U.S. patent application number 13/977168 was filed with the patent office on 2013-12-12 for combination of components for the prevention and treatment of frailty.
This patent application is currently assigned to N.V. NUTRICIA. The applicant listed for this patent is Mattheus Cornelis De Wilde, Martine Groenendijk, Robert Johan Joseph Hageman, Patrick Joseph Gerardus Hendrikus Kamphuis. Invention is credited to Mattheus Cornelis De Wilde, Martine Groenendijk, Robert Johan Joseph Hageman, Patrick Joseph Gerardus Hendrikus Kamphuis.
Application Number | 20130331352 13/977168 |
Document ID | / |
Family ID | 44510082 |
Filed Date | 2013-12-12 |
United States Patent
Application |
20130331352 |
Kind Code |
A1 |
Hageman; Robert Johan Joseph ;
et al. |
December 12, 2013 |
Combination of Components for the Prevention and Treatment of
Frailty
Abstract
Composition comprising at least two components, more preferably
at least three components, more preferably at least four
components, selected from the group of (i) a nucleoside equivalent,
(ii) an .omega.-3 polyunsaturated fatty acid selected from the
group of DHA, DPA and EPA, (iii) a vitamin B, (iv) a phospholipid,
(v) an antioxidant and (vi) a choline, with the proviso that at
least component (i) or (iii) is present, for use in the prevention
or treatment of frailty in a mammal, wherein frailty is determined
by compliance with at least 2 criterions, preferably 3 criterions,
selected from the group of muscle weakness, excessive feelings of
exhaustion or fatigue, abnormally low physical activity, slow or
unsteady gait, weight loss, and neurological dysfunction.
Inventors: |
Hageman; Robert Johan Joseph;
(Wageningen, NL) ; De Wilde; Mattheus Cornelis;
(Elst, NL) ; Groenendijk; Martine; (Barendrecht,
NL) ; Kamphuis; Patrick Joseph Gerardus Hendrikus;
(Utrecht, NL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Hageman; Robert Johan Joseph
De Wilde; Mattheus Cornelis
Groenendijk; Martine
Kamphuis; Patrick Joseph Gerardus Hendrikus |
Wageningen
Elst
Barendrecht
Utrecht |
|
NL
NL
NL
NL |
|
|
Assignee: |
N.V. NUTRICIA
Zoetermeer
NL
|
Family ID: |
44510082 |
Appl. No.: |
13/977168 |
Filed: |
December 28, 2011 |
PCT Filed: |
December 28, 2011 |
PCT NO: |
PCT/NL2011/050908 |
371 Date: |
August 29, 2013 |
Current U.S.
Class: |
514/51 |
Current CPC
Class: |
A61K 31/202 20130101;
A61P 25/28 20180101; A23V 2002/00 20130101; A61K 31/685 20130101;
A61K 31/355 20130101; A61K 31/519 20130101; A61K 31/683 20130101;
A61K 31/7072 20130101; A61K 45/06 20130101; A61K 31/14 20130101;
A23L 33/12 20160801; A23L 33/13 20160801; A61K 31/7056 20130101;
A61K 31/661 20130101; A61K 31/70 20130101; A61K 31/675 20130101;
A61K 31/20 20130101; A61K 31/7068 20130101; A61K 31/375 20130101;
A61K 33/04 20130101; A23L 33/15 20160801; A61K 31/4415 20130101;
C07H 19/052 20130101; C07H 19/06 20130101; A23L 33/40 20160801;
A61K 31/714 20130101; A61K 31/7072 20130101; A61K 2300/00 20130101;
A61K 31/202 20130101; A61K 2300/00 20130101; A61K 31/4415 20130101;
A61K 2300/00 20130101; A61K 31/714 20130101; A61K 2300/00 20130101;
A61K 31/519 20130101; A61K 2300/00 20130101; A61K 31/685 20130101;
A61K 2300/00 20130101; A61K 31/683 20130101; A61K 2300/00 20130101;
A61K 31/355 20130101; A61K 2300/00 20130101; A61K 31/375 20130101;
A61K 2300/00 20130101; A61K 31/14 20130101; A61K 2300/00 20130101;
A61K 33/04 20130101; A61K 2300/00 20130101; A23V 2002/00 20130101;
A23V 2200/316 20130101; A23V 2200/322 20130101; A23V 2250/1882
20130101; A23V 2250/304 20130101; A23V 2250/704 20130101; A23V
2002/00 20130101; A23V 2200/316 20130101; A23V 2200/316 20130101;
A23V 2200/322 20130101; A23V 2250/156 20130101; A23V 2250/1626
20130101; A23V 2250/1844 20130101; A23V 2250/1846 20130101; A23V
2250/1848 20130101; A23V 2250/185 20130101; A23V 2250/1852
20130101; A23V 2250/1868 20130101; A23V 2250/187 20130101; A23V
2250/304 20130101; A23V 2250/5424 20130101; A23V 2250/7052
20130101; A23V 2250/7058 20130101; A23V 2250/706 20130101; A23V
2002/00 20130101; A23V 2200/316 20130101; A23V 2200/316 20130101;
A23V 2200/322 20130101; A23V 2250/156 20130101; A23V 2250/1626
20130101; A23V 2250/1844 20130101; A23V 2250/1846 20130101; A23V
2250/1848 20130101; A23V 2250/185 20130101; A23V 2250/1852
20130101; A23V 2250/1868 20130101; A23V 2250/187 20130101; A23V
2250/308 20130101; A23V 2250/5424 20130101; A23V 2250/7052
20130101; A23V 2250/7058 20130101; A23V 2250/706 20130101 |
Class at
Publication: |
514/51 |
International
Class: |
A61K 31/7072 20060101
A61K031/7072; A61K 31/20 20060101 A61K031/20; A61K 31/14 20060101
A61K031/14; A61K 31/7056 20060101 A61K031/7056; A61K 31/661
20060101 A61K031/661 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 28, 2010 |
NL |
PCT/NL2010/050892 |
Aug 11, 2011 |
NL |
PCT/NL2011/050555 |
Aug 11, 2011 |
NL |
PCT/NL2011/050556 |
Claims
1. Nutritional or pharmaceutical composition comprising at least
two components selected from the group consisting of (i) a
nucleoside equivalent, (ii) an .omega.-3 polyunsaturated fatty acid
selected from the group consisting of DHA, DPA and EPA, (iii) a
vitamin B selected from the group consisting of vitamin B6, vitamin
B12 and vitamin B9, (iv) a phospholipid, (v) an antioxidant
selected from the group consisting of vitamin C, vitamin E and
selenium and (vi) a choline, with the proviso that at least
component (i) or (iii) is present.
2. (canceled)
3. (canceled)
4. (canceled)
5. (canceled)
6. (canceled)
7. (canceled)
8. (canceled)
9. (canceled)
10. (canceled)
11. Composition according to claim 1, wherein the composition
comprises UMP.
12. (canceled)
13. (canceled)
14. Composition according to claim 1, wherein the composition
comprises at least two different phospholipids selected from the
group consisting of phosphatidylserine, phosphatidylinositol,
phosphatidylcholine and phosphatidylethanolamine.
15. (canceled)
16. (canceled)
17. Composition according to claim 1, wherein the composition
comprises (i) UMP, (ii) DHA and EPA, (iii) vitamin B6, vitamin B12
and vitamin B9, (iv) at least two different phospholipids selected
from the group consisting of phosphatidylserine,
phosphatidylinositol, phosphatidylcholine and
phosphatidylethanolamine, (v) vitamin C, vitamin E and selenium and
(vi) choline chloride.
18. Composition comprising at least (i) a uridine equivalent, (ii)
an .omega.-3 polyunsaturated fatty acid selected from the group
consisting of DHA, DPA and EPA, (iii) a vitamin B, (iv) a
phospholipid, (v) an antioxidant selected from the group consisting
of vitamin C, vitamin E and selenium, and (vi) a choline.
19. Composition according to claim 1 being a nutritional
composition comprising at least a whey protein.
20. Composition according to claim 19, wherein the composition has
a nutritional value of at least 50 kcal per 100 ml.
21. A method of preventing or treating frailty in a mammal
comprising administering a composition comprising at least two
components selected from the group consisting of (i) a nucleoside
equivalent, (ii) an .omega.-3 polyunsaturated fatty acid selected
from the group consisting of DHA, DPA and EPA, (iii) a vitamin B,
(iv) a phospholipid, (v) an antioxidant and (vi) a choline, with
the proviso that at least component (i) or (iii) is present.
22. The method of claim 21 comprising administering the composition
comprising at least three components selected from the group
consisting of (i) a nucleoside equivalent, (ii) an .omega.-3
polyunsaturated fatty acid selected from the group consisting of
DHA, DPA and EPA, (iii) a vitamin B, (iv) a phospholipid, (v) an
antioxidant and (vi) a choline, with the proviso that at least
component (i) or (iii) is present.
23. The method of claim 21 comprising administering the composition
comprising at least four components selected from the group
consisting of (i) a nucleoside equivalent, (ii) an .omega.-3
polyunsaturated fatty acid selected from the group consisting of
DHA, DPA and EPA, (iii) a vitamin B, (iv) a phospholipid, (v) an
antioxidant and (vi) a choline, with the proviso that at least
component (i) or (iii) is present.
24. The method of claim 21 wherein frailty is determined by
compliance with at least 2 criterions selected from the group
consisting of muscle weakness, excessive feelings of exhaustion or
fatigue, abnormally low physical activity, slow or unsteady gait,
weight loss, and neurological dysfunction.
25. The method of claim 21 comprising administering the composition
to increase one or more of body weight, body mass index, lean body
weight, muscle mass, muscle strength or muscle function.
26. The method of claim 21 wherein the mammal is an elderly
human.
27. The method of claim 21 wherein the mammal is a human prone to
or suffering from cognitive decline or dementia.
28. The method of claim 21 wherein the mammal is a human prone to
or suffering from senile dementia.
29. The method of claim 21 wherein the mammal is a human prone to
or suffering from Alzheimer's disease.
30. The method of claim 21 wherein the mammal is suffering from a
prodromal form of dementia.
31. The method of claim 21 wherein the mammal has a BMI below 26
kg/m.sup.2.
32. The method of claim 21 wherein the mammal has a BMI below 23.5
kg/m.sup.2.
33. The method of claim 23 wherein the composition comprises UMP,
DHA, EPA, at least one vitamin selected from the group consisting
of vitamin B6, vitamin B12 and vitamin B9, and at least one
antioxidant selected from the group consisting of vitamin C,
vitamin E and selenium.
34. The method of claim 21 wherein the composition comprises at
least two different phospholipids selected from the group
consisting of phosphatidylserine, phosphatidylinositol,
phosphatidylcholine and phosphatidylethanolamine.
35. The method of claim 21 wherein the composition is a nutritional
composition comprising at least a whey protein.
36. The method of claim 21 wherein the composition has a
nutritional value of at least 50 kcal per 100 ml of
composition.
37. The method of claim 21 wherein the composition has a
nutritional value of at least 100 to 300 kcal per 100 ml of
composition.
Description
FIELD OF THE INVENTION
[0001] The invention relates to a combination of specific
components for use in the prevention or treatment of frailty in a
mammal, in particular for use in increasing one or more of body
weight, body mass index, lean body weight, muscle mass, muscle
strength, or muscle function, especially in an elderly human, more
in particular in a human prone to or suffering from cognitive
decline or dementia, in particular senile dementia, more in
particular Alzheimer's disease.
[0002] The invention also relates to the specific clinically
relevant benefits that can be achieved in such persons, like
improvement of stamina, an increased degree of activity during
daytime and associated change in lifestyle. The invention also
relates to a composition comprising said specific combination of
components, either as a nutritional or pharmaceutical composition,
which are suitable for achieving said effects in a frail mammal,
especially in an elderly human, most in particular in a human prone
to or suffering from dementia, in particular senile dementia, more
in particular Alzheimer's disease.
BACKGROUND OF THE INVENTION
[0003] Body weight of humans is determined by the weight of the
different parts in the body, like that of bones, muscle, organs,
vessels, adipose tissue, et cetera. During lifetime the
contributions of each body part to the total body weight changes.
After maturation of the human body has stopped, typically muscle
mass will gradually and steadily decrease with time. This decrease
results in a decrease of lean body mass (LBM, which is the body
mass minus the mass of adipose tissue), despite the fact that total
body mass (or body weight) may increase, e.g. due to an increase of
the mass of adipose tissue and changed masses of other parts of the
body. Ferruci et al. reported about the progression of loss of
muscle strength during aging (Ferruci et al. (1996) J Gerontol Med
Sci, 51AM123-M130). The strength of a muscle is considered to be
dependent on its mass. Its mass depends on the number of muscle
fibers, which decreases only after 55 years of age to about 50% at
the age of about 80 years, their length, which depends on their
trophic condition, and the cross-sectional area, which depends on
training (Faulkner et al. (2007) Proc Au P S, 38; 69-75). Muscle
strength (strength of handgrip or quadriceps) in normal persons
appeared to decrease about 0.5% per year after the 30.sup.th year.
Typically, this rate of decline of muscle strength increases with
age. After the 65.sup.th year of age, this decrease in muscle
strength has reached a magnitude of 1.5% per year for arm muscles
and about 3.5% for leg muscle (Skelton et al (1994) Age and Aging,
23, 371-377). Similar age-associated changes in body composition
and muscle strength have also been described by Evans, Cyr-Campbell
(1997), J American Dietetic Association, 97(6), 632, and by Campion
(1998) N Engl J med, 338(15), 1064-66.
[0004] It is important to note that, apart from these chronic
age-associated decreases in muscle mass and lean body weight, also
temporal and mostly reversible changes therein can occur, which in
most cases depend on the applied exercise efforts. For example,
Muller observed that during long term bed rest, muscle strength
decreased at a rate of about 1% per day (Muller (1970) Arch Phys
Med Rehabil, 51, 449-462).
[0005] These losses in body weight, lean body weight, muscle mass
and muscle strength during aging are considered to be normal and
physiological, though undesirable. However, in part of the human
population these losses have occurred at a greater speed or have
occurred for a longer period of time to reach a critical level.
This abnormally large weight loss is in most cases associated with
several health problems which occur at the same time. It is thought
that a complex general and non-specific malfunction of the human
body causes a low capability of the human body to adapt to the
prevalent circumstances to which the individual is exposed. This
general condition is recognized by physicians as an independent
health problem for which the word "frailty" was proposed. In the
past, different tools have been used to arrive at the diagnosis of
frailty (mild or moderate) or prefrailty.
[0006] Frailty is a large problem to the individual which
experiences it, to the environment and to society. It has a large
impact on the patient's life and creates huge costs for medical
care. For this reason, the problem is recognized in the prior art
as a geriatric syndrome that is distinct from disability and
comorbidity. In addition, a relatively low lean body mass and body
weight in elderly and especially in persons experiencing
neurological problems, is common and a large problem, which has not
yet been solved in the prior art.
[0007] Food intake, lifestyle and metabolic properties, including
energy expenditure, of an individual change with increasing age,
which may lead to what has been called a "physiologic anorexia of
aging". Dietary habits, nutrient intake, life style and the aging
process are interrelated. For example, with decreasing activity
during the applied life style, and the age-associated decline in
basal metabolic rate, neuro-endocrine function, immune function and
taste and smell perception, older people tend to consume less food,
and consequently fewer nutrients, which may lead to a nutritional
status, which does not the specific requirements of the elderly of
the frail individuals. This complex combination of events which is
specific to aging individuals, can result in a further decrease in
body weight, lean body mass or body mass index (BMI). This may even
result in frailty, as defined above.
[0008] In one embodiment of the invention, it is therefore an
objective to meet the specific nutritional requirements associated
with aging above 65 years of age, preferably of aging above 75
years and to include the active components in a food for this
special medical purpose, and to include them in such amounts to
compensate for the deficiencies, which would eventually arise when
conventional food patterns would be applied, as already applied in
the prior art. In this way, a nutritional composition according the
invention preferably comply with the regulations for Food of
Special Medical Purposes (FSMP), as currently valid in the European
Union. In addition, the invention aims to increase lean body mass
or significantly decrease the rate of loss of lean body mass,
muscle mass or body weight.
[0009] Involuntary weight loss during aging above 65 years is
strongly associated with decreased immuno-competence, impaired mood
and low stamina and an increased prevalence of health complications
in the same patient. Involuntary weight loss is therefore typically
a great concern to the clinical practitioner and has been included
in the list of symptoms for diagnosed frailty by Fried and others
(Fried et al. (2001) J Gerontol, 56, M146-156).
[0010] Weight loss may already be present in the early stages of
dementia and increases with the severity and progression of AD.
[0011] Many studies have been carried out to compare the annual
weight variation in Alzheimer's disease patients and healthy
control subjects. These studies reported that weight loss
frequently occurs in the first stages of the disease, although
patients usually have adequate energy intakes. In addition, there
is no compelling evidence that energy expenditure is abnormally
elevated relative to body size in Alzheimer's disease patients.
[0012] Typically, the prognosis of developing more diseases, or
developing more severe grades of disease, or experiencing a more
rapid progression of diseases increases with lower BMI, in
particular when it starts to become lower than 23.5 kg/m.sup.2.
This is especially true for patients suffering from a neurological
problem, such as an impairment of brain function or the function of
peripheral nerves. An example of such neurological dysfunction may
be an impaired cognitive function, like a form of cognitive
impairment or dementia.
[0013] Though the prior art is consistent about the progression of
loss of lean body mass during Alzheimer's disease or dementia, and
the increased risk of co-morbidity when lean body mass
deteriorates, it is inconsistent about the risk of developing more
or a more rapid cognitive decline when BMI increases. For example,
the review of Gorospe and Dave (2007) Age and Aging, 36, 23-29)
concluded that increased BMI is independently associated with
increased risk of dementia. In one embodiment of the invention, the
specific combination of components according to the invention was
found not only to increase BMI in frail elderly suffering from
dementia, with a subsequent improvement of the activities of daily
living (ADL), but in addition to improve the cognitive function.
