US00593.9426A United States Patent (19) 11 Patent Number: 5,939.426 McCullough (45) Date of Patent: Aug. 17, 1999

54 METHODS FORTREATING URINARY Ebert, W., 1977, “Soft Elastic Gelatin Capsules: A Unique INCONTINENCE USING Dosage Form”, Pharmaceutical Technology 1:44-50. DESCARBOETHOXYLORATADINE Goodman and Gilman's, 1996, The Pharmacological Basis of Therapeutics, 9th Ed. pp. 148, 588-592. 75 Inventor: John R. McCullough, Worcester, Mass. Herzog, A.R. et al., 1989, “Urinary Incontinence: Medical and Psychosocial Aspects”, Annu. Rev. Gerontol. Geriatr. 73 Assignee: Sepracor Inc., Marlborough, Mass. 9:74-119. Hilbert, J. et al., 1987, "Pharmacokinetics and Dose Pro 21 Appl. No.: 08/808,116 portionality of Loratadine”, J. Clin. Pharmacol. 27:694-698. 22 Filed: Feb. 28, 1997 Knowles, S., 1992, " and Terfenadine-Induced Cardiovascular Effects”, Canadian J. Hospital Pharmacy (51) Int. Cl." ...... A61K 31/44 45:33-34. 52 U.S. Cl...... 514/290 Kohl and MacDonald, 1991, “New Pharmacologic 58 Field of Search ...... 514/290 Approaches to the Prevention of Space/Motion Sickness”, J. Clin. Pharmacol. 31:934-946. 56) References Cited Kubo, N. et al., 1987, "Antimuscarinic Effects of Antihis U.S. PATENT DOCUMENTS tamines: Quantitative Evaluation by Receptor-Binding Assay”, Japan J. Pharmacol. 43:277-282. 3,536.809 10/1970 Applezweig. 3,598,123 8/1971 Zaffaroni. Lathers, C. et al., 1989, “Pharmacology in Space', TiPS, 3,845,770 11/1974 Theeuwes et al.. 10:243-250. 3,916,899 11/1975 Theeuwes et al.. Levin and Wein, 1982, “Direct Measurement of the Anti 3,940,485 2/1976 Levinson et al...... 424/250 Activity of a Series of Pharmacological Com 4,008,796 2/1977 Aylon. pounds on the Canine and Rabbit Urinary Bladder”, J. 4,282,233 8/1981 Vilani. Urology 128:396-398. 4,659,716 4/1987 Villani et al.. 4,777,170 10/1988 Heinrich ...... 514/226.2 Lunde, I., 1990, “Antihistamines”, Side Effects of Drugs 5,595.997 1/1997 Aberg et al...... 514/290 14:135-138. Massad, C. et al., 1992, “The Pharmokinetics of Intravesical FOREIGN PATENT DOCUMENTS and Oral Chloride”, J. Urology 148:595-597. WO 92/20377 11/1992 WIPO. McCue, J., 1996, “Safety of Antihistamines in the Treatment WO 96/20708 7/1996 WIPO. of Allergic Rhinitis in Elderly Patients”, Arch. Fam. Med. 5:464–468. OTHER PUBLICATIONS Mirakhur and Dundee, 1983, “Glycopyrrolate: Pharmacol Andersen and Feingold, 1995, “Adverse Drug Interactions ogy and Clinical Use', Anaesthesia 38:1195-1204. Clinically Important for the Dermatologist', Arch. Derma Mitchelson, F., 1992, “Pharmacological Agents Affecting tol. 131:468-473. Emesis', Drugs 43:443-463. Berge, S. et al., 1977, “Pharmaceutical Salts”, J. of Phar Muskat, Y. et al., 1996, “The Use of in the maceutical Sciences 66:1-19. Treatment of Detrusor Instability”, J. Urology Brandes, L. et al., 1992, “Stimulation of Malignant Growth 1.56:1989-1990. in Rodents by Antidepressant Drugs at Clinically Relevant Neiemans, F.A., 1988, “Antiallergic and Antitussive Drugs”, Doses', Cancer Research 52:3796-3800. Side Effects of Drugs 12:144-147. Brandes, L. et al., 1994, "Enhanced Cancer Growth in Mice Peggs and Shimp, 1995, “Antihistamines: The Old and The Administered Daily Human-Equivalent Doses of Some New', American Family Physician 52:593-600. H-Antihistamines: Predictive In Vitro Correlates”, J. Natl. Quercia and Broisman, 1993, "Focus on Loratadine: A New Cancer Institute 86:770–775. Second-Generation Nonsedating H-Receptor Antagonist”, Carmeliet, 1992, “Voltage- and Time-Dependent Block of Hosp. Formul. 28:137-153. the Delayed K Current in Cardiac Myocytes by Dofetilide', Resnick, N., 1995, “Urinary Incontinence”, The Lancet J. Pharmocol. Exper. Ther. 262:809–817. 346:94-99. Cheung, B.S.K., et al., 1992, “Investigation of Anti-Motion Roman and Danzig, 1993, “Loratadine”, Clinical Reviews in Sickness Drugs in the Squirrel Monkey”, J. Clin. Pharmacol. Allergy 11:89-110. 32:163-175. Clissold et al., 1989, “Loratadine: A Preliminary Reivew of (List continued on next page.) its Pharmacodynamic Properties and Therapeutic Efficacy”, Drugs 37:42–57. Primary Examiner Minna Moezie Cohen, B. et al., 1972, “ and Placebo in Treating Attorney, Agent, or Firm-Pennie & Edmonds LLP Vertigo of Vestibular Origin”, Arch. Neurol. 27:129-137. 57 ABSTRACT Cooke, R.D., 1983, “Glycopyrrolate in Bladder Dysfunc tion”, S. Afr. Med. J. 63:3. Methods for treating urinary incontinence comprising Craft, T., 1986, "Torsade de Pointes after Astemizole Over administering a therapeutically effective amount of dose”, British Medical Journal 292:660. deScarboethoxyloratadine, or a pharmaceutically acceptable Dörje, F. et al., 1991, “Antagonist Binding Profiles of Five Salt thereof. Cloned Human Muscarinic Receptor Subtypes”, J. Pharma cology and Experimental Therapeutics 256:727-733. 7 Claims, 1 Drawing Sheet 5,939.426 Page 2

OTHER PUBLICATIONS Yarker, Y. et al., 1995, “Oxybutynin', Drugs & Aging 6:243-262. Simons, F.E.R. et al., 1988, “Astemizole-Induced Torsade de Pointes', The Lancet 2:624. M.N.G. Dukes et al., “Side Effects of Drugs Annual 12.” Simons, F.E.R., 1994, “H-Receptor Antagonists”, Drug Elsevier Science Publishers B.V.: 142-143 (1988). Safety 10:350–380. Petrin, A., 1974, "Motion Sickness and its Treatment', Wein, A., 1995, “Pharmacology of Incontinence', Urol. Schweiz. Med. 63:79-81. Clin. N. Am. 22:557-577. Wood, C.D. et al., 1987, "Mechanisms of Antimotion Sick Wood, C., 1979, “Antimotion Sickness and Antiemetic ness Drugs”, Aviation, Space, and Envir. Med. 58 (9, Suppl.) Drugs", Drugs 17:471-479. pp. A262-A265. U.S. Patent Aug. 17, 1999 5,939.426 K RABBT VENTRICULAR CELL (%) (7) (7) E = -50 V 1 OO - -, (7) H

80 period 30s 60

40 Xs = 8.818 EM-6 20 COeff. = 1.836

O ------10-7 10-6 10-5 10-4 10-3 conc. loratadine (M) FIG.

