicinal use of 5-HT3 receptor antagonists, in particular cilansetron, or their pharmacologically compatible derivatives like salts and/or solvates, f or the treatment and/or prophylaxis of non-digestive tract derived abdominal disorders associated with pain, in particular Interstitial Cystitis, Chronic Pelvic Pain Syndrome and/or abdominal pain associated with endometriosis.
Regarding the therapeutic potential of 5-HT3 receptor antagonists, it is already widely known that those can play a beneficial role in i.a. the treatment of gastrointestinal disorders (see e.g. ~.H. Israili, Curr. Med. Chem. - CNS Agents 1 (2001) 171-199 for a review).
From EP 0 467 365 A2 the use of 5-HT3 receptor antagonists for the treatment of urinary incontinence is already known.
Johansen et al. (see Current Opinion in Urology, 12/1 (2002) 63-67, cited as "Johansen et al." hereinafter) are discussing a relation between the possible aetiological role of mast cells in Interstitial Cystitis and the importance of serotonin as a therapeutic agent in Interstitial Cystitis and Chronic Pelvic Pain Syndrome.
Of non-digestive tract derived abdominal disorders associated with pain, Interstital Cystitis, Chronic Pelvic Pain Syndrome and abdominal pain associated with endometrio-sis may best be cured by administration of 5-HT3 receptor antagonists. Therapy of Inter-stitial Cystitis is preferred. According to the invention, "therapy° is meant to comprise both, prophylaxis and treatment of a disorder.
Interstitial Cystitis is a chronic disorder of the urinary bladder characterised by symptoms of urinary frequency and urgency, suprapubic pain, dyspareunia (anticipation of pain during sexual intercourse), nocturia and chronic pelvic pain (see e.g.
G.
Newsome, Journal of the American Academy of Nurse Practitioners, 15(2) (2003) 64-71).
Interstitial Cystitis occurs primarily in women but also in men. Several pathophysiological mechanisms have been proposed in the past few years including epithelial dysfunction, activation of mast cells, neurogenic inflammation, autoimmunity, occult (viral or bacterial) infection, toxin exposure and pelvic floor dysfunction. Onset of Interstitial Cystitis is pre-dominately in adulthood although it does occur in childhood. The prevalence of Interstitial Cystitis has ranged from about 8 - 60 cases/100,000 female patients depending on the population evaluated. About 10% of patients have severe symptoms that are associated with Hunner's ulcers on bladder biopsy; the rest could be grouped in those with or without bladder inflammation. Interstitial Cystitis in men is probably underdiagnosed and is most commonly misdiagnosed as prostatitis. Symptoms of Interstitial Cystitis are exac-erbated by stress, certain foods and ovulatory hormones. Many patients also experience allergies, irritable bowel syndrome (IBS) and migraines. There have been various reports indicating dysfunction of the bladder glycosaminoglycan (GAG) protective layer and ma-ny publications showing a high number of activated bladder mast cells.
Diagnosis is by history, physical examination, laboratory tests, and cystoscopic ex-amination; it thus largely remains a diagnosis of exclusion. Approved treatments so far include intravesical administration of dimethylsulphoxide (DMSO) or oral pentosanpoly-sulphate (PPS) but today's management of Interstitial Cystitis also may include dietary changes, antihistamines, tricyclic antidepressants, oral and intravesicle glucosaminogly-cans, hydrodistention, pain management and emotional support. Criteria for diagnosis of Interstitial Cystitis have been established by the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases (Gillenwater et al. J. Urol 140 (1988) 203-208).
These include glomerulations or Hunner's Ulcer on cystoscopic examination and pain associ-ated with bladder or urinary urgency. Recently, Interstitial Cystitis is often divided into two subtypes: classical and nonulcer disease (Peeker and Fall J. Urol. 167 (2002) 2472).
Chronic Pelvic Pain Syndrome is a syndrome often related to Interstitial Cystitis.
