The use of cannabinoids in the treatment of epilepsy

Abstract

To provide a pharmaceutical composition containing cannabidiol (CBD) for reducing the total seizure frequency in treatment of treatment-resistant epilepsy (TRE).SOLUTION: A pharmaceutical composition containing cannabidiol (CBD) to be used for treating treatment-resistant childhood epilepsy, where the CBD is present at an amount of reducing the total seizure frequency by more than 50% for the frequency of seizure achieved by a combined antiepileptic drug (AED). The treatment-resistant childhood epilepsy includes Dravet syndrome, epilepsy with myoclonic absence, Lennox-Gastaut syndrome and the like, and the CBD is used in combination with one kind or a plurality of antiepileptic drugs (AED).SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention provides a method for reducing total seizure frequency in the treatment of "treatment-resistant epilepsy" (TRE). In one embodiment, the present invention relates to the use of cannabidiol (CBD) for the treatment of TRE. Patients affected include children and young adults. CBD is a condition in which TRE is associated with Dravet syndrome; myoclonic This is particularly useful in cases of absence seizures or febrile infection-associated epilepsy syndrome (FIRES). In these indications, the total seizure frequency is surprisingly high in a significant number of patients. In fact, at the end of the 3-month treatment, At times, significant numbers of patients were seizure-free.

[0002] Preferably, the CBD used is one in which CBD is present at greater than 98% (w / w) of the total extract. It is a form of highly purified cannabis extract, as in the case of the other constituents of the extract. The compounds have been characterized. In particular, tetrahydrocannabinol (THC) is present in 0.1 It has been substantially removed to a level of 5% (w / w) or less. Alternatively, it can be This CBD is made from

[0003] In use, CBD is used in combination with one or more other antiepileptic drugs (AEDs). Alternatively, CBD may be administered separately, sequentially, or simultaneously with one or more AEDs. The combination may be formulated for administration in a single unit, or the combination may be provided in a single unit dosage form. CBD can be formulated for separate, sequential, or simultaneous administration. CBD is available as a kit for administering one or more components as directed. The product may be provided separately or together with instructions. [Background technology]

[0004] Epilepsy affects approximately 1% of the world's population (Thurman et al., 2011), and 70% of people with epilepsy have their symptoms adequately controlled with currently available antiepileptic drugs (AEDs). However, 30% of this patient population (Eadie et al., 2012) are unable to obtain Seizures cannot be eliminated with available AEDs, and therefore, the condition is called "treatment-resistant epilepsy" ( They are said to suffer from TRE.

[0005] Treatment-resistant epilepsy was defined in 2009 by the International League Against Epilepsy (ILAE) as a “patient-resistant epilepsy.” Tolerable treatment (either as monotherapy or in combination) to achieve sustained seizure freedom Failure to properly test two highly suitable and appropriately selected AED schedules" (K wan et al., 2009).

[0006] Individuals who develop epilepsy during the first few years of life are often difficult to treat, Children who experience frequent seizures during childhood are often referred to as treatment-resistant. There is often residual neurological damage that can result in behavioral and motor retardation.

[0007] Childhood epilepsy has a prevalence of approximately 700 per 100,000 people in children and young adults. It is a relatively common neurological disorder in the United States. This means that 100% of adults in the population suffer from epilepsy. It is twice the number.

[0008] When a child or young adult presents with seizures, investigations are usually carried out to determine the cause. Childhood epilepsy can be caused by many different syndromes and genetic mutations. Therefore, diagnosing these children may take some time.

[0009] One such childhood epilepsy is Dravet syndrome. Almost always, it occurs in previously healthy, developmentally normal infants, with clonic and tonic-clonic seizures that last a lifetime. The disease develops during the first year of life (Dravet, 2011). Symptoms peak at approximately 5 months of age. Other seizures, such as prolonged cognitive impairment focal seizures and brief absence seizures, Onset occurs between 1 and 4 years of age.

[0010] Attacks progress to become frequent and treatment-resistant, which means that attacks do not respond well to treatment. These seizures also tend to be prolonged, lasting more than 5 minutes. This can lead to status epilepticus, which is a seizure that lasts for more than a minute or occurs in rapid succession. obtain.

[0011] The poor prognosis is that approximately 14% of children die from infection or from sudden, uncertain causes. Death often occurs during an attack due to unrelenting neurological deterioration. Intellectual disability varies, with 50% of patients experiencing severe , with moderate and mild intellectual disability each accounting for 25% of cases.

