WO2012076916A1

WO2012076916A1 - Therapeutic association of 5 - hydroxy - tryptophan and caffeine for the treatment of the symptom of parkinson's disease, daytime sleepiness

Info

Publication number: WO2012076916A1
Application number: PCT/IB2010/003185
Authority: WO
Inventors: Marco Scarselli; Giovanni Umberto Corsini; Giovanni Cavalli
Original assignee: Brainet Discovery Srl
Priority date: 2010-12-09
Filing date: 2010-12-09
Publication date: 2012-06-14
Also published as: WO2012076916A8

Abstract

Use of an association with a base of 5- hydroxytryptophan and caffeine, with enhancing effect on the latter, for the treatment of the secondary symptoms of Parkinson's disease, such as daytime sleepiness and the phenomenon of nodding-off induced by dopamine mimetics.

Description

THERAPEUTIC ASSOCIATION OF 5 - HYDROXY - TRYPTOPHAN AND CAFFEINE FOR THE TREATMENT OF THE SYMPTOM OF PARKINSON'S DISEASE, DAYTIME SLEEPINESS

Description

Field of the invention

The present invention relates to a pharmacological association for improving the treatment of Parkinson's 5 disease. In particular, the invention envisages the use of an association with a base of caffeine and 5- hydroxy-tryptophan (5-HTP) in racemic form, laevorotatory and dextrorotatory, or the precursor tryptophan, said association having a synergistic

10 effect between the two compounds. Said medicament, by enhancing the effect of caffeine, can be used for the treatment of secondary symptoms correlated to Parkinson's disease, such as daytime sleepiness and "nodding-off " induced by dopamine mimetics, and is able

15 to act as an adjuvant to augment the effect of already existing therapeutic agents. The invention extends also to a pharmaceutical formulation in the form of a chewing gum or nasal spray.

Background of the invention

20 Parkinson's disease afflicts approximately 1% of the population aged over sixty. It is a disorder of the central nervous system, principally characterized by degeneration of some nerve cells situated in a deep area of the brain referred to as "black substance".

25 These cells produce a neurotransmitter, known as dopamine, responsible for activation of a circuit that controls movement. With the reduction of at least 50% of the dopaminergic neurones, adequate stimulation of the receptors that are located in an area of the brain known as area striata comes to cease.

· Primary and secondary symptoms

Parkinson's disease is characterized by primary symptoms that affect movement and other functions. As regards motor complications of the disease, the cardinal symptoms are tremors at rest, rigidity, slowing-down of movements, and postural instability.

Associated to this picture are other symptoms, defined as "secondary symptoms"; in particular amongst the secondary disorders the following may be cited: daytime sleepiness, nodding-off induced by the use of dopamine-mimetic drugs, dyskinesiae, cognitive disorders (for example, dementia) , and affective disorders (for example, depression) (1 and 2) .

• Therapy

There does not exist a specific treatment that slows down the course of the disease.

The therapy most frequently used is of a pharmacological type, which does not treat the illness but leads to a significant symptomatological improvement (3-5) . In any case, pharmacological treatment is not always effective and entails considerable side effects. In particular, treatment with L-dopa can lead to long-term motor complications (such as dyskinesiae) , whereas dopamine-agonists can induce drowsiness and hallucinations.

Even though Parkinson's disease is not considered fatal, it progresses inexorably with significant worsening and with a shortening of the life expectancy as compared to the general population. This having being said, it is evident how at the current state of the art a formulation that can slow down the course of the illness is not present on the market. In addition, the side effects of the existing therapy are significant and frequently add to the symptomatological picture of the illness (consider, for example, drowsiness, which, in addition to forming part of the symptomatological picture, is frequently a side effect of dopamine-agonist therapy) .

Summary of the invention

The purpose of the present invention is to improve the current therapy used in the case of Parkinson's disease, with particular attention paid to the search for new associations that are able to eliminate daytime sleepiness in parkinsonian patients and nodding-off induced by the use of dopamine-mimetic drugs in order to improve the quality of life of the patients.

