Field of the Invention

The present invention is directed to a composition for treating headaches and migraines, and more particularly, to a mrtraceutical preparation and methods of using same for preventative use to decrease the frequency, duration and severity of headaches and migraines in children and adults.

Background of the In vention

Thirty-eight million Americans suffer from migraine. ¹ Up to 20% of children aged 5-17 are prone to headaches. Of these, approximately 5-10% experience migraine, with up to _. 4% of children being diagnosed with chronic migraine. About 10-15% of children experience tension type headaches, ^" ' ^3"4 . A -recognized risk factor for an occasionally occurring headache changing into a chronic and difficult to manage headache is suboptimal treatment during the child and adolescent years.

Current daily preventative pharmaceutical options for pediatric headache are both limited in efficacy and harbor significant side effects. ⁷ In addition, it may take up to 3 months for a prescription preventative medication to demonstrate maximal benefit, allowing a window for starting synergistically acting natural vitamin supplements (nutraceuticals). ^s

Although nistraceuticals have been proven safe and effective for treatment of pediatric headaches ⁹ , the quantity of pills often advised and the limitation, of available and safe combination pills with appropriate pediatric dosing impinges upon patient compliance. Thus, there is a product gap for a combined nutraceuiical to prescribe to children for the prevention of headache and migraine before resorting to pharmaceuticals.

The present invention of a combination nutraceutical for children ^' s headache-, bridges this gap. It allows for safe and easy use of natural, supplement with scientific and clinical, evidence for the prevention of headache in. children.

Complementary and Alternative Medicine (CAM) The financial burden of migraine has been estimated to exceed $4 billion annually in health care services and surpasses $14.5 billion annually for employers. ¹ '" American Migraine Prevalence and Prevention Study showed that 40% of those with episodic migraine have unmet treatment needs, with 15% being dissatisfied with current treatment. ^{1 1} In the U.S., spending on CAM comprises $13.9 to $33.9 billion annually. CAM use has become more prevalent over the past decade worldwide, especially among those with chronic pain syndromes. " ^{' ! ' 1 5 - U,, 1 ;} In the overall headache population, approximately 80-85% of patients use CAM intervention ^{,ι '!} , In the pediatric headache cohort,.30-75% of patients report using CAM. ²⁰ " ²¹

Nutraceut al Options in Headache

Natural products for prevention of headache are widely supported in the literature, with consensus statements outlining levels of: evidence and recommended doses. ^"-'"' ' ^{"' **} " ^"' These guidelines are based on pediatric and adults trials on both single

■ . 2t>. 27.2S , 2' . W . i 1 .32. 3.34.15, 3ή, Τ?,·?Κ . ^' ϊ'ϊ j . ^■ « . ■¾! 4] supplements " ^' and combination products. Eit!cacy, safety and tolerabiiity is known for the following supplements at the following doses: Riboflavin (B2) (Doses studied: 5Q-400mg/day, Level B evidence), Coenzyme Q10 (Q.10) ( 1 mg kg day-300mg/day, Level C), Magnesium Citrate (Mg) ( mg kg divided BID - 600mg, Level B) and Melatonin (0.3m ^' g kg- lOmg, Level U). In. addition, nutraceuticals have been shown in three prior randomized control trials (RCT's), to have comparative, if not superior efficacy to pharmaceuticals for prevention, of primary headache, with less side effects (propranolol vs. riboflavin, bisoprolol/metoprolo! vs. riboflavin and melatonin vs. amitriptyline). ' ^{, ',,'} * ⁴ Currently there are two combination, products available to consumers, one marketed to adults which, includes Butterbur ^"1" ' , and another marketed to children, called Migralief, ⁴⁶ which includes Feverfew. A recent study on a combination product including Mg, Vitamin B2 and Coenzyme Q 10, revealed no serious adverse ^' events.*'

Extrapolation from the adult literature, given similar disease pathophysiology, in conjunction with the published pediatric evidence ^" *" informs the development of our combination nutraceutica!, comprised of: Riboflavin (B2), Magnesium (Mg), Co- Enzyme Q10 (CoQIO) and Melatonin.

