AU2005224061B2 - 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

Description

WO 2005/089732 PCT/EP2005/051263 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 The present invention relates to a novel medicinal use of 5-HT 3 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-HT 3 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. Z.H. Israili, Curr. Med. Chem. - CNS Agents 1 (2001) 171-199 for a review). From EP 0 467 365 A2 the use of 5-HT 3 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-HT 3 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, WO 2005/089732 PCT/EP2005/051263 2 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 14Q (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) 2470 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 Ill Prostati tis" (see J.N. Krieger et al., JAMA 22 (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, WO 2005/089732 PCT/EP2005/051263 3 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 3/4 (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 men 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 endometriosis 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- 4 mon treatments are surgery or anti-inflammatory and/or hormonal therapy or a combination thereof. It has now surprisingly been discovered that 5-HT 3 receptor antagonists can serve as treatment and/or prophylaxis for non-digestive tract derived abdominal disorders associated 5 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-HT 3 receptor antagonist or a pharmacologically compatible derivative thereof like a salt and/or a solvate, for the treatment and/or prophylaxis of non-digestive tract derived abdominal disorders associated with pain, 10 in particular Interstitial Cystitis, Chronic Pelvic Pain Syndrome and/or abdominal pain associated with endometriosis, in larger mammals and humans. The present invention is directed to: e use of a 5-HT 3 receptor antagonist selected from the group consisting of alosetron, azasetron, bemesetron, cilansetron, dolasetron, fabesetron, galdansetron, granisetron, 15 indisetron, itasetron, lerisetron, Jurosetron, ondansetron, palonosetron, ramosetron, ricasetron, tropisetron, zacopride and zatosetron, or a pharmacologically compatible derivative thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of an abdominal disorder selected from the group consisting of Interstitial Cystitis, Chronic Pelvic Pain Syndrome and/or abdominal pain associated with 20 endometriosis; e a method of treatment of an abdominal disorder selected from the group consisting of Interstitial Cystitis, Chronic Pelvic Pain Syndrome and/or abdominal pain associated with endometriosis which method comprises administering an effective amount of a 5

HT

3 receptor antagonist selected from the group consisting of alosetron, azasetron, 25 bemesetron, cilansetron, dolasetron, fabesetron, galdansetron, granisetron, indisetron, itasetron, lerisetron, lurosetron, ondansetron, palonosetron, ramosetron, ricasetron, tropisetron, zacopride and zatosetron, or a pharmacologically compatible derivative thereof, to a person in need of such treatment; e a 5-HT 3 receptor antagonist selected from the group consisting of alosetron, azasetron, 30 bemesetron, cilansetron, dolasetron, fabesetron, galdansetron, granisetron, indisetron, itasetron, lerisetron, lurosetron, ondansetron, palonosetron, ramosetron, ricasetron, tropisetron, zacopride and zatosetron, or a pharmacologically compatible derivative thereof, when used for the treatment and/or prophylaxis of an abdominal disorder selected from the group consisting of Interstitial Cystitis, Chronic Pelvic Pain Syndrome 35 and/or abdominal pain associated with endometriosis; 4a 0 a 5-HTa receptor antagonist selected from the group consisting of alosetron, azasetron, bemesetron, cilansetron, dolasetron, fabesetron, galdansetron, granisetron, indisetron, itasetron, lerisetron, Furosetron, ondansetron, palonosetron, ramosetron, ricasetron, tropisetron, zacopride and zatosetron, or a pharmacologically compatible derivative 5 thereof, when used for the treatment and/or prophylaxis of an abdominal disorder, which is Interstitial Cystitis; and * a 5-HT 3 receptor antagonist or a pharmacologically compatible derivative thereof when used for the treatment and/or prophylaxis of an abdominal disorder selected from the group consisting of Interstitial Cystitis, Chronic Pelvic Pain Syndrome and/or abdominal 10 pain associated with endometriosis, wherein the 5-HT 3 receptor antagonist is cilansetron or a pharmacologically compatible acid addition salt and/or a solvate thereof. Suitable 5-HT 3 receptor antagonists according to the invention are in particular selected from the group consisting of alosetron, azasetron, bemesetron, cilansetron, dolasetron, 15 fabesetron, galdansetron, granisetron, indisetron, itasetron, lerisetron, lurosetron, ondansetron, palonosetron, ramosetron, ricasetron, tropisetron, zacopride and zatosetron. Cilansetron is the preferred 5-HT 3 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-1 0-[(2-methyl-1 H-imidazol-1 -yl)methyl]-1 1 H-pyrido-[3,2, 1 -jk]-carbazol-1 1-one. 20 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-HT 3 receptor antagonists according to the invention can be demonstrated e.g. by an in vivo animal test model predictive for the therapeutic potential 25 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-HT 3 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 30 et al., J Auton Nerv Syst 38 (1992) 201) using male Wistar rats weighing 300-350 g. Rats were anesthetized with urethane delivered subcutaneously in saline (1.2 g/kg) and their temperature was maintained at 37 0 C. Following a midline abdominal incision a WO 2005/089732 PCT/EP2005/051263 5 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 pl/min 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-HT 3 receptor antagonists on rats with cyclo phosphamide-induced cystitis Group Pretreatment 48 h be- Acute treatment fore acute treatment I (control) vehicle vehicle 2 (cystitis control) Cyclophosphamide vehicle 150 mg/kg i.p. 3 (cystitis + reference compound) Cyclophosphamide HOE140 130 pg/kg i.v 150 mg/kg i.p. 4 (cystitis + cilansetron 0.01 mg/kg Cyclophosphamide Cilansetron 0.01 mg/kg i.v. i.v.) 150 mg/kg i.p. 5 (cystitis + cilansetron 0.1 mg/kg i.v.) Cyclophosphamide Cilansetron 0.1 mg/kg 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- WO 2005/089732 PCT/EP2005/051263 6 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, Thi5, D-Tic7, Oic8] 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 transvesi cal perfusion of warm saline at 50 pl/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 1 st 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 I group 2 group 3 group 4 group 5 cyclophos- cyclophos cyclophos phamide phamide phamide cyclophos- cystitis + cystitis + cystitis phamide cilansetron cilansetron vehicle control cystitis + 0.01 mg/kg 0.1 mg/kg control HOE140 i.v. t.v. basal pressure [mmHg] 13 19 16 16 14 threshold pressure [mmHg] 15 20 17 17 15 frequency hourss] 15 35 30 26 28 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 1 It 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.