For this purpose, the present invention envisages the use of an association that comprises caffeine and 5-hydroxytryptophan (5-HTP).

Caffeine is the alkaloid substance contained in coffee beans. It is very similar to theobromine, the alkaloid substance contained in cocoa and to theophylline, the alkaloid of tea leaves. These three alkaloids, which are very widespread in the vegetable world, are called xanthines because they have a molecular structure that can be considered as deriving from xanthine. Caffeine, theobromine, and theophylline are xanthines bound to methyl groups and are hence referred to as methyl-xanthines . Caffeine is 1,3,7- trimethyl-xanthine, theobromine is 3 , 7-dimethyl- xanthine, and theophylline is 1 , 3-dimethyl-xanthine .

L-5-hydroxytryptophan or L-a-amino-b- ( 5- hydroxyindolyl ) propionic acid, in brief 5-HTP, derives from tryptophan, an essential amino acid, known for being the precursor of hydroxytryptamine, or serotonin (5-hT) ; more precisely 5-HTP represents the precursor in the transformation of tryptophan into serotonin, a transformation that occurs at an intracellular level.

Recently, the scientific community has directed considerable attention to caffeine. The interest in this psychotropic substance with a bland psychostimulating effect has emerged from epidemiological scientific evidence that has demonstrated an inverse correlation between the use of caffeine and the incidence of Parkinson's disease (6) . These statistical data would appear to indicate a potential neuroprotective effect of caffeine in regard to neurodegenerative diseases, such as Parkinson's disease .

The protective effect of caffeine has been demonstrated also on animal models of the disease (7) .

Furthermore, caffeine exerts a stimulating effect on motor activity, and in animal models of Parkinson's disease induces a significant improvement in motor functions. If we moreover consider the undesirable aspects of the disease, such as daytime sleepiness and nodding-off induced by the use of dopamine-mimetic drugs, it is known that significant doses of caffeine are able to counterbalance said secondary symptoms, but in turn determine undesirable side effects in many categories of patients.

Instead, 5-hydroxytryptophan has been used at the start in anti-Parkinson therapy in combination with L- dopa because it increases the bioavailability of the latter by inhibiting catabolism thereof at a hepatic level. Subsequently, there has been demonstrated, in animal models, an increase of motor activity following upon administration of 5-hydroxytryptophan (8). Furthermore, said compound possesses antidepressive properties and consequently could prove useful in the forms of Parkinson's disease to which also depression is associated. As regards drowsiness, the effect of 5- HTP has not been studied in a systematic way; however, the use of said compound for pathological conditions, such as depression and migraine, has been widely reported (9-10) .

In the light of said knowledge, the interest of the inventors has focused on the possible use of an association of caffeine and 5-hydroxytryptophan, for the preparation of drugs to be used in the pharmacological treatment of Parkinson's disease, with the aim of improving, as regards various critical aspects, current anti-Parkinson therapy. The idea of using an association of caffeine and 5- hydroxytryptophan derives from the fact that a possible synergistic effect between the two compounds would entail a reduction of the doses of caffeine in order to be effective, consequently reducing its undesirable effects, particularly for cardiopathic patients, hypertensive patients, and also patients suffering from gastric problems.

In fact, with this association a response is provided to some problematical aspects that concern persons affected by Parkinson's disease (symptoms of the illness and side effects of the therapies used) . In particular, there is posed the primary objective of improving the current therapy as regards the side effects of the therapy itself and the secondary symptoms generally associated to the illness. A particular task of the present invention is hence to:

- counterbalance daytime sleepiness; and

- eliminate nodding-off induced by the use of dopamine-mimetic drugs.

