WO1997032593A2

WO1997032593A2 - Composition containing iso-flavonoids and lignans

Info

Publication number: WO1997032593A2
Application number: PCT/GB1997/000622
Authority: WO
Inventors: Michael Stafford Morton; Keith Griffiths; Carl Herman Thomas Adlercreutz
Original assignee: Energiser Plc
Priority date: 1996-03-08
Filing date: 1997-03-10
Publication date: 1997-09-12
Also published as: WO1997032593A3; AU2100997A

Abstract

There is provided a composition and method of treatment useful to combat disease states, such as cancer, especially before such disease states are clinically detectable or alternatively when they are less advanced. The composition is capable of elevating the levels of iso-flavonoids (e.g. genistein) and lignans (e.g. enterolactone) in the body to therapeutically useful levels. Conveniently the composition of the present invention is presented in the form of a foodstuff, conveniently in the form of a biscuit or 'cookie' and contains a soya component, together with a flaxseed component and/or a rye component.

Description

COMPOSITION CONTAINING ISO-FLAVONOIDS AND LIGNANS

The present invention relates to a composition and method of treatment useful to combat disease states, such as cancer, especially before such disease states are clinically detectable or alternatively when they are less advanced.

It has been noted that significant variations in specific types of disease states, notably certain cancers, occur throughout the world on a geographical basis. One possible explanation for such variation may be the presence of dietary factors which contribute to, or help prevent, particular forms of disease and it has been suggested that up to 70% of cancer deaths may be attributed to dietary factors. However, to date, no firm conclusions regarding the effect of diet has been made and much of the evidence remains contradictory.

It is probably well accepted that epidemiological research in relation to diet has, indeed, produced some contradictory, possibly inconclusive results, but it must also be recognized that there are inherent difficulties associated with such research with regard to the precise evaluation of dietary intake. The epidemiologist does not have available the more decisive animal methodology of the experimental researcher but, on the other hand, animal data cannot be readily extrapolated to the human without considerable caution. Although animal investigations, or the induction of cellular mutations in micro- organisms, can identify dangerous genotoxic substances, few such potential dietary carcinogens have been unequivocally proved to cause cancer in humans. It would certainly appear that epidemiological research has not, as yet, resolved whether fat, or some of the various fatty components of a diet, constitute a cancer risk. Such research has, however, had a significant role in directing attention to the relationship between cancer and diet and this has particularly evoked the interest of those concerned with intervention therapy or with chemopreventive approaches to health care.

In general terms, the "Western diet" has been considered to be one in which the fat consumption is high, whereas the "fibre" intake is low. In contrast, the proportion of the total calorific intake related to fat in the more vegetarian-style "Eastern diet" is comparatively low and the "fibre", and fruit and vegetable content of the diet is high, or high in relation to fat intake (see Yu et al, Int J. Epidemiol 127 : 42-49 (1988)). Predictably, therefore. Western diseases such as cancers of the breast and of the prostrate gland, and also colorectal carcinoma and cardiovascular disease, are associated with fat as a causative factor. Only relatively recently has it been recognized that constituents of the Eastern diet could possibly be protective against certain diseases and it is the lack of such constituents, rather than the high fat intake, that may be the important factor. It has now surprisingly been found that two components of the Eastern diet may have a very significant effect on the incidence of certain diseases.

The present invention provides a composition to combat cancer (especially breast cancer), benign prostatic hyperplasia, cardiovascular disease and post-menopausal symptoms, said composition being capable of elevating the levels of iso-flavonoids and lignans (eg enterolactone and/or enterodiol) in the body.

Thus, administration of the composition causes an increase in the amount of available iso-flavonoids and lignans, ie of iso-flavonoids and lignans circulating in the bloodstream.

By the term "iso-flavonoids " we refer to isoflavonic phyto-oestrogens .

Generally, the daily dosage of said composition is selected so that the levels of iso-flavonoids and lignans (eg enterolactone and/or enterodiol) are maintained at therapeutically useful concentrations. For example, the composition may provide a daily dosage of 10-50 mg iso-flavonoids, conveniently 20-30 mg iso- flavonoids. The composition may further provide a daily dosage of 2-5 mg lignans, conveniently 3-4 mg lignans.

The composition of the present invention may be used as a prophylactic (ie preventative) measure or may be used to treat, hinder or prevent existing cancer developments. In the latter case, the composition of the present invention maybe used in combination with other conventional treatments, such as radiotherapy for cancer etc. In a preferred aspect, the composition of the present invention is presented in the form of a foodstuff, conveniently in the form of a biscuit or "cookie". Generally the composition may contain a soya-based component and a flaxseed-based or rye-based component as major ingredients; since these components are capable of providing the iso-flavonoids and lignans (such as enterolactone and enterodiol) respectively. Additionally, it is preferred that the composition further contains rye bran, which in combination with the flaxseed or rye, and soya-based components is particularly efficacious. Alternative ingredients which are also good sources of iso-flavonoids may be used to replace the soya-based component, whilst alternative ingredients which are good sources of enterolactone may be used instead of the flaxseed-based component. Rye is preferred as a source of lignans. The foodstuff will normally also contain other ingredients to produce a palatable product.