RABBT VENTRICULAR CELL

EH= -50 mV

(11)

period 30S

-6

20 - COeff. = 1.032 O - ---G- 10-7 10-6 10-5 10-4 10-3 Conc. descarboethoxyloratadine (M) FIG. 2 5,939.426 1 2 METHODS FOR TREATING URINARY Muskat et al. State that when the drug is administered by an INCONTINENCE USING oral or Systemic route, it causes Severe side-effects and also DESCARBOETHOXYLORATADNE discuss the contradictory reports regarding the transdermal administration of Scopolamine. Muskat et al. report that FIELD OF THE INVENTION although Scopolamine is known to cause cycloplegia and dryneSS of the mouth, the Side-effects in its Study were not The present invention relates to methods for treating So Severe to require discontinuation of the medication (Id. at urinary incontinence, Vertigo and motion Sickness. 1990). Scopolamine is also reported as being used widely for motion SickneSS and as effective for the treatment of Vertigo BACKGROUND OF THE INVENTION (Id.). However, it has also been reported that Scopolamine Urinary incontinence, Such as incontinence caused by has unwanted sedative effects (see Lathers et al., TIPS bladder detrusor muscle instability, is a prevalent problem 10:243–250 (1989)). that affects people of all ages and levels of physical health, Certain first generation H-receptor antihistamines, Such both in healthcare Settings and in the community at large. At as and , have been reported present, urinary incontinence afflicts 15-30% of elderly as having Significant affinity for the muscarinic receptors people living at home, one-third of those living in acute-care 15 (Kubo et al., Japan J. Pharmacol. 43:277–282 (1987)). Settings, and at least one-half of those in long-term care Some first generation H receptor antihistamines, Such as institutions (Resnick, R. M., Lancet 346:94 (1995)). , and meclizine, have also been Medically, it predisposes perSons to urinary tract infections, found to be effective for treating either vertigo or motion pressure ulcers, perineal rashes, and uro Sepsis. sickness (Id; Wood, C., Drugs 17:471-479 (1979); Cohen et PsychoSocially, urinary incontinence is associated with al., Archives of Neurology 27: 129-135 (1972); see also embarrassment, Social Stigmatization, depression, and with Goodman & Gilman's, The Pharmacological Basis of the risk of institutionalization (Herzo et al., Annu. Rev. Therapeutics, 9th Ed. p. 588, 592 (1996)). Gerontol. Geriatr. 9:74 (1989)). Economically, the costs are Peggs et al. (American Family Physician 52(2):593-600 great; in the United States alone, over S15 billion is spent per (1995)), note that classic antihistamines, which have a annum managing incontinence. 25 greater propensity to croSS the blood-brain barrier, would Treatments for incontinence include drugs with bladder appear to be better indicated for the treatment of these relaxant properties, i.e., which help to control bladder detru conditions. However, the first generation H antihistamines sor muscle overactivity. Such drugs are effective in 80 to have undesirable side-effects, Such as Sedation (see Good 85% of patients with uninhibited bladder contractions. Anti mans & Gilman's, The Pharmacological Basis of cholinergic medications represent the mainstay of this type Therapeutics, 9th Ed. p. 590 (1996). of treatment. The major proportion of the neurohumoral The Second generation H-receptor antihistamines, Such Stimulus for physiologic bladder contraction is as terfenadine, astemizole and loratadine, while having -induced Stimulation of post ganglionic mus fewer Sedative effects, are reported as having weak or no carinic receptor Sites on bladder Smooth muscle. For effect on muscarinic receptors (Goodman & Gilman's, The example, Such as 35 Pharmacological Basis of Therapeutics, 9th Ed. p. 588 and glycopyrrolate, and combination Smooth muscle (1996); Simons, F. E., Drugs Safety 10(5):350–380 (1994)). relaxant/anticholinergicS Such as racemic oxybutynin and This is consistent with the findings that Such compounds do dicyclomine, have been used to treat urge incontinence. not possess any significant affects (see (See, e.g., Wein, A. J., Urol. Clin. N. Am. 22:557-577 40 Simons, F. E., Drug Safety 10(5):350–380 (1994); Roman et (1995); Levin et al., J. Urol. 128:396-398 (1982); Cooke et al., Clinical Reviews in Allergy 11:89–110 (1993)). Quercia al., S. Afr. Med. J. 63:3 (1983); R. K. Mirakhur et al., et al. (Hosp. Formul. 28:137-153 (1993)) reported that Anaesthesia 38:1195–1204 (1983)). loratadine does not exhibit Substantial anticholinergic or However, none of the existing commercial drug treat alpha-adrenergic effects Since it has only a weak affinity for ments for incontinence has achieved complete Success with 45 alpha-adrenoreceptor and acetylcholine receptors. all classes of incontinent patients, nor has treatment occurred Astemizole has been reported to alleviate chronic vertigo without significant adverse (side) effects. For example, (see Mitchelson F., Drugs 43(4):443–463 (1992)). However, adverse effects, Such as drowsiness, dry mouth, constipation, astemizole and terfenadine have also been reported as inef blurred vision, headaches, tachycardia, and cardiac arrhyth fective at preventing motion Sickness (Cheung et al., J. Clin. mia which are related to the anticholinergic activity of Such 50 Pharmacol. 32:163–175 (1992)). Kohl et al. (J. Clin. Phar drugs, occur frequently and can be Sufficiently troublesome macol. 31:934-946 (1991)) reported moderate efficacy of a to necessitate discontinuing treatment in up to 25% of single 300 mg dose of terfenadine (which is five fold higher patients, depending on the dosage. Yet, despite the occur than the recommended single dose) for motion sickness and rence of unwanted anticholinergic effects in many patients pronounced individual response differences. Such drugs are currently prescribed for patients with bladder 55 Kubo et al. (Japan J. Pharmacol. 43:277–282 (1987)) detrusor muscle hyperactivity when pharmacological State that the anti-motion Sickness activity of Some of the H therapy is indicated (Cf. Yarlur et al., Drugs Aging 6:243 receptor antagonistS may be related to their antimuscarinic (1995)). ability. Kubo et al. also state that Since histamine H receptor The effects of acetylcholine are prevented when musca blockade is Suggested to be associated with the Sedative rinic receptor antagonists block its binding to muscarinic 60 activity, a drug which has both antimuscarinic and antihis cholinergic receptors at certain neuroeffector Sites Such as in taminic effects may be more effective in the treatment of the urinary bladder (see Goodman & Gilman's, The Phar motion Sickness. macological Basis of Therapeutics, 9th Ed. p. 148 (1996)). Clinical efficacy trials indicated that loratadine is an Scopolamine, a , has been reported effective Hantagonist (see Clissold et al., Drugs 37:42-57 to be effective, when administered transdermally, in the 65 (1989)). Loratadine binds preferentially to peripheral rather treatment of detrusor instability in female patients (Muskat than to central H receptors (Quercia et al., Hosp. Formul. et al., The Journal of Urology 156: 1989-1990 (1996)). 28:137-153 (1993)). 5,939.426 3 4 Loratadine is well absorbed but is extensively metabo neSS based on the unexpected finding that a metabolite of lized (Hilbert, et al., J. Clin. Pharmacol. 27:694-98 (1987)). loratadine, descarboethoxyloratadine (“DCL), provides a The main metabolite, descarboethoxyloratadine, which has Superior treatment of urinary incontinence, and Vestibular been identified, is reported to be pharmacologically active disorders, Such as vertigo and motion Sickness, than drugs (Clissold, Drugs 37:421457 (1989)). It is also reported previously associated with the treatment of Such disorders. as having antihistaminic activity in U.S. Pat. No. 4,659,716. The methods of the present invention comprise adminis This patent recommends an oral dosage range of 5 to 100 tering a therapeutically effective amount of DCL. mg/day and preferably 10 to 20 mg/day. Chemically, DCL is 8-chloro-6,11-dihydro-11-(4- AS explained, Supra, the Second generation H piperidylidene)-5H-benzo 5,6cyclohepta1,2-bipyridine, antagonists, Such as loratadine, possess no or weak anticho and has the following Structure: linergic effects. Furthermore, astemizole and terfenadine, have been known to cause Severe cardiac electrophysiologic adverse Side-effects. These adverse side-effects are associ ated with a prolonged QT interval, and include, but are not Z C limited to, Ventricular fibrillation and cardiac arrhythmias, Such as Ventricular tachyarrhythmias or torSade de pointes. 