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Methods of diagnosing and treating migraine

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Methods of diagnosing and treating migraine


The present invention provides methods of diagnosing migraine attacks and determining predisposition of an individual to the development of migraine based on sodium level in the cerebrospinal fluid (CSF) and/or brain extracellular fluid. The invention also provides methods of treating migraine, wherein the individual is selected for treatment based in the individual's sodium level in the CSF and/or brain extracellular fluid. The CSF sodium level may be based on the sodium concentration in the saliva.
Related Terms: Cerebrospinal Fluid Migraine

Inventors: Michael G. Harrington, Alfred N. Fonteh
USPTO Applicaton #: #20120270816 - Class: 514 26 (USPTO) - 10/25/12 - Class 514 
Drug, Bio-affecting And Body Treating Compositions > Designated Organic Active Ingredient Containing (doai) >O-glycoside >Cyclopentanohydrophenanthrene Ring System

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The Patent Description & Claims data below is from USPTO Patent Application 20120270816, Methods of diagnosing and treating migraine.

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CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 60/794,965, filed Apr. 25, 2006, the content of which is herein incorporated by reference In its entirety.

TECHNICAL FIELD

This application pertains to methods of diagnosing and treating migraine. Specifically, the application pertains to methods of diagnosing and treating migraine based on sodium levels in the cerebrospinal fluid, the brain extracellular fluid, and/or the saliva.

BACKGROUND

Migraine is a chronic, episodic, and debilitating primary headache syndrome that affects about 15 to 20% of the world population. Arunagiri et al., Curr. Opin. Ophthalmol 14:344-352 (2003). Migraine has two main types. One type, migraine without aura (previously known as common migraine), affects about 15% of the population. In migraine without aura, the headache is unilateral, pulsating, and moderate to severe in intensity, and may last a few hours to 3 days. The headache may also be associated with nausea, vomiting, photophobia, phonophobia, and other symptoms. The second type, migraine with aura (previously known as classic migraine), affects about 8% of the population. In migraine with aura, one or more auras, such as visual, somatosensory, and motor symptoms, develop prior to the development of a migraine attack. Migraine without aura and migraine with aura co-occur in 13% of migraineurs.

The two prevailing views of migraine pathophysiology are the neuronal and trigeminovascular theories. In the neuronal hypothesis, cortical spreading depression (CSD), a slowing of electroencephalographic activity that propagates across the cortex at 3-5 mm/min, has been recorded during migraine aura. The trigeminovascular hypothesis asserts that an altered modulation of the perivascular nerves of the intracranial vessels sensitizes the nociceptive perivascular fibers\' projection to the trigeminal caudate nucleus, which propagates the headache. The current model of migraine is an integration of these two theories linking the intrinsic brain activity of CSD with trigeminal meningeal afferents. In addition, Moskowitz and colleagues present logic to explain the loss/gain of functions found in two different familial hemiplegic migraine genes with the migraine phenotype. However, the basis for hypersensitivity features of migraine,—pain, photophobia, phonophobia, osmophobia, nausea, vomiting, and confusion—remains unexplained.

Calcium channel, sodium transporter, and sodium channel gene mutations have been found in familial hemiplegic migraine. For example, mutations in the slow calcium channel gene (CACNA1A), the Na+, K+-ATPase transporter gene (ATP1A2), or the voltage-gated sodium channel gene (SCN1A) underlie cases of the rare familial hemiplegic migraine. Pharmaceuticals with calcium or sodium channel blocking activities have also been shown to be useful in migraine prophylaxis. Although these studies suggest that ion transport may be implicated in migraine pathogenesis, a link between sodium homeostasis and migraine has never been established.

Campbell and colleagues reported in 1951 that blood sodium levels in migraine are increased, and were accompanied by a decrease in protein that they attributed to overhydration. Campbell et al., Br. Med. J. 1951, 4745:1424-1429. The reference used a gavimetric method based on pyroantimonate, which has now been abandoned as being indirect. The reference also did not address variations of sodium levels from circadian rhythm fluctuation, a phenomenon that had not been identified at the time of the study. Meanwhile, Jowett reported that sodium and potassium levels were within normal ranges when measured by flame photometry in cerebrospinal fluids from 20 patients during migraine attack. Jowett, Brain, 1967, 90(4):785-94. That study did not compare the levels of well with sick migraineurs, and its controls were ill-defined. Brainard reported salt loading as a trigger of migraine. Brainard J. B., Minn. Med. 1976, 59(4):232-233. He correlated this phenomenon with increased plasma angiotensin and aldosterone levels rather than sodium levels. None of these references provide a correlation between sodium level in the brain extracellular fluid/cerebrospinal fluid and migraine.

