Note: Descriptions are shown in the official language in which they were submitted.
CA 02503746 2005-04-05
_ METHODS FOR TREATING URINARY INCONTINENCE AND OTHER DISORDERS
USING TROSPIUM
FIELD OF THE INVENTION.
This invention relates to a compound named Trospium Chloride and having the
formula:
C1
w
HO
0
0
Trospium Chloride
The generic name Trospium Chloride (CAS-10405-02-4; TNN) refers to an
anticholinergic
compound with the chemical name 3a-hydroxy-spiro[laH,SaH-nortropane-8,1'-
pyrrolidinium]
chloride benzilate; C25H3oC1NO3; MW = 42'1.97. In this document, the name
trospium refers to
Trospium Chloride.
The synthesis of trospium was described by Pfleger R. et al. in US patent
3,480,626 and by
Bertholdt H. et al. in Arzneimittel-Forsch, 1967, 17: 719-726. The preclinical
pharmacology and
toxicology of trospium was described by Antweiler H. in Arzneimittel-Forsch,
1966, 16:1581-
1591.
Trospiurn may be purchased from Galen Ltd, Craigavon, UK. or from Madaus AG,
Koln,
Germany. Trospium can also be extracted from tablets (Regurin~, Madaus)
available in Germany,
using methods commonly known to those skilled in the art.
CA 02503746 2005-04-05
Trospium has several known metabolites, the most well known being the
spiroalcohol,
which is a metabolite formed by ester hydrolysis. The spiroalcohol metabolite
has antimuscarinic
activity that may contribute to the therapeutic activity of trospium.
Since trospium is a quaternary compound, it does not easily cross the blood-
brain barrier
and has therefore fewer CNS side effects than oxybutynin (Todorova A., et al.,
,T. Clin.
Pharrnacol. 2001, 41: 636-644).
Specifically, the present invention relates to the therapeutic use of trospium
and the active
metabolites thereof, and pharmaceutical compositions containing at least one
of said compounds
for treating smooth muscle hyperactivity disorders, such as for example
urinary disorders,
including urinary incontinence and pollakiuria and gastrointestinal disorders,
including
gastrointestinal hyperactivity, and other smooth muscle hyperactivity or
hyperreactivity disorders
including those occurring in conjunction with asthma, urolithiasis,
cholelithiasis and
choledocholithiasis, while avoiding certain serious cardiac side effects of
current anticholinergic
medication. The risk for such side effects being particularly high in patients
with pre-existing
Long QT Syndrome and in patients taking medication, such as for example
ketoconazole or
erthromycin, that through metabolic interaction may increase the risk for QT
prolongation by
antimuscarinic drugs for urinary urge incontinence, like oxybutynin
(Ditropan~) and tolterodine
(Detrol~).
BACKGROUND OF THE INVENTION
Trospium has been shown to reduce bladder hyperactivity in patients suffering
from
urinary incontinence and exerts spasmolytic effects on the bladder by
inhibiting the effects of
acetylcholine on smooth muscle. Trospium has selectivity for muscarinic
receptors over
2
CA 02503746 2005-04-05
nicotinic receptors and as a result, no blocking effects are observed at
skeletal neuromuscular
junctions. Active metabolites of trospium exert antimuscarinic activities that
may account for
part of the therapeutic activity of trospium.
In particular, compounds within the class of antimuscarinic drugs for urinary
incontinence, including terodiline, tolterodine and oxybutynin, cause severe
cardiac
electrophysiological side effects. These adverse side effects are associated
with prolonged QT
interval and include but are not limited to ventricular fibrillation and
cardiac arrhythmias, such
as torsades de pointes. This is the same type of potentially lethal cardiac
side effects that led to
the withdrawal of several medications from the market; examples of drugs that
have been
withdrawn of that reason are the antihistamine drug terfenadine, the
antihistamine drug
astemizole, the prokinetic drug cisapride and the incontinence drug terodiline
that is mentioned
above.
