U.S. patent application number 10/480774 was filed with the patent office on 2004-08-12 for compositions based on amino acids for improving the myocardial ventricular function in patients suffering from diabetes.
Invention is credited to Conti, Franco, Dioguardi, Francesco Saverio.
Application Number | 20040157903 10/480774 |
Document ID | / |
Family ID | 11458964 |
Filed Date | 2004-08-12 |
United States Patent
Application |
20040157903 |
Kind Code |
A1 |
Conti, Franco ; et
al. |
August 12, 2004 |
Compositions based on amino acids for improving the myocardial
ventricular function in patients suffering from diabetes
Abstract
Compositions based on amino acids are described, for improving
the myocardial ventricular function in patients suffering from
diabetes, particularly but not exclusively II type diabetes. The
compositions according to the invention comprise up to 75% of the
branched chain amino acids leucine, isoleucine and valine, as
active ingredients. Preferably, the compositions also comprise, as
further active ingredients, up to 50% of threonine and lysine.
Other essential amino acids are preferably also provided, in
particular methionine, phenylalanine, histidine, tryphtophan, as
well as non essential amino acids, in particular tyrosine and/or
cyst(e)ine (i.e., cystine and cysteine). Other amino acids can be
added, provided that their sum is in a percentage being lower than
20% with respect to the other active ingredients, and less than 10%
for each single amino acid.
Inventors: |
Conti, Franco; (Milano,
IT) ; Dioguardi, Francesco Saverio; (Milano,
IT) |
Correspondence
Address: |
Sughrue Mion Zinn
Macpeak & Seas
2100 Pennsylvania Avenue NW
Washington
DC
20037-3202
US
|
Family ID: |
11458964 |
Appl. No.: |
10/480774 |
Filed: |
December 15, 2003 |
PCT Filed: |
June 10, 2002 |
PCT NO: |
PCT/IB02/02149 |
Current U.S.
Class: |
514/400 ;
514/419; 514/561; 514/562; 514/564 |
Current CPC
Class: |
A61K 31/198 20130101;
A61P 9/00 20180101; A61P 9/04 20180101; A61P 3/10 20180101; A61K
31/198 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/400 ;
514/419; 514/561; 514/564; 514/562 |
International
Class: |
A61K 031/4172; A61K
031/405; A61K 031/198 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 15, 2001 |
IT |
T02001A000580 |
Claims
1. Use of the branched chain amino acids leucine, isoleucine and
valine, in combination with threonine and lysine and one or more
other essential aminoacids selected in the group consisting of
methionine, phenylalanine, histidine and tryphtophan, as active
ingredients for the manufacture of compositions for improving the
myocardial ventricular function in patients suffering from
diabetes, particularly but not exclusively II type diabetes,
wherein the sum of the amounts in molecular weights of threonine
and lysine is greater than the sum of the amounts of said other
essential amino acids being provided, but lower than the sum of the
amounts of said branched chain amino acids.
2. Use, according to claim 1, wherein said branched chain amino
acids are present up to 75% of the amino acids or active
ingredients being provided, by expressing the value in molecular
weights.
3. Use, according to claim 1, wherein threonine plus lysine are
present up to 50% of the amino acids or active ingredients being
present, by expressing the value in molecular weights.
4. Use, according to claim 3, wherein methionine, phenylalanine,
histidine and tryphtophan are provided as further active
ingredients.
5. Use, according to claim 4, wherein tyrosine and/or cyst(e)ine
are provided as further active ingredients.
6. Use, according to at least one of the previous claims, wherein
the amounts in molecular weight of threonine and of lysine are each
greater than the single amounts of said other essential amino acids
being provided, but lower than the single amounts of said branched
chain amino acids.
7. Use, according to claim 5, wherein one or more further amino
acids are provided, the sum of which, in molecular weight, is in a
percentage lower than 20% with respect to the other active,
ingredients, and less than 10% for each single further amino
acid.
8. Use, according to claim 1, characterized in that leucine,
sioleucine and valine are in a stoichiometric ratio 2:1:1 among
them.
