Methods for Treating Nerve Agent-Induced Seizures

Abstract

The present disclosure relates to a method of treating a disease (e.g., seizures) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, alone or in combination with a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 208,885, filed June 9, 2021, the disclosure of which is incorporated herein by reference.

[0002] government support This invention was made with Government support under HHSO100201800008 awarded by the Biomedical Advanced Research and Development Authority. The Government has certain rights in this invention. [Background technology]

[0003] Disruption of normal cortical and subcortical function in the central nervous system (CNS) can result from various injuries (e.g., head trauma), pathologies (e.g., childhood epilepsy), other physiological stimuli (e.g., electrolyte imbalance), or external chemical stimuli (e.g., nerve agents) that can induce a seizure state in a subject. Tezanepanel is a competitive antagonist at the kainate and AMPA subtypes of glutamate receptors. Thus, there is a need for novel uses of Tezanepanel in the treatment of seizures and the potential prevention of more permanent brain damage resulting from the induction of a seizure state from various physical or pharmacological stimuli. Summary of the Invention [Means for solving the problem]

[0004] In some aspects, the present disclosure provides a method for treating a subject comprising: (i) a therapeutically effective amount of tezampanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof; and (ii) providing a method for treating a disorder (e.g., seizures) in a subject in need thereof, comprising administering a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof;

[0005] In some aspects, the disclosure provides a method of treating a disease resistant to treatment with a benzodiazepine (e.g., seizures) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of tespanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof.

[0006] In some aspects, the disclosure provides a method of treating a disease resistant to treatment with tesanpanel (e.g., seizures) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof.

[0007] In some aspects, the disclosure provides a combination for treating a disease in a subject in need thereof, the combination comprising: (i) a therapeutically effective amount of tezampanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof; and (ii) A therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof.

[0008] In some aspects, the disclosure provides a tesanpanel, a pharma- ceutically acceptable salt, or a prodrug thereof, for use in treating a disease resistant to treatment with a benzodiazepine (e.g., seizures) in a subject in need thereof.

[0009] In some aspects, the present disclosure provides a benzodiazepine, a pharma- ceutically acceptable salt, or a prodrug thereof, for use in treating a disease (e.g., seizures) resistant to treatment with tesanpanel in a subject in need thereof.

[0010] In some aspects, the disclosure provides for the use of a combination in the manufacture of a medicament for treating a disease (e.g., stroke) in a subject in need thereof, the combination comprising: (i) a therapeutically effective amount of tezampanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof; and (ii) A therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof.

[0011] In some aspects, the disclosure provides for the use of tesanpanel, a pharma- ceutically acceptable salt, or a prodrug thereof, in the manufacture of a medicament for treating a disease resistant to treatment with a benzodiazepine (e.g., seizures) in a subject in need thereof.

[0012] In some aspects, the disclosure provides the use of a benzodiazepine, a pharma- ceutically acceptable salt, or a prodrug thereof in the manufacture of a medicament for treating a disease resistant to treatment with tesanpanel (e.g., seizures) in a subject in need thereof.

[0013] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. In this specification, the singular form also includes the plural form unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. References cited herein are not admitted to be prior art of the claimed invention. In case of conflict, the present specification, including definitions, will prevail. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In case of conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure will prevail.

[0014] Other features and advantages of the present disclosure will be apparent from the following detailed description and claims. [Brief description of the drawings]

[0015] [Figure 1]FIG. 1 is a graph showing electroencephalogram (EEG)-derived seizure severity measured by a 7-point Likert scale in rodents with nerve agent-induced seizures that have been successfully treated with Texanel. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] In some aspects, the disclosure provides a method of treating a disease (e.g., stroke) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of tezampanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof.

[0017] In some aspects, the present disclosure provides a method for treating a subject comprising: (i) a therapeutically effective amount of tezampanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof; and (ii) providing a method for treating a disorder (e.g., seizures) in a subject in need thereof, comprising administering a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof;

[0018] In some aspects, the disclosure provides a method of treating a disease resistant to treatment with a benzodiazepine (e.g., seizures) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of tespanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof.

[0019] In some aspects, the disclosure provides a method of treating a disease resistant to treatment with tesanpanel (e.g., seizures) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof.

[0020] Subjects and diseases to be treated In some embodiments, the subject is an animal.

[0021] In some embodiments, the subject is a human.

[0022] In some embodiments, the disease is stroke.

[0023] In some embodiments, the seizures are drug-induced seizures (ie, seizures that are induced by an inducing agent).

[0024] In some embodiments, the inducing agent is a nerve agent, ie, an agent that disrupts the mechanism by which nerves transmit messages to organs.

[0025] In some embodiments, the inducer is an insecticide.

[0026] In some embodiments, the inducer (eg, an insecticide) is a carbamate.

[0027] In some embodiments, the inducer (eg, a carbamate) is aldicarb, carbofuran, carbaryl, ethienocarbo, fenobucarb, oxamyl, or methomyl.

[0028] In some embodiments, the inducer (eg, insecticide) is an organophosphate.

[0029] In some embodiments, the inducer (eg, organophosphate) is parathion, malathion, methyl parathion, chlorpyrifos, diazinon, dichlorvos, phosmet, fenitrothion, tetrachlorvinphos, azimethaphos, azinphos-methyl, or terbufos.

[0030] In some embodiments, the inducing agent is a nerve agent, ie, an agent that disrupts the mechanism by which nerves transmit messages to organs.

[0031] In some embodiments, the inducing agent (eg, nerve agent) is an organophosphate.

[0032] In some embodiments, the inducing agent (eg, nerve agent) is a G-series nerve agent.

[0033] In some embodiments, the inducing agent (eg, a G-series nerve agent) is tabun (GA), sarin (GB), soman (GD), or cyclosarin (GF).

[0034] In some embodiments, the inducing agent (eg, nerve agent) is a V-series nerve agent.

[0035] In some embodiments, the inducing agent (e.g., a V-series nerve agent) is VE, VG, VM, VP, VR, VS, or VX.

[0036] In some embodiments, the inducer (e.g., nerve agent) is a Novichok class agent.

[0037] In some embodiments, the inducer (eg, a nerve agent) is a carbamate.

[0038] In some embodiments, the inducer (e.g., a carbamate) is EA-2192, EA-3148, EA-3990, or EA-4056.

[0039] In some embodiments, the seizures are refractory to treatment without texanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof.

[0040] In some embodiments, the seizures are refractory to treatment with a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, without texanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof.

[0041] Administration of Tezampanel Tezampanel Dosage In some embodiments, a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof reduces the frequency, severity, or duration of attacks.

[0042] In some embodiments, a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, prevents seizures.

[0043] In some embodiments, a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, ameliorates a side effect of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof.

[0044] In some embodiments, the side effect is sedation.

[0045] In some embodiments, a therapeutically effective amount of tezampanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is administered in an oral dosage form (eg, a tablet).

[0046] In some embodiments, the prodrug of tezampanel is dasolam penel or a pharmaceutically acceptable salt thereof. In some embodiments, a therapeutically effective amount of dasolam penel, or a pharmaceutically acceptable salt thereof, is administered in an oral dosage form (e.g., a tablet).

[0047] In some embodiments, the tesampanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof (e.g., dasolampanel) is administered at a dose of about 2.5 mg / kg or less, about 2.4 mg / kg or less, about 2.3 mg / kg or less, about 2.2 mg / kg or less, about 2.1 mg / kg or less, about 2.0 mg / kg or less, about 1.9 mg / kg or less, about 1.8 mg / kg or less, about 1.7 mg / kg or less, about 1.6 mg / kg or less, about 1.5 mg / kg or less, about 1.4 mg / kg or less, about 1.3 mg / kg or less, about 1.2 mg / kg or less, about 1.1 mg / kg or less, about 1.0 mg / kg or less, about 0.9 mg / kg or less, or about 1.2 mg / kg or less. g / kg or less, about 0.8 mg / kg or less, about 0.7 mg / kg or less, about 0.6 mg / kg or less, about 0.5 mg / kg or less, about 0.4 mg / kg or less, about 0.3 mg / kg or less, about 0.2 mg / kg or less, about 0.1 mg / kg or less, about 0.09 mg / kg or less, about 0.08 mg / kg or less, about 0.07 mg / kg or less, about 0.06 mg / kg or less, about 0.05 mg / kg or less, about 0.04 mg / kg or less, about 0.03 mg / kg or less, about 0.02 mg / kg or less, or about 0.01 mg / kg or less (e.g., human dosages (human oral dosages)).

[0048] In some embodiments, tesampanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof (e.g., dasolampanel) is administered at a dose of about 0.01 mg / kg or more, about 0.02 mg / kg or more, about 0.03 mg / kg or more, about 0.04 mg / kg or more, about 0.05 mg / kg or more, about 0.06 mg / kg or more, about 0.07 mg / kg or more, about 0.08 mg / kg or more, about 0.09 mg / kg or more, about 0.1 mg / kg or more, about 0.2 mg / kg or more, about 0.4 mg / kg or more, about 0.5 mg / kg or more, about 0. ...7 mg / kg or more, about 0.8 mg / kg or more, about 0.09 mg / kg or more, about 0.1 mg / kg or more, about 0.2 mg / kg or more, about 0.4 mg / kg or more, about 0.5 mg / kg or more, about 0.6 mg / kg or more, about 0.7 mg / kg or more, about 0.8 mg / kg or more, about 0.8 mg / kg or more, about 0.9 mg / kg or more, about 0.1 mg / kg or more, about 0.2 mg / kg or more, about 0.4 mg / kg or more, about 0.5 mg / kg or more, about 0.6 mg / kg or more, about 0.7 mg / kg or more, about 0.8 mg / kg or more g or more, about 0.3 mg / kg or more, about 0.4 mg / kg or more, about 0.5 mg / kg or more, about 0.6 mg / kg or more, about 0.7 mg / kg or more, about 0.8 mg / kg or more, about 0.9 mg / kg or more, about 1.0 mg / kg or more, about 1.1 mg / kg or more, about 1.2 mg / kg or more, about 1.3 mg / kg or more, about 1.4 mg / kg or more, or about 1.5 mg / kg or more (e.g., human dosages (human oral dosages)).

