U.S. patent application number 15/906350 was filed with the patent office on 2018-07-05 for pharmaceutical compositions for combination therapy.
The applicant listed for this patent is SANIONA A/S. Invention is credited to Bo Hjorth Bentzen, Morten Grunnet, Henrik Bjork Hansen, Lars Hyveled-Nielsen, Jorgen Buus Lassen, Claus Sundgreen.
Application Number | 20180185304 15/906350 |
Document ID | / |
Family ID | 48983571 |
Filed Date | 2018-07-05 |
United States Patent
Application |
20180185304 |
Kind Code |
A1 |
Hansen; Henrik Bjork ; et
al. |
July 5, 2018 |
PHARMACEUTICAL COMPOSITIONS FOR COMBINATION THERAPY
Abstract
This invention relates to the use of pharmaceutical compositions
comprising a therapeutically effective combination of Tesofensine
and Metoprolol for preventing the cardiovascular side effects of
Tesofensine, while leaving the robust inhibitory efficacy on food
intake and body weight loss unaffected.
Inventors: |
Hansen; Henrik Bjork;
(Kobenhavn N, DK) ; Grunnet; Morten; (Kobenhavn O,
DK) ; Bentzen; Bo Hjorth; (Espergaerde, DK) ;
Hyveled-Nielsen; Lars; (Lyngby, DK) ; Lassen; Jorgen
Buus; (Bagsvaerd, DK) ; Sundgreen; Claus;
(Frederiksberg, DK) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SANIONA A/S |
Ballerup |
|
DK |
|
|
Family ID: |
48983571 |
Appl. No.: |
15/906350 |
Filed: |
February 27, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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15206477 |
Jul 11, 2016 |
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15906350 |
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|
14936963 |
Nov 10, 2015 |
9387184 |
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15206477 |
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14379032 |
Aug 15, 2014 |
9211271 |
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PCT/EP2013/052941 |
Feb 14, 2013 |
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14936963 |
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61599623 |
Feb 16, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/138 20130101;
A61P 3/04 20180101; A61K 31/46 20130101; A61P 3/00 20180101; A61P
3/06 20180101; A61P 9/10 20180101; A61P 9/00 20180101; A61P 3/10
20180101; A61K 31/135 20130101; A61K 31/46 20130101; A61K 2300/00
20130101; A61K 31/135 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/138 20060101
A61K031/138; A61K 31/46 20060101 A61K031/46; A61K 31/135 20060101
A61K031/135 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 16, 2012 |
DK |
PA201270076 |
Claims
1. A method of inducing hypophagia in a human comprising:
administering Tesofensine, or a pharmaceutically acceptable salt
thereof, to the human; in combination with Metoprolol, or a
pharmaceutically acceptable salt thereof, wherein the combination
is effective in inducing hypophagia and wherein the combination is
effective in preventing or alleviating drug-induced cardiovascular
side-effects.
2. The method of claim 1, wherein the Tesofensine, or
pharmaceutically acceptable salt thereof, is administered at dosage
of 0.1 mg to 1 mg daily, based on the amount of free base.
3. The method of claim 1, wherein the Tesofensine, or
pharmaceutically acceptable salt thereof, is administered at dosage
of 0.1 mg to about 0.5 mg daily, based on the about of free
base.
4. The method of claim 1, wherein the Metoprolol, or
pharmaceutically acceptable salt thereof, is administered at dosage
of 0.25 mg to 200 mg daily, based on the amount of free base.
5. The method of claim 1, wherein the Metoprolol, or
pharmaceutically acceptable salt thereof, is administered at dosage
of 25 mg to 100 mg daily, based on the amount of free base.
6. The method of claim 1, wherein the human is a pre-obese human,
an obese human, or a morbidly obese human.
7. The method of claim 1, wherein the human suffers from
over-eating disorders, bulimia nervosa, binge eating disorder,
compulsive over-eating, impaired appetite regulation, metabolic
syndrome, type 2 diabetes, dyslipidemia, atherosclerosis, or
drug-induced obesity.
8. The method of claim 1, wherein the human suffers from an
over-eating disorder, bulimia nervosa, binge eating disorder, or
compulsive over-eating.
9. The method of claim 1, wherein the drug-induced cardiovascular
side effects are increased heart rate, increased diastolic blood
pressure, or increased systolic blood pressure, or a combination
thereof.
10. The method of claim 1, wherein the Tesofensine or the
pharmaceutically acceptable salt thereof and the Metoprolol or the
pharmaceutically acceptable salt thereof are administered
separately.
11. The method of claim 1, wherein the Tesofensine or the
pharmaceutically acceptable salt thereof and the Metoprolol or the
pharmaceutically acceptable salt thereof are administered in a
combined form.
12. The method of claim 1, wherein the Tesofensine or the
pharmaceutically acceptable salt thereof is administered once
daily.
13. The method of claim 1, wherein the Metoprolol or the
pharmaceutically acceptable salt thereof is administered once
daily.
14. The method of claim 1, wherein the Tesofensin or the
pharmaceutically acceptable salt thereof and the Metoprolol or the
pharmaceutically acceptable salt thereof are administered
orally.
15. The method of claim 14, wherein the Tesofensin or the
pharmaceutically acceptable salt thereof and the Metoprolol or the
pharmaceutically acceptable salt thereof are each administered as a
tablet or capsule.
16. The method of claim 1, wherein the human is administered a
pharmaceutically acceptable salt of Tesofensine and the
pharmaceutically acceptable salt of Tesofensine is Tesofensine
citrate.
17. The method of claim 1, wherein the human is administered a
pharmaceutically acceptable salt of Metoprolol and the
pharmaceutically acceptable salt of Metoprolol is metoprolol
succinate.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/206,477, fled Jul. 11, 2016, which is a
continuation of U.S. patent application Ser. No. 14/936,963, filed
Nov. 10, 2015, now U.S. Pat. No. 9,387,184, which is a continuation
of U.S. patent application Ser. No. 14/379,032, filed Aug. 15,
2014, now U.S. Pat. No. 9,211,271, which is the national stage
entry of International Patent Application No. PCT/EP2013/052941,
filed Feb. 14, 2013, which claims the benefit of priority to U.S.
Provisional Patent Application No. 61/599,623, filed Feb. 16, 2012,
and Denmark Application No. PA201270076, filed Feb. 16, 2012, the
entireties of which are incorporated herein by reference.
TECHNICAL FIELD
[0002] This invention relates to the use of pharmaceutical
compositions comprising a therapeutically effective combination of
Tesofensine and Metoprolol for preventing the cardiovascular side
effects of Tesofensine, while leaving the robust inhibitory
efficacy on food intake and body weight loss unaffected.