[0012] Currently, there are no FDA-approved treatments specifically indicated for Dravet syndrome. The standard treatment is anticonvulsants such as clobazam, clonazepam, levetiracetam, and topi A combination of lamate and valproic acid is usually required.

[0013] Stiripentol, in combination with clobazam and valproic acid, is indicated for the treatment of Dravet syndrome. In the United States, stiripentol was approved in 2008. In 2013, the drug received orphan drug designation for the treatment of Dravet syndrome, but the FDA has not been approved.

[0014] Powerful sodium channel blockers used to treat epilepsy may actually cause Dravet syndrome. These drugs increase the frequency of seizures in patients with the syndrome. These are bamazepine, lamotrigine and rufinamide.

[0015] Management may include a ketogenic diet, physical stimulation, and vagus nerve stimulation. In addition to anticonvulsants, many patients with Dravet syndrome also receive psychotropic, stimulant, and other medications. It is treated with sleep aids and insomnia medications.

[0016] Common AEDs, defined by their mechanism of action, are described in the table below.

[0017] [Table 1]

[0018] [Table 2]

[0019] [Table 3]

[0020] Over the past 40 years, non-psychotropic cannabinoids, such as cannabinoids, have been used to treat seizures. Numerous animal studies have been conducted on the use of CBD. Sroe et al. (1982) reported that CBD inhibited the activity of mice after administration of convulsants or electrical current. They found that this could prevent seizures in dogs.

[0021] Studies using CBD in adults with epilepsy have also been conducted over the past 40 years. Nha et al. reported that administering CBD to eight adult patients with generalized epilepsy improved their condition. reported that the drug produced a significant reduction in seizures in four of the patients (Cunha et al., 1980 year).

[0022] In a 1978 study in which four adult patients were given 200 mg / day of pure CBD, Two of the patients became seizure-free, while the remaining two had no change in seizure frequency. (Mechoulam and Carlini, 1978).

[0023] In contrast to the studies mentioned above, an open-label study found that 200 mg / day of pure CBD reported that it was ineffective in controlling seizures in 12 adult patients admitted to the facility. (Ames and Cridland, 1986).

[0024] The last study to look at the effectiveness of CBD in patients with epilepsy was Based on the fact that CBD has proven unable to control seizures, CB There is no expectation that D could be useful as an anticonvulsant.

[0025] Over the past 40 years, more than 30 drugs have been approved for the treatment of epilepsy. None of these compounds are cannabinoids. In fact, it is likely that the designated properties of these compounds and / or THC, a known psychoactive substance, has been considered a convulsant ( Consroe et al., 1977), preconceived notions about cannabinoids It seems to exist.

[0026] Recently published research has shown that cannabis, which is rich in cannabidiol, is effective in treating epilepsy. Porter and Jacobson (2013) suggested that this may be effective. (2017) reported the use of CBD-enhanced cannabis in children with treatment-resistant epilepsy. The survey was conducted through a Facebook group investigating the issue. Sixteen of the 19 parents surveyed reported improvement in their child's epilepsy. All of the children studied for this paper were found to have a high level of CBD and It contains high concentrations of CBD, although other components, including THC, are unknown. In fact, the CBD levels ranged from 0.5 to 28 The THC levels ranged from 0.6 mg / kg / day (in the extracts tested), The reported dose was as high as 0.8 mg / kg / day.

[0027] Cannabinoids containing THC, which have been described as convulsants (Consroe et al., 1977), Even small amounts of Nabis extract, let alone a potentially psychoactive dose of 0.8 mg / kg / It is extremely dangerous to provide CBD to children with TRE for days, and therefore There is a real need to determine whether it actually works.

[0028] To date, no controlled clinical trials have been conducted on CBD in children and young adults with TRE. Not yet. Summary of the Invention

[0029] According to a first aspect of the present invention, a therapeutic agent is provided, which is febrile infection-associated epilepsy syndrome (FIRES). Cannabidiol (CBD) for use in the treatment of treatment-resistant epilepsy (TRE) is available will be done.

[0030] According to a second aspect of the present invention, in the treatment of epilepsy that is treatment-resistant epilepsy (TRE), Cannabidiol (CBD) for use in patients with epilepsy who are taking concomitant antiepileptic drugs (AEDs) present in an amount that reduces total convulsive seizure frequency by more than 50% relative to the seizure frequency achieved by Cannabidiol (CBD) is provided.