This helps to obtain a superior effect of the composition according
the invention on the rate and extent of decrease of frailty,
compared to prior art compositions, because at least 2 symptoms
which contribute to the diagnosis of frailty are simultaneously
improved. This applies also to the effect of the composition
according to the invention on other criterions that define frailty,
like the effect on exhaustion or fatigue, as will be explained
below. In one embodiment of the invention, the efficacy of the
composition according to the invention can be represented as done
in FIG. 1.
[0014] In frail elderly, the combination of low stamina, low drive
to perform normal activities to keep independence and low abilities
of skeletal muscles to allow the activities of daily living may
result in a low degree of activity during daily life, including the
ability to purchase, prepare or consume adequate food quality and
quantity.
[0015] Function, mass and strength of a skeletal muscle also
depends on its use. Fiatarone et al (1994) N Engl J Med, 330 (25),
1769-750 found that high intensity training indeed decreased muscle
weakness in frail elderly people, but administration of a soy
protein based vitaminized energy drink (360 kcal) did not. However,
high intensity exercise programmes and protocols become more
difficult to apply, when the patients become older or experience
more severe cognitive dysfunction or when the patients suffer from
low stamina or depression and become little motivated. Application
of the protocols demands special equipment and skilled personnel to
make them more successful. Despite the availability of these
programs, the problem of frailty and too low body mass index
persists in the elderly population and impairs the amount of
activities that are applied during daytime, especially in disabled
or institutionalized aged persons and persons having moderate to
severe dementia. This illustrates the desirability for having
available a composition, preferably a nutritional or pharmaceutical
composition, which supports the treatment of frailty and prefrailty
and that may have a positive effect on the amount of activities
done in daily living and to the degree frail individuals can live
independently.
[0016] Though frailty is associated with an increased risk for
experiencing e.g. a stroke, Alzheimer's disease and other
dementias, a delirium, Parkinson's Disease, hip fracture,
incontinence, pneumonia and dehydration, pre-death, and several end
stage diseases, frailty has to be considered as an independent
state of the body. It is known in the prior art that the
"nutritional status", in terms of concentrations of nutrients in
blood (plasma), in frail elderly does not comply with the values
that are typically measured in the blood of healthy elderly or
healthy middle-aged adults. It is also known that bad nutritional
status, in terms of blood concentrations of specific nutrients is
associated with specific diseases, though in most cases causal
relationships are difficult to recognize, if present at all.
Nevertheless attempts have been made in the past to normalize
nutrient concentrations in blood in frail persons and especially
frail elderly, and subsequently improve BMI and the amount of
activities of daily living, but this has appeared to be very
difficult. For example Fiatarone, et al, have reported in 1994 a
failure to achieve this, when a protein energy supplement with 30%
of the recommended intake of vitamins per serving is
administered.
[0017] Borsheim et al. reported an improvement of lean body mass,
muscle mass and muscle strength, but this study was not
placebo-controlled and in 12 glucose-intolerant elderly subjects
having a relatively high body weight of 74 kg. The positive effects
were observed when for 16 weeks every day 2 times 11 g free amino
acids (8 essential amino acids and arginine, of which about 1/3 was
leucine) were administered; these are so unpalatable, that
typically compliance to a therapeutic protocol using the effective
amount of amino acids is low and thus efficacy in clinical practice
is not obtained (BOrsheim et al. (2008) Clin Nutr. 27,
189-195).
[0018] In a small study (5 healthy active non-frail elderly) Volpi
E, et al found that oral administration of 40 g crystalline amino
acids together with glucose in small protions every 10 minutes
during 3 hours, resulted in a small decrease of leg muscle
catabolic rate (Volpi et al. (2007) J Clin Endocrinol Metab 85
(12), 4481-90). De Jong and co-workers have compared the effect of
administrating mineral and vitamin-enriched food products (fruit
and dairy products) and non-enriched foods and found no difference
in lean body mass (de Jong et al. (2000) Am J Public health, 90
(6), 947-954) in frail elderly. Promoting and stimulating eating
more volumes or more healthy and regular food products does also
not work to improve body weight, BMI or frailty
characteristics.
[0019] Therefore, there is a need to effectively improve the
nutritional status in frail patients, in elderly having a low BMI
and in frail elderly in particular, but in such a way that health
is improved, as can be recognized by increasing lean body mass,
healthy body weight, muscle capacity, and decreasing frailty score.
Preferably, these effects are achieved in frail or prefrail
persons, frail or prefrail elderly or elderly having a BMI below 26
and more specifically below 23.5 kg/m.sup.2. More preferably, these
improvements in health result in a higher amount of activities
during daytime, especially during wake time and in general a better
functioning in life and quality of life.
[0020] This specific improvement of the nutritional status of a
frail or prefrail person or elderly person having a relatively low
body weight is defined to be the nutritional management of the
frail or prefrail consumer. Disease-specific requirements, in
particular frailty-specific requirements are met, by administering
the composition according the invention. In one embodiment of the
invention, the nutritional composition according to the invention
achieves the nutritional management of frailty and prefrailty. This
is done so not by providing nutrients in general which have been
attempted in the prior art, but failed or had severe
disadvantages.
[0021] In the nutritional management of frail persons, and
especially frail elderly it is also important to recognize the
problem of xerostomia or a dry mouth in general or during eating,
and the problem of hypochlorhydria, i.e. the reduced secretion of
hydrochloric acid by the stomach, in general or after food intake
or after smelling or seeing the food. In one embodiment of the
invention it is an objective to provide a nutritional or
pharmaceutical composition which, when consumed, is well tolerated
and even appreciated by persons who suffer from xerostomia or
hypochlorhydria.
[0022] It is known in the prior art that supplementation of protein
and energy to elderly who are at risk from malnutrition produces a
small but consistent weight gain (Milne et al. (2009) Cochrane
review). Healthy persons like athletes can increase their BMI, when
very high amounts of specific proteins, peptides or amino acids are
consumed, in particular when this is combined with an exercise
protocol. The known approach to supplement additional protein and
energy demands consumption of food on top of daily meals, and a
proper organ function, for dealing with the large amount of
dietetic protein (i.e. nitrogen). As explained above, the elderly,
and especially the elderly with impaired cognitive function and the
frail elderly generally experience difficulties with consuming
large quantities or volumes of food, may suffer from impairments in
body and organ function or from early satiety and low appetite,
have practical problems with cooking and with consuming the food
products, and are not keen on or capable of applying exercise
programs (Holmes (2008) Nursing standard, 22 (26), 47-57).
[0023] Accordingly, there is a need for an alternative way of
nutritional management of elderly which are in need of an increased
body weight, body mass index, lean body weight, muscle mass or
muscle strength, to perform appropriately, especially frail
elderly, in particular the frail elderly which experiences
cognitive decline or a dementia. Hence, this forms a way of
treatment of frailty, when body weight increases to such extent
that this criterion of frailty is no longer fulfilled.
[0024] Preferably, the composition according the invention achieves
all benefits as described above at about the same time. This is
observed in elderly in general (above 65 years of age), but also in
a subgroup thereof, the oldest one (persons above 75 years of age).
In a preferred embodiment, the nutritional or pharmaceutical
composition according to the invention is to be used for treating
at least two symptoms of frailty, i.e. for increasing low body
weight or BMI and for improving activities of daily living (ADL),
especially in persons older than 50 years of age, more in
particular those older than 65 years of age (elderly) and in
particular older than 75 years of age (the oldest). The composition
according to the invention may also be used to combat other
symptoms of frailty, such as exhaustion or fatigue by its effect on
muscle power, and thrive or stamina and the effect on neurological
performance, in particular cognition, as disclosed before. Thus, it
constitutes a composition that not only solves these symptoms, but
also provides superior effectivity against frailty in comparison to
prior art compositions, and without adverse effect.
BACKGROUND PRIOR ART
[0025] In WO2009/002146 (NV Nutricia), a composition is disclosed
which comprises DHA or EPA, in combination with uridine or its
equivalent and optionally a range of other components to support
activities of daily living. The composition can be administered to
elderly and locomotor function appeared improved by administering
these components. Also, protein could be included in the
composition of the invention, in order to improve muscle strength,
when administered to frail elderly. In order to achieve this, in
particular 1 to 5 g protein per 100 ml of a liquid composition was
included, wherein the protein comprises more than 80 weight %
milk-derived proteins.
[0026] WO2010/002257 (NV Nutricia) discloses the use of a
nutritional preparation comprising more than 18 energy percent
protein (preferably 22 to 32 en %), whey protein, at least 12 g
leucine per 100 g proteinaceous matter and a lipid fraction which
comprises at least one of EPA, (n-3)DPA, DHA, and (n-3) ETA for
improving muscle function in a mammal. The improvement of the
function of muscle was in terms of maximum force, maximum
contraction velocity and maximum relaxation velocity, all corrected
for muscle mass. This improvement was claimed to occur when the
patient suffered from specific diseases, in particular cancer or
during "aging" and was claimed to result in improving daily
activity, physical performance and quality of life. Frail
individuals as such were not mentioned and neither were elderly
with a low BMI or elderly being frail. The composition as disclosed
comprises preferably the components as mentioned and in addition
specific indigestible oligosaccharides, glutamine, cysteine,
oligosaccharides, carnitine and taurine. Though soy protein and
wheat protein were mentioned the inclusion of casein instead of
these vegetable proteins was preferred. Nucleotides and uridine
sources were not mentioned.
[0027] WO 2005/060952 (NV Nutricia) relates to a composition
comprising in a daily dosage form 14 to 1000 mg panthothenic acid
(vitamin B5) for stimulating appetite, whereby body weight and
muscle mass is increased in specific groups of diseased humans.
This was surprising, since panthothenic acid had been reported
before as a hunger suppressant. The composition may further
comprise folic acid, vitamin C (as antioxidant), and vitamin B6 and
B12 as part of a common vitamin premix.
[0028] WO2007/073178 (NV Nutricia) discloses a drink liquid for
Alzheimer patients (Example 3) comprising a nucleoside equivalent
(UMP), fish oil comprising DHA and EPA, vitamin B6, folic acid and
vitamin B12, phospholipids, vitamin C (as antioxidant), and
choline. The claimed effect is not disclosed.
[0029] WO2004/026294 (Nestec S.A.) discloses a nutritional
composition which comprises leucine and at least one of isoleucine,
lysine, methionine, phenylalanine, threonine, tryptophan, valine or
histidine in free or salt form, wherein free leucine is present in
an amount of 10 to 35 weight % of the total amount of amino acids.
Such composition was claimed to be useful for controlling
tumour-induced weight loss, for stimulating protein synthesis,
ameliorating loss of muscle in a human or for the dietary
management of malnutrition.
SUMMARY DESCRIPTION OF THE INVENTION
[0030] It has now been found that lean body mass (LBW) or the body
mass index (BMI) can be increased in frail mammals, or frailty can
effectively be treated therapeutically or prophylactically by
providing a nutritional or pharmaceutical composition comprising a
specific combination of active components. Accordingly, the present
invention relates to a composition comprising at least two,
preferably three, and more preferably four components (as active
ingredients) selected from the group of (i) a nucleoside
equivalent, (ii) an .omega.-3 polyunsaturated fatty acid selected
from the group of DHA, DPA and EPA, (iii) a vitamin B, (iv) a
phospholipid, (v) an antioxidant and (vi) a choline, with the
proviso that at least component (i) or (iii) is present, for use in
the prevention or treatment of (pathological) frailty in a mammal,
in particular for use in increasing one or more of body weight,
body mass index, and lean body weight, especially in a human,
especially in an elderly human.
[0031] Preferably, the vitamin b is selected from the group
consisting of vitamin B6, vitamin B9 and vitamin B12. Further
preferably, the anti-oxidant is selected from the group of vitamin
C, vitamin E and selenium (including selenium compounds)
[0032] Further, it has been found that LBW or BMI can be increased.
Accordingly, the invention in particular relates to a composition
comprising at least two, preferably three, and more preferably four
components (as active ingredients) selected from the group of (i) a
nucleoside equivalent, (ii) an .omega.-3 polyunsaturated fatty acid
selected from the group of docosahexaenoic acid (DHA),
docosapentaenoic acid (DPA) and eicosapentaenoic acid (EPA), (iii)
a vitamin B, preferably selected from the group of vitamin B6,
vitamin B9 and vitamin B12, (iv) a phospholipid, (v) an
antioxidant, preferably selected from the group of vitamin C,
vitamin E and selenium (including selenium compounds) and (vi) a
choline, with the proviso that at least component (i) or (iii) is
present, for use in increasing one or more of the following: body
weight, body mass index, and lean body weight, especially in a
human, especially in an elderly human.
[0033] A use according to the invention can be accomplished by
administering the components used according to the invention,
wherein the components are administered to the mammal in a diet
without essentially increasing the daily caloric intake of the
mammal respectively patient. The combination can be used for
increasing body weight for a medical reason, in particular can be
administered to a subject that is underweight and as a result
thereof has a medical problem, or has an increased risk of
acquiring a health problem. For example the subject may be
anorexic, or a frail or prefrail person, having a body weight that
is undesirably low.
[0034] In particular, elderly with an age above 65 years of age,
preferably with an age may benefit from a use according to the
invention.
[0035] In particular the increase in or maintenance of in body
weight comprises one or more of: (i) increasing or maintaining lean
body weight and (ii) increasing or maintaining muscle mass. In case
the subject is a human, the use preferably comprises increasing or
maintaining the body mass index.
[0036] In a specific embodiment of the invention at least two
components selected from the group of: (i) nucleoside equivalents,
(ii) n-3 polyunsaturated fatty acids selected from the group of
DHA, DPA and EPA, (iii) vitamins B, (iv) phospholipids, (v)
antioxidants and (vi) cholines--with the proviso that at least one
(i) nucleoside or at least one (iii) vitamin B is present--are used
for improving the ability to perform an activity of daily living of
a mammal, for maintaining the ability to perform an activity of
daily living (ADL) of a mammal, or for reducing a deterioration in
the ability to perform an activity of daily living of a mammal.
[0037] The ADL-status of a subject or a change in ADL of a subject
may be determined with a score-test such as the Katz score or the
PASE score.
[0038] The Katz Index of Independence in Activities of Daily
Living, commonly referred to as the Katz ADL, is the most
appropriate instrument to assess functional status as a measurement
of the client's ability to perform activities of daily living
independently. Clinicians typically use the tool to detect problems
in performing activities of daily living and to plan care
accordingly. The Index ranks adequacy of performance in the six
functions of bathing, dressing, toileting, transferring,
continence, and feeding. Clients are scored yes/no for independence
in each of the six functions. A score of 6 indicates full function,
4 indicates moderate impairment, and 2 or less indicates severe
functional impairment, see `M. Wallace et al. `Try This: Best
Practices in Nursing Care to Older Adults, Issue Number 2, revised
2007, from the Hartford Institue for Geriatric Nursing, New York
University, College of Nursing`.
(http://consultgerirn.org/uploads/File/trythis/try_this.sub.--2.pdf)
[0039] In general, a medical use regarding ADL involves treatment
of a subject that has a severe functional impairment. Common causes
of severe functional impairment are motor dysfunctional causes,
e.g. because of joint problems (e.g. due to arthrosis or
rheumathoid arthritis), severe vascular problems (e.g. diabetic
feet) or severe obesity (Quetelet Index>40). In particular, the
subject of a medical use for improving the ability to perform an
activity of daily living of a mammal, for maintaining the ability
to perform an activity of daily living of a mammal, or for reducing
a deterioration in the ability to perform an activity of daily
living of a mammal according to the invention may have a score of 2
or less on the Katz scale, or a PASE score of less than 30, in
particular of less than 27.5 (for women) or less than 30 (for
men).
[0040] Further, the invention relates to a nutritional composition
comprising (i) at least two components selected from the group of
uridine and iuridine monophosphate, (ii) DHA and EPA, (iii) a
vitamin B, (iv) a phospholipid, v) an antioxidant, and (vi) a
choline.
[0041] The term `active ingredient` or `active component` is used
herein in particular for (i) nucleoside equivalents, (ii) n-3
polyunsaturated fatty acids selected from the group of DHA, DPA and
EPA, (iii) vitamins B, (iv) phospholipids, (v) antioxidants and
(vi) cholines, which are effective in one or more of the claimed
uses.
[0042] If a specific compound falls in more than one of these
groups (i)-(vii) of active ingredients it typically provides an
active ingredient of both groups. The actual dosage or
concentration provided for each group can be determined based on
how the compound is used/metabolised after administration. For
example, phosphatidyl choline (PC) is both a phospholipid and a
choline. As a phospholipid it can be active in the
distrubution/emulsification of lipids, and thereafter it can be
metabolised to release the choline, which is an essential component
for mammals, such as humans. Thus, a composition comprising PC
comprises both an active ingredient of the group of phospholipids
and of the group of cholines. Another example of a compound
providing more than one type of active ingredients is citicoline
(cytidine diphosphate-choline), which provides both choline and a
nucleoside equivalent.
[0043] In an advantageous embodiment, a nutritional or
pharmaceutical composition for use according the invention
(hereafter also called "composition according to the invention")
not only has an effect on LBW or the BMI in (frail) elderly, or may
be used to treat frailty, especially in an elderly mammal, but that
the administration of a nutritional or pharmaceutical composition
of the invention wherein a uridine-source and .omega.-3 type
polyunsaturated fatty acids (.omega.-3 PUFAs) are present, results
in a further improvement in the amount of activities of daily
living that can be performed and an increased muscle mass, muscle
strength or muscle function, when also a specific protein amount is
included in the composition according to the invention. In
particular, the composition according the invention may be used to
improve stamina, to increase degree and frequency of feeling more
energetic, to decrease duration, severity or frequency of feeling
tired or exhausted or feeling fatigue, or to increase eagerness to
demonstrate initiatives and become more active. In addition the
composition according the invention can improve gait.
