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    • 专利摘要:
    The present invention relates to the use of cannabidiol (CBD) in combination with a 5-HT2B receptor agonist. This combination provides protection against the adverse effects caused by 5-HT2B receptor agonists. The invention further relates to the use of CBD in combination with an amphetamine or an amphetamine derivative in the treatment of epilepsy. In one embodiment, CBD is used in combination with amphetamine-derived fenfluramine to produce a significant reduction in seizures. Preferably, the CBD used is in the form of a highly purified cannabis extract, so that CBD is present in more than 98% of the total extract (w / w) and the other components of the extract are characterized. In particular, the cannabinoid tetrahydrocannabinol (THC) has been substantially removed, to a level not greater than 0.15% (w / w) and the CBD propyl analog, cannabidivarin (CBDV) is present in quantities of up to 1% . Alternatively, the CBD can be a synthetically produced CBD. In use, CBD in combination with a 5-HT2B receptor agonist, amphetamine or amphetamine derivative can be formulated for administration separately, sequentially or simultaneously with the amphetamine or amphetamine derivative, or the combination can be provided in a form single dosage. When CBD is formulated for administration separately, sequentially or simultaneously, it can be provided as a kit or in conjunction with instructions for administering the one or more components in the manner indicated.
    公开号:BR112020006105A2
    申请号:R112020006105-0
    申请日:2018-10-01
    公开日:2020-09-29
    发明作者:Benjamin Whalley；Geoffrey Guy；Volker Knappertz；Royston GRAY；Rohini RANA
    申请人:GW Research Limited；
    IPC主号:
    专利说明:

    [001] [001] The present invention relates to the use of cannabidiol (CBD) in combination with a 5-HT receptor agonist> 5g. This combination provides protection against the adverse effects caused by 5-HT receptor agonists. The invention further relates to the use of CBD in combination with an amphetamine or an amphetamine derivative in the treatment of epilepsy. In one embodiment, CBD is used in combination with the amphetamine derivative and the 5-HT> 5g fenfluramine receptor agonist to produce a significant reduction in epileptic seizures.
    [002] [002] Preferably, the CBD used is in the form of a highly purified cannabis extract, so that CBD is present in more than 98% of the total extract (w / w) and the other components of the extract are distinguished. In particular, the cannabinoid tetrahydrocannabinol (THC) has been substantially removed, to a level not greater than 0.15% (w / w) and the CBD propyl analog, cannabidivarin (CBDV) is present in quantities of up to 1% . Alternatively, the CBD can be a synthetically produced CBD.
    [003] [003] In use, CBD in combination with the 5-HT receptor agonist, amphetamine or amphetamine derivative can be formulated for administration separately, sequentially or simultaneously with the amphetamine or amphetamine derivative or the combination can be provided in one single dosage form. When CBD is formulated for administration separately, sequentially or simultaneously, it can be provided as a kit or in conjunction with instructions for administering the one or more components in the manner indicated. BACKGROUND OF THE INVENTION
    [004] [004] Epilepsy occurs in approximately 1% of the population worldwide (Thurman et al., 2011), of which 70% are able to adequately control their symptoms with the available antiepileptic drugs (FAE). However, 30% of this group of patients (Eadie et al., 2012) are unable to obtain freedom from epileptic seizures with the available FAE and, as such, are termed as having intractable or “treatment-resistant” epilepsy (TRE) .
    [005] [005] Intractable or treatment-resistant epilepsy was defined in 2009 by the International League Against Epilepsy (ILAE) as “failure to adequately test two FAE schemes tolerated and chosen and used appropriately (either as monotherapy or in combination) to obtain prolonged freedom from epileptic seizures ”(Kwan et al., 2009).
    [006] [006] Individuals who develop epilepsy during the first years of life are often difficult to treat and, as such, are often referred to as treatment-resistant. Children who experience frequent epileptic seizures in childhood often suffer neurological damage that can cause cognitive, behavioral and motor delays.
    [007] [007] Childhood epilepsy is a relatively common neurological disorder in children and young adults, with a prevalence of approximately 700 per 100,000. This is twice the number of adult epileptics per population.
