Note: Descriptions are shown in the official language in which they were submitted.
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WO 03/066045 PCT/EP03/00587
Description
Combination product of the sodium-hydrogen exchange inhibitor cariporide with
ACE
inhibitors for preventing heart faiiure and other age-related organ
dysfunctions, age-
related disorders and for prolonging life
The invention describes a combination of cariporide (Hoe 642), an inhibitor of
the
cellular sodium-hydrogen exchanger, the ACE inhibitor ramipril, and to the use
thereof
in human and veterinary medicine for preventing heart failure and other age-
related
functional disturbances and dysfunctional changes in organs of the body and
for
preventing age-related disorders and for prolonging life while preserving an
improved
quality of life.
WO 00/38661 describes the use of inhibitors of the sodium-hydrogen exchanger
(NHE)
for producing a medicament for preventing age-related organ dysfunction, age-
related
disorders and for prolonging life. In this case, inhibitors of the cellular
sodium-hydrogen
exchanger are described for the production of a medicament for preventing age-
related
functional disturbances and dysfunctional changes in organs of the body and
for
preventing age-related disorders and for prolonging life while preserving an
improved
quality of life. Typical representatives of NHE inhibitors which are mentioned
are
cariporides and their pharmaceutically acceptable salts, e.g. cariporide
mesilate having
the following formula:
CH3
H3C / ~ O
ii
H C-OS ~ N~ NH X H3C-S=O
s ~~ 2 OH
O O NHz
In the text which follows, the free base of cariporide and its
pharmaceutically
acceptable salts, including cariporide mesilate, are included in the term
cariporide.
WO 00138661 recorded the biological findings on normotensive healthy rats.
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Angiotensin converting enzyme (ACE) inhibitors, for example ramipril, have, in
contrast
to NHE inhibitors, no protective effect at all on the described pathological
age-related
organ changes in old normotensive rats. Furthermore, WO 00138661 considers
combination of NHE inhibitors, with medicaments which lower blood pressure,
sucf-r as
with ACE inhibitors, angiotensin receptor antagonists etc., in order to
utilize, in addition
to the protective effect of NHE inhibitors against ageing, the possible
benefit of a
lowering effect on blood pressure by hypotensive agents. An increase in a life-
prolonging effect or a protective effect on pathological age-related organ
changes was
not expected.
It has been known for some time from the literature that ramipril, having the
formula
~O O
N O
I O
\ ~ H H N , ~v . H
O
y
H
significantly prolongs the life span of spontaneously hypertensive rats which
is
shortened as a consequence of their hypertensive disorder.
It is now shown in the present experimental findings that NHE inhibitors, on
their own
and in combination with ACE inhibitors, likewise cause a significant life-
prolonging
effect and a protective effect on pathological age-related organ changes in
spontaneously hypertensive rats (SHR). In order to exclude a blood pressure-
lowering
effect by the ACE inhibitor ramipril as secondary effect for a possible
prolonging of life,
ramipril was used in a subthreshold dose in relation to lowering blood
pressure. There
were moreover, in a surprising way, significantly more favorable age-
protective effects
on combination treatment with the NHE inhibitor cariporide and the ACE
inhibitor
ramipril while there was no lowering effect on blood pressure. The combination
treatment is significantly superior to the two individual products.
A subthreshold dose, not lowering the blood pressure, of ramipril in rats is
normally in
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a range from 1 to 50 ~g per kg of body weight and per day. In humans, a
subthreshold
dose of ramipril on administration to a person with a body weight of about 70
kg is
generally in a range from 0.1 to 1.0 mg per day and person, preferably 0.3 to
0.7 mg
per day and person, for example 0.625 mg per day and person.
For the experiments, old spontaneously hypertensive rats (age = 18 months)
were
treated either with the NHE inhibitor cariporide, or with a subthreshold dose,
which did
not lower the blood pressure, of the ACE inhibitor ramipril or with a
corresponding
combination of the two active ingredients. This hypertensive rat model is
generally
regarded as representative for human essential hypertension. 27 hypertensive
rats 18
months old were employed for each experimental group. 3 months after the start
of
treatment, when the number of surviving animals in the placebo control group
was only
7, an interim analysis was carried out on 7 animals from each group. The
hearts of the
SHRs treated with low ramipril doses showed a significant reduction in the
force of
mycocardial contraction compared with the placebo control hearts. In contrast
to this,
cariporide and the ramipril/cariporide combination significantly improved the
function of
the heart.
Likewise, the myocardial fibrosis, which correlates with heart failure, was
significantly
reduced by cariporide monotherapy and by the ramipril/cariporide combination.
