Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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Agent and process for optimizing the tissue mass of organs within
the range of genetic variation in humans and animals.
It is known, from the Merck Index, 9th Edition, Rahway,
N.Y., U.S.A., 1976, that orotic acid, that is to say a uracil-
carboxylic acid of the formula:
H
0~0
~N-H
COOH
has been proposed as a feed additive, combined with methionine,
for promoting the growth of calves. The addition of a thiouracil-
carboxylic acid, its non-toxic salt and/or its alkyl ester to the
feed is proposed, in Swiss Patent Specification No.505,560, for im-
proving the growth and other advantageous properties of usefulanimals. In addition, if desired, a biological methylating agent,
such as methionine, and/or a uracilcarboxylic acid, its non-toxic
salt and/or its alkyl ester can be added.
It has now been found that certain oligonucleotides,
nucleic acid bases, and carboxyl derivatives and amino derivative
of nucleic acid bases can be used to optimize the tissue mass of
organs of humans and animals within their range of genetic varia-
tion. It is well known that there is a variation in the extent of
materialization, during protein biosynthesis, of the genetic
information which is encoded in the DNA of humans and animals, and
this results in a certain range of variation in respect of the
development of the relevant organs. The abovementioned active com-
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pounds now make it possible to materialize genetic information to
an optimal extent.
It has also emerged that adenine, as well as its
carboxyl derivatives and amino derivatives, and oligonucleotides
which contain adenine as the terminal bases, cannot be used for
the invention. Thus the invention relates to an agent for optimiz-
ing the tissue mass of organs within the range of genetic varia-
tion of humans and animals, which agent contains and/or at least
one oligonucleotide, the terminal bases of which differ from
adenine, and/or at least one nucleic acid base, with the exception
of adenine, and/or at least one carboxyl derivative of a nucleic
acid base, with the exception of adenine, and/or at least one
amino derivative of a nucleic acid base, with the exception of
adenine, as the active compound(s), combined with a vehicle.
Furthermore, the invention relates to a process for
optimizing the tissue mass of organs within the range of genetic
variation of humans and animals, which comprises introducing and/or
at least one oligonucleotide, the terminal bases of which differ
from adenine, and/or at least one nucleic acid base, with the
exception of adenine, and/or at least one carboxyl derivative of a
nucleic acid base, with the exception of adenine and/or at least
one amino derivative of a nucleic acid base, with the exception of
adenine, as the active compound(s) into the human or animal body.
"Oligonucleotides" are well known to include linear
sequences of a maximum of 20 units which, depending on the chain
length, are denoted di-, tri-, tetra-, penta-nucleotides etc. The
terminal sugars are phosphorylated in these ologonucleotides.
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The action of the abovementioned active compounds can be
explained by their penetration into the cells and their inhibition
there of the lytic enzymes, particularly the deaminases. Thus,
these enzymes are unable, or in any event are less able, to decom-
pose aminoacids which derive from digested proteins. As a result,
more aminoacids are available for constructive metabolism, which
leads to more rapid multiplication and improved differentiation of
the affected cells.
Pancreatic ribonucleases, which degrade ribonucleic acid
to nucleotides, are present in the digestive tract of humans and
animals. Thus, it could be assumed that, by administration of
ribonucleic acid from yeast or other sources, the same effects
could be achieved as with the active compounds used according to
the invention, since the ribonucleic acids are certainly also de-
graded to nucleotides. However, surprisingly, it has emerged that
this is not the case.
In principle, the abovementioned active compounds affect
assemblages of cells which are undergoing extensive division or
rapid growth. When the active compounds are administered to the
mother animals before delivery and/or to the young immediately
after delivery, they bring about an intensive development of the
endocrine glands and of the lymphatic system in the embryonal
state or shortly after delivery. The active compounds also pro-
mote the growth of voluntary muscles. However, depending on the
composition of the active compounds, the effect extends preferenti-
ally to a variety of organs. For example, nucleic acid bases and
di- to tetranucleotides particularly affect embryonal tissue,
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while octa- ~o tetradecanucleoti~es particll1arly act on voluntary
muscles. The expert is able to determine straightforwardly by
experiment the tissue on which particular active compounds exert
an especially potent effect.
When the development of particular organs has been pro-
moted in the embryonal state by the above active compounds, then
the following effects emerge:
Improved development of the pituitary leads to greater
production of somatotrophic hormone, the natural growth hormone.
Improved development of the sex organs brings about
better results of breeding.
Improved development of pancreatic tissue causes in-
creased secretion of insulin which favors more rapid growth.
Improved development of lymphatic system and thymus pro-
vide increased resistance against diseases.
It has been found, for example, that, on administration
of a mixture of nucleic acid bases with di-, tri- and, possibly,
tetranucleotides to BALB/c mice or Swiss mice, there is a
statistically significant increase in the spleen cells which pro-
duce antibodies.