[0031] Preferably, CBD is combined with two or more concomitant antiepileptic drugs (AEDs). CBD may be used in combination with one or more AEDs separately, sequentially, or simultaneously. The combination may be formulated for administration in a single dosage form. can be done.

[0032] Preferably, the seizure type to be treated is complex partial seizures (focal seizures with functional impairment). do.

[0033] Preferably, CBD will reduce seizure frequency achieved by concomitant antiepileptic drugs (AEDs). More preferably, CBD is present in an amount that reduces total seizure frequency by more than 70% relative to the , total seizure frequency relative to the seizure frequency achieved with concomitant antiepileptic drugs (AEDs) Even more preferably, the CBD is present in an amount that reduces the level of seizure activity by more than 90%. A 100% reduction in total seizure frequency relative to the seizure frequency achieved by AEDs It exists in an amount that

[0034] In one embodiment, the CBD is a cannabis extract containing at least 98% (w / w) CBD. It is present as a highly purified extract of

[0035] The one or more AEDs are preferably clobazam; levetiracetam; topiramate ;Stiripentol;Phenobarbital;Lacosamide;Valproic acid;Zolamine It is selected from the group consisting of nisamide; perampanel; and fosphenytoin.

[0036] Preferably, CBD is used in combination with clobazam.

[0037] Preferably, a number of different antiepileptic drugs or AEDs used in combination with CBD More preferably, the reduced dose of the AED is less than the dose of clobazam. is.

[0038] Preferably, the dose of CBD is greater than 5 mg / kg / day. For individuals, doses of CBD exceeding 75 mg per day are provided, e.g., 10 mg / mg. / kg / day, >15mg / kg / day, >20mg / kg / day and >25mg / kg / day Doses greater than 5 mg / kg / day, such as greater than 5 mg / kg / day, are also expected to be effective.

[0039] According to a third aspect of the present invention, a method for treating cannabidiol (CBD) comprising administering cannabidiol (CBD) to a subject. A method for treating treatment-resistant epilepsy, wherein the epilepsy is febrile infection-associated epilepsy. A method is provided in which the patient is diagnosed with FIRES syndrome.

[0040] According to a fourth aspect of the present invention, one or more concomitant antiepileptic drugs (AEDs) For the seizure frequency achieved, administer the drug at a dose sufficient to reduce the total seizure frequency by more than 50%. Treating treatment-resistant epilepsy, including administering cannabidiol (CBD) to a subject. A method is provided.

[0041] definition Definitions of some of the terms used to describe this invention are set out below.

[0042] The cannabinoids mentioned in this application are listed below with their common abbreviations:

[0043] [Table 4]

[0044] The above table is not exhaustive and is for reference only. To date, over 60 different cannabinoids have been identified, These cannabinoids are divided into different groups (phytocannabinoids; endocannabinoids and and synthetic cannabinoids (novel cannabinoids or synthetically produced phytocannabinoids) cannabinoids or endocannabinoids).

[0045] "Phytocannabinoids" are naturally occurring cannabinoids found in the cannabis plant. Phytocannabinoids are isolated from plants and purified to produce highly purified extracts. It can be produced or synthetically reproduced.

[0046] "High-purity cannabinoids" are extracted from cannabis plants and contain high-purity cannabinoids. Other cannabinoids and cannabinoids must be present in the product to ensure a purity of at least 98% (w / w). Cannabinoids that have been purified to the extent that non-cannabinoid components that co-extract with the cannabinoids are removed. It is defined as a narbinoid.

[0047] "Synthetic cannabinoids" are compounds that have cannabinoid or cannabinoid-like structures. It is produced using chemical means rather than by plants.

[0048] Phytocannabinoids can be found in their neutral (decarboxylated) form, or in a form that can be used to extract cannabinoids. Depending on the method used, it can be obtained in the carboxylic acid form. For example, By heating the carboxylic acid form, most of the carboxyl groups are removed, resulting in a neutral It is known to take shape.

[0049] "Treatment-resistant epilepsy" (TRE) is defined as a condition in which treatment with one or more AEDs is adequately successful. Uncontrolled epilepsy, as defined by the 2009 ILAE guidance .