[0049] In some embodiments, the tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof (e.g., dasolampanel) is administered at a dose of about 1.2±1.1 mg / kg, about 1.2±1.0 mg / kg, about 1.2±0.9 mg / kg, about 1.2±0.8 mg / kg, about 1.2±0.7 mg / kg, about 1.2±0.6 mg / kg, about 1.2±0.5 mg / kg, about 1.2±0.4 mg / kg, about 1.2±0.3 mg / kg, about 1.2±0.2 mg / kg, The compound is administered at a dosage (e.g., a human dosage (human oral dosage)) of about 1.2±0.1 mg / kg, about 1.2±0.09 mg / kg, about 1.2±0.08 mg / kg, about 1.2±0.07 mg / kg, about 1.2±0.06 mg / kg, about 1.2±0.05 mg / kg, about 1.2±0.04 mg / kg, about 1.2±0.03 mg / kg, about 1.2±0.02 mg / kg, or about 1.2±0.01 mg / kg (e.g., about 1.2 mg / kg).

[0050] In some embodiments, tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof (e.g., dasolampanel) is administered at a dose of about 0.8±0.7 mg / kg, about 0.8±0.6 mg / kg, about 0.8±0.5 mg / kg, about 0.8±0.4 mg / kg, about 0.8±0.3 mg / kg, about 0.8±0.2 mg / kg, about 0.8±0.1 mg / kg, about 0.8±0.09 mg / kg , about 0.8±0.08 mg / kg, about 0.8±0.07 mg / kg, about 0.8±0.06 mg / kg, about 0.8±0.05 mg / kg, about 0.8±0.04 mg / kg, about 0.8±0.03 mg / kg, about 0.8±0.02 mg / kg, or about 0.8±0.01 mg / kg (e.g., about 0.8 mg / kg) (e.g., a human dosage (human oral dosage)).

[0051] In some embodiments, tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof (e.g., dasolampanel) is administered at a dosage (e.g., a human dosage (human oral dosage)) of about 0.4±0.3 mg / kg, about 0.4±0.2 mg / kg, about 0.4±0.1 mg / kg, about 0.4±0.09 mg / kg, about 0.4±0.08 mg / kg, about 0.4±0.07 mg / kg, about 0.4±0.06 mg / kg, about 0.4±0.05 mg / kg, about 0.4±0.04 mg / kg, about 0.4±0.03 mg / kg, about 0.4±0.02 mg / kg, or about 0.4±0.01 mg / kg (e.g., about 0.4 mg / kg).

[0052] In some embodiments, the tesampanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof (e.g., dasolampanel) is administered at a dose of about 0.16±0.15 mg / kg, about 0.16±0.14 mg / kg, about 0.16±0.13 mg / kg, about 0.16±0.12 mg / kg, about 0.16±0.11 mg / kg, about 0.16±0.10 mg / kg, about 0.16±0.09 mg / kg, about 0.16±0.20 mg / kg, about 0.16±0.22 mg / kg, about 0.16±0.24 mg / kg, about 0.16±0.26 mg / kg, about 0.16±0.28 mg / kg, about 0.16±0.29 mg / kg, about 0.16±0.30 mg / kg, about 0.16±0.31 mg / kg, about 0.16±0.32 mg / kg, about 0.16±0.33 mg / kg, about 0.16±0.34 mg / kg, about 0.16±0.35 mg / kg, about 0.16±0.36 mg / kg, about 0.16±0.37 mg / kg, about 0.16±0.38 mg / kg, about 0.16±0.39 mg / kg, about 0.16±0.40 mg / kg, about 0.16±0.41 mg / kg, about 0.16±0.42 mg / kg, about 0.16±0.43 mg / kg, about 0.16±0.44 mg / kg, about 0.16±0.45 mg / kg, about 0.16±0.46 mg / kg, about 0.16±0.47 mg The compound is administered at a dosage (e.g., human dosage (human oral dosage)) of about 0.16±0.08 mg / kg, about 0.16±0.07 mg / kg, about 0.16±0.06 mg / kg, about 0.16±0.05 mg / kg, about 0.16±0.04 mg / kg, about 0.16±0.03 mg / kg, about 0.16±0.02 mg / kg, or about 0.16±0.01 mg / kg (about 0.16 mg / kg).

[0053] In some embodiments, tezampanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof (e.g., dasolampanel) is administered at a dosage (e.g., a human dosage (human oral dosage)) of about 110 mg or less, about 105 mg or less, about 100 mg or less, about 95 mg or less, about 90 mg or less, about 85 mg or less, about 80 mg or less, about 75 mg or less, about 70 mg or less, about 65 mg or less, about 60 mg or less, about 55 mg or less, about 50 mg or less, about 45 mg or less, about 40 mg or less, about 35 mg or less, about 30 mg or less, about 25 mg or less, about 20 mg or less, about 15 mg or less, about 10 mg or less, about 9 mg or less, about 8 mg or less, about 7 mg or less, about 6 mg or less, about 5 mg or less, about 4 mg or less, about 3 mg or less, about 2 mg or less, or about 1 mg or less.

[0054] In some embodiments, tezampanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof (e.g., dasolampanel) is administered in a dosage (e.g., a human dosage (human oral dosage)) of about 1 mg or more, about 2 mg or more, about 3 mg or more, about 4 mg or more, about 5 mg or more, about 6 mg or more, about 7 mg or more, about 8 mg or more, about 9 mg or more, about 10 mg or more, about 15 mg or more, about 20 mg or more, about 25 mg or more, about 30 mg or more, about 35 mg or more, about 40 mg or more, about 45 mg or more, about 50 mg or more, about 55 mg or more, about 60 mg or more, about 65 mg or more, about 70 mg or more, about 75 mg or more, about 80 mg or more, about 85 mg or more, about 90 mg or more, about 95 mg or more, or about 100 mg or more.

[0055] In some embodiments, a therapeutically effective amount of tezampanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is administered in a parenteral dosage form (eg, an intravenous, intramuscular, subcutaneous, or intradermal dosage form).

[0056] In some embodiments, tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is administered at a dosage (e.g., a human dosage (human parenteral dosage)) of about 0.8 mg / kg or less, about 0.7 mg / kg or less, about 0.6 mg / kg or less, about 0.5 mg / kg or less, about 0.4 mg / kg or less, about 0.3 mg / kg or less, about 0.2 mg / kg or less, about 0.1 mg / kg or less, about 0.09 mg / kg or less, about 0.08 mg / kg or less, about 0.07 mg / kg or less, about 0.06 mg / kg or less, about 0.05 mg / kg or less, about 0.04 mg / kg or less, about 0.03 mg / kg or less, about 0.02 mg / kg or less, or about 0.01 mg / kg or less.

[0057] In some embodiments, the tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is administered at a dosage (e.g., a human dosage (human parenteral dosage)) of about 0.01 mg / kg or more, about 0.02 mg / kg or more, about 0.03 mg / kg or more, about 0.04 mg / kg or more, about 0.05 mg / kg or more, about 0.06 mg / kg or more, about 0.07 mg / kg or more, about 0.08 mg / kg or more, about 0.09 mg / kg or more, about 0.1 mg / kg or more, about 0.2 mg / kg or more, about 0.3 mg / kg or more, about 0.4 mg / kg or more, about 0.5 mg / kg or more, about 0.6 mg / kg or more, or about 0.7 mg / kg or more.

[0058] Frequency of Tezampanel administration In some embodiments, administration of a therapeutically effective amount of tezampanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated one or more times during treatment.

[0059] In some embodiments, administration of a therapeutically effective amount of tezampanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated once, twice, three times, four times, five times, six times, seven times, or eight times during treatment.

[0060] In some embodiments, administration of a therapeutically effective amount of tezampanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated once during treatment.

[0061] In some embodiments, administration of a therapeutically effective amount of tezampanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated twice during treatment.

[0062] In some embodiments, administration of a therapeutically effective amount of tezampanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated three times during treatment.

[0063] In some embodiments, the therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is administered every hour, every two hours, every three hours, every four hours, every five hours, every six hours, every seven hours, every eight hours, every nine hours, every ten hours, every eleven hours, every 12 hours, every 13 hours, every 14 hours, every 15 hours, every 16 hours, every 17 hours, every 18 hours, every 19 hours, every 20 hours, every 21 hours, every 22 hours, every 23 hours, or every 24 hours.

[0064] In some embodiments, administration of a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated every four hours.

[0065] In some embodiments, administration of a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated every six hours.

[0066] In some embodiments, administration of a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated every eight hours.

[0067] Benzodiazepines As used herein, the term "benzodiazepine" refers to compounds that have a core chemical structure that is the fusion of a benzene ring and a diazepine ring.

[0068] In some embodiments, the benzodiazepine is clorazepate, diazepam, flurazepam, halazepam, prazepam, lorazepam, lormetazepam, oxazepam, temazepam, clonazepam, flunitrazepam, nimetazepam, nitrazepam, adinazolam, alprazolam, estazolam, triazolam, climazolam, loprazolam, or midazolam.