Summary of the invention

The combination product of the present invention is a nutraeeuiieal formulated specifically for children in a day/night kit, and includes: Riboflavin lOOmg piil, Magnesium l OOrog ^' pil , Coenzyme QiO SOmg piU and Melatonin 2mg pill. The formulation may be a gummy, free of headache triggering aspartame and food dye. There is emerging evidence that melatonin may he useful tor treating headache and that it is a safe and tolerable treatment of other conditions in children ^4,1 ''*' ³ ' . The selected components of the present formulation ail have different mechanisms of action on the pathophysiological drivers of primary headache, outlined in detail below, supporting their use in a combination product for headache prevention. Clinical experience with these doses, and safety evidence from the literature suggest this combination will be well tolerated.

Riboflavin (B2) and Coenzyme Q iO interplay with migraine through actions on energy generation and consumption. It is well accepted in tile literature that migraineurs are in a state of mitochondrial energy depletioii. ^? '' ^''3'i', ' ^{"'',''n':' '',''!S'3'i} As such, it. is believed that failure of generation of mitochondrial energy, via oxidarive- reduction reactions, contributes to migraine pathogenesis. ^w ' ⁶ · · ^«63 , Riboflavin is comprised of two active coenzyme forms: flavin adenine dinucleotide (FAD) and riboflavin-5'- phosphate. Both are cofactors in oxidation-reduction reactions of ilavoprotems during metabolic processes, such as in the Krebs cycle and the electron transport chain. Thus, Riboflavin is a vital in replenishing raitochondrial/ ^' celiular energy production. ^0" " ^'' In addition, to the mitochondrial energy mechanism of action; animal studies have demonstrated both analgesic and anti-inflammatory properties of riboflavin. "^ ^6, Overall, in adult studies of riboflavin, response rates are generally quoted as between 53-80%, including four small open label trials and a RCT ^t¾ ' ⁶ " ^, ' ^t ''" ^* '_. _{β re v} i _{e v} ij3g t e only single-agent randomized placebo-controlled trial for riboflavin, Schoenen et al., ( 1998) administered 400mg of riboflavin once daily COD) to 55 adults with migraine and found it to be statistically superior to placebo in reducing headache attack frequency (59% responder rate vs. 15% p=0.0002). in addition, they reported that the most profound statistical effect was seen in a decrease in migraine duration, possibly consistent with the energy depletion and restoration theory of riboflavin. ^Ί ' In pediatrics, Condo et aL, (2009) looked at Riboflavin in 41 children (aged 8- 18 years old) at doses of either 200mg (21 patients) or 400mg (20 patients) OD in a retrospective open label study design. They found that use of riboflavin lead to a reduction in headache frequency (68.4%) and headache intensity (21.0%) compared to baseline. In this trial. 2/41 patients had side effects of vomiting and increased appetite, which were deemed by investigators to be unrelated to riboflavin. No other side effects were reported except for change in urine color. '" Conversely, a randomized control trial (RCT) by .aeLennou et al, (2008) randomized 48 children, aged 5- 15 years old, to 2G0mg/day of riboflavin verses placebo. Riboflavin was found to be not more effective than placebo in reducing migraine attacks (44% in 82 vs 66.6% of placebo group, ρ=0.125). In terms of side effects in this trial, 4/48 had change in urine color. No other significant side effects were reported in the exposed children. Authors in this study theorize that a higher dose may have positively influenced their efficacy data. ⁷⁵ Given the lack of efficacy at 200mg in children, coupled with the efficac and safety seen at 40Gmg/day seen in both the aduit and pediatric trial, plus our knowledge of the short half-life (Tl/2= 1 - 2hrs) of riboflavin, our invention contains a goal dose of 400mg of B2 divided BID for headache prophylaxis in children.