BACKGROUND ART
[0003] Within the past decades the prevalence of obesity has risen
in virtually all ethnic, racial and socioeconomic populations, in
both genders and in all age groups. Obesity is associated with a
significantly elevated risk for type 2 diabetes, coronary heart
diseases, hypertension and numerous other major illnesses and
overall mortality from all causes. Therefore, weight reduction is
critical for the obese patient. Thus there is impetus for creating
new and alternative treatments for management of obesity.
[0004] Tesofensine, i.e.
(1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-2-(ethoxymethyl)-8-methyl-8-azabicyc-
lo[3.2.1]octane], first described in WO 97/30997, is a triple
monoamine reuptake inhibitor in development for the treatment of
obesity.
[0005] WO 2005/070427 describes the use of certain monoamine
neurotransmitter re-uptake inhibitors for obtaining a sustained
reduction of body weight. WO 2009/065845 describes the use of
certain monoamine neurotransmitter re-uptake inhibitors for the
treatment of over-eating disorders. WO 2009/080691 describes the
use of certain monoamine neurotransmitter re-uptake inhibitors in a
combination with additional anti-obesity agents for the treatment
of obesity.
[0006] Tesofensine effectively produces a weight loss in obese
individuals of about twice of that seen with currently marketed
anti-obesity drugs. Results from clinical studies with Tesofensine
also showed that the compound has a good safety profile and is well
tolerated. However, though no clinically relevant cardiovascular
adverse events or changes in either blood pressure or pulse were
seen, some cardiovascular effects were measured with slight
increases in heart rate and trends in blood pressure. Although such
small effects have no immediate risk to the patient, some medical
and regulatory concerns have been raised based on observational
studies, that even small changes in cardiovascular parameters may
have long term implications on patients' benefit/risk
evaluation.
[0007] Preclinical and clinical data suggest that appetite
suppression is an important mechanism by which Tesofensine exerts
its robust weight reducing effect. Notably, the strong hypophagic
response (i.e. less appetite, decreased feeding) to Tesofensine
treatment is demonstrated to be linked to central stimulation of
noradrenergic and dopaminergic neurotransmission. However, the
sympathomimetic mode of action of Tesofensine may also associate
with the elevated heart rate and blood pressure observed in
clinical settings.
[0008] WO 2009/080693 describes pharmaceutical compositions
comprising certain monoamine neurotransmitter re-uptake inhibitors
in a combination with certain beta blockers, and WO 2011/100659
describes a method for ameliorating drug-induced elevation of blood
pressure or increase in heartbeat by administration of an
antihypertensive drug.
[0009] As such combination therapies seem tempting, drug
combinations of Tesofensine with antihypertensive agents
representing different mechanisms of action have been investigated.
Based on these experiments it was found that some antihypertensive
agents actually happen to interfere with the anti-obesity effects
of Tesofensine, and thus are not suited for such combination
therapy. Moreover, other antihypertensive agents are actually
unable to reverse the increase in systolic blood pressure and heart
rate induced by Tesofensine.
[0010] Metoprolol, i.e.
1-(Isopropylamino)-3-[4-(2-methoxyethyl)-phenoxy]-propan-2-ol,
branded under various trade names, is a selective .beta.1
(adrenergic) receptor blocker normally used in the treatment of
various disorders of the cardiovascular system, and in particular
hypertension.
SUMMARY OF THE INVENTION
[0011] It has now surprisingly been found that the use of
Metoprolol, in a specific combination therapy with Tesofensine, for
the treatment of obesity, shows promising results in terms of
preventing the cardiovascular effects induced Tesofensine, while
leaving the robust inhibitory efficacy of Tesofensine on food
intake and body weight loss unaffected.
[0012] Therefore, in one aspect, the invention provides a method of
treatment, prevention or alleviation of obesity, or an obesity
associated disorder, and for treatment, prevention or alleviation
of the cardiovascular side effects of Tesofensine, in a living
animal body, including a human, which method comprises the step of
administering to such a living animal body in need thereof, a
therapeutically effective amount of Tesofensine, or a
pharmaceutically acceptable salt thereof; in a combination therapy
with Metoprolol, or a pharmaceutically acceptable salt thereof.
[0013] In another aspect the invention provides a combination of
Tesofensine, or a pharmaceutically acceptable salt thereof, and
Metoprolol, or a pharmaceutically acceptable salt thereof, the
treatment, prevention or alleviation of obesity, or an obesity
associated disorder, and for treatment, prevention or alleviation
of the cardiovascular side effects of Tesofensine.
[0014] In a third aspect the invention provides a combination of
Tesofensine, or a pharmaceutically acceptable salt thereof, and
Metoprolol, or a pharmaceutically acceptable salt thereof, for use
as a medicament.
[0015] In a fourth aspect the invention provides a combination of
Tesofensine, or a pharmaceutically acceptable salt thereof; and
Metoprolol, or a pharmaceutically acceptable salt thereof; for the
treatment, prevention or alleviation of obesity, or an obesity
associated disorder, and for treatment, prevention or alleviation
of the cardiovascular side effects of Tesofensine, in a mammal,
including a human.
[0016] In a fifth aspect the invention relates to the use of a
combination of Tesofensine, or a pharmaceutically acceptable salt
thereof; and Metoprolol, or a pharmaceutically acceptable salt
thereof; for the manufacture of a medicament for the treatment,
prevention or alleviation of obesity, or an obesity associated
disorder, and for treatment, prevention or alleviation of the
cardiovascular side effects of Tesofensine, in a mammal, including
a human.
[0017] In a sixth aspect the invention provides a pharmaceutical
composition comprising Tesofensine, or a pharmaceutically
acceptable salt thereof, for use in a combination therapy together
with a pharmaceutical composition comprising Metoprolol, or a
pharmaceutically acceptable salt thereof, for the treatment,
prevention or alleviation of obesity, or an obesity associated
disorder, and for treatment, prevention or alleviation of the
cardiovascular side effects of Tesofensine.
[0018] In an eight aspect the invention provides a pharmaceutical
composition comprising a therapeutically effective amount of
Tesofensine, or a pharmaceutically acceptable salt thereof, and a
therapeutically effective amount of Metoprolol, or a
pharmaceutically acceptable salt thereof, together with one or more
adjuvants, excipients, carriers and/or diluents.
[0019] In a ninth aspect the invention provides a kit of parts
comprising at least two separate unit dosage forms (A) and (B),
wherein (A) comprises Tesofensine, or a pharmaceutically acceptable
salt thereof; and (B) comprises Metoprolol, or a pharmaceutically
acceptable salt thereof; and optionally (C) instructions for the
simultaneous, sequential or separate administration of the
Tesofensine of (A) and the Metoprolol of (B), to a patient in need
thereof.
