AU631755B2 - Antidepressant - Google Patents

Abstract

The use of nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide phosphate or of a physiologically tolerated salt thereof for the treatment of depression.

Description

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AUSTRALIA

Patents Act 1990 P/00/011 28/5/91 Regulation 3.2(2) 631755

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT Application Number: Lodged: Invention Title:

ANTIDEPRESSANT

The following statement is a full description of this invention, including the best method of performing it known to me

ANTIDEPRESSANT

The invention relates to the novel use of nicotinamide-adenine-dinucleotide, nicotinamide-adenine-dinucleotide phosphate or a physiologically cxnpatible salt thereof.

Depression is a neuropsychiatric complaint, which influences the entire behaviour, activity and emotional welfare of the person in question. It is known from a number of studies that neurotransmitters, such as epinephrin (adrenaline), norepinephrin (noradrenaline), dopamine, serotonin or GABA -aminobutyric acid) play a part in the formation of depressive symptoms Rierderer, W. Birkmayer and E. Neumeyer, "The Tyrosin-Tryptophan- Diagram in a Longtime Study with Depressed Patients", Journal of Neural Transminsion, 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 neurotransmitters in patients suffering frcm depression revealed that the neurotransmitter equilibrium is disturbed in these patients.

t Modern medicanentous treatment of depressive diseases is largely based on o s inhibiting the decomposition of the neurotransmitters in the neurone, so as to enrich the stored neurotransmitters. This is brought about by administering so-called MAO inhibitors, which block the enzyme mcnoamine oxidase (MAO), which is largely responsible for the deccmposition of catecholamines and other substances in the neurone. However, although this treatment method is effective, it suffers fran several serious disadvantages. Firstly the inhibiting of the deccmposition of neurotransmitters present in the neurone only influences the overall concentration thereof, but has a lesser influence on the equilibrium of the individual neurotransnitters, so that e.g. it is not possible to compensate a deficit of a specific neurotransmitter as a result of functional disorders in production. The carrying out of therapy with MAO inhibitors must consequently take place in a very variable manner and must be specifically adjusted to each individual patient by a possible combination with other medicaments. Therefore such medicaments can only be administered under continuous medical control, because overdoses can quickly occur and which then lead to unpleasant side-effects, such as restlessness and inscrnia. In addition, MAO inhibitor therapy constitutes a massive action in the neuronal functions of the -2patient, whose effects have not yet been fully researched.

Therefore there was a need for a readily dosable antidepressant, which requires no constant medical control or monitoring and which causes no sideeffects.

It has surprisingly been found that the use of nicotinamide-adeninedinucleotide, nicotinamide-adenine-dinucleotide phosphate or a physiologically compatible salt thereof is eminently suitable for the treatment of depressions.

It is known that nicotinamide-adenine-dinucleotide (NADH) can be successfully used in the treatment of Parkinson's disease (EP 89 730 051.3).

a t Parkinson's disease is based on a disturbed dcpaminergic neurotransmission Clo in the basal ganglions, generally due to an increasing decline of the dopaminergic neurones initially in the substantia nigra, but during the S disease also in other areas.

It has surprisingly been found in clinical research that the medicanents proposed for the treatment of Parkinson's disease can be very successfully used in the treatment of depressions, in which the causes are of a very varied nature.

S Preferably the nicotinamide-adenine-dinucleotide, the nicotinamide-adeninedinucleotide phosphate or the physiologically acceptable salt thereof i S supplied to the body in a quantity of 1 to 50 mg, preferably 5 to 12.5 ig as a single dose.

Further advantages and features of the invention can be gathered from the following description of clinical tests carried out in this connection.

A first series of tests covered 15 patients suffering from depressions having different origins. For assessing the disease use was made of the so-called Birkmayer depression scale, which can be gathered frcm the bottcm of table 1. The patients were tested before therapy and after a given treatment time.

The first group of patients consisted of 5 women and 10 men. The youngest patient was 26, the oldest 76. All patients received either parenterally or orally the reduced form of nicotinamide-adenine-dinucleotide (NADH).

The results are given in table 2. A second group of 15 patients, consisting of 8 women and 7 men (youngest patient 25, oldest 68) the reduced form of nicotina-ide-adenine-dinucleotide phosphate (NADPH) was administered, once again either parenterally or orally. The results are given at the bottom of table 3.

The therapy periods lasted between 2 and 12 weeks. The individual appraisal on the basis of the Birkmayer scale before NADH or NADPH treatment aTounted to 19 to 41 of a possible 80 points. Testing after therapy revealed a 63 to 97% improvenent capared with the values established before therapy.

Three (first group) or five (second group) of patients returned to an almost S completely normal behaviour with only one point in the 80 point scale, 0 point indicating an absolutely normal behaviour.

The results reveal that the treatnent of depressions with NADH or NADPH provided convincing improvenents to the clinical picture after only a very short time.

In each case 6 patients in each group received the NADH or NADPH intraventi ously, 2 intramuscularly and the rest orally. The dosage fluctuated between 1 and 50 mg, the best results being obtained when 5 to 12.5 mg were administered. The intravenous administration took place in the form of an infusion of 10 mg of NADH or NADPH in 200 ml of Elehest. Intravenous administration took place three times weekly. Oral administration took place daily or every other day. On the basis of the present results the nature of the administration does not appear to have any significant influence on the improvement to the clinical picture. No side-effects were observed (even after 12 weeks treatment).