Similar to riboflavin, coenzyme q l O (CoQlO) works to sustain mitochondrial energy stores and cellular energy metabolism through its action as an electron carrier in. the mitochondrial electron transport chain. ' In addition, the redo activity of coenzyme Q lO allows for anii-oxidaot qualities, which may provide an inflammatory mechanism of action in migraine ' '. Recognized .-side effects of CoQ! O are accepted as rare {<!%), and include anorexia, dyspepsia, nausea and diarrhea. CoQlO is tolerated at .higher doses than those used in headache in mitochondrial, cardiovascular and other neurological diseases, greater than 1000mg/day. ^7h Coenzyme QlO has been shown to be effective in adults in an open label trial at closes of 150mg QD, with no significant side effects reported. ^,v Sandor et al., (2005) completed a randomized, placebo controlled study, with 50 adults aged 18-60 years old, with migraine, who were given 300 nig of CoQ lO per day (100 mg T1D). They demonstrated a greater reduction in migraine attack frequency in the CoQl O group verses placebo (48% compared to 14% in placebo). In this study, only one adverse event was reported, whereby one patient had a rash, with uncertain relation to treatment . ^λ · ^η in. the pediatric age group, Hershy et al., (2007), studied 252 children, aged 3-22 years old with primary headache in an open label design with l -3mg/kg day of Coenzyme Ql O. They demonstrated significantly reduced migraine frequency and pediatric migraine disability assessment scores (PedMIDAS) after the treatment period ( 19.2 vs. 1 2.5. p<0.01). Slater et al., ( 201 1) conducted a cross over RCT in 120 children, aged 6- 17 years old, where l OOmg of coenzyme q l O was given daily. They found a trend toward improvement in headache with coenzyme q ! O compared to placebo, but failed to show a significant treatment effect. No adverse events were reported, in their conclusion, given the superior safety profile observed, they recommend studying higher doses for migraine prevention in ^' children. - Extrapolated from the adult and child literature, our invention contains a goal dose of 200mg a. day of coenzyme q lO.

Magnesium (Mg) represents a different mechanism of action in migraine pathogenesis, relating primarily to exeitotoxcity and gltaamate functioning. Magnesium, depletion leads to ^' neuronal injury by causing NMDA-coupled calcium channels to open, leading to an increased, influx of calcium and release of glulamate, causing neuronal hyper-excitability and cytotoxicity via the generation nitric, oxide free radicals. A magnesium deficiency could therefore mediate migraine pathogenesis and susceptibility via excess glutamate and altered mitochondrial metabolism leading to facilitation of cortical spreading depression. ⁸⁴ Magnesium has also been shown to inhibit nociceptive trigeminal neurotransmission after direct application to the trige inocervical complex . ^5,< * Magnesium intake is inadequate in -50% of the population.* ^' ^ It is well established that both pediatric migraine patients ^8v ' ⁹⁰ ' ^{9 "} and adult migraine patients are deficient in magnesium.

· · ' ' ^■ " Overall, a recognized side eitect or. magnesium is minor gastrointestinal upset, namely soft stools and diarrhea that resol ves after cessation of use,, but no major adverse events have been reported. Multiple adult RCT's, with doses up to 600mg of elemental magnesium given twice daily (formulated as Magnesium citrate, oxide, L-aspartate hydrochlor ^' ide-trihydrate, Triraagnesium dieitrate, and Magnesium pyrrolidone carboxylic acid), have, shown efficacy of magnesium in headache frequency reduction. '^-' ⁰⁹ · ^{1 10< :} ' ¹ j ₀ these adult trials, non-severe gastrointestinal side effects were common, in ~l/4 of participants, but less than 4% had to stop taking the supplement. ¹ In the pediatric migraine magnesium trials, magnesium oxide and magnesium pidolate have been studied in varying doses, ranging from 9mg kg day divided TID to 366mg OD. The open label trial by Castelli et al„ ( 1993 ) ^{U 3} showed efficacy, but the RCT by Wang et ai., (2003.) ^{1 1} only displayed a trend towards efficacy, in terms of safety, ~20% of children in the Wang et al. trial reported diarrhea compared with 7% of the control patients. Our invention contains the goal daily dose of 400mg magnesium citrate divided BID for prevention of pediatric headache.

