Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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INTRAVENOUS CARNITINE FOR THE TREATMENT OF CHRONIC URAEMIC
PATIENTS UNDERGOING PERIODICAL DIALYSIS
The present invention relates to an improved
therapeutic method for the treatment of chronic uraemic
patients undergoing periodical dialysis.
Background of the invention
It is known that patients affected by chronic
uraemia, undergoing periodic dialysis, frequently develop a
clinical picture characterized by marked muscular asthenia
and a sensation of torpor, particularly evident immediately
following dialysis and which may often last even for several
hours, so making difficult, if not impossible, a full
resumption of working activity.
The clinical experts recognise this problem as
"post-dialytic syndrome".
A method for treating the post-dialytic syndrome
is disclosed in US 4,272,549, issued on June 9, 1981.
US 4,272,549 teaches to treat the "post-dialytic
syndrome" by compensating the loss of carnitine occurring
during dialytic session.
US 4,272,549 claims a method for alleviating
asthenia and muscle weakness in a chronic uraemic patient
under regular dialysis treatment, which comprises submitting
said patient with a polysaline dialytic solution which
contains a quantity of carnitine (intended as L-carnitine
throughout the present application), or a
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pharmaceutically acceptable salt thereof, sufficient to render the
molar concentration of carnitine in said solution at least equal to the
molar concentration of the plasma carnitine of the patient under
dialytic treatment. Preferred embodiments of the invention provides
that the concentration of carnitine in the dialytic solution is
substantially equimolar to the concentration of carnitine in the
patient's plasma, but a certain excess of carnitine is also provided,
for example between 50 and 100 mole per liter of solution. An
embodiment of the invention provides the administration of from 3
io to 6 grams of carnitine or an equivalent amount of a
pharmaceutically acceptable salt thereof. The preferred embodiment
of the invention provides the oral administration of carnitine, in
particular on days between haemodialysis of from 3 to 6 grams of
carnitine per day.
The oral treatment is coupled with a rather complex treatment
with carnitine during the dialytic session, which comprises the
administration of carnitine by slow infusion.
On the days of haemodialytic session, carnitine may also be
administered partly by the oral route and partly by slow infusion. In
this case, the overall quantity of carnitine administered shall not
exceed approximately 10 g.
"Slow infusion" stands for an infusion in which the solution
containing carnitine, or any of its pharmaceutically acceptable salts,
is administered at the rate of 20 to 40 drops per minute.
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Particularly favourable therapeutic results were achieved by a
method in which carnitine is administered by the oral route to the
patient under haemodialytic treatment only on those days during
which the patient is not submitted to a dialytic session, while during
the actual dialytic session, a dialysing liquid containing carnitine is
used.
Such preferred therapeutic method for the treatment of chronic
uraemic patients undergoing haemodialysis, included more
particularly the following steps:
1) on the days between one haemodialytic session and the
next, administration by the oral route to these patients of 3 to 6 g
per day of carnitine or any of its pharmaceutically acceptable salts;
2) on the days of haemodialytic session, submission of these
patients to dialysis using, as dialysing liquid, a solution containing a
quantity of carnitine or of any of its pharmaceutically acceptable
salts, sufficient to make a molar concentration of carnitine in the
said solution at least equal to the molar concentration of the plasma
carnitine of the patient under dialytic treatment.
By operating in such a manner, it is possible to avoid the loss
of plasma carnitine which otherwise takes place during a
haemodialytic session; the concentration of plasma carnitine
remaining practically unchanged during the dialytic session.
In this manner, it is possible to avoid the tissue carnitine
depletion, which is the long-term consequence of repeated losses of
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carnitine the patienl: undergoes during the successive dialytic
sessions he is submitted to over a prolonged period of time.
Although for this purpose it is shown to be sufficient that the
solution for the haemodialysis be equimolar in carnitine with respect
to the blood of the patient under dialytic treatment, it is preferred to
operate with a slightly more concentrated solution.
In practice, the haemodialysis solution contains 50 to 100,
preferably 60 - 80 moles/litre of carnitine or of any of its
pharmaceutically acceptable salts.
On the days of haemodialytic session, carnitine may also be
administered partly by the oral route and partly by slow infusion. In
this case, the overall quantity of carnitine administered shall not
exceed approximately 10 g.