[0069] In some embodiments, the benzodiazepine is clorazepate, diazepam, flurazepam, halazepam, or prazepam.

[0070] In some embodiments, the benzodiazepine is lorazepam, lormetazepam, oxazepam, or temazepam.

[0071] In some embodiments, the benzodiazepine is clonazepam, flunitrazepam, nimetazepam, or nitrazepam.

[0072] In some embodiments, the benzodiazepine is adinazolam, alprazolam, estazolam, or triazolam.

[0073] In some embodiments, the benzodiazepine is climazolam, loprazolam, or midazolam.

[0074] Benzodiazepine Dosage In some embodiments, a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof reduces the frequency, severity, or duration of seizures.

[0075] In some embodiments, a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, inhibits seizures.

[0076] In some embodiments, the therapeutically effective amount of the benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof mitigates a side effect of the benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof.

[0077] In some embodiments, the side effect is sedation.

[0078] In some embodiments, a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is administered in an oral dosage form (eg, a tablet).

[0079] In some embodiments, a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is administered in a parenteral dosage form (eg, an intravenous, intramuscular, subcutaneous, or intradermal dosage form).

[0080] Frequency of benzodiazepine use In some embodiments, administration of a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated one or more times during treatment.

[0081] In some embodiments, the administration of a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated once, twice, three times, four times, five times, six times, seven times, or eight times during treatment.

[0082] In some embodiments, administration of a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated once during treatment.

[0083] In some embodiments, administration of a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated twice during treatment.

[0084] In some embodiments, administration of a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated three times during treatment.

[0085] In some embodiments, the administration of a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is administered every hour, every 2 hours, every 3 hours, every 4 hours, every 5 hours, every 6 hours, every 7 hours, every 8 hours, every 9 hours, every 10 hours, every 11 hours, every 12 hours, every 13 hours, every 14 hours, every 15 hours, every 16 hours, every 17 hours, every 18 hours, every 19 hours, every 20 hours, every 21 hours, every 22 hours, every 23 hours, or every 24 hours.

[0086] In some embodiments, the administration of a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated every four hours.

[0087] In some embodiments, the administration of a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated every six hours.

[0088] In some embodiments, the administration of a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated every eight hours.

[0089] Exemplary Association Between Tezampanel Administration and Benzodiazepine Administration In some embodiments, (i) a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, and (ii) a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, are administered simultaneously.

[0090] In some embodiments, (i) a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, and (ii) a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, are administered sequentially.

[0091] In some embodiments, (i) a therapeutically effective amount of tespanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, and (ii) a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, are alternatively administered.

[0092] In some embodiments, (i) a therapeutically effective amount of tespanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, and (ii) a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, are administered in close temporal proximity.

[0093] In some embodiments, a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is administered within about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 18 hours, or about 24 hours after administration of a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof.

[0094] In some embodiments, the therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is administered within about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 18 hours, or about 24 hours after administration of a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof.

[0095] In some embodiments, (i) a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, and (ii) a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, are administered by different routes of administration.

[0096] In some embodiments, (i) a therapeutically effective amount of tespanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof (e.g., dasolampanel) and (ii) a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof are administered by the same route of administration (e.g., oral administration).

[0097] In some embodiments, (i) a therapeutically effective amount of tespanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, and (ii) a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, are administered in separate formulations.

[0098] In some embodiments, (i) a therapeutically effective amount of tespanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, and (ii) a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, are administered in a co-formulation.

[0099] Other aspects of the method In some embodiments, the method further comprises administering supportive care to the subject.

[0100] In some embodiments, the supportive care includes an anticholinergic agent, hi some embodiments, the supportive care includes atropine.

[0101] In some embodiments, the supportive therapy comprises an oxime capable of protecting the active site of acetylcholinesterase (e.g., by competing with the action of an organophosphate or carbamate). In some embodiments, the supportive therapy comprises pralidoxime.

[0102] In some embodiments, the supportive care includes an anticonvulsant, hi some embodiments, the supportive care includes diazepam.

[0103] In some embodiments, supportive care includes supplemental oxygen (eg, to treat shortness of breath or hypoxia).

[0104] In some embodiments, supportive care includes heat, hydration, or a combination thereof.

[0105] In some embodiments, the supportive care includes heating. In some embodiments, the supportive care includes a heat source (e.g., to maintain body temperature). In some embodiments, the supportive care includes a blanket.

[0106] In some embodiments, supportive care includes hydration.

[0107] In some embodiments, supportive care includes intravenous fluids (eg, to counter fluid loss due to vomiting or diarrhea).

[0108] Effect of administration In some embodiments, administration reduces the frequency, severity, or duration of attacks.

[0109] In some embodiments, a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, prevents seizures.

[0110] In some embodiments, the frequency, severity, and / or duration of seizures in a subject is measured by the Likert Scale Score (LSS) set forth in Table 1 below. [Table 1]

[0111] In some embodiments, the administration results in a reduction in the subject's LSS.

[0112] In some embodiments, the subject has a lower LLS (e.g., about 1, about 2, about 3, about 4, about 5, or about 6) about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, or about 48 hours after administration of the tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, compared to a comparable subject (e.g., who has not been administered the tesanpanel, a pharma-ceutically acceptable salt thereof, or a prodrug thereof).

[0113] In some embodiments, the subject has an LLS of about 6 or less, about 5 or less, about 4 or less, about 3 or less, or about 2 or less (e.g., about 1) about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, or about 48 hours after administration of the tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof.

[0114] In some embodiments, the subject has an LLS of about 5 or less, about 4 or less, about 3 or less, or about 2 or less (e.g., about 1) about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, or about 48 hours after administration of the tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof.

[0115] In some embodiments, the subject has an LLS of about 4 or less, about 3 or less, or about 2 or less (e.g., about 1) about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, or about 18 hours after administration of the tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof.

[0116] In some embodiments, the subject has an LLS of about 3 or less, or about 2 or less (e.g., about 1) about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours after administration of Tezampanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof. Exemplary embodiments Exemplary embodiment number 1. A method of treating a disease in a subject in need thereof, comprising administering to the subject (i) a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, and (ii) a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof. Exemplary embodiment number 2. A method for treating a disease resistant to treatment with benzodiazepines in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of tesanpanel, a pharma- ceutical acceptable salt thereof, or a prodrug thereof. Exemplary embodiment number 3. A method for treating a disease resistant to treatment with tesanpanel in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof. Exemplary embodiment number 4. A combination for treating a disease in a subject in need thereof, comprising: (i) a therapeutically effective amount of tespanel, a pharma- ceutical acceptable salt thereof, or a prodrug thereof; and (ii) a therapeutically effective amount of a benzodiazepine, a pharma- ceutical acceptable salt thereof, or a prodrug thereof. Exemplary embodiment number 5. TEZAMPANE, a PHARMACEUTICALLY ACCEPTABLE SAL, OR A PRODRUG THEREOF, FOR USE IN THE TREATMENT OF A DISEASE RESISTANT TO TREATMENT WITH BENZODIAZEPINES IN A SUBJECT IN NEED THEREOF. Exemplary embodiment number 6. A benzodiazepine, a pharma- ceutically acceptable salt, or a prodrug thereof, for use in treating a disease resistant to treatment with tesanpanel in a subject in need thereof. Exemplary embodiment number 7. Use of a combination in the manufacture of a medicament for treating a disease in a subject in need thereof, the combination comprising: (i) a therapeutically effective amount of tezampanel, a pharma- ceutical acceptable salt thereof, or a prodrug thereof; and (ii) a therapeutically effective amount of a benzodiazepine, a pharma- ceutical acceptable salt thereof, or a prodrug thereof. Exemplary embodiment number 8. 20. Use of tesanpanel, a pharma- ceutically acceptable salt, or a prodrug thereof, in the manufacture of a medicament for treating a disease resistant to treatment with benzodiazepines in a subject in need thereof. Exemplary embodiment number 9. 2. Use of a benzodiazepine, a pharma- ceutically acceptable salt, or a prodrug thereof, in the manufacture of a medicament for treating a disease resistant to treatment with tesanpanel in a subject in need thereof. Exemplary embodiment number 10. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-9, wherein the subject is an animal. Exemplary embodiment number 11. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1 to 10, wherein the subject is a human. Exemplary embodiment number 12. The method, combination, teczantanel, benzodiazepine, or use of any one of exemplary embodiments 1-11, wherein the disease is seizures. Exemplary embodiment number 13. The method, combination, teczantanel, benzodiazepine, or use of any one of exemplary embodiments 1-12, wherein the seizures are drug-induced seizures. Exemplary embodiment number 14. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-13, wherein the inducing agent is a nerve agent. Exemplary embodiment number 15. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-14, wherein the inducer is an insecticide. Exemplary embodiment number 16. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-15, wherein the insecticide is a carbamate. Exemplary embodiment number 17. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-16, wherein the carbamate is aldicarb, carbofuran, carbaryl, ethienocarb, fenobucarb, oxamyl, or methomyl. Exemplary embodiment number 18. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-17, wherein the insecticide is an organophosphate. Exemplary embodiment number 19. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-18, wherein the organophosphate is parathion, malathion, methyl parathion, chlorpyrifos, diazinon, dichlorvos, phosmet, fenitrothion, tetrachlorvinphos, azimethaphos, azinphos-methyl, or terbufos. Exemplary embodiment number 20. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-19, wherein the inducing agent is a nerve agent. Exemplary embodiment number 21. The method, combination, teczantanel, benzodiazepine, or use of any one of exemplary embodiments 1-20, wherein the nerve agent is an organophosphate. Exemplary embodiment number 22. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-21, wherein the nerve agent is a G-series nerve agent. Exemplary embodiment number 23. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-22, wherein the G-series nerve agent is tabun (GA), sarin (GB), soman (GD), or cyclosarin (GF). Exemplary embodiment number 24. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-23, wherein the nerve agent is a V-series nerve agent. Exemplary embodiment number 25. The method, combination, teczanne, benzodiazepine, or use of any one of exemplary embodiments 1-24, wherein the V-series nerve agent is VE, VG, VM, VP, VR, VS, or VX. Exemplary embodiment number 26. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-25, wherein the nerve agent is a Novichok class agent. Exemplary embodiment number 27. The method, combination, teczantanel, benzodiazepine, or use of any one of exemplary embodiments 1-26, wherein the nerve agent is a carbamate. Exemplary embodiment number 28. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-27, wherein the carbamate is EA-2192, EA-3148, EA-3990, or EA-4056. Exemplary embodiment number 29. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-28, wherein the seizures are resistant to treatment without tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof. Exemplary embodiment number 30. The method, combination, teczantelane, benzodiazepine, or use of any one of exemplary embodiments 1-29, wherein the seizures are resistant to treatment with a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, without teczantelane, a pharma-ceutically acceptable salt thereof, or a prodrug thereof. Exemplary embodiment number 31. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-30, wherein a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof reduces the frequency, severity, or duration of seizures. Exemplary embodiment number 32. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-31, wherein a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, inhibits seizures. Exemplary embodiment number 33. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1 to 32, wherein a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, alleviates a side effect of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof. Exemplary embodiment number 34. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-33, wherein the side effect is sedation. Exemplary embodiment number 35. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-34, wherein a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is administered in an oral dosage form. Exemplary embodiment number 36. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-35, wherein the prodrug of tesanpanel is dasolam penel or a pharma- ceutically acceptable salt thereof. Exemplary embodiment number 37. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-36, wherein a therapeutically effective amount of dasolampanel, or a pharma- ceutically acceptable salt thereof, is administered in an oral dosage form. Exemplary embodiment number 38. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-37, wherein the oral dosage form is a tablet. Exemplary embodiment number 39.