[0020] Other objects of the invention will be apparent to the
person skilled in the art from the following detailed description
and examples.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] The present invention is further illustrated by reference to
the accompanying drawing, in which:
[0022] FIGS. 1A-1E show that Tesofensine (given 1.0-5.0 mg/kg,
p.o.) dose-dependently inhibits food intake, reduces body weight,
and stimulates locomotor activity in telemetrized rats. FIG. 1A
depicts mean cumulative food intake (2 hour intervals) measured
over 48 hours after acute dosing of tesofensine or saline vehicle.
FIG. 1B depicts mean food intake measured over 48 hours, averaged
in the 12 hours dark and light phase intervals, respectively. FIGS.
1C and 1D depict net body weight gain given relative (%) and
absolute values (grams), respectively, compared to body weight
measured prior to dosing on day 0. FIG. 1E depicts mean locomotor
activity measured over 48 hours, averaged in the corresponding 12
hours dark and light phase intervals, respectively. Dark and white
horizontal bars below the x-axis indicate 12 hours dark and light
phases, respectively. Abbreviations: VEH, vehicle; TESO,
tesofensine. *p<0.05, **p<0.01, ***p<0.001 (compared to
VEH)];
[0023] FIGS. 2A-2C-show that Tesofensine (given 1.0-5.0 mg/kg,
p.o.) dose-dependently elevates heart rate and blood pressure in
telemetrized rats. FIG. 2A depicts mean heart rate .+-.S.E.M.
averaged in 12 hours intervals. FIG. 2B depicts mean diastolic
blood pressure averaged in 12 hours intervals. FIG. 2C depicts mean
systolic blood pressure averaged in 12 hours intervals. Dark and
white horizontal bars below the x-axis indicate 12 hours dark and
light phases, respectively. Abbreviations: VEH, vehicle; TESO,
tesofensine; bpm, beats per minute. *p<0.05, **p<0.01,
***p<0.001 (compared to VEH)];
[0024] FIGS. 3A-3E show dose-response effects of Metoprolol (given
10, 20 mg/kg, p.o.) in combination with Tesofensine (3.0 mg/kg,
p.o.), and that Metoprolol does not affect the hypophagic and
weight-lowering effects of tesofensine, but blocks
tesofensine-induced locomotor activity in telemetrized rats. FIG.
3A depicts mean cumulative food intake (2 hours intervals) measured
over 48 hours after acute administration of Metoprolol+Tesofensine
combinations or saline vehicle. FIG. 3B depicts mean food intake
measured over 48 hours, averaged in the 12 hours dark and light
phase intervals, respectively. FIGS. 3C and 3D depict net body
weight gain given in relative (%) and absolute values (grams)
compared to body weight measured prior to dosing on day 0. FIG. 3E
depicts mean locomotor activity measured over 48 hours, averaged in
the 12 hours dark and light phase intervals, respectively. Dark and
white horizontal bars below the x-axis indicate 12 hours dark and
light phases, respectively. Abbreviations: VEH, vehicle, TESO,
tesofensine; MET, Metoprolol. **p<0.01, ***p<0.001 (compared
to VEH+VEH); #p<0.05, ##p<0.01 (compared to VEH+TESO
3.0)];
[0025] FIGS. 4A-4C show that Metoprolol dose-dependently blocks
tesofensine-induced rise in heart rate and blood pressure in
telemetrized rats. FIG. 4A depicts mean heart rate .+-.S.E.M.
averaged in 12 hours intervals. FIG. 4B depicts mean diastolic
blood pressure averaged in 12 hours intervals. FIG. 4C depicts mean
systolic blood pressure averaged in 12 hours intervals. Dark and
white horizontal bars below the x-axis indicate 12 hours dark and
light phases, respectively. Abbreviations: VEH, vehicle; TESO,
tesofensine; MET, Metoprolol. **p<0.01, ***p<0.001 (compared
to VEH+VEH); #p<0.05, ##p<0.01, ###p<0.001 (compared to
VEH+TESO 3.0)];
[0026] FIGS. 5A-5E show dose-response effects of Telmisartan (1.0,
3.0 mg/kg, p.o.) in combination with tesofensine (3.0 mg/kg, p.o.),
and that Telmisartan does not affect the hypophagic and
weight-lowering effects of Tesofensine, and has no effect on
tesofensine-induced locomotor activity in telemetrized rats. FIG.
5A depicts mean cumulative food intake (2 hours intervals) measured
over 48 hours after acute administration of Telmisartan+Tesofensine
combinations or saline vehicle. FIG. 5B depicts mean food intake
measured over 48 hours, averaged in the 12 hours dark and light
phase intervals, respectively. FIGS. 5C and 5D depict net body
weight gain given in relative (%) and absolute values (grams)
compared to body weight measured prior to dosing on day 0. FIG. 5E
depicts mean locomotor activity measured over 48 hours, averaged in
the 12 hours dark and light phase intervals, respectively. Dark and
white horizontal bars below the x-axis indicate 12 hours dark and
light phases, respectively. Abbreviations: VEH, vehicle; TESO,
tesofensine; TEL, Telmisartan. *p<0.05, **p<0.01,
***p<0.001 (compared to VEH+VEH)]; and
[0027] FIGS. 6A-6C show effects of combined Tesofensine+Telmisartan
drug treatment on heart rate and blood pressure in telemetrized
rats. FIG. 6A depicts mean heart rate .+-.S.E.M. averaged in 12
hours intervals. FIG. 6B depicts mean diastolic blood pressure
averaged in 12 hours intervals. FIG. 6C depicts mean systolic blood
pressure averaged in 12 hours intervals. Dark and white horizontal
bars below the x-axis indicate 12 hours dark and light phases,
respectively. Dark and white horizontal bars below the x-axis
indicate 12 hours dark and light phases, respectively.
Abbreviations: VEH, vehicle; TESO, tesofensine; TEL, Telmisartan.
*p<0.05, **p<0.01, ***p<0.001 (compared to VEH+VEH);
#p<0.05 (compared to VEH+TESO 3.0)].
DETAILED DISCLOSURE OF THE INVENTION
[0028] Tesofensine is a centrally acting triple monoamine reuptake
inhibitor (MRI) with intrinsic inhibitory activity on
noradrenaline, serotonin and dopamine transporter function. When
corrected for placebo and diet effects, long-term Tesofensine
treatment produces a weight loss of about 10% in obese patients,
which is twice as much as that achieved by currently marketed
anti-obesity drugs.
