Methods of treating epilepsy or status epilepticus

Abstract

Described herein are methods of treating epilepsy or status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus, e.g., super-refractory generalized status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; periodic lateralized epileptiform discharges; a seizure, e.g., acute repetitive seizures, cluster seizures, the method comprising administering to the subject a neuroactive steroid.

1 . A method of treating a subject having a seizure-related disorder, the method comprising:
 administering to said subject, an effective amount of allopregnanolone,   wherein, concurrent with said administering, said subject is under general anesthesia, thereby treating said subject.   
     
     
         2 . A method of treating a subject having a seizure-related disorder, the method comprising:
 administering a first load dose of allopregnanolone;   administering a second dose of allopregnanolone, which is lower than said first dose; and   administering a third downward taper dose of allopregnanolone, said allopregnanolone doses being sufficient to treat said subject.   
     
     
         3 . The method of  claim 2 , wherein said subject is not under general anesthesia for one or both of: at least a portion of the second dose and at least a portion of the third dose. 
     
     
         4 . The method of  claim 2 , wherein said subject is under general anesthesia during the administration of the first dose and during administration of a portion of the second dose. 
     
     
         5 . The method of  claim 2 , wherein the second dose is administered over a period of time that is at least 60, 65, 70, 80, 90, 100, 110, or 120 times longer in duration than that of said first dose. 
     
     
         6 . The method of  claim 2 , wherein the second dose is administered over a period of time that not more than 80, 90, 100, 110, 120, 130, or 140 times longer in duration than that of said first dose. 
     
     
         7 . The method of  claim 2 , wherein the second dose is administered over a period of time that is at least 2, 3, 4, 5, 6 times longer in duration than that of said third dose. 
     
     
         8 . The method of  claim 2 , wherein the second dose is administered over a period of time that is not more than 5, 6, 7, 8, 9, or 10 times longer in duration than that of said third dose. 
     
     
         9 . The method of  claim 2 , wherein the amount of allopregnanolone delivered/unit time in the second dose, as measured in μg/kg/hour, is at least 2, 3, 4, 5, or 6 times lower than that of the first dose. 
     
     
         10 . The method of  claim 2 , wherein one, two or all of said doses are injected administrations. 
     
     
         11 - 14 . (canceled) 
     
     
         15 . The method of  claim 2 , further comprising a weaning period in which said subject is weaned from said general anesthesia. 
     
     
         16 . The method of  claim 15 , wherein said weaning period is initiated during the administration of said second dose. 
     
     
         17 . The method of  claim 15 , wherein said weaning period is completed during the administration of said second dose. 
     
     
         18 - 52 . (canceled) 
     
     
         53 . The method of  claim 2 , said first dose is administered over a period of time that is not longer than 6, 5, 4, 3, 2, or 1 hour. 
     
     
         54 . (canceled) 
     
     
         55 . The method of  claim 2 , said first dose is administered over a period of time that is 30 to 120 minutes, 45 to 100 minutes, or 50 to 70 minutes, in duration. 
     
     
         56 - 59 . (canceled) 
     
     
         60 . The method of  claim 2 , wherein the administration said second dose is initiated within a preselected time period, wherein said time period begins with: the administration of said anesthetic; the induction of general anesthesia; the beginning of the first dose; the end of the first dose; or the achievement of a predetermined level of allopregnanolone in the plasma. 
     
     
         61 . The method of  claim 60 , wherein said time period begins with the end of the first dose. 
     
     
         62 - 64 . (canceled) 
     
     
         65 . The method of  claim 2 , wherein the second dose begins 50 to 70, 55 to 65, or 60 minutes after the beginning or end of the administration of the first dose. 
     
     
         66 - 67 . (canceled) 
     
     
         68 . The method of  claim 2 , wherein the first dose and the initiation of the second dose are performed with the same delivery device. 
     
     
         69 . The method of  claim 2 , wherein said second dose is administered for a period of time that is between 48 and 192 hours, 60 and 144 hours, 60 and 120 hours, 80 and 110 hours, or 90 and 100 hours. 
     
     
         70 . The method of  claim 2 , wherein said second dose is administered for 95+/−5 hours. 
     
     
         71 - 87 . (canceled) 
     
     
         88 . The method of  claim 2 , wherein said second dose is administered at the same amount of allopregnanolone/unit time over the entire second dose. 
     
     
         89 - 91 . (canceled) 
     
     
         92 . The method of  claim 2 , wherein said downward taper dose comprises administering a continuously decreasing amount of allopregnanolone. 
     
     
         93 . (canceled) 
     
     
         94 . The method of  claim 2 , wherein said downward taper dose comprises administering a plurality of step doses, wherein each subsequent step dose is lower than the step dose that precedes it. 
     
     
         95 . (canceled) 
     
     
         96 . The method of  claim 94 , comprising administering a first, second, and third step dose. 
     
     
         97 . (canceled) 
     
     
         98 . The method of  claim 96 , wherein:
 the amount of allopregnanolone delivered/unit time in said first step dose is 60 to 90% of the amount of allopregnanolone delivered/unit time in said second/maintenance dose;   the amount of allopregnanolone delivered/unit time in said second step dose is 40 to 70% of the amount of allopregnanolone delivered/unit time in said second/maintenance dose; and   the amount of allopregnanolone delivered/unit time in said third step dose is 10 to 40% of the amount of allopregnanolone delivered/unit time in said second/maintenance dose.   
     
     
         99 - 102 . (canceled) 
     
     
         103 . The method of  claim 96 , wherein, after the completion of said third step dose, no allopregnanolone is administered to the subject for at least 10, 20, 30, 40, 50, or 60 days, or until the patient has a subsequent episode of SRSE. 
     