Melatonin is the final component in the combination product of the present invention. This supplement, produced naturally in the pineal gland, and regulated by the hypothalamus, has two important and likely mutually exclusive mechanisms of action on migraine, pathogenesis. First, Melatonin is related to migraine via its function on sleep. Poor sleep is common among those with primary headache, comorbid in up to 80% in one study of adult nurses. " ^" ' In children, up to 25% of children have at least one type of sleep problem. "" Both headache and sleep share pathophysiological neuroanatomies] substrates and neurotransmitters. ^{l u} In addition, sleep disruption is both a common risk and trigger for the expression of a primary headache disorder. ^{l i h} By working to optimize the homeostafic properties of sleep, headache burden has the potential to be concurrently decreased. ' ^l? Independent to sleep, other mechanisms of action of melatonin that are involved in migraine pathophysiology include anti-inflammatory and antioxidant properties, inhibition of nitric oxide synthase ( OS) activity and dopamine release leading to increased ^' membrane stability, potentiation of GAB A and opioid analgesia, protection against glutamate neurotoxicity, regulation of neurovascular function by 'modulating 5-HT, and pain modulation through its action at MT1/MT2 melatonin receptors ^!~!,' ' " More recently, a temporal correlation between melatonin levels and acute migraine attacks has also been shown, in that urinary melatonin (6~sulphatoxym.elat.Qain, aMT6s) levels are significantly decreased the day prior to a migraine attack, compared to those with migraine without pain (non-ictal), and controls. ¹ " in an open label trial in adults, Peres et ah, (2004), showed that, melatonin 3mg OD lead to a significant reduction in headache frequency, in this trial, 1 patient withdrew due to sleepiness. 1 from alopecia and 3 patients reported increase in libido. ^{i 2j} An open label trial for .migraine prevention in. children was completed by Fallah et a.L (2015). In this trial, 60 children received 0.3rag/kg day of melatonin, which leas to a reduction in migraine attack frequency and reduction in ail other primary endpoints. ^' Non-severe side effects were seen in 23% of patients including sleepiness (7), vomiting (4), mild hypotension. (2) and constipation O ). .Excessive daytime sleepiness was seen in 3 patients). Gi en the multifactorial mechanisms of action, safety, and efficacy in migraine, our invention includes melatonin. 2-4mg, for prevention of headache children.

Combination Products on the Market and in the Literature Currently, there is one other natural health product on the market for prevention of children's headache, titled Migralief. '^ Taking two capsules of this product gives 180mg/day of magnesium (citrate & oxide), 200mg day of riboflavin (Vitamin B2), and SOmg/day of puracol feverfew (a proprietary extract ^■ *· whole leaf). The doses used in this supplement are less that the commonly prescribed doses and the known efficacious doses from the literature. In addition, the presence of feverfew harbors potential for intolerance and is not commonly prescribed in pediatric headache clinics. ' ³⁰ Although not completed in children, a randomized control trial of a similar combination product was completed in adults, using a 400 mg of riboflavin, 300mg of magnesium, and lOOmg of feverfew. The placebo in this trial contained 25 mg riboflavin. This study showed no advantage, in headache reduction over the control group (achieved by 42% of the treatment group and 44% of the control group, p=0.87). The reasons for non-significance arc likely due to the fact that 25% of the control patients and 38% of treatment group patients were taking concomitant migraine prophylaxis, that they used an active comparator (.82). and because the study was underpowered for analysis. ^1'7