[0044] It has also been found that mammals physically benefit from
treatment with a specific combination of active ingredients such
that one or more of body weight, body mass index, or lean body
weight are better maintained or even increased without the need to
increase the daily caloric intake of said mammals. It has also been
found that the specific combination of components is simultaneously
capable of decreasing other symptoms of frailty, like an
improvement of neurological dysfunction or an improvement of longer
term muscle use leading to an increase in the amount of activities
that are applied during wake time. This is mandatory to the
effective treatment of frailty. For this reason, the specific
combination of active ingredients may be used for the treatment of
frailty or prefrailty, thus resulting in achieving a lower risk of
developing frailty in the course of time.
[0045] The components as described above can be combined with a
specific protein composition to obtain a stronger effect on LBM or
BMI.
[0046] In a very specific embodiment, the invention relates to a
composition comprising at least (i) a uridine equivalent, (ii) an
.omega.-3 polyunsaturated fatty acid selected from the group of
DHA, DPA and EPA, (iii) a vitamin B, (iv) a phospholipid, (v) an
antioxidant, preferably selected from the group consisting of
vitamin C, vitamin E and selenium, and (vi) a choline, for use in
the prevention or treatment of (pathological) frailty in a mammal,
wherein the mammal is a patient suffering from dementia, in
particular from Alzheimer's disease, the patient having an BMI
below 26 and more preferably below 23.5.
[0047] In a very specific embodiment, the invention also relates to
a composition comprising at least (i) a uridine equivalent, (ii) an
.omega.-3 polyunsaturated fatty acid selected from the group of
DHA, DPA and EPA, (iii) a vitamin B, (iv) a phospholipid, (v) an
antioxidant, preferably selected from the group consisting of
vitamin C, vitamin E and selenium, and (vi) a choline, for
improving the (pathological) frailty in a mammal, and/or the
quality of life, amd/or the daily activities (ADL), wherein the
mammal is a patient suffering from dementia, in particular from
Alzheimer's disease, the patient having an BMI below 26 and more
preferably below 23.5.
[0048] The term "or", as used herein, means also "and", unless
specified otherwise or the context dictates otherwise. Hence,
"option A or B" means any of the options A, B and A and B.
[0049] The term "a" or "an", as used herein, means "at least one"
unless specified otherwise.
[0050] When referring to a noun (e.g. a compound, an additive etc.)
in singular, the plural is meant to be included, unless specified
otherwise.
[0051] When referring hereinafter to a `vitamin B`, in general a
vitamin B selected from the group of vitamin B6(pyridoxins),
vitamin B9 (folates) and vitamin B12 (Cobalamines) is meant, unless
specifically stated otherwise. When referred hereinafter to an
`antioxidant`, in general an antioxidant selected from the group of
vitamin C (ascorbates), vitamin E (tocopherols) and selenium
(including selenium compounds) (v) is meant, unless specifically
stated otherwise.
[0052] When referring herein to an acid, e.g. a fatty acid or folic
acid, this term is meant to include the conjugated bases of said
acid (e.g. folate), salts of the acids and derivatives of the acid
of which the body is capable of converting it into the acid (e.g.
fatty acid esters, such as triglycerides), unless specified
otherwise.
[0053] When referring herein to dosages, these are in particular
intended for adult humans. The skilled person will be able to
determine a suitable dosage for other mammals based on common
general knowledge, the information disclosed herein and optionally
a limited amount of routine testing.
[0054] When referring to a mammal, preferably the mammal is a human
mammal, more preferably an elderly human mammal.
DETAILED DESCRIPTION OF THE INVENTION
Definition of Frailty
[0055] For the purpose of this document, the inventors apply the
following definition for frailty, which includes the practical
approaches of many scientists (like Fried, Ory, and Chin A Paw). A
person is deemed to be frail when the individual's condition in a
recent period of time complies with at least 3 of the following
list of (6) classes of symptoms (frailty criterions):
[0056] 1. Muscle weakness,
[0057] 2. Excessive feelings of exhaustion or fatigue,
[0058] 3. Abnormally low physical activity,
[0059] 4. Slow or unsteady gait,
[0060] 5. Weight loss, and
[0061] 6. Neurological dysfunction
The degree of malfunction of each of the mentioned classes of
symptoms can be measured by applying recognized methods that are
known in the prior art. For the purpose of this invention, the
application of the following methods is preferred:
[0062] Criterion 1 (muscle weakness)--For determining muscle
weakness one of the following list: a) for muscles of the arm: hand
grip strength or quadriceps strength, b) for the leg the method as
described by BOrsheim et al. (2008) Clin Nutr. 27, 189-195; or as
described in Pijnappels et al. (2008) Eur J Appl Physiol. 102(5):
585-592 can be applied. Belonging to the lower 20% of the group of
age and gender matched persons resulted in fulfilment of this
frailty criterion.
[0063] Criterion 2 (feeling of exhaustion or fatigue)--For
determining the degree of exhaustion or fatigue, one can assess one
or more of a) mental fatigue, b) the perception of exerting a
standardized exercise protocol, muscle capacity or muscle power, or
c) lung capacity. Preferably, method a) is done by applying a
questionnaire as known in the prior art, e.g. the CES-D scale as
described by Roberts (1980) Psychiatr Res, 2, 125-134, so scoring
on statements like "I cannot get going" or "I feel that everything
I do is an effort". This measure is strongly related to the degree
of stamina of the individual. Method b) is a measure of physical
exhaustion and can for example be done by applying the Borg scale
for measuring perceived exertion (Borg (1998) Human kinetics,
Champaign, Ill.; Nybo (2003) Med Sci Sports Exerc, 35, 589-594).
Method c) is a measure of the capacity of a human being to provide
sufficient oxygen (air) to the body. The preferred method for
applying it, is measuring forced expiratory volume (FEV1) in one
second, which should be below 30% of the normal value, for
individuals of similar age and gender, in order to meet the
criterion.
[0064] Measurement of the degree of physical exhaustion or fatigue,
as recommended in method b) can be done in several ways, which all
represent ways that reflect the capacity of the neuro-muscular
system to exert labour and be active. For example, the amount of
physical activities can be measured, by attachment of devices to
the person to be tested, and measuring the amount of physical
activity which is voluntarily applied normally during wake time.
This amount can also be related to the amount of sleep or rest that
is needed to recover from it, and be put in a score. Secondly, the
capacity of the muscle to maintain a certain force for a certain
time is a useful measure. Preferably, this force that needs to be
maintained is at 15 to 80% of the maximal force the muscle can
provide, in order to reflect better the activities as applied in
normal life. Thirdly, the speed with which physical exhaustion is
developed can be determined. For example, the amount of power a
muscle can exert in a certain period of time can be determined;
e.g. by measuring the force multiplied with the distance (in a
movement) that the force was exerted, e.g. by swinging a leg at a
certain velocity. Equipment for measuring these advanced parameters
is commercially available. The speed with which a muscle can become
tired, or in other words, the time that a certain force can be
maintained, is a valuable measure of the capability of an organism
to apply daily activities. When the measured values for these
parameters in the tested person belong to the lower 20% of such
values for a group of persons of similar age and gender, the person
is deemed to comply with this criterion of frailty.
[0065] It is important to recognise that larger muscle strength
does not in all circumstances necessarily lead to a higher muscle
capacity or power or a better endurance. The larger force which is
provided by the muscle may have exhausted endogenous energy
supplies more, which deteriorates the time or distance that the
muscle can exert the force, and therefore does not increase muscle
capacity or power. A larger force may also increase negative
feedback signals from peripheral joints, muscles and tendons.
Muscle capacity or muscle power also better reflects the muscle
effort that needs to be done to apply an activity of daily living
(Theou et al. (2008) Appl Physiol, Katsiaris, et al, 2005).
Therefore, muscle capacity or muscle power, and not muscle
strength, provides useful information about the state of exhaustion
and fatigue, and especially physical exhaustion and fatigue of a
patient. The force that a skeletal muscle can apply also influences
the maximal velocity with which a certain movement can be made. A
high movement velocity does not automatically result in a large
endurance or a good recovery after exercise, which are required for
performing a large amount of activities or showing a high mobility
during wake time over the day.
[0066] Criterion 3 (physical activity)--For determining the
magnitude of physical activity of a human, one or more methods of
the following list can be applied: a) determination of the amount
of basic activities as applied during daily life (as described
above), and b) determination of the amount of instrumental
activities, as applied during daily life. Especially the
measurement of instrumental activities is a valuable measure. A
reliable method to do this is assessment of the "Physical Activity
Scale for the Elderly" (PASE), as described by Washburn et al.
(1999) J Clin Epidemiol 52, 643-651; "The physical activity scale
for the elderly; evidence for validity". For men, a score of less
than 30 and belonging to lowest 20% part fulfilled this criterion
for frailty. For women, the threshold value was <27.5 (Graham et
al. (2009) Gerontol, 55, 644-651).
[0067] Criterion 4 (gait)--For determining the gait of a human,
tests can be applied, like those described in the "Modified
Physical Performance Test" (PTT), as disclosed by Binder et al.
(1999) J Gerontol, 54, M428-432, like the preferred a) measure of
"balance", as e.g. done by determining the way how a frail person
is capable of taking a penny from the floor, or b) time and way to
walk 5 to 15 meters, or c) time and way to raise from a chair. For
example, for method b) the criterion for frailty was fulfilled when
the person belonged to 20% of persons with regard to the time
needed. The threshold values per gender as mentioned in Graham et
al. (2009) Gerontol, 55, 644-651 can suitably be applied.
[0068] Criterion 5 (Weight loss)--For determining the presence of
undesired weight loss, it is important to avoid confusion with
acute weight loss as caused by a (serious) disease or trauma or an
underlying pre-death syndrome. In one embodiment of the invention,
frailty as the result of cachexia is excluded from the group of
persons wherein the composition according to the invention is
effective. In one embodiment of the invention, this exclusion of
persons who have become frail because of cachexia is preferred. In
this way, frail individuals which comply with the definition as
given above differ from the individuals which have developed a
frailty that results from these diagnosed conditions, related to
acute phases during diseases and briefly before death.
[0069] With regard to determining the value of BAB, which should
give concerns for becoming "frail", it is important to be aware of
the fact that optimal BMI values change with age. While at young
and middle age a BMI value between 20 to 25 kg per square meter is
considered to be most healthy, at older age, e.g. above 65 years of
age and especially above 75 years of age, a BMI below 26 and more
specifically below 23.5 is considered to be undesirable (Chin A Paw
et al. (2003) J Nutr Health Aging 7(1), 55-60, or Chin (1999) J
Clin Epidemiol 52 (11), 1015-1021). The preferred list of
diagnostic tools for establishing a too low body weight, lean body
mass or muscle mass aims to be suitable for the aged
population.
[0070] For the purpose of the invention, the inventors feel that it
is desirable to look carefully at the metabolic condition of the
individual who suffers from a low BMI, body weight or muscle
capacity. When such low body weight is the result of an acute
process, the metabolic condition of the patient differs on
essential points from that of a person who experiences a more
generalized metabolic problem. This difference has also been made
by others, for example for Alzheimer patients (Guerin et al. (2005)
Am J Clin Nutr, 82 (2), 435-441). Part of the Alzheimer patients
appear to experience sudden and severe weight loss as a result of
intercurrent events, like institutionalization, a major change in
life style, a trauma or the presence of a major disease, while a
different part suffered from a more chronic weight loss. Therefore
it is preferred that the BMI value, as proposed as a limit for
meeting one criterion of frailty, is assessed in the absence of an
acute phase condition, i.e. the absence of a diagnosed disease
selected from a cancer, AIDS, a COPD, an infection, pre-death,
pre-death associated with anorexia, surgery, an accident and
similar major trauma, or in an alternative embodiment the acute
phases during these diseases or conditions. The presence of the
acute phase during these diseases can be determined by measuring a
biomarker as known in the prior art, e.g. measuring plasma
concentrations of acute phase proteins, like tranthyretin,
alphal-acid glycoprotein, C-reactive protein, or measuring
concentrations of cytokines which are representative of acute
infections or severely progressed disease, like IL-1, IL-6 or
TNF-.alpha.. It is important to note that a disease, like cancer,
chronic obstructive pulmonary diseases, AIDS and other diseases or
pre-death, at some stage can cause a frailty condition that is
acute and severe. The inventors find that the metabolic condition
of such individual is completely different from that of an
individual suffering from a frailty that origins from a generalized
metabolic inability to cope with the daily stresses from the
outside world. Therefore, in the context of this invention,
frailty, which is treated and solved by administering the
nutritional or pharmaceutical composition according the invention,
is not this acute-, and disease- or trauma-related type of advanced
weight loss or frailty. Instead, it is the frailty as defined below
and caused by a general and complex deterioration of the body to
adapt the external stresses, as can have been acquired during life
e.g., by applying bad life style including bad dietary habits,
exposure to toxicants or as a result of time, as occurs during
aging, in particular by aging after 65 years of age and more in
particular the frailty as caused by a chronic deterioration of
adaptive responses.
[0071] Further, a method for determining involuntary weight loss
can be used for assessing whether criterion 5 applies, is applying
the criterion of 4.5 kg undesired weight loss in the previous year
or 5-10% of body weight within 6-12 months or less. Involuntary
weight loss of a subject is weight loss occurring despite the
subject's aim to maintain or to increase its body weight (on the
subject's own behalf or after advice of carer or health care
professional). Such weight loss can be determined routinely by
comparing present weight with the weight 1-2 years earlier and
asking the subject whether he/she aimed to maintain or increase the
body weight.
[0072] Further, a method can be used applying the criterion of 6 kg
undesired or unexplainable weight loss during previous 2 years.
Such weight loss can be determined routinely by comparing present
weight with the weight in a period 2 years earlier and asking the
subject whether he/she aimed to maintain or increase the body
weight. A pre-death condition can be diagnosed by a physician.
Measurement of transthyretin and .alpha.1-acid glycoprotein in
blood plasma of both genders and the determination of low blood
albumin and high C-reactive protein in blood of males, as applied
by Carriere (POLA Group) et al. (1998) Arch Ophthalmology, 116,
1031) is recommended for establishing predeath risk.
[0073] Criterion 6 (Neurological dysfunction)--For determining the
degree of neurological dysfunction application of the following
list is preferred: a) establishment of a tremor or a locomotor
dysfunction different from the balance and performance tests
applied in measuring gait performance; b) measurement of cognitive
function (impairment); c) determination of verbal fluency; d)
measurement of speed of conductance of electrical signals over
nerves; e) analyses of sensory functioning, to establish a problem
related to hearing, vision, tasting, smelling and touch); f)
measurement of a emotional or psychological condition, like
establishing the presence of major depression, an affect disorder
or an anxiety disorder; g) determination of incontinence or the
daily occurrence of significant involuntary urinary loss, and h)
the presence of a major sleep disorder, like chronic insomnia or
sleep apnea. Methods to assess neurological dysfunction have been
described in the prior art and include the DSM IV methods, and the
measurements as described in the corresponding domains in common
frailty assessment methods, like the Groningen frailty indicator
(Schuurmans et al. (2004) J Gerontol, Biol Sci, Med Sci, 59,
M962-5), the comprehensive geriatric assessment (FI-SGA: Goggins et
al. (2005) 60, 1046; Jones et al. (2004) J Am Geriatr Soc, 52,
1929-33) or the clinical global impression of change in physical
frailty (CGIC-PF: Studenski et al. (2004) J AM Geriatr Soc, 52,
1560-6). Involuntary urine loss is deemed to be significant when it
exceeds 10 ml a day.
[0074] A patient is considered to meet this neurological
dysfunction criterion of frailty when b) is met (cognitive
impairment) or, when a combination of at least two of the other
criterions has been fulfilled Cognitive impairment can be assessed
by methods known in the prior art, for example by applying measures
of the domains related to the measurement of verbal memory,
visuospatial memory and attention-executive abilities. Preferred
methods include application of the ADAS-cog assessment, the MMSE
assessment, the Montreal cognition assessment or the CERAD
methods.
[0075] The analyses of sensory function can be applied by using
methods known in the prior art to determine threshold values for
tastes, odours and sounds, or to determine the ability to
differentiate between different odours and tastes.
[0076] A person is considered to be mildly frail when it complies
with three of the six criterions, and moderately frail when it
complies with four criterions or when the score of the three
symptoms is so bad, that it seriously impairs the patient's
condition, as diagnosed by the clinician or physician.
[0077] A person is considered to be in a prefrail condition or
prodromal frail condition, when his or her condition complies with
only two of the six frailty criterions. When the composition
according to the invention treats prefrailty, it is defined to act
in a preventive manner on the development of frailty. So,
prefrailty and prodromal frailty is defined to be synonymous.
[0078] A person is defined to be a frail elderly when it complies
with the above-mentioned criterions for frailty and in addition is
older than 65, preferably 75 years of age.
[0079] An individual is defined to be a prefrail elderly when the
person's condition complies with the criterions of prefrailty and
the person is older than 65, preferably 75 years of age.
[0080] Within the context of this invention, the term "frailty" or
"frail" refers to pathological conditions, and is used to comprise
conditions indicated above as prefrail, prodromal frail, mildly
frail or moderately frail.
[0081] Though some scientists recognize various forms of frailty,
including medical, functional, social, psychological and physical
frailty (Faber et al. (2006) Arch Phys Med Rehabil. 87, 885-96),
the composition according the invention aims to have its efficacy
only in those patients which comply exactly with the criterions as
set above.