    [008] [008] When a child or young adult has an epileptic seizure, investigations are usually carried out to investigate the cause. Childhood epilepsy can be caused by many different syndromes and genetic mutations and, as such, the diagnosis of these children can take some time.
    [009] [009] The main symptom of epilepsy is repetitive seizures. To determine the type of epilepsy or the epileptic syndrome a patient suffers from, an investigation is carried out into the type of epileptic seizure the patient is experiencing. Clinical observations and electroencephalography (EEG) tests are performed and the type (s) of epileptic seizures are classified according to the ILAE classification described below.
    [0010] [0010] The international classification of types of epileptic seizures proposed by ILAE was adopted in 1981 and a revised proposal was published by ILAE in 2010 and has not yet replaced the 1981 classification. is adapted from the 2010 proposal for revised terminology and includes the proposed changes to replace terminology from partial to focal. In addition, the term “simple partial epileptic seizure” has been replaced by the term “focal epileptic seizure in which perception / responsiveness is not impaired” and the term “complex partial epileptic seizure” has been replaced by the term “focal epileptic seizure in which perception / consciousness is impaired ”.
    [0011] [0011] Generalized epileptic seizures, in which the epileptic seizure originates from and quickly involves networks distributed bilaterally, can be divided into six subtypes: tonic-clonic epileptic seizures (great evil); epileptic seizures of absence (small mal); clonic epileptic seizures; tonic epileptic seizures; atonic epileptic seizures and myoclonic epileptic seizures.
    [0012] [0012] Focal (partial) epileptic seizures, in which the epileptic seizure originates in networks limited to only one hemisphere, are also divided into subcategories. Here, the epileptic seizure is distinguished according to one or more characteristics of the epileptic seizure, including aura, mobility, autonomy and perception / responsiveness. When an epileptic seizure begins as a localized epileptic seizure and rapidly evolves to be distributed in bilateral networks, this seizure is known as bilateral seizure seizure, which is the proposed terminology to replace secondary generalized epileptic seizures (generalized epileptic seizures that have evolved from focal epileptic seizures and no longer remain localized).
    [0013] [0013] Epileptic syndromes generally have many different types of epileptic seizures and identifying the types of epileptic seizures that a patient suffers from is important, as many of the standard FAEs are directed towards treatment or are effective only against a certain type / subtype of epileptic seizure.
    [0014] [0014] One of these childhood epilepsies is Dravet's syndrome. The onset of Dravet's syndrome almost always occurs during the first year of life with clonic and tonic-clonic epileptic seizures in previously healthy and normal babies in development (Dravet, 2011). Symptoms peak at five months of age. Other epileptic seizures develop between one and four years of age, such as prolonged focal discognitive seizures and epileptic seizures of brief absence.
    [0015] [0015] In the diagnosis of Dravet's syndrome, focal and generalized epileptic seizures are considered mandatory; Dravet patients may also experience epileptic seizures of atypical absence, epileptic seizures of myoclonic absence, atonic seizures and non-convulsive epileptic status.
    [0016] [0016] Epileptic seizures progress to be frequent and resistant to treatment, which means that they do not respond well to treatment. They also tend to be prolonged, lasting more than 5 minutes. Prolonged epileptic seizures can lead to an epileptic state, which is an epileptic seizure that lasts more than 30 minutes, or epileptic seizures that occur in sequence, one after the other.
    [0017] [0017] The prognosis is poor and approximately 14% of children die during an epileptic seizure, due to infection, or suddenly due to uncertain causes, usually because of the relentless neurological decline. Patients develop intellectual disabilities and epileptic seizures throughout life. Intellectual impairment ranges from severe in 50% of patients to mild and moderate intellectual disability, each representing 25% of cases.
    [0018] [0018] Currently, there are no FDA approved treatments specifically indicated for Dravet's syndrome. The standard of care usually involves a combination of the following anticonvulsants: clobazam, clonazepam, levetiracetam, topiramate and valproic acid.
    [0019] [0019] Stiripentol is approved in Europe for the treatment of Dravet's syndrome in conjunction with clobazam and valproic acid. In the USA, stiripentol received an Orphan Designation for the treatment of Dravet's syndrome in 2008; however, the drug is not approved by the FDA.