15 (Knowles, Canadian Journal Hosp. Pharm. 45:33,37 (1992); Craft, British Medical Journal 292:660 (1986); Simons et al., Lancet, 2:624 (1988); and Unknown, Side Effects of Drugs Annual 12:142 and 14:135). McCue, J. (Arch. Fam. Med. 5:464–468 (1996)) reports that loratadine does not appear to have adverse electrocardiographic effects. Quercia et al. (Hosp. Formul. 28:137,142 (1993)) noted that Serious cardiovascular adverse Side-effects, including torSade de pointes and other ventricular arrhythmias, were reported in “healthy” patients who received terfenadine 25 In one aspect the invention relates to a method for treating concurrently with either ketoconazole or erythromycin. urinary incontinence which comprises administering to a Quercia et al. States that arrhythmias have also been reported human in need of Such treatment a therapeutically effective with the concomitant administration of astemizole and amount of DCL or a pharmaceutically acceptable Salt erythromycin or erythromycin plus ketoconazole. Thus, he thereof. cautions against using loratadine concurrently with In another aspect, the present invention provides a method ketoconazole, itraconazole, and macrollides, Such as eryth for treating vertigo comprising administering to a human in romycin. McCue, J. (Arch. Fam. Med. 5:464–468 (1996)) need of Such treatment a therapeutically effective amount of reported that coadministration of loratadine with DCL or a pharmaceutically acceptable Salt thereof. ketoconazole, erythromycin and cimetidine revealed no In a further aspect, the present invention provides a clinically relevant changes in cardiac repolarization or other 35 method for treating motion Sickness comprising administer electrocardiographic effects. ing to a human in need of Such treatment a therapeutically Additionally, it is known that ketoconazole, itraconazole, effective amount of DCL or a pharmaceutically acceptable and/or erythromycin interfere with cytochrome P450, and Salt thereof. thereby inhibit the metabolism of non-sedative antihista In another aspect, DCL can be used in accordance with mines Such as terfenadine, astemizole, and loratadine (see 40 this invention to effectively treaturinary incontinence while Andersen et al., Arch. Dermatol. 131:468–473 (1995)). Substantially reducing or avoiding the adverse side-effects Thus, there exists a potential for adverse interactions asSociated with existing drugs for the treatment of urinary between loratadine and Such drugs. incontinence Such as Scopolamine and racemic oxybutynin. Brandes et al., (Cancer Res. (52):3796-3800 (1992)), DCL can also be used in accordance with this invention to showed that the propensity of drugs to promote tumor 45 effectively treat Vertigo and motion Sickness, including, but growth in Vivo correlated with potency to inhibit concanava not limited to, space motion sickness (or space adaptation lin A Stimulation of lymphocyte mitogenesis. Brandes et al., Syndrome) and Sea Sickness, while Substantially reducing the (J. Nat'l Cancer Inst. 86(10):771–775 (1994)), assessed adverse side-effects that primarily arise from drugs that are loratadine in an in Vitro assay to predict enhancement of in asSociated with the treatment of Vertigo and motion Vivo tumor growth. This reference also reported that lora 50 Sickness, Such as Scopolamine and meclizine. The adverse tadine (at a dose of about 10 mg/day) and astemizole are effects include, but are not limited to, Xerostomia, mydriasis, asSociated with growth of both melanoma and fibrosarcoma drowsiness, nausea, constipation, palpitations and tachycar tumors, in Vivo. dia. DCL also has the additional therapeutic benefit of not Based upon the above discussion, it is clear that there is causing Side-effects associated with certain Second genera a need for an effective drug for the treatment of urinary 55 tion antihistamines Such as cardiac arrythmia, associated incontinence, Vertigo, and motion Sickness which does not with astemizole and terfenadine, or the potential to promote possess the adverse Side-effects of the drugs previously tumors, associated with loratadine. prescribed for Such disorders. There is also a need for a drug The present invention also encompasses compositions for for the treatment of these conditions, which, in contrast to use in the methods for treating motion Sickness, comprising the Second generation antihistamines, has anticholinergic 60 a therapeutically effective amount of DCL or a pharmaceu activity, yet does not cause the adverse effects associated tically acceptable Salt thereof, a therapeutically effective with administration of the first or Second generation anti amount of ephedrine, and a pharmaceutically acceptable histamines. carrier. The present invention also encompasses compositions for SUMMARY OF THE INVENTION 65 use in the methods of the present invention for treating The present invention provides methods for the effective motion Sickness, comprising a therapeutically effective treatment of urinary incontinence, Vertigo and motion Sick amount of DCL or a pharmaceutically acceptable Salt 5,939.426 S 6 thereof, a therapeutically effective amount of a drug Selected human in need of Such treatment a therapeutically effective from the group consisting of amphetamines, amphetamine amount of DCL, or a pharmaceutically acceptable Salt Salts and amphetamine analogs, and a pharmacologically thereof. acceptable carrier. The present invention also encompasses a method for The present invention also encompasses compositions for treating vertigo which comprises administering to a human use in the methods for treating motion Sickness, comprising in need of Such treatment a therapeutically effective amount a therapeutically effective amount of DCL or a pharmaceu of DCL, or a pharmaceutically acceptable Salt thereof. tically acceptable Salt thereof, a therapeutically effective Another embodiment of the present invention is a method amount of an amphetamine agent, and a pharmaceutically of treating motion SickneSS which comprises administering acceptable carrier. to a human in need of Such treatment, a therapeutically The present invention also encompasses compositions for effective amount of DCL, or a pharmaceutically acceptable use in the methods of the present invention for treating Salt thereof. One advantage of using DCL to treat motion motion Sickness, comprising a therapeutically effective Sickness is that it lackS Sedative effects. amount of DCL or a pharmaceutically acceptable Salt The present invention also relates to methods for treating the reof, a therapeutically effective amount of a 15 urinary incontinence, Vertigo and/or motion SickneSS while psychoStimulant, and a pharmaceutically acceptable carrier. avoiding the adverse effects associated with existing drugs In a further aspect, the present invention provides a used to treat these indications. method for treating motion Sickness comprising administer The present invention also encompasses the use of DCL, ing to a human in need of Such treatment a therapeutically or compositions containing DCL, to treat the above effective amount of DCL or a pharmaceutically acceptable described conditions while avoiding cardiac arrhythmias Salt thereof and a therapeutically effective amount of a and tumor promotion. Thus, the present invention also decongestant. relates to the use of DCL to treat Such conditions in a human having a higher then normal propensity for or incidence of In a further aspect, the present invention provides a CCC. method for treating motion Sickness comprising administer 25 ing to a human in need of Such treatment a therapeutically The present invention also relates to methods of treating effective amount of DCL or a pharmaceutically acceptable urinary incontinence, Vertigo, motion Sickness while avoid Salt thereof and a therapeutically effective amount of ephe ing adverse events associated with co-administration of a drine. drug that inhibits cytochrome, P450, including, but not Additionally, the present invention is directed to a method limited to, ketoconazole, itraconazole, erythromycin, and for treating motion SickneSS comprising administering to a others known by those skilled in the art. human in need of Such treatment a therapeutically effective The present invention is also related to a method for amount of DCL or a pharmaceutically acceptable Salt thereof treating urinary incontinence, Vertigo and/or motion Sick and a therapeutically effective