9. Compositions based on amino acids manufactured in accordance
with one or more of claims 1 to 8, for use as a medicament in the
improvement of the myocardial ventricular function in patients
suffering from diabetes, particularly but not exclusively II type
diabetes, characterized by comprising: from 40 to 60% of leucine in
molecular weight, from 20 to 40% of isoleucine in molecular weight,
from 20 to 40% of valine in molecular weight, the sum of the
amounts of the branched chain amino acids leucine, isoleucine and
valine being comprised between 30 to 60% of the sum in molecular
Weight of all the active ingredients being provided.
10. Compositions, according to claim 9, characterized by comprising
threonine plus lysine in a molar ratio (Mw/Mw) with said branched
chain amino acids between 20 and 50%, in particular with a
threonine to lysine ratio in which lysine is from 10 to 50% more
represented than threonine.
11. Compositions, according claim 9, characterized in that said
branched chain amino acids plus threonine and lysine are in a molar
ratio. (Mw/Mw) from 50 to 70% with histidine.
12. Compositions, according to claim 9, characterized in that
histidine is present in molar ratio (Mw/Mw) up to 50% of the
following amino acids: cyst(e)ine (i.e., cystine and cysteine) and
methionine, phenylalanine and tyrosine, tryphtophan.
13. Compositions, according to claim 12, characterized in that
cyst(e)ine is represented on a basis from 50 to 200% in molar ratio
(Mw/Mw) of the amount of methionine.
14. Compositions, according to claim 12, characterized in that
tyrosine is represented up to 50% of the molar-weight of
phenylalanine.
15. Compositions, according to claim 9, characterized by having a
pH in water solution comprised between 6.5 and 8.5, with or without
excipients suitable for the preparation of tablets, capsules,
powders, etc., in any pharmacological form suitable for oral or
parenteral use.
Description
[0001] The present invention refers to compositions based on amino
acids for improving the myocardial ventricular function in patients
suffering from diabetes, in particular II type diabetes.
[0002] Experimental studies carried out on patients of the
indicated type have shown, at myocardium level, a depression of the
energetic metabolism, a reduction of the synthesis velocity and an
increase of the proteins degradation. A general degradation of the
mechanical function of the cardiac muscle derives from the above,
whose main pathogenic mechanisms are the reduced availability of
energetic material and the presence of contractile proteins having
low ATPhase activity.
[0003] At present, no therapeutic approaches are known aimed at
producing a noticeable improvement of the ventricular myocardial
function in patients suffering from diabetes, in order to favorably
influence the natural story of said patients, by retarding or
preventing the appearance of cardiac insufficiency, which
represents the main cause of morbidity and mortality within said
population of patients.
[0004] The present invention has the aim of indicating an
absolutely innovative therapeutic approach to the above mentioned
problem.
[0005] Within this frame, a first aim of the invention is that of
indicating compositions capable of determining a noticeable
improvement of the myocardial ventricular function in patients
suffering from diabetes, particularly but not exclusively II type
diabetes.
[0006] A further aim of the invention is that of indicating
compositions capable of determining, in patients of the above type,
a noticeable increase of the ventricular ejection fraction, at rest
and at peak of the isometric exercise.
[0007] A further aim of the invention is that of indicating
compositions capable of eliminating the reduction of the
ventricular ejection fraction which, in patients suffering from
diabetes, occurs during isometric strain.
[0008] The inventors arrived at the formulation of compositions
based on amino acids, as per the enclosed claims which are an
integral part of the present description, which prove to be
particularly effective for the proposed purposes.
[0009] Said compositions, being provided either for oral and
parenteral use, are characterized by comprising, as main active
ingredients, the branched chain amino acids leucine, isoleucine and
valine, up to 75% of all the amino acids or active ingredients
being present, by expressing the value in molecular weights.
[0010] Preferably, the compositions according to the invention also
comprise, as further active ingredients, threonine and/or lysine,
where in particular threonine plus lysine are present up to 50% of
all the amino acids or active ingredients being present, by
expressing the value in molecular weights.