Secondarily to said main effects, determined by the assumption of the association described, there has moreover been found in some cases also the improvement of depressive symptoms that are frequently associated in the context of Parkinson's disease and the reduction of onset of dyskinesiae due to L-dopa, which is the drug most widely used in Parkinson's disease. As is known, after some years of treatment with L-dopa, parkinsonian patients develop uncontrolled involuntary movements (dyskinesiae) . Recently, an important Swedish research group has demonstrated in animal models that the cause of dyskinesiae could be dopamine, which is formed from the L-dopa administered and is released by serotoninergic nerve cells (i.e., cells that normally release serotonin) (11) . In this case, the administration of 5-hydroxytryptophan (precursor of serotonin) has proven able to prevent the accumulation of L-dopa in serotoninergic cells, preventing onset of dyskinesiae. This is because 5-HTP (precursor of serotonin) is normally taken from serotoninergic cells and can thus exert an antagonistic effect in the absorption of L-dopa.

The use of xanthines in combination with agonists of neuronal receptors in order to restore motor and sensorial functions lost following upon damage to the central nervous system is known and described in the U.S. patent No. US 4, 742, 054.

Disclosed in the U.S. patent No. US 4 472 387 is a pharmaceutical composition for increasing the production of cerebral serotonin comprising xanthine and a precursor of serotonin, which produces a significant increase in the amount of serotonin released with respect to the levels produced by administration of the precursor of serotonin by itself.

Also described in the international patent application No. WO9908681 is a composition comprising neurotransmitter precursors, one or more xanthines in combination with histamine, glutamine, and/or aspartate administered for the purpose of improving the function of the neurotransmitters in the case of deficiency.

The U.S. patent application No. US 2007/0116779 describes the use of a nutraceutical composition comprising, among other ingredients, taken from an extended list, also tryptophan and caffeine or theophylline, which can be administered by themselves or in different combinations. The use of the composition, which is proposed to inhibit specific factors responsible for degenerative processes due to phenomena of cellular toxicity associated to Parkinson's disease, finds its premises in experimental discoveries that have identified protective agents in models that are applied to the complex Parkinson's disease.

Yet, if on the one hand it is known that xanthines in association with neurotransmitter precursors enhance various neuronal activities, the mechanism through which they exert their action is not clear.

Surprisingly, the inventors of the present disclosure have found that the combination of caffeine and 5-HTP has a significant and specific synergistic effect on an animal model of drowsiness induced by acetaldehyde, since, in association, these two active principles perform an augmented action as compared to the individual administrations. It should be noted that in said animal model, the synergistic action of caffeine and 5-HTP occurs at doses in which caffeine is practically ineffective if administered by itself. This model reproduces in a realistic way the situations of daytime sleepiness and nodding-off induced by the use of dopamine-mimetic drugs, present in patients affected by Parkinson's disease.

Detailed description of the invention

The results of the observations and of the experiments conducted by the inventors are highlighted by the graphs of the figures, described below.

Figure 1 shows the effect of the association of caffeine (10 mg/kg) and 5-HTP (10 mg/kg) on a model of sleep induced by acetaldehyde in rats. The data are presented as mean ± standard error. The experimental data obtained show the significant reduction of the time of sleep to approximately 50% in animals subjected to administration of the two compounds in association as compared to the control group (time of sleep assumed as 100%) and to the group of animals that received just one of the two compounds, caffeine or 5-HTP (time of reduction of sleep of approximately 10% with respect to the controls but not statistically significant). The datum obtained experimentally clearly indicates the synergistic effect of the two compounds in determining the reduction of the time of sleep that is greater than the summation of the effects produced by the two molecules when administered singly. In this animal model, the synergistic action of caffeine and 5-HTP causes the positive effect to be established at doses in which caffeine is practically ineffective if administered by itself, i.e., at doses that are not likely to induce in patients the typical side effects due to an overdosage of caffeine (e.g., raising of blood pressure, cardiopathies). Furthermore, as emerges from the graph, the effect produced by the association according to the present invention is also stable and prolonged in time and enables it to be proposed for useful application thereof in the treatment of parkinsonian patients in order to solve the problem of drowsiness, induced above all by the use of dopamine- agonistic drugs of which somnolence is a serious, invalidating, and dangerous side effect. Consequently, the administration of an association of caffeine and 5- HTP can improve the quality of life of parkinsonian patients .