According to the classification of the US National Institiute of Health as "Type III Prostati-tis" (see J.N. Krieger et al., JAMA 282 (1999) 236-237) it is to be regarded as a chronic, abacterial prostatitis. Patients with non-inflammatory Chronic Pelvic Pain Syndrome are the largest group of prostatitis patients according to the US National Institute of of Diabe-tes and Digestive and Kidney Diseases classification and are characterized by the ab-sence of objective findings. Interestingly, for the majority of patients, no objective find-ings link the symptoms of prostatitis to the prostate gland or to the male genital tract and thus, no findings seem to link the symptoms of Chronic Pelvic Pain Syndrome to the male in particular. Mounting evidence instead suggests, that a significant overlap may exist between Interstitial Cystitis and Chronic Pelvic Pain Syndrome in epidemiology, pathophysiology and even therapy. In fact, both conditions might represent different manifestations of the same disease process. For example, very similar theories of pathogenesis exist for both conditions: occult infections, epithelial dysfunction, neuro-genic inflammation mast cell activation and autoimmunity are features that seem to play a role in the formation of Interstital Cystitis as well as in the formation of Chronic Pelvic Pain Syndrome (see e.g: Johansen et al.; R.M. Moldwin, Current Urology Reports (2002) 313-318). Similar medications for both conditions will therefore seem promising.
For a review on Chronic Pelvic Pain Syndrome see for example M. McNaughton-Collins et al., Ann. Intern. Med. 133 (2000) 367-381.
Endometriosis is a well-known gynaecological disorder that affects 10 to 15%
of women in the reproductive age. It is a benign disease defined as the presence of viable uterine tissue, e.g. endometrial gland and stroma cells outside the uterine cavity. It is most frequently found in the pelvic area, in particular in the ovaries. In women developing endometriosis, the endometrial cells entering the peritoneal cavity by retrograde me n-struation (the most likely mechanism) have the capacity to adhere to and invade the peri-toneal lining, and are then able to implant and grow. The implants respond to steroid hormones of the menstrual cycle in a similar way as the endometrium in the uterus. The infiltrating lesions and the blood from these lesions which are unable to leave the body cause inflammation of the surrounding tissue. The most common symptoms of endome-triosis are dysmenorrhoea, dyspareunia and (chronic) abdominal pain. The occurrence of these symptoms is not related to the extent of the lesions. Some women with severe endometriosis are asymptomatic, while women with mild endometri osis may have severe pain. Up to now, no reliable and easy to use non-invasive test is available to diagnose endometriosis. Laparoscopy has to be performed to diagnose the disease.
Endometrio-sis is classified according to the 4 stages set up by the American Fertility Society (AFS).
Stage I corresponds to minimal disease while stage IV is severe, depending on the loca-tion and the extent of the endometriosis. Endometriosis is found in up to 50%
of the women with infertility. However, currently no causal relation has been proven between mild endometriosis and infertility. Moderate to severe endometriosis can cause tubal damage and adhesions leading to infertility. Despite extensive research, the cause of endometriosis is still largely unknown. Several theories for the origin of endometriosis have been proposed, although no single hypothesis explains all cases of the disease completely. However, the key event in all these theories seems to be the occurrence of retrograde menstruation. The aims of treatment of endometriosis are currently pain relief, resolution of the endometriotic tissue and restoration of fertility (if desired). The two com-mon treatments are surgery or anti-inflammatory and/or hormonal therapy or a combina-tion thereof.
It has now surprisingly been discovered that 5-HT3 receptor antagonists can serve as treatment and/or prophylaxis for non-digestive tract derived abdominal disorders associated with pain, in particular Interstitial Cystitis, Chronic Pelvic Pain Syndrome and/or abdominal pain associated with endometriosis.
The object of the invention is thus the novel use of a 5-HT3 receptor antagonist or a pharmacologically compatible dernrative thereof like a salt and/or a solvate, for the treatment and/or prophylaxis of non-digestive tract derived abdominal disorders associated with pain, in particular Interstitial Cystitis, Chronic Pelvic Pain Syndrom and/or abdominal pain associated with endometriosis, in larger mammals and humans.
Suitable 5-HT3 receptor antagonists according to the invention are in particular selected from the group consisting of alosetron, azasetron, bemesetron, cilansetron, dolasetron, fabesetron, galdansetron, granisetron, indisetron, itasetron, lerisetron, lurosetron, ondansetron, palonosetron, ramosetron, ricasetron, tropisetron, zacopride and zatosetron.
Cilansetron is the preferred 5-HT3 receptor antagonist. Cilansetron comes within the scope of European Patent EP 0 297 651 B1 and has the chemical name (R)-(-)-4,5,6,8,9,10-hexahydro-10-[(2-methyl-1H-imidazol-1-yl)methyl]-11H-pyrido-[3,2,1 jk]-carbazol-11-one. Cilansetron may preferably be used in the form of its hydrochloride.