[0029] The anti-obesity effect of Tesofensine is likely explained
by dose-dependent hypophagia due to stimulation of satiety,
suggesting that Tesofensine acts as an appetite suppressant to
produce a negative energy balance. In addition, Tesofensine is also
demonstrated to increase nocturnal energy expenditure in human
subjects. These findings have recently been corroborated and
extended in preclinical settings, demonstrating that Tesofensine
induces a robust and sustained weight loss in a rat model of
diet-induced obesity (DIO) of which the long-lasting drop in body
weight is caused by appetite suppression with a gradually increase
in energy expenditure. Notably, the hypophagic effect of
Tesofensine in DIO rats is critically dependent on stimulated al
adrenoceptor activity, and to a less extend dopamine D1 receptor
function, indicating that enhancement of central noradrenergic and
dopaminergic neurotransmission constitute important mechanisms
underlying the robust appetite-suppressing effect of
Tesofensine.
[0030] Overall, chronic Tesofensine treatment is associated with
minor adverse events, and with minimal cardiovascular effects,
suggesting that Tesofensine may be a well-tolerated long-term
treatment for obesity. However, in this regard, dose-dependent
elevations in heart rate and significant increases in blood
pressure at the highest dose tested have been reported in obese
individuals. We therefore speculated whether the sympathomimetic
effects of Tesofensine might also associate with the reported
effects on cardiovascular function.
[0031] To address this hypothesis, we simultaneously monitored
effects on food intake and body weight regulation in conjunction
with cardiovascular parameters in telemetrized (i.e. spontaneously
hypertensive) rats following administration of Tesofensine alone,
or in drug combinations of Tesofensine with antihypertensive agents
representing different mechanisms of action, i.e. Metoprolol (i.e.
a .beta.1 adrenoceptor antagonist) and Telmisartan (i.e. an
angiotension AT1 receptor antagonist).
[0032] It has now surprisingly been found that use of Metoprolol,
in a specific combination therapy with Tesofensine, for the
treatment of obesity or obesity associated disorders, shows
promising results in terms of preventing the cardiovascular effects
induced Tesofensine, while leaving the robust inhibitory efficacy
of Tesofensine on food intake and body weight loss unaffected.
[0033] Therefore, in one aspect, the present invention relates to a
combination therapy using Tesofensine and Metoprolol for the
treatment, prevention or alleviation of obesity or an obesity
associated disorder in a subject suffering from such disorders.
[0034] In another aspect the invention relates to the of a
combination of Tesofensine, or a pharmaceutically acceptable salt
thereof; and Metoprolol, or a pharmaceutically acceptable salt
thereof; for the manufacture of a medicament for the treatment,
prevention or alleviation of obesity, or an obesity associated
disorder, and for treatment, prevention or alleviation of the
cardiovascular side effects of Tesofensine, in a mammal, including
a human.
Obesity and Obesity Associated Disorders
[0035] Obesity is a medical condition in which excess body fat has
accumulated to the extent that it may have an adverse effect on
health, leading to reduced life expectancy and/or increased health
problems. Body mass index (BMI), a measurement which compares
weight and height, defines people as overweight (pre-obese) if
their BMI is between 25 and 30 kg/m.sup.2, and obese when it is
greater than 30 kg/m.sup.2.
[0036] In a preferred embodiment, the combination therapy according
to the invention is contemplated useful for the treatment of
pre-obese subjects, i.e. having a BMI between 25 and 30
kg/m.sup.2.
[0037] In another preferred embodiment, the combination therapy
according to the invention is contemplated useful for the treatment
of obese subjects, i.e. having a BMI of above 30 kg/m.sup.2.
[0038] In a third preferred embodiment, the combination therapy
according to the invention is contemplated useful for the treatment
of morbid obese subjects, i.e. having a BMI of above 35
kg/m.sup.2.
[0039] In the context of this invention an obesity associated
disorder is a disorder or condition selected from the group
consisting of over-eating disorders, bulimia nervosa, binge eating
disorder, compulsive over-eating, impaired appetite regulation,
metabolic syndrome, type 2 diabetes, dyslipidemia, atherosclerosis
and drug-induced obesity, e.g. following therapy with
antidepressive or antipsychotic drugs.
Pharmaceutically Acceptable Salts
[0040] The active compounds for use according to the invention may
be provided in any form suitable for the intended administration.
Suitable forms include pharmaceutically (i.e. physiologically)
acceptable salts, and pre- or prodrug forms of the compound of the
invention.
[0041] Examples of pharmaceutically acceptable addition salts
include, without limitation, the non-toxic inorganic and organic
acid addition salts such as the hydrochloride, the hydrobromide,
the nitrate, the perchlorate, the phosphate, the sulphate, the
formate, the acetate, the aconate, the ascorbate, the
benzenesulphonate, the benzoate, the cinnamate, the citrate, the
embonate, the enantate, the fumarate, the glutamate, the glycolate,
the lactate, the maleate, the malonate, the mandelate, the
methanesulphonate, the naphthalene-2-sulphonate, the phthalate, the
salicylate, the sorbate, the stearate, the succinate, the tartrate,
the toluene-p-sulphonate, and the like. Such salts may be formed by
procedures well known and described in the art.
[0042] Examples of pharmaceutically acceptable cationic salts of a
chemical compound of the invention include, without limitation, the
sodium, the potassium, the calcium, the magnesium, the zinc, the
aluminium, the lithium, the choline, the lysinium, and the ammonium
salt, and the like, of a chemical compound of the invention
containing an anionic group. Such cationic salts may be formed by
procedures well known and described in the art.
[0043] In the context of this invention the "onium salts" of
N-containing compounds are also contemplated as pharmaceutically
acceptable salts. Preferred "onium salts" include the alkyl-onium
salts, the cycloalkyl-onium salts, and the cycloalkylalkyl-onium
salts.
[0044] Examples of pre- or prodrug forms of the chemical compound
for use according to the invention include examples of suitable
prodrugs of the substances for use according to the invention
include compounds modified at one or more reactive or derivatizable
groups of the parent compound. Of particular interest are compounds
modified at a carboxyl group, a hydroxyl group, or an amino group.
Examples of suitable derivatives are esters or amides.
[0045] The chemical compounds for use according to the invention
may be provided in dissoluble or indissoluble forms together with a
pharmaceutically acceptable solvent such as water, ethanol, and the
like. Dissoluble forms may also include hydrated forms such as the
monohydrate, the dihydrate, the hemihydrate, the trihydrate, the
tetrahydrate, and the like. In general, the dissoluble forms are
considered equivalent to indissoluble forms for the purposes of
this invention.