The inventors have analysed the effect of the association of caffeine and 5-HTP also on other parameters that are very important and typical of the course of Parkinson's disease, the results of which are summed up in Figure 2.

Figure 2 shows the effect of the association of caffeine (15 mg/kg) and 5-HTP (25 mg/kg) on contralateral turning (number of turns) in the model of rats treated with 6-hydroxydopamine toxin (animal model of Parkinson's disease) . The data are presented as mean ± standard error.

An animal model of Parkinson's disease was used that would reproduce some of the motor symptoms present in the illness (12) . In particular, in said model the animals (rats) were subjected to lesions on just one side of the brain (in the nigro-striatal cerebral area) using 6-hydroxydopamine toxin, which inexorably destroys the nigro-striatal neurones. In the 6- hydroxydopamine model substances or associations were tested to determine whether they had an anti-Parkinson effect. In particular, substances possessing anti- Parkinson potential are able to induce the so-called "contralateral turning" phenomenon in this animal model. If the substance has an effect on motor functions, the animal is able to perform a movement by turning over on the side opposite with respect to the side of the lesion.

Initial experiments were conducted at different dosage of caffeine and 5-HTP to determine the conditions to be used in the experiment of the association. Caffeine started to be effective in this Parkinson animal model at the dose of 15 mg/kg, and this was the dose used in the experiment of the association. Instead, 5-HTP did not induce any effect up to the dose of 100 mg/kg. The experiment of the association of caffeine and 5-HTP was conducted at doses of caffeine of 15 mg/kg and doses of 5-HTP of 25 mg/kg. As control the two substances were used by themselves at the same dosage. In this experiment, approximately 30 animal were used, 10 per experiment. The caffeine/5-HTP association revealed an enhancement of the motor effects as compared to caffeine and 5-HTP by themselves. In particular, as may be noted from Figure 2, caffeine produced 4 contralateral turns, 5- HTP produced no effect, whilst the association produced 6 contralateral turns inducing a further increase by 50% with respect to the number of turns produced following upon assumption of caffeine alone. Said scientific indication on the caffeine/5-HTP association suggests that said combination can lead to a further improvement in the pharmacological therapy particularly on the primary motor symptoms of Parkinson's disease.

According to the present invention, the combined use of the two active principles caffeine and 5- hydroxytryptophan for the preparation of a medicament for the treatment of secondary symptoms of Parkinson's disease is consequently claimed. Said association has a synergistic effect between the two compounds with enhancement of the caffeine effect.

Other formulations for administrations in the form of chewing gum, syrup, gel, and spray with caffeine-to^¬ ll tryptophan ratios of 16:50 and 32:100, will be indicated hereinafter by way of illustration.

Pharmaceutical forms and dosages of the association in question

CHEWING GUM

A particularly preferred embodiment of the invention described herein is the pharmaceutical form contained in chewing gums, which is particularly indicated in the treatment of Parkinson's disease, in so far as, the process of chewing enables raising of the threshold of attention, so providing a targeted response to the problems of daytime sleepiness, a secondary symptom of the disease and a side effect of the therapy with dopamine-agonists , to which problem the association of the two molecules described in this invention proposes a solution.

The formulation in chewing gum is characterized by the addition of excipients, characterized by an enhancer action (e.g., vitamin E) and by a technique of 'masking' of the bitter taste of caffeine.

A preferred formulation of chewing gum substantially consists of:

- a water-insoluble gum base;

- a water-soluble portion; and

- flavouring agents.

The water-soluble portion dissolves with a part of the flavouring agent of the gum for a period of time during the chewing process.