Usually, cilansetron hydrochloride monohydrate is used. Further pharmacologically compatible acid addition salts of cilansetron are known from e.g. EP 0 297 651 B1.
The beneficial influence of 5-HT3 receptor antagonists according to the invention can be demonstrated e.g. by an in vivo animal test model predictive for the therapeutic potential of test compounds in non-digestive tract derived abdominal disorders associated with pain, in particular of Interstitial Cystitis. In this test model, the effect of 5-HT3 receptor antagonists on rats with cyclophosphamide-induced cystitis was investigated.
Inflammation of the bladder responsible for bladder overactivity was induced by an intraperitoneal (i.p.) cyclophosphamide injection (150 mg/kg, i.p.) 48h before testing (Maggi et al., J Auton New Syst 38 (1992) 201 ) using male Wistar rats weighing 300-350 g. Rats were anesthetized with urethane delivered subcutaneously in saline (1.2 glkg) and their temperature was maintained at 37°C. Following a midline abdominal incision a catheter was inserted through the bladder dome and sealed with a tie. The catheter was connected via a T-tube to a pressure transducer and a syringe pump, to allow filling of the bladder with warm (37°C) saline at 50 NUmin simultaneously with recording of i n-travesical pressure. This catheter was later used for cystometry.
For each voiding and non-voiding contraction, the threshold pressure (ThP, corre-sponding to the bladder pressure at the onset of the voiding contraction (mm Hg), the maximal voiding pressure (MP, defined by the maximal bladder pressure reached during voiding contraction {mm Hg)) the basal pressure (BaP, defined by the lowest bladder pressure reached after the voiding contraction (mm Hg) and the area under the curve of the bladder pressure {AUP) during voiding (mm Hg x s) was calculated for each rat and averaged for each condition. In addition, the frequency of contractions was determined.
Test groups consisting of 10 rats each were used. Drug treatments were performed as described in the following table 1.
Table 1: Group design for test model of 5-HT3 receptor antagonists on rats with cyclo-phosphamide-induced cystitis Group Pretreatment 48 Acute treatment h be-fore acute treatment 1 (control) vehicle vehicle 2 (cystitis control) Cyclophosphamide vehicle 150 mg/kg i.p.
3 (cystitis + reference Cyclophosphamide HOE140 130 Ng/kg compound) i.v 150 mg/kg i.p.
4 (cystitis + cilansetronCyclophosphamide Cilansetron 0.01 0.01 mg/kg mglkg i.v.
i.v.) 150 mg/kg i.p.
5 (cystitis + cilansetronCyclophosphamide Cilansetron 0.1 0.1 mg/kg i.v.) mglkg i.v.
150 mg/kg i.p.
In groups 2-5 cystitis was induced by cyclophosphamide 150 mg/kg intraperito-neally {i.p.) 48h before the experiment; group 1 served as a control group.
Drugs or ve-hicle to be tested were injected 10 minutes before the beginning of cystometry. Besides three doses of cilansetron (group 4-5), HOE 140 {D-Arginyl-[Hyp3, This, D-Tic7, OicB]-bradykinin), a bradykinin 2 receptor antagonist, was used as a reference standard known to be active in this model. During the cystometry the pressure changes due to transves i-cal perFusion of warm saline at 50 NI/min were recorded over 60 minutes.
Parameters (as outlined above) were analysed for each bladder filling.
Cyclophosphamide pretreatment consistently changed all parameters of cystometry but micturition pressure. Compared to the vehicle control group (group 1) the basal pres-sure, threshold pressure and frequency of bladder contraction in the cystitis group were consistently increased in the cystitis group (group 2) (see Table 2), whereas the area under the curve of the bladder contractions as well as the volume of perFusion at the on-set of the 1St micturition was consistently decreased in the cystitis group (group 2) (see Table 2) Thus cystitis resulted in decreased bladder compliance (i.e. greater bladder pressures were reached with smaller volumes of perfusion) and bladder overactivity.