[0082] Elderly or the aged population is a group that is defined in
different ways in the prior art. For the purpose of defining the
invention, the inventors have applied the following definition.
Elderly or the aged population is defined to be all persons being
older than 65 years of age. The "oldest old" are those persons
being older than 75 years. The claimed combination for use in
accordance with the invention is in particular suitable for
treatment of a mammal. In a preferred embodiment, said combination
is to be used for the treatment of a human, in particular an
elderly person. In the context of this application, an elderly
person is a person of the age of 50 or more, in particular of the
age of 55 or more, more in particular of the age of 60 or more,
more in particular of the age of 65 or more. This rather broad
definition takes into account the fact that the average age varies
between different populations, on different continents, etc. Most
developed world countries have accepted the chronological age of 65
years as a definition of `elderly` or older person (associated with
the age at which one may begin to receive pension benefits), but
like many westernized concepts, this does not adapt well to e.g.
the situation in Africa. At the moment, there is no United Nations
(UN) standard numerical criterion, but the UN agreed cut-off is 60+
years to refer to the older population in Western world. The more
traditional African definitions of an elder or `elderly` person
correlate with the chronological ages of 50 to 65 years, depending
on the setting, the region and the country.
[0083] With the "nutritional management of frail individuals,
prefrail individuals and persons experiencing a too low LBM or BMI"
according the invention is meant the administration of nutritional
components to frail individuals, prefrail individuals or persons
having a too low BMI or LBM, in such a way that not only the
endogenous concentrations of nutritional components are influenced,
but that also the health-beneficial effect is obtained in persons
suffering from frailty, frailty symptoms, prefrail persons or
individuals suffering from a too low LBM or BMI as claimed in this
application. This means that the composition according the
invention may induce a concentration in blood of that nutrient,
which is outside the normal range as typically observed in the same
tissue of healthy individuals, for example of healthy individuals
which consume regular food or a normal diet. In the context of this
invention, an alternative way of saying the same is that the
composition according to the invention also aims to therapeutically
nourish frail or prefrail persons or persons having too low LBM or
BMI.
[0084] It is important to notice that many elderly have become
malnourished and have developed deficiencies in one or more
nutrients like protein, energy or micro-ingredients or combinations
thereof, like PEM (protein-energy malnourishment). Such
"malnourishment" is currently assessed by using tools like the
"MUST" or "MNA", but it is envisaged by the inventors that
alternative tools will be developed, like one that is specifically
focussing on nourishment status and one other tool which
specifically focusses on general and quick screening of the
condition of an individual in order to assess whether a condition
is present wherein additional nutrition or other therapy can be
useful. Therefore, in one embodiment of the invention the
composition according to the invention is used in combination with
an assessment of malnourishment of a mammal, preferably using MUST
or MNA. In this embodiment, the invention comprises at least the
following steps: [0085] 1--Assessment of the nutritional status of
a mammal, and [0086] 2--Intervention with the nutritional or
pharmaceutical composition according the invention.
[0087] Preferably, the assessment of nutritional status is applied
at least twice in combination and relation to the nutritional
intervention. More preferably, the assessment is done at least one
time before and at least one time after the intervention to measure
any changes in nutritional status. The initial nutritional
assessment may reveal deficiencies which can be resolved by
adapting the intervention composition according to the invention.
In order to allow such nutritional management according the
invention, separate tools have been defined which is a specific
nutritional assessment tool and a module of food components which
allows convenient adaptation and fortification of the nutritional
intervention composition according to the invention.
[0088] A preferred tool for assessing nutritional status comprises
several parts, including a questionnaire, which asks the right
questions to assess nutritional status, a database which is filled
in by answering the questions, and an algorithm which compares the
answers with predefined normal values. Optionally conclusions are
drawn to arrive at an advice. These functionalities can be
incorporated into an electronic device like a computer or
minicomputer, by loading and running an appropriate software
program. The questions to ask are at least covering biomarkers for
the determination of nutrient status using methods as applied in
the state of the prior art clinical chemistry laboratories.
[0089] Apart from the "nutritional management", the inventors also
identify the "therapeutic management" of frailty and prefrailty. In
this definition of "therapeutic management", the management of the
individual to be treated comprises at least the following
steps:
[0090] a) diagnosis for frailty, using an assessment of the six
criterions defined above for assessing the presence of frailty,
[0091] b) an intervention using the composition according the
invention, and
[0092] c) measurement of progress made by assessing at least again
the same symptom classes as done in step a).
[0093] Preferably, the assessment of symptoms is done by using the
tool, in particular a form or document or an electronic device
loaded with appropriate software, as described below.
[0094] Optionally, in the therapeutic management of frailty and
prefrailty, the intervention with the nutritional composition
according to the invention can be combined with one or more of 1)
an exercise program, 2) a program to improve social interactions,
3) a program to become more exposed to sunlight and fresh air, 4)
an adaptation of the diet or of the general food intake practices
of the patient, and 5) an intervention with a drug or medicine. It
is preferred that the therapeutic management comprises at least a
program to be exposed to sunlight and fresh air or an exercise
program as a fourth and fifth step in the therapeutic management of
the condition of the patient.
[0095] In principle, the mammal to be treated may suffer from any
of the frailty symptoms as defined above. In particular, the mammal
is a human which suffer from at least a neurological or brain
problem and one selected from the group of weight loss and an
abnormally low physical activity. Preferably, the patient
experiences all three types of symptoms. When the patient
experiences a neurological or brain problem, this is preferably a
form of dementia, in particular senile dementia. For the purpose of
the invention, persons that suffer from "senile dementia" are
defined as suffering from one or more dementias. Senile dementia or
dementia is considered to comprise Alzheimer's disease (AD).
[0096] The dementia may be in any stage. In particular, the mammal
may be in a prodromal stage of dementia. A "prodromal dementia
patient" is a person who does not suffer from a senile dementia as
defined above, but has an increased likelihood to develop senile
dementia. Likewise, a "prodromal Alzheimer patient" is a person who
does not suffer from AD, but has an increased likelihood to develop
AD. In principle, any diagnostic tool for determining prodromal
dementia patient may be used. Several diagnostic tools that can be
used to classify the patients as prodromal dementia patients are
described below and include an accurate diagnosis of brain lesions
and biochemical problems and careful setting of criteria. Hence,
the invention is independently directed at prodromal dementia
patients or prodromal Alzheimer's patients.
[0097] In particular, persons that score positively on at least
one, preferably at least two, more preferably at least three of the
following criteria, are considered to be prodromal dementia
patients as defined herein: [0098] a level of more than 350 ng
Total-tau per litre cerebrospinal fluid (CSF); [0099] a weight
ratio of abeta-42/Phospho-tau-181 of less than 6.5 in CSF; [0100]
presence of medial temporal lobe (MTL) atrophy, existing of volume
loss of hippocampus, entorhinal cortex, or amygdala evidenced on
Magnetic Resonance Imaging (MRI) with either qualitative ratings
using visual scoring (referenced to well characterised population
with age norms) or quantitative volumetry of regions of interest
(referenced to well characterized population with age norms) [0101]
presence of fronto-temporal lobe (FTL) atrophy evidenced on MRI
with qualitative ratings or quantitative volumetry; [0102] a level
of more than 25 pg F2-iso-prostane (F2-IsoP, isoprostane
8,12-iso-iPF2alpha-VI) per mL CSF.
[0103] Further explanations of the significance of concentrations
of T-tau, P-tau181, Abeta42 and F2-Isoprostane in CSF for future
development of Alzheimer's disease can be found in Hansson et al.
(2006) Lancet Neurol 5:228-234; and in Pratico et al. (2002) Arch
Neurol 59:972-976.
[0104] In the context of this document, patients who are in a
prodromal state of Alzheimer's Disease (AD) are defined to be in a
predementia stage of AD. The values of the biomarkers indicate a
condition of the body, in particular the central nervous system,
wherein the risk of developing Alzheimer's disease is significantly
increased, no matter whether the final form of Alzheimer's disease
will be typical Alzheimer's disease, atypical Alzheimer's disease
or mixed Alzheimer's disease. This predementia state of the body
can be without significant clinical symptoms, the so called
preclinical state of Alzheimer's disease, wherein a patient is
asymptomatic at risk for Alzheimer's disease or is experiencing
presymptomatic Alzheimer's disease. It is also important to note
that a patient may experience mild cognitive impairment without
having an increased risk for developing Alzheimer's disease as
determined by measuring the above-mentioned parameters (Dubois et
al. (2010) Lancet Neurol, 9, 1118-1127).
[0105] The composition according the invention has its effects on
body weight and frailty, no matter the patient is a real
Alzheimer's disease patient, is a prodromal Alzheimer's disease
patient, is a normal elderly which experiences age-associated
memory impairment or mild cognitive decline without having
increased risk of developing AD, or is in the preclinical state of
being at increased risk of developing Alzheimer's disease or a
different dementia, like a vascular dementia.
[0106] In a preferred embodiment, a prodromal Alzheimer patient can
be identified as such because he meets at least the first two
criteria (total tau and ratio abeta-42/P-tau-181). More preferably,
one of the three other criteria (MTL atrophy, FTL atrophy, F2-IsoP)
also applies.
[0107] In addition to or instead of one or more of the above
criteria, the following can be advantageously used: [0108] reduced
glucose metabolism in bilateral temporal parietal areas of the
brain, as is detectable by Positron Emission Tomography (PET);
[0109] reduced glucose metabolism in the posterior cingulate
cortex, as is detectable by PET; [0110] impaired blood flow in the
brain as measurable by applying Single-Photon Emission Computed
Tomography (SPECT), for example by applying the radioisotope 99
mTc-HMPAO); [0111] impaired glucose metabolism in the brain as
measurable by applying SPECT; [0112] abnormalities in the histology
of the medial or inferior temporal lobes as can be determined by
MRI or in the rate of glucose utilisation; [0113] abnormalities in
histology or glucose utilization in the temporal parietal cortex or
posterior cingulate cortex.
[0114] Abnormalities in the condition of the brain or parts thereof
can be established by either taking the person's own condition
under healthy circumstances as a reference, or, when this is not
available, by taking the average condition of a representative
group (so matched for e.g. age) as a reference. The latter will
occur most frequently. By comparison of the patient's condition
with the reference situation and the average situation when the
pathological condition would have been developed to its full
extent, the clinician is capable of recognizing a prodromal phase.
In particular an intermediate situation wherein the patient
demonstrates a deviation of x % from the value of a healthy
individual in the direction of the pathological conditions is for
the purpose of this invention considered to be a prodromal patient.
The value of x for the determination of blood flow and glucose
metabolism is 20% when determined under standardised conditions in
terms of feeding and exercise.
[0115] It is important to notice that the effect of the composition
according to the invention on body weight occurs in the presence of
relatively little energy and protein in the composition according
to the invention and that this effect on body weight occurs
simultaneously with an effect on other symptoms of frailty, like
neurological or brain function, or the physical activity, in
particular instrumental activities, which makes it suitable for the
treatment of frailty and prefrailty.
[0116] Composition According to the Invention
[0117] The composition according the invention is a nutritional or
a pharmaceutical composition. When referring to pharmaceutical
composition, it is understood that such composition has only a
medical effect or benefit, i.e. the composition comprises
essentially no ingredients which provide a substantial source of
energy, other than the active components. When referring to
nutritional composition, it is understood that such composition has
both a nutritional and a medical effect or benefit, i.e. the
composition comprises macronutrients which provide a substantial
source of energy, other than the active components, in particular
proteinaceous matter, fat, other than component (ii), and
digestible carbohydrates. It preferably comprises food grade
components, which make it suitable for safe oral intake or enteral
administration. The components can also be dissolved in a matrix
which makes it suitable for parenteral administration.
[0118] The composition according to the invention can have any form
or physical condition. Preferably, it is a sterile composition or a
composition which comprises a defined micro-organism population,
like a dairy product, for example which is fermented under
controlled conditions or a dry product to which probiotics have
been added. An example of such fermented product is a yoghurt. The
composition according the invention can be solid, semi-solid or a
drink. Such forms have been widely disclosed in the prior art.
Preferably it is a drink, though for patients which experience
dysphagia, a high-viscosity product or a semi-solid form is
preferred.
[0119] The composition according to the invention may also be a
kit-of-parts comprising the components according to the invention,
packed for simultaneous or sequential administration to a person in
need thereof. Hence, each component may be packed separately, or
some may be packed together, for example in a sachet, bottle,
etc.
[0120] The composition according the invention is preferably a
composition which complies with the criterions as set for the
ruling regulations for food for special medical purposes or of a
medical food. These regulations are distributed by the Food and
Drug Administration or as directives from the European Union or by
recognized authorities in other jurisdictions. In particular the
composition according to the invention provides those nutrients and
those amounts as required by the patient because of the specific
disease state of the patient. These amounts of the active
components cannot be consumed by adapting the normal diet.
[0121] In an embodiment, the composition according the invention is
meant to therapeutically improve one or more of body weight, body
mass index, lean body weight, muscle mass, muscle strength or
muscle function. This improvement can occur in elderly, in
particular frail elderly. The composition according to the
invention can suitably be used in the nutritional management of
individuals suffering from frailty symptoms or the therapeutic
management of frailty (or prefrailty), by providing a certain
amount of the active components per day, and preferably per period
of about 4 hours.
[0122] A daily amount as described herein means in particular an
amount in a daily dosage unit provided by the combination of the
invention. Such a daily dosage unit may be a single dosage, but it
may also be divided over two or three, or even more daily servings.
If the combination, according to a preferred embodiment, is
intended for administration as a single unit, the daily amounts as
described herein are preferably the amounts present in the
(preferably packaged) combination unit.
[0123] It has been found that the administration of at least two
components selected from the group of (i) a nucleoside equivalent,
(ii) an .omega.-3 polyunsaturated fatty acid selected from the
group of DHA, DPA and EPA, (iii) a vitamin B, preferably selected
from the group of vitamin B6, B11 and B12, (iv) a phospholipid, (v)
an antioxidant, preferably selected from the group of vitamin C and
vitamin E and (vi) a choline, with the proviso that at least
component (i) or (iii) is present, is suitable for use in the
prevention or treatment of frailty in a mammal, in one embodiment
together with or as part of a diet providing energy sources
(carbohydrate, protein, fat), compared to the same isocaloric diet
without said combination. Thus, it is concluded that the
composition according to the invention is effective, without
needing an increase in caloric intake. Accordingly, in a specific
embodiment, the effect of said combination on increasing one or
more of body weight, body mass index, or lean body weight is not
attributed to an increase in caloric intake.
(i) Nucleoside Equivalent
[0124] The composition according to the invention may comprise a
nucleoside equivalent. As used herein, nucleosides include
nucleosides as such deoxynucleosides as such, and equivalents of
nucleosides as such or deoxynucleosides as such. Thus, when
referring to a nucleoside, this term is meant to include the
corresponding deoxynucleoside.
[0125] Equivalents in particular are compounds comprising a
nucleobase, such as mononucleotides (mono-, di- or triphosphates of
nucleosides), oligonucleotides, polynucleotides, nucleobases and
physiologically acceptable derivatives thereof that may be
converted into the nucleoside as such or a nucleotide as such in
vivo. Examples of such derivatives include various esters. WO
2002/088159 (Trommsdorff GmbH) relates to uridine esters, which may
be used in accordance with the present invention. The contents of
this publication regarding (deoxy)uridine esters is incorporated by
reference. Such equivalents are capable of increasing endogenous
levels of the active forms of nucleosides in body tissues such as
blood, liver and brain. Also synthetic compounds can be suitably
included as nucleoside source, e.g. acylated derivatives of the
nucleosides, for example triacetyl-uridine.
[0126] The composition according to the invention preferably
comprises a pyrimidine nucleoside or equivalent thereof, such as
cytidine or equivalent thereof or a uridine or equivalent
equivalent. More preferably, the composition according to the
invention comprises a uridine or an equivalent thereof, preferably
at least one uridine or an equivalent thereof selected from the
group consisting of uridine (i.e. ribosyl uracil), deoxyuridine
(deoxyribosyl uracil), uridine phosphates (UMP, dUMP, UDP, UTP),
nucleobase uracil and acylated uridine derivatives. Preferably, the
composition according to the invention comprises an uridine
phosphate selected from uridine monophosphate (UMP), uridine
diphosphate (UDP) and uridine triphosphate (UTP). Most preferably,
the composition according to the invention comprises UMP, as UMP is
most efficiently being taken up by the body after oral
administration. Hence, inclusion of UMP in the composition
according to the invention enables a high efficacy at the lowest
dosage, the administration of a low volume to the subject or both.
Uridine derivatives like UDP, which is readily formed from dietetic
UMP, also appear to be important, in particular for transport of
glycoproteins and glycolipids within the cell and availability
thereof in the cytosol and plasma membrane.
[0127] Preferably, at least 20 weight % of the uridine or an
equivalent thereof in the composition according to the invention is
provided by UMP, more preferably at least 50 weight %, most
preferably at least 90 weight %.
[0128] Preferably, the present use comprises the daily
administration of uridine or an equivalent thereof in a daily
dosage of 0.08 to 3 g per day, preferably 0.1 to 2 g per day, more
preferably 0.12 to 1 g per day.
[0129] Preferably, the present use comprises the daily
administration of UMP in a daily dosage of 1.3 to 37.5 mg UMP per
kilogram body weight of the subject to be treated. The required
dosages of the equivalents of uridine on a weight basis can be
calculated from the daily dosage for UMP by taking equimolar
amounts using the molecular weight of the equivalent and of UMP,
the latter being 324 Dalton. The daily dosage of equivalents is
preferably 3 to 115 .mu.mol per kg body weight per day, preferably
5 to 35 .mu.mol per kg body weight per day, or 0.25 to 9 mmol,
preferably 0.3 to 6, most preferably 0.45 to 2.8 mmol per day.
