Methods of treating patients suffering from a disease condition or disorder that is associated with an increased glutamate level
The present invention relates to use of biopterin compounds such as 4-Amino-(6R,S)-5,6,7,8-tetrahydro-L-biopterin or 4-Amino-(6R,S)-7,8-dihydro-L-biopterin for treating a human patient suffering from a disease condition or disorder that is associated with an increased glutamate level. The invention also relates to the use of such biopterin compounds in a method of treating or preventing glutamate excitotoxicity (glutamate storm) in a patient suffering from a condition that has the potential to result in a pathologically high glutamate level in the brain.
1 . A method of treating a human patient suffering from a brain injury that is associated with an injury-induced extracellular brain glutamate level >10 μmol/L, wherein the method comprises:
selecting the human patient on the basis of a patient age of 18-39 years and a time from injury of ≤12 hours; and
intravenously administering to the patient a therapeutically effective amount of a compound of formula (I):
and/or a compound of formula (II):
for a period of 48 hours, wherein administering the therapeutically effective amount of the compound of formula (I) and/or of formula (II) results in an odds ratio for having an extracellular brain glutamate level >10 μmol/L that remains less than 1 for a period beginning at 24 hours after the start of the administration and extending to 96 hours after the start of the administration, wherein the odds ratio is determined by measuring an extracellular brain glutamate level by microdialysis of cerebrospinal fluid or brain extracellular fluid in a corresponding treatment patient population.
2 . The method of claim 1 , wherein the extracellular brain glutamate level is measured by microdialysis of cerebrospinal fluid.
3 . The method of claim 1 , wherein the brain injury is acute brain injury.
4 . The method of claim 1 , wherein the brain injury is selected from the group consisting of traumatic brain injury, surgical brain injury, non-traumatic brain injury, elevated intracranial pressure, and secondary brain injury.
5 . The method of claim 4 , wherein the secondary brain injury comprises a condition selected from the group consisting of edema formation from local or global hypoxia, from insufficient local or global perfusion leading to ischemia related to low perfusion pressure or vasoconstriction, from excessive perfusion due to higher perfusion pressure or vasodilation with hyperemia, from inflammation with infection, inflammation without infection, from neoplasms and side effects of a therapeutic treatment.
6 . The method of claim 5 , wherein the neoplasm is selected from the group consisting of benign neoplasms, and malignant neoplasms and metastases of such neoplasms.