IE882989L

IE882989L - Treatment of lipoprotein disorders

Info

Publication number: IE882989L
Application number: IE882989A
Authority: IE
Inventors: Manfred Berger; Daniele Spielmann; Helmut Traitler
Original assignee: Nestle Sa
Priority date: 1987-10-16
Filing date: 1988-10-03
Publication date: 1989-04-16
Also published as: DE3868827D1; CH673223A5; CA1314229C; AU2343388A; EP0311866A1; AU611204B2; GR3003990T3; JPH075471B2; IE61682B1; EP0311866B1; JPH01132530A; ATE72987T1; ES2036650T3

Abstract

Blackcurrant seed oil has been found particularly effective in the treatment of lipoprotein anomalies linked to cholesterol metabolism. Its administration makes it possible to increase significantly the cholesterol in high-density lipoproteins while reducing cholesterol in low-density lipoproteins, and thus reduces the cardiovascular risk.

Description

61 6 8 2 This invention relates to the use of a lipid of the blackcurrant in the treatment of lipoprotein disorders associated with cholesterol metabolism.

Lipids circulate in the blood in the form of lipopro-5 teins soluble in aqueous medium which consist of a lipidic nucleus of cholesterol esterified by fatty acids and triglycerides surrounded by a layer of proteins* phospholipids and free cholesterol«. The arrangement of the various components characterizes the type of lipoprotein. Numerous 10 epidemiological studies have demonstrated the preponderant role played by the lipoproteins in the development of atherosclerosis.

In simple terms, it is known that certain !lipoproteins, known as low-density lipoproteins (LDL) , represent a cardio-15 vascular risk factor because there is a positive correlation between their presence at high levels in the bloodstream and atherosclerosis- By contrast, high-density 1 apoproteins (HDL.) represent an anti-cardiovacular risk factor because there is a negative correlation between their levels and the 20 disease. There is thus a "good cholesterol6' transported by the HDL which drain the cholesterol from the arterial wall and return it to the liver where it is catabolized. By contrast , the LDL deposit the cholesterol on the arterial wall.

It is known that oils rich in polyunsaturated fatty 25 acids have the effect of reducing the total plasmatic cholesterol level (7C) 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 CIDL with no modifi-30 cation of the CHDL. According to D.V- Horrobin et al in Lipidss Vol. 18, No. 8, pages. 538-561» this last case - z - v*ould 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. 5 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 disorders associated with cholesterol metabolism.

In the context of the invention», lipoprotein disorders 10 associated with cholesterol metabolism are understood to include.:. essential hypercholesterolemia (type 11a) characterized by a normal triglyceride level (TG), an increase in the TC corresponding to an increase in the CLDL and to a reduction 15 in, or normal level of, the CHDL., - mixed hyperlipidemia (type lib) characterised by an increase 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, 20 - dys-beta-lipoprotei nemia (type III) characterized by an increase in the T6 and in the TC, the latter being distinctly 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-25 currant is understood to be the oil of blackcurrant seeds (Ribas 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 oi1 and obtained, for example, in accordance with European patent application no. 178 442 or in accordance with European patent application no 271 747. . 7 a pharmaceutcially acceptable salt of the fatty acids mentioned above* an oil obtained by re-ester ification of such a mixture of fatty acids with glycerol, a mixture of the lipids mentioned above. 5 The blackcurrant lipid may advantageously be protected against oxidation by a liposoluble antioxidant, for example ascorby 1 pa Imitates, tocopherols or a mixture of such ant i -oxidants.

The dietetic compositions may be formulated as emul-10 sions9 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* enterals rectal or parenteral. For examples, it is possible to prepare capsules., gelatin-coated 15 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-20 ness of the anomaly to be treated. It may comprise from I to 25 g 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 25 in which the parts and percentages are by weights unless otherwise indicated.

Example Experimental conditions Patients having an initial TC level of more than 300 30 mg/dl are treated for 12 weeks with an average daily dose of six gelatin capsules containing either 450 mg blackcurrant seed oil ( BCO'J and 200 ppm (parts per minion) ascorby 1 pal-mitate or 450 mg grapeseed oil (GS0) and 200 ppm ascorby! . palmitate.

BCO consists of triglycerides of the following fatty acids (by weight): linoleic acid, C, Q.9 ^ s 45% a W a t j n ™ o gamma-linolenic acid, 3 n_g 17% with 38% in the beta-position alpha-1inolenic acid, Cjg.3 n„3 13% with 11% in the beta-position 10 3.5X stearidonic acid ? Cjg.^ n_3 3.5% with 32% in the beta-position Gamma-linolenic acid is the reaction product of delta-6-15 desaturase with linoleic acid.

Stearidonic acid is the reaction product"of delta-6-desaturase with alpha-1inolenic acid.