     
         104 - 109 . (canceled) 
     
     
         110 . The method of  claim 96 , wherein the administration of the third/taper dose begins no longer than 90, 80, 70, 60, or 30 minutes after the administration or end of the second dose. 
     
     
         111 . (canceled) 
     
     
         112 . The method of  claim 96 , wherein the administration of the second dose and the initiation of third/taper dose are performed with the same delivery device. 
     
     
         113 - 116 . (canceled) 
     
     
         117 . The method of  claim 2 , wherein the allopregnanolone is provided in a composition comprising a cyclodextrin. 
     
     
         118 . The method of  claim 2 , wherein the allopregnanolone is provided at a concentration of 0.1 to 10 mg/mL allopregnanolone. 
     
     
         119 - 123 . (canceled) 
     
     
         124 . The method of  claim 117 , wherein the cyclodextrin is present in the composition at 1-30% by weight of cyclodextrin per volume of composition. 
     
     
         125 - 133 . (canceled) 
     
     
         134 . The method of  claim 1 , further comprising evaluating the subject, wherein the evaluating comprises performing EEG. 
     
     
         135 - 139 . (canceled) 
     
     
         140 . A method of treating a subject having, status epilepticus (SE), refractory status epilepticus (RSE) or super-refractory status epilepticus (SRSE), comprising:
 administering a first bolus, dose concurrent with general anesthesia, wherein administration of said first dose: begins 2-120 hours after induction of general anesthesia and lasts for 30-90 minutes;   administering a second/maintenance dose, wherein, the administration of said second dose begins not longer than 1-60 minutes after the end of the second dose and lasts for 1-6 days; and   administering a third downward taper dose, wherein, the administration of said third downward taper dose begins not longer than 1-60 minutes after the end of the third dose and lasts for 10-100 hours;   wherein, collectively, the administrations are provided in sufficient amount to treat said subject.   
     
     
         141 - 143 . (canceled) 
     
     
         144 . The method of claim  143 , comprising:
 administering a first/load dose concurrent with general anesthesia, wherein administration of said first dose lasts for 60+/−5 minutes;   administering a second/maintenance dose, wherein, the administration of said second dose begins not longer than 30 minutes after the end of the second dose and lasts for 96+/−4 hours;
 administering a third downward taper dose, wherein, the administration of said third downward taper dose begins not longer than 1-60 minutes after the end of the third dose and lasts for 24+/−2 hours and: 
 the amount of allopregnanolone delivered/unit time in said first step dose is 75% of the amount of allopregnanolone delivered/unit time in said second/maintenance dose; 
 the amount of allopregnanolone delivered/unit time in said second step dose is 50% of the amount of allopregnanolone delivered/unit time in said second/maintenance dose; and 
 the amount of allopregnanolone delivered/unit time in said third step dose is 25% of the amount of allopregnanolone delivered/unit time in said second/maintenance dose. 
   
     
     
         145 . The method of  claim 140 , further comprising,
 administering an amount of a composition selected from benzodiazepines, propofol, and barbiturates, sufficient to place said subject under general anesthesia;   
     
     
         146 . A kit comprising one or more of: a preparation of allopregnanolone at concentrations suitable for use at the first, second, and third doses. 
     
     
         147 - 154 . (canceled) 
     
     
         155 . A method of making a series of dosages, the method comprising combining a diluent and allopregnanolone in proportions to from dosage forms suitable for use as the first, second and one or more step doses for said third dose. 
     
     
         156 . A method of adjusting the amount of diluents and or allopregnanolone flowing into or out of a delivery device, the method comprising altering, the flow rate of allopregnanolone flowing into the delivery device, so as to release in succession, two or more of a first dose, a second dose and one or more step doses of the third dose. 
     
     
         157 . The method of  claim 2 , wherein the administration of said first dose is initiated while said subject is under general anesthesia. 
     
     
         158 . The method of  claim 2 , wherein the administration of said first dose is initiated prior to said subject undergoing general anesthesia. 
     
     
         159 . The method of  claim 2 , wherein the administration of the first dose is initiated prior to the initiation of the administration of an anesthetic. 
     
     
         160 . The method of  claim 2 , wherein the administration of the first dose is initiated after the initiation of the administration of an anesthetic. 
     
     
         161 . The method of  claim 2 , wherein the administration of the first dose, and the administration of an anesthetic, are initiated at the same time. 
     
     
         162 . The method of  claim 2 , wherein the administration of the first dose, and the administration of an anesthetic, are initiated within, 5, 10, 60, 120, 180, 240, or 300 minutes of one another. 
     
     
         163 . The method of  claim 162 , wherein the administration of the first dose is initiated prior to the initiation of administration of an anesthetic. 
     
     
         164 . The method of  claim 162 , wherein the administration of the first dose is initiated after the initiation of administration of an anesthetic. 
     
     
         165 . The method of  claim 1 , wherein said disorder is status epilepticus (SE), refractory status epilepticus (RSE) or super-refractory status epilepticus (SRSE). 
     
     
         166 . The method of  claim 2 , wherein said disorder is status epilepticus (SE), refractory status epilepticus (RSE) or super-refractory status epilepticus (SRSE). 
     
     
         167 . The method of  claim 117 , wherein said cyclodextrin is a β-cyclodextrin. 
     
     
         168 . The method of  claim 117 , wherein said cyclodextrin is a sulfo butyl ether β-cyclodextrin. 
     
     
         169 . The method of  claim 117 , wherein said cyclodextrin is CAPTISOL.