Use of sodium pump inhibitors to treat various diseases has been disclosed in U.S. Pat. No. 5,872,103, U.S. Pat. Pub. No. 2003/0229029, and WO05/102371.

The disclosures of all publications, patents, patent applications and published patent applications referred to herein are hereby incorporated herein by reference in their entirety.

BRIEF

SUMMARY

OF THE INVENTION

The present invention provides methods of diagnosing migraine in an individual or determining predisposition of an individual to the development of migraine, wherein the diagnosis or determination is based on the CSF or brain extracellular fluid sodium level of the individual. In some embodiments, the method is for diagnosing migraine attack in an individual exhibiting one or more symptoms of migraine. In some embodiments, the method is for determining predisposition of an individual to the development of migraine.

In one aspect, the invention provides methods of diagnosing and treating migraine attack. In some embodiments, the invention provides a method of diagnosing migraine attack in an individual exhibiting one or more symptoms of migraine (such as headache), comprising comparing the cerebrospinal fluid (CSF) sodium level in the individual with the CSF sodium level in the same individual at a symptom free stage, wherein an increase in CSF sodium level above the level at a symptom free stage is indicative of a migraine attack. In some embodiments, the invention provides a method of diagnosing migraine attack in an individual exhibiting one or more symptoms of migraine (such as headache), comprising: a) determining the CSF sodium level in the individual, and b) comparing the CSF sodium level in the individual with the CSF sodium level in the same individual at a symptom free stage, wherein an increase in CSF sodium level above the level at a symptom free stage is indicative of a migraine attack. In some embodiments, the invention provides a method of diagnosing migraine attack in an individual exhibiting one or more symptoms of migraine (such as headache), comprising: a) comparing the CSF sodium level in the individual with the CSF sodium level in the same individual at a symptom free stage, and b) determining whether the individual has a migraine attack based on an increase in CSF sodium level above the level at a symptom free stage. In some embodiments, there is provided a method of providing information for diagnosis of a migraine attack in an individual exhibiting one or more symptoms of migraine (such as headache), comprising: a) determining the CSF sodium level in the individual, and b) providing information about the CSF sodium level of the individual, wherein an increase in CSF sodium level above the level at a symptom free stage is indicative of a migraine attack.

In some embodiments, the CSF sodium level is based on the sodium concentration in the CSF of the individual. In some embodiments, an increase in sodium concentration in the CSF by at least about any of 1 mmol/L, 2 mmol/L, 3 mmol/L, 4 mmol/L, 5 mmol/L, 6 mmol/L, 7 mmol/L, 8 mmol/L, 9 mmol/L, 10 mmol/L, or more is indicative of a migraine attack. In some embodiments, an increase in sodium concentration by at least about any of 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, or more is indicative of a migraine attack. In some embodiments, the increase in CSF sodium level is based on the increase in molar ratio of sodium to another analyte (such as potassium ion) in the CSF of the individual.

In some embodiments, the CSF sodium level is based on the sodium concentration in saliva of the individual. For example, in some embodiments, the invention provides a method of diagnosing migraine attack in an individual exhibiting one or more symptoms of migraine (such as headache), comprising comparing the saliva sodium concentration in said individual with the saliva sodium concentration in the same individual at a symptom free stage, wherein an increase in saliva sodium concentration above the level at the symptom free stage is indicative of a migraine attack. In some embodiments, an increase in sodium concentration in saliva by at least about any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or 30 mmol/L is indicative of a migraine attack. In some embodiments, an increase in saliva sodium concentration by at least about any of 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, or more is indicative of a migraine attack. In some embodiments, the increase in CSF sodium level is based on the increase in molar ratio of sodium to another analyte (such as potassium ion) in the saliva of the individual.