[0036] Tezampanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is about 2.5 mg / kg or less, about 2.4 mg / kg or less, about 2.3 mg / kg or less, about 2.2 mg / kg or less, about 2.1 mg / kg or less, about 2.0 mg / kg or less, about 1.9 mg / kg or less, about 1.8 mg / kg or less, about 1.7 mg / kg or less, about 1.6 mg / kg or less, about 1.5 mg / kg or less, about 1.4 mg / kg or less, about 1.3 mg / kg or less, about 1.2 mg / kg or less, about 1.1 mg / kg or less, about 1.0 mg / kg or less, about 0.9 mg / kg or less, about 0.8 mg / kg or less, about 0.7 mg / kg or less, about 0.8 mg / kg or less, about 0.9 ... 39. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-38, wherein the benzodiazepine is administered at a dosage of about 0.6 mg / kg or less, about 0.5 mg / kg or less, about 0.4 mg / kg or less, about 0.3 mg / kg or less, about 0.2 mg / kg or less, about 0.1 mg / kg or less, about 0.09 mg / kg or less, about 0.08 mg / kg or less, about 0.07 mg / kg or less, about 0.06 mg / kg or less, about 0.05 mg / kg or less, about 0.04 mg / kg or less, about 0.03 mg / kg or less, about 0.02 mg / kg or less, or about 0.01 mg / kg or less. Exemplary embodiment number 40. Tezampanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is about 0.01 mg / kg or more, about 0.02 mg / kg or more, about 0.03 mg / kg or more, about 0.04 mg / kg or more, about 0.05 mg / kg or more, about 0.06 mg / kg or more, about 0.07 mg / kg or more, about 0.08 mg / kg or more, about 0.09 mg / kg or more, about 0.1 mg / kg or more, about 0.2 mg / kg or more, about 0.3 mg / kg or more, about 0.4 mg / kg or more or about 0.5 mg / kg or more, about 0.6 mg / kg or more, about 0.7 mg / kg or more, about 0.8 mg / kg or more, about 0.9 mg / kg or more, about 1.0 mg / kg or more, about 1.1 mg / kg or more, about 1.2 mg / kg or more, about 1.3 mg / kg or more, about 1.4 mg / kg or more, or about 1.5 mg / kg or more. Exemplary embodiment number 41. Tezampanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is administered at a dose of about 1.2±1.1 mg / kg, about 1.2±1.0 mg / kg, about 1.2±0.9 mg / kg, about 1.2±0.8 mg / kg, about 1.2±0.7 mg / kg, about 1.2±0.6 mg / kg, about 1.2±0.5 mg / kg, about 1.2±0.4 mg / kg, about 1.2±0.3 mg / kg, about 1.2±0.2 mg / kg, about 1.2±0.1 mg / kg, about 1.2± 0.09 mg / kg, about 1.2±0.08 mg / kg, about 1.2±0.07 mg / kg, about 1.2±0.06 mg / kg, about 1.2±0.05 mg / kg, about 1.2±0.04 mg / kg, about 1.2±0.03 mg / kg, about 1.2±0.02 mg / kg, or about 1.2±0.01 mg / kg. Exemplary embodiment number 42. Tezampanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is administered at a dose of about 0.8±0.7 mg / kg, about 0.8±0.6 mg / kg, about 0.8±0.5 mg / kg, about 0.8±0.4 mg / kg, about 0.8±0.3 mg / kg, about 0.8±0.2 mg / kg, about 0.8±0.1 mg / kg, about 0.8±0.09 mg / kg, about 0.8±0.08 mg / kg, about 0. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-42, wherein the tesanpanel is administered in a dosage of about 8±0.07 mg / kg, about 0.8±0.06 mg / kg, about 0.8±0.05 mg / kg, about 0.8±0.04 mg / kg, about 0.8±0.03 mg / kg, about 0.8±0.02 mg / kg, or about 0.8±0.01 mg / kg. Exemplary embodiment number 43. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-42, wherein the tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is administered at a dosage of about 0.4±0.3 mg / kg, about 0.4±0.2 mg / kg, about 0.4±0.1 mg / kg, about 0.4±0.09 mg / kg, about 0.4±0.08 mg / kg, about 0.4±0.07 mg / kg, about 0.4±0.06 mg / kg, about 0.4±0.05 mg / kg, about 0.4±0.04 mg / kg, about 0.4±0.03 mg / kg, about 0.4±0.02 mg / kg, or about 0.4±0.01 mg / kg. Exemplary embodiment number 44. Tezampanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is about 0.16±0.15 mg / kg, about 0.16±0.14 mg / kg, about 0.16±0.13 mg / kg, about 0.16±0.12 mg / kg, about 0.16±0.11 mg / kg, about 0.16±0.10 mg / kg, about 0.16±0.09 mg / kg, about 0.16±0.08 mg / kg, about 0.16±0.09 mg / kg, about 0.16±0.11 mg / kg, about 0.16±0.12 mg / kg, about 0.16±0.13 mg / kg, about 0.16±0.14 mg / kg, about 0.16±0.15 mg / kg, about 0.16±0.16 ... The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-43, wherein the tesanpanel is administered at a dosage of about 0.16±0.07 mg / kg, about 0.16±0.06 mg / kg, about 0.16±0.05 mg / kg, about 0.16±0.04 mg / kg, about 0.16±0.03 mg / kg, about 0.16±0.02 mg / kg, or about 0.16±0.01 mg / kg. Exemplary embodiment number 45. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-44, wherein the tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is administered in a dosage of about 110 mg or less, about 105 mg or less, about 100 mg or less, about 95 mg or less, about 90 mg or less, about 85 mg or less, about 80 mg or less, about 75 mg or less, about 70 mg or less, about 65 mg or less, about 60 mg or less, about 55 mg or less, about 50 mg or less, about 45 mg or less, about 40 mg or less, about 35 mg or less, about 30 mg or less, about 25 mg or less, about 20 mg or less, about 15 mg or less, about 10 mg or less, about 9 mg or less, about 8 mg or less, about 7 mg or less, about 6 mg or less, about 5 mg or less, about 4 mg or less, about 3 mg or less, about 2 mg or less, or about 1 mg or less. Exemplary embodiment number 46. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-45, wherein the tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is administered in a dosage of about 1 mg or more, about 2 mg or more, about 3 mg or more, about 4 mg or more, about 5 mg or more, about 6 mg or more, about 7 mg or more, about 8 mg or more, about 9 mg or more, about 10 mg or more, about 15 mg or more, about 20 mg or more, about 25 mg or more, about 30 mg or more, about 35 mg or more, about 40 mg or more, about 45 mg or more, about 50 mg or more, about 55 mg or more, about 60 mg or more, about 65 mg or more, about 70 mg or more, about 75 mg or more, about 80 mg or more, about 85 mg or more, about 90 mg or more, about 95 mg or more, or about 100 mg or more. Exemplary embodiment number 47. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1 to 46, wherein a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is administered in a parenteral dosage form. Exemplary embodiment number 48. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-47, wherein the parenteral dosage form is an intravenous, intramuscular, subcutaneous, or intradermal dosage form. Exemplary embodiment number 49. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-48, wherein the tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is administered at a dosage of about 0.8 mg / kg or less, about 0.7 mg / kg or less, about 0.6 mg / kg or less, about 0.5 mg / kg or less, about 0.4 mg / kg or less, about 0.3 mg / kg or less, about 0.2 mg / kg or less, about 0.1 mg / kg or less, about 0.09 mg / kg or less, about 0.08 mg / kg or less, about 0.07 mg / kg or less, about 0.06 mg / kg or less, about 0.05 mg / kg or less, about 0.04 mg / kg or less, about 0.03 mg / kg or less, about 0.02 mg / kg or less, or about 0.01 mg / kg or less. Exemplary embodiment number 50. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-49, wherein the tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is administered at a dosage of about 0.01 mg / kg or more, about 0.02 mg / kg or more, about 0.03 mg / kg or more, about 0.04 mg / kg or more, about 0.05 mg / kg or more, about 0.06 mg / kg or more, about 0.07 mg / kg or more, about 0.08 mg / kg or more, about 0.09 mg / kg or more, about 0.1 mg / kg or more, about 0.2 mg / kg or more, about 0.3 mg / kg or more, about 0.4 mg / kg or more, about 0.5 mg / kg or more, about 0.6 mg / kg or more, or about 0.7 mg / kg or more. Exemplary embodiment number 51. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-50, wherein administration of a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated one or more times during treatment. Exemplary embodiment number 52. The method, combination, tespanel, benzodiazepine, or use of any one of exemplary embodiments 1-51, wherein administration of a therapeutically effective amount of tespanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated once, twice, three times, four times, five times, six times, seven times, or eight times during treatment. Exemplary embodiment number 53. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-52, wherein administration of a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated once during treatment. Exemplary embodiment number 54. The method, combination, tespanel, benzodiazepine, or use of any one of exemplary embodiments 1 to 53, wherein administration of a therapeutically effective amount of tespanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated twice during treatment. Exemplary embodiment number 55. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-54, wherein administration of a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated three times during treatment. Exemplary embodiment number 56. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-55, wherein administration of a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated every hour, every two hours, every three hours, every four hours, every five hours, every six hours, every seven hours, every eight hours, every nine hours, every ten hours, every eleven hours, every 12 hours, every 13 hours, every 14 hours, every 15 hours, every 16 hours, every 17 hours, every 18 hours, every 19 hours, every 20 hours, every 21 hours, every 22 hours, every 23 hours, or every 24 hours. Exemplary embodiment number 57. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1 to 56, wherein administration of a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated every four hours. Exemplary embodiment number 58. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1 to 57, wherein administration of a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated every six hours. Exemplary embodiment number 59. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-58, wherein administration of a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated every eight hours. Exemplary embodiment number 60. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-59, wherein the benzodiazepine is clorazepate, diazepam, flurazepam, halazepam, prazepam, lorazepam, lormetazepam, oxazepam, temazepam, clonazepam, flunitrazepam, nimetazepam, nitrazepam, adinazolam, alprazolam, estazolam, triazolam, climazolam, loprazolam, or midazolam. Exemplary embodiment number 61. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-60, wherein the benzodiazepine is clorazepate, diazepam, flurazepam, halazepam, or prazepam. Exemplary embodiment number 62. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-61, wherein the benzodiazepine is lorazepam, lormetazepam, oxazepam, or temazepam. Exemplary embodiment number 63. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-62, wherein the benzodiazepine is clonazepam, flunitrazepam, nimetazepam, or nitrazepam. Exemplary embodiment number 64. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-63, wherein the benzodiazepine is adinazolam, alprazolam, estazolam, or triazolam. Exemplary embodiment number 65. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-64, wherein the benzodiazepine is climazolam, loprazolam, or midazolam. Exemplary embodiment number 66. The method, combination, teczanne, benzodiazepine, or use of any one of exemplary embodiments 1-65, wherein a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof reduces the frequency, severity, or duration of seizures. Exemplary embodiment number 67. The method, combination, teczanne, benzodiazepine, or use of any one of exemplary embodiments 1-66, wherein a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, inhibits seizures. Exemplary embodiment number 68. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-67, wherein a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, ameliorates a side effect of the benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof. Exemplary embodiment number 69. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-68, wherein the side effect is sedation. Exemplary embodiment number 70. