FR2862873A1 - USE OF POLYUNSATURATED FATTY ACIDS OMEGA 3 IN THE APNEA OF SLEEP - Google Patents

Abstract

The present invention relates to the use of omega-3 polyunsaturated fatty acids for the preparation of a medicament intended for the treatment of sleep apnea syndrome. The polyunsaturated omega 3 fatty acids are advantageously chosen from the group consisting of EPA, DHA and their mixtures.

Description

The present invention relates to the use of polyunsaturated fatty acids

  in omega 3 for the preparation of a medicament for the treatment of sleep apnea syndrome

  Sleep apnea syndrome is a common condition, affecting mainly mature men. The prevalence of this syndrome, estimated by several epidemiological studies, is of the order of 7% of the general adult population. The older the adult population, the greater the prevalence of this syndrome. In particular, it is greater than 10% for a population over 65 years old.

  The disease is characterized by breathing pauses during sleep. The frequency of these breaks is very variable from one individual to another, but can reach figures of up to more than 30 breaks per hour of sleep.

  The respiratory arrest leads to a periodic desaturation of the blood in oxygen leading to a real intermittent hypoxia, that is to say to an intermittent fall of the arterial pressure, which becomes lower than 70 mmHg or 9,31 kPa, of the rate of oxygen in the blood and therefore also to an intermittent decrease in the amount of oxygen in the tissues.

  During a sleep period, patients with sleep apnea syndrome experience a significant number of episodes of oxygen desaturation that can lead to repeated ischemia in certain organs, such as the brain or heart. Ischemia is a stop or decrease in arterial blood supply to a tissue or organ.

  The clinical consequences of this syndrome are multiple and disabling. Frequent and repeated awakenings lead to a non-restorative sleep resulting in particular in daytime sleepiness and sometimes incoercible sleepiness, intellectual deterioration, difficulties of concentration, an increased risk of traffic accidents, an increased risk of high blood pressure or an association with this pathology, a risk of cardiovascular or cerebrovascular accidents, a risk of sudden death, erectile dysfunction. Sleep apnea syndromes have two main causes.

  First, sleep apnea can be obstructive. In this case, the respiratory arrest is related to hypotonia, that is to say to a decreased tonicity, of the muscles of the oropharyngeal sphere which causes an obstruction of the upper respiratory tract of inspiration. This obstruction of the upper airways coexists with a maintenance of the muscular activity of the thoracic cage, that is to say the diaphragm and the intercostal muscles. This is the most common cause of sleep apnea.

  Second, sleep apnea can be of central origin. In this case, the respiratory arrest is linked to a stop of the operation of all the muscles of the thoracic cage by intermittent suspension of the central control.

  The exact cause (s) of the occurrence of sleep apnea syndrome is poorly understood, although a number of risk factors are identified, such as obesity, male sex, and facial dysmorphism.

  The treatment of this symptom is essentially based on mechanical restrictive means such as, in particular, night ventilation assisted by the positive pressure mask, as described, for example, in US Pat. No. 6,427,689, or devices for holding the jaw in an advanced position. Treatment may also be based on surgical measures when an anatomical factor narrowing the upper airway is identified.

  The success of these techniques depends on the nature and severity of existing anatomical abnormalities.

  Sleep apnea syndrome can also be treated by more flexible therapeutic means. For example, European Patent Application EP 01 090 638 discloses the use of (R) -zacopride, or (R) -N- [1azabicyclo (2,2,2) oct-3-yl] -2-methoxy- 4-amino-5-chloro-benzenamide, or pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment of sleep apnea syndrome. The use of such a drug can reduce the number of apneic episodes per hour of sleep.

  US Patent 5,075,290 discloses the use of dipyridamole in the medical treatment of sleep apnea and related symptoms such as snoring. US Pat. Nos. 5,502,067 and 5,407,953 teach the use of pilocarpine in the preparation of a medicament intended in particular for the treatment of sleep apnea syndrome. US Pat. No. 5,356,934 describes the use of (R) -fluoxetine molecules in the treatment of sleep apnea.