On investigation of the susceptibility of complement-
dependent immunohemolysis in vitro to effects by the same active
compounds, using human complement, potent activation of complement
emerged even at a low concentration.
The active compounds used according to the invention are
known and can be prepared in a manner known per se.
The agents or active compounds according to the inven-
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tion can be administered by in~usion or injection or per os.
Depending on the mode of administration, suitable vehicles for the
active compounds according to the invention are the known vehicles
which are acceptable for pharmaceutical or veterinary use, or, for
animals, also the feed or the drinking water. Examples of suit-
able vehicles are lactose, potato starch and corn starch, talc,
gelatin, stearic acid, silica, sterile fluids, such as pyrogen-
free water, or oils, for example peanut oil.
The agents according to the invention can be in the form
of concentrates or dose units, such as capsules, uncoated or
coated tablets, etc. In this case, as a rule, they contain 1 to
200 mg, preferably 30 to 150 mg, in particular about 80 mg, of
active compound(s) per g. On the other hand, when they are in the
form of feedstuff ready for use or drinking water, they normally
contain 1 to 200 mg, preferably 30 to 150 mg, in particular about
80 mg, of active compound(s) per kg. Usually, the active com-
pounds are administered in amounts of 0.02 to 10 mg, preferably 2
to 6 mg, in particular about 3 mg, per kg of body weight and day.
Preparation of the active compounds
.
The nucleic bases and oligonucleotides were prepared and
separated by the methods given in Die Hefen (The Yeasts), Volume I:
Die Hefen in der Wissenschaft (Yeasts in Science), published by
Hans Carl, Nurnberg 1960 (pages 415 ff, 435 ff and 439, and list
of references on pages 440 to 445). A low molecular weight frac-
tion (LF) and a high molecular weight fraction (HF) from the
enzymatic cleavage of yeast RNA were used in the examples. The
ratios of amounts of the individual units were unchanged and were
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the same as those in the RNA used as starting materiaL. The LF
comprised nucleic acid bases, and mono-, di-, tri- and tetra-
nucleotides. The HF contained the higher oligonucleotides, octa-
to tetra- octa- to tetradecanucleotides.
Example 1
A homogeneous mixture was produced of 80 g of HF dry sub-
stance with 25 g each of the nucleic acid bases uracil and guanine
together with 870 g of whey powder. 500 g of this mixture were
incorporated into 1,000 kg of a complete feed for fattening pig-
lets. Piglets of 25 kg live weight were fed with this feed mix-
ture up to a finishing weight of 100 kg.
The longissimus dorsi muscle (the loin) of the
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p;glets which had been fed with the feed containing the
agent according to the invent;on ~as much more greatly
developed than in piglets which had been fed with the same
feed without the add;tion of the agent according to the
S invention up to the same finishing weight. The method
~hich is customary among special;sts for detect;ng this
effect comprises measuring the so-called area of the Loin,
that is to say the cross-sectional area of the longissimus
dorsi muscle. In the present example, a statistically
significant increase in the area of the loin from 31.8 cm2
to 35.5 cm2 was achieved.
Example 2
A homogeneous m;xture was produced from 100 9 of `
LF dry substance with 45 9 of the nucleic acid base
uracil and 40 9 of uracilcarboxylic acid together with
815 9 of "distillers' dried solubles" as the vehicle.
500 9 of this concentrate were mixed into 1,ûO0 kg of a
complete feed for breeding pigs which was nutritiona~ly
adequate in every aspect. Pregnant breeding sows were
fed with this until they littered.
The total glandular mass of the piglets, comprising
the thymus, lymph nodes, pituitary, adrenals, pancreas
and liver, was increased by 15 to 25Z, that is to say to
the upper limit of the range of genetic variation. It is
also possible to use aminouracil in place of uracilcar-
boxylic acid.
Example 3
100 9 of LF, 38 9 of the nucleic acid base thymine,
22 9 of the nucleic acid base guanine and 15 9 of the
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nucleic acid base uracil were permanently suspended in
water w;th the addition of protect;ve co~Loids and emulsi-
fiers, preservatives were added and the voLume was made
up to 1 l;ter. 100 ml of th;s concentrated suspension was
5 stirred into 100 liters of drinking water for geese.
The birds which were treated w;th th;s drinking
water dur;ng rear;ng unt;l they reached adult ~eight
developed the genetically optimal mass of liver substance
(on average more than 20X more liver tissue of the highest
10 biologic quality).
Example 4
Enteric gelatin capsules were each filled ~ith
150 mg of HF dry substance. Adult humans who ~ere taking
pa-rt in "body-building" training received admi`nistrations
15 of one capsule three times a day. With otherwise identi-
cal nutrition, movement and exercise, the tissue mass
tvolume) of all the strong voluntary muscles was ;ncreased,
and this was clearly visible and easily measurable. This
was also evident from an increase in performance which could
be objectively measured.
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