[0011] In case, the compositions can provide for, as further active
ingredients, other essential amino acids, in particular methionine
and/or phenylalanine and/or histidine and/or tryphtophan, and non
essential amino acids, in particular tyrosine and/or cyst(e)ine
(i.e. cystine and cysteine).
[0012] Preferably, the sum of the amounts expressed in molecular
weights of threonine and lysine is greater than the sum of the
single amounts of the other essential amino acids being provided,
but in any case lower than the sum of the single amounts of the
branched chain amino acids being provided. In addition, the amounts
expressed in molecular weight of threonine and of lysine can be
each greater than the single amounts of the other essential amino
acids being provided, but in any case lower than the single
quantities of the branched chain amino acids being provided.
[0013] The compositions according to the invention can also
comprise one or more further amino acids, with respect to those as
previously indicated, the sum of which, expressed in molecular
weight, is preferably lower than 20% with respect to the active
ingredients, and less than 10% for each single further amino
acid.
[0014] It should be noticed that, in general terms, a mixture of
amino acids particularly suitable for nutritional use in humans
should satisfy different requirements:
[0015] the pH of the solution of the mixture should be
substantially neutral, in order to prevent urinary calcium
losses;
[0016] the mixture should be safe, in respect to calcium balance
(i.e.: with no urinary losses) and homocyst(e)ine production (i.e.,
preferably related to the amount of all amino acids, a strictly
correct ratio of sulphur containing amino acids, with a ratio
cyst(e)ine/methionine of at least 2:1 on a stoichiometric
basis).
[0017] In addition, the content of essential amino acids in the
mixture should be preferably in an adequate ratio to fulfill real
human nutritional needs (and this can be optimized by the
co-operative adjunction of adequate and small ratios of some non
essential amino acids).
[0018] Within this frame, a preferred formulation of the
compositions according to the invention, comprising essential amino
acids (leucine, isoleucine, valine, threonine, lysine, methionine,
phenylalanine, histidine, tryphtophan) and some non essential amino
acids (tyrosine and cyst(e)ine), in different but fixed and
co-operative molar ratios among them, is the following one:
[0019] branched chain amino acids leucine (40-60% in molecular
weight), isoleucine (20-40% in molecular weight) and valine (20-40%
in molecular weight), preferentially in a stoichiometric ratio
2:1:1 among them, covering from 30 to 60% of the weight of the
whole mixture;
[0020] threonine plus lysine, preferably in a molar ratio with the
said branched chain amino acids between 20 and 50%, preferably in a
threonine to lysine ratio in which lysine is from 10 to 50% more
represented than threonine;
[0021] the above said branched chain amino acids plus threonine and
lysine, whose sum of the molecular weight is in a stoichiometric
ratio of 50 to 70% of a mixture also comprising histidine and other
amino acids, were histidine is present in molar fraction up to 50%
of the following amino acids:
[0022] cyst(e)ine (i.e., cystine and cysteine) and methionine, up
to 50% of histidine (the ratio between cyst(e)ine and methionine
should be preferably of 50 to 200% greater for cyst(e)ine in molar
ratio),
[0023] phenylalanine and tyrosine, in molar ratio up to 50% of
histidine (in which tyrosine is preferably represented up to 50% of
the molar weight of phenylalanine),
[0024] tryphtophan, up to 10% of the weight of all the other amino
acids, on a molar weight basis.
[0025] It has to be noticed that any other amino acid can be added
to the above formulation, without altering the expected effects,
provided that the sum of the additional amino acids is in a
percentage lower than 20% with respect to the other active
ingredients (less that 10% for each single amino acid).
[0026] It should also be noticed that a significant characteristic
of the above said formulation is that of having a pH in water
solution comprised between 6.5 and 8.5, and therefore suitable for
a safe oral or parenteral use, in humans or animals, according to
needs. This feature prevents the excessive calcium urinary losses
induced by protein sources of amino acids.
[0027] The effects of an amino acids mixture according to the above
suggested formulation were the subject of a comparative study.