[0130] Preferably, the present use comprises the daily
administration of a combination comprising uridine or an equivalent
thereof in an amount of 0.06 to 2.4 g UMP per 100 ml liquid
composition, preferably 0.08 to 1.6 g UMP per 100 ml liquid
composition, more preferably 0.12 to 0.8 g per 100 ml liquid
composition. Alternatively, the optimal dose for uridine
monophosphate per 100 g dry matter is 0.18 to 7.2 g, preferably
0.24 to 5.4 g and more preferably 0.36 to 2.4 g.
[0131] As a suitable cytidine equivalent cytidine can be used, for
example as free base or as a salt, as an ester, as a phosphate
derivative, like CMP, CDP or CTP, as cytosine, and as choline
derivative, e.g. as citicoline. However, when both an uridine
equivalent and a cytidine equivalent are included simulateously in
the composition according to the invention it is preferred that the
weight ratio of the sum of uridine and equivalents thereof to the
sum of cytidine and equivalents thereof is larger that 1.0, more
preferably at least 2.0, most preferably more than 5.0. Although
cytidine is a precursor of uridine, it is more efficient and
effective to include uridine in the composition according to the
invention, because it passes more easily the blood brain
barrier.
[0132] In some embodiments of the invention, useful sources of
nucleosides include extracts of plant, animal, bacterial, algae or
yeast material, e.g. in a composition according to the invention
for individuals which don't suffer from a kidney disease. Examples
of such extracts include heat-treated aqueous extracts from baker's
yeast or brewer's yeast. In a further preferred embodiment, the
composition according to the invention preferably does not contain
high amounts of other nucleotides. Hence, preferably the weight
ratio sum of uridine and equivalents thereof to adenosine or its
equivalents in the composition according to the invention is below
0.1, more preferably below 0.01, most preferably 0. Preferably, the
weight ratio of the sum of the amount of uridine and equivalents
thereof to the amount of guanosine or its equivalents in the
composition according to the invention is below 0.1, more
preferably below 0.01, most preferably 0. Preferably, the weight
ratio of sum of uridine and equivalents thereof to inosine in the
composition according to the invention is below 0.1, more
preferably below 0.01, most preferably 0.
(ii) .omega.-3 polyunsaturated fatty acids (.omega.-3 PUFA's)
[0133] The composition according to the invention may comprise an
.omega.-3 polyunsaturated fatty acid (.omega.-3 PUFA), in
particular an .omega.-3 long chain polyunsaturated fatty acid
(LCPUFA), more in particular selected from the group of
docosahexaenoic acid (22:6 .omega.-3; DHA), docosapentaenoic acid
(22:5 .omega.-3; DPA) and eicosapentaenoic acid (20:5 .omega.-3;
EPA). Useful sources include fish oil, algae oil, eggs lipids and
genetically modified organisms.
[0134] Preferably, the composition according to the invention
comprises at least DHA, preferably DHA and EPA. More preferably,
the combination comprises DHA and at least one precursor of DHA
selected from EPA and DPA. More preferably, the composition
according to the invention comprises DHA and EPA. The inventors
recognized that only a part of the DHA incorporated in the brain
originates from orally ingested DHA. An important part of the DHA
incorporated in the brain is derived from conversion of DPA to DHA
in the brain. In a further aspect, the composition according to the
invention preferably contains a significant amount of EPA. EPA is
converted to DPA (.omega.-3), increasing subsequent conversion of
DPA (.omega.-3) to DHA in the brain. Hence, the composition
according to the invention preferably also contains a significant
amount of EPA, so to further stimulate in-vivo DHA formation.
[0135] The .omega.-3 PUFA's, in particular the LCPUFA's, more in
particular DHA, DPA and EPA, may be provided in any form such as,
but not limited to, triglycerides, diglycerides, monoglycerides,
free fatty acids or their salts or esters, phospholipids,
lysophospholipids, glycerol ethers, lipoproteins, ceramides,
glycolipids or combinations thereof. Preferably, the composition
according to the invention comprises at least DHA in triglyceride
form.
[0136] Preferably, the present method comprises the daily
administration of 200 to 5000 mg, more preferably 400 to 3000 mg,
most preferably 800 to 2500 mg of the sum of DHA and EPA. The
proportion of (DHA+EPA) relative to the total amount of fatty acids
in the combination is preferably 5 to 50 weight %, more preferably
10 to 45 weight %, most preferably 15 to 40 weight %. Preferably,
the present method comprises the daily administration of 100 to
4000 mg, more preferably 120 to 1800 mg of DHA.
[0137] Preferably, the composition according to the invention
comprises 1 to 40 weight % DHA based on total amount of fatty
acids, preferably 3 to 36 weight % DHA based on total amount of
fatty acids, more preferably 10 to 30 weight % DHA based on total
amount of fatty acids in the composition according to the
invention. The composition according to the invention preferably
comprises 0.5 to 20 weight % EPA based on total amount of fatty
acids, preferably 2 to 10 weight % EPA based on total amount of
fatty acids, more preferably 5 to 10 weight % EPA based on total
fatty acids. The weight ratio of DHA to the sum of EPA and DPA is
preferably larger than 1.0, more preferably 1.2 to 10, more
preferably 2 to 8. The above-mentioned ratios and amounts take into
account and optimise several aspects, including taste (too high
LC-PUFA levels reduce taste, resulting in a reduced compliance),
balance between DHA and precursors thereof to ensure optimal
effectiveness in relation to maximum dosage and possibility of
product formulations such as liquid form, bar or capsule.
[0138] In one embodiment, the composition according to the
invention contains a low amount of arachidonic acid (AA; 20:4
.omega.-6). Arachidonic acid is believed to counteract the effects
of the composition according to the invention. The present subjects
normally ingest sufficient AA, or precursors thereof, and an excess
daily dosage may stimulate inflammatory responses, inhibiting daily
activities. Preferably, the weight ratio DHA/AA in the composition
according to the invention is at least 5, preferably at least 10,
more preferably at least 15, up to e.g. 100. Preferably, the weight
ratio EPA/AA is at least 2. The present method preferably comprises
the administration of a composition comprising less than 5 weight %
AA based on total amount of fatty acids, more preferably below 2.5
weight %. The .omega.-6/.omega.-3 weight ratio of long-chain
polyunsaturated fatty acids with at least 20 carbon atoms in the
composition according to the invention is advantageously below 0.5,
preferably below 0.2. If the long-chain polyunsaturated fatty acids
with 18 carbon atoms are also included in the ratio, the preferred
.omega.-6/.omega.-3 weight ratio is 0.05 to 1, more preferably 0.1
to 0.6, most preferably 0.15 to 0.4.
(iii) Vitamin B
[0139] The composition according to the invention comprises at
least one vitamin B. The vitamin B is selected from the group of
vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin
or niacinamide), vitamin B5 (pantothenic acid), vitamin B6
(pyridoxine, pyridoxal, or pyridoxamine, or pyridoxine
hydrochloride), vitamin B7 (biotin), vitamin B9 (folic acid or
folate), and vitamin B12 (various cobalamins). Preferably, at least
one vitamin B is selected from the group of vitamin B6, vitamin B12
and vitamin B9. In particular, good results have been achieved with
a combination comprising vitamin B6, vitamin B12 and vitamin B9.
Advantageously, vitamin B12 and vitamin B9 are included because low
plasma B12 or vitamin B9 levels are a risk factor for the
development of Alzheimer's disease.
[0140] The vitamin B is to be administered in an effective dose,
which dose depends on the type of vitamin B used. As a rule of
thumb, a suitable minimum or a maximum dose may be chosen based on
known dietary recommendations, for instance as recommended by
Institute of Medicine (IOM) of the U.S. National Academy of
Sciences or by Scientific Committee on Food (a scientific committee
of the EU), the information disclosed herein and optionally a
limited amount of routine testing. A minimum dose may be based on
the estimated average requirement (EAR), although a lower dose may
already be effective. A maximum dose usually does not exceed the
tolerable upper intake levels (UL), as recommended by IOM.
[0141] If present in the nutritional or pharmaceutical composition
according to the invention, the vitamin B6 is usually present in an
amount to provide a daily dosage in the range of 0.5 to 100 mg, in
particular in the range of 0.75 to 25 mg, more in particular in the
range of 0.9 to 5 mg. If present in the nutritional or
pharmaceutical composition according to the invention, the vitamin
B12 is usually present in an amount to provide a daily dosage in
the range of 0.5 to 1000 .mu.g, in particular in the range of 1 to
100 .mu.g, more in particular in the range of 1.5 to 10. If present
in the nutritional or pharmaceutical composition according to the
invention, the vitamin B9 is usually present in an amount to
provide a daily dosage in the range of 50 to 5000 .mu.g, in
particular in the range of 150 to 1000 .mu.g, more in particular in
the range of 200 to 1000 .mu.g
[0142] In a preferred embodiment of the invention, the active
components are included in a drink, preferably having a volume of
about 125 ml, or in an alternative preferred embodiment in a
product having a dry mass content of about 30 g, per packaging each
of them being for consumption once a day. This means that the
amounts per daily dose as mentioned above can be recalculated to a
concentration per millilitre, by dividing the above-mentioned value
with 125, or to a concentration per g dry mass of the product by
dividing by 30.
[0143] This way of calculation also applies to the other active
components (i) to (vi) in the composition according to the
invention when a desired dose per daily dose is disclosed.
(iv) Phospholipids
[0144] The composition according to the invention may comprise a
phospholipid. As used herein, the term phospholipid includes
lyso-phospholipids, de-acylated phospholipids and
glycerophospholipids. It is preferred to include a phospholipid
which is capable of increasing chylomicrons formation in elderly
after administration of triglyceride lipids and can provide useful
fatty acids. In particular, the phospholipid is selected from the
group consisting of phosphatidylcholine(PC),
phosphatidylethanolamine (PE), phosphatidylserine (PS),
phosphatidic acid (phosphatidate), phosphoinositides (such as
phosphatidylinositol (PI), phosphatidylinositol phosphate,
phosphatidylinositol bisphosphate, phosphatidylinositol
triphosphate) and sphingomyelin. In particular, the combination
according to the invention comprises at least two different
phospholipids selected from the group consisting of
phosphatidylserine, phosphatidylinositol, phosphatidylcholine and
phosphatidylethanolamine. Preferably the combination according to
the invention comprises phosphatidylcholine,
phosphatidylethanolamine and phosphatidylserine. Good results have
been achieved with a combination of phosphatidylcholine (PC) and
phosphatidylserine (PS), preferably in a weight ratio of 3:1.
[0145] For instance, lecithin may be used as a source for the
phospholipids. Optionally the phospholipids are fortified with one
or more phospholipids, such as a ceramide, a sphingolipid or a
specific phospholipid, such as a phosphatidylcholine.
[0146] The phospholipid is to be administered in an effective dose.
Usually, the total phospholipid daily dosage is in the range of 50
to 5000 mg, in particular in the range of 100 to 2000 mg, more in
particular in the range of 150 to 1200 mg
[0147] Inclusion of phospholipids further beneficially improves
membrane function, thereby enabling an improved functioning of the
different parts of the brain that may be affected in prodromal
subjects. Furthermore, the phospholipids improve stability and
shelf life of the composition according to the invention.
Phospholipids further enable the manufacturing of palatable
compositions. Also, phospholipids are a source for choline and
prevent the decline in plasma choline levels after exercise.
Choline is necessary for the formation of acetylcholine, a
neurotransmitter involved in learning and memory and in the
activation of muscles. These advantages are already achieved at
relatively low phospholipid levels.
(v) Anti-Oxidant
[0148] The composition according to the invention may comprise an
antioxidant, in particular one or more antioxidants selected from
the group of vitamin C, vitamin E and selenium. The vitamin C may
be present as free acid (ascorbic acid) or as a salt, e.g. sodium
ascorbate or potassium ascorbate. Suitable sources of vitamin E
include (alpha-) tocopherol and tocotrienol. Suitable sources of
selenium include selenate and selenite.
[0149] The anti-oxidant is to be administered in an effective dose.
As a rule of thumb, a suitable minimum or a maximum dose may be
chosen based on known dietary recommendations, for instance as
recommended by the Institute of Medicine (IOM) of the U.S. National
Academy of Sciences or by the Scientific Committee on Food (a
scientific committee of the EU), the information disclosed herein
and optionally a limited amount of routine testing. A minimum dose
may be based on the estimated average requirement (EAR), although a
lower dose may already be effective. A maximum dose usually does
not exceed the tolerable upper intake levels (UL), as recommended
by IOM. If present in the combination, vitamin C is usually present
in an amount to provide a daily dosage in the range of 20 to 1200
mg, in particular in the range of 30 to 400 mg, more in particular
in the range of 35 to 120 mg. If present in the nutritional or
pharmaceutical composition according to the invention, the vitamin
E is usually present in an amount to provide a daily dosage in the
range of 8 to 200 mg, in particular in the range of 20 to 140 mg,
more in particular in the range of 35 to 100 mg.
[0150] If present in the nutritional or pharmaceutical composition
according to the invention, the selenium is usually present in an
amount to provide a daily dosage in the range of 40 to 400 .mu.g,
in particular in the range of 50 to 200 .mu.g, more in particular
in the range of 55 to 80 .mu.g.
[0151] Optionally one or more antioxidants may be present other
than (v) the antioxidant selected from the group of vitamin C,
vitamin E and selenium.
(vi) Choline
[0152] The nutritional or pharmaceutical composition according to
the invention may comprise a choline. Choline refers to the various
quaternary ammonium salts containing the
N,N,N-trimethylethanolammonium cation. More specifically, choline
is selected from the group of the choline cation, choline salts or
esters, such as choline chloride, choline bitartrate, choline
stearate or the like, or compounds that dissociate to choline, such
as choline alfoscerate, sphingomyelin, cytidine-diphospho-choline
or citicoline or CDP-choline, acylglycerophosphocholines, e.g,
lecithin, lysolecithin, glycerophosphatidylcholine, and any mixture
thereof. It is preferred to include a choline salt or choline
alfoscerate into the composition according to the invention.
[0153] In particular, choline is to be administered in an amount to
provide a daily dosage of 100 to 4000 mg, more in particular of 200
to 2000 mg.
[0154] Furthermore, the nutritional or pharmaceutical composition
according to the invention may comprise one or more further
micronutrients, for instance one or more micronutrients selected
from the group of vitamins, minerals, and trace elements, taurine
and inositol.
Protein and Energy Content
[0155] The composition, preferably the nutritional composition
according to the invention allows improvement of BMI, or LBM, or
frailty, without demanding to consume large amounts of protein or
additional energy. Actually, the amount of energy in the
composition according to the invention can remain limited to a
value of less than 400 kcal (1680 kJ), preferably less than 280
kcal (1178 kJ) or more preferably less than 210 kcal (882 kJ), all
expressed per daily dose for an adult human. The amount of energy
is not needed to create the effect (as can be concluded from the
experiment, which has an isocaloric control), but is simply the
result of incorporating the active components into a small sized
food product, which is thus used as a vehicle. In one embodiment,
the components (i) to (v) are included in a pharmaceutical
composition according to the invention having an energy content per
serving unit of less than 130 kcal (546 kJ) or preferably less than
80 kcal (336 kJ).
[0156] In one embodiment, the amount of active components (defined
as components (i) to (v)), which is needed to achieve the effect on
BMI, etc, delivers more than 50%, preferably more than 58%, most
preferably 62 to 88% of the total amount of calories of the
composition as claimed. For the calculation of energy, the
inventors use 9 kcal (37.8 kJ) per g of lipids or phospholipids,
zero kiloJoule per g of nucleosides, vitamins and a choline
equivalent, 4 kcal (16.8 kJ) per g of protein and digestible
carbohydrate and 2 kcal (8.4 kJ) per g of fibre.
[0157] The protein amount in the composition according to the
invention, if present, can remain relatively low, which can have
important advantages to the largest part of individuals which
suffer from weight loss or symptoms of frailty. In particular, it
is preferred that composition according to the invention should not
impair normal eating patterns, allow manufacture of a palatable
product and not induce heartburn or gastrointestinal discomfort
after consumption thereof. The composition according the invention
appears effective, also when the concentration of protein in the
composition according to the invention remains below 11 g per 100
ml and preferably below 9, more preferably 3 to 8.4 g, and most
preferably 5.2 to 8.2 g per 100 ml of the composition according to
the invention.
[0158] For concentrates, semi-dry and dry products, it is more
convenient to express the concentration of protein on gram dry
matter basis. The amount of protein is in these cases usually less
than 400 mg, preferably less than 360 mg, more preferably 100-340,
most preferably 150 to 330 mg per g dry matter. Simple proteins can
be used in these amounts like milk protein. These technical
features of the composition according to the invention result in
good compliance with the feeding protocol with such composition
according to the invention and in very little adaptation of the
normal diet after the composition according to the invention have
been consumed according their recommended use.
[0159] In order to avoid an undesired satiating effect, especially
in elderly, the amount of caseinates preferably is 4.5 weight % or
vol % or less for liquid formula, and more preferably 0.5 to 4.0
weight % or vol % or most preferably 0.8 to 3.3 weight % or vol %.
Therefore, but also for efficacy reasons, it is preferred to
include a non-caseinate in the composition according to the
invention, which is elaborated below.
[0160] The effect of the active components (specific combinations
of nucleosides, LC-PUFAs, phospholipids, vitamins and a choline
equivalent) allows efficacy by administering a nutritional
composition according to the invention with the minimum amount of
food volume, e.g. less than 150 ml per serving unit, which is also
important because elderly, and especially frail elderly experience
much earlier satiety when consuming food. In one embodiment of the
invention the actives are provided to the consumer, in a ready to
use serving unit which provides 15 to 160 g of the effective
composition according to the invention.