[0050] "Childhood epilepsy" refers to the many different syndromes and conditions that can cause epilepsy in childhood. Some examples of these include Dravet syndrome; myoclonic absence syndrome; Epilepsy; Lennox-Gastaut syndrome; Generalized epilepsy of unknown etiology; CDKL5 mutation; Icardi syndrome; bilateral polymicrogyria; Dup15q; SNAP25; and febrile infection association FIRES (Fever and Epilepsy Syndrome); Benign Rolandic Epilepsy; Juvenile Myoclonic Epilepsy infantile spasms (West syndrome); and Landau-Kleffner syndrome. This list is non-exhaustive as there are many different childhood epilepsies. DETAILED DESCRIPTION OF THE INVENTION

[0051] Preparation of high-purity CBD extracts The following are compounds with known and consistent compositions that were used in the expanded access studies described in the Examples below: describes the production of a highly pure (>98% w / w) cannabidiol extract.

[0052] In summary, the drug substance used in the study was further refined by solvent crystallization to obtain CBD. Produced by Cannabis sativa L. It is a liquid carbon dioxide extract of high-CBD species. The crystallization process is specifically , and other cannabinoids and plant components are removed to obtain over 98% CBD. .

[0053] The Cannabis sativa L. plant is cultivated, harvested, and processed to produce plant extracts (intermediates). is made and then purified by crystallization to obtain CBD (drug substance).

[0054] Plant starting materials are called botanical raw materials (BRM), and plant extracts are intermediates and are used in pharmaceutical products. The active ingredient (API) is the active pharmaceutical ingredient, CBD.

[0055] Both the plant starting material and the plant extract are controlled by specifications. The results are listed in Table 1 below.

[0056] [Table 5]

[0057] The achieved purity of the CBD drug substance is greater than 98%. Expected impurities include: Cannabinoids (CBDA, CBDV, CBD-C4 and THC).

[0058] Different chemical species of the Cannabis sativa L. plant produce specific chemical constituents called cannabinoids. One type of plant is primarily CBD. Only the (-)-trans monomer occurs naturally, and furthermore, the stereochemistry of CBD is Unaffected during refining.

[0059] Preparation of intermediates The steps for making the plant extract intermediate are outlined below. 1. Cultivation 2. Decarboxylation 3. Extraction No. 1 - Using Liquid CO2 4. Extraction No. 2 - "Dewaxing" with Ethanol 5. Filtration 6. Evaporation

[0060] High-CBD chemotypes are grown, harvested, dried, and stored in dry rooms until desired consistency is reached. The plant raw materials (BRM) were finely milled using an Apex mill equipped with a 1 mm screen. The crushed BRM was stored in a freezer for up to 3 months before extraction.

[0061] Decarboxylation of CBDA to CBD was performed using a large-capacity Heraeus tray oven. The Heraeus decarboxylation batch size is approximately 15 kg. Place in a bun and heat to 105°C; it took 96.25 minutes for the BRM to reach 105°C. The temperature was held at 105°C for 15 minutes. The oven was then set to 150°C. It took 75.7 minutes for the BRM to reach 150°C; the BRM was held at 150°C for 130 minutes. Total time in the oven was 380 minutes, including 45 minutes of cooling and 15 minutes of degassing.

[0062] Extraction number 1 was carried out using liquid CO2 at 60 bar / 10°C to extract the botanical drug substance (BDS ) was prepared and used for crystallization to obtain test materials.

[0063] The crude CBD BDS was extracted under standard conditions (-20°C for approximately 50 hours, 2 volumes of ethanol). The resulting mixture was dewaxed in extraction number 2. The precipitated wax was removed by filtration and rotary evaporator. The solvent was evaporated using an evaporator (water bath at a maximum of 60°C) to give BDS.

[0064] Preparation of drug substance The manufacturing steps for making the drug substance from the intermediate plant extract are as follows: do. 1. Crystallization using linear or branched C5-C12 alkanes 2. Filtration 3. Optional recrystallization from linear or branched C5-C12 alkanes 4.Vacuum drying

[0065] The intermediate plant extract (12 kg) produced using the above procedure was added to a 30 liter flask. Straight or branched C5 to C12 alkanes in a stainless steel container (9000 ml, 0.75 v ol).

[0066] The mixture is stirred by hand until all lumps are broken down, and then the closed container is It was then placed in the freezer for 48 hours.

[0067] The crystals were isolated by vacuum filtration and aliquots of cold linear or branched C5-C12 alkyl acrylate were added. Wash with lecithin (total 12000 ml) and dry under vacuum above 10 mb at 60°C. After this, the drug substance was submitted for analysis.