amount of a drug Selected ness in a patient having a higher than normal propensity for from the group consisting of amphetamines, amphetamine 35 Long QT Syndrome as a result of either genetic and/or Salts and amphetamine analogs. environmental factors. The present invention also involves compositions having The present invention is also directed to a method for anticholinergic activity for use in Such methods which treating motion Sickness comprising administering to a comprise a therapeutically effective amount of DCL, or a human in need of Such treatment a therapeutically effective pharmaceutically acceptable Salt thereof, and a pharmaceu amount of DCL or a pharmaceutically acceptable Salt thereof 40 tically acceptable carrier. and a therapeutically effective amount of an amphetamine The present invention also encompasses compositions for agent. use in the methods for treating motion Sickness, comprising In another aspect, the present invention provides a method a therapeutically effective amount of DCL or a pharmaceu for treating motion Sickness, comprising administering to a tically acceptable Salt thereof, a therapeutically effective human in need of Such treatment a therapeutically effective 45 amount of ephedrine, and a pharmaceutically acceptable amount of DCL or a pharmaceutically acceptable Salt thereof carrier. and a therapeutically effective amount of a psychoStimulant. The present invention also encompasses compositions for According to the present invention, DCL may be admin use in the methods for treating motion Sickness, comprising istered parenterally, rectally, intravesically, transdermally, 50 a therapeutically effective amount of DCL or a pharmaceu orally, intravascularly, by inhalation, or by aeroSol, at a rate tically acceptable Salt thereof, a therapeutically effective of about 0.1 mg to about 100 mg per day. Oral and amount of a drug Selected from the group consisting of transdermal are the preferred routes for the treatment of amphetamines, amphetamine Salts, and amphetamine Vertigo and motion Sickness. Oral, intravenous and intra analogs, and a pharmaceutically acceptable carrier. vesically are the preferred routes for the treatment of urinary 55 The present invention also encompasses compositions for incontinence at the same dosage range. use in the methods for treating motion Sickness, comprising a therapeutically effective amount of DCL or a pharmaceu BRIEF DESCRIPTION OF THE FIGURES tically acceptable Salt thereof, a therapeutically effective FIG. 1 represents the effect of loratadine on the delayed amount of an amphetamine agent, and a pharmaceutically rectifying K' current (I) in rabbit ventricular myocytes. 60 acceptable carrier. FIG. 2 represents the effect of DCL on the delayed The present invention also encompasses compositions for rectifying K current (I) in rabbit ventricular myocytes. use in the methods for treating motion Sickness, comprising a therapeutically effective amount of DCL or a pharmaceu DETAILED DESCRIPTION OF THE tically acceptable Salt thereof, a therapeutically effective INVENTION 65 amount of a psychoStimulant, including, but not limited to, The present invention encompasses a method for treating pemoline and methylphenidate and a pharmaceutically urinary incontinence which comprises administering to a acceptable carrier. 5,939.426 7 8 In a further aspect, the present invention provides a treat urinary incontinence and/or vertigo and/or motion method for treating motion Sickness comprising administer Sickness, which are not part of the desired therapeutic effect ing to a human in need of Such treatment a therapeutically of the drug. Such adverse effects, include, for illustrative effective amount of DCL or a pharmaceutically acceptable purposes, drowsiness, epistaxis, Xerostomia, mydriasis, Salt thereof and a therapeutically effective amount of a cycloplegia, unstable cardiovascular status Such as tachy decongestant Such as, but not limited to, pseudoephedrine cardia and cardiac arrhythmia, increased ocular pressure, and phenylpropanolamine. The administration of DCL and nausea, constipation, decreased SWeating, impotence, and/or decongestant in the methods of the present invention for dermal manifestations Such as urticaria. treating motion Sickness may be either concurrent or The term “cardiac arrhythmias” includes, but is not lim Sequential, i.e., DCL and decongestant may be administered ited to, Long QT Syndrome, Ventricular tachyarrhythmias, as a combination, concurrently but separately, or by the torSade de pointes and Ventricular fibrillation. Sequential administration of DCL and decongestant or the The term “epistaxis' refers to nosebleeds, e.g., hemor Sequential administration of decongestant and DCL. rhage from the nose. Epistaxis is a side effect of anticho In a further aspect, the present invention provides a linergics in children. method for treating motion Sickness comprising administer 15 ing to a human in need of Such treatment a therapeutically The term “xerostomia' refers to dryness of the mouth due effective amount of DCL or a pharmaceutically acceptable to lack of normal Secretion. Salt thereof and a therapeutically effective amount of ephe The term “mydriasis” refers to dilation of the pupil, and drine. The administration of DCL and ephedrine in the often results in blurred vision. methods of the present invention for treating motion Sick The term "cycloplegia' refers to paralysis of the ciliary neSS may be either concurrent or Sequential, i.e., DCL and muscle; paralysis of accommodation. ephedrine may be administered as a combination, concur The term “urinary incontinence” means the inability to rently but Separately, or by the Sequential administration of prevent the discharge of urinary excretions, and includes, DCL and ephedrine or the Sequential administration of but is not limited to, bladder detrusor muscle instability ephedrine and DCL. 25 incontinence, StreSS incontinence, urge incontinence, over In another aspect, the present invention provides a method flow incontinence, enuresis, and post-prostectomy inconti for treating motion SickneSS comprising administering to a CCC. human in need of Such treatment a therapeutically effective The term “enuresis” refers to the involuntary discharge of amount of DCL or a pharmaceutically acceptable Salt thereof urine, and "nocturnal enuresis” refers to involuntary dis and a therapeutically effective amount of a drug Selected charge of urine during sleep. from the group consisting of amphetamines, amphetamine The term “vertigo” means an abnormal Sensation of rotary Salts, and amphetamine analogs. The administration of DCL movement associated with difficulty with balance, gait and and Such a drug in the methods of the present invention for navigation in the environment. The term also includes a treating motion Sickness may be either concurrent or disturbance in which the individual has a Subjective impres Sequential, i.e., DCL and the drug may be administered as a 35 Sion of movement in Space or of objects moving around the combination, concurrently but Separately, or by the Sequen individual, usually with a loss of equilibrium. This results tial administration of DCL and the drug or the Sequential from a disturbance Somewhere in the equilibratory appara administration of the drug and DCL. tus: Vestibule, Semicircular canals, 8th nerve; Vestibular In a further embodiment, the present invention provides a nuclei in the brainstem and their temporal lobe connections, method for treating motion Sickness comprising administer 40 and eyes. This term includes, but is not limited to, Vertigo ing to a human in need of Such treatment a therapeutically which results from Meniere's disease. effective amount of DCL or a pharmaceutically acceptable The term “Meniere's Disease” means disorders charac Salt thereof and a therapeutically effective amount of an terized by recurring prostrating vertigo, Sensory hearing amphetamine agent. The administration of DCL and loSS, and tinnitus, associated with generalized dilation of the amphetamine agent in the methods of the present invention 45 membranous labyrinth. for treating motion Sickness may be either concurrent or The term “motion Sickness” means a disorder caused by Sequential, i.e., DCL and amphetamine agent may be admin repetitive angular and linear acceleration and deceleration istered as a combination, concurrently but Separately, or by and excessive Stimulation of the vestibular apparatus by the Sequential administration of DCL and amphetamine 50 