[0161] It has been suggested before, that additional protein of
specific quality could improve LBM or increase body weight in
elderly. Focus in the most relevant papers in this field is on the
amount of protein (which should preferably be more than a few dozen
g additional protein per daily dose), inclusion of L-leucine or
including a large portion of essential amino acids in the protein
amount, e.g. more than 15 g of the pure crystalline amino acids.
Complying to such diet can be very demanding to many frail elderly,
also because the taste of free amino acids is often considered as
offensive or because consumption of such large amounts of protein
has a significant impact on the consumption of regular diet.
[0162] The invention therefore provides a solution for the problem
that an undesired amount of additional protein has to be
administered for anabolic purposes, i.e. the improvement in BMI of
elderly and it increases the improvement of the brain function as
observed in frail elderly by consuming the combination of one or
more of the active components (i) to (v) according to the
invention.
[0163] The protein amount preferably comprises a non-caseinate
protein for supporting an effect of the composition according the
invention on BMI in frail elderly. In particular, specific whey
protein relatively low in phosphorous, fish proteins, in particular
cod protein, or a protein derived from eggs and proteins derived
from vegetables, like potato, soy, pea, beans, lupin, quinoa and
amaranth appeared suitable. The proteins can be intact, either
heat-treated or non-denatured, or be partially hydrolyzed.
Hydrolyses of the intact protein aims to improve its solubility,
but degree of hydrolyses should be kept to the minimum, preferably
to a degree of hydrolyses between 2 and 12, in order to maintain
good organoleptic properties of the ready to use composition
according to the invention. In a preferred embodiment, the amount
of non-dairy protein is more than 21 weight %, more preferably more
than 25 weight %, most preferably more than 42 weight %, in
particular more than 51 weight % of the protein amount.
[0164] Suitable whey proteins include those which have a
phosphorous content less than 400 mg/l when 100 g of the protein is
dissolved in one litre of water. Preferably, this phosphorous
content is 70 to 340 mg/l. The amount of protein can be calculated
from the label of the product, or, when this is impossible or not
justified by measuring Kjeldahl nitrogen by a method accepted as
preferred in the prior art for the specific matrix, and multiplying
this by 6.25 for mixtures of proteins and peptides.
[0165] If dairy proteins are included, it is preferred to include a
whey protein. Such protein is preferably enriched in serum albumin
or alpha lactalbumin. Such dairy amount also preferably comprises a
lactoferrin. The concentration of alpha-lactalbumin as fraction of
all whey proteins is preferably more than 25 weight %, that of
serum albumin 5 to 12 weight %. The concentration of lactoferrin is
preferably in the range 0.25 to 3 weight %, preferably 0.29 to 1.4
weight %, more preferably 0.34 to 1.2 weight % of the protein
amount.
[0166] In cases where the fatty acids comprise that much omega 3
fatty acids that the ratio of the weight amounts of omega 3 to
omega 6 exceed 5, the amount of whey protein is preferably less
than 50 weight % of the protein amount, in order to keep the
satiating character of the composition according to the invention
as low as possible, while maintaining efficacy of the composition
according to the invention.
[0167] It is also useful to include non-essential amino acids or
their salts or esters. Examples of suitable amino acids include
serine and aspartic acid. These amino acids can be administered as
L-isomer or as a racemic mixture of L and D isomers of the
particular amino acid. The amount aspartate plus asparagine in the
composition according to the invention is preferably more than 8.4,
more preferably 9.0 to 16, most preferably 9.5 to 15 g per 100 g
amino acids in the composition according to the invention. The
amount of serine in the ready to use composition according to the
invention is preferably more than 4.1 g per 100 g amino acids. The
presence of these two amino acids in the formula is thought to be
at least partially responsible for the anabolic character of the
formula and the observed efficacy in treating symptoms of frailty.
Increasing the concentrations to the indicated amounts in the
preferred embodiment increases their effect. In this respect, the
effect on neurological symptoms in the low BMI elderly includes the
effect on depressed mood, stamina and the activities of daily
living. The inventors believe that an effect on metabolic pathways
is responsible for this, in particular an effect on glucose
metabolism and gene expression and not the amount of calories or
amount of protein that are provided by the composition according
the invention.
[0168] The selected types and amounts of protein appeared to have
the unexpected advantage in that long term administration to
persons experiencing frailty or low body weight, especially in the
aged population achieved better results in increasing BMI, lean
body mass or body weight and muscle function, muscle strength and
muscle mass, than most high protein dairy protein based formula,
fortified with essential amino acids, and demonstrated less adverse
effects in sensitive persons.
[0169] It is of importance that in a preferred embodiment, the
protein amount contributes to a better functioning of metabolism in
order to support the maintenance of BMI, and lean body mass, and
other symptoms of frailty, like exhaustion and fatigue and
neurological function. Therefore, the protein preferably comprises
a whey protein and more preferably a whey protein and a vegetable
protein.
[0170] In a preferred embodiment, the osmotic value of the
composition according to the invention is as low as possible, in
order to facilitate easy stomach emptying. In a preferred
embodiment, the composition according to the invention demonstrates
an osmolality below 450 mEq/l.
[0171] In addition, the buffer strength of the composition
according to the invention preferably low, in order to achieve
rapid digestion and gut transfer of the composition according to
the invention after consumption. This is done by using the amounts
and types of proteins as indicated above and by preventing the use
of high salt loads, in particular of citrates and phosphates. The
amount of phosphorous in the composition according to the invention
is preferably less than 150 mg, more preferably 20 to 110 mg, most
preferably 50 to 72 mg per 100 ml. In one embodiment, the
nucleotides in the composition according to the invention, like a
uridine phosphate, or cytidine phosphate are replaced by their
base. In a preferred embodiment, the composition according to the
invention comprises a nucleobase and a nucleoside or nucleotide. In
a preferred embodiment, the ratio of the weight amount of
nucleobase to the sum of the corresponding nucleosides and
nucleotides is more than 0.06, preferably 0.2 to 0.9.
[0172] The amount of organic acids, like citrates, is preferably
less than 2, more preferably less than 1.2 weight %, most
preferably 0.1 to 0.9 weight % of the digestible carbohydrate
amount. These features are in particular relevant when the elderly
suffer from diagnosed anchlorhydria. This is a major problem in
elderly and in particular in institutionalized elderly or elderly
having a BMI under 23.5 kg/m2 or frail elderly.
[0173] In a preferred embodiment, the composition according the
invention is a liquid formula having a viscosity of less than 60,
more preferably 2 to 30 mPas, measured at 20 degrees .degree. C. As
used herein, the viscosity is the viscosity as measurable using a
Anton Paar Physica MCR301 rheometer with aCP50-1/PC cone (diameter
50 mm, 1.degree. difference between middle and outside) at
20.degree. C. at 100 s.sup.-1.
Dosage Form
[0174] Further, one or more additional ingredients may be present
that are commonly used in the prior art, dependent on the
form--nutritional or pharmaceutical composition--in which the
combination is provided.
[0175] If the dosage form is a pharmaceutical composition, the
pharmaceutical composition may comprise one or more excipients
known in the prior art to provide a pharmaceutical composition in a
dosage form of choice. The pharmaceutical composition is preferably
for enteral application (orally or via tube-feeding). Examples of
solid formulations are tablets, capsules (e.g. hard or soft shell
gelatine capsules), pills, sachets, powders, granules and the like
which contain the active ingredients together with a conventional
carrier. Any conventional carrier material can be utilized. The
carrier material can be organic or inorganic inert carrier material
suitable for oral administration. Suitable carriers include water,
gelatine, gum Arabic, lactose, starch, magnesium stearate, talc,
vegetable oils, and the like. Additionally, additives such as
flavouring agents, preservatives, stabilizers, emulsifying agents,
pH-buffers and the like may be added in accordance with accepted
practices of pharmaceutical compounding. While the individual
active ingredients are suitably administered in a single
composition they may also be administered in individual dosage
units.
[0176] If the dosage form is a nutritional composition, the
composition generally comprises at least one macronutrient for
providing (additional) energetic value to the nutritional
composition. The macronutrient may suitably be selected from the
group of proteinaceous matter (proteins, peptides, amino acids),
fat, other than component (ii), and digestible carbohydrates.
[0177] Suitable proteinaceous matter, lipids and carbohydrates, and
suitable concentrations of the macronutrients may be based on known
dietary guidelines for food products, in particular for food
products for the elderly. Suitable formulations may e.g. be based
on known commercially available clinical foods, or foods advertised
for feeding elderly people or for feeding people suffering from
dementia.
[0178] Regarding the lipid, preferably one or more triglycerides
are present. These may be selected from vegetable oils and fats and
animal oils and fats.
[0179] Regarding the digestible carbohydrates, these may in
particular be selected from digestible pentoses, digestible hexoses
digestible oligosaccharides, e.g. digestible disaccharides and
digestible trisaccharides. and digestible polysaccharides (e.g.
starch). More specifically one or more digestible carbohydrates may
be chosen selected from the group of galactose, mannose, ribose
sucrose, trehalose, palatinose, lactose, maltodextrose, maltose,
glucose, fructose, including oligomers and polymers thereof.
[0180] Optionally, a nutritional composition according to the
invention comprises one or more non-digestible carbohydrates
(dietary fibres) such as oligosaccharides. As used herein, the term
oligosaccharides in particular refers to saccharides comprising 3
to 25 monosaccharide units per molecule. The oligosaccharide(s) may
in particular be selected from the group of fructo-oligosaccharides
(FOS), galacto-oligosaccharides (GOS),
trans-galacto-oligosaccharide s (TOS), xylo-oligosaccharides (XOS),
soy oligosaccharides, and the like. Optionally, also higher
molecular weight compounds such as inulin, resistant starch and the
like may be incorporated in the composition according to the
invention.
[0181] Further, the nutritional composition may comprise a
probiotic.
[0182] Further, the nutritional composition may comprise one or
more additives commonly used in food technology, such as one or
more additives selected from the group of flavourings, stabilisers,
preservatives, colourants, emulsifiers, pH-buffers etc.
[0183] The nutritional composition for use in a accordance with the
invention may be a solid composition. a semi-solid composition
(such as a paste or a gel) or a liquid composition, such as a
beverage of a drinkable food product.
[0184] The nutritional composition according to the invention may
in particular be intended for enteral administration (orally or by
tube feeding). Alternative forms of administration may be applied,
in particular parenteral administration. The skilled person will be
able to formulate a suitable product for parenteral administration,
in particular by preventing inclusion of non-endogenous
proteinaceous material which may induce an allergic reaction or
other adverse effects. The administration may be carried out based
on a manner known per se for a specific type of nutritional
composition.
[0185] In particular, the nutritional composition may be selected
from the group of spreads; yoghurts, custards, ice-creams, butter,
and other dairy products; dairy-substitute products; drinks, such
as fruit drinks; candy bars; cookies, cakes and other bakery
products; and drinkable foods.
[0186] The total energetic value of the composition may be chosen
within wide limits and may range, e.g., from 0.2 to 4 kcal/g. In
particular, the energetic value may be at least 0.4 kcal/g, more in
particular at least 0.8 kcal/g. In particular, the energetic value
may be 5 kcal/g or less, more in particular 3 kcal/g or less.
[0187] In case the nutritional composition is a fluid, it usually
has a nutritional value of at least 20 kcal/100 ml, preferably of
at least 50 kcal/100 ml, in particular of at least 75 kcal/100 ml
or at least 100 kcal/100 ml. For a fluid composition the
nutritional value is usually 300 kcal/100 ml or less, in particular
200 kcal/100 ml or less, more in particular 150 kcal/100 ml or
less.
[0188] Suitable dosage forms, active ingredients, further
components that may be co-administered and ways of administration
are as described for the nutritional or pharmaceutical composition
as described herein above, the claims, or the examples herein
below.
[0189] The vitamin B, the phospholipid, the antioxidant and--if
present--further active ingredients, may be administered under the
supervision of a medical specialist or be self-administered.
[0190] Specific Embodiment: Nutritional Composition
[0191] As mentioned above, the invention also relates to a
nutritional composition comprising (i) at least one component
selected from the group of uridine and iuridine monophosphate, (ii)
DHA and EPA (which may be present in bound for e.g. as a
triglyceride ester) (iii) a vitamin B, (iv) a phospholipid, v) an
antioxidant, and (vi) a choline. Preferred sources, preferred
specific compounds for each group, concentrations, dosages and
other product properties may generally be as described herein
above. The nutritional composition according to the invention
usually also comprises, protein. Further, digestible carbohydrate
and fibre. are usually present
[0192] Preferably, the nutritional composition comprises i-a) the
nucleoside uridine and i-b) the nucleotide uridine monophosphate.
i-a) Uridine and i-b) uridine monophosphate are preferably present
in a weight to weight ratio in the range of 0.2:1 to 0.7:1. The
presence of both i-a) uridine and i-b) uridine monophosphate,
especially in said ratio, is in particular advantageous because it
provides a more uniform bioavailability after oral administration,
which increases the number of responders to the composition (used)
according to the invention (subjects reacting positively on
treatment with a compsition in accordance with the invention),
without any unacceptable adverse effects. In addition, the
nucleoside uridine may decreases activation of P2Y receptors in the
gut.
[0193] In a preferred embodiment, the total content of uridine plus
uridine monophosphate is in the range of 5-30 mg per gram dry
weight, more preferably in the range of 8-20 mg per gram dry
weight, in particular in the range of 10-18 mg per gram dry
weight
[0194] The total content of uridine plus UMP as a weight percentage
of total nucleoside equivalents preferably is more than 28 wt. %,
more preferably 40-100 wt. %, most preferably 60-100 wt. %, in
order to obtain a selective effect of the nucleotide fraction in
the product of the invention, such as in order to avoid triggering
an undesired effect in the enterocytes or liver or the enteral
nervous system, due to activation of receptors, for example the P2X
or P2Y receptors, by adenosine-based or guanosine-based
nucleotides.
[0195] The weight to weight ratio of UMP to GMP
(guanosinemonophosphat) preferably is more than 10. The weight to
weight ratio of UMP to UMP (inosine monophosphate preferably is
more than 10.
[0196] In a specific embodiment, the nutritional composition
according to the invention, comprises 3-14 mg EPA per gram dry
matter, preferably 5-10 mg EPA per gram dry matter and 12-56 mg DHA
per gram dry matter, preferably 2.5-20 mg DHA per gram dry matter.
Preferably, the sum of DHA and EPA is 5-50 wt. % based on total
fatty acids.
[0197] A composition according to the invention preferably has a
low arachidonic acid (AA), content, if present at all, especially
in an embodiment wherein on or more of component (ii) .omega.-3
PUFAs selected from EPA, DHA and DPA are present. AA is thought to
have a disadvantageous effect on the effectiveness of these
components in a use according to the invention. In view thereof,
the weight to weight ratio of the sum of DHA+DPA+EPA to AA
preferably is higher than 5, in particular 6 or higher, more in
particular 12 or higher. In a particularly preferred embodiment,
the weight to weight ratio of DHA to AA is higher than 5. The ratio
long chain .omega.-6 PUFAs to long chain .omega.-3 PUFAs preferably
is 0.05 to 1. The term `long-chain` is used herein for PUFA's
having a carbon chain of at least 20 carbon atoms. In a
particularly preferred embodiment, the weight to weight ratio of
DHA to AA is higher than 5. The ratio .omega.-6 PUFAs to .omega.-3
PUFAs preferably is 0.05 to 1.
[0198] The ratio [uridine monophosphate+uridine]/[phospholipds] of
a nutritional composition according to the invention is usually
less than 5.9, preferably 0.15-4, in particular 0.20-2.4, more in
particular 0.25-0.71. A relatively low ratio of [uridine
monophosphate+uridine]/[phospholipds] is in particular preferred in
a composition comprising a protein. In particular in such
embodiment, it contributes to a better efficacy with respect to a
use of the invention, in particular with respect to providing a
palatable effective product a decrease of uridine concentration and
an increase of phospholipid concentration allows better tasting
while maintaining efficacy. A relatively low ratio is also is
advantageous for improving the palatability, especially during
shelf-life.
[0199] The nutritional composition of the invention usually has an
energy density of less than 13 kcal per gram dry matter, preferably
of 3-9.3 kcal per gram dry matter, more preferably of 4.0-7.0 kcal
per gram dry matter.
[0200] The nutritional composition according to the invention
preferably has a phospholipid content in the range of 3.3-67
mg/gram dry matter, more preferably in the range of 5-33 3.3-67
mg/gram dry matter, in particular in the range of 7-14 mg/gram dry
matter.
[0201] In a specific embodiment, the nutritional composition
according to the invention, comprises phosphatidylcholine (PC). In
such embodiment the weight to weight ratio phosphatidylcholine to
choline is usually more than 0.1, preferably more than 0.26, in
particular 0.30-6, more preferably 0.36-3. Herein, the amount of
choline in grams is to be calculated as the molar contribution of
choline as provided by all choline sources (when orally digested
and assuming 100% bioavailability, including PC), times the
molecular weight of choline (104 g/mol). Herein, the molecular
weight of PC 810 gram/mol. So for example, including 400 mg choline
chloride and 200 mg phosphatidylcholine and 200 mg PL's other than
PC would then result in a weight ratio of PC to choline of
200/[(104/139.6).times.400+(104/810).times.200]=200/[298+25.7]=0.62
[0202] The presence of PC is in particular preferred as a source
for choline, because less PC is required than equimolar choline
ingredient (i.e. N,N,N-trimethylethanolammonium cation) for
obtaining the same choline concentrations in blood. Herewith
choline (salt) content can be reduced, whilst still providing a
choline source. Advantageous thereof include avoiding a fishy odour
of product and/or subject treated with the product; avoiding
irritation of the mucous membranes in case of xerostomia.