The therapeutic method disclosed in US 4,272,549 is effective
in treating "post-dialysis syndrome", but presents a cumbersome
schedule of treatment. This fact makes some problems to occur. The
compliance of the patients, whose quality of life is already heavily
affected, about the necessity of taking care by themselves of the oral
self administration of a prescribed dosage of carnitine between the
2o dialytic sessions. There is also the problem of carnitine
bioavailability through the oral route, which is subject to saturation
mechanism and to some restrictions as to the absorption sites
(Harper at al. Eur. J. Clin. Pharmacol. 1988; 35(5):555-62 and
Matsuda Et Al. Biol Pharm. Bull 1998, Jul; 21 (7):752-5).
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Also, the oral administration of carnitine to a chronic uraemic
patient may give rise to the accumulation of toxic metabolites.
A recent work by Sloan et al. (Am. J. Kidney Dis. 1998, Aug;
32(2):265-72) demonstrated that oral supplementation of carnitine is
5 effective in improving the quality of life of patients in the early stage
of treatment, but the perceived effect was not sustained through
long term treatment (six months).
Summary of the invention
It has now been found in a totally unexpected manner an
io improved therapeutic method for the treatment of chronic uraemic
patients undergoing periodical dialysis.
The method for the treatment of chronic uraemic patients
undergoing periodical dialysis is useful for preventing and/or
treating carnitine deficiency in patients with end stage renal disease
who are undergoing dialysis.
The method according to the present invention comprises
administering an effective dose of carnitine intravenously into the
venous return line after each dialysis session.
As dialysis session both haemodialysis and peritoneal dialysis
zo are intended.
The method according to the present invention provides the
surprising improvement with respect to the method disclosed in US
4,272,549 to eliminate the need of the oral treatment, without
affecting the maintenance of the correction of carnitine deficiency
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obtained by the administration of carnitine through
intravenous route.
In one aspect, the invention provides use of from
to 20 mg/kg body weight of L-carnitine or a
5 pharmaceutically acceptable salt thereof in a venous return
line after a dialysis session for preventing or treating L-
carnitine deficiency in a chronic uraemic patient undergoing
periodic dialysis, wherein the use is repeated twice a week
every 44 hours and then after 68 hours, and wherein the use
10 is repeated after 3 to 4 weeks with 5 mg/kg of body weight
of L-carnitine as a maintenance dosage.
In a further aspect, the invention provides use of
L-carnitine or a pharmaceutically acceptable salt thereof in
a venous return line after a dialysis session for preventing
or treating L-carnitine deficiency in a chronic uraemic
patient undergoing periodic dialysis, wherein the amount of
L-carnitine or a pharmaceutically acceptable salt thereof is
effective to restore the blood level of L-carnitine in the
patient to at least a pre-dialytic level and thereafter
using a maintenance dosage of L-carnitine or a
pharmaceutically acceptable salt thereof in the venous
return line sufficient to maintain blood L-carnitine at the
pre-dialytic level.
In a still further aspect, the invention provides
use of L-carnitine or a pharmaceutically acceptable salt
thereof in a venous return line after a dialysis session for
preventing or treating L-carnitine deficiency in a chronic
uraemic patient undergoing periodic dialysis, wherein from
10 to 20 mg/kg of body weight of L-carnitine or a
pharmaceutically acceptable salt thereof, calculated as L-
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carnitine, is used to restore the blood level of L-carnitine
in the patient to at least a pre-dialytic level and
thereafter using a maintenance dosage of L-carnitine or a
pharmaceutically acceptable salt thereof sufficient to
maintain blood L-carnitine at the pre-dialytic level.
According to one aspect of the present invention,
there is provided use of L-carnitine or a pharmaceutically
acceptable salt thereof in a venous return line after a
dialysis session for preventing or treating L-carnitine
deficiency in a chronic uraemic patient undergoing periodic
dialysis, wherein the L-carnitine or the pharmaceutically
acceptable salt thereof is for administration in an amount
of 400 to 3000 mg and is for administration after each
dialysis session over a three or four week period three
times a week at 44 hour intervals followed by a delay of 68
hours before the next week's first session, and when the
three or four week period is over, the L-carnitine or the
pharmaceutically acceptable salt is for administration in an
amount of 200 to 750 mg as a maintenance dosage following
each dialysis session.
According to another aspect of the present
invention, there is provided use of L-carnitine or a
pharmaceutically acceptable salt thereof in a venous return
line after a dialysis session for preventing or treating L-
carnitine deficiency in a chronic uraemic patient undergoing
pericdic dialysis, wherein the L-carnitine or the
pharmaceutically acceptable salt thereof is for
administration in an amount effective for restoration of the
blood level of L-carnitine in the patient to at least a pre-
dialytic level and thereafter wherein the L-carnitine or the
pharmaceutically acceptable salt thereof is for
administration in an amount effective as a maintenance
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dosage of in the venous return line sufficient for
maintenance of blood L-carnitine at the pre-dialytic level.