  The effectiveness of the various pharmaceutical treatments of the prior art depends in particular on the level of severity and the age of the disorder, as well as the different stages of sleep.

  The lack of adequate therapeutic treatment for sleep apnea, whether obstructive or central, remains an unsatisfied public health problem in a satisfactory manner.

  Polyunsaturated omega 3 fatty acids are derived from alphalinolenic acid (ALA), an essential fatty acid that the body can not synthesize and which must therefore be provided by external sources, such as food.

  Polyunsaturated fatty acids in omega 3 can also be brought directly by the diet. For example, fatty fish have two major types of omega 3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

  Omega 3 polyunsaturated fatty acids have many roles in modulating the properties of cell membranes. Their effects are well documented at the cardiovascular level, but also cerebral with regard to their role in central nervous system maturation phenomena and vision.

  The application WO 01/78530 describes the use of omega 3 polyunsaturated fatty acids for the preparation of an improved nutritional composition intended to nourish and reinforce the neurological development of premature infants. Said composition advantageously comprises docosahexaenoic acid (DHA), arachidonic acid (AA) and precursors such as alpha-linolenic acid (ALA) and linoleic acid (LA). The use of such an improved nutritional composition allows an increase in premature infants, infants and young children neurodevelopment, including vision development, motor development and language development without observing a decrease in the anthropometric growth.

  Japanese Application JP 61 065 821 discloses the use of a synthetic surfactant prepared from choline phosphoglyceride, phospholipidic acid and fatty acids. Said surfactant is used in cases of atelectasis, that is to say in the case of pulmonary histological lesions, especially in cases of atelectasis caused by ingestion of foreign bodies.

  The essential fatty acids are also used for prophylactic purposes of the morphological and physiological manifestations of chronic stress syndrome in rats (Kresiun VI, Iurlov VM, Tishchenko, The stress-protective effect of a new derivative of n-3-polyunsaturated fatty acids). AV, Ole'nik NN, Biull Eksp Biol Med (1993), September 116: 9, 274-7).

  A comparative study of boys aged 6 to 12 shows that boys with polyunsaturated fatty acid deficiencies in omega 3 have behavioral problems, sleep problems, learning disabilities and health problems (Omega-3-fatty acids in boys with behavior, learning, and health problems, Stevens LJ, Zentall SS, Abate ML, Kuczek T, JR Burgess, Physiology Behavior, 59: 4-5, 915-20).

  Essential fatty acids also play an important role in the functional development of the retina and the occipital cortex (Uauy R, Peirano P, Hoffman D, Mena P, Birch D Birch E, Lipids (1996), March 31 Suppl: S1, 67-76).

  Polyunsaturated omega 3 fatty acids have never been described in the prior art as having an effect on the central or peripheral regulation of the respiratory system and in particular the automatisms of the respiratory function.

  However, the inventors have surprisingly found that these omega 3 polyunsaturated fatty acids play a regulatory role on these systems.

  Also, the object of the present invention is to provide patients with a drug for the treatment of sleep apnea syndrome use more flexible and safer than surgery. The drug also has the advantage of treating sleep apnea syndrome in all patients, regardless of the level of severity and the age of the disorder.

  The present invention relates to the use of omega 3 polyunsaturated fatty acids for the preparation of a medicament for the treatment of sleep apnea syndrome.

  In a particular embodiment of the invention, the medicament contains one or more omega 3 polyunsaturated fatty acids selected from the group consisting of linolenic acid, EPA, DPA, DHA, the other acids. with a first double bond in omega 3 and their mixtures.

  In another particular embodiment of the invention, the omega 3 polyunsaturated fatty acids are chosen from EPA, DHA and mixtures thereof.

  In another embodiment of the invention, omega 3 polyunsaturated fatty acids may optionally be combined with omega 3 fatty acids, either free or in the form of esters with alcohol ligands, for example ethyl esters. , triglycerides, phospholipids and other alcohols.

