Note: Descriptions are shown in the official language in which they were submitted.
1314~29
,
Treatment of lipoprotein disorders associated with cholesterol
metabolism
1 This invention relates to the use of a lipid of the
blackcurrant in the treatment of lipoprotein disorders
associated with chol~sterol metabolism.
Lipids circulate in the blood in the form of lipopro-
teins soluble in aqueous medium which consist of a lipidic
nucleus of cholesterol esterified by fatty acids and tri-
glycerides surrounded by a layer of proteins, phospholipids
and free cholesterol. The arrangement of the various com-
ponents characterizes the type of lipoprotein. Numerous
epidemiological studies have demonstrated the preponderant
role played by the lipoproteins in the development of athero-
sclerosis.
In simple terms, it is known that certain lipoproteins,
known as low-density lipoproteins (LDL) , represent a cardio-
vascular risk factor because there is a positive correlationbetween their presence at high levels in the bloodstream and
atherosclerosis. By contrast, high-density lipoproteins
(HDL ) represent an anti-cardiovacular risk factor because
there is a negative correlation between their levels and the
disease. There is thus a ~good cholesterol~ transported by
the HDL which drain the cholesterol from the arterial wall
and return it to the liver where it is catabolized. By con-
trast, the LDL deposit the cholesterol on the arterial wall.
It is known that oils rich in polyunsaturated fatty
acids have the effect of reducing the total plasmatic chol-
esterol level (TC). However, studies have shown that the
fall in the TC is due either to a concomitant reduction in
the cholesterol of the LDL (CLDL) and the cholesterol of
the HDL (CHDL) or to a reduction in the CLDL with no modifi-
cation of the CHDL. According to D,Y. Horrobin et alin Lipids, Vol. 18, No. 8, pages 55~-561, this last case
13~4229
1 would be that of evening primrose oil.
We have surprisingly found that the administration of
blackcurrant seed oil produced a a reduction in the CLDL
while significantly increasing the CHDL.
Accordingly, the present invention relates to the use
of a lipid of the blackcurrant for preparing a dietetic or
pharmaceutical composition for the treatment of lipoprotein
disorder~ associated with cholesterol metabolism. - -
In the context of the invention, lipoprotein disorders
associated with cholesterol metabolism are understood to
include
- essen~;al hypercholesterolemia (type IIa) characterized
by a normal triglyceride level ~TG~, an increase in the TC
corresponding to an increase in the CLDL and to a reduction
in, or normal level of, the CHDL,
- mi~}ed hyperlipidemia (type IIb) characterized by an in-
crease in, or normal level of, the TG , an increase in, or
normal level of, the TC corresponding to an increase in the
CLDL and to a reduction in the CHDL,
dys-beta-lipoproteinemia (type III) characterized by an
increase in the TG and in the TC, the latter being dis-
tinctly less frequent than the other two,
- the anomaly corresponding to a low level of HDL.
In the context of the invention, lipid of the black-
currant is understood to be
- the oil of blackcurrant seeds (Ribes nigrum) obtained
by extraction from blackcurrant residues and refining, for
example as described in European patent 92 085 or European
patent application 137 862,
- a mixture of fatty acids emanating from the hydrolysis
or fractionation of blackcurrant seed oil and obtained, for
example, in accordance with European patent application no.
178 442 or in accordance with European patent application
no 271 747.
- a pharmaceutc;ally acceptable salt of the fatty acids
131~229
1 mentioned above,
- an oil obtained by re-esterification of such a mixture
of fatty acids with glycerol,
- a mixture of the lipids mentioned above.
The blackcurrant lipid may advantageously be protected
against oxidation by a liposoluble antioxidant, for example
ascorbyl palmitate, tocopherols or a mixture of such anti-
oxidants.
The dietetic compositions may be formulated as emul-
sions, for example sauces, mayonnaises or margarines.
The pharmaceutical compositions may be made up in
various forms according to the method of administration,
for example oral, enteral, rectal or parenteral. For exam-
ple, it is possible to prepare capsules, gelatin-coated
tablets, suppositories or syrups. In the case of enteral or
parenteral administration, the compositions are formulated
as physically and chemically stabilized, apyrogenic and
sterile solutions or emulsions.
The dose administered depends upon the type and serious-
ness of the anomaly to be treated. It may comprise from 1to 25 9 blackcurrant lipid and preferably from 2 to 5 g
blackcurrant oil daily in a single dose or preferably in
two to three separate doses.
The invention is illustrated by the following Example
in which the parts and percentages are by weight, unless
otherwise indicated.