Migravent/ Dolovent, is another combination product, marketed for adults. Two capsules of this product consist of a proprietary blend of 876 mg (Riboflavin, Magnesium, Coenzyme Q10), and 150mg Butterbur. The most recent clinical trial by the group removed the butterbur component and studied daily doses of 400mg of Riboflavin, 600mg Magnesium and 150mg Coenzyme q l O in a combination tablet. They also included multivitamin/irace elements. The target group was adults with migraine aged 18-65 years old. The results of the clinical trial were nonsignificant for the primary endpoint, reduction in migraine days, but there was a trend towards significance, and there was a significant reduction in maximal pain intensity and migraine burden (H1T-6) and a statistically significant evaluation of efficacy by the patients. The most frequent side effects were diarrhea and chromaturia. No serious adverse events (SAE) were observed in this trial. ^!iS - ' ⁱ⁹ ' ^!j

The Market

Up to 20% of children aged 5-17 in the U.S. are prone to headaches. Based on a U.S. estimate of 75 million children currently living, this comprises -10 million children. Of these, approximately 5-10% experience migraine, with u to 4% of children being diagnosed with chronic migraine. About 10-15% of children experience tension type headaches. ¹ ' ^{!j i:} ' ^""' Detailed Description of the invention

The present invention is directed to natural supplements (nutraceuSicats), formulated tor daily preventative (prophylactic} use, for reducing the severity, duration and frequency of headaches, inchtd ^' ing migraine, in children and adults. The invention is the first combination including melatonin, and is the first formulation with specific pediatric dosing for children aged 6 to 18 years old. Daytime and nighttime formulations are provided together in a kit. The supplement of the present invention is available in ^' the form of gummies, sprinkles, liquid suspensions, pills, capsules, captets or tablets or transdermal application.. Generally, the formulations of the present invention include daytime dosages containing Vitamin B2 (Riboilaviii), Magnesium Citrate and Coenzyme Q I O and nighttime dosages containing Vitamin B2 (Riboflavin), Magnesium Citrate, Coenzyme Q IO and melatonin.

Coenzyme QIO works to sustain -mitochondrial energy stores and cellular energy metabolism through its action as an electron carrier (from complexes 1 and II to complex ill) in the mitochondrial electron transport chain. Recognized side effects of CoQiO. Rare (<I ¾): Anorexia, dyspepsia, nausea and diarrhea. In one study, a rash was seen in one participant. CoQ l O is tolerated at higher doses in mitochondrial, cardiovascular and neurological diseases. Doses up to 1200, 1 800, 2400, and 3000 mg day have been used in 17 adult patients with Parkinson's: unrelated adverse effects included dyspepsia (1 patient), orthostatic hypotension (.1 patient, nutrition related) and subjective report of cognitive confusion, despite normal MMSE (1 paiient, felt to be unrelated to coQl O), and iaehycardia ( 1 patient, felt to be unrelated to coQ IO) and low calcium levels, unchanged with coenzyme ql O use of uncertain relation to supplementation (4 patients). ^{' 3 '}

Magnesium is required for proper Glutamate functioning by facilitating calcium channel and N-methyl-D-aspartate f MDA) receptor blockade. Magnesium also inhibits neuroinflamtnation, nitric oxide activity, serotonin receptor affinity, and endogenous hormone regulation. Magnesium depletion leads to neuronal injury by causing NMDA-coupled calcium channels to open, leading to an. increased influx of calcium and release of glutamate, causing neuronal hyper-excttahility and cytotoxicity via the generation nitric oxide free radicals. ^! Magnesium may mediate migraine pathogenesis and susceptibility via excess glutamate and altered mitochondrial metabolism leading to facilitation of cortical spreading depression. ^{' '} '' Magnesium also inhibits nociceptive trigeminal neurotransmission after niieroiontophoieiic application in the trigeminocervtcal complex. '- ^J ^ Magnesium intake ^' is inadequate in -50% of the population, ''"' h is well established that both, pediatric migraine patients ' ^{" '} and adult migraine patients are deficient in magnesium.

Recognized side effects ot .Mg include minor gastrointestinal side effects associated with oral magnesium, namely soft stools and diarrhea, but no major adverse events.