As the composition is digested by the patient, after normal oral consumption thereof, the micro-flora in the gut of the patient breakdown or otherwise act upon the soya and flaxseed- or rye-based components, producing iso-flavonoids and lignans which are then absorbed and taken up into the bloodstream of the patient. Thus, the concentrations of iso-flavonoids and lignans in the patient's bloodstream is deliberately elevated.

Preferably, the composition contains 15% to 35% by weight of a soya based component (for example 20% to 30%, especially about 25% by weight), together with 8% to 16% by weight of a flaxseed based component (for example 11% to 13%, especially about 12% by weight) and /or 6% to 13% by weight of a rye based component (for example 8% to 10%, especially about 9% by weight). Optionally, the composition provides 20-30 mg iso- flavonoids (preferably substantially genistein and daidzein) and 3-4 mg lignans per day per patient.

A 25-30 g cookie made from ingredients including 8-10 g soya and a total of 4-8 g linseed flour and rye bran would provide the required amounts of iso-flavonoids and lignans .

Desirably, the composition of the present invention also contains a significant amount (for example 20-40% of the recommended daily intake, usually approximately 25% of the recommended daily intake) of fibre. In particular it is convenient that rye provides both the lignans required and also the fibre component.

The fibre content of the cookie would typically be rye or wheat bran. The bran is believed to prevent the reabsorption of oestrogen by the gut - lowering plasma oestrogens by hindering reabsorption by the enterohepatic circulation. Lower plasma oestrogen may be effective in preventing breast cancer development. There are also certain effects, on bile acid metabolism, considered favourable in preventing colon cancer.

With regard to health benefits, the concept relates to the marked differences in the incidence of breast and prostate cancer, clinical BPH (benign prostatic hyperplasia) and cardiovascular disease between the Asian countries where there is little incidence of these diseases, and the Western developed countries of Northern Europe and the USA, where these diseases are, except for BPH, principal killers.

There are marked differences in the levels of iso- flavonoids and lignans in urine and plasma, that relate to the prevalence of the different diseases. The composition essentially increases the levels of iso- flavonoids and lignans in the plasmas of Western people to those concentrations of both as measured in the plasma of Asian people and of lignans in vegetarians.

The composition could therefore favourably influence

a) the initiation and progression of breast cancer;

b) the development of clinical BPH with associated bladder outlet obstruction;

c) the progression of prostate cancer;

d) cardiovascular disease; and

e) postmenopausal symptoms and osteoporosis.

Generally, the preferred form of iso-flavonoid is genistein, but other iso-flavonoids may also be used. Mention may be made of daidzein, biochanin A and formonentein as being other iso-flavonoids of interest.

A combination of genistein and daidzein in the ratio of 0.3:0.7 to 0.7:0.3, especially 0.5-0.6:0.5-0.4 has been found to be effective.

The composition of the present invention has been found to have the following beneficial effects:

i) exercising "weak" anti-oestrogen effects similar to tamoxifen, a drug used in the management of breast cancer and as preventative therapy for women at risk of breast cancer. ii) eliciting weak 5 -reductase activity - (similar effect to finasteride/Proscar) restraining the conversion of testosterone to DHT, the active androgen in the prostate gland.

ϋi) weak aromatase inhibitor (like aminoglutethimide) - inhibiting oestrogen production of fatty tissues.

iv) weak inhibition of 17 J-hydroxysteroid dehydrogenase (the enzyme responsible for converting oestrone to oestradiol)

v) acting as a weak tyrosine kinase inhibitor.

vi) angiogenesis inhibitor (preventing blood vessels growing out to support tumour growth) .

In a further aspect, the present invention provides a method of combatting cancer in a human or non-human (preferably mammalian) animal body, said method comprising elevating the levels of iso-flavonoids and lignans (eg enterolactone and/or enterodiol) in said body.

In another aspect the present invention provides a method of relieving postmenopausal symptoms in a human or non-human (preferably mammalian) female animal body, said method comprising elevating the levels of iso- flavonoids and lignans (eg enterolactone and/or enterodiol) in said body.

Generally, the levels of iso-flavonoids and lignans (eg enterolactone) are elevated in situ in the body to therapeutically useful levels, by the administration of a suitable source, for example a sufficient quantity of alternative or in addition to rye as a source of lignans. Conveniently the iso-flavonoid and lignans (eg enterolactone and/or enterodiol) source(s) may be presented in the form of a foodstuff which is consumed by the patient.

The combination of elevated iso-flavonoid and lignans (eg enterolactone and/or enterodiol) levels has been found to be of particular benefit in combatting cancers, benign prostatic hyperplasia, cardiovascular disease and postmenopausal symptoms.