Example
Experimental conditions
Patients having an initial TC level of more than 300
mg/dl are treated for 12 weeks with an average daily dose of
six gelatin capsules containing either 450 mg blackcurrant
seed oil ( BCO`) and 200 ppm (parts per million) ascorbyl pal-
mitate or 450 mg grapeseed oil (GS0) and 200 ppm ascorbyl
palmitate.
BCO consists of triglycerides of the following fatty
131~229
-- 4 --
1 acids (by weight):
linoleic acid~ C18 2~n-
~
5 gamma-linolenic acid, C18 3,n 6
with 38% in the beta-position
alpha-linolenic acid, C18 3 n-3 13%
with 17% ;n the beta-position
3.5%
stearidonic acid~ C18:4,n-3
with 32% in the beta-position
Gamma-linolenic acid is the reaction product of delta-6-
desaturase with linoleic acid.
Stearidonic acid is the reaction product of delta-6-
desaturase with alpha-linolenic acid.
GS0 contains approximately 70% by weight linoleic acid,
1 to 2% by weight alpha-linolenic acid, but no gamma-
linolenic acid or stearidonic acid.
All the patients were given an information sheet of
dietetic recommendations.
The group receiving the ~c6 consisted of 5 patients
comprising 3 femalesand 2 males with an average age of 61
years (from 36 to 76). The group receiving the GS0 consisted
of 7 patients, 4 females and 3 males, with an average
age of 55 years (from 48 to 62). In the two groups, the initial
TC was similar. In the two groups, the majority of patients
were of the IIb type defined above.
Blood samples were taken at intervals of 0, 4, 8 and 12
weeks for analysis of the parameters.
Results
Table 1 below shows the mean values of the parameters
indicated (X) and the s~andard deviations (SD) for each
visit and the probability of the statistical ~est (T test)
13~4229
1 for the two groups. The T test provides an answer to the
question: is there any difference between the means of the
groups studied and that for each visit? The significant
cases (probability < 0.05) are underlined.
The TC (mg/dl) is measured enzymatically from the serum
by colorimetry using the enzymes cholesterolesterase, chol-
esteroloxidase and the indicator 4-aminophenazine.
The CHDL (mg/dl) is measured in the same way as the TC
on the fraction containing the HDL collected after ultra-
cen~rifugation of the serum at 12,000 r.p.m.
The CLDL (mg/dl) is deduced from the value of the
CHDL in accordance with Friedewald and Fredrickson.
131422~
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1314229
-- 7 --
1 Table 2 relates to the probabilities of the paired
T tests between the visits V4. Y8, V12 and O
of these statistical tests is to find the differences between
the visit VO and the successive visits V4, V8 and V12 for
S each group taken separately, i.e. the evolution of the phen-
omenon as a function of time. Once again the significant
cases are underlined (probability < 0.05).
1314229
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131~22~
1 Table 3 below studies the CLDL ratio known as the
~standard atherogenicity risk" and the probabilities
of the T test. Table 4 below shows the probabilities of the
paired T tests. The significant cases are underlined.
Table 3
Groups ,, CLDL/CHDL
''n 0 4 8 12
==================~========================================
X ',5 6.34 5.63 4.24 3.48
BCO ,,
SD ,,5 0.44 0.95 0.34 0.38
,, .
X ',7 6.86 6.97 6.35 6.93
15 GS0 ll
S~ ',7 0.45 0.42 0.49 0.56
Probab;lity " 0.445 0.184 0.010 0.010
Table 4
BCO group
Between visits '' V4-Vo V8-VO V12 VO
==================~================================
Probability''n=5 0.259 <0.001 <0.001
ll
GS0 group
Probab;lityn=7 0.298 0.155 0.740
Conclusions
In the BCO group, the mean of the CHDL increased dis-
tinctly (+43.5%), the means of the CLDL and the TC decreased
~-23.5% and -15.6%, respectively) and the mean of the stand-
ard atherogenicity risk factor decreased from 6.34 to 3.48
` 1314229
- 10 -
1 during the treatment.
By comparison, the corresponding values of the GSO
group were:
CHDL (-3.2%), CLDL (-1.9%), TC (-3.5~)
The mean of the standard atherogenicity risk factor
showed hardly any change (from 6.86 to 6.93).
It can thus be seen that the administration of BCO
leads to a reduction in the TC due solely to a decrease in
the CLDL without participation of the CHDL which, by con-
trast, increases substantially. The standard atherogenicity
risk thus decreases considerably.
By contrast, the administration of GSO produces no
improvement in the pathological state of the patients.