The
significantly smaller weights of the hearts likewise show the antifibrotic
effect, which is
directed against the development of heart failure, of the ramipril/cariporide
combination
and of cariporide.
The individual products ramipril and cariporide lead to an improvement in the
survival
rate compared with the placebo treatment. No significant differences in the
survival
rates with cariporide and ramipril were detectable in this case. Suprisingly,
the
cariporide/ramipril combination leads to a significant increase in the
survival rate
compared with the effects produced by the individual compounds.
Cariporide can thus be used according to the invention together with ramipril
in an
advantageous manner as pharmaceutical in animals, preferably in mammals, and
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especially in humans. The invention relates to the combination of cariporide
and
ramipril for use in human medicine and veterinary medicine, for example in
dogs. The
two active ingredients can be combined in such a way that cariporide and
ramipril are
administered together in one medicament (combination product) or that a
medicament
which comprises one active ingredient cariporide and a separate medicament
which
comprises ramipril are administered concurrently or successively in any
sequence.
Administration successively includes a combination in which the individual
medicaments are administered at different times and by different routes in
order to
achieve a better effect. However, it may also be expedient firstly to
administer a
suitable dose of one medicament and subsequently to administer the other
medicament, e.g. by infusion, until the desired combination effect, e.g.
improved heart
function, has occurred. Depending on the circumstances of the individual case,
it may
be more beneficial to administer cariporide and ramipril in the form of a
pharmaceutical
combination product in which the two active ingredients are present in a fixed
ratio of
amounts, or to administer them in the form of separate individual
pharmaceutical
products. In the latter case, in which the ratio of amounts of the two active
ingredients
can be varied, it is possible for the individual products to be present in
suitable primary
packaging and, where appropriate, together with instructions for use,
referring to the
use according to the invention, in a joint package, or for the individual
products where
appropriate to be present, each together with the instructions for use,
referring to the
use according to the invention, in separate packages. All such products and
presentations are encompassed by the present invention.
The ratio by weight of cariporide to ramipril in the combinations of the
invention is
normally in a range from 1:0.0001 to 1:1, preferably between 1:0.0001 and
1:0.1, for
example between 1:0.0005 and 1:0.01
The present invention further relates to pharmaceutical preparations which
comprise
as active ingredient both cariporide and ramipril in addition to conventional
pharmaceutically acceptable carriers and excipients. The pharmaceutical
preparations
normally comprise 0.01 to 90 percent by weight of cariporide and ramipril. The
pharmaceutical preparations can be produced in a manner known per se. For this
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purpose, the active ingredients are converted together with one or more solid
or liquid
pharmaceutical carriers and/or excipients into a suitable administration form
or dosage
form which can then be used as pharmaceutical in human medicine or veterinary
medicine. Corresponding statements apply tc pharmaceutical preparations
comprising
5 the active ingredients cariporide and ramipril separately and employed
according to the
invention.
Particularly claimed are cariporide and ramipril combination products for
inhibiting the
development of age-related disorders in human or veterinary medicine, for
inhibiting
the development of age-related organ damage, for prolonging life and/or for
preventing
or inhibiting further progression of heart failure and partial regression of
the disorder.
The present invention also relates to the use of cariporide and ramipril for
producing a
pharmaceutical preparation and to the use thereof as medicament for inhibiting
the
development of age-related disorders in human or veterinary medicine, for
inhibiting
the development of age-related organ damage, for prolonging life andlor for
preventing
or inhibiting further progression of heart failure and partial regression of
the disorder.
The dosage of the active ingredients cariporide andlor ramipril to be
administered
depends on the individual case and should be adapted to the circumstances of
the
individual case as usual for an optimal effect. Thus, it depends of course on
the
frequency of administration and on the nature of the pharmaceutical
formulations
employed in each case for therapy or prophylaxis, but also on the nature and
severity
of the disease to be treated, and on the sex, age, weight and individual
response of the
person or animal to be treated and on whether the therapy is acute or chronic
or the
aim is prophylaxis. On use of the inventions as pharmaceuticals in animals,
preferably
in mammals, and especially in humans, the dosage of ramipril may vary in the
range
from 0.1 to 10 mg per day and per person (with a body weight of about 70 kg),
preferably from 0.1 to 5 mg per day and person, particularly preferably from
0.2 to
2.5 mg per day and person. The ramipril dose may also be given in a
subthreshold
range from 0.1 to 1 mg per day and person, preferably from 0.3 to 0.7 mg per
day and
person. The dose of cariporide may vary between 50 mg and 1 g per day and
person,
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preferably between 100 to 500 mg per day and person. It is possible for
example for
the ramipril dose to be 0.625 mg per day and person and for the cariporide
dose to be
200 mg per day and person.
