Seizure control compositions and methods of use

Abstract

The anti-seizure composition comprises a therapeutically effective combination of a halogenated ether, a benzodiazepine, and a barbiturate. The halogenated ether can be selected from one or more of isoflurane, desflurane, and sevoflurane. The benzodiazepine can be diazepam, and the barbiturate can be phenobarbital. Also, a method for treating a seizure event can include administering a therapeutically effective amount of the combination.

Description

[Technical field]

[0001]

[0001] The present invention relates to seizure control compositions and methods, more particularly to compositions and methods for the treatment of status epilepticus, and even more particularly to compositions and methods for the treatment of status epilepticus involving triple drug combinations. [Background technology]

[0002]

[0002] Terrorism and other international conflicts have made the use of chemical weapons against civilians and / or military personnel a concern that requires appropriate preparation. Nerve agents used in chemical warfare often result in organophosphate poisoning. Exposure to nerve agents such as G-series agents (i.e., tabun (GA), sarin (GB), cyclosarin (GF), soman (GD)) and V-series agents (i.e., VX gas) induces a cholinergic crisis. Specifically, inhibition of acetylcholinesterase (AChE), the main metabolic enzyme for the cholinergic neurotransmitter acetylcholine. The resulting accumulation of acetylcholine leads to excessive release of the excitatory neurotransmitter glutamate from nerve cells. This abundance of glutamate causes hyperexcitability in the brain. One outcome of this hyperexcitability can be status epilepticus (SE). SE is a neurological emergency defined as either continuous seizure activity for more than 30 minutes or recurrent seizure activity without return to baseline between events. SE is independently associated with high mortality and morbidity. SE must be treated immediately and effectively to prevent adverse outcomes, including cognitive impairment, subsequent epilepsy, and even death. Release of a chemical nerve agent in a nonmilitary and / or military setting would result in nearby treatment facilities being overwhelmed with a significant number of casualties exhibiting clinical signs of SE. While the above discussion is directed to exposure to chemical agents during wartime, it should be noted that SE can occur without any known cause.

[0003]

[0003] Exposure by any route is considered highly neurotoxic. When the drug is inhaled, the estimated LC t 50 is 10 mg min / m for VX in any exposed population 3 to 40 mg min / m for GA 3 If the agent comes into direct contact with an individual's skin, a single drop (40-50 μl) of VX can be fatal, whereas 1-10 mL of GA, GB, or GD can be fatal. The onset and severity of symptoms depend on the concentration of the agent and the route of exposure.

[0004]

[0004] Current treatments in the art include the military Mark I NAAK kit (nerve agent antidote kit), which contains an auto-injector with atropine and pralidoxime chloride (2-PAM). Atropine can treat seizures, but only in a very narrow time window, i.e., within 5 minutes of exposure, which is primarily important for preventing the systemic effects of nerve agents (i.e., muscle contractions, excessive production of mucus, tears, saliva, and sweat). 2-PAM, an oxime agent for dissociating nerve agents from cholinesterase molecules, has no therapeutic effect against SE. Thus, the Mark I NAAK kit is ineffective in preventing and treating status epilepticus.

[0005]

[0005] A separate auto-injector of the benzodiazepine diazepam (DZP) is also available, but studies of SE have shown that benzodiazepines alone are ineffective in up to 40% of cases, which are medically considered to have refractory status epilepticus (RSE).

[0006]

[0006] In RSE cases, the logistics of acute care are significantly complicated. At present, there is no way to present and differentiate which cases will respond to benzodiazepine treatment from those that will become refractory. Triage can only be performed after DZP has been given and sufficient time has been allowed to differentiate between the two populations. Current treatment protocols also require placing RSE victims in a barbiturate / anesthetic coma for several hours / days to reduce seizure activity. Due to the large amount of nerve gas exposure, this would quickly saturate the intensive care unit resources available to maintain such cases. Furthermore, although nerve gas induced SE may result in higher rates, mortality remains at 23% despite such RSE treatment. In addition, survivors are more likely to have cognitive decline (85% of RSE vs. 61% of responsive SE) and post-SE epilepsy (87.5% vs. 22%).

[0007]

[0007] What is needed, therefore, is a more effective form of first-line SE treatment that will abort responsive and refractory SE cases indiscriminately, and that also has a favorable safety profile that minimizes side effects, improves overall mortality, and minimizes post-SE neurological deficits and new cases of epilepsy. Summary of the Invention

[0008] Briefly, the anti-seizure composition includes a therapeutically effective combination of a halogenated ether, a benzodiazepine, and a barbiturate. The halogenated ether may be selected from one or more of isoflurane, desflurane, and sevoflurane. The benzodiazepine may be diazepam and the barbiturate may be phenobarbital. In accordance with one aspect of the invention, the halogenated ether may have a concentration of between about 0.1% and about 5%.