    [0020] [0020] Potent sodium channel blockers used to treat epilepsy increase the frequency of epileptic seizures in patients with Dravet's Syndrome. The most common are phenytoin, carbamazepine, lamotrigine and rufinamide.
    [0021] [0021] Management may also include a ketogenic diet and physical stimulation of the vagus nerve. In addition to anticonvulsant drugs, many patients with Dravet's syndrome are treated with antipsychotic drugs, stimulants and drugs to treat insomnia.
    [0022] [0022] Common FAE defined by their mechanisms of action are described in the following tables: Table 1. Examples of ONE-clonic ononic-clonic limited-spectrum FAE * Onion-clonic mixed epileptic streaks | Mixed epileptic ICises
    [0023] [0023] The 5-HT receptor, also known as serotonin receptor, has three different subtypes, the 5-HT> a receptor, the 5-HT2g receptor and the 5-HTxc receptor. Some compounds have affinity for all three receptor subtypes, others only for one or two of the subtypes. These receptors are stimulated by monoamine neurotransmitters, which include serotonin, dopamine and norepinephrine. 5-HT receptor agonists are common targets for pharmaceutical drugs, since 5-HT receptor agonism; has been shown to benefit many conditions therapeutically, including obesity, psychiatric disorders, sexual dysfunction and urinary incontinence.
    [0024] [0024] However, the activation of these receptors is associated with serious and potentially fatal adverse effects. Activation of 5- HT7a receptors can induce hallucinations, and activation of 5-HT receptors, 55 has been implicated in valve heart disease and pulmonary hypertension.
    [0025] [0025] There are many known 5-HT receptor agonists, some of which have been developed as pharmaceutical drugs. As for agomelatine that has therapeutic use as an antidepressant, this compound is an agonist of the 5-HTxc receptor. Guanfacine, a sympatholytic drug used to treat hypertension and attention deficit hyperactivity disorder (ADHD), is a 5-HT5g receptor agonist. Pergolide, an ergoline-based dopamine receptor agonist used to treat Parkinson's disease, has agonist properties at the 5-HT> xg receptor. Fenfluramine and norfenfluramine are derivatives of amphetamine which are potent agonists of the 5-HT> 2a, 5-HT26 and 5-HTxc receptors.
    [0026] [0026] The amphetamine derivative fenfluramine was approved as an anoretic used to treat obesity in 1973. The drug was withdrawn in 1997 after adverse reports of heart valve disease and pulmonary hypotension that affected 12% of men and 20% of women in use. The mechanism of action of fenfluramine is to produce the release of serotonin, interrupting the vesicular storage of the neurotransmitter and reversing the function of the serotonin transporter, resulting in a feeling of fullness and a reduced appetite.
    [0027] [0027] A low dose between 0.25 and 1.0 mg / kg / day of fenfluramine has been shown to reduce the frequency of epileptic seizures in patients with Dravet's syndrome (Schoonjans et al. 2017).
    [0028] [0028] Currently, there is no approved therapeutic use of the drug fenfluramine.
    [0029] [0029] Amphetamines and amphetamine derivatives include all derivative compounds that are formed by exchanging or replacing one or more hydrogen atoms in the amphetamine core structure with substituents. The compounds in this class span a variety of pharmacological subclasses, including stimulants, empathogens and hallucinogens. Examples of amphetamine derivatives are amphetamine, methamphetamine, ephedrine, cathinone, phentermine, mephentermine, bupropion, methoxyphenamine, selegiline, amfepramone, fenfluramine, pyrovalerone, MDMA (ecstasy) and DOM (STP).
    [0030] [0030] CBD and its human metabolite 7-hydroxy cannabidiol (7-0OH CBD) have been found to be antagonists at the 5-HTxg receptor. Surprisingly, the use of CBD can protect against the adverse effects associated with the use of 5-HT> 26 agonists, while maintaining the agonist's therapeutic effects. Such therapeutic effects of 5-HT> 2g receptor agonists, such as fenfluramine and norphenfluramine, include suppressing appetite and reducing epileptic seizures.
