Note: Descriptions are shown in the official language in which they were submitted.
2057456
_ ANTIDEPRESSANT
The invention relates to the novel use of nicotinamide-adenine-dinucleotide,
nicotinamide-adenine-dinucleotide pho~phAte or a physiologically compatible
salt thereof.
Depression is a neuroQsychiatric complaint, which influences the entirebehaviour, activity and emotional welfare of the person in question. It is
known from a number of studies that ne~lol ~-Rm;tters, such as epinephrin
(adrenaline), norepinephrin (noradrenaline), dopamine, serotonin or G~BA
( ~ -~m;nob~tyric aci~) play a part in the formation of depressive symptcms
(p ~;~r~rer~ W. Birkmayer and E. Neumeyer, "The Tyrosin-Tryptophan-
Diagram in a Longtime Study with Depressed Patientsn, Jcurnal of Neural
Tr~nRm;~sion, 34, pp 31-48, 1973 (with the indication of further literature
references)). Both biochemical analyses of the brains of dead depressive
patients and blood and urine tests on precursors and metabolites of said
ne~loLL~lsmitters in patients suffering frcm depression revealed that the
ne~lo~ smitter equilibrium is disturbed in these patients.
Mcdern m~;c~mPntous treatment of depressive diseases is largely based on
inhibiting the deccmposition of the ne~lu~L~lsmitters in the neurone, so as
to enrich the stored neulu~l~lsmitters~ This is brought about by adminis-
tering so-called MAO inhibitors, which block the e~7y--.e monoamine oxidase
(MAO), which is largely responsible for the deccmposition of cate~h~l~m;nes
and other substances in the neurone. However, although this treatment
method is effective, it suffers frcm several seric~us disadvantages. Firstly
the inhibiting of the deccmposition of n~u~ smitters present in the
neurone only ;nfl~ nceR the overall concentration U,el~L, but has a lesser
influence on the ~ ;hrium of the in~dividual neLluLl~lsmitters, so that
e.g. it is not possible to compensate a deficit of a specific neurotrans-
mitter as a result of functional ~;Ror~rs in production. The carrying out
of therapy with M~O inhibitors must consequently take place in a very
variable manner and must be specifically adjusted to each individual
patient by a pssR;ble comh;n~tion with other ~e~;c~m~nts. Therefore such
mr~ ents can only be ~m;n;Rtered under cont;~llols mF~;c~l control,
because over~os~R can quickly occur and which then lead to lmple~R~nt
side-effects, such as restl~sRness and insomnia. In addition, MAO inhibitor
Ul~Lq~y constitutes a massive action in the neuronal functions of the
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patient, whose effects have not yet been fully researched.
Therefore there was a need for a readily dosable antidepressant, which
requires no constant m~;cal control or monitoring and which causes no side-
effects.
It has surprisingly been found that the use of nicotinamide-adenine-
dinucleotide, nicotinamide-adenine-dinucleotide ph~ph~te or a physiolog-
ically compatible salt thereof is eminently suitable for the treatment of10 depressions.
It is known that nicotinamide-adenine-dinucleotide (NADH) can be success-
fully used in the treatment of Parkinson's disease (EP 89 730 051.3).
Parkinson's disease is based on a disturbed dcpaminergic ne~loLl~l~nission
in the basal ~gl;~ns~ generally due to an increasing decline of the
~op~m;nergic neurones initially in the substantia nigra, but during the
disease also in other areas.
It has surprisingly been found in clinical research that the me~;~Am~nts
proposed for the treatment of Parkinson's disease can be very successfully
use in the treatment of depressions, in which the causes are of a very
varied nature.
Preferably the nicot;n~m;~e~adenine-dinucleotide, the nicot;n~m;~e-adenine-
dinucleotide L~h~slJh~te or the physiologically acc~able salt thereof is
sl~pl;e~ to the bcdy in a quantity of 1 to S0 mg, preferably 5 to 12.5 mg
as a single dose.
Further advantages and features of the invention can be y~Ule~d frcm the
following des~Li~ion of cl;n;~l tests carried out in this connection.
A first series of tests c~rered 15 patients suffering frcn depressions
having different origins. For assessing the disease use was ma~e of the
so-called Bilhl~y~l depressian scale, which can be gathered fmm the bottam
of table 1. The patients were tested before therapy and after a given
treatment time.
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The first group of patients consisted of 5 wanen and 10 men. The youngest
patient was 26, the oldest 76. All patients received either parenterally
or or~lly the reduced fonn of nicotinamide-adenine-dinucleotide (NADH).
The results are given in table 2. A second group of 15 patients, consisting
of 8 wanen and 7 men (youngest patient 25, oldest 68) the reduced fonn of
nicotinamide-adenine-dinucleotide phosphate (NADPH) was ~mini~tered~ once
again either parenterally or or~lly. The results are given at the bottan
of table 3.
m e therapy pericds lasted between 2 and 12 weeks. The individual appraisal
on the basis of the Birhmayer scale before NADH or NADPH LLea~ t amcunted
to 19 to 41 of a possible 80 points. Testing after therapy revealed a 63
to 97~ improvement campared with the values es~hl;~hf~ before therapy.
m ree (first grcup) or five (second group) of patients retu m ed to an a~nost
completely norm~l behaviour with only one point in the 80 point scale, 0
point indicating an absolutely nonnal behaviour.