[0009] In a further aspect of the invention, a method for treating a seizure event may include administering a therapeutically effective amount of a combination of a halogenated ether, a benzodiazepine, and a barbiturate. The halogenated ether may be selected from one or more of isoflurane, desflurane, and sevoflurane. The benzodiazepine may be diazepam and the barbiturate may be phenobarbital. The halogenated ether has a concentration of between about 1% and about 5% and may be administered via one or more of inhalation, subcutaneous injection, oral ingestion, intravenous injection, intramuscular injection, intraperitoneal injection, and transdermal absorption.

[0010]

[0010] The above and other features, advantages of the present invention, and the manner in which they are accomplished will become apparent and better understood by reference to the following description of the invention taken in conjunction with the accompanying drawings, in which: [Brief description of the drawings]

[0011] [Figure 1]

[0011] EEG tracings of two rats after induction of status epilepticus (SE) are shown. [Diagram 2]

[0012] 1 shows EEG tracings of the same rats as shown in FIG. 1, with rat 1 being administered a three-component drug regimen according to the present invention. [Diagram 3]

[0013] Shown are EEG tracings from the same rats shown in Figures 1 and 2, where both rats were administered the three-component drug regimen. [Figure 4]

[0014] Shown are EEG tracings from the same rats as shown in Figures 1-3, 2 days after induction of SE and administration of the three component drugs. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012]

[0015] As mentioned above, typical treatment for SE involves administration of a combination of two standard antiepileptic drugs (AEDs), diazepam (DZP) and phenobarbital (PB). Alternatively, as in clinical practice, DZP may be administered first to interrupt seizure activity. PB may be added if DZP alone is ineffective. In either event, this combination controls the immediate onset of SE in only about 60% of cases. The remaining approximately 40% of cases are referred to as refractory SE (RSE). In these instances, patients are at increased risk for cognitive decline, recurrent unprovoked seizures (i.e. epilepsy), and death.

[0013]

[0016] According to one embodiment of the present invention, the treatment of status epilepticus (SE) includes a therapeutically effective combination of a halogenated ether, a benzodiazepine such as DZP, and a barbiturate such as PB. The halogenated ether is selected from one or more of isoflurane, desflurane, and sevoflurane, and according to one embodiment, isoflurane. The halogenated ether can be administered via any suitable delivery method, including, but not limited to, inhalation, subcutaneous injection, oral ingestion, intravenous injection, intramuscular injection, intraperitoneal injection, and transdermal absorption. The concentration of the halogenated ether can range from about 0.1% to about 5%, more specifically from about 1.5% to about 3.5%, and even more specifically from about 2% to about 3%. When the ether is inhaled, the remainder of the inhaled gas is usually oxygen.

[0014]

[0017] As described in the Examples below, treatment of status epilepticus involves administration of a therapeutically effective amount of a triple drug combination. By way of example, and not limitation, one effective triple drug combination includes DZP:PB:isoflurane. EXAMPLES

[0015] Experimental Example 1

[0018] Adult male Sprague Dawley rats (approximately 200-250 grams) underwent surgery to implant epidural screw electrodes into the skull for EEG recording to detect seizure-induced electrographic changes. Rats were housed singly after surgery, with free access to food and water, and maintained on a 24-h diurnal light cycle, lights on from 0700 to 1900 daily. All animal procedures were performed in accordance with the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals, 8th Edition (2011), The Association for Assessment and Accreditation of Laboratory Animal Care Guidelines, and the Institutional Animal Care and Use Committee.

[0016]

[0019] Treatment responses and concentrations were based on a single animal model of SE. The incidence and intensity of chronic epilepsy was determined by longitudinally monitoring rats for 3 months after induction and treatment of SE. This period was chosen to detect progressive long-term changes as a result of treatment. Episodes of SE were chemically induced, and then rats were treated with systemic injections of standard antiepileptic drugs DZP and PB combined with inhaled isoflurane / oxygen to interrupt the later stages of RSE, as measured by frequency and EEG characteristics.

[0017]

[0020] A lithium pilocarpine protocol was used to produce generalized convulsive status epilepticus (GCSE) in rats. Tylenol (1–2 mg per ml) was added to the drinking water the day before surgery and for 3 days after surgery. One week after electrode implantation surgery, a baseline EEG was recorded for 15 min. Status epilepticus was then induced by an intraperitoneal (IP) injection of lithium chloride (3 mmol / kg) followed 20–24 h later by a subcutaneous (SC) injection of pilocarpine (30 mg / kg). After injection of pilocarpine, the EEG of each rat was continuously monitored by placing it in a recording cage and connecting it to clinical EEG equipment by a flexible cable suspended from the top of the cage. The cage was fitted with an interposition commutator system to allow the rat to move around freely without twisting the cable.

[0018]

[0021] GCSE was terminated by IP injection of a binary drug combination of standard antiepileptic drugs (AEDs) diazepam (DZP) and phenobarbital (PB) along with inhalation of an isoflurane / oxygen mixture according to the present invention. For example, but not limited to, after each animal had progressed to complete the seizure pattern of SE on EEG, each rat was administered 10 mg / kg DZP, 25 mg / kg PB and an isoflurane concentration of 2-3%. Each animal was monitored continuously for the next 4-6 hours. Following the immediate experiment, each rat was monitored longitudinally.