    [0031] [0031] The applicant has demonstrated that co-administration of CBD with a 5-HT> 36 receptor agonist, such as fenfluramine, would reduce or prevent the risk of heart valve disease associated with 5-HT receptor agonism. This is due to the CBD's ability to block 5-HT> 3g receptors, preventing agonists such as fenfluramine from activating receptors.
    [0032] [0032] Furthermore, coadministration of CBD with pharmaceutical agents such as fenfluramine would not adversely affect its beneficial effects on therapeutic targets, such as epileptic seizures, as we have shown that CBD does not act on 5-HTxc receptors through which it is proposed that fenfluramine exerts its effects on epileptic seizures.
    [0033] [0033] In addition, the applicant has demonstrated that co-administration of CBD with an amphetamine or an amphetamine derivative, such as fenfluramine, produces a synergistic reduction in epileptic seizures in an animal model of epilepsy. BRIEF DESCRIPTION SUMMARY
    [0034] [0034] According to a first aspect of the present invention, cannabidiol (CBD) is provided in combination with a 5-HT receptor agonist, an amphetamine or an amphetamine derivative for use in the treatment of epilepsy.
    [0035] [0035] Preferably, the combination is for use in preventing or reducing side effects associated with 5-HT> 3g receptor agonism.
    [0036] [0036] Preferably, the 5-HT3 receptor agonist, amphetamine or amphetamine derivative is one or more of: guanfacine; 3,4-methylenedioxymethamphetamine (MDMA); methylenedioxyanphetamine (MDA); 2,5-dimethoxy-4-ethoxy-amphetamine (MEM); pergolide; cabergoline;
    [0037] [0037] Most preferably, the 5-HT3g receptor agonist, amphetamine or amphetamine derivative is norphenfluramine or fenfluramine.
    [0038] [0038] Preferably, the side effects that are prevented or reduced are heart valve diseases.
    [0039] [0039] In one embodiment, the CBD is in the form of a highly purified cannabis extract that comprises at least 98% (w / w) CBD. Preferably, the highly purified extract comprises less than 0.15% THC and up to 1% CBDV.
    [0040] [0040] In a separate modality, CBD is present as a synthetic compound.
    [0041] [0041] Preferably, epilepsy is treatment-resistant epilepsy (TRE). Most preferably, TRE is one of the following: Dravet's syndrome; Epilepsy with myoclonic absence; Lennox-Gastaut syndrome; Generalized epilepsy of unknown origin; CDKL5 mutation; Aicardi syndrome; tuberous sclerosis complex; bilateral polymicrogyria; Dup15qg; SNAP25; febrile infection-related epilepsy syndrome (FIRES); benign rolandic epilepsy; juvenile myoclonic epilepsy; infantile spasm (West syndrome); and Landau-Kleffner syndrome.
    [0042] Preferably, the ratio of CBD to 5-HT receptor agonist, amphetamine or amphetamine derivative is between 20: 1 and 1:20, more preferably 10: 1 and 1:10, even more preferably 3: 1 and 1 : 3e 2: 1a 1:22, more preferably the ratio is approximately 1: 1.
    [0043] Preferably, the CBD dose is between 5 and 50 mg / kg / day and the dose of a 5-HT5r receptor agonist, amphetamine or amphetamine derivative is less than 0.01 and 1 mg / kg / day.
    [0044] [0044] According to a second aspect of the present invention, a method is provided for treating epilepsy comprising administering cannabidiol (CBD) in combination with a 5-HT> 56 receptor agonist, an amphetamine or an amphetamine derivative to an individual. Preferably the individual is a human. BRIEF DESCRIPTION OF THE DRAWINGS
    [0045] [0045] Modalities of the invention are described below with reference to the accompanying drawings, in which: Figure 1 shows the effect of CBD and 7-OH-CBD on the recombinant human 5-HT receptor; Figure 2 shows the inhibition of specific binding at 5-HT26 (A) and 5-HT> x receptors: (B) human recombinants by CBD and 7-OH-CBD; Figure 3 shows the dose-dependent effects of CBD and FEN using mouse MES; Figure 4 shows the anticonvulsant efficacies of the CBD / FEN ratio dose combinations in the mouse MES; and Figure 5 shows the isobologram of the normalized dose of CBD / FEN for combinations of ratios not constant in the mouse MES. DEFINITIONS
    [0046] [0046] Definitions of some of the terms used to describe the invention are detailed below:
    [0047] [0047] The cannabinoids described in this application are listed below, along with their standard abbreviations. Table 4. Cannabinoids and their abbreviations
    [0048] [0048] The table above is not exhaustive and only details the cannabinoids identified in this application for reference. So far, more than 60 different cannabinoids have been identified and these cannabinoids can be divided into different groups as follows: Phytocannabinoids; Endocannabinoids and synthetic cannabinoids (which may be new cannabinoids or phytocannabinoids or synthetically produced endocannabinoids).