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-69, wherein a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is administered in an oral dosage form. Exemplary embodiment number 71. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-70, wherein the oral dosage form is a tablet. Exemplary embodiment number 72. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-71, wherein a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is administered in a parenteral dosage form. Exemplary embodiment number 73. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-72, wherein the parenteral dosage form is an intravenous, intramuscular, subcutaneous, or intradermal dosage form. Exemplary embodiment number 74. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-73, wherein administration of a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated one or more times during treatment. Exemplary embodiment number 75. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-74, wherein the administration of a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated once, twice, three times, four times, five times, six times, seven times, or eight times during treatment. Exemplary embodiment number 76. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-75, wherein the administration of a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated once during treatment. Exemplary embodiment number 77. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-76, wherein administration of a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated twice during treatment. Exemplary embodiment number 78. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-77, wherein administration of a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated three times during treatment. Exemplary embodiment number 79. The method, combination, teczanel, benzodiazepine, or use of any one of exemplary embodiments 1-78, wherein administration of a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated every hour, every two hours, every three hours, every four hours, every five hours, every six hours, every seven hours, every eight hours, every nine hours, every ten hours, every eleven hours, every 12 hours, every 13 hours, every 14 hours, every 15 hours, every 16 hours, every 17 hours, every 18 hours, every 19 hours, every 20 hours, every 21 hours, every 22 hours, every 23 hours, or every 24 hours. Exemplary embodiment number 80. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-79, wherein administration of a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated every four hours. Exemplary embodiment number 81. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-80, wherein administration of a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated every six hours. Exemplary embodiment number 82. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-81, wherein administration of a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is repeated every eight hours. Exemplary embodiment number 83. The method, combination, tespanel, benzodiazepine, or use of any one of exemplary embodiments 1-82, wherein (i) a therapeutically effective amount of tespanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, and (ii) a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, are administered simultaneously. Exemplary embodiment number 84. The method, combination, tespanel, benzodiazepine, or use of any one of exemplary embodiments 1-83, wherein (i) a therapeutically effective amount of tespanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, and (ii) a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, are administered sequentially. Exemplary embodiment number 85. The method, combination, tespanel, benzodiazepine, or use of any one of exemplary embodiments 1-84, wherein (i) a therapeutically effective amount of tespanel, a pharma- ceutically acceptable salt, or a prodrug thereof, and (ii) a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt, or a prodrug thereof, are alternatively administered. Exemplary embodiment number 86. The method, combination, tespanel, benzodiazepine, or use of any one of exemplary embodiments 1 to 85, wherein (i) a therapeutically effective amount of tespanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, and (ii) a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, are administered in close temporal proximity. Exemplary embodiment number 87. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-86, wherein the therapeutically effective amount of the tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is administered within about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 18 hours, or about 24 hours after administration of the therapeutically effective amount of the benzodiazepine, a pharma- ceutically acceptable salt thereof. Exemplary embodiment number 88. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-87, wherein the therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof is administered within about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 18 hours, or about 24 hours after administration of the therapeutically effective amount of the tesanpanel, a pharma- ceutically acceptable salt thereof. Exemplary embodiment number 89. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-88, wherein (i) a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof and (ii) a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof are administered by different routes of administration. Exemplary embodiment number 90. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-89, wherein (i) a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, and (ii) a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, are administered by the same route of administration (e.g., oral administration). Exemplary embodiment number 91. The method, combination, tespanel, benzodiazepine, or use of any one of exemplary embodiments 1-90, wherein (i) a therapeutically effective amount of tespanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, and (ii) a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, are administered in separate formulations. Exemplary embodiment number 92. The method, combination, tespanel, benzodiazepine, or use of any one of exemplary embodiments 1-91, wherein (i) a therapeutically effective amount of tespanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, and (ii) a therapeutically effective amount of a benzodiazepine, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, are administered in a co-formulation. Exemplary embodiment number 93. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-92, wherein the method further comprises administering supportive care to the subject. Exemplary embodiment number 94. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-93, wherein the supportive therapy comprises an anticholinergic.The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-93, wherein the supportive therapy comprises atropine. Exemplary embodiment number 95. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-94, wherein the supportive therapy comprises an oxime capable of protecting the active site of acetylcholinesterase. Exemplary embodiment number 96. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-95, wherein supportive care comprises pralidoxime. Exemplary embodiment number 97. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-96, wherein the supportive care comprises an anticonvulsant. Exemplary embodiment number 98. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-97, wherein supportive care comprises diazepam. Exemplary embodiment number 99. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-98, wherein supportive care includes oxygen supplementation. Exemplary embodiment number 100. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-99, wherein supportive care includes heating, hydration, or a combination thereof. Exemplary embodiment number 101. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-100, wherein supportive care comprises heating. Exemplary embodiment number 102. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-101, wherein the supportive care comprises a heat source. Exemplary embodiment number 103. The method, combination, tesantanel, benzodiazepine, or use of any one of exemplary embodiments 1-102, wherein supportive care comprises a blanket. Exemplary embodiment number 104. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-103, wherein supportive care includes hydration. Exemplary embodiment number 105. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-104, wherein supportive care comprises intravenous fluids. Exemplary embodiment number 106. The method, combination, teczantelane, benzodiazepine, or use of any one of exemplary embodiments 1-105, wherein administering reduces the frequency, severity, or duration of attacks. Exemplary embodiment number 107. The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-106, wherein a therapeutically effective amount of tesanpanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof, inhibits seizures. Exemplary embodiment number 108. The method, combination, teczanel, benzodiazepine, or use of any one of exemplary embodiments 1-107, wherein the frequency, severity, and / or duration of seizures in a subject is measured by Likert scale score (LSS). Exemplary embodiment number 109. The method, combination, tezampanel, benzodiazepine, or use of any one of exemplary embodiments 1-108, wherein administration results in a reduction in the subject's LSS. Exemplary embodiment number 110. The subject is administered 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, 48 ​​hours, 49 hours, 50 hours, 51 hours, 52 hours, 53 hours, 54 hours, 55 hours, 56 hours, 57 hours, 58 hours, 59 hours, 60 hours, 61 hours, 62 hours, 63 hours, 64 hours, 65 hours, 66 hours, 67 hours, 68 hours, 69 hours, 70 hours, 71 hours, 72 hours, 73 hours, 74 hours, 75 hours, 76 hours, 77 hours, 78 hours, 79 hours, 80 hours, 81 hours, 82 hours, 83 hours, 84 hours, 85 hours, 86 hours, 87 hours, 88 hours, 89 hours, 90 hours, 91 hours, 92 hours, 93 hours, 94 hours, 95 hours, 96 hours, 97 hours, The method, combination, tesanpanel, benzodiazepine, or use of any one of exemplary embodiments 1-109, wherein the subject has an LLS of about 3 or less, about 2 or less, or about 1 or less, at about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, or about 48 hours, compared to a comparable subject who has not been administered the tesanpanel, a pharmacologic acceptable salt thereof, or a prodrug thereof. Exemplary embodiment number 111. The method, combination, tespanel, benzodiazepine, or use of any one of exemplary embodiments 1-110, wherein the subject has an LLS of about 6 or less, about 5 or less, about 4 or less, about 3 or less, about 2 or less, or about 1 or less about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, or about 48 hours after administration of the tespanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof. Exemplary embodiment number 112. The method, combination, tespanel, benzodiazepine, or use of any one of exemplary embodiments 1-111, wherein the subject has an LLS of about 5 or less, about 4 or less, about 3 or less, about 2 or less, or about 1 or less about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42 hours, or about 48 hours after administration of the tespanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof. Exemplary embodiment number 113. The method, combination, tespanel, benzodiazepine, or use of any one of exemplary embodiments 1-112, wherein the subject has an LLS of about 4 or less, about 3 or less, about 2 or less, or about 1 or less about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, or about 18 hours after administration of the tespanel, a pharma- ceutically acceptable salt thereof, or a prodrug thereof. Exemplary embodiment number 114. The method, combination, tespanel, benzodiazepine, or use of any one of exemplary embodiments 1-113, wherein the subject has an LLS of about 3 or less, about 2 or less, or about 1 or less about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours after administration of the tespanel, a pharmacologic acceptable salt thereof, or a prodrug thereof.