No known reference teaches or enables the methods of the present invention
comprising
administering trospium to a human while avoiding said adverse cardiac side
effects; nor do the
published references alone or in combination suggest these methods.
SUMMARY OF THE INVENTION
Pharmacological studies of trospium have now been performed in comparison with
known and marketed antimuscarinic drugs with therapeutic activity against
cholinergically
mediated diseases, such as for example urinary incontinence. The present
studies have
confirmed that trospium, as well as terodiline, tolterodine and oxybutynin,
have potent
antimuscarinic activity.
3
CA 02503746 2005-04-05
It has now been found that while the antimuscarinic drugs oxybutynin,
tolterodine and
terodiline cause a prolongation of the QTc-interval of the ECG, trospium,
surprisingly, does not
cause this side effect. Prolongation of the QTc interval is highly indicative
of risk for a type of
fatal cardiac arrhythmias that is called torsades des pointes, as described
for the antihistamine
terfenadine by Woosley et al. 1993, JAMA 269: 1532-1536 and for the
antimuscarinic drug
terodiline by Connolly et al. 1991, Lancet 338:344-345. It is therefore
concluded that trospium
will offer anticholinergic treatment for muscarinic disorders, including
urinary voiding disorders
such as urinary urge incontinence and for gastrointestinal disorders,
including gastric motility
disorders such as diarrhea, while avoiding the concomitant liability of
adverse side effects
associated with currently used antimuscarinic drugs. Trospium will therefore
offer potential for
anticholinergic treatment for smooth muscle disorders, including urinary
incontinence and'
gastrointestinal smooth muscle disorders and kidney and gall bladder
disorders, while being
devoid of the cardiac side effects of the presently used medication.
The fact that no cases of prolonged QTc or no cases of torsades de pointes may
have
been found in clinical studies of a few thousand patients is irrelevant in the
present context,
since both prolongation of QTc and Torsades are very rare - but much feared -
side effects of
drug therapy. Thus terfenadine (Seldane~) was withdrawn from the market even
though this
drug caused torsades de pointes arrhythmias in only one out of 200,000
patients and 25 out of
1000 patients may have expressed a significant, drug-induced QTc-prolongation
with QTc
duration exceeding 440 milliseconds (Morganroth J. pers. communication.)
Trospium is to some degree undergoing hepatic metabolism, resulting in the
formation of
the spiroalcohol, which is an active (antimuscarinic) metabolite formed by
ester hydrolysis. On
the contrary, both tolterodine (Postlind et al. Drug Metab Dispos 1998, 26:
289-293) and
4
CA 02503746 2005-04-05
oxybutynin (Lukkari et al. Pharmacol Toxicol 1998, 82: 161-166) undergo
extensive P450-
mediated metabolism.
The effects of trospium on CYP 450: induced metabolism of various drugs has
been
investigated, using human liver microsomes enzymes and drugs that are
metabolized by known
P450 enzymes. The CYP 2D6-mediated metabolism of 3-[2-NN-diethyl-N-(methyl-
ammonium)
ethyl]-7-methoxy-4-methyl-coumarin was inhibited by trospium with an IC50
value of about
20~M, which is significantly higher than the expected therapeutic plasma
concentration of
trospium that is the range of a few nM. Trospium had even more negligible
inhibitory effects on
drug metabolism by CYP3A4. As pointed out above, it has been found that
tolterodine and
oxybutynin potently inhibit both CYP 2D6 and CYP 3A isoenzyme metabolism.
Metabolic
inhibition of this type is known to increase the concomitant liability of
cardiac arrhythmias of
drugs that cause QT-prolongation (Woosley et al. JAMA 1993, 269: 1532-1536).
The present
results demonstrate that trospium will not cause this type of drug
interaction. Trospium may
therefore be administered together with drugs Iike ketoconazole, itraconazole
or erythromycin
without enhanced risk for cardiac arrhythmias caused by QT-prolongation.