[0028] To this purpose, 18 patients suffering from II type diabetes
mellitus were recruited (M/F 16/2, age 62.+-.6 years, body mass
index (BMI) 27.4.+-.3.0 kg/m.sup.2). The average duration of the
disease was 12.+-.8 years. Glycate haemoglobin was 8.2.+-.0.8%.
After the basal evaluation, patients were randomized at the
treatment with a composition of amino acids according to the above
said preferred formulation of the invention (12 g/die) or with
placebo, for a period of 3 weeks. The treatment was subsequently
exchanged and maintained for a further period of 3 weeks.
[0029] The analyzed main metabolic parameters were: glycaemia,
insulinemia, C-peptide, free fatty acids (FFA), total and
fractioned cholesterol, triglycerids and fibrinogen.
[0030] The left ventricular function was evaluated by means of 2D
echocardiography, using a Hewlett-Packard Sonon 5500 system, with
dedicated program for the execution of echo-stress methodologies
and the quantification of ventricular images. The echocardiographic
studies were encoded and blind analyzed, by two independent
observers, without knowing the identity of the patient and the
experimental condition. The echocardiographic analysis was carried
out using a digital cine-loop method (Prevue System, Nova
Microsonics Inc.). The ventricular volumes were calculated, in the
various experimental conditions, with a biplane area-length method,
from which the ejection fraction (EF) was derived as index of
ventricular pump function: EF=VTD-VTS/VTD, wherein VTD and VTS
represent the telediastolic and telesistolic volume of the left
ventricle, respectively.
[0031] The parietal contractile function was evaluated by analyzing
the myocardium sistolic thickening, in each segment obtained by
subdividing the left ventricle into 16 segments (according to the
American Society of Echocardiography standards) and by using a
semiquantitative score system (1=normal, 2=hypocinesia, 3=akinesia,
4=dyscinesia).
[0032] The general and regional ventricular function was studied at
rest conditions and during isometric strain through hand-grip
test.
[0033] After having determined the maximal voluntary contraction by
means of a dynamometer, an isometric strain at 40% was carried out
for 3 minutes. During strain, ventricular function was monitored by
2D echocardiography and the arterial pressure was monitored through
a continuous oscillometric method (Nippon Colin Co. Ltd).
[0034] The results of the study are expressed as mean.+-.SD. The
multiple comparisons were carried out by means of the two-way
variance analysis for repeated measures, followed by the Fisher's
test. A two-tailed value .ltoreq.0.05 as been considered as a
significant one.
[0035] None of the metabolic parameters was significantly modified,
neither by the treatment with the amino acids mixture according to
the invention, nor by the administration of placebo.
[0036] As it is apparent from Table 1 which follows, the treatment
with the mixture according to the invention did not brought to
significant variations, concerning glycaemia at fast, insulinemia
and sensitivity to insulin considered through the insulin tolerance
test technique.
[0037] Also concerning lipidic metabolism, no variations were
observed in relation to total cholesterol, HDL, triglycerids, free
fatty acids and Lp(a). In addition, no substantial modifications
occurred concerning both pressure values and body mass index.
1TABLE 1 Clinical characteristics of patients Placebo Invention P
Demography Age (years) 62 .+-. 6 Clinical characteristics Disease
duration (years) 10 .+-. 7 Body mass index (SD) (kg/m.sup.2) 27
.+-. 3 27 .+-. 3 n.s. Anti-hypertension treatment (%) 77% Sistolic
pressure (SD) (mm Hg) 151 .+-. 12 154 .+-. 17 n.s. Diastolic
pressure (SD) (mmHg) 84 .+-. 5 84 .+-. 6 n.s. HbA1c (SD) (%) 8.7
.+-. 1.7 8.6 .+-. 1.6 n.s. Insulinemia (SD) (.mu.m/ml) 14 .+-. 8 20
.+-. 15 n.s. Cholesterolemia (SD) (mg/dl) 225 .+-. 27 214 .+-. 24
n.s. HDL cholesterol (SD) (mg/dl) 47 .+-. 13 46 .+-. 15 n.s.