  The use of omega 3 polyunsaturated fatty acids for the preparation of a medicament for the treatment of sleep apnea syndrome leads to an improvement in the pathological parameters observed in this condition. Thus, said use results in a decrease in the number of apnea-hypopnoea episodes observed during the polysomnographic recording.

  The use of omega 3 polyunsaturated fatty acids according to the invention also makes it possible to reduce the index of oxygen desaturation, that is to say to reduce the number of times when the saturation of the blood oxygen falls. 4% or more above baseline, and increase the minimum oxygen saturation, which is the lowest oxygen hemoglobin saturation figure found during sleep.

  It also causes a decrease in heart rate at all stages of sleep, whether during light sleep, during REM sleep or during deep sleep.

  These effects are accompanied by more than a subjective improvement of the general condition of the patients.

  In the context of the present invention, said medicament is administered orally or intravenously. It may be administered in unit or multidose administration forms in admixture with suitable pharmaceutical carriers known to those skilled in the art. For oral administration, suitable unit dosage forms include, optionally, scored tablets, capsules, powders, granules, and oral solutions or suspensions. For oral administration, the appropriate multidose forms of administration include oral drops, emulsions and syrups. For intravenous administration, suitable unit or multidose forms of administration include, but are not limited to, injectables, solutions or emulsions, injectable infusions, solutions or emulsions, and injectable preparations.

  Usable dosage forms may be in oily or dry forms, such as powders, granules, tablets and capsules. The release of the active ingredient can be accelerated, slowed down or delayed.

  During the preparation of tablets, the omega 3 polyunsaturated acids according to the invention are mixed with a pharmaceutically acceptable vehicle such as, in particular, gelatin, talc, starch, lactose, magnesium stearate, gum arabic. or their analogues. The tablets may optionally be coated, that is to say covered with several layers of various substances such as sucrose, to facilitate the setting or storage. The tablets may still have a more or less complex formulation intended to modify the rate of release of the active ingredient. The release of the active ingredient of said tablet can be accelerated, slowed down or delayed depending on the desired absorption.

  A preparation in capsules is obtained by mixing the omega 3 polyunsaturated acids according to the invention with a diluent. The mixture thus obtained is poured into soft or hard gelatin capsules.

  A syrup preparation may contain the omega 3 polyunsaturated acids according to the invention together with a sweetener, preferably an acaloric sweetener, a flavoring agent and a suitable colorant.

  The water-dispersible powders or granules may comprise the omega 3 polyunsaturated acids according to the invention mixed with dispersants or wetting agents, suspending agents, such as polyvinypyrrolidone, or sweeteners. or taste correctors.

  The amount of omega 3 polyunsaturated acids according to the invention to be administered depends on the weight of the patient. It can depend on the severity of the disorder and can be tailored to each patient's response to treatment. It can be independent of the age of the disorder.

  The treatment of patients suffering from mild or severe sleep apnea syndrome by omega 3 fatty acids consists of administering said drug at a rate of 300 to 5400 mg of omega 3 fatty acids per day, advantageously 180 to 3240 mg of eicosapentaenoic acid (EPA) and / or 120 to 2160 mg of docosahexaenoic acid (DHA), still more preferably 1200 mg of EPA and DHA per day in one or more times in an EPA: DHA ratio included between 0: 100 and 100: 0.

  In a particularly advantageous manner, the administration of said medicament at doses as defined above is divided into two daily doses.

  The following examples illustrate the invention without limiting its scope.

  EXAMPLE 1 Effect of omega 3 polyunsaturated fatty acids on the respiratory system 1) Measuring apparatus: A polysomnograph is an apparatus for simultaneously recording several biological parameters such as electroencephalographic, electromyographic, electrocardiographic activity. Respiratory rhythm, including abdominal, thoracic or nasobuccal rhythm, blood oxygen saturation, eye movements, cutaneous and / or rectal temperature, body position, etc. All of these parameters require specific acquisition modules such as high-pass and low-pass filters, samplings, and so on. The equipment can be fixed, the patient is then obliged to remain in the specialized department, which guarantees a medical, paramedical and videoscopic recording. The equipment can also be ambulatory, the subject then carries for a specified period, frequently 24 or 48 hours, a system recording and storing the data. This data is then transferred and interpreted into a more efficient device. Ambulatory equipment is simple, reliable, and it allows not to change the lifestyle of the patient, however, there is no clinical control.

