Diagnositc methods for determining susceptibility to convulsive conditions
First Claim
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1. A method of diagnosing a convulsive condition or susceptibility thereto in a subject comprising the steps of a. analyzing a bodily fluid from a subject for the presence or amount of a neuro-active molecule, or the relative amounts of neuro-active molecules, associated with a convulsive condition;
- and b. diagnosing the subject as at risk of a convulsive condition or susceptibility thereto when the amount of said compound indicates a likelihood of same in said subject.
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Abstract
The present invention exploits the discovery that amounts of uracil and thymine metabolites, especially β-aminoisobutyric acid, in various bodily fluids, especially urine, are correlated with the occurrence of epilepsy when compared to matched control subjects. Analytical and diagnostic protocols, including a novel high performance liquid chromatography system, for use in the invention are disclosed.
31 Citations
40 Claims
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1. A method of diagnosing a convulsive condition or susceptibility thereto in a subject comprising the steps of
a. analyzing a bodily fluid from a subject for the presence or amount of a neuro-active molecule, or the relative amounts of neuro-active molecules, associated with a convulsive condition; - and
b. diagnosing the subject as at risk of a convulsive condition or susceptibility thereto when the amount of said compound indicates a likelihood of same in said subject.
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2. A method of modulating the onset of a convulsive condition in a subject comprising the steps of
analyzing a bodily fluid from a subject at risk of a convulsive condition for the presence or amount of a neuro-active molecule, or the relative amounts of neuro-active molecules, associated with a convulsive condition; -
determining from the amount of said compound in said bodily fluid whether said subject is at risk of a convulsive condition; and
treating said subject, if at risk of a convulsive condition, to modulate the onset of said convulsive condition in said subject.
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3. A method of diagnosing a convulsive condition or susceptibility thereto in a subject comprising the steps of
analyzing a bodily fluid from a subject for the presence or amount of a β - -amino acid, or the relative amount of β
-amino acid; and
diagnosing the subject as at risk of a convulsive condition when the amount of said β
-amino acid indicates a likelihood of same in said subject.
- -amino acid, or the relative amount of β
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4. A method of modulating the onset of a convulsive condition in a subject comprising the steps of
analyzing a bodily fluid from a subject at risk of a convulsive condition for the presence or amount of a β - -amino acid, or the relative amount of β
-amino acid;
determining from the amount of said β
-amino acid in said bodily fluid whether said subject is at risk of a convulsive condition, andtreating said subject, if at risk of a convulsive condition, so as to modulate the onset of said convulsive condition in said subject.
- -amino acid, or the relative amount of β
- 5. The method of any claim herein, wherein said neuro-active molecule is a metabolite of uracil or thymine, or a derivative thereof.
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6. The method of any claim herein, wherein said compound is an amino acid or a derivative thereof.
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9. The method of any claim herein, wherein said convulsive condition is selected from the group consisting of epileptogenic associated disorders, epileptogenesis, and non-epileptic convulsions.
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10. The method of any claim herein, wherein said convulsive condition is an epileptogenic-associated disorder selected from epilepsy, head trauma, stroke, multiple sclerosis, amyotrophic lateral sclerosis, psychoses, cerebral ischemia, motor neuron disease, Alzheimer'"'"'s disease, chicken-pox, measles, encephalitis, pertussis encephalitis, infections of the CNS, meningitis, encephalitis, subdural haematoma, brain tumour, birth defects, anoxic brain injury dementia, or other disorders in which altered activity of neuro-active molecules is a cause, at least in part, of the disorder.
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11. The method of any claim herein, wherein said convulsive condition is selected from the group consisting of epilepsy and non-epileptic convulsions.
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12. The method of any claim herein, wherein said subject has not yet developed seizures.
- 13. The method of any claim herein, wherein said treatment step comprises administering an effective amount of an anti-convulsive pharmaceutical composition.
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14. The method of any claim herein, wherein said treatment step comprises administering an effective amount of an anti-epileptogenic pharmaceutical composition.
- 15. The method of any claim herein, further comprising the steps of deproteinizing said bodily fluid.
- 18. The method of any claim herein, further comprising derivatizing said amino acid prior to analyzing it.
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21. The method of any claim herein, wherein said bodily fluid is urine, blood, plasma, blood serum, cerebrospinal fluid, sweat, lymph, amniotic fluid, synovial fluid, conjunctival fluid, salivary fluid, vaginal fluid, stool, seminal fluid, bile, tears, or mixtures thereof.
- 24. The method of any claim herein, wherein said subject is an animal or human.
- 26. The method of any claim herein, wherein said subject has suffered a head trauma.
- 28. The method of any claim herein, wherein said seizure is selected from the group consisting of complex partial, simple partial, absence, secondary generalized tonic clonic, primary generalized tonic clonic, myoclonic, and atonic.
- 29. The method of any claim herein, wherein the analyzing step comprises chromatography, spectroscopy, spectrometry, or colorimetry.
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31. The method of any claim herein, wherein said treating is carried out when the amount of said amino acid is substantially different from the average amount present in a matched control population.
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34. A method of quantifying β
- -alanine or β
-aminoisobutyric acid comprising the steps ofcollecting a urine sample;
deproteinizing said urine sample;
derivatizing the amino acids present in said deproteinized urine sample; and
analyzing said derivatized amino acids by high performance liquid chromatography, said chromatography system comprising a reversed phase column, acetate buffer and methanol mobile phases, an internal standard, and a separation program which produces a resolution for each of β
-alanine and β
-aminoisobutyric acid with all other amino acids and molecules present in said urine of equal to or greater than one. - View Dependent Claims (35, 36)
- -alanine or β
- 37. A kit for use according to the invention comprising internal or external standards or derivatizing reagents, and instructions for use in the method of any claim herein.
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40. The method of any claim herein, wherein said step of determining or diagnosing is positive when the urinary concentration of β
- -alanine is greater than 0.8 μ
mol/mmol creatinine or β
-aminoisobutyric acid is greater than 10 μ
mol/mmol creatinine.
- -alanine is greater than 0.8 μ
Specification