    [0049] [0049] "Phytocannabinoids" are cannabinoids originating in nature and can be found in the cannabis plant. Phytocannabinoids can be isolated from plants to produce a highly purified extract or can be reproduced synthetically.
    [0050] [0050] "Extract of highly purified cannabinoids' are defined as cannabinoids that have been extracted from the cannabis plant and purified as other cannabinoids and non-cannabinoid components" that are co-extracted with cannabinoids have been substantially removed, so that the cannabinoid is highly purified is greater than or equal to 98% (w / w) pure.
    [0051] [0051] "Synthetic cannabinoids" are compounds that have a cannabinoid or cannabinoid-like structure and are manufactured using chemical means, not by the plant.
    [0052] [0052] Phytocannabinoids can be obtained as the neutral form (decarboxylated form) or carboxylic acid, depending on the method used to extract the cannabinoids. For example, it is known that heating the carboxylic acid form will cause most of the carboxylic acid form to decarboxylate in neutral form.
    [0053] [0053] "Treatment-resistant epilepsy" (TRE) or "intractable epilepsy" is defined according to the 2009 ILAE guidelines as epilepsy that is not adequately controlled by trials from one or more FAE.
    [0054] [0054] "Childhood epilepsy" refers to the many different syndromes and genetic mutations that can occur to cause childhood epilepsy. Examples of some of them are as follows: Dravet's syndrome; Epilepsy with myoclonic absence; Lennox-Gastaut syndrome; Generalized epilepsy of unknown origin; CDKLS5 mutation; Aicardi syndrome; tuberous sclerosis complex; bilateral polymicrogyria; Dupl5q; SNAP25; febrile infection-related epilepsy syndrome (FIRES); benign rolandic epilepsy; juvenile myoclonic epilepsy; infantile spasm (West syndrome); and Landau-Kleffner syndrome. The above list is not exhaustive, as there are many different childhood epilepsies.
    [0055] [0055] The term "5-HT5g receptor agonist" refers to any compound, with or without pharmaceutical or therapeutic use. Examples of such compounds include, but are not limited to: guanfacine; 3,4-methylenedioxymethamphetamine (MDMA); methylenedioxyanphetamine (MDA); 2,5-dimethoxy-4-ethoxy-amphetamine (MEM); pergolide; cabergoline; norphenfluramine; fenfluramine; chlorphentermine; aminorex; meta-chlorophenylpiperazine (nCPP); bromo-dragonfly; N, N-dimethyltryptamine (DMT); S-methoxy-N, N-dimethyltryptamine (5-MeO-DMT); lysergic acid diethylamide (LSD-25); and psilocin.
    [0056] [0056] The term "amphetamine" or "amphetamine derivative" refers to compounds of the amphetamine class or are formed by exchanging or replacing one or more hydrogen atoms in the amphetamine core structure with substituents. The compounds in this class cover a variety of subclasses - pharmacological, including stimulants, empathogens and hallucinogens. Examples of these include amphetamine; methamphetamine; ephedrine; cathinone; phentermine; mephentermine; bupropion; methoxyphenamine; selegiline; amfepramone; fenfluramine, n-fenfluramine; pyrovalerone; MDMA (ecstasy) and DOM (STP).
    [0057] [0057] “Heart valve disease” refers to a distinct valve abnormality caused by a thickening of the cusp and tendinous cords. When one or more heart valves become sick or damaged, it affects the way blood flows through the heart. This causes extra tension in the heart and causes symptoms such as chest pain, difficulty breathing and tiredness. DETAILED DESCRIPTION PREPARATION OF HIGHLY PURIFIED CBD EXTRACT
    [0058] [0058] The following describes the production of the highly purified cannabidiol extract (> 98% w / w), which has a known and constant composition used in the Examples below.
