Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
P58 63
.
New Indications for Carnitine
: :
The invention relates to novel applications for the inherently known
pharmaceutical active substance carnitine.
~ ~ Carnitine is a normal and important constituent of the mammalian
musculature, from which it was ~irst isolated and studi0d~from 1905 to 1907
by R. Krimberg and coworkers. It is a question of an amino acid deriva-
tive,~a so-called betaine, ~-oxy-gamma-butyrobetaine, which also occurs in
squids, in some shellfish and in the sardine. When dogs are fed with meat
extract, L-carnitine appear~ in the urine. L-carnitine is commercially
avai~lable,~ for instance in the form of the preparation Biocarn ~ of the
Medice Company (Iserlohn).
L-carnitine is employed for the oxidative produciion of energy from
:,
fatty acids, which for their part are an important source of energy for
athletes trained for endurance. This energy requirement, for example at
the end of a~marathon run, may be met for up to 80 X by combustion of fats. i~
Such an~athlete~hence needs L-carnitine.~
A human being is a carnivore, that is to say a meat eater. In this
manner he~may cover his need for L-carni~tine from normal nutrition. A
20 human is~howèver~also able to form L-carnit1né himself, a task~able to be ~;~
performed by different organs:~such L-carnitine may~be termed endogenous
carn1tlne in~contradistinction to exogenous~L-carniti~ne supplied~in normal
i~ nutrition.~Furthermore there~is L-carnitine supplied in the form of prepa-
rations and not contained in~normal food.
~ The substitution of~minera1s~wi~11 serve~to make~clear a classical
example for the replacement of lost e~lements during sporting endurance
activities. Carbohydrates are listed after minerals in this connection.
As regards the necessity for a supply of protein or amino acids hardly
anything was known until a few years ago when the s;ignificance of L-carnit-
ine was dlscovered (26). (The numbers in brackets refer to the list of
., : .:. :. .:: . ,: ,, .,: . ." ",: , . . .
; '2
literature references herein).
L-carnitine is an essential co-factor in mitochondrial transport and
in the oxidation oF long~chained fatty acids, more particularly in skeletal
and cardiac muscle. The human organism synthesizes this amino acid deriva-
tive itself or assimilates it from meat in food by an active and a passivetransport mechanism: endogenous and exogenous carnitine. Both serve to
meet the needs of the organism, the latter more particularly in the case
physical endurance exercise. In our view it is possible to distinguish
between different L-carnitine deficiency conditions, it being clear that
the therapeutic administration of L-carnitine constitutes a true substitu-
tion of an essential biocarrier which primes metabolism and which can pre-
vent damage to health. These carnitine deficiency conditions are listed in
scheme1. From this there may be seen to be various different therapeutic
aspects.
15 scheme l-
Different forms of L-carnitine deficiencY Phenomena~ which necessitate a
theraoy with L-carnitine substitution.
;~ I. Primary L-carnitine deficiency:
Hereditary, primary carnitine deficiency syndrome.
20 II. Secondary L-carnitine deficiency:
1) Endurance and high performance sport (26)
2) Diabetes mellitus and dialysis patients
3) AIDS patients (11)
4) Deficient uptake of L-carnitine (high performance vege-
tarian athletes) or inhibition of transport to organs.
Furthermore the therapeutic application of L-carnitine may be em-
ployad for some further purposes as compiled in scheme 2.
Scheme 2 .
Additive-suPportive substitution with a theraceutic effect.
1) For cardiac insufficiency (15)
2) In connection with weight reduction (1)
3) In the treatment of arteriosclerosis (lowering cholesterol level,
increasing HDL, reduction in hypertriglyçedridemia in the case of
dyslipidemias) (4; 17)
4) In Alzheimer's disease (8)
5) For the improvement of performance in the case of disturbances in
peripheral circulation (9)~
6) For the stimulation of regeneration of the liver following partial
hepatectomy in experiments on animals (7)
7) In order to protect cardiac mitochondria against the cytotoxic e~fect
,
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of adriamycine (2).
Some brief observations will now be made on these therapeutic ef-
fects. In the treatment of cardiac and circulatory diseases there is not
only the benefit of the energetic effect for the heart muscle but further-
more there is a general effect on the body fats which may be termed anti-
arteriosclerotic, which however furthermore emphasizes an important preven-
tive aspect, the improvement in the degradation of fat during therapeutic
fasting also having a favorable effect (table 2).
