COMPOSITION COMPRISING DIAMINE OXIDASE FOR USE IN THE TREATMENT OR PREVENTION OF FIBROMYALGIA OR CHRONIC FATIGUE SYNDROME

Abstract

A composition includes diamine oxidase for use in prevention or treatment of symptoms and disorders caused by fibromyalgia or chronic fatigue syndrome.

Claims

1. A method of preventing or treating the symptoms and disorders caused by fibromyalgia or chronic fatigue syndrome, comprising administering a composition comprising diamine oxidase (DAO).

2. The method according to claim 1, wherein said DAO is administered orally in the form of tablets, capsules or sachets.

3. The method according to claim 1, wherein said DAO is administered at a dose of between 0.1 and 50 mg.

4. The method according to claim 1, wherein said composition also contains caffeine.

5. The method according to claim 1, wherein said composition also contains caffeine which is administered at a dose of between 1 and 100 mg.

6. The method according to claim 1, wherein said DAO has a gastric protection.

7. The method according to claim 1, wherein said DAO is used in free form, in powder, lyophilised powder, microcapsules, nanocapsules or liposomes.

8. The method according to claim 1, wherein said administration of the composition of the present invention is carried out together with a diet low in histamine-rich and/or histamine releasing food.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0060] A first aspect is the use of oral compositions comprising DAO for the preparation of a composition for the prevention or treatment of the symptoms and disorders caused by fibromyalgia or chronic fatigue syndrome, preferably fibromyalgia.

[0061] The DAO used in the present invention can be either of biotechnological origin or extracted from animals or plants.

[0062] If the DAO used is of non-plant origin, it is preferably in the form of a lyophilised powder. If the DAO used is of plant origin, it may also be in liquid form.

[0063] The different compositions comprising DAO to be used in the preparation of a composition for the prevention or treatment of symptoms or disorders caused by fibromyalgia or chronic fatigue syndrome, preferably fibromyalgia, are in the form of tablets, capsules or sachets containing free DAO in powder, lyophilised powder, microcapsules, nanocapsules or liposomes of DAO with gastric protection.

[0064] The different compositions comprising DAO may also contain caffeine to potentiate the effects of prevention and treatment of the symptoms and disorders caused by fibromyalgia or chronic fatigue syndrome, preferably fibromyalgia.

[0065] Caffeine is an alkaloid of the xanthine group that has vasoconstriction capacity. Histamine produces vasodilation and this vasodilation produces pain. Caffeine contributes to vasoconstriction and therefore to alleviate the pain.

[0066] The DAO content in compositions of the present invention is between 0.1 and 50 mg per dose, preferably between 2 and 20 mg.

[0067] The caffeine content in the compositions of the present invention is between 1 and 100 mg per dose, preferably between 5 and 50 mg.

[0068] Compositions comprising DAO for use in the prevention and treatment of the symptoms and disorders caused by fibromyalgia or chronic fatigue syndrome, preferably fibromyalgia, can be taken before, after or with meals.

[0069] The use of compositions comprising DAO of the present invention directly affects the histamine level in blood and therefore the symptoms and disorders caused by fibromyalgia or chronic fatigue syndrome, preferably fibromyalgia, as a consequence of accumulated histamine levels.

[0070] The compositions of the present invention are prepared from free DAO, in powder, lyophilised powder, microcapsules, nanocapsules or liposomes of DAO that have an enteric coating layer that protects the DAO from gastric acidity, so that the different forms can be packaged directly in sachets or put into a capsule or compressed to give tablets. The enteric coating layer that coats the different forms rapidly disintegrates or dissolves in a neutral or alkaline medium.

[0071] In the case of microgranules, the cores can be inert cores based on sugar or similar base over which the DAO is applied or these cores can already contain DAO mixed with other excipients. These excipients can be binders, surfactants, filling materials, disintegrants, alkaline additives or other pharmaceutically acceptable ingredients either alone or in a mixture. The binders can be cellulose in type such as hydroxypropyl methylcellulose, hydroxypropyl cellulose and sodium carboxymethyl cellulose, polyvinylpyrrolidone, sugars, starches and other pharmaceutically acceptable substances with cohesive properties. Suitable surfactants can be from the groups of ionic or non-ionic acceptable surfactants such as, for example, sodium lauryl sulphate.

[0072] Alternatively, DAO can be mixed with alkaline compounds and additionally mixed with constituents suitable for formulation in a core material. These core materials can be produced by extrusion/spheronization or by compression using different processing equipment.

