Methods for treating neurological conditions and exposure to nerve agents
View Patent ↗Described are methods of treating or reducing the toxic effects of exposure to a nerve agent, comprising administering to a subject in need thereof (i) an AMPA/GluR5(GluK1) kainate receptor antagonist (such as LY293558) and (ii) an NMD A receptor antagonist (such as an antimuscarinic compound, such as caramiphen), as well as methods of treating, reducing the risks of, or preventing a neurological condition such as epilepsy, seizures, post-traumatic stress disorder, status epilepticus, depression, or anxiety, comprising administering to a subject in need thereof (i) an AMPA/GluR5(GluK1) kainate receptor antagonist (such as LY293558) and (ii) an NMDA receptor antagonist (such as an antimuscarinic compound, such as caramiphen). The methods may further comprise administering a positive allosteric modulator of synaptic GABA A receptors, such as a benzodiazepine, such as midazolam, to the subject. The methods are suitable for use in children and adults. Related compositions and uses also are described.
1. A method of treating or reducing the toxic effects of exposure to a nerve agent, or treating or reducing the risks of a neurological condition, comprising administering to a mammalian subject in need thereof (i) an AMPA/GluR5(GluK1) kainate receptor antagonist and (ii) an NMDA receptor antagonist, and, optionally, further comprising administering a positive allosteric modulator of synaptic GABAA receptors to the subject, wherein the AMPA/GluR5(GluK1) kainate receptor antagonist and the NMDA receptor antagonist and, optionally, the positive allosteric modulator of synaptic GABA A receptors, are administered by intramuscular injection.
2. The method of claim 1 , wherein the method is for treating a neurological condition selected from epilepsy, seizure, post-traumatic stress disorder, status epilepticus, depression, or anxiety.
3. The method of claim 1 , wherein the AMPA/GluR5(GluK1) kainate receptor antagonist is LY293558.
4. The method of claim 1 , wherein the NMDA receptor antagonist is an antimuscarinic compound.
5. The method of claim 1 , wherein the NMDA receptor antagonist is caramiphen.
6. The method of claim 1 , wherein the optional positive allosteric modulator of synaptic GABA A receptors is administered.
7. The method of claim 6 , wherein the positive allosteric modulator of synaptic GABA A receptors is a benzodiazepine.
8. The method of claim 6 , wherein the positive allosteric modulator of synaptic GABA A receptors is midazolam.
9. The method of claim 1 , wherein the AMPA/GluR5(GluK1) kainate receptor antagonist is LY293558 and the NMDA receptor antagonist is caramiphen, and the optional positive allosteric modulator of synaptic GABA A receptors, if administered, is midazolam.
10. The method of claim 1 , wherein the method is for treating or reducing the toxic effects of exposure to a nerve agent that comprises an organophosphorus toxin.
11. The method of claim 1 , wherein the nerve agent comprises one or more selected from soman and sarin.
12. The method of claim 1 , wherein the subject has been exposed to the nerve agent.
13. The method of claim 1 , wherein the subject is suspected of having been exposed to a nerve agent or is at risk of exposure to a nerve agent.
14. The method of claim 1 , wherein the method is effective to treat or reduce the toxic effects of exposure to the nerve agent selected from one or more of seizures, status epilepticus, brain damage, neurological effects, behavioral effects, difficulty breathing, nausea, loss of control of bodily functions, and death.
15. A method of treating or reducing the toxic effects of exposure to a nerve agent that comprises an organophosphorus toxin in a mammalian subject that has been exposed to the nerve agent, comprising administering to the subject (i) an AMPA/GluR5(GluK1) kainate receptor antagonist and (ii) an NMDA receptor antagonist, and, optionally, further comprising administering a positive allosteric modulator of synaptic GABA A receptors to the subject, wherein administration of the AMPA/GluR5(GluK1) kainate receptor antagonist and NMDA receptor antagonist occurs within a time period selected from within two hours or less, within one hour or less, or within 20 minutes or less of exposure to the nerve agent.