Th0 neurological mechanisms are of interest, which can be affected by
L-carnitine and acetyl-L-carnitine (14). On the basis of the stereospecif-
ic similarity with acetylcholine workers have not only suspected a cholino-
mimetic activity but furthermore actually detected it (19). The influence
of L-carnitine on cholinergic pathophysiology also plays a part in Alzheim-
er's disease, as has already been alluded to by Janri et al. (14) and has
even given rise to therapeutic concepts (8).
One object of the present invention is to indicate novel therapeutic
effects of carnitine, in addition to these inherently known effects there-
of, which will provide novel applications therefor.
This object is to be attained by the applications as defined in more
detail in the claims.
In accordance with the invention the phagocytosis function of mono-
cytes and granulocytes and furthermore the stimulation of T- and B-lympho-
cytes was investigated. These effects may be attributed to a membrane
effect of L-carnitine.
Materials and Methods
L-carnitine: Biocarn ~ of the Medice Company (Iserlohn).
T- and B-cell stimulation tests: in accordance with Schumacher and
coworkers (20) using Phythemagglutinin (PHA) (Welcome Diagnostics) and
pokeweed mitogen (Sigma, L-9397).
Macrophage function tests: as described by Van Mil and Uhlenbruck
(25) and Uhlenbruck et al. (23).
Granulocyte function tests: as described by Oben and Foreman (18),
the evaluation being performed microscopically.
Measurement of the phagocytosis with the aid of chemiluminescence: in
this case the method described by Beuth et al. (5) was employed.
Chromium release test with natural killer (NK) cells: This test procedure
was performed as described by Cosentino and Catheart (10).
Free-flow cell electrophoresis: this was performed as described by
Hannig (12), that is to say once for isolation of human B-lymphocytes (3)
and once to be able to prove a membrane effect of L-carnitine. For this
.. . .
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purpose human erythrocytes and blood cells as employed in the preceding
tests were incubated ~or 30 minutes with a 1 % solution of L-carnitine at
37 C, then centrifuged and washed with the corresponding electrophoresis
buffer (12).
Results:
The ~ranulocvte function and L-carnitine:
Firstly the granulocytes of 10 healthy donors were tested as regards
their ability to phagocytize bacteria of the type Micrococcus Lysodeikticus
(ML), it turning out that the values varied considerably from individual to
individual, for the result was able to be reproduced by double assays with
an offset in time. 2 x 200 cells were evaluated with the aid of micro-
scopic counting. The pre-incubation of the granulocytes (human granulocy-
tes = MG) with L-carnitine was performed For one hour at 37' C in a shaken
water bath.
For this on the one hand the MG were pretreated with 0.1 % L-carnit-
ine and on the other hand the MG were pretreated in the same manner (second
and third items in table 1, wherein these results are show as a whole).
The first column o-F table 1 contains the normal values as percentage of the
phagocytizing cells. Pre-incubation of the MG with L-carnitine increases
the phagocytosis rate substantially, but howeYer it is increased even fur-
ther if it is not the MG but the ML to be phagocytized which are pre-incu-
bated with 0.1 ~ L-carnitine.
The whole is represented once again graphically in figure 1 which
also demonstrates that L-carnitine has a direct effect 1ncreasing phagocy-
tosis both on the MG and also on the ML.
Table 1. Increase of bacterio-phagocytosis by granulocytes with the
aid of L-carnitine in pre-incubation tests.
Donor MG + ML MG/L-carnitine MG/ML/L-carnitine
0.15 ~ ML 0.1 %
1 36 % 58 % 71 %
2 38 % 54 % 70 %
3 39 % 47 % 63 %
4 54 % 75 ~ 88 %
35 5 56 % 78 % 89 %
6 63 % 87 % 92 %
7 57 % 80 % 79 %
8 52 % 75 % 90 %
9 46 ~ 78 % 85 %
40 10 45 % 87 % 91 %
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MG - human granulocytes
ML = Micrococcus lysodeictus
It will be seen that pre incubation for one hour of the MG with 0.1
of L-carnitin~ increases the phagocytosic capacity of the MG by 20 to 9~ %
(MW - 40 %). This is dependent on the lower value: the lower the base
value, the higher the increase being, as will be seen from the following
tests.
It is of interest that the pre-incubation of the FITC-marked ML bac-
teria leads to a substantially increased rate of the phagocyti7ing MG: 50-
100 % (MW - 70 %).