Trospium can also be
used together with antimuscarinic agents like oxybutynin or tolterodine
without increased risk
for QT-prolongation and such co-administration may preferably substitute for
high doses of
oxybutynin or tolterodine.
Patients suffering from the disease called Long QT Syndrome should not use
medication
that may cause further prolongation of the QT-interval of the ECG, but can use
trospium without
aggravating their pre-existing risk for torsades de pointes cardiac
arrhythmias.
Since sudden pain such as the severe and sudden pain in connection with
urolithiasis or
cholelithiasis, can cause increased risk for cardiac arrhythmias (Ionescu,
Drug Metab Dispos
S
CA 02503746 2005-04-05
1998, 26: 289-293), trospium will be particularly useful to treat these
conditions, since this drug
has now been shown not to cause prolongation of the cardiac QT-interval, which
would
predispose the patient for unwanted cardiac events, like Torsades de pointes
ventricular
fibrillation. In cases where urgent treatment is preferred, trospium can be
administered
parenterally and preferentially by the intravenous route to alleviate the
smooth muscle spasm and
the pain pain in connection with urolithiasis or cholelithiasis.
Since muscarinic receptors have been shown to play a significant role in the
etiology
of acute pancreatitis (Gronroos et al., Dig Dis 1992, 10: 38-45), trospium
will be an ideal
drug for the treatment of this disease since pancreatitis is not seldom
accompanied by cardiac
arrhythmias (Imperadore et al., Ital Heart J. 2000,1: 419-422.)
Certain individuals are predisposed fir card~ac arrhythmias. Thus, individuals
suffering
from long QT syndrome (LQT) are particularly vulnerable for torsades de
pointes arrhythmias.
Their risk for lethal torsades de pointes arrhythmias is further increased if
these individuals are
using medication that further lengthens their cardiac QT interval. However,
since trospium has
now been shown not to cause QT-prolongation, the risks for torsades de pointes
arrhythmias in
predisposed patients are not further increased by trospium.
Trospium is a quaternary compound and consequently the drug does not easily
pass the
blood-brain barrier. It is therefore expected that trospium - contrary to
drugs like oxybutynin and
tolterodine ~= will not cause CNS side effects, such as for example memory
loss, which is of
particular importance in elderly patients (Pietzsko A et al. Eur J Clin
Pharmacol 1994, 47: 337-
343, Todorova A., et al., J. Clin. Pharmacol. 2001, 41: 636-644).
6
CA 02503746 2005-04-05
Trospium may cause less pronounced side effects of the types that are typical
for
antimuscarinic drugs (e.g. dry mouth, blurry vision) and clinical studies have
shown this to be
the case (Madersbacher H et al., Br J Urol. 1995, 75: 452-456 and Hofner K.
International
Continence Society, Finland, 2000; Abstract Neurourol Urodyn 2000, 19: 487-
488). However,
antimuscarinic drugs for urinary incontinence are usually given in doses that
are as high as
possible and side effects such as dry mouth and blurry vision are often the
dose-limiting side
effect of these drugs.
The magnitude of a prophylactic or therapeutic dose of a compound of the
present
invention in the acute or chronic management of disease will vary with the
severity and nature of
the condition to be treated and the route of administration. The dose and the
frequency of the
dosing will also vary according to the age, body weight and response of the
individual patient.'
Doses as low as 1 mg twice daily to as high as 60 mg twice daily may be
administered to patients
in need of such therapy. In general, the daily oral dose of trospium is one 20-
mg tablet twice
daily to patients suffering from urinary urge incontinence. In managing the
patient, the therapy
may be initiated at a lower dose, perhaps at about 5 mg to about 10 mg, twice
daily, and is
usually increased up to 20 mg depending on the patient's global response. It
is further
recommended that patients over 65 years and those with impaired renal or
hepatic function
initially receive low doses and that they be titrated based on individual
responses) and plasma
drug level(s). It may be necessary to use dosages outside these ranges in some
cases, as will be
apparent to those skilled in the art. Further, it is noted that the clinician
or treating physician will
know how and when to interrupt, adjust, or terminate therapy in conjunction
with individual
patient response.