Pharmaceutical Compositions
[0046] In another aspect the invention relates to a combination of
Tesofensine, or a pharmaceutically acceptable salt thereof, and
Metoprolol, or a pharmaceutically acceptable salt thereof, for use
as a medicament.
[0047] In a further aspect the invention provides pharmaceutical
compositions comprising Tesofensine, or a pharmaceutically
acceptable salt thereof, for use in a combination therapy together
with a pharmaceutical composition comprising Metoprolol, or a
pharmaceutically acceptable salt thereof, for the treatment,
prevention or alleviation of obesity, or an obesity associated
disorder, and for treatment, prevention or alleviation of the
cardiovascular side effects of Tesofensine.
[0048] In a yet further aspect the invention provides
pharmaceutical compositions comprising a therapeutically effective
amount of Tesofensine, or a pharmaceutically acceptable salt
thereof, and a therapeutically effective amount of Metoprolol, or a
pharmaceutically acceptable salt thereof, together with one or more
adjuvants, excipients, carriers and/or diluents.
[0049] While the compounds for use according to the invention may
be administered in the form of the raw compound, it is preferred to
introduce the active ingredients, optionally in the form of
physiologically acceptable salts, in a pharmaceutical composition
together with one or more adjuvants, excipients, carriers, buffers,
diluents, and/or other customary pharmaceutical auxiliaries.
[0050] In a preferred embodiment, the invention provides
pharmaceutical compositions comprising the active compounds or
pharmaceutically acceptable salts or derivatives thereof, together
with one or more pharmaceutically acceptable carriers therefore,
and, optionally, other therapeutic and/or prophylactic ingredients,
know and used in the art. The carrier(s) must be "acceptable" in
the sense of being compatible with the other ingredients of the
formulation and not harmful to the recipient thereof.
[0051] The pharmaceutical composition of the invention may be
administered by any convenient route, which suits the desired
therapy. Preferred routes of administration include oral
administration, in particular in tablet, in capsule, in drage, in
powder, or in liquid form, and parenteral administration, in
particular cutaneous, subcutaneous, intramuscular, or intravenous
injection. The pharmaceutical composition of the invention can be
manufactured by the skilled person by use of standard methods and
conventional techniques appropriate to the desired formulation.
When desired, compositions adapted to give sustained release of the
active ingredient may be employed.
[0052] Further details on techniques for formulation and
administration may be found in the latest edition of Remington's
Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa.).
[0053] The dosage of the compound of Formula I is determined as the
API (Active Pharmaceutical Ingredient), i.e. calculated as the free
base. The actual dosage of each of the active ingredients depends
on the nature and severity of the disease being treated, the exact
mode of administration, form of administration and is within the
discretion of the physician, and may be varied by titration of the
dosage to the particular circumstances of this invention to produce
the desired therapeutic effect.
[0054] It is currently believed that a daily dosage of Tesofensine
in the range of from about 0.1 to about 1 mg active ingredient,
preferably of from about 0.1 to about 0.5 mg active ingredient, is
suitable for therapeutic treatments. The daily dosage of
Tesofensine may be administered in one or several doses, such as
two, per day. In one embodiment, the daily dosage is administered
in one dose.
[0055] The daily dosage of Metoprolol is presently contemplated to
be in the range of from about 25 to about 200 mg of active
ingredient, preferably of from about 25 to about 100 mg active
ingredient. The daily dosage of Metoprolol may be administered in
one or several doses, such as two, per day. In one embodiment, the
daily dosage is administered in one dose.
Pharmaceutical Kits of Parts
[0056] According to the invention there is also provided a kit of
parts comprising at least two separate unit dosage forms (A) and
(B), wherein
[0057] (A) comprises Tesofensine, or a pharmaceutically acceptable
salt thereof; and
[0058] (B) comprises Metoprolol, or a pharmaceutically acceptable
salt thereof; and optionally
[0059] (C) instructions for the simultaneous, sequential or
separate administration of the Tesofensine of (A) and the
Metoprolol of (B), to a patient in need thereof.
[0060] Tesofensine for use according to the invention and
Metoprolol for use according to the invention may preferably be
provided in a form that is suitable for administration in
conjunction with the other. This is intended to include instances
where one or the other of two formulations may be administered
(optionally repeatedly) prior to, after, and/or at the same time as
administration with the other component.
[0061] Also Tesofensine for use according to the invention and
Metoprolol for use according to the invention may be administered
in a combined form, or separately or separately and sequentially,
wherein the sequential administration is close in time or remote in
time. This may in particular include that two formulations are
administered (optionally repeatedly) sufficiently closely in time
for there to be a beneficial effect for the patient, that is
greater over the course of the treatment of the relevant condition
than if either of the two formulations are administered (optionally
repeatedly) alone, in the absence of the other formulation, over
the same course of treatment. Determination of whether a
combination provides a greater beneficial effect in respect of, and
over the course of treatment of, a particular condition, will
depend upon the condition to be treated or prevented, but may be
achieved routinely by the person skilled in the art.
[0062] When used in this context, the terms "administered
simultaneously" and "administered at the same time as" include that
individual doses of Tesofensine and are administered within 48
hours, e.g. 24 hours, of each other.
[0063] Bringing the two components into association with each
other, includes that components (A) and (B) may be provided as
separate formulations (i.e. independently of one another), which
are subsequently brought together for use in conjunction with each
other in combination therapy; or packaged and presented together as
separate components of a "combination pack" for use in conjunction
with each other in combination therapy.
Methods of Therapy
[0064] In another aspect the invention provides methods of
treatment, prevention or alleviation of obesity or an obesity
associated disease of a living animal body, including a human,
which method comprises the step of administering to such a living
animal body in need thereof, a therapeutically effective amount of
a combination of Tesofensine, or a pharmaceutically acceptable salt
thereof, and Metoprolol, a pharmaceutically acceptable salt
thereof.
[0065] In a preferred embodiment the obesity associated disorder is
a disorder or condition selected from the group consisting of
over-eating disorders, bulimia nervosa, binge eating disorder,
compulsive over-eating, impaired appetite regulation, metabolic
syndrome, type 2 diabetes, dyslipidemia, atherosclerosis and
drug-induced obesity.
[0066] It is currently believed that a daily dosage of Tesofensine
in the range of from about 0.1 to about 1 mg active ingredient,
preferably of from about 0.1 to about 0.5 mg active ingredient, is
suitable for therapeutic treatments. The daily dosage of
Tesofensine may be administered in one or several doses, such as
two, per day. In one embodiment, the daily dosage is administered
in one dose.
[0067] The daily dosage of Metoprolol is presently contemplated to
be in the range of from about 25 to about 200 mg of active
ingredient, preferably of from about 25 to about 100 mg active
ingredient. The daily dosage of Metoprolol may be administered in
one or several doses, such as two, per day. In one embodiment, the
daily dosage is administered in one dose.