It was now to be examined whether this enhancing effect of L-carnit-
ine is specific with respect to the bacterio-phagocytosis by MG or whether
the acetylcholine employed is able to produce a similar effect. For this
purpose four more granulocyte samples from the donors were examined. The
result is to be seen in table 2. It will be clearly seen that acetylcho-
line has no phagocytosis enhancing e-~fect. In this respect it is again
made clear that the increase in rate due to L-carnitine is dependent on the
initial value: the lower the latter, the more efficient the increase.
Table 2: direct increase in granulocyte bacterio-phagocytosis by L-
carnitine, but without using acetylcholine pre-incubation.
Donor MG + ML MG/L-carnitine MG~acetylcholine
0.1 % + ML 0.1 % + ML
1 32 % 60 % 30 %
2 27 % 52 % 25 æ
3 56 % 66 % 51 %
4 61 % 7~ % 62 %
Chemiluminescence tests for the Phagocvtosis ca~acitY of ~ranulocvtes and
monocvtes.
The increase found in the preceding tests in bacterio-phagocytosis by
L-carnitine was examined again with the aid of the chemilumines-
cence method.
In this respect it was to be seen from preliminary tests that human
monocytes are not directly stimulated in their function by incubation with
L-carnitine. As an example human monocytes are used, whose phagocytosis
function was not capable of being substantially modified with respect to
EAC (charged with erythrocyte/antibody/complement), with respect to E-anti-
D (human erythrocytes sensitized with incomplete anti-D) and with respect
to ERDE (ovine erythrocytes treated with neuraminidase) (25) either by pre-
incubation with L-carnitine or by acetylcholine (see figure 3). Here as
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well the percentages of phagocytizing cells are given.
The individual valu0s for figure 3 may be seen from table 3, the
monocytes having been pre-incubated -for cne hour at 37 C in an incubator
(flushed with C02) with L-carnitine and, respectively, acetylcholine (1 %).
The phagocytosis index is derived from the number of phagocytized erythro-
cytes in relation to the phagocytosis activated monocytes.
Table 3: Phagocytosis function test3with human monocytes and pre-
incubation with L-carnitine and acetylcholine.
Medium L-carnitine 0.~ % acetylcholine 0.1 %
æ pos. No. Index % pos. No. Index X pos. No. Index
monoc. ery. monoc. ery. monoc. ery.
EAC 85 236 2.8 90 244 2.7 80 161 2.0
EAnti D 75 122 1.6 73 115 1.6 77 133 1.7
15 ERDE 82 i93 2.4 88 238 2.7 83 200 2.4
After these preliminary investigations a chemiluminescence test was
employed to determine whether monocytes are not directly activatable by
pre-incubation with 0.1 ~ L-carnitine or, respectively, acetylcholine with-
out opsonization with serum. The result is shown in figure 4. It will be
gathered that monocytes, which undergo pre-incubation with 0.1 % L-carnit-
ine, achieve 73 X of the zymosan stimulation, whereas monocytes, which
underwent pre-incubation with 0.1 % acetylcholine only achieved 24 % of the
zymosan stimulation.
In the case of the MG there was no such direct activation by L-carni-
tine or acetylcholine, whereas however the functional capacity after pre-
incubation both of the MG and also of the ML was significant-
ly stimulated by L-carnitine.
In the case of the human monocytes just the reverse is the case.
They are directly activated by L-carnitine, whereas their function could
; 30 not be substantially improved by the methodic test conditions employed by
us .
The chemiluminescence test in the case of the MG on the other hand
show ~ an increase of bacterio-cytosis by 34 % with the use of ML, some-
thing that is graphically illustrated in figure 5. Acetylcholine does not
exhibit this effect. Accordingly the initially indicated results are con-
firmed.
T- and B-lymphocvte stimulation test.
Firstly T-lymphocyte stimulation tests were performed in the conven-
tional manner with the aid of PHA, whereas stimulation tests were performed
in parallel with the same cells, after the lymphocytes had been incubated
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with different concentrations of L-carnitine. As a control pre-incubation
with acetylcholine was again employed. The pre-incubation steps lasted one
hour and took place at 37 C in a C02 incubator. The result of these tests
is indicated in one example in table 4.
Table 4: Stimulation of T-lymphocytes by PHA and the influence there-
on by L-carnitine and acetylcholine.
Concentration L-carnitine Acetylcholine
PHA
10 ~gPHA/culture 1 % 0.1 æ 0.01 % 0.1 %
_
Stimulation index
0.01 7 3 9 10 6
15 0.1 24 11 26 31 21
0.2 36 14 67 96 32
0.5 19 10 34 56 20
1.0 13 8 27 38 14
2.0 12 6 24 31 1
20 5.0 12 6 21 27 9
10.0 9 5 16 19 7
20.0 8 3 6 5 6
Medium
These findings are presented once again in figure 6 graphically.