[0117] definition As used herein, the term "about" generally means ±10% of the stated value. In some embodiments, "about" or "approximately" generally means ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1% of the stated value.

[0118] Tezampanel could be identified using its IUPAC name, (3S,4aR,6R,8aR)-6-[2-(1H-tetrazol-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid, its CAS number 150131-78-5, and / or the following chemical structure: [ka]

[0119] In some embodiments, a prodrug of tesampanel may be administered. In some embodiments, the prodrug of tesampanel is dasolampanel. It is believed that dasolampanel can be identified using the IUPAC name (3S,4aS,6S,8aR)-6-(3-chloro-2-(1H-tetrazol-5-yl)phenoxy)decahydroisoquinoline-3-carboxylic acid, CAS number 503294-13-1, and / or the following chemical structure: [ka]

[0120] Nitrogen-containing compounds of the disclosure can be converted to N-oxides by treatment with an oxidizing agent (e.g., 3-chloroperoxybenzoic acid (mCPBA) and / or hydrogen peroxide) to provide other compounds of the disclosure. Thus, all nitrogen-containing compounds shown and claimed, when permitted by valence and structure, include both the shown compounds and their N-oxide derivatives (N→O or N + -O -(which may be designated as N-hydroxy or N-alkoxy). Additionally, in other examples, the nitrogen in the compounds of the present disclosure may be converted to N-hydroxy or N-alkoxy compounds. For example, N-hydroxy compounds may be prepared by oxidation of the parent amine with an oxidizing agent such as m-CPBA. All nitrogen-containing compounds shown and claimed are also considered to cover both the compounds shown and their N-hydroxy (i.e., N-OH) and N-alkoxy (i.e., N-OR, where R is a substituted or unsubstituted C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, 3-14 membered carbocyclic or 3-14 membered heterocyclic) derivatives, when permitted by valence and structure.

[0121] In this specification, the structural formula of a compound may represent a specific isomer for convenience in some cases, but the present disclosure includes all isomers such as optical isomers, stereoisomers, tautomers, etc. based on asymmetric carbon, and it is understood that not all isomers may have the same level of activity.In addition, crystal polymorphism may exist for the compound represented by formula.It should be noted that any crystal form, mixture of crystal forms, or its anhydride or hydrate are included in the scope of the present disclosure.

[0122] As used herein, the term "isomers" means compounds that have identical molecular formulae but differ in the sequence of bonds of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of one another are called diastereoisomers, and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is called a "racemic mixture."

[0123] As used herein, the term "chiral center" refers to a carbon atom bonded to four nonidentical substituents.

[0124] As used herein, the term "chiral isomer" refers to a compound having at least one asymmetric center. Compounds having more than one asymmetric center can exist either as individual diastereomers or as a mixture of diastereomers called a "diastereomeric mixture". When one asymmetric center is present, a stereoisomer can be characterized by the absolute configuration (R or S) of that asymmetric center. Absolute configuration refers to the arrangement in space of the substituents attached to the asymmetric center. The substituents attached to the asymmetric center under consideration are ranked according to the Cahn, Ingold and Prelog ordering rules. (Cahn et al.,Angew.Chem.Inter.Edit.1966,5,385;errata 511;Cahn et al.,Angew.Chem.1966,78,413;Cahn and Ingold,J.Chem.Soc.1951(London),612;Cahn et al.,Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0125] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another. This conversion results in a formal shift of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomeric sets in solution. In solutions where tautomerization is possible, a chemical equilibrium of tautomers is reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerization is called tautomerism. Of the various types of tautomerism possible, two are commonly observed. In keto-enol tautomerism, a simultaneous shift of electrons and hydrogen atoms occurs. Ring-chain tautomerism occurs as a result of an aldehyde group (-CHO) in a sugar molecule reacting with one of the hydroxyl groups (-OH) in the same molecule to give the cyclic (ring-shaped) form exhibited by glucose.

[0126] It should be understood that the compounds of the present disclosure may be represented as different tautomers. When a compound has tautomeric forms, it should also be understood that all tautomeric forms are intended to be included within the scope of the present disclosure, and the naming of a compound does not exclude any tautomeric form. It is understood that certain tautomers may have a higher level of activity than others.

[0127] Any formula compound described herein should be understood to include the compound itself, as well as its salts and solvates, if applicable.Salts can be formed, for example, between an anion and a positively charged group (e.g., amino) on a substituted benzene compound.Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0128] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between a cation on a substituted benzene compound and a negatively charged group (e.g., a carboxylate). Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations, such as tetramethylammonium. Substituted benzene compounds also include those salts that contain a quaternary nitrogen atom.

[0129] As used herein, the term "analog" refers to a compound that is structurally similar to another compound but differs slightly in composition (such as in the replacement of one atom with another atom in the presence of a different element or specific functional group, or the replacement of one functional group with another functional group). Thus, an analog is a compound that is similar or equivalent in function and appearance, but not similar or equivalent in structure or origin to the reference compound.

[0130] As used herein, the term "derivative" refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0131] As used herein, unless otherwise indicated, phrases such as "one or more of A, B, or C," "one or more of A, B, or C," "one or more of A, B, and C," "one or more of A, B, and C," "selected from the group consisting of A, B, and C," "selected from A, B, and C," and the like are used interchangeably and all refer to selection from the group consisting of A, B, and / or C, i.e., one or more A, one or more B, one or more C, or any combination thereof.

[0132] It should be understood that throughout the description, where a composition is described as having, including, or comprising a particular component, it is contemplated that the composition also consists essentially of, or consists of, the recited components. Similarly, where a method or process is described as having, including, or comprising particular process steps, the process also consists essentially of, or consists of, the recited processing steps. Furthermore, it should be understood that the order or sequence of steps for performing certain acts is not important so long as the invention remains operable. Moreover, two or more steps or acts can be performed simultaneously.

[0133] It should be understood that the compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or readily prepared intermediates by utilizing standard synthetic methods and techniques that are known to those of skill in the art or that will be apparent to those of skill in the art in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or standard textbooks in the field. Examples of such methods and procedures include, but are not limited to, any one or several sources, such as Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5, incorporated herein by reference. th edition,John Wiley & Sons:New York,2001;Greene,TW,Wuts,PGM,Protective Groups in Organic Synthesis,3 rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and other classic textbooks are useful and are recognized as reference textbooks on organic synthesis known to those skilled in the art.

[0134] Those skilled in the art will note that the order of certain steps, such as the introduction and removal of protecting groups, may be altered during the reaction sequences and synthetic schemes described herein. Those skilled in the art will recognize that certain groups may require protection from reaction conditions through the use of protecting groups. Protecting groups may also be used to distinguish similar functional groups in a molecule. A list of protecting groups, as well as methods for introducing and removing these groups, can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons: New York, 1999.

[0135] Unless otherwise stated, it should be understood that any description of a method of treatment includes the use of the compounds to provide treatment or prophylaxis as described herein, as well as the use of the compounds to prepare a medicament for treating or preventing such conditions. Treatment includes the treatment of humans or non-human animals, including rodents and other disease models.