7
CA 02503746 2005-04-05
The terms "a therapeutically effective amount" and "an amount sufficient to
treat the
disorder but insufficient to cause adverse effects" are encompassed by the
above-described
dosage amounts and dose frequency schedule.
Any suitable route of administration may be employed for providing the patient
with an
effective dosage of the compounds of the present invention. For example, oral,
sublingual,
parental (i.e. subcutaneous, intramuscular, intravenous, etc.), transdermal,
vaginal, aerosol and
like forms of administration may be employed. Additionally, the drug may be
administered
directly into the bladder, as described for oxybutynin by Massad C.A., et al.
J. Urol. 148, 595-
597 (1992) and for trospium by Schwantes U., et al. US Patent 5,998,430 or
rectally directly into
the gastrointestinal canal as known in the art. Dosage forms include tablets,
troches, dispersions,
suspensions, solutions, capsules, suppositories, microencapsulated systems,
slow-release and
controlled release systems, transdermal delivery systems, and the like.
Prodrugs of trospium or the spiroalcohol metabolite can be prepared by those
skilled in
the art, as has been described for an active metabolite of tolterodine by
Sparf B. et al. in EP 0957
073 Al. Such prodrugs may offer certain advantages over trospium, such as for
example
improved bioavailability.
The pharmaceutical compositions of the present invention comprise of trospium
or a
metabolite thereof as the active ingredient, or any pharmaceutically
acceptable salt thereof, and
may also contain a pharmaceutically acceptable carrier, and optionally, other
therapeutic
ingredients.
The terms "pharmaceutically acceptable salts" or "pharmaceutically acceptable
salt
thereof' refer to salts prepared from pha:-maceuti~ally acceptable non-toxic
acids. Suitable
pharmaceutically acceptable acid addition salts for the compound of the
present invention
8
CA 02503746 2005-04-05
include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric,
ethanesulfonic,
fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic,
malefic, malic,
mandelic, methanesulfonic, mucic, nitric, pamoic, pathothenic, phosphoric, p-
toluenesulfonic,
succinic, sulfuric, tartaric, and the like. The hydrochloride is particularly
preferred.
The compositions of the present invention include suspensions, solutions,
elixirs or solid
dosage forms. Carriers such as starches, sugars, and microcrystalline
cellulose, diluents,
granulating agents, lubricants, binders, disintegrating agents, and the like
are suitable in the case
of oral solid preparations (such as powders, capsules, and tablets), and oral
solid preparations are
preferred over the oral liquid preparations. Because of their ease of
administration, tablets and
capsules represent the more advantageous oral dosage unit forms, in which case
solid
pharmaceutical carriers are employed. If desired, tablets may be coated by
standard aqueous or
nonaqueous techniques.
In addition to the common dosage forms set out above, the compounds of the
present
invention may also be administered by controlled release means and delivery
devices to obtain
improved phannacokinetic profiles (such as sustained and stable plasma levels
or prolonged
duration of activity) or decreased side effects.