[0019]

[0022] The rats were fed a mash containing rat biscuits and water and continuously monitored for 12 weeks by EEG recordings to detect the onset of chronic epilepsy. The number, frequency and duration of seizures were recorded daily for each rat.

[0020]

[0023] Turning now to the figures, FIG. 1 shows EEG tracings of two rats following induction of status epilepticus (SE). Traces 1-4 are for rat 1, and traces 5-8 are for rat 2. As can be seen, each rat is in a full SE seizure state. FIG. 2 shows tracings of the same rat 1 and rat 2, where rat 1 was administered a three-component drug regimen according to the present invention consisting of 10 mg / kg DZP, 25 mg / kg PB, and 2-3% isoflurane in oxygen. It should be understood by those skilled in the art that the above compositions are illustrative and should not be considered limiting in any manner. It should be further noted that alternative concentrations or concentration ranges may be utilized, provided such compositions are therapeutically effective according to the present invention.

[0021]

[0024] As can be seen, the EEG tracings from rat 1 show a return to a normal EEG pattern while rat 2 continues in a fully seizure state. Figure 3 shows the same rat 1 and rat 2 tracings, each administered a three-component drug regimen according to the present invention. As can be seen, each rat has returned to a normal EEG background pattern. Finally, Figure 4 shows the EEG tracings two days after induction of SE and administration of the three-component drug regimen. Each rat continues to show normal EEG activity with no evidence of seizures for approximately 48 hours. Rats 1 and 2 were followed for an additional 17 weeks with no recurrence of spontaneous seizures or other signs of epilepsy.

[0022]

[0025] In contrast, rats given only a standard AED 60 min after pilocarpine injection have no effect on the observed seizure EEG morphology. In the animals, the seizure pattern continues uninterrupted until the point when brain resources begin to become exhausted. The flat line "breaks" between the seizure patterns then become wider and more frequent over the next few hours. The flat line breaks then become continuous and are occasionally punctuated with sharp spikes. These spikes are known clinically as PEDs or periodic epileptiform discharges. The presence of PEDs indicates that death is imminent, and despite being administered an AED, the rodent dies a total of 4.5-5 hours after pilocarpine injection. It should be noted that although the above was described with reference to the lithium / pilocarpine-induced model, similar seizure patterns may be induced with other models / chemical agents, and full seizure activity progresses at different rates / times.

[0023]

[0026] Although the invention has been described by reference to various specific embodiments, it should be understood that numerous modifications can be made within the spirit and scope of the described inventive concept. It is therefore intended that the invention not be limited to the described embodiments, but rather have full scope defined by the language of the following claims. The claims as filed are set forth below. [Claim 1] An anti-seizure composition comprising a therapeutically effective combination of a halogenated ether, a benzodiazepine, and a barbiturate. [Claim 2] 2. The anti-seizure composition of claim 1, wherein the halogenated ether is selected from one or more of isoflurane, desflurane, and sevoflurane. [Claim 3] 3. The anti-seizure composition of claim 2, wherein the halogenated ether is isoflurane. [Claim 4] 2. The anti-seizure composition of claim 1, wherein the benzodiazepine is diazepam. [Claim 5] 2. The anti-seizure composition of claim 1, wherein the barbiturate is phenobarbital. [Claim 6] 2. The anti-seizure composition of claim 1, wherein the halogenated ether has a concentration of between about 0.1% and about 5%. [Claim 7] 1. A method for treating a seizure event comprising administering a therapeutically effective amount of a combination of a halogenated ether, a benzodiazepine, and a barbiturate. [Claim 8] 8. The method of claim 7, wherein the halogenated ether is selected from one or more of isoflurane, desflurane, and sevoflurane. [Claim 9] 9. The method of claim 8, wherein the halogenated ether is isoflurane. [Claim 10] 8. The method of claim 7, wherein the benzodiazepine is diazepam. [Claim 11] 8. The method of claim 7, wherein the barbiturate is phenobarbital. [Claim 12] 8. The method of claim 7, wherein the halogenated ether has a concentration of between about 1% and about 5%. [Claim 13] 8. The method of claim 7, wherein the halogenated ether is administered via one or more of inhalation, subcutaneous injection, oral ingestion, intravenous injection, intramuscular injection, intraperitoneal injection and transdermal absorption.

Claims

1. A composition for the treatment of status epilepticus comprising a therapeutically effective combination of a halogenated ether, a benzodiazepine, and a barbiturate, said three drug combinations being administered together.

2. 2. The composition of claim 1, wherein the halogenated ether is selected from one or more of isoflurane, desflurane, and sevoflurane.

3. The composition of claim 2 , wherein the halogenated ether is isoflurane.

4. 2. The composition of claim 1, wherein the benzodiazepine is diazepam.

5. 2. The composition of claim 1, wherein the barbiturate is phenobarbital.

6. The composition of claim 1, wherein the halogenated ether has a concentration of between about 0.1% and about 5%.

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