Table 2: : Effects of test compounds in rats with cyclophosphamide-induced cystitis group group group group group cyclophos-cyclophos-cyclophos phamide phamide phamidecyclophos-cystitis cystitis + +
cystitisphamide cilansetroncilansetron vehiclecontrolcystitis 0.01 mg/kg0.1 mglkg +
control HOE140 i.v. i.v.
basal pressure mmH 13 19 16 16 14 threshold pressure mmH 15 20 17 17 15 frequency I
[hours I 15 I 35 I 30 I 26 28 ~l Treatment with HOE140 decreased the cystitis induced changes basal pressure and threshold pressure, as well as frequency of bladder contractions by 50, 60 and 25%, respectively (see Tables 2 and 3). Micturition pressure area under the curve and 1St mic-turition volume were not affected by HOE140 treatment. It can be concluded that HOE140 partially alleviated some of the effects of cystitis as it changed key parameters of micturition towards values observed in the control group.
150 mg/kg i.p.
In groups 2-5 cystitis was induced by cyclophosphamide 150 mg/kg intraperito-neally {i.p.) 48h before the experiment; group 1 served as a control group.
Drugs or ve-hicle to be tested were injected 10 minutes before the beginning of cystometry. Besides three doses of cilansetron (group 4-5), HOE 140 {D-Arginyl-[Hyp3, This, D-Tic7, OicB]-bradykinin), a bradykinin 2 receptor antagonist, was used as a reference standard known to be active in this model. During the cystometry the pressure changes due to transves i-cal perFusion of warm saline at 50 NI/min were recorded over 60 minutes.
Parameters (as outlined above) were analysed for each bladder filling.
Cyclophosphamide pretreatment consistently changed all parameters of cystometry but micturition pressure. Compared to the vehicle control group (group 1) the basal pres-sure, threshold pressure and frequency of bladder contraction in the cystitis group were consistently increased in the cystitis group (group 2) (see Table 2), whereas the area under the curve of the bladder contractions as well as the volume of perFusion at the on-set of the 1St micturition was consistently decreased in the cystitis group (group 2) (see Table 2) Thus cystitis resulted in decreased bladder compliance (i.e. greater bladder pressures were reached with smaller volumes of perfusion) and bladder overactivity.
Table 2: : Effects of test compounds in rats with cyclophosphamide-induced cystitis group group group group group cyclophos-cyclophos-cyclophos phamide phamide phamidecyclophos-cystitis cystitis + +
cystitisphamide cilansetroncilansetron vehiclecontrolcystitis 0.01 mg/kg0.1 mglkg +
control HOE140 i.v. i.v.
basal pressure mmH 13 19 16 16 14 threshold pressure mmH 15 20 17 17 15 frequency I
[hours I 15 I 35 I 30 I 26 28 ~l Treatment with HOE140 decreased the cystitis induced changes basal pressure and threshold pressure, as well as frequency of bladder contractions by 50, 60 and 25%, respectively (see Tables 2 and 3). Micturition pressure area under the curve and 1St mic-turition volume were not affected by HOE140 treatment. It can be concluded that HOE140 partially alleviated some of the effects of cystitis as it changed key parameters of micturition towards values observed in the control group.
Table 3: Inhibition of cystitis efFects inhibition of c stitis effects group 3 group 4 group 5 cyclophos- cyclophos-phamide phamide cyclophos- cystitis cystitis + +
phamide cilansetroncilansetron cysti-tis + HOE1400.01 m /k 0.1 m /k i.v. i.v.
basal ressure 50 50 83 threshold ressure60 60 100 frPnuPncv 25 45 35 Treatment with cilansetron in a concentration as low as 0.01 mg/kg i.v.
decreased cystitis induced changes in basal pressure and threshold pressure, as well as frequency of bladder contractions by 50, 60 and 45%, respectively (see Tables 2 and 3).
Thus, it was similarly effective as or even more effective than the reference compound HOE 140.
At 0.1 mg/kg i.v. cilansetron was even more potent in decreasing the cystitis evoked changes in basal pressure and threshold pressure by 83 and 100% respectively (see Tables 2 and 3).
Acute treatment with HOE140 130 Ng/kg reduced the symptoms of bladder overac-tivity associated with cyclophosphamide pretreatment. The dosing of 0.01 and 0.1 mg/kg cilansetron reduced these symptoms to an equivalent or slightly greater extent. Thus in the foregoing animal test model on cystometry in rats with cyclophosphamide-induced cystitis, cilansetron showe d a beneficial effect even superior to the efFect caused by HOE140.