With the combination treatments of the invention it is possible for cariporide
and
ramipril to be administered in lower doses than on administration of only one
of the two
active ingredients.
With the combination treatment of the invention it is possible for the daily
dose of the
active ingredients to be administered all at once or for it to be divided into
a plurality of,
for example, two, three or four, administrations.
Pharmaceuticals which comprise cariporide and ramipril combinations of the
invention
can be administered orally, parenterally, e.g. intravenously, rectally,
transdermally or
topically, the preferred administration being dependent on the individual
case.
The excipients suitable for the desired pharmaceutical formulation are
familiar to the
skilled worker on the basis of his expert knowledge. Besides solvents, gel
formers,
suppository bases, tablet excipients and other active ingredient carriers, it
is possible
to use for example antioxidants, dispersants, emulsifiers, antifoams, masking
flavors,
preservatives, solubilizers, agents for achieving a depot effect, buffer
substances or
colors.
For a form for oral use, the active compounds are mixed with the additives
suitable for
this purpose, such as carriers, stabilizers or inert diluents, and converted
by
conventional methods into the suitable administration forms such as tablets,
coated
tablets, hard gelatin capsules, aqueous, alcoholic or oily solutions. Examples
of inert
carriers which can be used are gum arabic, magnesia, magnesium carbonate, .
potassium phosphate, lactose, glucose or starch, especially corn starch.
Preparation is
preferable both as dry and as wet granules. Examples of suitable oily carriers
or
solvents are vegetable or animal oils such as sunflower oil or fish liver oil.
Examples of
suitable solvents for aqueous or alcoholic solutions are water, ethanol or
sugar
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solutions or mixtures thereof. Examples of further excipients, also for other
administration forms, are polyethylene glycols and polypropylene glycols.
For subcutaneous or intravenous administration, the active compounds ara
converted,
if desired with the substances usual for this purpose, such as solubilizers,
emulsifiers
or further excipients, into a solution, suspension or emulsion. Examples of
suitable
solvents are water, physiological saline or alcohols, e.g. ethanol, propanol,
glycerol, as
well as sugar solutions such as glucose or mannitol solutions, or else
mixtures of the
various solvents mentioned.
Experimental data
The effect of a combination of ramipril and cariporide on the survival rate,
fibrosis and
the heart weights of rats with genetically related hypertension was
investigated.
For this purpose, old spontaneously hypertensive rats (age = 18 months) were
treated
either with the NHE inhibitor cariporide, or with a subthreshold dose, which
did not
lower the blood pressure, of the ACE inhibitor ramipril or with a
corresponding
combination of the two active ingredients. 27 hypertensive rats 18 months old
were
employed for each of the four treatment methods. 400 mg/kg of body weight of
cariporide were administered via the feed (0.6% cariporide in standard rat
diet) and
10 Ng/kg of body weight of ramipril were administered via the drinking water
as daily
dose. Three months after the start of treatment, when only n = 7 surviving
animals
remained in the placebo control group, an interim analysis was carried out
with n = 7
animals from each group. The treatment methods indicated above were applied
continuously from the 18th month for the remaining rats still surviving in
each group.
To demonstrate that the ramipril dose did not lower the blood pressure,
regular
measurements of the rats' blood pressure were carried out by the tail cuff
method, with
no significant differences being detectable in the four treatment groups.
Thus, 20 rats 18 months of age were employed for investigating the survival
rate for
each experiment group (Table 1 ). The results of observation are compiled in
Table 2.
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Group Treatment N
1 Placebo 20
2 Ramipril 20
3 Cariporide 20
4 Combination 20
Tab. 1: Experimental groups
Age Placebo CariporideRamipril Combination
(month)
18 20 20 20 20
19 10 18 18 20
20 4 16 15 18
21 0 12 11 18
22 0 8 9 18
23 0 7 4 16
24 0 7 0 14
25 0 5 0 13
26 0 0 0 8
27 0 0 0 7
28 0 0 0 3
29 0 0 0 0
Tab. 2: Number of surviving rats
An investigation of whether an improvement in the survival rate compared with
placebo
is detectable for the product groups, and whether an improvement in the
survival rate
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compared with the individual products is detectable for the combination
follows.