It will be clearly seen that acetylcholine has practically the same
curve with PHA, whereas a concentration (1 %t clearly suppresses normal PHA
~; stimulation. Therefore the result with concentrations of L-carnitine ofthe order of 0.1 % and 0.01 % was all the more unexpected. These values
are made apparent in the two upper curves, a surprising increase of lympho-
cyte stimulation by PHA having to be noted. It seems that there is a con-
centration-dependent process at the T-lymphocyte membrane, which inhibits
PHA stimulation at high dosages, whereas on the other hand at low ones it
is responsible for a significant increase in PHA stimulation.
This result was produced again and again with other T-lymphocyte
samples: inhibition by 1 % L-carnitine pre-incubation and an increase of
PHA stimulation by lower concentrations of L-carnitine (from 0.5 % upwards)
was always to be observed. It is interesting that the increase is dosage-
dependent (dilution series 0.01 % - 20 ~m/culture) and is specific, since
acetylcholine does not exhibit this effect.
In comparison with the T-lJmphocytes human B-lymphocytes were also
.. . . ,, . .. ., ~ . ,
~9~27
stimulated with pokeweed mitogen (PWM) and tested to see if this stimula-
tion was to be influenced positively in the same way by L-carnitine. The
result is shown in figure 7 and in table 5.
Table 5: B-lymphocyte stimulation test with PWM and pre-incubation of
L-carnitine or, respectively, acetylcholine. The pre-incubation was per-
formed in the same manner as with the T-lymphocytes.
Concentration L-carnitine Acetylcholine
PWM
~gPHA/culture 0.01 ~ 0.1 æ o. 1
Stimulation index (cpm sample: cpm med.)
.
0.1 8 20 10 16
1 15 39 18 32
24 49 26 49
28 71 26 37
56 26 37
Medium
Figure 7 also indicates that there is a substantial increase in lym-
phocyte stimulation by L-carnitine at a concentration of 0.01 %. However
the control with acetylcholine also increases the PWM stimulation of B-
lymphocytes, whereas at a concentration of 0.1 % L-carnitine practically
coincides with the normal stimulation curve, that is to say it fails to
have any effect at this concentration. It is to be expected that 1 % L-
carnitine would inhibit stimulation again. The B-lymphocyte population was
produced with the aid of cell electrophoresis pr~paratively.
Since these tests provide a clear indication that L-carnitine is
~ responsible for an increase in the biological function by a membrane ef-
fect, which frequently may e~en be non-specific, as is shown by the posi-
tive control tests with acetylcholine, human erythrocytes, T- and B-lympho-
cytes, as well as various different bacteria were then investigated to see
whether the electrophoretic migration velocity, that is to say the zeta
potential, was changed afterincubation with L-carnitine and, respectively,
acetylcholine.
The tests so far performed have, in the case of human blood cells
after pretreatment with these substances not shown that there are any modi-
fications in the electrophoretic migration velocity. Furthermore different
bacteria employed for phagocytosis did not, after pretreatment with L-carn-
itine, show any basic modification in the zeta potential, although in some
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cases small departures (a decrease of up to 5 % in mobility) were observed.NK cell tests and the effect thereon of L-carnitine and acetYlcho-
line~
In order to make a still ~urther investigation of the suspected cell
membrane effect of L-carnitine or, respectively, acetylcholine, with the
aid of chromium release tests human killer cells (NK cells) were investi-
gated as regards their effect on target cells (T). The result is indicated
in figure 8. It will be seen from the first column (I) that the normal
target cell Iysis by NK cells amounts to 38 % (see furthermore table 6).
10 The pretreatment of the NK cells with L-carnitine and acetylcholine
(0.1 ~) leads to a significant increase in NK cell lysis. If on the other
hand the target cells are treated with chromium5~ and if then L-carnitine
or, respectively, acetylcholine are added, values will be obtained which
are distinctly lower (column III). It is therefore to be seen that one
hour's pre-incubation of the NK cells significantly steps up lysis, whereas
pre-incubation with chromium5~ and L-carnitine or, respectively, ace~ylcho-
line is less effective. It will hence be seen that these two substances
attack both the membrane of the NK cells as well as the membrane of the
target cells, the chromium loss from the target cel-ls owing to the pre-
incubation being taken into account as well. The notion that both sub-
stances, L-carnitine and furthermore acetylcholine, are responsible for a
membrane effect in the case of these cells, is confirmed by the two columns
IV in figure 8. Here it was apparent that a pre-incubation of the target
cells with 0.1 % L-carnitine followed by the addition of chromium51 led to
a 129 % increase in lysis, whereas in the case of 0.1 % acetylcholine pre-
incubation also led to an increase in lysis by 100 ~. The corresponding
figures are presented in table 6.