Melatonin is produced in the pineal gland, and is regulated by the hypothalamus. It readily crosses all biological barriers, including the blood-brain ^' barrier and the placenta. It is metabolized in the l iver to 6-hydiOxymelatooin and is excreted by the kidney forming urine metabolites called; 6- sulphatoxyraelatonin (aMT6s). " ^{' !} It has ami-inflammatory and antioxidant effects, inhibits Nitric oxide synthase (NOS) activity and dopamine release leading to increased membrane stability, potentiates GABA and opioid analgesia, protects against ghitamate neurotoxicity, and regulates neurovascular function by modulating 5-.HT. "* ^A The hypothalamus has been implicated as a brain substrate for migraine generation. ' ¹ '' Melatonin has been shown to be low in those wish chronic migraine as well as low in those with common comorbidities seen with migraine (depression, anxiety and fatigue). Between migraine attacks, it ha been shown that nocturnal plasma melatonin levels are decreased. ¹ * A temporal correlation between melatonin levels and acute migraine attacks has also been shown, in thai urinary melatonin (6- sulphatoxymelatonin, aMT6s) levels are decreased the day prior to a migraine attack compared to those with migraine without pain, and controls (significantly [ 14.0 ± 7.3 vs. 49.4 ί 19.0, F= 0.001]. "* In addition, melatonin varies with the menstrual cycle in migraine patients "" ' ^'168 and seasonally, in. association with migraine frequency fluctuations. ^!{, '" ^,! Although a recent study in pediatrics looking at urinary melatonin failed to show a. correlation with migraine, sleep disturbances (par oninias), do seem to impact the degree of migraine disability. ¹⁷¹ Further supporting the role of melatonin in migraine, Ramekeon, a tricyclic synthetic melatonin analog that acts specifically as an MT1 and ΜΪ2 melatonin receptor agonist, has been recently licensed in the US for insomnia. A phase il study in migraine prevention is currently under way (clinical irials.gov).

According to one. aspect of the invention, there is provided a method for preventing and reducing the severity, duration, and frequency of primary headaches such as migraines and tension type headaches. ^' The method includes administering to a patient 100-200 rng Vitamin B2 (Riboflavin), 100-200 mg Magnesium Citrate and 50-100 ng Coenzyme Q10, in the morning, and 100-200 mg Vitamin B2 (Riboflavin), .100-200 mg Magnesium Citrate and 50-100 mg Coenzyme Q 10 ^' , and 2- 4mg of melatonin, once nightly. The daily doses may be taken with or without food. The nighttime doses may be taken at dinner or bedtime, with or without food.

According to another aspect of the invention, there is provided a kit for preventing and reducing the severity, duration and frequency of headaches, the kit containing daytime and nighttime dosages. Each daytime dosage may consist of two pills, each pill including .100 mg Vitamin B.2 (Riboflavin.), 100 mg Magnesium Citrate and. 50 mg Coenzyme Q10. Two daytime pills may be taken with breakfast. The night time dosage may consist of two pills, each pill including 100 -mg Vitamin 82 (Ribofla vin), 100 mg Magnesium Citrate, 50 mg Coenzyme Q10 and 2rng of Melatonin,

According to yet another aspect of the invention, there is provided a kit for preventing and reducing the severity, duration and frequency of headaches, the kit containing daytime and nighttime dosages. Each daytime dosage may consist of one pill, including 200 mg Vitamin B2 (Riboflavin), 200 mg Magnesium Citrate and iOOmg Coenzyme Q10. Each night time dosage may consist of one pill, including 200 mg Vitamin B2 (Riboflavin), 200 mg Magnesium Citrate, .100 mg Coenzyme QiO and 4mg of Melatonin, This kit is may be used by teens and adults.