Descriptive analysis
Figure 1 shows the profile of the survival rate for all treatment groups in
detail. There
are evidently distinct differences between placebo and product groups on the
one hand
and between the individual products and the combination after the experiment
had
lasted only 3-4 months.
The combination treatment provided the best results throughout the
experimental
period. It is likewise evident that the placebo control was distinctly
inferior to all the
treatments.
Statistical analysis
Table 3 shows the results of all pairwise comparisons of respectively two
treatment
groups. The test results apply at a multiple significance level of 5%.
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Group vs. Group Test
Placebo Cariporide
Ramiprii
Combination
CombinationRamipril
Cariporide
Ramipril Cariporide n.s.
Tab. 3: Holm-adjusted log rank tests.
* indicates significant difference, n.s. = not significant
5 All the product groups are statistically significantly different from the
placebo group,
which can be interpreted together with figure 1 as efficacy of the treatments.
Figure 1
additionally reveals distinct advantages of the combination compared with the
individual products.
10 Median survival time
Table 4 shows estimates of the median dropout time, the time at which the
survival
rate in the population of experimental animals just reaches 50%.
Group Median 95% interval
Placebo 1.5 [1, 2)
Cariporide 4.0 [3, 7)
Ramipril 4.0 [3, 5)
Combination8.0 [6, 10)
Tab. 4: Median survival time
According to this, the proportion of surviving animals in the placebo group
has fallen to
50% after only 1.5 months, whereas this is not to be expected until after 8
months with
a combination treatment.
The individual products achieve a median survival time of 4 months which is
Less than
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half that of the combination product.
Statistical methods
The statistical analysis was carried out essentially using the SASISTAT
procedure
LIFETEST [SAS Institute Inc (1989): SASISTAT User's Guide, Version 6, 4th
Edition,
Volume 2; Cary, NC; SAS Institute Inc.]. The log rank tests were carried out
pairwise .
on respectively two experimental groups and adjusted to obtain a multiple
significance
level of 5% according to S. Holm (1979): A Simple Sequentially Rejective
Multiple Test
Procedure; Scand. J. Statist.; 6, pp. 65-70.
Conclusion on the survival rates
The individual products ramipril and cariporide lead to a statistically
significant
improvement in the survival rate compared with the placebo treatment. No
significant
differences in the survival rates with cariporide and ramipril were detectable
at the
chosen significance level. The combination treatment is significantly superior
to the two
individual products.
The chronic hypertension leads in the old spontaneously hypertensive animals
to
transformation processes in myocardial tissue which essentially correspond to
those
taking place in humans (In an early phase (months 10-15 of life) compensated
heart
failure with hypertrophy (NYHA stage I-II) and in the later phase (months16-21
of life)
decompensated heart failure with ventricular dilatation and fibrosis (NYHA
stage III-
IV)).
As mentioned above, an interim analysis with n = 7 animals from each group was
carried out 3 months after the start of treatment, when only n = 7 surviving
animals
remained in the placebo control group. Determinations were carried out inter
alia of the
total heart weight and the weights of the left and right ventricle and the
molar ratio of
hydroxyproline to ariginine in the heart tissue (determined by HPLC), which is
a marker
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12
of myocardial fibrosis. Interestingly, it was possible for a preexisting
fibrosis to be
reduced by late-onset treatment with cariporide, but not with ramipril and an
even
greater reduction in fibrosis was observed with the ramiprillcariporide
combination
(Fig. 2). These effects are also reflected in the weights ef the hearts (Fig.
3).
The captions and titles used in the drawings are as follows:
Fig. 1: Kaplan-Meier survival times
Y axis: survival rate (1 = 100%)
X axis: time in months from the start of treatment (start of treatment = 0,
identical to the
18th month of life)
Fig. 2: Effect of late treatment with cariporide and ramipril on myocardial
fibrosis in old
spontaneously hypertensive rats
Y axis: product groups
X axis: hyp/arg is the ratio of hydroxyproline to arginine and is regarded as
a fibrosis
marker
* means p < 0.05 vs placebo
n = 7 per group
Fig. 3: Effect of late treatment with cariporide and ramipril on the weight of
the hearts
of spontaneously hypertensive rats
Y axis: product groups
X axis: mg heart weight per 100 g body weight
CJ Complete heart
'~ Left ventricle
Right ventricle
* p < 0.05 vs placebo
n = 7 per group
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Summary of the results
The present results show that therapy with a combination of the NHE1 inhibitor
cariporide and ramipril has a life-prolonging effect and inhibits the
progression of or
partially reverses age-related organ damage, in particular heart failure even
with late-
onset therapy and/or hypertensive diseases.