[0203] The nutritional product usually comprises a protein. The
protein content is preferably less than 400 mg per gram dry matter,
more, preferably 100-340 mg protein per gram dry matter. A
relatively low protein content is preferred to decrease
consequences on diet intake. In particular, a relatively low
protein content is desired in view of a satiating effect a high
protein content has, which may cause the subject to consume an
insufficient amount of the nutritional product. For improved
palatability and/or for improving brain function. In a liquid
product, the protein content preferably is less than 11 g/100 ml,
more preferably 5.2-8.2 g/l. In a specific embodiment, the protein
content is more than 7 g/100 ml.
[0204] In an advantageous embodiment, the nutritional composition
comprises at least a whey protein. In a liquid product, the dairy
protein content (whey protein, casein, caseinate) preferably is
less than 4 wt./vol %.
[0205] In an advantageous embodiment, the nutritional composition
according to the invention comprises a protein selected from the
group of fish proteins (in particular cod protein), egg-protein and
vegetable proteins. If present, the total content of non-dairy
protein is usually more than 21 wt. % preferably 22-80 wt. %, in
particular 25-40 wt. %, based on total protein content. Non-dairy
proteins, such as vegetable, fish or egg protein is an advantageous
protein source, amongst others because they are less satiating than
dairy proteins. Another reason to include such non-dairy protein is
an improved endocrine response action, which results in good
postprandial glucose response. compared to a dairy protein, in
particular compared to casein/caseinate.
[0206] A vegetable protein may in particular be selected from the
group of potato protein, soy protein, pea protein, beans protein,
lupin protein, quinoa protein and amaranth protein.
[0207] A composition comprising whey protein and amaranth or pea
protein is in particular suitable for increasing BMI. The weight
ratio whey protein to the sum of amaranth and pea protein may in
particular be 50:50 to 90:10, more in particular 60:40 to
80:20.
[0208] A composition comprising whey protein, soy protein and pea
protein is in particular suitable for increasing ADL in subjects
suffering from early physical exhaustion after exercise. When
present in combination, the whey protein content preferably is
30-70 wt. % of the protein fraction, the pea protein fraction
preferably is 15-35 wt. % of the protein fraction, and the soy
protein fraction preferably is 15-35 wt. % of the protein fraction.
One or more other proteins from other sources may be present in a
product comprising proteins from these three protein sources, e.g.
casein, usually in a total concentration of up to 40 wt. % of the
protein fraction.
[0209] The dairy protein or the non-dairy protein may be
non-hydrolysed or may be partially hydrolysed. The degree of
hydrolysis may in particular be 2-12.
[0210] In a specific embodiment, a composition (for use) according
to the invention comprises at least one amino source providing
L-serine and/or L-aspartic acid. The amino acid source can be
selected from free amino acids, including salts thereof, peptides
(oligopeptides, polypeptides, proteins), comprising and L-serine
unit and/or L-aspartic acid units. If present, the L-serine content
preferably is higher than 4.1 g per 100 gram amino acids, including
amino acids in peptides and other compounds providing an amino acid
when digested. If present, the L-aspartic acid content is
preferably 8.4-15 g per 100 gram amino acids including amino acids
in peptides and other compounds providing an amino acid when
digested.
[0211] Preferably, the nutritional composition comprises 0.15-0.5 g
digestible carbohydrate per gram dry weight, in particular
0.20-0.40 g digestible carbohydrate per gram dry weight.
Preferably, the digestible carbohydrate fraction provides glucose,
fructose and galactose (present as monosaccharide or in
oligo/polysaccharide form).
[0212] Preferably 0.01-0.1 g fibre per g dry weight is present in a
composition according to the invention. In particular, the fibre
content may be in the range of 0.02-0.08 g per g dry weight.
[0213] The lipid content in a nutritional composition according to
the invention preferably is 0.15-0.3 g lipids per gram dry
weight.
[0214] Further, the composition may comprises additional vitamins
and/or minerals.
[0215] In particular good results have been achieved with a liquid
composition according to the invention.
[0216] The liquid composition usually has a dry matter content of
15-30 g per 100 ml. The dry matter content preferably is 24 g per
100 ml or less, in order to aid water homeostasis, in particular
16-24 g per 100 ml, more in particular 17-22 g per 100 ml.
[0217] The liquid compositon preferably has an osmolarity of less
than 450 mEq/l, in particular of 120 to 150 mEq/l.
[0218] The viscosity of a liquid nutritional composition according
to the invention is usually les than 200 mPas
[0219] The liquid composition may in particular be packaged as a
unit dose packaging, which may in particular have a liquid
composition content in the range of 50-250 ml, more in particular
in the range of 100-150 ml.
[0220] In a specific embodiment, the composition is a powder, in
particular a powder that is reconstitutable with water to provide a
liquid product according tot the invention
[0221] The invention will now be illustrated by the following
examples and the experimental part, without being bound or
restricted thereto.
EXPERIMENTAL
Example 1
[0222] APP/PS1 mice, a mouse model for AD, were provided with a
diet enriched with DHA and UMP (intake per day: DHA=22.8 mg;
UMP=23.1 mg) or with a control diet for 3 months The two diets were
isocaloric and differed only with respect to DHA and UMP content
The amount of fat, carbohydrates and protein was the same between
diets. During the 3 months of diet intervention body weight was
monitored as was food intake.
[0223] Results. Mice fed the enriched diet showed--on average--a
17.5% increase in body weight after 3 months compared to 14% for
the control mice. Food intake was slightly lower in the group which
were fed the enriched diet (on average 2.88 gram per day) compared
to control mice (on average 3.08 gram per day).
[0224] Conclusion. Alzheimer's disease mice showed an increase in
body weight when fed with the composition according to the
invention (the .omega.-3 polyunsaturated fatty acid DHA and the
nucleoside UMP), not attributed to a caloric increase in body
weight.
Example 2
[0225] APP/PS1 mice, a mouse model for AD, were provided with a
diet enriched with B-vitamins (B6, B12 and folic acid; intake per
day: B6=0.1 mg; B12=0.11 .mu.g; folic acid=18.1 .mu.g),
phospholipids (lecithin; intake per day: 12.4 mg) and antioxidants
(vitamin C, vitamin E, selenium; intake per day: vitamin C=4.8 mg;
vitamin E=4.5 mg; selenium=3.2 .mu.g) or with a control diet for 3
months. The two diets were isocaloric and differed only with
respect to B-vitamins, phospholipids and antioxidants content. The
amount of fat, carbohydrates and protein was the same between
diets. During the 3 months of diet intervention body weight was
monitored as was food intake.
[0226] Results. Mice fed the B-vitamins+phospholipids+antioxidants
enriched diet showed a 18% increase in body weight after 3 months
compared to 14% for the control mice. Food intake was slightly
lower in the B-vitamins+phospholipids+antioxidants group (on
average 2.86 gram per day) compared to control mice (on average
3.08 gram per day).
[0227] Conclusion. Alzheimer's disease mice showed an increase in
body weight when fed with the composition according to the
invention (B vitamins, a phospholipid, and antioxidants), not
attributed to a caloric increase in body weight.
Example 3
[0228] APP/PS1 mice, a mouse model for AD, were provided with a
diet enriched with DHA+UMP (intake per day: DHA=22.8 mg; UMP=23.1
mg) (as in Example 1), B-vitamins (B6, B12 and folic acid; intake
per day: B6=0.1 mg; B12=0.11 .mu.g; folic acid=18.1 .mu.g), and
phospholipids (lecithin; intake per day: 12.4 mg) or with a control
diet for 3 months. The two diets were isocaloric and differed only
with respect to DHA, UMP, B-vitamins and phospholipids content. The
amount of fat, carbohydrates and protein was the same between
diets. During the 3 months of diet intervention, body weight was
monitored as was food intake.
[0229] Results. Mice fed the enriched diet showed a 20% increase in
body weight after 3 months compared to 14% for the control mice.
Food intake was the same in the .omega.-3
PUFA+nucleoside+B-vitamins+phospholipids group (on average 3.02
gram per day) compared to control mice (on average 3.08 gram per
day).
[0230] Conclusion. Alzheimer's disease mice showed an increase in
body weight when fed with the composition according to the
invention (.omega.-3 polyunsaturated fatty acids, a nucleoside, B
vitamins, and phospholipids), not attributed to a caloric increase
in body weight.
Example 4
[0231] APP/PS1 mice, a mouse model for AD, were provided with a
nutritional composition comprising uridine-5'-monophosphate (intake
per day: UMP=23.1 mg); omega-3 fatty acids (including DHA) (intake
per day: DHA=22.8 mg); choline (intake per day: 12 mg);
phospholipids (intake per day: 12.4 mg); B vitamins (intake per
day: B6=0.1 mg; B12=0.11 .mu.g; folic acid=18.1 ug), and
antioxidants (intake per day: vitamin C=4.8 mg; vitamin E=4.5 mg;
selenium=3.2 ug) or with a control diet for 3 months. The two diets
were isocaloric. The amount of fat, carbohydrates and protein was
the same between diets. During the 3 months of diet intervention,
body weight was monitored as was food intake.
[0232] Results. Mice fed the nutritional composition showed a 25%
increase in body weight after 3 months compared to 14% for the
control mice. Food intake was the same in the group fed the
nutritional composition (on average 3.10 gram per day) compared to
control mice (on average 3.08 gram per day).
[0233] Conclusion. Alzheimer's disease mice showed an increase in
body weight when fed with the composition according to the
invention (nucleoside: UMP; .omega.-3 polyunsaturated fatty acids
(including DHA); choline; phospholipids; B vitamins, and
antioxidants), not attributed to a caloric increase in body
weight.
Example 5
[0234] Human patients older than 65 years of age and suffering from
a cognitive impairment were provided for 3 months with a once a day
drink (125 ml) enriched with EPA (300 mg) and DHA (1200),
phospholipids (160 mg lecithin), choline (400 mg), UMP (625 mg),
antioxidants (40 mg vitamin E, 80 mg vitamin C, 60 .mu.g selenium)
B-vitamins (3 .mu.g B12, 1 mg B6, and 400 .mu.g folic acid), and or
with a control drink (125 ml). The two drinks were isocaloric and
differed only with respect to DHA, UMP, B-vitamins, phospholipids
and antioxidants content. The amount of fat, carbohydrates and
protein was the same for both diets.
[0235] The compositions of the drinks were as given in Table 1.
[0236] Results Patients provided with the enriched drink showed an
increase in BMI compared to Alzheimer's disease patients provided
with the control drink (Table 2). Furthermore, the enriched drink
was effective on ADL (ADCS score) in elderly of BMI<26 (FIG.
2).
TABLE-US-00001 TABLE 1 Isocaloric drinks used in Example 5.
Component Invention Control Amount 125 ml 125 ml Macronutrients
Energy, kcal 125 125 Protein (caseinate/WPI), g 3.8 3.8
Carbohydrate, g 16.5 16.5 Fat, g 4.9 4.9 Components according to
invention EPA. mg 300 0 DHA, mg 1200 0 Phospholipids, mg 106 0
Choline, mg 400 0 UMP (uridine monophosphate), mg 625 0 Vitamin E
(alpha-TE), mg 40 0 Vitamin C, mg 80 0 Selenium, .mu.g 60 0 Vitamin
B12, .mu.g 3 0 Vitamin B6, mg 1 0 Folic acid, .mu.g 400 0 Minerals
Sodium, mg 125 125 Potassium, mg 187.5 187.5 Cloride, mg 156.3
156.3 Calcium, mg 100 100 Phosphorus, mg 87.5 87.5 Magnesium, mg
25.0 25.0 Other trace elements Iron, mg 2 2 Zinc, mg 1.5 1.5
Iodine, .mu.g 16.3 16.3 Manganese, mg 0.41 0.41 Copper, .mu.g 225
225 Molybdenum, .mu.g 12.5 12.5 Chromium, .mu.g 8.4 8.4 Other
vitamins Vitamin A, .mu.g 200 200 Thiamin (B1), mg 0.19 0.19
Riboflavin (B2), mg 0.20 0.20 Niacin (B3), mg NE 2.25 2.25
Pantothenic acid (B5), mg 0.66 0.66 Vitamin D, .mu.g 0.88 0.88
Biotin, .mu.g 5.0 5.0 Vitamin K, .mu.g 6.6 6.6 Abbreviations: EPA,
eicosapentaenoic acid; DHA, docosahexaenoic acid; TE tocopherol
equivalents, NE niacin equivalent.
TABLE-US-00002 TABLE 2 Results of BMI increase (Example 5) BMI
after 3 BMI after 6 BMI at Baseline months months Invention 26.198
26.469 26.58* Control 26.175 26.353 26.348 *p = 0.088
Example 6
Example Compositions According to the Invention
[0237] The following compositions according to the invention may be
used for the healthy improvement of body weight in an elderly
person experiencing one or more symptoms of frailty, preferably in
elderly having a BMI below 26 and more specifically below 23.5
kg/m.sup.2:
TABLE-US-00003 TABLE 3 Composition A (per 100 g of ready-to-use
composition) Pyrimidine nucleoside 0.3 g of a mixture of uridine
and uridine monophosphate Vitamin B 1 mg B6, 2 .mu.g B12 and 300
.mu.g folic acid or folate and optionally: A phospholipid 0.2 g
lecithin A choline 1 g choline as choline chloride Lipids 2 g
marine or algae oil, comprising 30-60 g of DHA, DPA or EPA per 100
g fatty acids
TABLE-US-00004 TABLE 4 Composition B (sip feed, amount per 100 ml)
Ingredient Amount Energy .gtoreq.150 kcal (.gtoreq.630 kJ) Protein
.gtoreq.3.5 g Digestible carbohydrates 16 g Fat 5.2 g DHA 300 mg
EPA 75 mg Phospholipids 50 mg UMP 160 mg Choline 100 mg Vitamin B6
0.3 mg Vitamin B12 0.8 .mu.g Folic acid 100 .mu.g Vitamin C 20 mg
Vitamin E 10 mg Selenium 15 .mu.g Vitamin D 1.2 .mu.g Calcium 200
mg
TABLE-US-00005 TABLE 5 Composition C to F Composi- Composi-
Composi- Components tion C tion D tion E Composition F
Macronutrients Energy (kcal) 140 100 150 140 Protein (g) 8 (milk 3
(milk 10 (ultra 8 (pea protein + protein) filtrated protein, blend
soy milk casein, prot/.alpha.-lac) protein + a-lac) free leucine)
Lipids (EPA, DHA, 5.8 3.9 5.1 5.1 phospholipids) (g) Digestible 14
13.2 16 14 carbohydrates (g) Fiber (g) 0.2 0 0.2 0 EPA (mg) 120 240
240 200 DHA (mg) 480 960 960 800 Phospholipids (mg) 210 128 128 160
Choline (mg) 200-300 320 320 260 UMP (mg) 250 500 500 400 Vitamin E
(mg .alpha.- 16 32 32 25 TE) 32 64 64 50 Vitamin C (mg) 67 48 48 50
Selenium (.mu.g) 2.4 2.4 2.4 2 Vitamin B12 (.mu.g) 0.8 0.8 0.8 1
Vitamin B6 (mg) 320 320 320 280 Folates (.mu.g) Sodium (mg) 100 100
100 100 Potassium (mg) 100-200 150 100-200 100-200 Chloride (mg)
100-150 125 100-150 100-150 Calcium (mg) 100-300 80 100-300 100-300
Phosphorus (mg) 100-300 70 100-300 100-300 Magnesium (mg) 32 23.2
23.2 23.2 Iron (mg) 1.6 1.6 1.6 1.4 Zinc (mg) 2.4 1.2 1.2 2 Iodine
(.mu.g) 26 13 13 20 Manganese (mg) 0.88 0.33 0.33 0.4 Copper
(.mu.g) 180 180 180 150 Molybdenum (.mu.g) 26 10 10 20 Chromium
(.mu.g) 6.7 6.7 6.7 8 Vitamin A (.mu.g) 160 160 160 140 Thiamine
(mg) 0.21 0.15 0.15 0.16 Riboflavin (mg) 0.23 0.16 0.16 0.18 Niacin
(mg) 2.5 1.8 1.8 2 Patothenic acid 1.4 0.53 0.53 0.6 (mg) 4-7 0.7
0.7 2 Vitamin D (.mu.g) 10.5 4.0 4 6 Biotin (.mu.g) 14 5.3 5.3 6
Vitamin K (.mu.g)
TABLE-US-00006 Composition G: Product comprising per 1000 litres
(about) Ingredient Amount (kg) Ultrafiltrated dairy protein 700
Superrefined Tuna Fish Oil 18 Lecithin Powder 0.9 Sugar 42
Maltodextrin 118 Municipal Water 164 Rapeseed Lear-Sunflower-High
Oleic Blend 32 Choline chloride 2 UMP 3.7 Potassium hydroxide 0.27
Citric Acid Monohydraat 1.3 Magnesium hydroxide 0.6 Tri-potassium
citrate. 1aq 0.9 Mineral Premix 0.2 Vitamin Premix 1.0 Vanilla
Flavour 1.2
Example 7
Tool for Assessing the Degree of Frailty of a Patient
[0238] Consists of answering a fixed set of questions, each related
to one or more of the aspects of frailty, and scoring the replies
by comparison with normal values.
[0239] In order to correctly answer the questions, specific
measurements are recommended, as described in the text.
[0240] The questions can be asked by an expert and orally replied
to; alternatively they can also be put on a paper or form and the
replies written down; however, preferably the questions can be
raised on a screen or monitor of an electronic device, like a small
computer, tablet or peripheral station of a central computer
system.
[0241] The electronic device can have the normal values stored and
can be equipped with software which allows automatic calculation of
scores per parameter and of the frailty index.