In order to work with the gum base and mix other ingredients therein, the material must be first softened . Once the gum base is rendered bendable, the other ingredients

- 5-hydroxytryptophan,

- caffeine,

- trehalose,

- xylitol (other sugars such as saccharose, dextrose, maltose, dextrin, dry invert sugar, fructose, laevulose, galactose, wheat syrup, corn syrup or sugar alcohols, such as sorbitol and mannitol),

- flavouring agents, and

- Stevia extracts and/or very intense sweeteners (thaumatin, dihydrochalcones , acesulphame potassium, aspartame, sucralose, alitame, saccharin, cyclamates, and other additives, for example polyols and glycerine, and buccal enhancers)

are added therein and mixed.

After mixing, the gum is cooled slightly prior to extrusion in various forms. Then the gum is conditioned and cured under controlled temperature and humidity.

The insoluble gum base generally comprises: elastomers, resins, fats and oils, waxes, softeners, and inorganic fillers.

The elastomers can comprise polyisobutylene, isobutylene-isoprene copolymer, and styrene-butadiene rubber, as likewise natural latexes as chicle. The resins include polyvinyl-acetate resins and terpene. Fats and oils can also be included in the gum base, including sego, hydrogenated and partially hydrogenated vegetable oils and cocoa butter.

Waxes commonly used comprise paraffin, and micro- crystalline and natural waxes, such as beeswax and carnauba wax.

The insoluble gum base is constituted from approximately 5 wt% to approximately 95 wt% with respect to the weight of the gum.

The gum base also comprises a filling component.

The filling component may be: calcium carbonate, magnesium carbonate, talcum, dicalcium phosphate or sodium pyrophosphate (SPP), and sodium acid pyrophosphate (SAPP) .

The filler may constitute between approximately

5 wt% and approximately 60 wt% with respect to the weight of the gum base.

The gum bases contain also softeners including glycerol monostearate and triacetin.

Furthermore, gum bases can also contain optional ingredients such as antioxidants, ascorbyl palmitate, etc., colours, and emulsifiers (polysorbate 60, polysorbate 80).

The present invention envisages in any case the use of any commercially acceptable gum base.

The part soluble in water of the chewing gum further comprises: softeners such as lecithin, in particular lysophosphatidylcholine, lysophosphatidylethanolamine, glycerine sweeteners, flavouring agents, and combinations thereof, buccal enhancers (see Table 1 appearing above) . Softeners are added to the chewing gum in order to optimize the chewing capacity and the chewing sensation of the gum. The softeners, also known in the sector as plastifiers or plastifying agents, generally constitute between approximately 0.5 wt% and approximately 15 wt% with respect to the weight of the chewing gum.

NASAL ADMINISTRATION IN SPRAY

Presented herein are two formulations in powder form for nasal administration via a mechanical insufflator.

The preparation must be in particulate amorphous form with a particle size ranging between 2 and 20 lm and a very narrow gaussian distribution. A) Caffeine-to-tryptophan weight ratio: 16:50

First nostril

Ingredients %w/

Caffeine 8 8 mg per puff

5-hydroxytryptophan 25 25 mg per puff Hydroxypropyl cellulose 0.5 0.5 mg per puff Mannitol 66. 66.5 mg per puff

Second nostril

Ingredients %w/

Caffeine 8 8 mg per puff

Total administration

Ingredients

Caffeine 16 mg

5-hydroxytryptophan 50 mg

Hydroxypropyl cellulose 1 mg

Mannitol 133 mg

Nasal insufflator : 100 mg per puff

B) Caffeine-to-tryptophan weight ratio: 32:100

First nostril

Ingredients %w/w

Caffeine 16 16 mg per puff

5-hydroxytryptophan 50 50 mg per puff

Hydroxypropyl cellulose 0.5 0.5 mg per puff

Mannitol 33.5 33.5 mg per puff Second nostril

Ingredients %w/w

Caffeine 16 16 mg per puff

5-hydroxytryptophan 50 50 mg per puff Hydroxypropyl cellulose 0.5 0.5 mg per puff Mannitol 33.5 33.5 mg per puff