Pharmaceutical compositions of the present invention, suitable for oral
administration,
may be presented as discrete unit dosage forms such as capsules, cachets,
suppositories, or
tablets, each containing a predetermined amount of the active ingredient, as a
powder or
granules, or as a solution or a suspension in an aqueous liquid, a non-aqueous
liquid, an oil-in-
water emulsion, or a water-in-oil liquid emulsion. Such compositions may be
prepared by any of
the methods of pharmacy, but all methods include the step of bringing into
association the active
ingredient with the carrier, which constitutes one or more necessary
ingredients. In general, the
9
CA 02503746 2005-04-05
compositions are prepared by uniformly and intimately admixing the active
ingredient with
liquid Garners or finely divided solid carriers or both, and then, if
necessary, shaping the product
into the desired presentation, just as is known for currently marketed
antimuscarinic drugs. For
example, a tablet may be prepared by compression or molding, optionally, with
one or more
accessory ingredients. Compressed tablets may be prepared by compressing in a
suitable
machine the active ingredient in a free-flowing form such as powder or
granules, optionally
mixed with a binder, lubricant, inert diluent, surface active agent or
dispersing agent. Molded
tablets may be made by molding, in a suitable machine, a mixture of the
powdered compound
moistened with an inert liquid diluent. All of the foregoing techniques are
well know to persons
of skill in the pharmaceutical art. Each tablet may contain from about 5 mg to
about 20 mg of
the active ingredient. An example of an oral unit dose formulation is shown
below.
Example 1.
Oral Unit Dosage Formulation (Tablets)
Ingredients per tablet per batch of
10,000 tablets
Trospium 20 mg 200 g
Microcrystalline cellulose30 mg 300 g
Lactose '70 mg 700 g
Calcium stearate 2 mg 20 g
FD&C Blue #1 Lake 0.03 mg 300 mg
Trospium is blended with lactose and cellulose until a uniform blend is
formed. The lake is
added and further blended. Finally, the calcium stearate is blended in, and
the resulting mixture
is compressed into tablets using, for example, a 9/32 inch (7 mm) shallow
concave punch.
CA 02503746 2005-04-05
Tablets of other strengths may be prepared by altering the ration of active
ingredient to the
excipients or altering the final weight of the tablet.
PHARMACOLOGICAL STUDIES OF TROSPIUM
1. Ligand Binding Studies: Affinity for muscarinic receptors.
The experiments were carned out on membranes prepared from SF9 cells that
expressed
human recombinant muscarinic receptor subtypes. After incubation with the test
article and the
proper radioligand (3H scopolamine methylchloride) and washing, bound
radioactivity was
determined with a liquid scintillation counter, using a commercial
scintillation cocktail. The
specific radioligand binding to a muscarinic receptor was defined as the
difference between total
binding and nonspecific binding determined in the presence of an excess of
unlabelled atropine.
ICS° values (concentrations required to inhibit 50% of specific
binding) were determined by non-
linear regression analysis of the competition curves, from which affinity
(pKi) values were
determined (Cheng Y. et al. Biochem Pharmacol 1073, 22: 3099-3108.)
Results:
Affinity (negative logarithm of the dissociation constant Ki) of trospium and
reference
compounds for human recombinant receptors
Test compound M-1 M-2 M-3 M-4
Trospium 9.1 9.2 9.3 9.0
Tolterodine 8.8 8.0 8.5 7.7
Oxybutynin 8.7 7.8 8.9 8.0
11
CA 02503746 2005-04-05
Conclusions:
Trospium had slightly higher affinity for human muscarinic receptors than the
reference
- compounds. The therapeutic activity of antimuscarinic dnigs in overactive
human bladders is
generally considered to be related to affinity for M-2/M-3 receptors, while
the side effect
xerostomia (dry mouth) is due mainly to inhibition of M-1 receptors in
salivary glands. (Napier,
Gupta)
2. Functional Characterization of Antimuscarinic and Antispasmodic Activities
on Bladder
Smooth Muscle Strips.
Experiments have now been performed using methods described by Kachur et al,
1988, J
Pharmacol Exp Ther 247: 867-872) and Noronha-Blob et al. J Pharmacol Exp Ther
256: 562-
567). Strips of tissue (approximately 10 mm long and 1.5 mm wide) were removed
from the
urinary bladder of male guinea pigs. The tissues were suspended in an
oxygenated buffer of the
following composition, in mM: NaCI 133; KCl 4.7; CaClz 2.5; MgS04 0.6; NaHzP04
1.3;
NaHC03 16.3; and glucose 7.7. The smooth muscle strips were maintained at or
about 37.5 °C
in tissue chambers and allowed to equilibrate with the bathing solution for
one hour before
proceeding with the experiment. Contractions induced by carbachol were used to
measure
anticholinergic actions of trospium and reference compounds (oxybutynin,
tolterodine) as
described by Smith et al., 1998.