According to still another aspect of the present
invention, there is provided use of L-carnitine or a
pharmaceutically acceptable salt thereof in a venous return
line after a dialysis session for preventing or treating L-
carnitine deficiency in a chronic uraemic patient undergoing
periodic dialysis, wherein from 400 to 3000 mg of the L-
carnitine or the pharmaceutically acceptable salt thereof,
calculated as L-carnitine, is for administration after the
dialysis session in restoration of blood level of L-
carnitine in the patient to at least a pre-dialytic level
and thereafter the L-carnitine or the pharmaceutically
acceptable salt thereof, calculated as L-carnitine, is for
administration as a maintenance dosage in an amount
sufficient for maintenance of blood L-carnitine at the pre-
dialytic level.
The invention shall be disclosed in detail, with
reference to Figures and Examples.
Brief description of the figures
Figure 1 illustrates the treatment schedule, where
the letters A-F denote the heart effluent sampling times for
the measurement of metabolites.
Figure 2 shows the effect of carnitine (A) and
carnitine fumarate (B) on creatine phosphate and ATP.
Figure 3 compares lactate (A) with succinate (B)
released by the heart, as measured in the effluent.
Figure 4 illustrates the release of malate.
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Figure 5 illustrates the release of LDH.
Figure 6 illustrates the production of lactate.
Detailed disclosure of the invention
The preferred starting dose is 10-20 mg/kg dry
body weight as a slow 2-3 minute bolus injection into the
venous return line after each dialysis session.
Initiation of the therapy may be prompted by
through (pre-dialysis) plasma carnitine concentrations that
are below normal (40-50 mol/L). Dose adjustments should be
guided by through (pre-dialysis) carnitine concentrations,
and downward dose adjustments
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(for example to 5 mg/kg after dialysis) may be made as early as the
third or fourth week of therapy.
Carnitine can be administered as inner salt or in any
pharmaceutically acceptable salts thereof.
In the above mentioned patents US 4272549 and US 4272549,
the invention is given in detailed manner as to put it into practice.
As far as carnitine is concerned, the active ingredient is mentioned
as "carnitine or any of its pharmaceutically acceptable salts" (see for
instance US 4272549, column 4, line 16), thus clearly teaching to
io the skilled person that any of the pharmaceutically acceptable salts
will do in the invention therein disclosed.
In the present invention we confirm that for the practice of the
improved method for the treatment of chronic uraemic patients
undergoing periodical dialysis, any of the pharmaceutically
acceptable salts of carnitine will do. But, in a particular embodiment
of the invention, the skilled person might have to face a problem
with some patients. During the dialytic session, some patients are
affected by hypervolemic heart, and this can give a severe outcome
as heart failure. Moreover, a number of patients undergoing
2o hemodialysis are affected by diabetes.
In a particular embodiment of the present invention, it has
been found that fumarate of L-carnitine exerts a surprising
beneficial effect on heart. Moreover, due to its physiologic role,
fumarate may have beneficial effects in diabetic patients.
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Accordingly, a particular embodiment of the present invention
relates to the method above disclosed, wherein fumarate is the
pharmaceutically acceptable salt of L-carnitine.
Suitable formulations of carnitine, or a pharmaceutically
acceptable salt thereof, are in the form of injectable compositions,
for example comprising an equivalent amount of carnitine of 200 mg
per 1 mL. A 2.5 or a 5 mL single dose ampoule may be convenient.
When a pharmaceutically acceptable salt of L-carnitine is used, such
as fumarate, the amount of active ingredient shall be calculated as
to to give an equivalent amount of L-carnitine as above specified.
Description of the preferred embodiment
Patients showing a pre-dialysis carnitine level equal or lower
than 40-50 M were treated with the method according to the
present invention with a 10-20 mg/kg dose of carnitine at the end of
the 4-hours dialytic session. According to a standard dialytic
schedule, the treatment was repeated twice a week every 44 hours,
then after 68 hours. This treatment was continued for 3-4 weeks,
monitoring pre-dialytic levels of carnitine. As a further embodiment
of the present invention, a maintenance method of treatment is
provided, giving, as a preferred example, a dose of 5 mg/kg of
carnitine.