  2) Experimental Protocol: Nine patients with mild or severe sleep apnea syndrome are treated with moderate omega-3 fatty acids, 1200 mg / day EPA and DHA (720 mg EPA and 480 mg of DHA) divided into two daily doses for 4 weeks.

  Using a polysomnograph, the number of apnea episodes per hour, the number of snoring per hour, the index of oxygen desaturation per hour and the oxygen saturation in the blood per hour before and after were measured. the treatment.

  3) Results: They are given in the following Table 1: Number of episodes Number of snoring Oxygen saturation Apnea oxygen desaturation index Severity Before After Before After Before After Before After treatment treatment treatment treatment treatment treatment treatment treatment treatment disorder Severe 74 66 404 374 51 60 79 74.6 Severe 62 47 233 318 66 72 56 43.9 Severe 33 20 230 0 63 66 52 38.1 Severe 37 17 230 152 70 63 36 19.9 Severe 22 25 284 126 58 72 42 48.8 Light 4 3 2 0 89 90 3 3 Light 13 1 1 3 84 86 42 3.6 Light 1 0, 4 65 101 86 90 9 4.9 Light 8 9 43 17 89 88 3 5.2

Table 1

  These results show a decrease in the number of apneashypopnea episodes observed during polysomnographic recording, a decrease in the oxygen desaturation index and an increase in the minimum oxygen saturation. These variations are statistically significant.

  The effect on the various parameters is constant, regardless of the level of severity and the age of the disorder.

  Example 2 Effect of Omega 3 Polyunsaturated Fatty Acids on the Cardiovascular System 1) Experimental Protocol: Eight patients suffering from mild or severe sleep apnea syndrome are treated with omega 3 fatty acids at a moderate dose, 1200 mg / day of EPA and DHA (720 mg of EPA and 480 mg of DHA) divided into two daily doses for 4 weeks.

  Using a polysomnograph, their heart rate was measured during light sleep, during REM sleep, and during deep sleep before and after treatment.

  2) Results: The results, expressed in number of beats per minute, are given in

following table 2:

  Light sleep Paradoxical sleep Deep sleep Severity of Before Before Before After Before after treatment treatment treatment treatment treatment Severe 91.5 78.8 82 64.9 103.7 68.2 Severe 88.2 66.6 64.1 58, 1 63.9 61.3 Severe 64.6 60 54.4 47.6 58.3 46.2 Severe 91 76.7 77.8 76.4 78.8 76.4 Slight 60.3 58.1 65, 2 51.9 52.1 52.6 Slight 72.6 72.6 72.1 66.1 72 69.1 Slight 81.9 70.3 70.1 63.9 69.2 64.4 Slight 72.7 66.6 68.4 59.2 64.3 61.3

Table 2

  These results show a decrease in heart rate at all stages of sleep. These results are statistically significant.

  The effect on the heart rate is constant, regardless of the level of severity and the age of the disorder.

Claims (4)

claims   1 Use of omega 3 polyunsaturated fatty acids for the preparation of a medicament for the treatment of sleep apnea syndrome.   2 Use according to claim 1, characterized in that the medicament contains one or more omega 3 polyunsaturated fatty acids chosen from the group consisting of linolenic acid, EPA, DPA, DHA and fatty acids. having a first omega 3 double bond, and mixtures thereof.   Use of omega 3 polyunsaturated fatty acids according to claims 1 or 2, characterized in that the omega 3 polyunsaturated fatty acids are advantageously selected from the group consisting of EPA, DHA and mixtures thereof.   4 Use of omega 3 polyunsaturated fatty acids according to any one of claims 1 to 3, characterized in that the medicament is administered orally or intravenously.