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Title:  Composition for the treatment of migraine

United States Patent:  6,465,517

Issued:  October 15, 2002

Inventors:  Van Der Zee; Luutsche (Arnhem, NL)

Assignee:  N.V. Nutricia (Zoetermeer, NL)

Appl. No.:  613573

Filed:  July 11, 2000


The present invention describes a novel composition for the treatment of migraine, a common neurovascular syndrome, which can be elicited by functional and/or structural (symptomatic) disorders. This composition comprises taurine, coenzyme Q10 and additionally creatine, L-carnitine, certain vitamins and minerals, carbohydrates, proteins, fats and herbal extracts. Furthermore, the invention describes a method for the treatment of migraine.


Adequate energy production by proper mitochondrial functioning is very important for the functioning and survival of every cell, particularly for highly active cells like myocytes and brain cells. Energy (ATP) production from the nutrients out of our food, is a well co-ordinated but very complicated process and needs the presence of a number of co-factors. Insufficient levels of factors like CoQ10 (antioxidant and key transducer for mitochondrial oxidative phosphorylation), taurine (important for calcium homeostasis), creatine (important as a high energy phosphate (P) shuttle and energy reservoir) and L-carnitine (regulating glycolysis and essential for transport of fatty acids across the mitochondrial membrane) reduce the energy producing capacity and therefore vitality of the cell.

Normalisation of only one factor is usually not sufficient to improve the energy production in the presence of abnormalities in more than one actor in the bioenergetic pathway. This pathway consists of a cascade of interlocking activities in which the nutrients and co-factors are highly dependent on each other and act synergistically. Therefore, the combination of the above mentioned components will interact to benefit the patient and the effect of the combination is expected to be greater than the sum of the effect of the individual ingredients alone. The invention pertains to a composition which provides a balanced combination of components enhancing the cellular energy status of neurons and other brain cells and facilitating maintenance of ion gradients, and thus providing alleviation of migraine. The composition of the invention contains one or more of the components CoQ10, L-carnitine, taurine and creatine (B-vitamins), of which taurine and CoQ10 are believed to be the most important ones. As mentioned before, the combination of the individual components addresses a cascading series of disruptions in cellular energetics that are present in patients with migraine and will therefore be more effective than treatment with a single component alone. Moreover, the composition of the invention is found to be safe and no side-effects have been reported for healthy volunteers in a recently performed clinical trial.


Taurine (2-aminoethanesulfonic acid) is the amino acid with the highest concentration in the human body. Its physiologic functions are not yet well understood. Taurine is considered to be important for the maintenance of the intracellular ion, in particular calcium, homeostasis. Taurine appears to do this by affecting several membrane systems. It modulates calcium and sodium channels through the cellular calcium/sodium-exchanger and a taurine/sodium-exchanger (Azuma, Satoh). Furthermore, taurine can act as an antioxidant and may react with a variety of potentially toxic intracellular aldehydes, including malonic dialdehyde (Ogasawara). Therefore, increased levels of cerebral taurine may dampen the hyperexcitation required to initiate SD by preventing derangements in ion gradients across the membrane and preventing calcium overload in the mitochondria, leading to malfunctioning of the mitochondria and cellular apoptosis.

Furthermore, taurine displays inhibitory neurotransmitter properties over sensitive pathways in the brain stem and spinal cord. It might therefore be possible that an increase of central and peripheral levels of taurine during painful events could represent a reactive defensive mechanism. Although there are few reports regarding taurine's action on SD, it is notable that taurine has anti-epileptic properties in many animal models. Patients with migraine have significantly higher taurine levels in plasma and cerebrospinal fluid than controls. No sex or age influence over the amino acid levels were observed. Plasma taurine levels in patients with classic migraine correlated negatively with severity of headache. Central taurine liberation during migraine crisis may be due to spontaneous depolarisation or a defensive reaction in the context of cerebral homeostatic processes. It is therefore important to prevent taurine depletion and guarantee optimal taurine supplementation in these patients. Instead of taurine itself taurates may be used in the composition of the invention.