[0242] The algorithm to calculate the final score can be subject to
individual medical expertise. However, it is preferred to operate
with a common algorithm to allow comparison of diagnosis. In the
text of the document, it is described how this can occur. It is
preferred to score the value of each individual parameter by
comparison with age-matched controls; when the patient scores
positive on two of the parameters as given below the patient is
defined to be prefrail and can be helped by the composition
according to the invention according the invention. When the
patient scores positive on at least three parameters, the
individual is diagnosed to be frail and to be receptive for
improvement by use of the composition according to the
invention.
TABLE-US-00007 TABLE 6 Example of a questionnaire for scoring
frailty. Normal value/ Parameter Measurements Score Muscle weakness
Muscle: method: Value Excessive feelings of Mental fatigue
exhaustion or fatigue Perceived fatigue after exercise: Activities
of daily living (ADL)/sleep needed Muscle capacity or power Speed
of developing fatigue Lung capacity Abnormally low physical
Voluntary normal activities activity Capabilities to apply
instrumental activities Slow or unsteady gait One or more or
combinations of balance, effort (walking time) and coordination
Weight loss Average involuntary weight loss (BMI, LBM) Absence of
acute weight loss or an acute phase response Neurological
dysfunction Cognitive impairment Memory disorder Sensory impairment
Motoric impairment Chronic pain Depression Sleep disorder Anxiety
disorder TOTAL SCORE Prefrail: 2 Mildly frail: 3 Moderately frail:
4 Severely frail: 5-6
Example: 8
Further Formulation Examples
TABLE-US-00008 [0243] TABLE 7 Ready to feed liquid formulations
Component Composition H.sup.1 Composition I.sup.2 Composition
J.sup.3 Volume per 125 ml 125 ml 125 m; packaging Energy density
1.0 1.6 1.6 (kcal/ml) Protein (g/100 ml) 7.5 10 8 Ingredients/ (i)
Whey and (ii) Whey protein Whey, -soy and wheat components amaranth
- or pea protein and casein protein (70/30) (35:20:20:25) Lipids
(g/100 ml) 5.1 8 8 Ingredients/ Phospholipids = 220 mg PL's 400 mg
Lecithin 420 mg components Fish oil/rape seed/lecithin Marine
oil/corn oil/ Marine oil/soy/canola/ 10:7:1 by palm oil/lecithin to
lecithin to get 600 mg wt, providing 600 mg result in 600 mg DHA
and 150 mg EPA DHA and 150 mg and 150 mg EPA EPA Digestible 6 after
hydrolyses of 9.5 11.5 Carbohydrates ingredients by (g/100 ml)
weight: 10% galactose, 60% glucose, 10% fructose, and 10% other
mono- saccharides Fiber (g/100 ml) 1.5 1.5 1.5 Inuline hydrolysate
+ Inuline hydrolysate + Inuline hydrolysate + galacto-OS and
galacto-OS and galacto-OS and manno manno OS (60:20:20 manno OS
(60:20:20 OS (60:20:20 by wt) by wt) by wt) Choline 200 200 200
(mg/100 ml) Choline alfosclerate Choline alfosclerate Choline
alfosclerate Uridine source 310 320 310 (mg/100 ml) Uridine + UMP
4:6 Uridine + UMP 2:8 Uridine + UMP 3:7 by by wt by weight weight
Vitamins Folates: 200 ug Folates: 200 ug Folates: 200 ug (per 100
ml) B12: 6 ug B12: 6 ug B12: 6 ug B6: 1 mg B6: 1 mg B6: 1 mg
Vitamin E: 20 mg Vitamin E: 20 mg Vitamin E: 20 mg Vitamin C: 40 mg
Vitamin C: 40 mg Vitamin C: 40 mg Vitamin premix Vitamin premix
Vitamin premix providing all providing all providing all vitamins
vitamins except the vitamins except the except the above in above
in 0.2xRDA of above in 0.2xRDA of 0.2xRDA of FDA 1988 FDA 1988 FDA
1988 Minerals Se: 30 ug Se: 30 ug Se: 30 ug (per 100 ml) Fe: 2 mg
Fe: 2 mg Fe: 2 mg Zn: 1.5 mg Zn: 1.5 mg Zn: 1.5 mg Mg: 25 mg Mg: 25
mg Mg: 25 mg Ca: 120 mg Ca: 120 mg Ca: 120 mg Na: 120 mg Na: 120 mg
Na: 120 mg K: 180 mg K: 180 mg K: 180 mg Cl: 150 mg Cl: 150 mg Cl:
150 mg P: 90 mg P: 90 mg P: 90 mg I: 16 ug I: 16 ug I: 16 ug Mn:
0.5 mg Mn: 0.5 mg Mn: 0.5 mg Cu: 0.23 mg Cu: 0.23 mg Cu: 0.23 mg
Mo: 13 ug Mo: 13 ug Mo: 13 ug Cr: 8 ug Cr: 8 ug Cr: 8 ug
.sup.1Product in particular suitable for increasing body mass index
.sup.2Product in particular suitable for increasing lean body mass
(LBM) in non-frail elderly .sup.3Product in particular suitable for
increasing ADL in persons suffering from early physical exhaustion
after exercise
Example 9
Improving BMI and/or ADL in Patients with Mild AD
Methods
[0244] The composition according to the invention shown in Example
5 (Table 1) was used for was used for a 12-week, double-blind,
randomized, controlled, multicenter study with a similarly
designed, exploratory optional 12-week extension period. The
detailed methodology and primary results of the study have been
described previously (Scheltens P, Kamphuis P J, Verhey F R, Olde
Rikkert M G, Wurtman R J, Wilkinson D, et al. Efficacy of a medical
food in mild Alzheimer's disease: A randomized, controlled trial.
Alzheimers Dement. 2010 January; 6(1):1-10 e1). Briefly, patients
with mild AD (MMSE score of 20-26) were recruited and randomized
1:1 to receive either the composition of the invention or an
iso-caloric control product as a 125 ml drink to be taken every
day. In line with current guidelines for clinical trials in
AD((CHMP) CfMPfHU. Guideline on Medicinal Products for the
Treatment of Alzheimer's Disease and Other Dementias (Document
CPMP/EWP/553/95 Rev 1). London, UK: European Medicines Agency;
2009.), the study included measures of cognition (modified
ADAS-cog, primary outcome) and functional abilities (23-item
ADCS-ADL, secondary outcome) (Mohs R C, Knopman D, Petersen R C,
Ferris S H, Ernesto C, Grundman M, et al. Development of cognitive
instruments for use in clinical trials of antidementia drugs:
additions to the Alzheimer's Disease Assessment Scale that broaden
its scope. The Alzheimer's Disease Cooperative Study. Alzheimer Dis
Assoc Disord. 1997; 11 Suppl 2:S13-21). This ADCS-ADL scale is
rated by the caregiver and ranges from 0 (need for extensive help)
to 78 (independent performance). Baseline height and weight
measurements were used to calculate BMI (kg/m.sup.2), which was
included as an exploratory outcome measure. Both ADCS-ADL and body
weight were assessed at baseline, Week 6, 12 and 24 (height was
measured at baseline only).
[0245] The study was conducted in accordance with the Declaration
of Helsinki and the International Conference on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals for
Human Use/WHO Good Clinical Practice (ICH-GCP) guidelines, as
appropriate to the legislation of the involved countries. The
clinical trial registration number is ISRCTN72254645.
Modeling Analysis
[0246] The primary analysis population was the intent-to-treat
(ITT) efficacy population from the proof-of-concept study, defined
as all patients who received at least one dose of study product and
one post-baseline assessment. The per protocol (PP) efficacy
population consisted of all patients who completed the study
without major protocol deviations. Patients who did not receive any
study product for >25% of days, and/or patients who received
<70% of the prescribed dosage overall, were excluded from the PP
group.
[0247] Data were analyzed using a repeated-measures mixed model
(RMMM), in which time was treated as a categorical variable and
represented by dummy codes. This model allows a comparison between
the active group and the control group at each individual time
point. Additional comparisons (active versus control group) were
performed using contrast statements. For example, comparisons of
the difference between baseline value and all post baseline values,
or comparisons of the difference between baseline and Week 6
ADCS-ADL (combined) and Week 12 and Week 24 ADCS-ADL (combined).
The Heterogeneous Compound Symmetry variance--covariance structure
was used as it provided the best fit to the data.
[0248] Prior to the modeling analyses, the ADCS-ADL data were
transformed using a quadratic transformation to adjust for the
skewed nature of the data. Similarly, a square-root transformation
was applied to BMI data.
Results
[0249] In the initial proof-of-concept study, 225 patients were
randomized to treatment, of which 112 received Souvenaid and 113
received control product. Overall, 161 patients completed the
24-week study. Of the 212 patients in the ITT efficacy population,
199 were included in the PP analysis population at Week 12 and 161
at Week 24. No statistically significant differences between active
or control groups were reported for any baseline characteristic
(Table 8).
TABLE-US-00009 TABLE 8 Baseline characteristics for the ITT
population. Randomized treatment group Control Characteristics
product Active product Total patient population (n = 106) (n = 106)
Men, n (%) 54 (51) 52 (49) Age .+-. SD, yr 74.1 .+-. 7.2 73.3 .+-.
7.8 MMSE, mean .+-. SD 23.8 .+-. 2.7 24.0 .+-. 2.5 Total ADCS-ADL
score 61.1 .+-. 10.5 61.9 .+-. 10.9 BMI 26.2 .+-. 4.8 26.2 .+-. 3.5
`low` baseline BMI group (n = 60) (n = 52) Men, n (%) 31 (52) 28
(56) Age .+-. SD, yr 74.9 .+-. 7.0 72.2 .+-. 8.4 MMSE, mean .+-. SD
23.9 .+-. 2.5 24.4 .+-. 2.4 Total ADCS-ADL, mean .+-. SD 60.7 .+-.
10.4 62.3 .+-. 11.5 BMI 23.2 .+-. 2.6 23.4 .+-. 1.7 `high` baseline
BMI group (n = 40) (n = 51) Men, n (%) 20 (50) 23 (45) Age .+-. SD,
yr 73.0 .+-. 7.5 74.3 .+-. 7.1 MMSE, mean .+-. SD 23.6 .+-. 2.5
23.5 .+-. 2.6 Total ADCS-ADL, mean .+-. SD 61.8 .+-. 11.2 61.9 .+-.
10.5 BMI 30.8 .+-. 3.5 29.0 .+-. 2.4 Intention-to-treat efficacy
population ADCS-ADL = Alzheimer's Disease Cooperative
Study-Activities of Daily Living (0-78; higher scores indicate
greater functioning); MMSE = Mini-Mental State Examination (0-30;
lower scores indicate greater cognitive dysfunction)
Treatment Effect on BMI
[0250] In the entire study population, data suggested an increased
BMI in the active study group versus the control group at Week 24.
(ITT population: p=0.07; PP population: p=0.03), but not at Week 12
(ITT population: p=0.39; PP population: p=0.42, Table 9).
Additional analysis indicated that this treatment effect was
primarily driven by changes observed in the `low` BMI subgroup (for
definition, see below), indicated by a trend towards an increase in
BMI in the PP subgroup population (ITT population: p=0.23; PP
population: p=0.07)
TABLE-US-00010 TABLE 9 Estimated marginal mean (95% confidence
interval) BMI scores over 24 weeks for patients receiving active or
control product (back transformed data; transformed [square-root]
data were squared). Estimated Marginal Mean BMI (overall ITT
population) n Control n Active Baseline 103* 26.1 (25.3-26.9) 100
26.0 (25.2-26.8) Week 6 97 26.2 (25.4-27.0) 96 26.2 (25.4-27.0)
Week 12 97 26.2 (25.4-27.0) 98 26.3 (25.5-27.1) Week 24 76 26.2
(25.4-27.0) 76 26.4 (25.6-27.2) BMI = Body mass index; ITT =
Intention to treat *BMI data were available for only part of the
ITT population
Treatment Effect on ADL
[0251] Overall, no treatment effect on ADCS-ADL was observed.
However, baseline BMI was found to be a significant treatment
effect modifier (ITT population: p=0.0393) indicating that BMI
significantly affected the ADCS-ADL response of the composition
according to the invention.
[0252] In order to study whether this effect was predominantly
driven by low or high BMI, patients were divided into two
subgroups: those with a baseline BMI less than or equal to the mean
(26.2 kg/m.sup.2) and those above the mean. No statistically
significant differences between active or control groups were
reported for any baseline characteristic in any of the BMI
subgroups (Table 8). The treatment effect of being in the `high` or
`low` baseline subgroup was analysed by including a
treatment*subgroup indicator interaction in the model.
Subgroup Analysis of Patients with `High` or `Low` Baseline BMI
[0253] There was no observed trend towards an intervention effect
in the subgroup of patients with `high` baseline BMI (ITT
population: p=0.1675; PP population: p=0.1701). Within the `low`
baseline BMI subgroup, the RMMM model indicated a treatment effect
at Week 12 (ITT population: p=0.0173; PP population: p=0.0184).
However, this difference was not found to be significant at Week 24
(ITT population: p=0.2049; PP population: p=0.1042; Table 10).
TABLE-US-00011 TABLE 10 Estimated marginal mean (95% confidence
interval) ADCS-ADL scores over 24 weeks for patients receiving
active or control product with a `low` (< mean) baseline BMI
score at baseline (back transformed data; transformed [squared]
data). Estimated Marginal Mean ADCS-ADL in `low` BMI subgroup (ITT
population) n Control n Active Baseline 52 63.4 (60.6-66.0) 60 61.7
(59.0-64.2) Week 6 50 64.5 (61.8-67.1) 57 63.5 (60.9-66.0) Week 12
49 62.8 (60.0-65.5) 56 64.0 (61.5-66.5) Week 24 37 62.5 (59.5-65.3)
45 62.5 (59.8-65.2) ADCS-ADL = Alzheimer's Disease Cooperative
Study-Activities of Daily Living (0-78; higher scores indicate
greater functioning); BMI = Body mass index; ITT = Intention to
treat
[0254] Exploratory analyses using contrast statements were
conducted to further investigate the effect of treatment on ADL
response in patients with `low` baseline BMI. When baseline
ADCS-ADL was contrasted against all post-baseline assessments, no
significant treatment effect was observed (ITT population:
p=0.0759, PP population: p=0.1289). However, a significant
treatment effect was observed when baseline and Week 6 ADSC-ADL
(combined) were contrasted against Week 12 and Week 24 ADCS-ADL
(combined) (ITT population: p=0.0326, PP population: p=0.0071).
These exploratory analyses suggest that the effect of the
composition on ADL performance within the `low` BMI subgroup is
observable after at least 6 weeks of treatment.
[0255] Sensitivity analyses showed that the results were
independent of transformation used and type of covariance structure
chosen.
Discussion
[0256] This example study presents the positive effects of a
multi-nutrient 1 food product according to the invention on BMI. In
addition, the modeling analyses presented here indicated that the
composition significantly improved ADCS-ADL performance in a
subgroup of mild AD patients with a `low` baseline BMI.
[0257] This is the first study to indicate that improved
(increased) BMI can be achieved with a specific combination of
nutrients, independent of the energy content of the product.
[0258] The mean BMI for the `low` baseline BMI subgroup was
approximately 23 kg/m.sup.2, which can be regarded as suboptimal
(Chin A P M J, Dekker J M, Feskens E J, Schouten E G, Kromhout D.
How to select a frail elderly population? A comparison of three
working definitions. J Clin Epidemiol. 1999 November;
52(11):1015-21.), as previous research has shown a BMI<23
kg/m.sup.2 to be associated with poorer 7-year survival in patients
with AD(Faxen-Irving G, Basun H, Cederholm T. Nutritional and
cognitive relationships and long-term mortality in patients with
various dementia disorders. Age Ageing. 2005 March; 34(2):136-41;
Irving G F, Freund-Levi Y, Eriksdotter-Jonhagen M, Basun H, Brismar
K, Hjorth E, et al. Omega-3 fatty acid supplementation effects on
weight and appetite in patients with Alzheimer's disease: the
omega-3 Alzheimer's disease study. J Am Geriatr Soc. 2009 January;
57(1):11-7.)
Example 10
[0259] Tablet comprising 500 mg uridinemonophosphate, uridine or
citicoline (cytidine diphosphate-choline), combined with 300
microgram sodium folate monglutamate and 5 microgram vitamin B12
and conventional tabletting aids, like binders, inert filling aids,
colorants, etc., to provide a tablet of about 1 g.
[0260] The tablet is in particular suitable for increasing BMI in
an elderly person. The skilled person will be able to provide a
different dosage form providing the same or similar active
ingredients in the same or other suitable dosage, based on the
information disclosed herein and common general knowledge.
Example 11
[0261] Tablet comprising 400 mg of a nucleoside equivalent, like
uridine, 6 mg vitamin B6, 200 micrrogram folate, 5 microgram
vitaminB12 and 400 mg of a choline equivalent included in
conventional tabletting aids to provide a tablet of about 1 g.
[0262] The tablet is in particular suitable for increasing BMI in
an elderly person. The skilled person will be able to provide a
different dosage form providing the same or similar active
ingredients in the same or other suitable dosage, based on the
information disclosed herein and common general knowledge.
Example 12
[0263] Capsule weighing about 1.9 g, comprising 700 mg marine oil,
300 mg soy lecithin, 100 mg of uridine, 100 mg of UMP, 100 micogram
of folate, 5 mg vitamin B6, 20 microgram vitamin B12, 10 mg vitamin
E (as alpha-tocopherol) and 20 mg vitamin C, the remainder being
cap sulating material, e.g. gelatin,
[0264] The capsule is in particular suitable for increasing BMI in
an elderly person. The skilled person will be able to provide a
different dosage form providing the same or similar active
ingredients in the same or other suitable dosage, based on the
information disclosed herein and common general knowledge.
* * * * *
References