Results:
It has been found that. all antimuscarinic compounds tested, potently
inhibited carbachol-induced
contractions with KB values between
12
CA 02503746 2005-04-05
1.5 nM and 5.5 nM. There were no differences of biological significance
between the test
compounds, thereby confirming the receptor binding studies in this functional
test system.
3. Cardiac side effects.
Male or female guinea pigs (450-550 g) were anesthetized with freshly prepared
dialurethane sodium. The jugular vein was catheterized for intravenous
administration of test
drugs and the trachea was exposed and cannulated to facilitate adequate
pulmonary ventilation.
Transdermal electrodes were positioned for Lead II electrocardiogram
recording, monitored on a
Grass Recorder, set at a paper speed of 50 mm/sec. The animals were allowed to
stabilize for 30
minute after completion of surgery, and three baseline ECG recordings were
made at 10-minute
intervals. The animals were then given a d~sP of the test compound or vehicle
as an intravenous
infusion over 30 min. ECG recordings were used to determine QT intervals and
heart rates. To
compensate for variations in heart rates, QTc intervals were calculated from
QT- and RR-
intervals as known to those skilled in the art (Bassett's formula).
Results:
It has now been found that terodiline, oxybutynin and tolterodine, but not
trospium, caused
statistically significant prolongation of the QTc interval of the ECG from
anesthetized guinea
pigs.
Compound N OQTc (%)
Vehicle 8 - 3 ~ 1
Terodiline 8 + 11 ~ 1
13
CA 02503746 2005-04-05
Oxybutynin 7 + 12 t 2
Tolterodine 7 + 16 ~ 1
Trospium 7 - 2 ~ 1
Discussion:
The present in vivo test method was introduced by Gayheart-Walsten et al
(1998), who
demonstrated a significant prolongation of QTc by terfenadine, but not by
norastemizole,
thereby validating the test method. In the present studies, terodiline also
caused significant
prolongation of QTc, thereby further validating this in vivo test method.
The present results confirm experimental results of Jones et al. (Br J
Pharmacol 2000,
131: 245-254), who found prolongation by terodiline and oxybutynin on action
potential
duration. Jones et al. (2000) did not test the effects of trospium.
Tolterodine prolonged QTc
more potently than oxybutynin and terodiline in the present study, but the
therapeutic doses
of tolterodine are lower than those of oxybutynin and terodiline. There were
no effects of
trospium or the vehicle on QTc, thereby, surprisingly, demonstrating that
trospium can be
used as a non-arrhythmogenic antimuscarinic incontinence drug. This is
particularly
important for a drug like trospium, since it is administered to the patient in
a relatively high
dose - 20 mg at least twice daily. Thus, the compound trospium can even be
used by patients
who are predisposed for long QT syndrome or patients who may also be taking
other drugs
that may already cause some QT-prolongation, such as for example erythromycin
or
ketoconazole.
Prolongation of QTc is indicative of a prolonged cardiac action potential, and
is caused
by the inhibition of one or more rectifier potassium channels. Prolongation of
QTc is the known
14
CA 02503746 2005-04-05
cause of torsades de pointes ventricular fibrillation by drugs such as
terfenadine, astemizole
cisapride and terodiline, all of which are now withdrawn from the market
because of QTc-
prolongation, and - consequently - high risk for lethal torsades de pointes
ventricular fibrillation.