Additional vitamins that may be added to the daily formulations include up to 80 meg/day Vitamin B12 (cyanocobalamin), up to 200 mg/day Vitamin C (calcium ascorbafe), up to 2000 lU/day Vitamin D3 (eholecalcifero!) and up to 4 mg/day of Folic Acid (folate). Additional vitamins that may be added to the night time formulations include 40 meg/day Vitamin B12 (cyanocobalamin), 100 mg day Vitamin C (calcium ascorbate), 1000 iU/'day Vitamin D3 (eholecalcifero!) and up to 2 mg/day of Folic Acid (folate),

It is further understood that the dosages listed above may be increased or decreased by up to 20% depending on the weight and age of the patient.

The formulations of the present invention are prepared in a pill dosage form, however it will be understood by those skilled in the art that other dosage forms may also be suitably prepared by known methods, for example, gummies, capsules, tablets, powders, pastes, liquids, transdermal patches and similar dosage forms. Solid dosage forms for oral administration include gummies, caplets, capsules, tablets, pills. powders., and granules. Solid dosage forms, of the present invention may be created using any pharmaceutically acceptable excipients such as fillers or extenders, binders, humectants, disrategral ing agents, wetting agents and lubricants. Suitable pharmaceutically acceptable excipients are described in "Remington: The Science and Practice of Pharmacy." Lippincott Williams & Wilkins. Baltimore, Md. i ^' 2000), incorporated herein by reference.

The solid dosage forms of tablets, capsules, powders and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredients only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifters. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

The compositions are preferably administered in spaced dosages throughout the day, for example, administered every eight to twelve hours, so as to maintain the level of active ingredients in the system of the host. Preferably, the dose is administered every twelve hours.

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http j m w.migrelie f. c om

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^* ** Gaul C, Diener HC. D nescn U. iyiigraverrt Study Group, improvement of migraine symptoms with a proprietary supplement containing riboflavin, magnesium and QIO: a Randomized, placebo- eontraikd, double-blind, nmUicenter trial. J Headache Pain. 2015. Dec 16.516

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Gaul C. Diener HC, Daneseh U; Migraventf ⁵ Study Group. Improvement of migraine symptoms with a proprietary supplement containing riboflavin, magnesium and Q 10: a randomized, ptecebo- eontvolied, double-blind, nralticeiiter trial. .1 Headache Fain. 2015 Dec; 16:5 16.

tutp_;-¾y w'v. headaches. ora/headaches-tB- ii jdrci;/

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'** Orr. S & Venkateswaran. Nutraeeuticals in the prophylaxis of pediatric migraine: Bvidence-based review and recommendations. Cephalgia 2014: 34 ( S): 568-583

^{, J>} Shults CW, Flint Beai M, Song D and Fontaine D. Pilot trial of high dosages of coenzyme Qi O in patients with Parkinson ^' s disease. Exp Neurol 2004: 188: 491-494.

m Taylor FR , Nufcaeeuiicais and headache: The biologies! basis. Headache 201 1: 51: 484-501.

Welch KM and Ramadan NM. Mitochondria, magnesium and migraine. J Neurol Sei 199.5; 134: 9-

14.

' * Storer R.l. Goadsby pj. -tnefhyl-D-aspartate receptor channel complex blockers including rnemantine and magnesiuminhibit nociceptive traffic in the trigeroinocervieal complex of t e rat. Cephalalgia 2009;29(suppi 1 ) ; 1 35.

Hoffmann J, Park JW, Storer RJ, Goadsby Pi. Magnesium and me man tine do not inhibit nociceptive neuronal activity in the trigeminoeervicai complex of the rat. The Journal ofHeadache and Pain 2 13 _. : ! 4(sttppi I ); P 1 . doi ; 10. 1 186/ 1 129-2377-14-S1-P7 I

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^M Ca!vo MS and Uribarri J. Public health impact of dietary phosphorus excess on bone and cardiovascular health in the genera! population. Am .1 Clin Nutr 2013; 98: 6- ! 5.

^! ' Aloisi P, Marre!ii A, Porto C, et si. Visual evoked potentials, and serum magnesium levels in juvenile migraine patients. Headache 1997: 37(6): 383-385.