[0136] As used herein, the term "subject" is interchangeable with the term "subject in need thereof," both of which refer to a subject having a disease or at risk of developing a disease. "Subject" includes a mammal. The mammal may be a human or a suitable non-human mammal, such as, for example, a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or pig. The subject may also be a bird or poultry. In one embodiment, the mammal is a human.

[0137] As used herein, the term "treat" or "treatment" describes the management and care of a patient for the purpose of combating a disease, condition, or disorder, and includes the administration of a compound of the present disclosure, or a pharma- ceutically acceptable salt, polymorph, or solvate thereof, to alleviate the symptoms or complications of the disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The term "treat" can also include the treatment of a cell in vitro or in an animal model.

[0138] As used herein, the term "temporal proximity" refers to administration of one therapeutic agent occurring within a period of time before or after administration of another therapeutic agent such that the therapeutic effects of one therapeutic agent overlap with the therapeutic effects of the other therapeutic agent. In some embodiments, the therapeutic effects of one therapeutic agent completely overlap with the therapeutic effects of the other therapeutic agent. In some embodiments, "temporal proximity" means administration of one therapeutic agent occurring within a period of time before or after administration of another therapeutic agent such that there is a synergistic effect between the one therapeutic agent and the other therapeutic agent. "Temporal proximity" may vary according to a variety of factors, including, but not limited to, the age, sex, weight, genetic background, medical condition, disease history, and treatment history of the subject to whom the therapeutic agent is to be administered, the disease or condition to be treated or ameliorated, the therapeutic result to be achieved, the dosage, frequency, and duration of administration of the therapeutic agent, the pharmacokinetics and pharmacodynamics of the therapeutic agent, and the route(s) by which the therapeutic agent is administered. In some embodiments, "proximal in time" means within about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 18 hours, or about 24 hours. In some embodiments, multiple administrations of one therapeutic agent may occur in temporal proximity to a single administration of another therapeutic agent. In some embodiments, the temporal proximity may vary during a treatment cycle or within a dosing regimen.

[0139] As used herein, the term "prodrug" refers to any agent that is converted, in whole or in part, to a target compound when administered to a mammal. In some embodiments, a prodrug of a compound is also a pharma- ceutically acceptable salt of the compound.

[0140] It is to be understood that the compounds of the present disclosure, or pharma- ceutically acceptable salts, can be used to prevent the relevant disease, condition or disorder, or can be used to identify suitable candidates for such purposes.

[0141] As used herein, the terms "preventing," "prevent" or "protect" describe reducing or eliminating the onset of symptoms or complications of such a disease, condition or disorder.

[0142] It should be understood that those skilled in the art can refer to general reference texts for detailed descriptions of known techniques or equivalent techniques discussed herein. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3 rd edition),Cold Spring Harbor Press,Cold Spring Harbor,New York(2000);Coligan et al.,Current Protocols in Immunology,John Wiley & Sons,NY;Enna et al.,Current Protocols in Pharmacology,John Wiley & Sons,NY;Fingl et al.,The Pharmacological Basis of Therapeutics(1975),Remington's Pharmaceutical Sciences,Mack Publishing Co.,Easton,PA,18 th edition (1990), Mandell, et al., Principles and Practice of Infectious Diseases, Saunders Publishing (8th edition, 2014). These texts may, of course, be referenced in the making or use of the embodiments of the present disclosure.

[0143] It should be understood that the present disclosure also provides pharmaceutical compositions comprising any of the compounds described herein in combination with at least one pharma- ceutically acceptable excipient or carrier.

[0144] As used herein, the term "pharmaceutical composition" refers to a formulation containing the disclosed compound in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form is any of a variety of forms, including, for example, capsules, IV bags, tablets, single pumps on aerosol inhalers, or vials. The amount of active ingredient (e.g., formulations of the disclosed compounds or salts, hydrates, solvates, or isomers thereof) in a unit dose of the composition is an effective amount and varies according to the specific treatment involved. Those skilled in the art will understand that it may be necessary to make routine variations in dosage depending on the age and condition of the patient. Dosage also depends on the route of administration. Various routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal administration of the compounds of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharma- ceutically acceptable carrier, and any preservatives, buffers, or propellants that are required.

[0145] As used herein, the term "pharmacologically acceptable" refers to compounds, anions, cations, substances, compositions, carriers, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio.

[0146] As used herein, the term "pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and not biologically undesirable and useful in the preparation of pharmaceutical compositions, including excipients that are acceptable for veterinary use as well as human pharmaceutical use. As used in the specification and claims, "a pharmaceutically acceptable excipient" includes both one such excipient and more than one such excipient.

[0147] It should be understood that the pharmaceutical composition of the present disclosure is formulated to suit its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application may contain the following components: sterile diluents such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium sulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates, and osmolality adjusters such as sodium chloride or dextrose. The pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral preparations can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic.

[0148] As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical preparation to treat, ameliorate, or prevent a specified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The exact effective amount for a subject will depend on the subject's weight, size, and health, the nature and extent of the condition, and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0149] Dosage and administration are adjusted to provide sufficient levels of active agent(s) or to maintain the desired effect.Factors that may be considered include the severity of the disease state, the subject's general health, the subject's age, weight, and sex, diet, time and frequency of administration, drug combination(s), reaction sensitivity, and tolerance / response to therapy.Long-acting pharmaceutical compositions may be administered every 3-4 days, every week, or once every two weeks, depending on the half-life and clearance rate of the particular formulation.

[0150] The pharmaceutical composition containing the active compound of the present disclosure can be prepared by a generally known method, for example, conventional mixing, dissolving, granulating, dragee making, elevating, emulsifying, encapsulating, supplementing or lyophilization process.The pharmaceutical composition can be formulated in a conventional manner using one or more pharmacologic acceptable carriers, including excipients and / or auxiliary agents that facilitate the processing of the active compound into pharmacologic preparations that can be used.Of course, the appropriate formulation depends on the selected route of administration.

[0151] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid as long as easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferable to include isotonic agents in the composition, such as sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride. Prolonged absorption of the injectable composition can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin, in the composition.

[0152] Sterile injection solution can be prepared by incorporating active compound in the required amount in a suitable solvent with one or a combination of the above-listed components as required, followed by filtration sterilization.Generally, dispersion is prepared by incorporating active compound into a sterile vehicle that contains a basic dispersion medium and other components required from the above-listed components.In the case of sterile powder for preparing sterile injection solution, the preparation method is vacuum drying and freeze-drying, which produces powder of active ingredient and any additional desired ingredients from the solution that has been previously sterilized and filtered.

[0153] Oral compositions generally contain an inert diluent or an edible pharma- ceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with an excipient and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, where the compound in the fluid carrier is applied orally, swirled, expectorated, or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like may contain any of the following ingredients: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, orange flavoring, or compounds of a similar nature.

[0154] The active compound can be prepared with a pharma- ceutically acceptable carrier that protects the compound from rapid elimination from the body, such as controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable biocompatible polymers, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid, can be used. Methods for preparing such formulations will be clear to those skilled in the art. Materials can be commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions, including liposomes that target infected cells and have monoclonal antibodies against viral antigens, can also be used as pharma-ceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0155] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate oral or parenteral compositions in dosage units.As used herein, dosage unit form refers to a physically separate unit suitable as a unitary dosage for the subject to be treated, and each unit contains a predetermined amount of active compound calculated to produce desired therapeutic effect in association with required pharmaceutical carrier.The specification of dosage unit form of the present disclosure is determined and directly depends on the unique characteristics of active compound and the specific therapeutic effect to be achieved.

[0156] In therapeutic applications, dosages of pharmaceutical compositions used in accordance with the present disclosure will vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or physician administering the therapy, among other factors that influence the dosage selected. In general, the dosage should be sufficient to slow, and preferably cause regression of, the symptoms of the disease, and preferably cause complete regression of the disease. Dosages may range from about 0.01 mg / kg per day to about 5000 mg / kg per day. An effective amount of a pharmaceutical formulation is one that produces an objectively identifiable improvement as described by a clinician or other qualified observer. Improved survival and growth indicate regression. As used herein, the term "effective mode of administration" refers to an amount of active compound to produce a desired biological effect in a subject or cell.

[0157] It should be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0158] For compounds of the present disclosure that are capable of further forming salts, it is to be understood that all of these forms are also contemplated within the scope of the present disclosure as claimed.

[0159] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of a compound of the present disclosure, in which the parent compound is modified by making an acid or base salt thereof. In some embodiments, the pharmaceutically acceptable salt of a compound is also a prodrug of the compound. Examples of pharmaceutically acceptable salts include, but are not limited to, rock salts or organic acid salts of basic residues such as amines, alkali salts or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example, formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolylarsanilic acid, hexylresorcylic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, These include, but are not limited to, those derived from inorganic and organic acids selected from laurylsulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, acetic, succinic, sulfamic, sulfanyl, sulfuric, tannic, tartaric, toluenesulfonic, and commonly occurring amino acids, such as glycine, alanine, phenylalanine, arginine, and the like.

[0160] Other examples of pharma- ceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, etc. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or is coordinated with an organic base, such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. It is understood that in the salt form, the ratio of compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, for example, 3:1, 2:1, 1:2, or 1:3.

[0161] It should be understood that the compounds of the present disclosure can also be prepared as esters, for example, pharma-ceutically acceptable esters. For example, a carboxylic acid function in a compound can be converted to its corresponding ester, for example, methyl, ethyl or other ester. Also, an alcohol group in a compound can be converted to its corresponding ester, for example, acetate, propionate or other ester.