In a further aspect the present invention provides the use of soya-components as a source of iso-flavonoids in the manufacture of a medicament to combat cancer, benign prostatic hyperplasia, cardiovascular disease and postmenopausal symptoms.

The present invention also provides the use of rye and/or flaxseed components as a source of lignans (eg enterolactone and/or enterodiol) in the manufacture of a medicament to combat cancer, benign prostate hyperplasia, cardiovascular disease and post-menopausal symptoms .

The composition of embodiments of the present invention are set out in the Examples.

EXAMPLE 1 A cookie type composition was produced by blending the ingredients set out in the table below and cooking the blended product (for example 180-220°C for 20-40 minutes) . Conveniently, a batch of mixture may be made by multiplying the quantities of said ingredients, cooking the mixture in a suitable tray or container, and dividing the mixture into conveniently sized cookies.

EXAMPLE 2

A cookie type composition was produced by blending the ingredients set out in the table below and cooking the blended product (for example 180-220°C for 20-40 minutes) .

EXAMPLE 3

Ingredients g/bar

Soya Grits 7.19

Flax Seed 3.67

Rye Bran 2.22

Rolled Oats 2.17

Crisp Rice 1.49

Wheat Flakes 0.61

Corn Syrup 3.60

Light Brown Sugar 3.82

Diced Evaporated Apples 2.77

Natural Flavourings 0.06

Bar Weight 30.00

EXAMPLE 4

Ingredients g/bar

Soya Grits 10.21

Flax Seed 4.79

Rye Bran 3.67

Rolled Oats 1.12

Crisp Rice 0.80

Wheat Flakes 0.42

Corn Syrup 3.66

Light Brown Sugar 3.04

Diced Evaporated Apples 2.20

Natural Flavourings 0.09

Bar Weight 30.00 EXAMPLE 5

Ingredients g/bar

Soya Grits 7.58

Flax Seed 3.55

Rye Bran 3.60

Rolled Oats 1.34

Crisp Rice 1.34

Wheat Flakes 0.51

Corn Syrup 5.26

Light Brown Sugar 3.92

Diced Evaporated Apples 2.80

Natural Flavourings 0.10

Bar Weight 30.00

EXAMPLE 6

A cookie type composition was produced by blending the ingredients set out in the tableb below and cooking the blended product (for example 180-220°C for 20-40 minutes) .

Ingredients g/bar

Soya Grits 7.68

Flax Seed 3.60

Rye Bran 2.76

Rolled Oats 2.04

Crisp Rice 1.68

Wheat Flakes 0.84

Corn Syrup 5.52

Light Brown Sugar 4.32

42 DE Corn Syrup 2.40

Diced Evaporated Apples 1.44

Natural Flavourings 0.12

Bar Weight 30.00

EXAMPLE 7

Ingredients g/bar

Soya Grits 7.54

Flax Seed 4.68

Rye Bran 2.81

Rolled Oats 2.04

Crisp Rice 1.68

Wheat Flakes 0.61

Corn Syrup 5.33

Light Brown Sugar 3.56

Diced Evaporated Apples 1.67

Natural Flavourings 0.08

Bar Weight 30.00

EXAMPLE 8

Ingredients g/bar

Soya Grits 9.86

Flax Seed 3.62

Rye Bran 2.57

Rolled Oats 1.46

Crisp Rice 1.22

Wheat Flakes 0.51

Corn Syrup 5.31

Light Brown Sugar 4.09

Diced Evaporated Apples 1.16

Natural Flavourings 0.20

Bar Weight 30.00 EXAMPLE 9

The cookies of the present invention illustrated may have a nutritional content as set out below:

Claims

1- A composition to combat cancer, benign prostatic hyperplasia, cardiovascular disease and post- menopausal symptoms, said composition being capable of elevating the levels of iso-flavonoids and lignans in said body.

2. A composition as claimed in Claim 1 comprising a soya component, together with a flaxseed and/or a rye component.

3. A composition as claimed in Claim 2 comprising a soya component, a flaxseed component and a rye component.

4. A composition as claimed in either one of Claims 2 and 3 wherein said rye component is rye bran or rye grits.

5. A composition as claimed in any one of Claims 1 to 4 in the form of a cookie or biscuit.

6. A composition as claimed in any one of the preceding Claims comprising of from 15 to 35% by weight of a soya component, together with 8 to 16% by weight of a flaxseed component and/or 6 to 13% by weight of a rye component.

7. A composition as claimed in any one of the preceding Claims capable of elevating the level of enterolactone and/or enterodiol in said body.

8. A composition as claimed in any one of the preceding Claims capable of elevating the level of genistein and daidzein in said body.

9. A method of combatting cancer in a human or non- human animal body, said method comprising administering a composition as claimed in any one of Claims 1 to 8 and so elevating the levels of lignans and iso-flavonoids in said body.

10. A method of combatting post-menopausal symptoms in a human or non-human animal body, said method comprising administering a composition as claimed in any one of Claims 1 to 8 and so elevating the levels of lignans and iso-flavonoids in said body.