CoQ10 (coenzyme Q10, ubiquinone 50, 2,3-dimethoxy-5-methyl6-pentacontdacaenyl-benzoquinone) plays a vital role as a rate-limiting carrier for the flow of electrons through the mitochondrial complexes I, II and II of the respiratory chain, hereby maintaining or improving energy (ATP) generation by the mitochondria. It is also a major lipophilic antioxidant. The molecule is located in the inner mitochondrial membrane but is also associated wit the membrane of other intracellular organelles. CoQ10 thus maintains redox activity and electron flow across different membranes (Villalba, Crane) and guaranteeing optimal mitochondrial functioning. In diseases like heart failure, mitochondrial dysfunction plays an important role in the reduced cardiac muscle contractility. Reduced levels (up to 50%) of CoQ10 in cardiac and skeletal muscle of patients with heart failure has been found (Folkers). Oral treatnent with CoQ10 has been shown to have beneficial effects on the course of cardiovascular disease in a wide variety of animal models. A meta-analysis of 8 controlled clinical trials (to 1997) revealed a significant improvement of several important cardiac parameters as ejection fraction, stroke volume, cardiac output and end-diastolic volume index by improving cellular energy metabolism (Soja).

The components indicated can be partly or wholly substituted by their functional equivalents. For example taurates can be used for taurine, and ubiquinones having isoprenoid side chains of 6-10 isoprenyl units can replace CoQ10; likewise L-carnitine equivalents include its base or salts such as the hydrochloride, as awell as its acylated forms, such as acetyl, propionyl, butyryl, succinyl L-carnitine and esters and the like or any L-carnitine that is able to transfer the blood-brain barrier, in particular lipophilic forms of L-carnitine, and creatine equivalents include the anhydrous or hydrated base or salts such as crystalline hemisulfate. The amounts of components to be used in the compositions are as indicated in the appending claims. In addition to taurine, CoQ10 and optionally creatine and carnitine, further components are preferably present such as ascorbic acid (vitamin C), tocopherols (vitamin E), selenium, thiamine, riboflavin, magnesium and potassium, either individually or in any combination.

In a preferred embodiment of the invention extracts of feverfew (Chrysanthemum parthenium) and/or ginger (Zingiber officinale) are incorporated in the compositions. Preferably, the feverfew extracts contain more than 0.4% parthenolides. Such a high percentage is obtained when the feverfew extracts are made of feverfew leaves. The compositions may contain at least 50 mg, preferably at least 100 mg and more preferably 150 mg up to about 500 mg of the above mentioned feverfew extract per (daily) serving. Other sources of parthenolides may also be used. Preferably, the ginger extracts contain more man 4% gingerols. Such a high percentage is obtained when the ginger extracts are made of ginger roots. The compositions preferably contain at least 50 mg, preferably at least 100 mg and more preferably about 150 mg, up to about 500 mg of the above mentioned ginger extract per serving.

The compositions can be pharmaceutical compositions, containing the active ingredients as such, together with suitable excipients, or they can be nutritional compositions containing the active ingredients together with one or more food components. These food components may include carbohydrates, in particular malto-dextrins, fats and/or proteins, and optionally further components such as vitamins, minerals, etc. The nutritional compositions can be complete foods containing e.g. 100-250 g carbohydrates, 75-225 g proteins and 25-75 g fats, or, preferably, food supplements, containing e.g. 10-100 g carbohydrates, 0-75 g proteins and 0-25 g fats, all on a daily basis. The product can be a liquid or a powder which can be reconstituted to a liquid or can be added to other food components. In case of a liquid or a reconstitutable liquid, the amount of ingredients given on a daily basis can be incorporated in a volume of e.g. 0.5 liter, 1 liter, or 1.5 liter or another unit volume. The product can also be a tablet, pill, capsule, sachet, syrup, liquid or the like, not containing further food components, wherein the daily amounts are incorporated in a single daily dosage unit, or divided over 2, 3 or more daily dosage units. The compositions of WO 98/43617 may also be used in the present invention.

The compositions can be administered curatively or, especially, preventively for a prolonged period of time to patients suffering from repeated of chronic migraine or to persons who are predisposed to migraine. The compositions may also be used to support medication in case of acute migraines.

Table 1 below shows general and preferred ranges for the major components according to the invention.


                             TABLE 1
                      Ranges per daily dose.
 components    broadest range   preferred range   preferred range
    taurine          0.1-10 g         0.8-6 g         1.2-4 g
    CoQ10             8-800 mg       15-300 mg       50-200 mg
    L-carnitine     0.01-10 g         0.5-8 g           1.6 g
    creatine         0.5-20 g          1-15 g        1.5-10 g
    vitamin C     20 mg-2 g       50 mg-1 g         100-500 mg
    vitamin E      100-1500 IU     150-1000 IU      180-700 IU
    thiamine          1-100 mg       1.5-30 mg       2.5-20 mg
    magnesium         5-500 mg


Claim 1 of 19 Claims

What is claimed is:

1. A method for the treatment of migraine, comprising administering to a patient in need thereof 0.1-10 g taurine and 8-800 mg CoQ10 per day.


If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.



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