Total administration

Ingredients

Caffeine

5-hydroxytryptophan

Hydroxypropyl cellulose

Mannitol Nasal insufflator : 100 mg per puff

ADMINISTRATION IN 200-mg TABLETS

C) Caffeine-to-tryptophan weight ratio : 16:50

Ingredients per tablet %w/w mg per tablet

Caffeine 8 16

5-hydroxytryptophan 25 50

Microgranular cellulose 5 10

Polyvinylpyrrolidone 0.5 1

Starch 33.5 67

Magnesium stearate 0.5 1

Talcum 25 50

Precipitated silica 2.5 5

Total weight 200

ADMINISTRATION IN 216-mg TABLETS

D) Caffeine-to-tryptophan weight ratio : 32:100

Ingredients per tablet %w/w mg per tablet

Caffeine 14.8 32

5-hydroxytryptophan 46.29 100

Microgranular cellulose 4.6 10

Polyvinylpyrrolidone 0.46 1

Starch 31,0 67

Magnesium stearate 0.46 1

Precipitated silica 2.3 5

Total weight 216

ADMINISTRATION IN SYRUP - dose per 10 ml

E) Caffeine-to-tryptophan weight ratio: 16:50 Ingredients %w/w mg for 10 ml Caffeine 0.16 16

5-hydroxytryptophan 0.5 50

Hydroxypropyl cellulose 0.5 5

PVP K90 0.2 20

Flavouring agent

Phosphate buffer pH 5.5-6

Depurated water Sufficient to reach 100 g

ADMINISTRATION IN GEL - dose per 10 ml

F) Caffeine-to-tryptophan weight ratio: 16:50

Ingredients %w/w mg per 10 ml Caffeine 16 16

5-hydrox tryptophan 5 50

Sodium alginate 100

Carbopol 2 20

Hypromellose 5 50

Flavouring agent as required Phosphate buffer pH 5 5-6.5

Depurated water Sufficient to reach 100 g

G) Caffeine-to-tryptophan weight ratio: 32:100

Ingredients %w/w mg per 10 ml

Caffeine 0.32 32

5-hydroxytryptophan 1 100

Sodium alginate 1 100

Carbopol 0.2 20

Hypromellose 0.5 50

Flavouring agent As required

Phosphate buffer pH 5.5-6.5

Depurated water Sufficient to reach 100 g ADMINISTRATION IN GUMS (each packet contains 5 gums)

H) Caffeine-to-tryptophan weight ratio: 16:50

Each gum weighs 2 g

Ingredients A

% mg/strip

Caffeine 0.8 16

L-5-hydroxytryptophan 2.5 50

Xylitol 6.25 125 Other sugar, sugar 48.37 967.5

alcohol

Gum base 34 680

Glycerine 1.75 35

Liquid lecithin 0.15 3.75

Lysolecithin 0.187 1.25

Mint 1.125 22.5

Total weight mg 2000

I) Caffeine-to-tryptophan weight ratio: 32:100

Ingredients Al

mg/ strip

Caffeine 1.6 32

L-5-hydroxytryptophan 5.0 100

Xylitol 6.25 125

Other sugar, sugar 48.37 901.5

alcohol

Gum base 34 680

Glycerine 1.75 35

Liquid lecithin 0.15 3.75

Lysolecithin 0.187 1.25

Mint 1.125 22.5

Total weight mg 2000

ADMINISTRATION IN GUMS WITH ADDITION OF VITAMIN E

L) Caffeine-to-tryptophan weight ratio: 16:50

Ingredients B

% mg/strip

"Vitamin E TPGS/caffeine 1.6 32 mg equal to 16 mg molten mass" of caffeine

L-5-hydroxytryptophan 3.25 50

Xylitol 6.25 125

Other sugar, sugar alcohol 43.35 1050.5

Gum base 34 680

Glycerine 1.75 35

Liquid lecithin 0.15 3.75

Lysolecithin 0.187 1.25

Mint 1.125 22.5

M) Caffeine-to-tryptophan weight ratio: 32:100

Ingredients Bl

% mg/strip "Vitamin E TPGS/caffeine 3.2 64 mg equal to 32 mg molten mass" of caffeine L-5-hydroxytryptophan 6.5 100