motion. The disorder is characterized primarily by nausea agent or the Sequential administration of amphetamine agent and vomiting. The term includes, but is not limited to Space and DCL. motion Sickness, also referred to as Space adaptation Syn In another embodiment, the present invention provides a drome. method for treating motion Sickness comprising administer In accordance with the present invention, DCL can be ing to a human in need of Such treatment a therapeutically 55 used to treat urinary incontinence, Vertigo and motion Sick effective amount of DCL or a pharmaceutically acceptable neSS by administration to a patient using any Suitable route Salt thereof, and a therapeutically effective amount of a of administration. (See, Remington. The Science and Prac psychoStimulant, including, but not limited to, pemoline and tice of Pharmacy, Nineteenth Edition, Chapters 83-95 methylphenidate. The administration of DCL and a psycho (1995)). A preferred method of administration is oral admin Stimulant in the methods of the present invention for treating 60 istration. Another preferred route of administration is intra motion SickneSS may be either concurrent or Sequential, i.e., venous administration. A particularly preferred method of DCL and psychoStimulant may be administered as a administration for the treatment of Vertigo and motion combination, concurrently but Separately, or by the Sequen Sickness is transdermal administration. tial administration of DCL and psychostimulant or the According to the present invention, DCL is preferably Sequential administration of psychoStimulant and DCL. 65 administered as a pharmaceutical formulation The term "adverse effects” as used herein, refers to the (composition). The phrase “pharmaceutically acceptable' is Side-effects associated with administration of drugs used to employed herein to refer to those compounds, materials, 5,939.426 9 10 compositions, and/or dosage forms which are, within the (14) buffering agents, Such as magnesium hydroxide and Scope of Sound medical judgment, Suitable for use in contact aluminum hydroxide; (15) alginic acid, (16) pyrogen-free with the tissueS of human beings and animals without water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl excessive toxicity, irritation, allergic response, or other ; (20) phosphate buffer solutions; and (21) other problem or complication, commensurate with a reasonable non-toxic compatible Substances employed in pharmaceuti benefit/risk ratio. cal formulations (see, Remington. The Science and Practice of Pharmacy, Nineteenth Edition, Chapter 80 (1995)). The term “pharmaceutically acceptable Salts', refers to Formulations of the present invention Suitable for oral the relatively non-toxic, inorganic and organic Salts of DCL. administration may be in the form of capsules, cachets, pills, Representative Salts include the bromide, chloride, tablets, lozenges (using a flavored basis, usually Sucrose and hydrobromide, hydrochloride, Sulfate, bisulfate, phosphate, acacia or tragacanth), powders, granules, or as a Solution or nitrate, acetate, Valerate, oleate, palmitate, Stearate, laurate, a Suspension in an aqueous or non-aqueous liquid, or as an benzoate, lactate, phosphate, tosylate, citrate, maleate, oil-in-water or water-in-oil liquid emulsion, or as an elixir or fumarate, Succinate, tartrate, naphthylate, meSylate, Syrup, or as pastilles (using an inert base, Such as a gelatin glucoheptonate, lactobionate, and laurylsulfonate Salts and and glycerin, or Sucrose and acacia), or as Soft elastic gelatin the like. (See, e.g., Berge et al., “Pharmaceutical Salts”, J. 15 capsules, and/or as mouth washes and the like, each con Pharm. Sci. 66:1–19 (1977).) taining a predetermined amount of a compound of the Formulations of the present invention include those Suit present invention as an active ingredient. DCL may also be able for oral, nasal, topical (including buccal and administered as a bolus, electuary or paste. Sublingual), rectal, vaginal, parenteral (including In Solid dosage forms of the present invention for oral Subcutaneous, intramuscular, intravenous), intravascularly, administration (capsules, tablets, pills, dragees, powders, intravesically, by aerosol and/or transdermal administration. granules and the like), the active ingredient is mixed with Additionally, the drug may be administered directly into the one or more pharmaceutically acceptable carriers, Such as bladder through the urethra, i.e., intravesically, as described Sodium citrate or dicalcium phosphate, and/or may also be by Massad et al., J. Urol. 148:595-597 (1992). The formu mixed with one or more of any of the following: (1) fillers 25 or extenders, Such as Starches, lactose, Sucrose, glucose, lations may conveniently be presented in unit dosage form mannitol, and/or Silicic acid; (2) binders, Such as, for and may be prepared by any methods well known in the art example, carboxymethylcellulose, alginates, gelatin, poly of pharmacy. The amount of active ingredient which is vinyl pyrrolidone, Sucrose and/or acacia; (3) humectants, combined with a carrier material to produce a Single dosage Such as glycerol; (4) disintegrating agents, Such as agar-agar, form will vary depending upon the host being treated, and calcium carbonate, potato or tapioca Starch, alginic acid, the particular mode of administration. The amount of active certain Silicates, and Sodium carbonate; (5) Solution retard ingredient which may be combined with a carrier material to ing agents, Such as paraffin; (6) absorption accelerators, Such produce a Single dosage form preferably will be that amount as quaternary ammonium compounds; (7) Wetting agents, of DCL which produces a therapeutic effect. Generally, the Such as, for example, cetyl alcohol and glycerol monoStear amount of the active ingredient will range from about 1% to 35 ate; (8) absorbents, Such as kaolin and bentonite clay; (9) about 99% of the total formulation, preferably from about lubricants, Such as talc, calcium Stearate, magnesium 5% to about 70%, and most preferably from about 10% to Stearate, Solid polyethylene glycols, Sodium lauryl Sulfate, about 30%. and mixtures thereof, and (10) coloring agents. In the case Methods of preparing these formulations or compositions of capsules, tablets and pills, the pharmaceutical composi include the Step of bringing into association DCL with a 40 tions may also comprise buffering agents. Solid composi pharmaceutically acceptable carrier and, optionally, one or tions of a similar type may also be employed as fillers in Soft more accessory ingredients. In general, the formulations are and hard-filled gelatin capsules using Such excipients as prepared by uniformly and intimately bringing into associa lactose or milk Sugars, as well as high molecular weight tion DCL with liquid carriers, or finely divided solid carriers, polyethylene glycols and the like. In another embodiment, or both, and any optional accessory ingredients, and then, if 45 lactose-free compositions containing DCL are administered. necessary, shaping the product. Release agents, coating agents, Sweetening, flavoring and The phrase “pharmaceutically acceptable carrier as used perfuming agents, preservatives and antioxidants can also be herein means a pharmaceutically acceptable material, com present in the compositions of the present invention. position or vehicle, Such as a liquid or Solid filler, diluent, Examples of pharmaceutically acceptable antioxidants excipient, Solvent or encapsulating material, involved in 50 include: (1) water Soluble antioxidants, Such as ascorbic carrying or transporting the DCL from one organ, or portion acid, cysteine hydrochloride, Sodium bisulfate, Sodium met of the body, to another organ or portion of the body. Each abisulfate sodium sulfite and the like; (2) oil-soluble carrier must be “acceptable' in the Sense of being compat antioxidants, Such as ascorbyl palmitate, butylated ible with the other ingredients of the formulation and not hydroxyanisole (BHA), butylated hydroxytoluene (BHT), injurious to the patient. 