Triglyceridemia (SD) (mg/dl) 165 .+-. 91 115 .+-. 66 n.s. Free
fatty acids (SD) (.mu.mol/l) 699 .+-. 395 656 .+-. 370 n.s. Lp (a)
(SD) (mg/dl) 12 .+-. 10 13 .+-. 10 n.s. Proteinuria (mg/die) 40
.+-. 35 45 .+-. 29 n.s. Anti-diabetes therapy (D/ADO/ADO + I/I)
2/9/3/4
[0038] By analyzing the general ventricular function of the
patients being the subject of the study, it was possible to draw
the following conclusions:
[0039] 1) the treatment with the amino acids mixture according to
the invention does not modify, in a significant manner, the
ventricular dimensions (considered as telediastolic volume),
neither at rest (77.+-.24 vs. 78.+-.24 ml/m.sup.2, p=ns), nor at
the peak of the isometric strain (86.+-.26 vs. 88.+-.25 ml/m.sup.2,
p=ns). In addition, the same increment induced by the isometric
strain is maintained;
[0040] 2) during treatment with the amino acids mixture according
to the invention, the ejection fraction increases in a significant
manner, both at rest (58.+-.8 vs. 52.+-.12%, p=0.009) and at the
peak of the isometric strain (58.+-.10 vs. 43.+-.13, p=0.0001); it
is then particular interesting that
[0041] 3) the reduction of the ejection fraction during isometric
effort is abolished, with respect to the basal condition (p=0.188),
which is instead maintained during placebo (p<0.0001).
[0042] Upon analyzing the regional myocardial contractile function
of the patients, the following remarks are possible:
[0043] the administration of the amino acids mixture according to
the invention determines a reduction of the extension of the
regional contractile dysfunction at rest (considered as wall motion
score index, WMSI) (1.32.+-.0.42 vs. 1.26.+-.0.41, p=0.005);
[0044] the isometric strain causes an extension of the regional
contractile dysfunction independently of the type of treatment, but
the extension of the contractile dysfunction at the strain peak is
smaller during the treatment with the amino acids mixture according
to the invention (1.49.+-.0.45 vs. 1.29.+-.0.41, p<0.05).
[0045] It results clear from the above that the oral administration
of the amino acids mixture according to the invention determines
remarkable variations of the myocardial and ventricular function in
diabetes patients, in particular II type diabetes.
[0046] Said administration has in fact positively influenced the
left ventricular myocardial function, both at rest and during
isometric strain. The fact is particularly interesting that said
administration prevents the depression of the function caused by
isometric strain which characterizes diabetes patients.
[0047] The above data also highlight a positive action on
myocardial inotropism and contractile recruitment during conditions
of increased load (such as during hand grip characterized by an
acute increase of the postload). This effect can be the result of
the combined action of an improvement of the energetic metabolism
and an inversion of the shift of the synthesis of contractile
proteins to the production of fast ATPhase activity elements.
[0048] The results deriving from the study of the regional
contractile function also highlight a reduction of the extension of
the reversible chronic contractile dysfunction, which is a sign of
a favorable influence on hibernating myocardium.
[0049] Finally, the administration of the amino acids mixture
according to the invention reduces the further extension of the
contractile dysfunction induced by acute ischemia during isometric
strain.
[0050] From the given description the features of the present
invention are clear, as well as its advantages. In particular, the
oral administration of the described mixture of amino acids
positively influences the myocardial ventricular function of
patients suffering from diabetes, in particular II type diabetes.
The positive influence is evident either at rest and during the
acute overload imposed by an isometric strain during hand-grip, and
also on the parietal contractile function, by means of a reduction
of the extension of myocardial hibernation phenomena and of the
extension of the contractile dysfunction induced by acute ischemia
during isometric strain.
[0051] It results therefore clear that the proposed treatment with
amino acids allows for favorably influencing the natural story of
diabetic patients, by retarding or preventing the appearance of
cardiac insufficiency, which represents the main cause of morbidity
and mortality within said population of patients.
* * * * *