As therapeutic agents, the 5-HT3 receptor antagonists or their pharmacologically compatible acid addition salts and/or their solvates may be administered in conventional pharmaceutical preparations. In an individual case, special dosage forms may be indi-cated. The doses to be used may vary individually and will naturally vary according to the type of condition to be treated and the substance used. In general, however, medicinal forms with an active substance content of 0.2 to 200 mg, in particular 1 to 50 mg, active substance per individual dose are suitable for administration to humans and larger mam-mals. The compounds may be contained according to the invention, together with con-ventional pharmaceutical auxiliaries and/or carriers, in solid or liquid pharmaceutical preparations. Examples of solid preparations are preparations which can be adminis-tered orally, such as tablets, coated tablets, capsules, powders or granules, or alterna-tively suppositories. These preparations may contain conventional pharmaceutical inor ganic and/or organic carriers, such as talcum, lactose or starch, in addition to conven-tional pharmaceutical auxiliaries, for example lubricants or tablet disintegrating agents.
Liquid preparations such as suspensions or emulsions of the active substances may con-tain the usual diluents such as water, oils and/or suspension agents such as polyethyl-ene glycols and the like. Other auxiliaries may additionally be added, such as preserva-tives, taste correctives and the like.
A 5-HT3 receptor antagonist or a pharmacologically compatible acid addition salt and/or a solvate thereof, preferably cilansetron, can be mixed and formulated with the pharmaceutical auxiliaries and/or can-iers in known manner. For the production of solid medicament forms, cilansetron or its acid addition salt can for example be mixed with the auxiliaries and/or carriers in conventional manner and can be wet or dry granulated. The granules or powder can be poured directly into capsules or be pressed into tablet cores in conventional manner. These can be coated in known manner if desired.
The following example is intended to explain the production of pharmaceutical preparations containing cilansetron hydrochloride.
Example I: Tablets containing cilansetron Composition:
Cilansetron hydrochloride monohydrate 4 parts Corn starch 30 parts Lactose 70 parts Kollidon 25~ 5 parts Magnesium stearate 2 parts Talcum 3 parts Total: 114 parts Preparation procedure:
The active substance was mixed with corn starch and fine-powdered lactose in a mixer.
The resulting mixture was moistened thoroughly with a 20% solution of polyvinylpyrroli-done (Kollidon 25~ by BASF) in demineralised water. If necessary, further demineralised water was added. The moist granules were passed through a 2 mm sieve, dried on trays at 40°C and then passed through a 1 mm sieve {Frewitt machine). Once the gra nules had been mixed with magnesium stearate and talcum, tablets of a weight of 114 mg were pressed therefrom, so that each tablet contained 4 mg active substance.
Likewise or preferably, other pharmaceutical preparations of cilansetron may be used, for example stabilised pharmaceutical preparations known from EP 0 895 782 A2.
phamide cilansetroncilansetron cysti-tis + HOE1400.01 m /k 0.1 m /k i.v. i.v.
basal ressure 50 50 83 threshold ressure60 60 100 frPnuPncv 25 45 35 Treatment with cilansetron in a concentration as low as 0.01 mg/kg i.v.
decreased cystitis induced changes in basal pressure and threshold pressure, as well as frequency of bladder contractions by 50, 60 and 45%, respectively (see Tables 2 and 3).
Thus, it was similarly effective as or even more effective than the reference compound HOE 140.
At 0.1 mg/kg i.v. cilansetron was even more potent in decreasing the cystitis evoked changes in basal pressure and threshold pressure by 83 and 100% respectively (see Tables 2 and 3).
Acute treatment with HOE140 130 Ng/kg reduced the symptoms of bladder overac-tivity associated with cyclophosphamide pretreatment. The dosing of 0.01 and 0.1 mg/kg cilansetron reduced these symptoms to an equivalent or slightly greater extent. Thus in the foregoing animal test model on cystometry in rats with cyclophosphamide-induced cystitis, cilansetron showe d a beneficial effect even superior to the efFect caused by HOE140.