55 , propyl gallate, alpha-tocopherol, and the like; and Some examples of materials which can Serve as pharma (3) metal chelating agents, such as citric acid, ethylenedi ceutically acceptable carriers include: (1) Sugars, such as amine tetraacetic acid (EDTA), Sorbitol, tartaric acid, phos lactose, glucose and Sucrose; (2) Starches, Such as corn phoric acid, and the like. Starch and potato starch; (3) cellulose, and its derivatives, A tablet may be made by compression or molding, option Such as Sodium carboxymethyl cellulose, ethyl cellulose and 60 ally with one or more accessory ingredients. Compressed cellulose acetate; (4) powdered tragacanth; (5) malt, (6) tablets may be prepared using binder (for example, gelatin gelatin; (7) talc.; (8) excipients, Such as cocoa butter and or hydroxypropylmethyl cellulose), lubricant, inert diluent, Suppository waxes; (9) oils, Such as peanut oil, cottonseed preservative, disintegrant (for example, Sodium starch gly oil, Safflower oil, Sesame oil, olive oil, corn oil and Soybean colate or cross-linked Sodium carboxymethyl cellulose), oil, (10) glycols, Such as propylene glycol, (11) polyols, 65 and/or Surface-active or dispersing agents. Molded tablets Such as glycerin, Sorbitol, mannitol and polyethylene glycol, may be made by molding in a Suitable machine a mixture of (12) esters, Such as ethyl oleate and ethyl laurate; (13) agar, the powdered DCL moistened with an inert, liquid diluent. 5,939.426 11 12 The pharmaceutical compositions of the present invention more Suitable non-irritating excipients or carriers may also be formulated in a Soft elastic gelatin capsule unit comprising, for example, cocoa butter, polyethylene glycol, dosage form by using conventional methods, well-known in a Suppository wax or a Salicylate. Such formulations of the the art (see, e.g., Ebert, Pharm. Tech. 1(5):44-50(1977)). present invention are Solid at room temperature, but liquid at Soft elastic gelatin capsules have a Soft, globular, gelatin body temperature and, therefore, will melt in the rectum or shell Somewhat thicker than that of hard gelatin capsules, vaginal cavity and release the active DCL. wherein a gelatin is plasticized by the addition of glycerin, Formulations of the present invention which are suitable Sorbitol, or a similar polyol. The hardness of the capsule for vaginal administration also include pessaries, tampons, shell may be changed by varying the type of gelatin and the creams, gels, pastes, foams or Spray formulations containing amounts of plasticizer and water. The Soft gelatin Shells may Such carriers as are known in the art to be appropriate. contain a preservative to prevent the growth of fungi, Such Dosage forms for the topical or transdermal administra as methyl- and propylparabens and Sorbic acid. The active tion of DCL include powders, sprays, ointments, pastes, ingredient may be dissolved or Suspended in a liquid vehicle creams, lotions, gels, Solutions, patches and inhalants. The or carrier, Such as Vegetable or mineral oils, glycols Such as active compound may be mixed under Sterile conditions polyethylene glycol and propylene glycol, triglycerides, 15 with a pharmaceutically acceptable carrier, and with any Surfactants Such as polySorbates, or a combination thereof. preservatives, buffers, or propellants which may be required. The tablets, and other dosage forms of the pharmaceutical compositions of the present invention, Such as dragees, Formulations of the present invention in the form of capsules, pills and granules, may optionally be Scored or ointments, pastes, creams and gels may contain, in addition prepared with coatings and shells, Such as enteric coatings to DCL, excipients, Such as animal and vegetable fats, oils, and other coatings well known in the pharmaceutical for waxes, paraffins, Starch, tragacanth, cellulose derivatives, mulating art. polyethylene glycols, Silicones, bentonites, Silicic acid, talc The pharmaceutical compositions of the present invention and/or Zinc oxide, or mixtures thereof. may also be formulated So as to provide slow or controlled Powders and Sprays may contain, in addition to DCL, 25 excipients Such as lactose, talc, Silicic acid, aluminum release of the active ingredient therein using, for example, hydroxide, calcium Silicates and polyamide powder, or mix hydroxypropylmethyl cellulose in varying proportions to tures of these Substances. SprayS may additionally contain provide the desired release profile, other polymer matrices, customary propellants, Such as, for example, liposomes and/or microSpheres. They may also be admin chlorofluorohydrocarbons, volatile unsubstituted istered by controlled release means and delivery devices hydrocarbons, hydrocarbon ethers and compressed gases. Such as those in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,796; and PCT published Transdermal patches have the added advantage of pro application WO92/20377. viding controlled delivery of the active DCL of the present The pharmaceutical compositions of the present invention invention to the body. Such dosage forms may be made by may also optionally contain opacifying agents and may be dissolving or dispersing the DCL in the proper medium. formulated Such that they release the active ingredient(s) 35 Absorption enhancers may also be used to increase the flux only, or preferentially, in a certain portion of the gastrointes of the DCL across the skin. The rate of Such flux can be tinal tract, optionally, in a delayed manner. Examples of controlled by either providing a rate controlling membrane embedding compositions which can be used include poly or dispersing the DCL in a polymer matrix or gel. meric Substances and waxes. The active ingredient can also Regardless of the route of administration Selected, the be in micro-encapsulated form, if appropriate, with one or 40 pharmaceutical compositions of the present invention are more of the above-described excipients. formulated into pharmaceutically acceptable dosage forms Liquid dosage forms for oral administration of DCL by conventional methods known to those of skill in the art. include pharmaceutically acceptable emulsions, Where necessary, the pharmaceutical compositions of the microemulsions, Solutions, Suspensions, Syrups and elixirs. present invention are Sterile or can be Sterilized before In addition to the active ingredient, the liquid dosage forms 45 administration to a patient. may contain inert diluents commonly used in the art, Such as, In a preferred embodiment, the DCL compositions of the for example, water or other Solvents, Solubilizing agents and present invention are provided in tablet or capsule form. The emulsifiers, Such as ethyl alcohol, isopropyl alcohol, ethyl capsules or tablets are preferably formulated with from carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, about 0.1 mg to about 100 mg of DCL, more preferably with propylene glycol, 1,3-butylene glycol, oils (in particular, 50 from about 0.5 mg to about 50 mg of DCL, and even more cottonseed, groundnut, corn, germ, olive, castor and Sesame preferably with from about 1 mg to about 25 mg of DCL. oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols In another preferred embodiment, the DCL preparations and fatty acid esters of Sorbitan, and mixtures thereof. of the present invention are provided in Soft elastic gelatin Besides inert diluents, the oral compositions of the 55 capsule form. The Soft elastic gelatin capsules are preferably present invention can also include adjuvants Such as wetting formulated with from about 0.1 mg to about 100 mg of DCL, agents, emulsifying and Suspending agents, Sweetening, more preferably with from about 0.5 mg to about 50 mg of flavoring, coloring, perfuming and preservative agents. DCL, and even more preferably with from about 1 mg to Suspensions, in addition to the active DCL, may contain about 25 mg of DCL. Suspending agents Such as, for example, ethoxylated isoS 60 Actual dosage levels of DCL in the pharmaceutical com tearyl alcohols, polyoxyethylene Sorbitol and Sorbitan esters, positions of the present invention may be varied So as to microcrystalline cellulose, aluminum metahydroxide, obtain an amount of the active ingredient which is effective bentonite, agar-agar and tragacanth, and mixtures thereof. to achieve the desired therapeutic response for a particular Formulations of the pharmaceutical compositions of the patient, composition, and mode of administration, without present invention for rectal and vaginal administration may 65 being toxic to the patient. be presented as a Suppository, which may be prepared by The Selected dosage level and frequency of administration mixing one or more compounds of the invention with one or will depend upon a variety of factors including the route of 5,939.426 13 14 administration, the time of administration, the rate of excre -continued tion of the particular compound being employed, the dura tion of the treatment, other drugs, compounds and/or mate rials used