EXAMPLES
[0068] The invention is further illustrated with reference to the
following example, which is not intended to be in any way limiting
to the scope of the invention as claimed.
Animal Care and Housing
[0069] Five months-old male normotensive Sprague-Dawley rats
(508.+-.18 g, Harlan, Horst, The Netherlands) were housed in solid
bottomed Plexiglas cages with dust free wood chippings and a
cardboard tube. Holding rooms were maintained under a 12-h
light/dark cycle (lights off: 1500 h). Ambient temperature was 18.0
to 22.0.degree. C. and relative air humidity of 40 to 60%. A dim
red light was the sole source of illumination during the dark
period. The rats had ad libitum standard chow (Altromin 1324, 10%
kcal from fat, energy density 2.85 kcal per g, Altromin GmbH, Lage,
Germany) and water. All experiments were approved (permission no.
2007/561-1343) and conducted in accordance with the guidelines of
the Animal Experimentation Inspectorate, Ministry of Justice,
Denmark.
Simultaneous Real-Time Feeding and Cardiovascular Monitoring in
Telemetrized Rats Telemetry Set-Up
[0070] The rats were implanted at Harlan laboratories, Horst, the
Netherlands, with Data Science International (DSI, St. Paul, USA)
Physiotel PA-C40 transmitters according to the manufactures
description. In brief, the rats were anaesthetized with isoflurane,
ventilated, and a laparotomy was performed under aseptic
conditions. A pressure catheter was inserted and sealed in place
with Vetbond (3M, St. Paul, USA) into the isolated abdominal aorta.
Finally, the transmitter was placed on top of the intestines, in
parallel to the long axis of the body, and secured to the abdominal
wall, where after the abdominal muscle layer and skin was closed
with solvable sutures. The animals were allowed full post-surgical
recovery before shipment. Blood pressure (systolic and diastolic
arterial blood pressure) and heart rate (pulse rate) data were
collected at a sampling rate of 500 Hz using Dataquest A.R.T
(v.4.3) and Ponemah software (v.5.0) (DSI, St. Paul, USA) using
factory-provided calibration values for the individual transmitters
and an Ambient Pressure Reference Monitor (DSI, St. Paul, USA) to
ensure accurate blood pressure measurements. Data were collected
continuously for 48 h and binned in 5 s intervals.
Real-Time Feeding Monitoring in Telemetrized Rats
[0071] Upon 2-3 weeks of post-surgery recovery, the rats were
transferred to fully automated food intake monitoring cages (HM-2,
MBRose, Faaborg, Denmark) modified to simultaneously determine
individualized food intake (by microchip, see below) and
cardiovascular condition (by telemetry). For combined telemetry
analysis, two receivers (RPC-1, Data Sciences International, St.
Paul, Minn.) were placed in the bottom of each HM-2 food intake
monitoring cages thereby fully covering the cage surface area. The
modified HM-2 food intake monitoring cages were placed in a
modified ventilated cabinet with lightproof doors and a light kit
for cabinet-based control of light-dark cycle (Scanbur BK,
Karslunde, Denmark) being similar to that in the holding rooms.
Cabinet temperature was 24.0 to 26.0.degree. C. and relative air
humidity of 40 to 60%. The animals were habituated to the HM-2 food
intake monitoring system for at least 5 days prior to initiation of
drug treatment procedures. Prior to re-housing to the fully
automated food intake monitoring cages, the rats were
subcutaneously injected with a microchip (#402575, eVet, Haderslev,
Denmark) to simultaneously identify, and in real-time mode to track
feeding behavior of each individual animal throughout the entire
experiment. Locomotor activity was detected by an integrated
infrared sensor placed above the cage. Standard HM-2 control unit
settings are reported previously in further details.sup.7. All
drugs and saline vehicle were administered 30 min before dark
onset. All rats received the same treatment in each individual
experiment, i.e. a parallel study design was used, and a wash-out
period of at least 5 days was used between treatments to assure
reestablishment of baseline levels of food intake, locomotor
activity, heart rate and blood pressure. The home cage was removed
from the HM-2 food intake monitoring system during the drug
administration procedure and returned immediately after completion
of the drug administration, whereupon automated monitoring of
feeding behavior and cardiovascular parameters of each individual
animal was resumed. Body weight was measured daily. Body weight and
microstructural food intake analysis was performed using a data
reporting software (HMView, MBRose, Faaborg, Denmark).
Statistics
[0072] Data were fed into a standard graphic and statistical
analysis program (Graph Pad Prism v.4.03). Body weight data were
calculated as absolute values (g) or daily body weight gain
relative (control level=100%) to the first day of drug
administration (day 0). Body weight gain and food intake were
expressed as means.+-.S.E.M of n individual animals. After
acquisition of telemetry data, 12-hour means were calculated using
Microsoft Excel 2007. Finally, statistical analysis and data
presentation (mean.+-.S.E.M.) was performed using GraphPad Prism
v.4.03). All data were evaluated using a repeated-measure one-way
ANOVA with Tukey's post-hoc test was applied to perform statistical
comparisons between treatment groups. A p-value less than 0.05 was
considered statistically significant.
Drugs
[0073] Tesofensine
(8-Azabicyclo[3.2.1]octane,3-(3,4-dichlorophenyl)-2-(ethoxymethyl)-8-meth-
yl-[1R-(2-endo,3-exo)]-2-hydroxy-1,2,3-propanetricarboxylate) is a
derivative of an azabicyclooctane citrate, synthesized at the
Department of Medicinal Chemistry, NeuroSearch A/S.
[0074] Metoprolol and Telmisartan were purchased from Sigma (St.
Louis, Mo.). Tesofensine and Metoprolol were dissolved in 0.9%
saline solution, whereas Telmisartan was dissolved in 1 N NaOH and
subsequently titrated with 1 N HCl to pH 7.4.
[0075] All drugs were administered p.o. (1.0 ml/kg). In drug
combination experiments, tesofensine and the anti-hypertensive drug
were administered simultaneously (<1 min apart) as separate drug
solutions.
Results
Effects on Food Intake and Body Weight
[0076] Acute tesofensine administration robustly triggered a
reduction of food intake in telemetrized rats (FIGS. 1A and 1B).