[0068] The dried product is sealed with FDA food-grade approved silicone seals and clamps. Store in a pharmaceutical grade stainless steel container equipped with a -20°C freezer. Ta.

[0069] The following Examples 1 to 3 describe the use of high-purity cannabis extracts containing cannabidiol (CBD). Cannabidiol is the most abundant non-psychoactive cannabinoid in the cannabis plant. Previous animal studies have demonstrated the efficacy of CBD in multiple species and models. It has been demonstrated to have anticonvulsant effects.

[0070] Example 1 was developed in an expanded access treatment program for children with TRE. The data is listed.

[0071] Examples 2 to 4 are for Dravet syndrome, myoclonic absence seizures, and FIRES, respectively. Demonstrating the effectiveness of CBD in affected children. [Example]

[0072] Efficacy of cannabidiol in children and young adults with treatment-resistant epilepsy material and method 27 children and adolescents with severe childhood-onset treatment-resistant epilepsy (TRE) Adults are treated with a highly purified extract of cannabidiol (CBD) obtained from the cannabis plant. Participants in this study were enrolled in an expanded access compassionate use program for CBD. was part of.

[0073] All patients entered a 4-week baseline period during which parents / caregivers were asked to complete all possible Attention was paid to the type of seizures linked to calculations, and a diary of predicted seizures was kept.

[0074] Patients were then assigned to receive a known and consistent antiepileptic drug (AED) regimen in addition to their baseline AED regimen. High-purity CBD extract (>98%) in sesame oil at a dose of 5mg / kg / day of a defined composition (w / w) CBD).

[0075] daily dose until intolerance occurs or a maximum dose of 25 mg / kg / day is reached was gradually increased in increments of 2 to 5 mg / kg.

[0076] Patients were examined at regular intervals of 2 to 4 weeks. Blood, liver, and kidney function and Clinical laboratory tests for concomitant AED levels were performed at baseline and at 4, 8, and 12 weeks. The study was conducted after CBD therapy.

[0077] result Twenty-seven children and young adults received at least three months of treatment, all of whom He had treatment-resistant epilepsy.

[0078] All patients were taking at least two concomitant antiepileptic drugs. Bazam; Levetiracetam; Topiramate; Stiripentol; Phenobarbital; Laco The mean concomitant antiepileptic medications taken included methadone; valproic acid; and zonisamide. The average number of cases was 2.7. The majority were taking clobazam and / or valproic acid. Ta.

[0079] CBD co-treatment with clobazam was a positive treatment with a responder rate of over 50% was a significant predictor of response; odds ratio (OR) was 3.3 for total seizure reduction; and 1.9 for seizures. ORs are the odds of a given event or outcome occurring between two Specifically, the event or outcome is evaluated to see if it is similar for each group. It measures the ratio of the odds of an event occurring to the odds of the event not occurring. An OR greater than 1 means Patients treated with a combination of CBD and clobazam experienced significant side effects after taking this combination of medications. would have better odds of having a clear reduction in seizures than if they had not This represents the following.

[0080] Before treatment, patients experienced a median of 30 attacks per month, and The recorded seizures ranged from 4 to 2,800 per day.

[0081] Efficacy results for the 27 patients are summarized in Table 2 below.

[0082] [Table 6]

[0083] Table 2 shows that after 3 months of therapy, 48% of patients had a >50% reduction in seizures. There are.

[0084] Remarkably, 2 out of 7% of patients were completely seizure-free at 3 months. It was being released.

[0085] None of the 27 subjects discontinued treatment during the 3-month period, and adverse events were mild. Common adverse events were drowsiness, fatigue, decreased appetite, and increased appetite. and diarrhea were mentioned.

[0086] The dose of clobazam in five subjects was reduced due to its sedative effects.

[0087] conclusion These preliminary results suggest that CBD may be effective in treating patients who have not responded well to existing AEDs. Cannabidiol has been shown to significantly reduce the number of seizures in a high percentage of patients. It was generally well tolerated at doses up to 25 mg / kg / day.

[0088] It is surprising that such a large proportion of this group of treatment-resistant patients could benefit. It was surprising that almost half of the patients (48%) reported having fewer attacks. The fact that both groups benefited from a 50% reduction was remarkable.

[0089] Furthermore, nearly a quarter of patients had seizures that were not controlled with at least two antiepileptic drugs. (22%) experienced a 90% reduction in the number of seizures they were experiencing, and 7% experienced a 90% reduction in the number of seizures they were experiencing within 3 months. At the end of the study period, the patient was completely seizure-free.