As therapeutic agents, the 5-HT3 receptor antagonists or their pharmacologically compatible acid addition salts and/or their solvates may be administered in conventional pharmaceutical preparations. In an individual case, special dosage forms may be indi-cated. The doses to be used may vary individually and will naturally vary according to the type of condition to be treated and the substance used. In general, however, medicinal forms with an active substance content of 0.2 to 200 mg, in particular 1 to 50 mg, active substance per individual dose are suitable for administration to humans and larger mam-mals. The compounds may be contained according to the invention, together with con-ventional pharmaceutical auxiliaries and/or carriers, in solid or liquid pharmaceutical preparations. Examples of solid preparations are preparations which can be adminis-tered orally, such as tablets, coated tablets, capsules, powders or granules, or alterna-tively suppositories. These preparations may contain conventional pharmaceutical inor ganic and/or organic carriers, such as talcum, lactose or starch, in addition to conven-tional pharmaceutical auxiliaries, for example lubricants or tablet disintegrating agents.
Liquid preparations such as suspensions or emulsions of the active substances may con-tain the usual diluents such as water, oils and/or suspension agents such as polyethyl-ene glycols and the like. Other auxiliaries may additionally be added, such as preserva-tives, taste correctives and the like.
A 5-HT3 receptor antagonist or a pharmacologically compatible acid addition salt and/or a solvate thereof, preferably cilansetron, can be mixed and formulated with the pharmaceutical auxiliaries and/or can-iers in known manner. For the production of solid medicament forms, cilansetron or its acid addition salt can for example be mixed with the auxiliaries and/or carriers in conventional manner and can be wet or dry granulated. The granules or powder can be poured directly into capsules or be pressed into tablet cores in conventional manner. These can be coated in known manner if desired.
The following example is intended to explain the production of pharmaceutical preparations containing cilansetron hydrochloride.
Example I: Tablets containing cilansetron Composition:
Cilansetron hydrochloride monohydrate 4 parts Corn starch 30 parts Lactose 70 parts Kollidon 25~ 5 parts Magnesium stearate 2 parts Talcum 3 parts Total: 114 parts Preparation procedure:
The active substance was mixed with corn starch and fine-powdered lactose in a mixer.
The resulting mixture was moistened thoroughly with a 20% solution of polyvinylpyrroli-done (Kollidon 25~ by BASF) in demineralised water. If necessary, further demineralised water was added. The moist granules were passed through a 2 mm sieve, dried on trays at 40°C and then passed through a 1 mm sieve {Frewitt machine). Once the gra nules had been mixed with magnesium stearate and talcum, tablets of a weight of 114 mg were pressed therefrom, so that each tablet contained 4 mg active substance.
Likewise or preferably, other pharmaceutical preparations of cilansetron may be used, for example stabilised pharmaceutical preparations known from EP 0 895 782 A2.
Claims (17)
1. A use of a 5-HT3 receptor antagonist or a pharmacologically compatible deriva-tive thereof in the manufacture of a medicament for the treatment and/or prophylaxis of non-digestive tract derived abdominal disorders associated with pain.
2. A use according to claim 1 wherein the abdominal disorder is Interstitial Cystitis, Chronic Pelvic Pain Syndrome and/or abdominal pain associated with endometriosis.
3. A use according to claim 1 or 2 wherein the abdominal disorder is Interstitial Cystitis.
4. Use according to claim 1 wherein the 5-HT3 receptor antagonist is selected from the group consisting of alosetron, azasetron, bemesetron, cilansetron, dolasetron, fabe-setron, galdansetron, granisetron, indisetron, itasetron, lerisetron, lurosetron, ondanse-tron, palonosetron, ramosetron, ricasetron, tropisetron, zacopride and zatosetron.
5. Use according to claim 1 wherein the 5-HT3 receptor antagonist is cilansetron or a pharmacologically compatible acid addition salt and/or a solvate thereof.
6. Use according to claim 5 of cilansetron hydrochloride.
7. Use according to claim 6 of cilansetron hydrochloride monohydrate.
8. A method of treatment of a non-digestive tract derived abdominal disorder asso-ciated with pain which comprises administering an effective amount of a 5-HT3 receptor antagonist or a pharmacologically compatible derivative thereof to a person in need of such treatment.
9. A method according to claim 8 wherein the abdominal disorder is Interstitial Cys-titis, Chronic Pelvic Pain Syndrome and/or abdominal pain associated with endometrio-sis.
10. A method according to claim 8 or 9 wherein the abdominal disorder is Interstitial Cystitis.
11 11. A method according to claim 8 wherein the 5-HT3 receptor antagonist is se-lected from the group consisting of alosetron, azasetron, bemesetron, cilansetron, do-lasetron, fabesetron, galdansetron, granisetron, indisetron, itasetron, lerisetron, lurose-tron, ondansetron, palonosetron, ramosetron, ricasetron, tropisetron, zacopride and za-tosetron.