The essential advantage of nicotinamide-adenine-dinucleotide and nicotinamide-edenine-dinucleotide phosphate compared with the presently preferred antidepressants, i.e. MAO inhibitors, is the biological origin thereof.

Nicotinamide-adenine-dinucleotide and nicotinamide-adenine-dinucleotide r- 4 It i i4 '44 it 4 I s I -4 phosphate occurs in natural form in the human body and is the enzyme cofactor for a large number of dihydrogenases. The administration of nicotinamide-adenine-dinucleotide, nicotinanide-adenine-dinucleotide phosphate or a physiologically canpatible 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 equilibrium. A treatment with nicotinamide-adenine-dinucleotide, nicotinamideadenine-dinucleotide phosphate or a physiologically acceptable salt thereof can therefore be controlled without any problem and even without medical supervision cannot lead to overdoses 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 enbodiments of the invention, either singly or in random ccmbination.

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I

TABLE1 Depression apraisal scale (Prof. W. Birkmayer) Appraisal numiber Appraisal paraneters 0 1 2 3 1. Listless 2. Glcmy 3. No interest 4. No drive Lack of concentration 6. Reduced efficiency 7. Sleepless 8. No appetite 9. Weight decrease Constipation 11. Loss of libidio 12. Evening remlission 13. Confpulsive munsing 14. General pessimism 15. Self-reproaches 16. Guilt feelings 17. Fear 18. Suicidal tendency 19. Hypochondriacal canrplaints Thcughts concerning the poinitlessness of life -6 TABLE 2: NArDf Therapy No. Sex Age Treatment 1 M 59 10 mg i.v.

3X weekly 2 M 53 6 mg i.m.

daily 3 M 26 6 mg i.v.

weekly 4 F 51 5 mg orally 3x weekly M 49 10 mg i.v.

3X weekly 6 M 71 10 mrg orally daily 7 M 76 6 mg i.v.

dai-ly 8 M 49 10 mg i.v.

9 M 47 5 mg orally daily F 69 12.5 mg i.v.

3X weekly 11 M 60 5 mg i.m.

3X weekly 12 F 36 5 mg orally every other day 13 F 55 1lmg i.m.

3X weekly 14 F 29 50 mg orally daily M 42 20 mg i.v.

3X weekly Treatment time 5Cwek 2 weeks 3 weeks 5 weeks 4 weeks 4 weeks 3 weeks 3 weeks 12 weeks 52 weeks 3 weeks 6 weeks 3 weeks 10 weeks Before 29 32 31 41 26 24 19 24 31 19 28 31 35 32 Af ter 1 10 3 5 1 18 3 3 11 7 1 3 4 6 Irrprovenents; 96.5 68.2 90.3 87.8 96.2 66.7 84.2 87.5 64.5 63.2 96.5 90.3 88.6 81.25 67.9 28 9 7 TABLE 3: NADPH THERAPY No. Sex Age Treatment Treatment Before After Improvements time 1 M 51 10 mg i.v.

3X weekly 2 M 25 6 mg i.m.

daily 3 M 42 6 mg i.v.

weekly 4 F 37 5 mg orally 3X weekly F 60 10 mg i.v.

3X weekly 6 M 65 10 mg orally daily 7 M 68 6 mg i.v.

daily 8 M 48 10 mg i.v.

daily 9 M 61 1mg orally daily F 53 50 mg i.v.

3X weekly 11 F 60 5 mg i.m.

3X weekly 12 F 48 3 mg orally every other day 13 F 53 7 mg i.m.

3X weekly 14 F 27 15 mg i.v.

3X weekly F 67 50 mg orally every other day 2 weeks 3 weeks 5 weeks 4 weeks 3 weeks 2 weeks 3 weeks 4 weeks 5 weeks 2 weeks 10 weeks 4 weeks 3 weeks 10 weeks 3 weeks 28 19 24 41 32 28 35 32 28 31 29 20 1 6 5 10 4 3 1 1 3 1 2 1 96.5 68.4 79.2 75.6 87.5 89.3 97.1 65.6 89.3 96.8 93.1 77.5 67.7 77.8 27 6

Claims (3)

1. A method of treatment of depressions by administration to a patient requiring such treatment of an effective amount of nicotinamide-adenine-dinucleotide (NADH), nicotinamide-adenine-dinucleotide phosphate (NADPH) or a physiologically compatible salt thereof.

2. Method according to claim 1, characterized in that the nicotinamide-adenine- dinucleotide (NADH), nicotinamide-adenine-dinocleotide phosphate (NADPH) or the physiologically compatible salt thereof is supplied to the body as a single dose in a quantity of 1 to 50 mg.

3. Method according to claim 2, characterized in that the single dose is 5 to 12.5 mg. DATED this 2nd day of October, 1992 JORG BIRKMAYER WATERMARK PATENT TRADEMARK ATTORNEYS THE ATRIUM 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRAUA AU9010991.WPC (DOC.021) LCG/KJS:EK