WO 2005/089732 PCT/EP2005/051263 7 Table 3: Inhibition of cystitis effects % inhibition of cystitis effects group 3 group 4 group 5 cyclophos- cyclophos phamide phamide cyclophos- cystitis + cystitis + phamide cysti- cilansetron cilansetron tis + HOE140 0.01 mg/kg iv. 0.1 mg/kg iv. basal pressure 50 50 83 threshold pressure 60 60 100 freuency 25 45 35 Treatment with cilansetron in a concentration as low as 0.01 mg/kg iLv. 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 Lv. 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 pg/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-HT 3 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 I 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- WO 2005/089732 PCT/EP2005/051263 8 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-HT 3 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 carriers 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 0 C and then passed through a 1 mm sieve (Frewitt machine). Once the granules 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.

9 Likewise or preferably, other pharmaceutical preparations of cilansetron may be used, for example stabilised pharmaceutical preparations known from EP 0 895 782 A2. Comprises/comprising and grammatical variations thereof when used in this specification are to be taken to specify the presence of stated features, integers, steps or 5 components or groups thereof, but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

Claims (12)

1. A use of a 5-HT 3 receptor antagonist selected from the group consisting of alosetron, azasetron, bemesetron, cilansetron, dolasetron, fabesetron, galdansetron, 5 granisetron, indisetron, itasetron, lerisetron, lurosetron, ondansetron, palonosetron, ramosetron, ricasetron, tropisetron, zacopride and zatosetron, or a pharmacologically compatible derivative thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of an abdominal disorder selected from the group consisting of Interstitial Cystitis, Chronic Pelvic Pain Syndrome and/or abdominal pain associated with 10 endometriosis.

2. A use according to claim 1 wherein the abdominal disorder is Interstitial Cystitis.

3. Use according to claim 1 wherein the 5-HT 3 receptor antagonist is cilansetron or a pharmacologically compatible acid addition salt and/or a solvate thereof.

4. Use according to claim 3 of cilansetron hydrochloride. 15

5. Use according to claim 4 of cilansetron hydrochloride monohydrate.

6. A method of treatment of an abdominal disorder selected from the group consisting of Interstitial Cystitis, Chronic Pelvic Pain Syndrome and/or abdominal pain associated with endometriosis which method comprises administering an effective amount of a 5-HT 3 receptor antagonist selected from the group consisting of alosetron, azasetron, bemesetron, 20 cilansetron, dolasetron, fabesetron, galdansetron, granisetron, indisetron, itasetron, lerisetron, lurosetron, ondansetron, palonosetron, ramosetron, ricasetron, tropisetron, zacopride and zatosetron, or a pharmacologically compatible derivative thereof, to a person in need of such treatment.

7. A method according to claim 6 wherein the abdominal disorder is Interstitial Cystitis. 25

8. A method according to claim 6 or claim 7, wherein the 5-HT 3 receptor antagonist is cilansetron or a pharmacologically compatible acid addition salt and/or a solvate thereof.

9. A 5-HT 3 receptor antagonist selected from the group consisting of alosetron, azasetron, bemesetron, cilansetron, dolasetron, fabesetron, galdansetron, granisetron, indisetron, itasetron, lerisetron, lurosetron, ondansetron, palonosetron, ramosetron, 30 ricasetron, tropisetron, zacopride and zatosetron, or a pharmacologically compatible derivative thereof, when used for the treatment and/or prophylaxis of an abdominal disorder selected from the group consisting of Interstitial Cystitis, Chronic Pelvic Pain Syndrome and/or abdominal pain associated with endometriosis. 11

10. A 5-HT 3 receptor antagonist selected from the group consisting of alosetron, azasetron, bemesetron, cilansetron, dolasetron, fabesetron, gaidansetron, granisetron, indisetron, itasetron, lerisetron, Jurosetron, ondansetron, palonosetron, ramosetron, ricasetron, tropisetron, zacopride and zatosetron, or a pharmacologically compatible 5 derivative thereof, when used for the treatment and/or prophylaxis of an abdominal disorder, which is Interstitial Cystitis.

11. A 5-HT 3 receptor antagonist or a pharmacologically compatible derivative thereof when used for the treatment and/or prophylaxis of an abdominal disorder selected from the group consisting of Interstitial Cystitis, Chronic Pelvic Pain Syndrome and/or abdominal pain 10 associated with endometriosis, wherein the 5-HT 3 receptor antagonist is cilansetron or a pharmacologically compatible acid addition sait and/or a solvate thereof.

12. A method of treatment of an abdominal disorder selected from the group consisting of Interstitial Cystitis, Chronic Pelvic Pain Syndrome and/or abdominal pain associated with endometriosis which method comprises administering an effective amount .5 of tablet(s) containing cilansetron, wherein the tablet(s) are substantially as hereinbefore described with reference to Example 1. SOLVAY PHARMACEUTICALS GMBH 0 WATERMARK PATENT AND TRADE MARKS ATTORNEYS P27536AUOO