The food intake in tesofensine-treated rats declined in a dose- and
time-dependent fashion with the highest oral dose (5.0 mg/kg) at 12
hours post-dosing reducing food intake to approximately 50% of the
control level (p<0.001). The hypophagic effect of tesofensine
was sustained for up to 12 hours (all doses), 24 hours (3.0-5.0
mg/kg) and 48 hours (5.0 mg/kg) after dosing, respectively,
whereupon food intake returned to baseline levels (FIG. 1B). The
hypophagic effect of tesofensine was paralleled by a corresponding
dose-dependent reduction in body weight (negative body weight gain)
with the highest doses (3.0-5.0 mg/kg) producing a significant net
body weight loss of 1.0-1.5% (equivalent to 8-11 g, compared to the
body weight of vehicle-treated rats) being evident for at least 48
hours after drug administration (FIGS. 10 and 1D). Tesofensine also
dose-dependently induced a significant, albeit short-lasting,
increase in locomotor activity in the dose-range of 3.0-5.0 mg/kg
(FIG. 1E).
[0077] The intermediate dose (3.0 mg/kg) of tesofensine was
selected for further characterization in acute drug combination
studies with the antihypertensive agents, Metoprolol (FIGS. 3A-3E)
and Telmisartan (FIGS. 5A-5E), respectively. These drug interaction
studies indicated that neither antihypertensive drug exhibited an
effect on food intake or body weight regulation per se, and did
also not affect tesofensine-induced reductions in food intake
(FIGS. 3A, 3B, 5A, 5B) and body weight (FIGS. 3C, 3D, 5C, 5D). In
contrast, Metoprolol (FIG. 3E, p<0.05 compared to tesofensine
alone), but not Telmisartan (FIG. 5E, p=0.98 compared to
tesofensine alone), completely prevented the locomotor activity
inducing effect by tesofensine.
Effects on Cardiovascular Parameters
[0078] As expected, the telemetric monitoring of blood pressure and
heart rate showed a clear diurnal variation (FIGS. 2A-2C), with
higher blood pressure and heart rate observed during the active
(nocturnal) period.
[0079] Acute treatment with tesofensine caused a dose-dependent
increase in heart rate at all doses tested, lasting for up to 48
hours after treatment (FIG. 2A). Similarly, a dose-dependent modest
increase in systolic blood pressure was observed up to 48 hours
after drug administration (3.0 mg/kg and 5.0 mg/kg) (FIG. 2C). The
effect of 3.0 mg/kg tesofensine on heart rate and systolic blood
pressure thereby outlasted the hypophagic effects of 3.0 mg/kg
tesofensine. A trend towards a dose-dependent rise in diastolic
blood pressure was also observed, although the highest dose did not
attain statistical significance (p=0.204, FIG. 2B).
[0080] Two combination drug studies were carried out in order to
investigate if antihypertensive treatment could prevent or reduce
the secondary hypertension and elevated heart rate caused by
tesofensine. Co-treatment with tesofensine (3.0 mg/kg) and the
.beta..sub.1 adrenoceptor antagonist Metoprolol (10 mg/kg and 20
mg/kg) fully reversed tesofensine-induced tachycardia (FIG. 4A).
The heart rate lowering effect of Metoprolol was, however, only
observed during the first 24 hours after administration, whereas
the heart rate was normalized to control levels in the
Metoprolol+Tesofensine combination groups (FIG. 4A). The
short-lasting effects of Metoprolol reflect the pharmacokinetic
properties in the rat. A normalization of the systolic blood
pressure was also observed after co-treatment with Metoprolol (20
mg/kg) for up to 24 hours (FIG. 4C). Similarly, the
tesofensine-evoked increase in the diastolic pressure during the
first light phase (12-24 hours post-treatment) was reversed by
co-treatment with Metoprolol (20 mg/kg, FIG. 4B). When administered
alone, Metoprolol (20 mg/kg) did not produce any significant
effects on diastolic blood pressure in the first 24 hours (FIGS.
4A-4C).
[0081] In a subsequent drug combinatorial study, tesofensine and
the AT1-receptor antagonist Telmisartan was investigated. As for
the Metoprolol study, a similar (3.0 mg/kg) dose of tesofensine was
found to significantly increase heart rate. Co-treatment with
Telmisartan (1.0 and 3.0) did not revert the rise in heart rate
after tesofensine administration, and with the highest dose of
Telmisartan combined with tesofensine we observed a significant
increase in heart rate as compared to tesofensine administration
alone (FIG. 6A). Although co-treatment with Telmisartan was found
to attenuate the increases in diastolic and systolic blood pressure
produced by Tesofensine, it did not lead to a significant
prevention of Tesofensine-induced hypertension (p>0.05, compared
to Tesofensine alone, FIGS. 6B, 6C). Telmisartan alone (3.0 mg/kg)
had no effect on heart rate and blood pressure (FIGS. 6A-6C).
Discussion
[0082] Weight loss is often accompanied by an increase in perceived
hunger and appetite sensations, which has been identified as an
important predictor of weight relapse, and suppression of appetite
function is therefore considered very important for the maintenance
of weight loss.
[0083] Recent clinical and preclinical reports have indicated that
Tesofensine acts as a strong appetite suppressant by triggering
satiety and fullness sensations, which is believed to be a key
mechanism underlying the robust anti-obesity effect of Tesofensine.
Hence, the present data on Tesofensine-induced anorexia in
telemetrized rats further supports this view. Tesofensine
dose-dependently triggered a rapid hypophagic response lasting for
up to 12-48 hours, depending on the dose administered. The
long-lasting anorexigenic effect of Tesofensine suggests that the
bioactive primary M1 metabolite (also being a triple MRI) of
Tesofensine contributed to the hypophagic and weight-lowering
effect in rats, as the M1 metabolite exhibits significantly higher
steady-state concentrations and longer T.sub.1/2 in rodents.
[0084] In contrast, the human steady-state plasma concentrations of
M1 are approximately 60% lower as compared to those of Tesofensine,
implying that the contribution of M1 to the overall activity might
be lower in humans. In addition, it is suggested that increased
energy metabolism may potentially contribute to the robust weight
loss induced by Tesofensine. Accordingly, a recent respiratory
calorimetry study indicated a moderate rise in fat oxidation and
nocturnal thermogenesis after short-term Tesofensine treatment in
overweight or moderately obese men. Also, while DIO rats show
long-term sustained reductions in body weight during chronic
Tesofensine treatment regimens, hypophagia is most pronounced
during the first week of treatment followed by a gradual
development of tolerance to the anorexigenic effect of Tesofensine,
thus being in indirect agreement with the clinical findings.
[0085] In the present study, Tesofensine dose-dependently increased
locomotor activity during the first 12 hours dark phase, and it may
thus be postulated that augmented locomotor activity may have
contributed to the weight loss in telemetrized rats, e.g. by
causing changes in food-seeking behavior or energy expenditure.