[0073] DAO can also be mixed with other pharmaceutically acceptable alkaline substances such as salts of phosphoric acid and sodium, potassium, calcium, magnesium and aluminium, carbonic acid, citric acid or other suitably weak organic or inorganic acids; a co-precipitate of aluminium hydroxide/sodium bicarbonate; substances normally used in anti-acid preparations such as aluminium, calcium and magnesium hydroxides; magnesium oxide or compound substances such as Al.sub.2O.sub.3.6MgO.CO.sub.2.12H.sub.2O, (Mg.sub.6Al.sub.2 (OH).sub.16CO.sub.3.4H.sub.2O, MgO.Al.sub.2O.sub.3.2SiO.sub.2.nH.sub.2O or similar compounds; pH buffering substances such as tris(hydroxymethyl)aminomethane, basic amino acids and their salts or other pharmaceutically acceptable pH buffering substances.

[0074] The enteric coating layers can contain pharmaceutically acceptable plasticizers to obtain the desired mechanical, flexibility and hardness properties. These plasticizers can be, for example, triacetin, citric acid esters, phthalic acid esters, cetyl alcohol, polyethylene glycols, polysorbates or other plasticizers.

[0075] The present invention also refers to a composition that comprises DAO according to any of the embodiments of the present invention for use in the prevention or treatment of the symptoms and disorders caused by fibromyalgia or chronic fatigue syndrome, preferably fibromyalgia.

[0076] The present invention also refers to a method of treatment that comprises administrating a composition comprising DAO, according to any of the embodiments of the present invention, to a patient who presents symptoms and disorders caused by fibromyalgia or chronic fatigue syndrome, preferably fibromyalgia, or who is at risk from suffering from them, in a therapeutically effective amount.

EXAMPLES

Example 1

[0077] Tablets of DAO were prepared from microgranules containing 4% DAO in accordance with the following formula:

TABLE-US-00001 DAO 4 mg Mannitol 40 mg Microcrystalline cellulose 25 mg Hydroxypropyl cellulose 10 mg Maize starch 10 mg Citric acid 6 mg

[0078] The microgranules were coated with hydroxypropyl methylcellulose.

[0079] To make the tablets, the DAO microgranules were compressed with microcrystalline cellulose and sodium stearyl fumarate.

Example 2

[0080] Tablets of DAO were prepared from microgranules containing 4% DAO and 10% caffeine in accordance with the following formula:

TABLE-US-00002 DAO 4 mg Caffeine 10 mg Mannitol 35 mg Microcrystalline cellulose 15 mg Hydroxypropyl cellulose 10 mg Hydroxypropyl 10 mg methylcellulose Ascorbic acid 6 mg

[0081] The microgranules were coated with a methacrylic acid copolymer.

[0082] To make the tablets, the DAO microgranules were compressed with microcrystalline cellulose and magnesium stearate.

Example 3

[0083] DAO sachets were prepared containing 100 or 150 mg of DAO microgranules prepared according to the first part of example 1.

Example 4

[0084] DAO and caffeine sachets were prepared containing 100 or 150 mg of DAO microgranules prepared according to the first part of example 2.

Example 5

[0085] DAO capsules were prepared containing 100 or 150 mg of DAO microgranules prepared according to the first part of example 1, filling the soft gelatine capsules with the microgranules.

Example 6

[0086] DAO and caffeine capsules were prepared containing 100 or 150 mg of DAO microgranules prepared according to the first part of example 2, filling the soft gelatine capsules with the microgranules.

Example 7

[0087] Determination of the efficacy of DAO compositions, which are an object of the present invention, in subjects diagnosed with fibromyalgia and who showed a deficit of DAO.

[0088] Oral compositions containing DAO, alone or associated with caffeine, which are an object of the present invention, were tested in a total of 65 subjects diagnosed with fibromyalgia, as out-patients.

[0089] Before assigning the subjects to the study, levels of histamine in blood were measured as well as the activity level of DAO in plasma. Those subjects with blood histamine values over 20 micrograms per decilitre and levels of DAO activity below 40 HDU/mL were included in the study.

[0090] After the first analysis, there were 42 selected subjects (38 women and 4 men, of ages between 21 and 45 years) who were randomly assigned DAO compositions or placebo.

[0091] The following tables show the results in relation to the reduction of symptoms and disorders caused by fibromyalgia after the administration of a dose protocol of 4 mg DAO twice a day in 21 subjects diagnosed with fibromyalgia and with DAO deficit in comparison with 21 subjects who were administered placebo.