[0090] Even more remarkable are the results for some defined subsets of this set of attributes. and these are presented in Examples 2-4 below. [Example]

[0091] Efficacy of cannabidiol in children and young adults with treatment-resistant Dravet syndrome effectiveness material and method Nine children and young adults with treatment-resistant Dravet syndrome were treated with the steroids described in Example 1. Expanded Access Compassionate Use Program for High-Purity CBD Extracts It was a part of it.

[0092] result All nine patients with Dravet syndrome were taking at least two concomitant antiepileptic drugs. These are AEDs that act mainly through GABA. , clobazam; levetiracetam; topiramate; stiripentol; phenobarbital Concomitant anticonvulsants taken included: lacosamide; valproic acid; and zonisamide. The average number of pills was 2.7.

[0093] Before starting treatment, these patients suffered an average of 35 attacks per month. The recorded seizure frequency ranged from 6 to 112 per month.

[0094] The efficacy results for the nine patients are summarized in Table 3 below.

[0095] [Table 7]

[0096] Table 3 shows that after 3 months of therapy, 56% of patients had a 50% or greater reduction in seizures, and one-third of patients The incidence of seizures was reduced by 90%, and remarkably, 22% were completely seizure-free at 3 months. This indicates that

[0097] None of the nine subjects discontinued treatment during the three-month period, and adverse events were mild. Common adverse events were drowsiness, fatigue, decreased appetite, increased appetite, and Symptoms included nausea and diarrhea.

[0098] conclusion These data suggest that in the subgroup of patients with treatment-resistant Dravet syndrome, A surprising number have demonstrated that they have been able to achieve a dramatic reduction in the number of seizures.

[0099] Nearly one-quarter of patients (22%) were completely seizure-free by the end of the three-month study period This meant taking many different anti-epileptic drugs and still taking 100mg of seizures a day. This was unexpected in a group of patients suffering from high or multiple seizures. [Example]

[0100] Cannabidiol in children and young adults with treatment-resistant myoclonic absence seizures Rule validity material and method Four children and young adults with treatment-resistant myoclonic absence seizures were treated with the method described in Example 1. Expanded Access Compassionate Use Protocol for High-Purity CBD Extracts as Described It was part of the gram.

[0101] result All four patients with myoclonic absence seizures were receiving at least two concomitant anticonvulsants. These were mainly AEDs that acted via GABA. Clobazam; Levetiracetam; Topiramate; Stiripentol; Phenobarbital These included tar; lacosamide; valproic acid; and zonisamide. The mean number of antiepileptic drugs was 2.7.

[0102] The efficacy results for the four patients are summarized in Table 4 below.

[0103] [Table 8]

[0104] Table 4 shows that after 3 months of therapy, half of the patients had a 50% or greater reduction in seizures, and one patient (25 %) indicates a 90% reduction at 3 months.

[0105] None of the four subjects discontinued treatment during the three-month period, and adverse events were mild. Common adverse events were drowsiness, fatigue, decreased appetite, increased appetite, and and diarrhea were listed.

[0106] conclusion These data suggest a surprising increase in this subgroup of patients with treatment-resistant MAS. Many have demonstrated that they have been able to achieve a dramatic reduction in the number of seizures. [Example]

[0107] Canker sore syndrome in children with treatment-resistant febrile infection-associated epilepsy syndrome (FIRES) Navidiol effectiveness Febrile infection-associated epilepsy syndrome (FIRES) presents with refractory status epilepticus A devastating epileptic encephalopathy of no identifiable cause occurs in a small proportion of all patients.

[0108] The syndrome occurs in previously healthy children, with 66–100% of survivors having developmental disabilities. Mortality is up to 30%. New therapies are urgently needed to treat this condition. It is being done.

[0109] material and method The three patients with FIRES ranged in age from 4 to 15 years and were previously described in Example 1. As reported, he was receiving treatment with CBD under the Expanded Access Program.

[0110] Safety studies, physical / neurological exams, 24-hour video / EEG and seizure types and The severity and frequency of CBD were assessed at baseline and one month after starting CBD.

[0111] A highly purified extract of CBD is available as an oral solution in sesame oil at a concentration of 25mg / mL. Used.

[0112] Treatment was initiated at a dose of 10 mg / kg / day given in two divided doses, with 5 doses every 3 days. The dose was increased by 1 mg / kg / day.