GSO contains approximately 70% by weight linoleic acids, 1 to 2% by weight alpha-1 inolenic acid9 but no gamma-20 1inolenic acid or stearidonic acid.

All the patients were given an information sheet of dietetic recommendations.

The group receiving the bco consisted of 5 patients comprising 3 females and 2 males with an average age of 61 25 years (from 36 to 76). The group receiving the GSO 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 lib type defined above.

Blood samples were taken at intervals of 09 4, 8 and 12 weeks for analysis of the parameters.

Resu Its Table 1 below shows the mean values of the parameters indicated (X) and the standard deviations (SD) for each 35 visit and the probability of the statistical test (T test) - 5 ~ for the two groups. The T test provides an answer to ths 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-10 centrifugal ion 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.

Table i GROUPS « CI » ii ti n i! 0 4 8 12 ?! 0 iL X 5H 309,20 293.40 279,20 261,00« 42,80 31 I' BCO •SD 51] 4,49 3,94 6,27 9.57 " 1,91 GSO SD 7. ) t 7 i 304,43 295.00 298.43 293.71 4,63 7,12 6,27 9,57 40,86 1,91 Probabi11ty 0,492 0,865 0,079 0,033 » 0,526 CHDL 4 8 50,20 56.40 12 CLDL 4 8 12 260,00 234,20 206,60 12,30 14,21 17,82 2,04 1,92 61,40 ij 270,20 ii 1,43 Ij 13,73 39,71 42,71 39.57 jj 276,57 A 2,04 1,92 1,43 || 13,73 273,00 267,14 271,28 12,29 14,21 17,82 0,130 0.029 0,001 " 0,790 0,593 0,191 0.021 Table 2 relates to the probabilities of the paired T tests between the visits V^, Vg, V,9 and VQ. The object of these statistical tests is to find the differences between the visit ,V0 and the successive visits V^, Vg and Vjg for each group taken separately,, i.e. the evolution of the phenomenon as a function of time. Once again the significant cases are underlined (probabi1ity < 0.05).

Table 2 bco GROUP Parameters 1 1 1 TC ti ii ii CHDL t! I] n CLDL e Between visits j I y .-v 4 o VVo ii V . - - V 11 12 q; 4 0 Vn-V 8 o V _ V II 12 o» V, - V 4 o Vvo V12-Vo Probabi 11ty n = 5 | i 0.003 0.040 o.oio!! II 0, 233 0,025 o © o o 1 0. 0 6 5 0, 0IS 0.002 00 GSO GROUP Probabi 11ty II II II 0.045 0=219 ii ii 0. 143 I! 0,030 0,408 0.233 !! 0.303 0,028 0.393 Table 3 below studies the ratio known as the CHDL "standard atherogemcity 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 II ;;n 0 4 8 12 II BCO » „ GSO " » X ii 5 6.34 5.63 4.24 3.48 SD Ss 0.44 Q„95 0.34 0.38 X J! 7 6.86 6. 97 6.35 6.93 II II SD ',17 0.45 0.42 0.49 0.56 Probability " 0.445 0.184 0.010 0.010 BCO group Table 4 Between visits " V4~V0 V8"Vo V|9~V0 Probability ;jn=5 0.259 <0.001 <0.001 II II GSO group Probability n=7 0.298 0.155 0.740 Conclusions .

In the bco group, the mean of the CHDL increased distinctly (+43.5%), the means of the CLDL and the TC decreased % (-23.5% and -15.6%, respectively) and the mean of the stand-35 ard atherogenicity risk factor decreased from 6.34 to 3.48 during the treatment.

By comparison,, the corresponding values of the GSO group were; CHDL (-3.2X), CLDL (-1.9&K TC (-3.5%) The njean 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-10 trast, increases substantially. The standard atherogenicity risk thus decreases considerably.

By contrasts the administration of GSO produces no improvement in the pathological state of the patients.

Claims

1. The use of a lipid of the blackcurrant for the preparation of a dietetic composition for the treatment of lipoprotein disorders associated with cholesterol metabolism.

2. The use of a lipid of the blackcurrant for the preparation of a pharmaceutical composition for the treatment of lipoprotein disorders associated with cholesterol metabolism.

3. The use claimed in claim 1 in a form suitable for oral, enteral or parenteral administration.

4. The use claimed in claim 2 in a form suitable for oral, rectal, enteral or parenteral administration.

5. The use claimed in claim 1 or 2 in a form providing a daily dose of 1 to 25 g blackcurrant lipid.

6.„ The use claimed in claim 5 in a form providing a daily dose of 2 to 5 g blackcurrant oil.

7. Use of a lipid of the blackcurrant substantially as hereinbefore described by way of Example. Dated this 3rd day of October, 198

8. BYz TOMKINS & CO., \ ,. ' 1 I (Signed) DUBLIN 6.