Table 6: chromium release tests after pre-incubation with L-carnitine and
acetylcholine.
Form of test
(NK:T - 25:1)
~ % lysis % increase
I NK : T 38
II NK + L-carnitine 0.1 %:T + Cr5~ 54 42
NK + acetylcholine 0.1 % + Cr51 53 39
III NK : T + Cr51 + L-carnitine 0.1 % 45 18
NK : T + CrS1 + acetylcholine 0.1 % 43 13
IV NK : T + L-carnitine 0.1 % + Cr51 87 129
NK : T + acetylcholine 0.1 % + CrS1 80 110
40 It would appear that pre-incubation in IV does not cause an enhanced
. : -
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uptake of chromium5l (there being the same values after SDS lysis), and it
is rather a ques~ion of the NK cells lysin~ more target cells owing to a
membrane effect. qhis being an effect which may even be employed for im-
proving the chromium release test and for economizing in the use of radio-
S active chromium, while the pre-incubation in III, as is shown by measure-
ments in the washing solution, also based on a membrane effect, in the case
of which however radioactive chromium is lost.
20 years ago it was pointed out for the first time (22~ that the
significant consequences of regular endurance training included "non-spe-
cific stimulation of the immune-competent body defense mechanism', in con-
nection with any protection caused which is effective against infections
and cancer. In the meantime we have now learned that moderate endurance
training may reduce the risk of infections and also the risk of cancer
~16), whereas excessive high performance stress may have the opposite re-
sult.
Therefore there has been no lack of concepts and systems for counter-
acting debility of the immune system by performance orientated popular
sport (24), be it in the form of immune stimulation or substitution (admin-
istration of immunoglobulins etc.) or by mental training. Therefore it
always appeared important for the inventors for all substances not affected
by the doping controversy, which are offered to high performance sportsman
and -women for substitution, stabilization of performance and for regenera-
tion, to be investigated as regards their effect on the immune system. In
this respect it was possible to show that aspirin as sometimes employed on
the triathlon scene does not have any effect on the immune system.
In the investigations reported on here with L-carnitine i~ was possi-
ble to show in accordance with the invention that this amino-acid deriva-
tive does in fact have an influence on the most different immunocompetent
cells. On the basis of the results produced here it is possible to note
three main effects, of which there has so far been no knowledge:
1. A phagocytosis increasing effect after action on human granulo-
cytes, and furthermore on the bacteria employed as target
cells: a sort of pseudo-opsonin effect, which must be specifi-
cally attributed to L-carnitine.
35 2. An effect activating stimulation of T-lymphocytes which is
specific too and which is also dosage rate-dependent and is
specific for L-carnitine, whereas a directly activating effect
was to be seen in the case of human monocytes. Less specific
was the action in human B-lymphocyte stimulation tests, as also
acetylcholine led to a clearer but however weaker effect.
2 ~ 2 ~
3. An interesting membrane effect was shown by L-carnitine in the
case of human killer cells (NK) or, respectively, the corre-
sponding target cells. Since acetylcholine exhibited the same
effect, these results must be interpreted as being non-speci~-
ic. A similar membrane permeability effect has furthermore
been assumed by other authors in the case of the mitochondrial
membrane (2~.
Supplementing endogenous and exogenous L-carnitine by an additional
supply of L-carnitine for high performance sportsmen and sportswomen is
consequently not only free of objections from the immunological point of
view but furthermore appears to have a reinforcing and activating effect,
in a manner which has so far not been elucidated, on immunological defense
mechanisms both specifically and non-specifically, by producing an effect
at the membrane of phagocytes, NK cells and monocytes in concentrations,
1~ which may become established in the case of supply by way of substitution
in blood as well, albeit temporarily (0.01 ~. Therefore it is an advan-
tage that acetylcholine, which is sometimes effective in the same manner
(NK cells) does not come into question for "therapeutic" purposes. The
fact that L-carnitine is effective at relatively low dosage rates, at the
2~ same time gives the lie to arguments which seek to attribute this effect to
various different preserving agents present in commercial preparations.