12. A method according to claim 8 or 11, wherein the 5-HT3 receptor antagonist is cilansetron or a pharmacologically compatible acid addition salt and/or a solvate thereof.
13. A use of a 5-HT3 receptor antagonist or a pharmacologically compatible deriva-tive thereof for the treatment and/or prophylaxis of a non-digestive tract derived abdomi-nal disorder associated with pain.
14. A use according to claim 13 wherein the abdominal disorder is Interstitial Cysti-tis, Chronic Pelvic Pain Syndrome and/or abdominal pain associated with endometriosis.
15. A use according to claim 13 wherein the abdominal disorder is Interstitial Cysti-tis.
16. A use according to claim 13 wherein the 5-HT3 receptor antagonist is selected from the group consisting of alosetron, azasetron, bemesetron, cilansetron, dolasetron, fabesetron, galdansetron, granisetron, indisetron, itasetron, lerisetron, lurosetron, on-dansetron, palonosetron, ramosetron, ricasetron, tropisetron, zacopride and zatosetron.
17. A use according to claim 13 wherein the 5-HT3 receptor antagonist is cilanse-tron or a pharmacologically compatible acid addition salt and/or a solvate thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP04101135.4 | 2004-03-19 | ||
EP04101135 | 2004-03-19 | ||
PCT/EP2005/051263 WO2005089732A1 (en) | 2004-03-19 | 2005-03-18 | Use of a 5-ht3 receptor antagonist for the manufacture of a medicament for the treatment of non-digestive tract derived abdominal disorders associated with pain |
Publications (1)
Publication Number | Publication Date |
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CA2560279A1 true CA2560279A1 (en) | 2005-09-29 |
Family
ID=34928913
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CA002560279A Abandoned CA2560279A1 (en) | 2004-03-19 | 2005-03-18 | Use of a 5-ht3 receptor antagonist for the manufacture of a medicament for the treatment of non-digestive tract derived abdominal disorders associated with pain |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP1727527A1 (en) |
JP (1) | JP2007529476A (en) |
CN (1) | CN1925846B (en) |
AU (1) | AU2005224061B2 (en) |
BR (1) | BRPI0508972A (en) |
CA (1) | CA2560279A1 (en) |
WO (1) | WO2005089732A1 (en) |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8701022D0 (en) * | 1987-01-19 | 1987-02-18 | Beecham Group Plc | Treatment |
EP1284732A2 (en) * | 2000-05-18 | 2003-02-26 | Glaxo Group Limited | Method for treating functional dyspepsia using alosetron |
MXPA05000477A (en) * | 2002-07-10 | 2005-03-23 | Warner Lambert Co | Combination of an allosteric inhibitor or matrix metalloproteinase-13 with a selective inhibitor of cyclooxygenase-2 that is not celecoxib or valdecoxib. |
EP1539181B1 (en) * | 2003-04-04 | 2007-06-27 | Dynogen Pharmaceuticals Inc. | Method of treating lower urinary tract disorders |
-
2005
- 2005-03-18 WO PCT/EP2005/051263 patent/WO2005089732A1/en not_active Application Discontinuation
- 2005-03-18 CN CN2005800066629A patent/CN1925846B/en not_active Expired - Fee Related
- 2005-03-18 BR BRPI0508972-7A patent/BRPI0508972A/en not_active IP Right Cessation
- 2005-03-18 EP EP05717101A patent/EP1727527A1/en not_active Withdrawn
- 2005-03-18 AU AU2005224061A patent/AU2005224061B2/en not_active Ceased
- 2005-03-18 JP JP2007503356A patent/JP2007529476A/en active Pending
- 2005-03-18 CA CA002560279A patent/CA2560279A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
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WO2005089732A1 (en) | 2005-09-29 |
BRPI0508972A (en) | 2007-08-28 |
AU2005224061A1 (en) | 2005-09-29 |
AU2005224061B2 (en) | 2011-01-27 |
CN1925846B (en) | 2011-11-16 |
JP2007529476A (en) | 2007-10-25 |
CN1925846A (en) | 2007-03-07 |
EP1727527A1 (en) | 2006-12-06 |
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