Nerve agent antidotes
Inventors
Niquet, Jerome • Wasterlain, Claude G.
Assignees
US Department of Veterans Affairs • University of California San Diego UCSD
Publication Number
US-9814729-B2
Publication Date
2017-11-14
Expiration Date
2033-03-14
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Abstract
The present invention includes compositions that are useful in treating, ameliorating, or preventing nerve agent poisoning. The present invention also includes methods of preventing, treating or ameliorating nerve agent poisoning in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition of the invention. The present invention also includes methods of preventing, treating or ameliorating a seizure induced by a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition of the invention. The present invention also comprises a kit comprising compositions of the invention.
Core Innovation
The invention provides compositions and methods for treating, ameliorating, or preventing nerve agent poisoning by administering a combination of at least one GABAA receptor agonist and at least one NMDA antagonist. This combination therapy is effective in addressing seizures induced by nerve agents, which are a primary symptom of such poisoning. The invention further encompasses the use of an anticonvulsant in combination with these agents, and optionally additional therapeutic agents such as muscarinic antagonists or agents that regenerate organophosphate-inactivated acetylcholinesterases.
The problem addressed is the ineffectiveness of current monotherapy treatments for seizures induced by nerve agent poisoning. Existing therapies, such as benzodiazepine monotherapy, are only effective if administered before the onset of seizures. Once seizures become self-sustaining, due in part to the internalization of synaptic GABAA receptors and increased synaptic NMDA receptor expression, they become resistant to these treatments. The invention solves this by combining a GABAA receptor agonist to enhance inhibition with an NMDA antagonist to reduce glutamatergic excitation, thus overcoming pharmacoresistance and improving seizure control.
Additionally, the invention relates to treating seizures induced by other diseases or disorders, including acute seizures, status epilepticus, epilepsy, stroke, traumatic brain injury, and cardiac arrest, as these seizures may share similar underlying mechanisms involving GABAA and NMDA receptor changes. The composition and method provide a novel therapeutic approach for these seizure types as well.
Claims Coverage
The patent includes three independent claims covering compositions for nerve agent poisoning and seizure treatment induced by various diseases, and a kit containing such compositions. The claims focus on combinations of GABAA receptor agonists, NMDA antagonists, and optional additional therapeutics.
Composition comprising a GABAA receptor agonist, NMDA antagonist, and additional therapeutic for nerve agent poisoning
The composition includes at least one GABAA receptor agonist (benzodiazepine), at least one NMDA antagonist (ketamine), and at least one additional therapeutic selected from anticonvulsants or antiepileptics.
Composition comprising a GABAA receptor agonist, NMDA antagonist, and additional therapeutic for treatment of seizures induced by disease or disorder
The composition includes at least one GABAA receptor agonist (benzodiazepine), at least one NMDA antagonist (ketamine), and at least one additional therapeutic selected from anticonvulsants or antiepileptics. The disease or disorder can include acute seizures, status epilepticus, epilepsy, stroke, traumatic brain injury, cardiac arrest, drug use or withdrawal, infections, tumors, metabolic or autoimmune encephalopathies, degenerative brain diseases, or gene defects.
Kit comprising a therapeutically effective composition and administration device
The kit contains a therapeutically effective amount of at least one GABAA receptor agonist (benzodiazepine), at least one NMDA antagonist (ketamine), and at least one additional therapeutic (anticonvulsant or antiepileptic), and optionally includes a device for administration such as an autoinjector.
The claims cover therapeutic compositions combining a benzodiazepine GABAA receptor agonist, ketamine as an NMDA antagonist, and anticonvulsants or antiepileptics for treating nerve agent poisoning and various seizure-inducing diseases, as well as kits with these compositions and devices for administration.
Stated Advantages
The combination therapy is more effective and less toxic than monotherapy for treating seizures induced by nerve agent poisoning and status epilepticus, especially when administered after seizures become pharmacoresistant to benzodiazepines.
The compositions have synergistic effects in reducing seizure severity and frequency, allowing for lower doses of individual drugs and reducing adverse effects.
The combination reduces seizure-associated brain damage and epileptogenesis better than monotherapy.
Documented Applications
Treatment, amelioration, or prevention of nerve agent poisoning in subjects exposed to organophosphate nerve agents such as sarin.
Treatment, amelioration, or prevention of seizures induced by diseases or disorders including acute seizures, status epilepticus, epilepsy, stroke, traumatic brain injury, cardiac arrest, drug-related causes, infections, tumors, metabolic encephalopathies, autoimmune and inflammatory processes, degenerative brain diseases, and genetic defects.
Use in kits comprising compositions and devices such as autoinjectors for rapid administration in battlefield or terrorism situations.
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