By way of conclusion it may be said that the two fields of applica-
tion so far ~or L-carnitine are to be supplemented by a third one (scheme 3).
Scheme 3. The positive effects of an exogenous L-carnitine supply.5 1. Cardiac, circulation and metabolic effects (cardiac insuffi-
ciency, diabetes, arteriosclerosis, diet, high per~ormance
sport),
2. Neurological ef~ect (AIDS, Alzheimer's disease, similarity to
acetylcholine), and0 3. ~Membrane effects in the case of phagocytes, immunocytes and
bacteria (effect enhancing the immune reaction).
In this connection it must be of interest that in high performance
spurt it is possible in this manner to not only stimulate metabolism (6)
but furthermore to activate those cells in the immune system, which partic-
ularly become involved in connection with inflammatory and acute phaseevents due to stress in sport: monocytes, granulocytes and NK cells. This
might provide a third argument in support o~ "theoretical therapy" (1; 13)
which is not accepted in all quarters.
Reference (21) relates to the action of L-carnitine as an aggregation
4û inhibitor in the case of myxomycetes and cells of the organism and erythro-
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cytes. In accordance with the invention it was possible to show that onthe administration of L-carnitine macrophages are no longer able to adhere
and can be dètached from tissue culture dishes with the aid of L-carnitine.
The inhibition tests described in the invention using L~carnitine,
even with different sets of c011s, would appear to be based on a direct
membrane effect. The fat metabolism aspect appears to play no part at all
and rather seems to be an electrostatic effect, which however would not
occur on the outer cell surface, for otherwise it would have been noticed
during cell electrophoresis during tests performed in acc~rdance with the
invention.
The activation described in the above for the first time of immuno-
competent cells constitutes a significant consequence of this membrane
effect, which may also be employed therapeutically, something which can
hardly fail to be of importance for sport medicine, since in this case
experience with the administration of L-carnitine in high performance sport
is available.
Thus it has been found in accordance with the invention that L-carni-
tine influences biological cell membranes in such a way, that is to say by
direct accumulation which leads to an activation of the membrane surface,
this in turn meaning that aggregation phenomena are inhibited, agglutina-
tion events are influenced, adhesion mechanisms are changed and cell mem-
brane metabolism events are caused to take place differently. A further
point to be considered is that owing to this membrane action the uptake of
substances into the cell and the release of substances from the cell is
improved or, respectively, changed, something which was proved by the above
; described chromium release tests. Moreover cells may be better stimulated~by pretreatment with L-carnitine, for instance by mitog0ns, lectines etc.
or they may be inhibited, for instance by cytostatica. From these results
it is possible to show that there are the following possibilities of appli-
cation:
1. L-carnitine as an a~regation inhibitor~ The aggregation o~ thrombo-
cytes, erythrocytes and white blood corpuscles is inhibited. This is im-
portant for the anti-arteriosclerotic effect of L-carnitine, far the pro-
phylactic treatment of cardiac thrombosis and more particularly for inhibi-
tion of metastatic spread of tumor cells by an influence of the membranestructure and also however fluidity, including the "docking" cells. Osmot-
ic resistance is increased.
2. Activation of the cell membrane plays a decisive role in the uptake
of medicaments. L-carnitine improves the uptake of different substances
into the cell, for instance of radioactively marked chromium into natural
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killer cells. In the case of the concentration of L-carnitine which may be
produced by administration, namely 0.01 to 0.001 ~, this uptake enhancing
effect would sésm to be a substantial advantage for the treatment of tumors
with cytostatica; more particularly leukemia and Hodgkin cells come to mind
in this connection. Carnitine leads to an opening of pores of cells and
therefore facilitates the entry of medicaments. This applies not only for
an influence on tumor cells, but furthermore in principle as an enhancing
effect as regards the action of other medicaments in connection with other
cells. We assume that this property plays a part in the case of the neuro-
logical effects of carnitine (on Alzheimer's disease, AIDS etc). Use inthe case of hemolytic anemia is also recommended.
3. The indirect immuno-modulatorv effect of carnitine: here there is an
activation of phagocytosis, such pseudo-opsonin effect being in relation to
bacteria on the one hand, which are better phagocytized and on the other
hand to the phagocytes themselves, which are also stimulated as regards
their phagocytic activity. A further point to be considered is that there
is an activation of T- and B-lymphocyte functions, of NK cells and of gran-
ulocytes: their functions and activities are improved with therapeutic
doses of carnitine, both quantitatively and qualitatively. It activates
immunocytes so that they are better able to fulfill their defense tasks.
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