16. The method of claim 15 , wherein the AMPA/GluR5(GluK1) kainate receptor antagonist and the NMDA receptor antagonist and, optionally, the positive modulator of synaptic GABA-A receptors, are administered orally.
17. The method of claim 15 , wherein the AMPA/GluR5(GluK1) kainate receptor antagonist and the NMDA receptor antagonist and, optionally, the positive modulator of synaptic GABA-A receptors, are administered intramuscularly.
18. The method of claim 15 , wherein the AMPA/GluR5(GluK1) kainate receptor antagonist is LY293558.
19. The method of claim 15 , wherein the NMDA receptor antagonist is an antimuscarinic compound.
20. The method of claim 15 , wherein the NMDA receptor antagonist is caramiphen.
21. The method of claim 15 , wherein the optional positive allosteric modulator of synaptic GABA A receptors is administered.
22. The method of claim 15 , wherein the positive allosteric modulator of synaptic GABA A receptors is a benzodiazepine.
23. The method of claim 22 , wherein the positive allosteric modulator of synaptic GABA A receptors is midazolam.
24. The method of claim 15 , wherein the AMPA/GluR5(GluK1) kainate receptor antagonist is LY293558 and the NMDA receptor antagonist is caramiphen, and the optional positive allosteric modulator of synaptic GABA A receptors, if administered, is midazolam.
25. The method of claim 15 , wherein the method is effective to treat or reduce the toxic effects of exposure to the nerve agent selected from one or more of seizures, status epilepticus, brain damage, neurological effects, behavioral effects, difficulty breathing, nausea, loss of control of bodily functions, and death.
26. The method of claim 25 , wherein the neurological effects are selected from one or more of post-traumatic stress disorder, depression, and anxiety.
27. A method of treating or reducing the toxic effects of exposure to a nerve agent, or treating or reducing the risks of a neurological condition, comprising administering to a mammalian subject in need thereof (i) an AMPA/GluR5(GluK1) kainate receptor antagonist and (ii) an NMDA receptor antagonist, and, optionally, further comprising administering a positive allosteric modulator of synaptic GABAA receptors to the subject, wherein the subject is a human child.
28. The method of claim 27 , wherein the AMPA/GluR5(GluK1) kainate receptor antagonist and the NMDA receptor antagonist and, optionally, the positive modulator of synaptic GABA-A receptors, are administered orally.
29. The method of claim 27 , wherein the AMPA/GluR5(GluK1) kainate receptor antagonist and the NMDA receptor antagonist and, optionally, the positive modulator of synaptic GABA-A receptors, are administered intramuscularly.
30. The method of claim 27 , wherein the AMPA/GluR5(GluK1) kainate receptor antagonist is LY293558.
31. The method of claim 27 , wherein the NMDA receptor antagonist is an antimuscarinic compound.
32. The method of claim 27 , wherein the NMDA receptor antagonist is caramiphen.
33. The method of claim 27 , wherein the optional positive allosteric modulator of synaptic GABA A receptors is administered.
34. The method of claim 27 , wherein the positive allosteric modulator of synaptic GABA A receptors is a benzodiazepine.
35. The method of claim 34 , wherein the positive allosteric modulator of synaptic GABA A receptors is midazolam.
36. The method of claim 27 , wherein the AMPA/GluR5(GluK1) kainate receptor antagonist is LY293558 and the NMDA receptor antagonist is caramiphen, and the optional positive allosteric modulator of synaptic GABA A receptors, if administered, is midazolam.
37. The method of claim 27 , wherein the method is effective to treat or reduce the toxic effects of exposure to the nerve agent selected from one or more of seizures, status epilepticus, brain damage, neurological effects, behavioral effects, difficulty breathing, nausea, loss of control of bodily functions, and death.
38. The method of claim 27 , wherein the method is for treating a neurological condition selected from epilepsy, seizure, post-traumatic stress disorder, status epilepticus, depression, and anxiety.