It should be pointed out that in vitro electrophysiological studies on the
effects of various
drugs are considered less predictive than in vivo studies with regard to
cardiac events leading to
torsades de pointes arrhythmias. Thus, various published studies describe the
effects of dings on
action potentials in isolated Purkinje fibers, although the role that the
Purkinje fiber action
potential plays in the prolongation of the cardiac QT interval is uncertain
(Gintant et al. J.
Cardiovasc Pharmacol. 2001, 37:608-618.) Numerous in vitro studies have
actually been unable
to demonstrate the cardiotoxic effects of terfenadine that was withdrawn from
the market because
of risks for QT-prolongation and Torsades de pointes arrhythmias (for review,
see Gintant et al.,
2001, page 616.) Similarly, Shuba et al., (J Pharmacol Exp Ther. 1999, 290:
1417-1426),
reported that terodiline in an in vitro study actually shortened the action
potential in a dose-
dependent manner, although that drug was also withdrawn because it caused
lengthening of the
cardiac action potential (QT-prolongation) and torsades de pointes in vivo in
patients (Hartigan-
Go et al., Clin Pharmacol Ther. 1996, 60: 89-98.) The validity of the present
in vivo test
methodology is evident from the fact that both terfenadine and terodiline
caused QT-
prolongation in the present studies as the same drugs have been shown to do in
vivo in humans
EQUIVALENTS
Those skilled in the art will recognize, or be able to ascertain, using no
more than routine
experimentation, many equivalents to the specifc embodiments of the invention
described
herein. Such equivalents include numerous pharmaceutically acceptable salt
forms e.g. sulfate,
CA 02503746 2005-04-05
fumarate, hydrobromide, hydrochloride, dihydrochloride, methanesulphonate,
hydroxynaphthoate, chlorotheophylline or where appropriate one or other of the
hydrate forms
thereof, see Merck Index 11th edition (1989.) items 9089, 209, 3927, 4628,
8223, 5053, 5836,
8142, 2347, ?765, 1840, 9720, 7461, 1317,4159, and 963 and references cited
therein and Am.
Rev. Resp. Dis. 1988, 137: (4;212) 32. Such equivalents also include the co-
administration of at
least one compound of the present invention with any other drug that is used
to combat diseases
in mammals, mentioned in this document. Such equivalents also include the co-
administration of
at least one compound of the present invention with any other compound or drug
that may be
used in combination with medication for urinary incontinence or intestinal
hyperactivity. Those
skilled in the art of medicine will also realize that higher or lower doses
than those indicated here
may be preferred and the doses may be given more or less frequently than
suggested here.
The spiroalcohol metabolite of trospium has antimuscarinic activity and is
therefore
expected to have therapeutic activity in patients suffering from conditions of
smooth muscle
hyperactivity. All active metabolites of trospium are included in this present
invention.
Those skilled in the art, will realize that smooth muscle motility disorders
include
disorders of the gastrointestinal tract, including diarrhea and irritable
bowel syndromes (IBS) and
disorders of the urinary ducts (e.g. "kidney stone pain"; urolithiasis) and
the gall fluid ducts (e.g.
"gall stone pains"; cholelithiasis and choledocholithiasis) and disorders of
the smooth muscle of
the airways (e.g. asthma, COPD and bronchitis).
Those skilled in the art of zoophysiology or veterinary medicine will realize
that
mammals, others than humans, may suffer from smooth muscle disorders, such as
urinary
incontinence, as well as pancreatitis and pain originating from kidney stones
(urolithiasis) or
gallstones (cholelithiasis).
16
CA 02503746 2005-04-05
Those skilled in the art of pharmacology, will realize that the compounds of
the
invention, having certain pharmacological properties (such as antimuscarinic
activity on various
receptor types, calcium antagonistic activity, spasmolytic activity on various
types of smooth
muscle ete.) may be useful for other indications than those listed here. Such
indications include
but are not limited to cardiovascular indications such as heart failure,
myocardial infarction and
stroke, and are equivalents to the specific embodiments of the present
invention.
All equivalents are intended to be included in this present invention.
17