TABLE-US-00003 TABLE 1 Comparative results of the symptoms and disorders caused by fibromyalgia between subjects taking DAO tablets, of Example 1, and those not taking DAO. Symptoms and disorders of Subjects taking Subjects not fibromyalgia DAO: 21 taking DAO: 21 Back pain 3 of 21 20 of 21 Lumbar pain 4 of 21 19 of 21 Neck pain 4 of 21 20 of 21 Knee pain 5 of 21 21 of 21 Fatigue 5 of 21 21 of 21 Histamine level in 2-20 >>20 blood micrograms/0.1 L micrograms/0.1 L

[0092] The degree of pain, both in the initial diagnosis of fibromyalgia and in monitoring the group treated with DAO and the placebo group, was determined using the McGill pain scales for measuring pain quality and the visual analogue scale (VAS) for measuring pain intensity.

[0093] The McGill pain questionnaire, which enables measurement of pain quality, is a questionnaire where the patient must choose a descriptor for each scale best representing their pain experience, deciding if the pain is throbbing, pulling, sharp, etc. and a second category measuring the emotional component where the patient describes the pain choosing between adjectives such as tiring, punishing or wretched, etc.

[0094] The Visual Analogue Scale (VAS) is the most commonly used instrument in clinical studies to evaluate the pain intensity of fibromyalgia. The patient is shown a horizontal or vertical line with the ends marked for the absence of pain and the worst possible or imaginable pain; they are asked to mark a point on the line reflecting their pain, and then the distance in millimetres from the no pain end to the point marked by the patient is measured.

[0095] Pain maps were also used to determine the location and spatial extension of the symptom; however, the maps are only an aid and do not replace a good clinical evaluation. Normally, a map is used with sensitive points for fibromyalgia, where serial evaluation of whether the pain reduces or increases can be evaluated in successive measurements in each of these points. These maps are very useful for monitoring pain.

[0096] Pain measurement tests were also based on tolerance to pressure applied at the point affected by the pain using a rubber probe. Patients with fibromyalgia require much less pressure to activate the neurones associated with acute pain in the brain than healthy patients. The magnitude of pain, sensitivity to pain and symptoms of depression were compared in the subjects using an exploratory scanner (MRI).

TABLE-US-00004 TABLE 2 Comparative results of the symptoms and disorders caused by fibromyalgia between subjects taking DAO and caffeine tablets, of Example 2, and those not taking DAO and caffeine. Subjects selected for this trial were diagnosed with fibromyalgia but without associated sleep disorders. Symptoms and Subjects taking Subjects not disorders of DAO and caffeine: taking DAO and fibromyalgia 21 caffeine: 21 Cephalea 2 of 21 20 of 21 Fatigue 4 of 21 21 of 21 Histamine level in 2-20 >>20 blood micrograms/0.1 L micrograms/0.1 L

Example 8

[0097] Determination of the efficacy of DAO compositions of the present invention in subjects diagnosed with chronic fatigue syndrome and who showed a deficit of DAO.

[0098] Oral compositions containing DAO of the present invention were tested in a total of 46 subjects diagnosed with chronic fatigue syndrome, as out-patients.

[0099] To evaluate the degree of affectation of chronic fatigue syndrome in candidate study subjects, the quality of life of these subjects was evaluated using a simple scale of 4 successive grades (I, II, III and IV), with criteria used in the clinic. This scale is used in the Chronic Fatigue Syndrome (CFS) Functional Unit in the Hospital Clinic.

[0100] The CLINIC scale consists of dividing the patients with chronic fatigue syndrome into four different grades of functional affectation depending on the effect of their fatigue on quality of life:

[0101] GRADE I: the patient is sometimes or occasionally fatigued, without significant limitation (<50%) of work or daily life activities.

[0102] GRADE II: persistent presence of fatigue, oscillating but without improvement, with marked effect (>50%) on work and also daily life activities.

[0103] GRADE III: marked fatigue that does not allow, even occasionally, performing any type of work, which limits autonomy and activities of daily life by more than 80%.

[0104] GRADE IV: extreme fatigue that requires the help of other people for basic personal activities and that makes autonomy and the activities of daily life impossible.

[0105] Improvement is evaluated when the patient passes from a higher to a lower grade in terms of the number of improvement grades.

[0106] The following table shows the results in relation to the number of grades of improvement on the CLINIC scale in 23 subjects diagnosed with chronic fatigue syndrome of grades II, III and IV and with DAO deficit, after the administration of a dose protocol of 4 mg DAO twice a day in comparison with 23 subjects administered placebo.

TABLE-US-00005 Number of grades of Subjects taking Subjects not improvement DAO: 23 taking DAO: 23 1 16 of 23 2 of 23 2 4 of 23 0 of 23 Histamine level in 2-20 >>20 blood micrograms/0.1 L micrograms/0.1 L