' Oallai V.-SarchieBi P. Coata G, et al. Serum and salivary magnesium levels in migraine. Results in a group of juvenile patients. Headache 1992; 32(3): 1 32-1 35,

4 Lodi R. .Montagna P, Soriani 8, et al. Deficit of brain and skeletal muscle bioenergeiks and low bruin magnesium in juvenile migraine; An in vivo 3 I P magnetic resonance spectroscopy interictal study. ediatr Res 1997: 42(6): 866-871 Te!gan and Bocs An evidence-based review of oral magnesium supplementation in. the preventive treatment of migraine, 2015. Cephalgia, 35 { 10). 91 2-922

^{1 ¾} Loci'. R, lolti S. Cottelli P, « at. Deficient energy membo!ism is associated with low free magnesium in the brains of patients with migraine and cluster headache. Brain Res Bull 2001 ; 54: 437-441.

" ^' Boska .MD, Welch KM, Barker PB. et al Contrasts in cortical magnesium, phospholipid a d energy metabolism between migraine syndromes. Neurology 2002; 58: 12 7-! 233.

Ga!iai V, SarehieSli P, Morucci P, et al. Magnesium content of mononuclear blood ceils in migraine patients. Headache .1994; 34: 160-465.

Mauskop A, Aitiira BT and Aitura B.Vi. Serum ionized magnesium levels and serum ionized calcium/ionized magnesium ratios in women with menstrual migraine. Headache 2002; 42: 242-248.

^{, 5l>} auskop A, Ainrra BT, Craeco RQ, et al. Deficiency in se um ionized magnesium but not total magnesium in patients wit migraines. Possible to e of ICa2. IMg2. ratio. Headache 1993; 33: 135- 138.

^1J! ishima K, Takeshims T, Shimomura T, et al. Platelet ionized magnesium, cyclic AMP, and cyclic GMP levels in migraine and tension-type headache. Headache 1 97; 37: 56) -564.

Qujeq D. Zandemami M, A hanger AA, et al. Evaluation of intracellular magnesium and calcium concentration in patients with migraine. Neuroscienees Riyadh) 20! 2: 17: 85-86.

' ^"Λ Samaie A, Asghari , Ghorbani , et al. Blood magnesium levels in migra incurs within and between the headache. attacks: A case controi study. Pan Afr Med J 2012; I i: 46.

Sarchtelii P, Coata G. Firenze C, et ai. Serum and salivary magnesium levels in migraine and tension-type headache. Results in a group of adult patients. Cephalalgia 1992; 12: 21-27.

Sc oenen J. Sianard-Gainko .1 and Lenaerts M. Blood magnesium levels in migraine. Cephalalgia 1991 ; 1 1 : 97-99.

S meets MC, Vemoov CB, Souverijn. JH, et ai. Intracellular and plasma magnesium in familial hemipiegic migraine and migraine with and without aura. Cephalalgia 1 94;. 54: 29-32.

^■ Taiebi M, Savadi-Osfcouei D. Farhoudi ivi, et al. Relation between serum magnesium level and migraine attacks. Neurosciences (Riyadh) 2011; 16: 320-323.

^>H Thomas 3, Thomas E and Tomb E. Serum and erythrocyte magnesium concentrations and migraine. Ma ones Res 1992; 5: 127-130

Trauninget A, Pfund Z, Koszegi T, et al. Oral magnesium load test in patients with migraine. Headache 2002; 42: 114-119.

Ilhan A, {Jr. E. Var A, et al. Diagnostic role of hair magnesium in migraine patients: Higher than scrum magnesium. Trace Elements and Electrolytes 2000; 17: 14-18.

Peres MF {2005} elatonin, the pineal gland and their implications for headache disorders Cephalalgia 25(6):403-4 ί 1

^,w Peres MF, Masruha MR, Zu.ken.nan E et al (2006} Potential ihempeittic use of melatonin in migraine and other headache disorders. Expert Opin Investig Drags 15:367-37

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