[0113] Following improvement in seizures, an average of two AEDs were discontinued.

[0114] result Before starting treatment with high-purity CBD, all patients had intractable seizures or severe epilepsy. These patients were treated with midazolam infusion, pentobarbital infusion, prothrombin time, and steroid therapy. The patient was receiving anesthesia treatment, including intravenous isoflurane and intravenous isoflurane. Additionally, patients were given lidocaine infusions and steroids, including methylprednisolone. roid, as well as ketamine, fosphenytoin, thiamine, rituximab, cyclophosphamide, He also received other treatments, including amides, intravenous immunoglobulin, and hypothermia protocols. there was.

[0115] When starting CBD, patients were taking levetiracetam, clobazam, perampanel, and phenobarbital. Bital, phenytoin, carbamazepine, felbame ketogenic diet, lamotrigine, valproic acid and vagus nerve stimulation therapy They were taking between three and five antiepileptic drugs, including:

[0116] A baseline 24-hour EEG was recorded for seizures. The seizures are shown in Table 5. Patient 1 experienced a reduction in the number of seizures from 7 to 0.3 over 24 weeks, with resolution. After starting treatment, the patient was seizure-free for almost the entire treatment period. After 4 weeks, seizures were reduced by 50%, but seizure frequency increased after a further 4 weeks, followed by After 16 weeks of treatment, the decrease began again. The most significant response was a decrease of 5600 from baseline. Patient 3, who had been suffering from seizures, experienced a dramatic reduction in the number of seizures after 4 weeks and a significant reduction at 24 weeks. At 12:00, the patient still showed a greater than 90% reduction in the number of seizures.

[0117] The type of seizures that occurred in the three FIRES patients were all complex partial seizures (with functional impairment). None of the FIRES patients had secondary generalized seizures or convulsive seizures. He did not suffer from focal seizures.

[0118] [Table 9]

[0119] Subsequent laboratory testing showed no changes in safety tests or concomitant AED levels. No treatment-related side effects were observed.

[0120] conclusion CBD treatment is very well tolerated and has been shown to improve refractory FIRES symptoms. Two of the three children who suffered from seizures or status epilepticus had clinical and electrographic seizures. It resulted in a dramatic and almost immediate improvement of over 90% in true seizures.

[0121] After the seizures were reduced, the patient was able to walk and talk again.

[0122] Summary table and conclusions Table 6 shows three subsets after 12 weeks of treatment as described in Examples 2-4 above. Dravet syndrome; myoclonic absence seizures (MAS) and febrile infection-associated epilepsy syndrome ( In addition, data from the FIRES study were compiled. Data for the remaining patients who received Dravet, MAS, and FIRES are detailed in the report. These data, excluding patients with epilepsy, are specific subgroups of the above specific subsets of epilepsy. The responder rate is much lower than that of the NIH set.

[0123] Notably, the responder rate for patients who achieved a greater than 90% reduction in seizures was The decline has been from 33% in patients with HIV to just 8% in the unspecified group. This suggests that subtypes of Dravet syndrome, myoclonic absence seizures or TR of FIRES may be involved. Patients with E had higher levels of CBD than patients with other epilepsy subtypes. This suggests that patients respond better to treatment with

[0124] [Table 10]