in combination with the DCL, the age, Sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. For example, the dosage regimen is likely to vary with pregnant women, nursing mothers and children relative to healthy adults. A physician having ordinary skill in the art can readily N determine and prescribe the effective amount of the phar maceutical composition required. For example, the physi H cian could start doses of the compound employed in the pharmaceutical composition of the present invention at DCL levels lower than that required in order to achieve the desired 15 therapeutic effect and gradually increase the dosage until the desired effect is achieved. Extraction of Commercially Available Claritin(R) A suitable daily dose of DCL will be that amount of the Tablets (600x10 ma) compound which is the lowest dose effective to produce a Tablets of loratadine, were diluted with water and chlo therapeutic effect. Such an effective dose will generally roform. The mixture was stirred, then filtered through celite, depend upon the factors described above. Generally, the rinsed with chloroform until the filtrate contained no lora total daily dose of DCL for the conditions described herein tadine. The Separated acqueous layer was extracted with may be from about 0.1 mg to about 100 mg, more preferably chloroform twice. The combined organic layer was washed from about 0.5 mg to about 50 mg, and more preferably from with water, brine and dried over Sodium Sulfate. The solvent about 1 mg to about 25 mg. A Suitable oral daily dose range 25 was evaporated to give pure loratadine as a white Solid. of decongestant, ephedrine, amphetamines, amphetamine Salts, amphetamine analogs, amphetamine agents or psycho Saponification of Loratadine stimulant is from about 1 mg to about 300 mg. Further, a Loratadine (4.0 g) was added to a Solution of Sodium Suitable oral daily dose of Such agents can also be readily hydroxide (5.9 g) in 280 mL of absolute ethanol and the determined by those skilled in the art. mixture was stirred at reflux for four days. The mixture was If desired, the effective daily dose of the active DCL may cooled and concentrated to remove ethanol. The residue was be administered as two or three Sub-doses administered diluted with water and aqueous layer was extracted with Separately at appropriate intervals throughout the day, methylene chloride five times. The combined organic layer optionally, in unit dosage forms. 35 was washed with water, brine and dried over Sodium Sulfate. The invention is further illustrated by reference to the The solvent was evaporated to give 2.82 g (87%) of pure following examples, which are provided by way of illustra loratadine derivative (or metabolite) as a pale-tan Solid. tion and not by way of limitation. Example 2 EXAMPLES 40 Muscarinic Receptor Binding Studies Example 1 The aim of this study was to assess the affinity of six compounds for human m, m and m muscarinic receptor Preparation of Loratadine and Its Metabolites Subtypes in radioligand binding assays. The method used Loratadine can be Synthesized, for example, by methods 45 herein is similar to that disclosed in Dorje et al. The Journal disclosed in U.S. Pat. No. 4,282,233. The metabolites are of Pharmacology and Experimental Therapeutics 256:2 prepared Similarly, by reaction Steps conventional in the art, 727-733 (1991). as described in U.S. Pat. No. 4,659,716 which is incorpo rated here by reference in its entirety. One common method Methods 50 of preparing DCL is to reflux loratadine in the presence of Samples were prepared and evaluated in a concentration Sodium hydroxide and ethanol as depicted below. range (0.1-3000 nM, half-log dilutions) on human recom binant m-m-, receptors expressed in mammalian CHO cells. These data were generated from binding inhibition of Z C radiolabelled ligand, where Hpirenzepine was used for m, HAF-DX 384 was used for m, and H4-DAMP (4-diphenylacetoxy-N-methylpiperidine) was used for m. Following incubation, the assays were rapidly filtered NaOH, EtOH under vacuum through GF/B glass fiber filters (Packard) and He washed with an ice-cold buffer using a Packard cell har reflux vester. Bound radioactivity was determined with a liquid N Scintillation counter (Topcount, Packard) using a liquid COEt scintillation cocktail (Microscint 0, Packard). The compounds were tested on each receptor at (ten) 10 Claritin' or 65 concentrations in duplicate to obtain competition curves. In Loratadine each experiment, the reference compound for the receptor under investigation was simultaneously tested at (eight) 8 5,939.426 15 16 concentrations in duplicate to obtain a competition curve in suspended in RPMI 1640 medium containing 2% fetal calf order to validate this experiment. The parameters of this serum (Grand Island Biological Co., Grand Island, N.Y.) and experiment are Summarized in Table 1. Seeded into replicate microwell plates (Nunc) to which concanavalin (Con) A (2 ug/ml, Sigma Chemical Co., St. TABLE 1. Louis, Mo.) was added. Cells were incubated (37° C., 95% Non- Incubation Reference air, 5% CO2) in the absence or presence of increasing Receptor Radioligand Conc. specific time/temp. Compound concentrations of the test agents dissolved in Saline or other vehicles. Forty-three hours after the addition of Con A, 0.25 ml H 2 nM 60 min? piren nm ol H- thymidine (6.7 Ci/n mol; ICN (1 uM) 25° C. Zepine m HAF- 3 nM atropine 60 min? methon Radiopharmaceuticals, Montreal, PQ) was added to each DX384 (1 uM) 25° C. tramine well. After an additional 5-hour incubation, the cells were m3 HA- 0.15 nM atropine 60 min? 4-DAMP washed from the Wells onto filter papers employing an DAMP (1 uM) 25° C. automated cell sorter. The filters were placed into vials containing 5 ml Scintillation fluid (ReadySafe, Beckman), The radioligands were from DuPont NEN; the cold 15 and radioactivity incorporated into DNA at 48 hours was ligands ere from Sigma or RBI. The drugs tested in this determined (n=3). ICso values for inhibition of mitogenesis experiment were astemizole; norastemizole; loratadine, were determined over wide range of concentrations (0.1 to DCL, (S)(-) terfenadine carboxylate, and (S)(-) terfenadine. 10 uM). Results TABLE 3 The Specific radioligand binding to the receptors was defined as the difference between total binding and nonspe Inhibition of Concanavalin A cific binding determined in the presence of an excess of Induced Stimulation of Lymphocytes (IC.so) unlabelled ligand. Results were expressed as a percentage of Loratadine 1.0 uM control Specific binding obtained in the presence of the DCL compounds. 25 5.6 uM ICs values (concentration required to inhibit 50% of specific binding) and Hill coefficients (nH) were determined These results indicate that DCL is 5-7 fold less active by non linear regression analysis of the competition curves. than loratadine at promoting tumor growth. These parameters were obtained by Hill equation curve fitting using Sigmaplot TM software (Jandel). Example 4 The estimated ICso values (in nM) for the compounds tested and for the reference compounds at human m, m- and Cardiovascular Effects m muscarinic receptor Subtypes are indicated in Table 2. The effects of DCL and loratadine on cardiac potassium 35 currents were Studied. TABLE 2 Methods (estimated ICso values in nM) m1 receptor m2 receptor ms receptor Single Ventricular myocytes of the guinea-pig and the Astemizole 900 148O 1210 rabbit were dissociated by enzymatic dispersion (see Norastemizole 110 238O 1350 40 Carmeliet, J. Pharmacol. Exper. Ther, 1992, 262, 809–817 (-)Terfenadine >3000 3OOO >3OOO which is incorporated herein by reference in its entirety). (S)(-) Terfenadine >3000 >3000 >3OOO carboxylate The Single Suction patch electrode, with a resistance of 2 to Loratadine >3000 >3000 >3OOO 5 MS2 was used for voltage clamp (AXoclamp 200A). Descarboethoxy- 85.O SO.4 755 P-clamp Software (Axon Instruments) was used to generate loratadine 45 Voltage-clamp protocols and to record and analyze data. The pirenzepine 10.6 not tested not tested methoctramine not tested 16.5 not tested standard Solution contained in mM: NaCl 137.6, KCl 5.4, 4-DAMP not tested not tested 3.2 CaCl. 1.8, MgCl, 0.5, HEPES 11.6 and glucose 5, and NaOH was added to pH 7.4. The intracellular solution contained: KCl 120, MgCl, 6, CaCl 0.154, NaATP 5, These results Surprisingly show that DCL has a greater 50 EGTA5, and HEPES 10, with KOH added until pH 7.2. affinity at m, m, m receptors than loratadine (the parent drug) or other Second or third generation