However, the hypophagic effect of Tesofensine was more potent and
longer lasting (up to 48 hours) as compared to the capacity of
Tesofensine to induce locomotor activity (up to 12 hours). In this
regard, it is likely that the different temporal pharmacodynamics
on food intake and locomotor activity is associated with the
pharmacokinetics of Tesofensine.
[0086] In comparison to Tesofensine, the M1 metabolite has a longer
T.sub.1/2 (see above) with a four- to five fold lower in vivo
potency on dopamine reuptake transporter inhibition, which argues
for the metabolite did not contribute significantly to
Tesofensine-induced locomotor activity. Also, the evidence that
Metoprolol completely prevented the locomotor stimulatory effect of
Tesofensine without affecting Tesofensine's efficacy on hypophagia
and body weight-reduction, indicates that the moderate increase
locomotor activity did not promote a rise in energy metabolism.
From these data we infer that locomotor effects had no influence on
the appetite suppressing and weight loss effects of Tesofensine. In
addition, it may be speculated that Metoprolol antagonized
Tesofensine-induced locomotor activity by indirect action on
striatal dopaminergic neurotransmission, as various .beta..sub.1
blockers are reported to inhibit rat striatal dopamine release.
[0087] The preclinical finding of cardiovascular effects of
Tesofensine in awake and freely moving rats is in accordance with
clinical findings, also showing significant dose-dependent
elevations in heart rate at lower dose levels than required to
raise diastolic and systolic blood pressure. Notably, the
cardiovascular effects outlasted the hypophagic effects following
acute administration of Tesofensine. Because Tesofensine and the M1
metabolite show equipotent inhibition of noradrenaline reuptake in
vitro, it is likely that the M1 metabolite contributed to the
cardiovascular effects of Tesofensine.
[0088] Because .beta..sub.1 adrenoceptor blockade by Metoprolol
co-administration fully prevented the cardiovascular effects of
Tesofensine, this strongly indicates that noradrenergic reuptake
inhibitory component of Tesofensine is far the most important
denominator for the cardiovascular adverse effects of
Tesofensine.
[0089] Whether Tesofensine would affect blood pressure and heart
rate differently in obese rats is not addressed in the present
report and must await further studies. It should also be noted that
the present observations are restricted to the acute effects of
Tesofensine, and do not exclude that the change in cardiovascular
parameters in telemetrized rats after chronic Tesofensine treatment
may closer mimic clinical findings. Also being in good agreement
with clinical and preclinical reports, Tesofensine produced a
strong hypophagic response with a corresponding body weight loss in
telemetrized rats. Using normal-weight rats fed with chow, the
efficacy and temporal pattern of Tesofensine-induced hypophagia and
weight reduction observed in the present study is in accordance
with similar findings in DIO rats, indicating that acute
anti-obesity effects of Tesofensine can also be studied in
telemetrized non-obese rats.
[0090] Overall, the experimental in vivo settings used in the
present study, allowing advanced synchronous monitoring of
cardiovascular and food intake parameters in real-time mode,
represent a rational and valid methodology for simultaneously
studying clinically relevant anti-obesity and vital sign effects of
anti-obesity drugs.
[0091] Interestingly, the present results suggest a different
pharmacodynamic profile of Tesofensine+.beta..sub.1 blocker
combinational therapy as compared with Sibutramine, a dual
serotonin and noradrenaline reuptake inhibitor. Sibutramine
exhibits a rather modest weight loss and significant elevates heart
rate and blood pressure in obese patients, which constitutes a
major concern in the clinical utility of Sibutramine.
[0092] A clinical study in obese hypertensive patients indicated
that Sibutramine treatment with combined Ca.sup.2+ channel
antagonist+ACE inhibitors or Metoprolol+hydrochlorothiazide
treatment, respectively, significantly attenuated Sibutramine's
anti-obesity effects. The latter combination most negatively
affected Sibutramine's weight-reducing efficacy which may be
explained by the common observation that .beta.-blockers can induce
weight gain per se.
[0093] In contrast, Metoprolol therapy did not significantly
interfere with Sibutramine's anti-obesity and metabolic effects in
a study on normotensive obese patients, leaving it so far
unresolved whether combined .beta..sub.1 blocker treatment is
feasible to reduce cardiovascular adverse effects of Sibutramine in
obese subjects. In this context, it should be noted that
anorexigenic effects of Sibutramine are believed to be closely
associated with stimulated .alpha..sub.1- and
.beta..sub.1-adrenoceptor function, as Sibutramine-induced
hypophagia is antagonized by Prazosin and Metoprolol,
respectively.
[0094] The implications from these studies may be that anti-obesity
drugs with noradrenergic activity will potentially have less
anti-obesity efficacy when combined with .beta.-blockers to
ameliorate any sympathetic cardiovascular effects. However, the
present study suggests that this may not be the case for
Tesofensine, because combined treatment with Metoprolol did not
affect the anti-obesity effects of Tesofensine. Hence, this
observation indicate a clear pharmacodynamic separation between two
distinct and important mechanisms of action of Tesofensine, namely
the anti-obesity effects associated with .beta..sub.1 adrenoceptor
stimulation and cardiovascular effects linked to augmented
.beta..sub.1 adrenoceptor function. The .beta..sub.1 adrenoceptor
effect of Tesofensine is suggested to be secondary to a blockade of
hypothalamic synaptic noradrenaline reuptake leading to inhibition
of intrahypothalamic appetite signaling circuits to evoke satiety
responses.
[0095] In contrast, it is most conceivable that the cardiovascular
effects of Tesofensine are being mediated via increased peripheral
noradrenergic tonus. Also being in contrast to Sibutramine, the
anorexigenic effect of Tesofensine requires stimulation of both
.beta..sub.1 adrenoceptor and dopamine D.sub.1 receptor function to
obtain full appetite-suppressing activity in DIO rats, hence
indirectly pointing to the possibility that Tesofensine treatment
leads to recruitment of dopaminergic neurotransmission. This is
relevant, as obese human subjects have indices of impaired central
dopaminergic activity thought to instigate overeating behavior to
compensate for a lowered hedonic drive.
[0096] In healthy human volunteers Tesofensine blocks the neuronal
dopamine uptake transporter (DAT) at doses causing weight loss in
obese individuals. This finding indicates that the dopamine
enhancing effect of tesofensine is involved in mediating the weight
reducing effect.
[0097] In conclusion, we demonstrate that combined Tesofensine and
Metoprolol treatment preserves Tesofensine's anti-obesity efficacy
while also preventing elevations in heart rate and blood pressure
in rats. These findings invite the possibility that combined
antihypertensive treatment with Tesofensine would also be effective
in obese patients.
* * * * *