The results reveal that the treatment of depressions with NADH or NADPH
provided convincing improvements to the ~l;n;cAl picture after only a very
short time.
In each case 6 patients in each group received the NADH or NADPH intraven-
cusly, 2 intramuscularly and the rest orally. The dosage fluctuated between
1 and 50 mg, the best results being obtained when S to 12.5 mg were admin-
istered. The intravenous A~m;n;~tration took place in the fonm of an
infusion of 10 mg of NADH or NADPH in 200 ml of Elehest. Intravenous admin-
istration took place three times weekly. Oral AAm;n;~tration took place
daily or every other day. On the basis of the present results the nature
of the ~m;n;~tration does not appear to have any significant influence on
the improve~ent to the cl;n;~Al picture. No side-effects were observed
(even after 12 weeks treatment).
The essential advantage of nicot;nAm;~e~ n;ne-dinucleotide and nicotin-
amide-adenine-dinucleotide pho~phAte compared with the presently preferred
antidepressants, i.e. MAO inhibitors, is the biological origin thereof.
Nicot;n~;~e-fl~n;ne-dinucleotide and nicot;n~m;~e-adenine-~;n~lrleot;~e
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_ - 4 -
phosphate occurs in natural fonm in the human body and is the enzyme
cofactor for a large number of dihydrogenases. The administration of
nicot;n*mi~e-adenine-dinucleotide, nicot;n~m;~e-adenine-dinucleotide phos-
phate or a physiologically compatible salt thereof does not directly affect
the neural functions of the human being and instead aids in an as yet
unexplained manner the making good of a disturbed neurotransmitter e~l;l;b-
rium. A treatment with nicotinamide-adenine-dinucleotide, nicot;n~m;~e-
adenine-~;nu~leotide ph~ph~te or a physiologically acceptable salt thereof
can therefore be controlled without any problem and even without m~;c~l
supervision cannot lead to owerdoses and therefore associated unpleasant
side-effects, as are known in connection with MAO inhibitors.
The inventive features disclosed in the description and claims can be
essential to the various embcdiments of the invention, either singly or in
randam combination.
_ _ 5 _ Z Q 5 ~ 4 5 6
TABLE 1
Depressian appraisal scale (Prof. W. Bilh-~yeL)
Appraisal number
Appraisal parameters 0 1 2 3
1. Listless
2. Gloomy
3. No interest
4. No drive
5. Lack of concentration
6. Reduced efficiency
7. Sleepless
8. No appetite
9. Weight decrease
10. Constipation
11. Loss of libido
12. Evening remission
13. Compulsive ~using
14. General pess~mism
15. Self-reproaches
16. Guilt feelings
17. Fear
18. ~l;r;~al t~n~ncy
19. Hypcchondriacal complaints
20. Thoughts concerning the pointlessness
of life
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TABLE 2: NADH Therapy
No. Sex Age Treatment Treatment Before After Improv~nents
time
1 M 59 10 mg i.v. 5 weeks 29 1 96.5
3X weekly
2 M 53 6 mg i.m. 2 weeks 32 10 68.2
daily
3 M 26 6 mg i.v. 3 weeks 31 3 90.3
weekly
4 F 51 5 mg orally 5 weeks 41 5 87.8
3X weekly
M 49 10 mg i.v. 4 weeks 26 1 96.2
3X weekly
6 M 71 10 mg orally 4 weeks 24 18 66.7
daily
7 M 76 6 mg i.v. 3 weeks 19 3 84.2
daily
8 M 49 10 mg i.v. 3 weeks 24 3 87.5
9 M 47 5 mg orally 12 weeks 31 11 64.5
daily
F 69 12.5 mg i.v. 5 weeks 19 7 63.2
3X weekly
11 M 60 5 mg i.m. 28 1 96.5
3X weekly
12 F 36 5 mg orally 3 weeks 31 3 90.3
every other
day
13 F 55 1 mg i.m. 6 weeks 35 4 88.6
3X weekly
14 F 29 50 mg or~lly 3 weeks 32 6 81.25
daily
M 42 20 mg i.v. 10 weeks 28 9 67.9
3X weekly
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TABLE 3: NADPH THER~PY
No. Sex Age Treatment Treatment E~efore After ~r~prwenents
time
M 5110 mg i.v. 2 weeks 28 1 96.5
3X wee3cly
2 M 25 6 mg i.m. 3 weeks 19 6 68.4
daily
3 M 42 6 mg i.v. 5 weeks 24 5 79.2
weekly
4 F 37 5 mg orally 4 weeks 41 10 75.6
3X weekly
F 60 10 mg i.v. 3 weeks 32 4 87.5
3X weekly
6 M 65 10 mg orally 2 weeks 28 3 89.3
daily
7 M 68 6 mg i.v. 3 weeks 35 1 97.1
daily
8 M 48 10 mg i.v. 4 wee~cs 32 11 65.6
da;ly
9 M 61 1 mg orally 5 weeks 28 3 89.3
da;lY
F 53 50 mg i.v. 2 weeks 31 1 96.8
3X weekly
11 F 60 5 mg i.m. 10 weeks 29 2 93.1
3X weekly
12 F 48 3 mg orally 4 weeks 20 1 95
every other
day
13 F 53 7 mg i.m. 3 weeks 40 9 77.5
3X weelcly
14 F 27 15 mg i.v. 10 weeks 31 10 67.7
3X weekly
F 67 50 mg orally 3 weeks 27 6 77.8
every other
day