Xylitol 6.25 125

Other sugar, sugar alcohol 43.35 968.5

Gum base 34 680

Glycerine 1.75 35

Liquid lecithin 0.15 3.75

Lysolecithin 0.187 1.25

Mint 1.125 22.5

Total weight mg 2000

The vitamin E TPGS/caffeine molten mass indicated among the ingredients of the last two formulations is obtained as described hereinafter.

Vitamin E TPGS/caffeine molten mass

Vitamin E TPGS and caffeine (or its salts) are hot mixed (at 40-45°C) in the ratio 1:1 until vitamin E TPGS melts completely to form a vitamin E TPGS/caffeine molten mass. The molten mass is then cooled up to formation of a solid mass.

As an alternative to the formulations appearing above, the inventors experimented also the possibility of using, instead of the two pure active principles, obtained by synthesis, two phytotherapeut ic principles with known titre of caffeine and 5-HTP. By way of non- limiting example we shall cite herein the Arabic Coffee, titred in caffeine (the dry part thereof contains on average 12ss of caffeine) and Griffona Simplici folia , titred in L-5-hydroxytryptophan (the dry extract is generally titred at 20% of 5-HTP, but there exist also forms with higher concentration, up to 97.98%) . This enables administration to the patients only freely usable natural products, which are commonly used in the herbal products today available on the market .

Some embodiments of the present invention have been described herein. On the other hand, it is evident that numerous other formulations can be employed, without thereby departing from the scope of the present invention as defined in the ensuing claims.

References

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2. Romigi A, Brusa L, Marciani MG, Pierantozzi M, Placidi F, Izzi F, Sperli F, Testa F, Stanzione P. Sleep episodes and daytime somnolence as result of individual susceptibility to different dopaminergic drugs in a PD patient: a polysomnographic study. J Neurol Sci. 2005. 228:7-10.

3. Schapira AH, Bezard E, Brotchie J, Calon F, Collingridge GL, Ferger B, Hengerer B, Hirsch E, Jenner P, Le Novere N, Obeso JA, Schwarzschild MA, Spampinato U, Davidai G. Novel pharmacological targets for the treatment of Parkinson's disease. Nat Rev Drug Discov. 2006. 5:845-54.

4. Schapira AH. Treatment options in the modern management of Parkinson disease. Arch Neurol. 2007.

64:1083-8.

5. Olanow CW, Obeso JA, Stocchi F. Continuous dopamine- receptor treatment of Parkinson's disease: scientific rationale and clinical implications. Lancet Neurol. 2006. 5:677-87.

6. Hancock DB, Martin ER, Stajich JM, Jewett R, Stacy MA, Scott BL, Vance JM, Scott WK. Smoking, caffeine, and nonsteroidal anti-inflammatory drugs in families with Parkinson disease. Arch Neurol. 2007. 64:576-80.

7. Aguiar LM, Nobre HV Jr, Macedo DS, Oliveira AA, Freitas RM, Vasconcelos SM, Cunha GM, Sousa FC, Viana GS . Neuroprotective effects of caffeine in the model of 6-hydroxydopamine lesion in rats. Pharmacol Biochem Behav. 2006. 84:415-9.

8. Schlosberg AJ, Harvey JA. Effects of L-dopa and L-5- hydroxytryptophan on locomotor activity of the rat after selective or combined destruction of central catecholamine and serotonin neurons. J Pharmacol Exp Ther. 1979. 211:296-304.

9. Turner EH, Loftis JM, Blackwell AD. Serotonin a la carte: supplementation with the serotonin precursor 5- hydroxy-tryptophan . Pharmacol Ther. 2006. 109:325-38.