The following table explains the preferred method for a 3-weeks
treatment:
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day of the week Dialysis Carnitine
administration
Monday X X
Tuesday
Wednesday X X
Thursday
Friday X X
Saturday
Sunday
Monday X X
Tuesday
Wednesday X X
Thursday
Friday X X
Saturday
Sunday
Monday X X
Tuesday
Wednesday X X
Thursday
Friday X X
Saturday
Sunday
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Wherein X shows a 4-hours dialytic session and the carnitine
intravenous administration according to the present invention at the
end of the session. 44 hours occur between two subsequent
carnitine administrations from Monday to Friday and 68 hours
5 occur between two subsequent carnitine administrations from
Friday to Monday.
As far as the particular embodiment of L-carnitine fumarate,
the following examples further illustrate the invention.
EXAMPLE 1
10 Effect of the administration of L-carnitine fumarate on the
perfused heart
In this example, the low-pressure or low-flow ischemia model
was used, which is a model recognised as valid for cardiac ischemia
(Bolukoglu, H. et al. Am. J. Physiol. 1996: 270; H817-26).
The treatment schedule is illustrated in Figure 1., in which the
letters A-F denote the heart effluent sampling times for the
measurement of metabolites. The hearts are removed from the
animals and mounted on a Langerdorff appliance. The perfusion
medium replacing the blood was a Krebs-Heinsleit standard
2o bicarbonate buffer containing glucose 12 mM as energy source for
cardiac metabolism.
After 30 minute perfusion at a pressure of 100 cm of water,
ischemia was induced by reducing the perfusion pressure of the
heart to 25 cm of water, thus reducing coronary flow from
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approximately 2 ml/min to approximately 0.3 ml/min. Reduction of
the perfusion pressure gives rise to ischemia, since the heart will
pump the fluid in the low-perfusion area rather than via the
coronary bloodstream, supplying the flow to the heart.
This control model was compared with hearts perfused with L-
carnitine 10 mM or L-carnitine fumarate 10 mM.
Cardiac function was tested in three different ways.
In the first, the NRM 31P signal was monitored in real time.
This signal provides the best indication of the energy status of
i o the heart.
In the second, the haemodynamics of the heart was measured
by means of a pressure transducer mounted to measure the
perfusion pressure. The haemodynamic measurements include heart
rate, relative dP/dt (measurement of the contraction force of the
is heart) and the cardiac contraction amplitude. Coronary flow was
also measured as an indicator of the heart's ability to provide oxygen
and energy for its own metabolism.
In the third type of test, the metabolites and the enzyme LDH
released by the heart were analysed in the effluent. The release of
2o LDH indicates damage to cardiac tissue. The release of metabolites
by the heart was tested by means of mass spectrometry coupled with
gas chromatography.
The results of the experiments show that the hearts treated
with carnitine fumarate have reduced release of LDH; the reserves of
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high-energy phosphai--e after 45 minutes of ischemia are greater in
treated hearts, as indicated by the increase in creatine phosphate
observed at NMR and the profile of the metabolites released
indicates that the treated heart generates less lactate, but more
malate. A high lactate level indicates intense anaerobic metabolism
and acidosis. The increase in malate indicates that fumarate is
metabolised by the heart to yield a system of intermediates of the
citric acid cycle favourable to the heart. Haemodynamic function, as
indicated by the postischemic cardiac contraction amplitude and by
1o coronary flow, is greater in hearts treated with carnitine fumarate.
EXAMPLE 2
The procedures of example 1 were substantially repeated, with
the addition of a treatment with carnitine alone as a further control.
The results are given in Figures 2-6, where:
Figure 2 illustrates the effect of carnitine (A) and carnitine
fumarate (B) on creatine phosphate and ATP. The data were
evaluated after 40 minutes of ischemia. CP indicates creatine
phosphate and a,(3 and y denote the phosphate peaks of ATP; as can
be seen in part (A) of the figure, the ATP peaks are lacking in the
2o absence of fumarate.
Figure 3 shows the comparison between lactate (A) and
succinate (B) released by the heart, as measured in the effluent. The
lactate reduction indicates the favourable effect of carnitine
fumarate. The low amount of succinate as compared to lactate
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indicates that the generation of ATP as a result of the reduction of
fumarate to succinate is not the main source of anaerobic ATP.
Figure 4 illustrates the release of malate. The greater malate
levels in the treated heart indicate that fumarate enters the cardiac
mitochondrion and is metabolised in the TCA cycle.
Figure 5 illustrates the release of LDH. The greater LDH levels
in controls indicate that carnitine fumarate affords protection
against ischemic damage.
Figure 6 illustrates lactate production.