In some embodiments, the CSF sodium level is intracranial CSF sodium level. For example, in some embodiments, the invention provides a method of diagnosing migraine attack in an individual exhibiting one or more symptoms of migraine (such as headache), comprising comparing the intracranial CSF sodium level in the individual with the intracranial CSF sodium level in the same individual at a symptom free stage, wherein an increase in intracranial CSF sodium level above the level at a symptom free stage is indicative of a migraine attack. In some embodiments, the intracranial CSF sodium level is based on intracranial sodium concentration determined by brain magnetic resonance spectrometry.

In some embodiments, there is provided a method of diagnosing migraine attack in an individual exhibiting one or more symptoms of migraine (such as headache) comprising comparing the brain extracellular fluid sodium level in said individual with the brain extracellular fluid sodium level in the same individual at a symptom free stage, wherein an increase in brain extracellular fluid sodium level above the level at a symptom free stage is indicative of a migraine attack. In some embodiments, the invention provides a method of diagnosing migraine attack in an individual exhibiting one or more symptoms of migraine (such as headache), comprising: a) determining the brain extracellular fluid sodium level in the individual, and b) comparing the brain extracellular fluid sodium level in the individual with the brain extracellular fluid sodium level in the same individual at a symptom free stage, wherein an increase in brain extracellular fluid sodium level above the level at a symptom free stage is indicative of a migraine attack. In some embodiments, the invention provides a method of diagnosing migraine attack in an individual exhibiting one or more symptoms of migraine (such as headache), comprising: a) comparing the brain extracellular fluid sodium level in the individual with the brain extracellular fluid sodium level in the same individual at a symptom free stage, and b) determining whether the individual has a migraine attack based on an increase in brain extracellular fluid sodium level above the level at a symptom free stage. In some embodiments, there is provided a method of providing information for diagnosis of a migraine attack in an individual exhibiting one or more symptoms of migraine (such as headache), comprising: a) determining the brain extracellular fluid sodium level in the individual, and b) providing information about the brain extracellular fluid sodium level of the individual, wherein an increase in brain extracellular fluid sodium level above the level at a symptom free stage is indicative of a migraine attack.

In some embodiments, the brain extracellular fluid sodium level is based on regional brain tissue sodium concentration. For example, in some embodiments, the invention provides a method of diagnosing migraine attack in an individual exhibiting one or more symptoms of migraine (such as headache), comprising comparing the regional brain tissue sodium concentration in the individual with the regional brain tissue sodium concentration in the same individual at a symptom free stage, wherein an increase in regional brain tissue sodium concentration above the level at a symptom free stage is indicative of a migraine attack. In some embodiments, the regional brain tissue sodium concentration is determined by brain magnetic resonance spectrometry.

The diagnosis methods described herein provide basis for treatment of migraine. Accordingly, in some embodiments, there is provided a method of treating or continuing to treat migraine attack in an individual exhibiting one or more symptoms of migraine (such as headache), comprising administering to the individual an effective amount of a migraine rescue drug (such as a sodium pump inhibitor), wherein determination of migraine attack is based on the comparison between the CSF sodium level (or brain extracellular fluid sodium level) in the individual with the CSF sodium level (or brain extracellular fluid sodium level) in the same individual at a symptom free stage, wherein an increase in CSF sodium level (or brain extracellular fluid level) above the level at a symptom free stage is indicative of a migraine attack. In some embodiments, the invention provides a method of treating or continuing to treat migraine attack in an individual exhibiting one or more symptoms of migraine (such as headache), comprising: a) comparing the CSF sodium level (or brain extracellular fluid level) in the individual with the CSF sodium level (or brain extracellular fluid level) in the individual with the CSF sodium level (or brain extracellular fluid level) in the same individual at a symptom free stage, wherein an increase in the CSF sodium level (or brain extracellular fluid level) above the level at a symptom free stage is indicative of a migraine attack, and b) administering to the individual an effective amount of a migraine rescue drug (such as a sodium pump inhibitor).

In some embodiments, the migraine rescue drug increases the flow of sodium into cells in the brain. In some embodiments, the migraine rescue drug decreases movement of intracellular sodium to the outside of the cell. In some embodiments, the migraine rescue drug is a sodium pump inhibitor. In some embodiments, the sodium pump inhibitor is steroid glycoside. In some embodiments, the steroid glycoside is any of (and in some embodiments selected from the group consisting of) ouabain, dihydroouabain, digoxin, proscillaridin, digitoxin, lanatoside, acetyldigitoxin, digitoxigenin, and digoxigenin. In some embodiments, the steroid glycoside is ouabain. In some embodiments, the steroid glycoside is digoxin. In some embodiments, a single dose of the migraine rescue drug (such as sodium pump inhibitor) is administered.