antihistamines. The Effect on the Delayed Rectifying K" Current, (I) present invention is based upon, inter alia, the Surprising in Rabbit Ventricular Myocytes antimuscarinic affinity of DCL. Without being limited by theory, it is believed that the antimuscarinic affinity of DCL 55 The Voltage clamp protocol consisted of Voltage Steps leads to its usefulness in the methods of treatment and from a holding potential of -50 mV to +10 mV for a duration compositions described herein. of 4 Sec. The change in tail current was measured as a function of the drug concentration. This concentration was Example 3 changed between 107 and 10M in five steps. Exposure to Tumor Promoting Activity 60 each concentration lasted 15 min. At the end, washout was attempted during 30 min. The results of this study are set Inhibition of lymphocyte mitogenesis was used to Screen forth in FIGS. 1 and 2 which indicate, respectively, that the the potencies of loratadine and DCL as tumor promoting ICso of loratadine is approximately 9x10 M and the ICso agents. of DCL is approximately 5x10 M. Mitogenesis Studies 65 The results from this study indicate that DCL is less active Fresh spleen cells (5x10) obtained from 5-week old than terfenadine in inhibiting the cardiac delayed rectifier BALB/c mice (Charles River, ST. Constant, PQ) were and thus has no potential for cardiac side-effects at the daily 5,939.426 17 18 dosages of the methods of the present invention. Thus, the incubation was determined and the percentage inhibition methods of the present invention are leSS toxic than methods relative to Solvent control was calculated. The ICso was which use other non-Sedating antihistamines. calculated by linear interpolation. Example 5 TABLE 4

Inhibition of Cytochrome P450 Loratadine This study was conducted to determine the extent that loratadine and DCL inhibit human cytochrome P4503A4 Concentration Pmole per Percent (CYP3A4). CYP3A4 is involved in many drug-drug inter- 1O (uM) Incubation Inhibition actions and quantitation of inhibition of CYP3A4 by lora O 2692, 2108 tadine or DCL provides an indication of the potential for the O.OO3 1975, 2148 18, 11 O.O1 2192, 1939 9, 19 occurrence of adverse effects due to Such drug-drug inter O.O3 1992, 2658 17, -11 actions. Inhibition was Studied by measuring the metabolism O1 2279, 2023 5, 16 of the model Substrate testosterone by cIDNA-derived human O.3 2476, 2010 -3, 16 CYP3A4 in microsomes prepared from a human lympho 15 1. 2093, 1912 13, 20 3 2109, 1850 12, 23 blastoid cell line designated h3A4V3. 1O 1547, 1584 36, 34 Study Design 3O 1110, 1304 54, 46 1OO 643, 643 73, 73 The inhibition study consisted of the determination of the 50% inhibitory concentration (ICs) for the test substance. A The ICso for loratadine was calculated to be 30 iM. Single testosterone concentration (120 uM, approximately twice the apparent Kim) and ten test Substance TABLE 5 concentrations, Separated by approximately 72 log, were tested in duplicate. Testosterone metabolism was assayed by DeScarboethoxyloratadine (DCL the production of the 6(B)-hydroxytestosterone metabolite. Concentration Pmole per Percent This metabolite was readily quantitated via HPLC separa (uM) Incubation Inhibition tion with absorbance detection. O 1882, 2005 Storage/Preparation of the Test Substances and O.OO3 2010, 2053 -3, -6 Addition to the Incubations 3O O.O1 21OO. 21.51 -8, -11 O.O3 1950, 2261 0, -16 The test Substances were Stored at room temperature. The O1 2111, 1966 -9, -1 test Substances were dissolved in ethanol for addition to the O.3 2055, 1959 -6, -1 incubations. The addition of acid was not found to be 1. 2029, 1982 -4, -2 needed. The Solvent concentration was constant for all 3 1748, 1948 10, O 35 1O 1478, 1557 24, 20 concentrations of the test Substance. 3O 759, 671 61, 66 1OO 319, 225 84, 88 ICso Determination Final test Substance concentrations were 100, 30, 10, 3, 1, The ICs for DCL was calculated to be 23 u.M. 0.3, 0.1, 0.03, 0.01, 0.003 and 0 uM. Each test concentration This study demonstrates that there is little difference was tested in duplicate incubations in accordance with the 40 between the actions of loratadine and DCL on the inhibition method below: of cytochrome P4503A4, and thus confirms that both do not Method themselves contribute to the potential for the occurrence of adverse effects due to drug-drug interactions. A 0.5 ml reaction mixture containing 0.7 mg/ml protein, Useful pharmaceutical dosage forms for administration of 1.3 mM NADP+, 3.3 mM glucose-6-phosphate, 0.4 U/ml 45 the compounds used in the methods of the present invention glucose-6-phosphate dehydrogenase, 3.3 mM magnesium can be illustrated as follows: chloride and 120 uM testosterone in 100 mM potassium phosphate (pH 7.4) was incubated at 37° C. for 30 min. A Example 6 known quantity of 11(B)-hydroxytestosterone was added as Soft Gelatin Capsules an internal Standard to correct for recovery during extrac 50 tion. The reaction mixture was extracted with 1 ml methyl A mixture of active ingredient in a digestible oil Such as ene chloride. The extract was dried over anhydrous magne Soybean oil, lecithin, cottonseed oil or olive oil is prepared sium Sulfate and evaporated under vacuum. The Sample was and injected by means of a positive displacement pump into dissolved in methanol and injected into a 4.6x250 mm 5u gelatin to form Soft gelatin capsules containing 0.1 to 25 C18 HPLC column and separated at 50° C. with a mobile 55 milligrams of the active ingredient. The capsules are washed phase methanol/water at a flow rate of 1 ml per min. The and dried. retention times were approximately 6 min for the 6(B)- Example 7 hydroxy, 8 min for 11(B)-hydroxy and 12 min for testoster one. The product and internal Standard were detected by Tablets their absorbance at 254 nm and quantitated by correcting for 60 Compressed DCL tablets are prepared using conventional the extraction efficiency using the absorbance of the 11(B)- direct compression techniques, Such that each dosage unit hydroxy peak and comparing to the absorbance of a Standard contains 0.1 mg to 25 mg of DCL. For example, tablets are curve for 6(B)-hydroxytestosterone. prepared using 10 mg DCL, 80 mg microcrystalline cellulose, 5 mg Stearic acid and 1 mg colloidal Silica. All of Data Reporting 65 the ingredients are blended in a suitable blender. The result For each test Substance concentration, the concentration ing mixture is compressed into tablets, using a %2-inch (7 of 6(B)-hydroxytestosterone metabolite in each replicate mm) punch. 5,939.426 19 20 Tablets and capsules of other Strengths may be prepared able salt thereof, administered is from about 0.1 mg to about by altering the ratio of active ingredient to the excipients or 100 mg per day. to the final weight of the tablet. 3. The method according to claim 2, wherein the amount The embodiments of the present invention described of descarboethoxyloratadine, or a pharmaceutically accept above are intended to be merely exemplary and those skilled able salt thereof, administered is from about 0.5 mg to about in the art will recognize, or be able to ascertain using no 50 mg per day. more than routine experimentation, numerous equivalents to 4. The method according to claim 2, wherein the Specific procedures described herein. All Such equiva deScarboethoxyloratadine, or a pharmaceutically acceptable lents are considered to be within the Scope of the present Salt thereof, is administered by inhalation or by intravesical, invention and are covered by the following claims. 1O parenteral, transdermal, rectal or oral administration. The contents of all references described herein are hereby 5. The method according to claim 4, wherein incorporated by reference. deScarboethoxyloratadine, or a pharmaceutically acceptable What is claimed is: Salt thereof, is administered by oral administration. 1. A method for treating urinary incontinence which 6. The method according to claim 4, where in comprises administering to a human in need of Such treat 15 deScarboethoxyloratadine, or a pharmaceutically acceptable ment a the rapeutically effective a mount of Salt thereof, is administered by transdermal administration. deScarboethoxyloratadine, or a pharmaceutically acceptable 7. The method according to claim 4, wherein Salt thereof. deScarboethoxyloratadine, or a pharmaceutically acceptable 2. The method according to claim 1, wherein the amount Salt thereof, is administered by intravesical administration. of descarboethoxyloratadine, or a pharmaceutically accept k k k k k