[0162] Compound or its pharmaceutically acceptable salt is administered orally, intranasally, transdermally, pulmonary, inhalation, buccal, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, intrathecally and parenterally.In one embodiment, compound is administered orally.Those skilled in the art will recognize the advantages of certain administration routes.

[0163] Dosage regimens utilizing the compounds are selected according to a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient, the severity of the condition to be treated, the route of administration, the renal and hepatic function of the patient, and the particular compound or salt thereof employed. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

[0164] Techniques for formulation and administration of the disclosed compounds of this disclosure are described in Remington: The Science and Practice of Pharmacy, 1999. th edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein, and their pharma- ceutically acceptable salts, are used in pharmaceutical preparations in combination with a pharma- ceutically acceptable carrier or diluent. Suitable pharma- ceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds are present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

[0165] All percentages and ratios used herein are by weight unless otherwise indicated.Other features and advantages of the present disclosure are apparent from different examples.The examples provided show different components and methodologies useful for implementing the present disclosure.The examples do not limit the disclosure claimed.Based on the present disclosure, those skilled in the art can identify and utilize other components and methodologies useful for implementing the present disclosure.

[0166] Once the compounds designed, selected and / or optimized by the above methods are produced, they can be characterized using various assays known to those skilled in the art to determine whether the compounds have biological activity.For example, the molecules can be characterized by conventional assays, including but not limited to the assays described below, to determine whether they have the expected activity, binding activity and / or binding specificity.

[0167] Furthermore, high-throughput screening can be used to speed up the analysis using such assays.As a result, it may be possible to rapidly screen the molecules described herein for activity using techniques known in the art.The general methodology for performing high-throughput screening is described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and US Patent No. 5,763,263.High-throughput assays can use one or more different assay techniques, including but not limited to those described below.

[0168] All publications and patent documents cited herein are incorporated by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is relevant prior art, nor does it constitute any admission as to its contents or date. Although the invention has been described by the description set forth herein, those skilled in the art will recognize that the invention can be practiced in various embodiments, and that the foregoing description and the following examples are for illustrative purposes only and are not intended to limit the scope of the following claims. EXAMPLES

[0169] Example 1. Effect of tezampanel on the development of nerve agent-induced seizures in rodents. EEG Implant Surgery: The rat is draped with sterile drapes and fenestrated to expose the dorsal cranial surgical field. An incision is made in the mid-midline near the occipital bone, extending rostrally toward the interorbital region, and the underlying tissue is peeled away to expose the dorsal cranial suture junctions (i.e., lambda and bregma). Five holes are drilled into the skull, grooved to avoid penetrating the dura. Stainless steel screws are placed in the following locations: slightly posterior to bregma in each hemisphere, rostral to lambda in each hemisphere, and a reference screw placed above the forehead. The screws are attached to insulated stainless steel electrode wires. The screws and attached pedestals are cemented in place with dental cement (e.g., Dentron Plus®), osteosynthesis (e.g., Zimmer Palacos R+G®), or another similar material. The skin is closed with absorbable monofilament sutures (e.g., 4-0 Monocryl).

[0170] Administration of Sarin, Atropine, Pralidoxime and Midazolam: After 1 week of recovery from EEG implant surgery, animals receive a subcutaneous dose of 1x LD50 (160 µg / kg) Sarin, followed 1 min (± 0.25 min) later by atropine methyl nitrate (2.53 mg / kg, IM; this dose corresponds to 2 mg / kg of atropine base) and pralidoxime (25 mg / kg, IM). Seizure activity typically begins 10-15 min after sarin administration. All animals receive a single injection of midazolam (0.66 mg / kg, IM) 50 min after sarin administration.

[0171] Treatment group assignment: 60 minutes after sarin exposure, animals were randomized to receive either saline (control group) by IM route or a dose of Tezampel (2.5, 5, 7.5 or 15 mg / kg) by IM route. In one cohort, administration of Tezampel was delayed 6 hours after sarin to determine whether Tezampel remained effective when given in a very delayed manner.

[0172] EEG monitoring: In all animals, EEG was monitored by a computerized data acquisition system to capture the initiation and subsequent attempts to arrest nerve agent-induced seizures. EEG data were analyzed using a 7-point Likert scale and condensed into hourly averages over a 24-hour period (see Figure 1).

[0173] Equivalent It should be understood that the present invention may be embodied in other specific forms without departing from its spirit or essential characteristics.The foregoing embodiments are therefore to be considered in all respects as illustrative rather than limiting the invention described herein.The scope of the present invention is therefore indicated by the appended claims rather than the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. A composition for treating a disease in a subject in need thereof, comprising: (i) tezampanel, a pharmaceutically acceptable salt thereof, or a prodrug thereof; and (ii) a benzodiazepine, a pharmaceutically acceptable salt thereof, or a prodrug thereof.

2. A composition for treating a disease resistant to treatment with a benzodiazepine in a subject in need thereof, comprising tezampanel, a pharmaceutically acceptable salt thereof, or a prodrug thereof.

3. A composition for treating a disease resistant to treatment with tezampanel in a subject in need thereof, comprising a benzodiazepine, a pharmaceutically acceptable salt thereof, or a prodrug thereof.

4. A combination for treating a disease in a subject in need thereof, comprising: (i) a therapeutically effective amount of tezampanel, a pharmaceutically acceptable salt thereof, or a prodrug thereof; and (ii) a therapeutically effective amount of a benzodiazepine, a pharmaceutically acceptable salt thereof, or a prodrug thereof.

5. Use of a combination in the manufacture of a medicament for treating a disease in a subject in need thereof, wherein the combination comprises: (i) a therapeutically effective amount of tezampanel, a pharmaceutically acceptable salt thereof, or a prodrug thereof; and (ii) a therapeutically effective amount of a benzodiazepine, a pharmaceutically acceptable salt thereof, or a prodrug thereof.

6. Use of tezampanel, a pharmaceutically acceptable salt thereof, or a prodrug thereof in the manufacture of a medicament for treating a disease resistant to treatment with a benzodiazepine in a subject in need thereof.

7. Use of a benzodiazepine, a pharmaceutically acceptable salt thereof, or a prodrug thereof in the manufacture of a medicament for treating a disease resistant to treatment with tezampanel in a subject in need thereof.

8. The composition according to any one of claims 1 to 3, the combination according to claim 4, or the use according to any one of claims 5 to 7, wherein the subject is a human.

9. The composition according to any one of claims 1 to 3, the combination according to claim 4, or the use according to any one of claims 5 to 7, wherein the disease is an epilepsy.

10. The composition, combination, or use according to claim 9, wherein the epilepsy is drug-induced epilepsy.

11. The composition, combination, or use according to claim 10, wherein the inducer is a nerve agent.

12. The composition, combination, or use according to claim 9, wherein the seizure is resistant to treatment without using the tizanidine panel, its pharmaceutically acceptable salt, or its prodrug.

13. The composition, combination, or use according to claim 9, wherein the seizure is resistant to treatment using the benzodiazepine, its pharmaceutically acceptable salt, or its prodrug and without using the tizanidine panel, its pharmaceutically acceptable salt, or its prodrug.

14. The composition, combination, or use according to claim 9, wherein the tizanidine panel, its pharmaceutically acceptable salt, or its prodrug is characterized by reducing the frequency, severity, or duration of the seizure.

15. The composition, combination, or use according to claim 9, wherein the tizanidine panel, its pharmaceutically acceptable salt, or its prodrug is characterized by suppressing the seizure.

16. The composition according to any one of claims 1 to 3, the combination according to claim 4, or the use according to any one of claims 5 to 7, wherein the tizanidine panel, its pharmaceutically acceptable salt, or its prodrug is characterized by alleviating the side effects of the tizanidine panel, its pharmaceutically acceptable salt, or its prodrug.

17. The composition according to any one of claims 1 to 3, the combination according to claim 4, or the use according to any one of claims 5 to 7, wherein the benzodiazepine is chlorazepate, diazepam, flurazepam, halazepam, prazepam, lorazepam, lormetazepam, oxazepam, temazepam, clonazepam, flunitrazepam, nimetazepam, nitrazepam, adinazolam, alprazolam, estazolam, triazolam, climazolam, loprazolam, or midazolam.

18. The composition, combination, or use according to claim 9, wherein the benzodiazepine, its pharmaceutically acceptable salt, or its prodrug is characterized by reducing the frequency, severity, or duration of the seizure.

19. The composition, combination, or use according to claim 9, wherein the benzodiazepine, its pharmaceutically acceptable salt, or its prodrug suppresses the seizure.

20. The composition according to any one of claims 1 to 3, the combination according to claim 4, or the use according to any one of claims 5 to 7, wherein the benzodiazepine, its pharmaceutically acceptable salt, or its prodrug alleviates the side effects of the benzodiazepine, its pharmaceutically acceptable salt, or its prodrug.

21. The composition, combination, or use according to claim 20, wherein the side effect is a sedative effect.

22. The composition according to any one of claims 1 to 3, the combination according to claim 4, or the use according to any one of claims 5 to 7, wherein the composition, combination, or medicament is administered in combination with supportive therapy to the subject.

23. The composition, combination, or use according to claim 9, wherein the administration of the composition, combination, or medicament reduces the frequency, severity, or duration of the seizure.

24. The composition, combination, or use according to claim 23, wherein the frequency, severity, and / or duration of the seizure in the subject are measured by the Likert Scale Score (LSS).

25. The composition according to any one of claims 1 to 3, the combination according to claim 4, or the use according to any one of claims 5 to 7, wherein the administration of the composition, combination, or medicament results in a reduction in the LSS of the subject.

Images