In another aspect, there is provided a method of determining predisposition of an individual to the development of migraine by monitoring the sodium level in an individual who has been exposed to a challenging condition (such as administration of a challenging agent). For example, in some embodiments, there is provided a method of determining predisposition of an individual to the development of migraine, comprising: a) subjecting the individual to a challenging condition sufficient to trigger migraine at a symptom free stage; b) monitoring the CSF sodium level in said individual for a certain period of time, wherein a characteristic change in the CSF sodium level in the individual is indicative that the individual is predisposed to the development of migraine. In some embodiments, there is provided a method of determining predisposition of an individual to the development of migraine, comprising: a) administering a sufficient amount of a challenging agent to the individual at a symptom free stage; b) monitoring the CSF sodium level in said individual for a certain period of time, wherein a characteristic change in the CSF sodium level in the individual is indicative that the individual is predisposed to the development of migraine. In some embodiments, the method further comprises the step of determining a baseline CSF sodium level in the individual prior to, during, or immediately after subjecting the individual to a challenging condition (such as administering a challenging agent to the individual).

In some embodiments, there is provided a method of determining predisposition of an individual to the development of migraine, comprising monitoring the CSF sodium level in said individual for a certain period of time, wherein said individual has been subject to a challenging condition sufficient to trigger migraine at a symptom free stage, and wherein a characteristic change in the CSF sodium level in the individual is indicative that the individual is predisposed to the development of migraine. In some embodiments, there is provided a method of determining predisposition of an individual to the development of migraine, comprising monitoring the CSF sodium level in said individual for a certain period of time, wherein the individual has been administered with a sufficient amount of a challenging agent at a symptom free stage, and wherein a characteristic change in the CSF sodium level in the individual is indicative that the individual is predisposed to the development of migraine.

In some embodiments, the CSF sodium level is based on the sodium concentration in the CSF of the individual. In some embodiments, the change (such as increase) of CSF sodium level is based on the change (such as increase) of the molar ratio of sodium to another analyte (such as potassium ion) in the CSF of the individual.

In some embodiments, the CSF sodium level is based on the sodium concentration in the saliva of the individual. In some embodiments, the change (such as increase) of CSF sodium level is based on the change (such as increase) of the molar ratio of sodium to another analyte (such as potassium ion) in the saliva of the individual. For example, in some embodiments, there is provided a method of determining predisposition of an individual to the development of migraine, comprising: a) subjecting the individual to a challenging condition sufficient to trigger migraine at a symptom free stage; b) monitoring the saliva sodium concentration in said individual for a certain period of time, wherein a characteristic change in the saliva sodium concentration in the individual is indicative that the individual is predisposed to the development of migraine. In some embodiments, there is provided a method of determining predisposition of an individual to the development of migraine, comprising: a) administering a sufficient amount of a challenging agent to the individual at a symptom free stage; b) monitoring the saliva sodium concentration in said individual for a certain period of time, wherein a characteristic change in the saliva sodium concentration in the individual is indicative that the individual is predisposed to the development of migraine.

In some embodiments, the CSF sodium level is intracranial sodium level, for example the intracranial sodium level determined by brain magnetic resonance spectrometry. For example, in some embodiments, there is provided a method of determining predisposition of an individual to the development of migraine, comprising: a) subjecting the individual to a challenging condition sufficient to trigger migraine at a symptom free stage; b) monitoring the intracranial CSF sodium level in said individual for a certain period of time, wherein a characteristic change in the intracranial CSF sodium level in the individual is indicative that the individual is predisposed to the development of migraine. In some embodiments, there is provided a method of determining predisposition of an individual to the development of migraine, comprising: a) administering a sufficient amount of a challenging agent to the individual at a symptom free stage; b) monitoring the intracranial CSF sodium level in said individual for a certain period of time, wherein a characteristic change in the intracranial CSF sodium level in the individual is indicative that the individual is predisposed to the development of migraine.



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stats Patent Info
Application #
US 20120270816 A1
Publish Date
10/25/2012
Document #
13413571
File Date
03/06/2012
USPTO Class
514 26
Other USPTO Classes
International Class
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Drawings
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Cerebrospinal Fluid
Migraine


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