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Claims

1) Use of an association with a base of 5- hydroxytryptophan (5-HTP; in racemic form, laevorotatory and dextrorotatory) and caffeine, with enhancing effect on the latter, for the treatment of the secondary symptom of daytime sleepiness present in Parkinson's disease.

2) Use of an association with a base of 5- hydroxytryptophan (5-HTP; in racemic form, laevorotatory and dextrorotatory) and caffeine, according to Claim 1, characterized in that the secondary symptom is the phenomenon of nodding-off induced by dopamine mimetics.

3) Use of a methylxanthine in combination with 5-hydroxytryptophan (5-HTP; in racemic form, laevorotatory and dextrorotatory) for the treatment of secondary symptoms present in Parkinson's disease.

4) Use of a methylxanthine in combination with 5-hydroxytryptophan (5-HTP; in racemic form, laevorotatory and dextrorotatory) for the treatment of secondary symptoms present in Parkinson's disease, as per Claim 3, where methylxanthine is chosen between theophylline and theobromine.

5) A pharmaceutical preparation for the treatment of secondary symptoms of Parkinson's disease such as daytime sleepiness and nodding-off induced by dopamine-mimet ics , characterized in that it comprises caffeine in association with hydroxytryptophan in a weight ratio of between 0.25 and 0.50.

6) The pharmaceutical preparation for the treatment of secondary symptoms of Parkinson's disease such as daytime sleepiness and nodding-off induced by dopamine-mimetics , characterized in that it comprises caffeine in association with hydroxytryptophan preferably in a weight ratio of between 0.30 and 0.40.

7) The pharmaceutical preparation for the treatment of secondary symptoms of Parkinson's disease such as daytime sleepiness and nodding-off induced by dopamine-mimetics , characterized in that it comprises caffeine in association with hydroxytryptophan more preferably in a weight ratio of 0.32.

8) The pharmaceutical preparation for the treatment of secondary symptoms of Parkinson's disease such as daytime sleepiness and nodding-off induced by dopamine-mimetics according to Claim 5, wherein caffeine is in an amount of between 10 and 100 mg per administered dose.

9) The pharmaceutical preparation for the treatment of secondary symptoms of Parkinson's disease such as daytime sleepiness and nodding-off induced by dopamine-mimetics according to Claim 5, comprising 5- hydroxytryptophan in an amount of between 25 and 200 mg per administered dose.

10) The pharmaceutical preparation according to Claims 5-9, characterized in that it is in the form of chewing gum.

11) The pharmaceutical preparation according to Claim 10, characterized in that it comprises a base of insoluble gum, a portion of soluble gum, trehalose, xylitol, or other sugar chosen in the group of saccharose, dextrose, maltose, dextrin, dry invert sugar, fructose, laevulose, galactose, wheat syrup, or sugar alcohols, such as sorbitol, mannitol, flavouring agents, and at least one high-intensity sweetener.

12) The pharmaceutical preparation according to Claim 10, characterized in that it has the following composition:

Ingredients A

mg/ strip

Caffeine 0.8 16

L-5-hydroxytryptophan 2.5 50

Xylitol 6.25 125

Other sugar alcohol 48.37 967.5

Gum base 34 680

Glycerine 1.75 35

Liquid lecithin 0.15 3.75

Lysolecithin 0.187 1.25

Mint 1.125 22.5

Total weight (mg) 2000

13) The pharmaceutical preparation according to Claim 9, characterized in that it is in the form of powder for nasal administration via mechanical insufflator; said powder being constituted by amorphous particles of a size ranging between 2 and 20 lm with a very narrow gaussian distribution.

14) The pharmaceutical preparation according to Claim 9, characterized in that it is in the form of a syrup with the following composition:

Ingredients %w/w mg per 10 ml Caffeine 0.16 16

5-hydroxytryptophan 0.5 50

Hydroxypropyl cellulose 0.5 5

PVP K90 0.2 20

Flavouring agent

Phosphate buffer pH 5.5-6.5

Depurated water Sufficient to reach 100 g