[0125] [References] [Table 11] The scope of the patent claims at the time of filing is as follows: [Claim 1] Cannabidiol (CBD) for use in the treatment of treatment-resistant epilepsy, which is febrile infection-associated epilepsy syndrome (FIRES). [Claim 2] 1. Cannabidiol (CBD) for use in the treatment of epilepsy that is treatment-resistant epilepsy (TRE), wherein the CBD is present in an amount that reduces total convulsive seizure frequency by more than 50% relative to the seizure frequency achieved with concomitant antiepileptic drugs (AEDs). [Claim 3] CBD for use according to claim 1 or claim 2 in combination with two or more concomitant antiepileptic drugs (AEDs). [Claim 4] CBD for use according to claim 3, wherein the type of seizure to be treated is complex partial seizures (focal seizures with functional impairment). [Claim 5] 5. The CBD for use according to any one of claims 1 to 4, wherein the CBD is present in an amount that reduces total convulsive seizure frequency by more than 70% relative to the seizure frequency achieved with concomitant antiepileptic drugs (AEDs). [Claim 6] 6. The CBD for use according to any one of claims 1 to 5, present in an amount that reduces total convulsive seizure frequency by more than 90% relative to the seizure frequency achieved with concomitant antiepileptic drugs (AEDs). [Claim 7] 7. The CBD for use according to any one of claims 1 to 6, wherein the CBD is present in an amount that reduces total convulsive seizure frequency by 100% relative to the seizure frequency achieved by concomitant antiepileptic drugs (AEDs). [Claim 8] 8. CBD for use according to any one of claims 1 to 7, present as a highly purified extract of cannabis containing at least 98% (w / w) CBD. [Claim 9] 3. The CBD for use according to claim 2, wherein the one or more AEDs are selected from the group consisting of clobazam, levetiracetam, topiramate, stiripentol, phenobarbital, lacosamide, valproic acid, zonisamide, perampanel, and fosphenytoin. [Claim 10] CBD for use according to claim 9, wherein one of the AEDs is clobazam. [Claim 11] CBD for use according to any one of claims 1 to 10, in which the number of different antiepileptic drugs used in combination with CBD is reduced. [Claim 12] CBD for use according to any one of claims 1 to 11, in which the dose of an antiepileptic drug used in combination with CBD is reduced. [Claim 13] CBD for use according to claim 12, wherein the dose of AED that is reduced is the dose of clobazam. [Claim 14] CBD for use according to any one of claims 1 to 13, wherein the dose is between 5 mg / kg / day and 25 mg / kg / day. [Claim 15] 1. A method of treating treatment-resistant epilepsy comprising administering cannabidiol (CBD) to a subject, wherein the epilepsy is febrile infection-related epilepsy syndrome (FIRES). [Claim 16] 1. A method of treating treatment-resistant epilepsy, comprising administering cannabidiol (CBD) to a subject in an amount sufficient to reduce total convulsive seizure frequency by more than 50% relative to the seizure frequency achieved with one or more concomitant antiepileptic drugs (AEDs).

Claims

1. A pharmaceutical composition comprising cannabidiol in combination with one or more concomitant antiepileptic drugs for use in the treatment of treatment-resistant childhood epilepsy selected from Dravet syndrome, myoclonic absence seizures (MAS), and febrile infection-related epilepsy syndrome (FIRES), wherein the cannabidiol is present as a highly purified extract of cannabis having a purity of at least 98% (w / w) cannabidiol and contains 0.15% (w / w) or less of tetrahydrocannabinol or is a synthetic cannabidiol, the dose of the cannabidiol is 5 mg / kg / day to 25 mg / kg / day, and the concomitant antiepileptic drugs are existing antiepileptic drugs that are available.

2. 10. The pharmaceutical composition of claim 1, wherein the cannabidiol is present in an amount that reduces total convulsive seizure frequency by more than 50% relative to the seizure frequency achieved with concomitant antiepileptic drugs. 。

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the cannabidiol is used in combination with two or more concomitant antiepileptic drugs.

4. 4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the seizure type to be treated is complex partial seizures (focal seizures with functional impairment).

5. 5. A pharmaceutical composition according to any one of claims 1 to 4, wherein cannabidiol is present in an amount that reduces total convulsive seizure frequency by more than 70% relative to the seizure frequency achieved with concomitant antiepileptic drugs.

6. 6. A pharmaceutical composition according to any one of claims 1 to 5, wherein cannabidiol is present in an amount that reduces total convulsive seizure frequency by more than 90% relative to the seizure frequency achieved with concomitant antiepileptic drugs.

7. 7. A pharmaceutical composition according to any one of claims 1 to 6, wherein cannabidiol is present in an amount that reduces total convulsive seizure frequency by 100% relative to the seizure frequency achieved with concomitant antiepileptic drugs.

8. 8. The pharmaceutical composition of claim 1, wherein the concomitant antiepileptic drug is selected from the group consisting of clobazam, levetiracetam, topiramate, stiripentol, phenobarbital, lacosamide, valproic acid, zonisamide, perampanel, and fosphenytoin.

9. The pharmaceutical composition of claim 8, wherein one of the concomitant antiepileptic drugs is clobazam.

10. A pharmaceutical composition described in any one of claims 1 to 9, in which the number of different concomitant antiepileptic drugs used in combination with cannabidiol is reduced.

11. A pharmaceutical composition described in any one of claims 1 to 10, in which the dose of a concomitant antiepileptic drug used in combination with cannabidiol is reduced.

12. 12. The pharmaceutical composition according to claim 11, wherein the dose of the concomitant antiepileptic drug that is reduced is the dose of clobazam.

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