    [0059] [0059] In summary, the drug substance used is a liquid carbon dioxide extract from Cannabis sativa L. chemotypes containing a high content of CBD, which was later purified by a solvent crystallization method to produce CBD. The crystallization process specifically removes other cannabinoids and plant components, producing more than 98% CBD. Although CBD is highly purified because it is produced from a cannabis plant, and not synthetically, there is a small amount of other cannabinoids that are co-produced and co-extracted with CBD. The details of these cannabinoids and the quantities in which they are present in the drug are as follows: NMQ - no more than EXAMPLE 1: FUNCTION OF CBD AND 7-0H-CBD IN THE HUMAN 5- HTx RECEPTOR
    [0060] [0060] Evaluation of CBD and 7-OOH-CBD activity at the human 5-HT receptor was performed on transfected CHO cells. Such activity as an agonist or antagonist was determined by measuring its effects on the production of PI] using the HTRF detection method. Materials and Methods Antagonistic effects:
    [0061] [0061] The cells were suspended in a buffer containing 10 mM Hepes / NaOH (pH 7.4), 4.2 mM KCI, 146 mM NaCl, 1 mM CaCl2, 0.5 mM MgCl2, 5.5 mM glucose and LiCl 50 mM, then distributed in microplates at a density of 4.104 cells / well and pre-incubated for 5 minutes at room temperature in the presence of buffer (baseline control), test compound or reference antagonist.
    [0062] [0062] Thereafter, the reference 5-HT agonist is added to a final concentration of 30 nM. For baseline control measurements, the separate test wells do not contain 5-HT. After 30 minutes of incubation at 37ºC,
    [0063] [0063] After 60 minutes at room temperature, fluorescence transfer is measured at Aex = 337 nm and at = 620 e) at 665 nm using a microplate reader (Rubystar, BMG).
    [0064] [0064] The IP1 concentration is determined by dividing the signal measured at 665 nm by that measured at 620 nm (ratio).
    [0065] [0065] The results are expressed as a percentage of inhibition of the control response at 30 nM 5-HT. The standard reference antagonist is SB 206553, which is tested in each experiment at various concentrations to generate a concentration-response curve from which its IC50 value is calculated. Agonist effects:
    [0066] [0066] The cells were suspended in a buffer containing 10 mM Hepes / NaOH (pH 7.4), 4.2 mM KCI, 146 mM NaCl, 1 mM CaClI2, 0.5 mM MgCl2, 5.5 mM glucose and LiCIl 50 mM, then distributed in microplates at a density of 4.104 cells / well and incubated for 30 minutes at 37ºC in the presence of buffer (baseline control), test compound or reference agonist.
    [0067] [0067] For stimulated control measurement, separate test wells contain 1 µM 5-HT. After incubation, the cells are lysed and the fluorescence acceptor (D2-labeled IPl) and the fluorescence donor (europium cryptate-labeled anti-IP1 antibody) are added.
    [0068] [0068] After 60 minutes at room temperature, fluorescence transfer is measured at À ex = 337 nm and à em = 620 and 665 nm using a microplate reader (Rubystar, BMG).
    [0069] [0069] The concentration of IP1 is determined by dividing the signal measured at 665 nm by that measured at 620 nm (ratio).
    [0070] [0070] Results are expressed as a percentage of the control response at 1 µM 5-HT. The standard reference agonist is 5-HT, which is tested in each experiment at various concentrations to generate a concentration-response curve from which its ECS50 value is calculated. Results
    [0071] [0071] The Figure | describes the data produced by the antagonist and agonist assays.
    [0072] [0072] It was found that CBD and 7-OH-CBD have Kb values of 3.7 (Figure 1A) and 0.69 µM (Figure 1B), respectively, for the 5-HT> 2g receptor. The Kb value represents the molar concentration of an antagonist (a drug that blocks a receptor target) necessary for 50% of the target protein (receptor) to have the ligand attached to it at any time.
    [0073] [0073] Neither CBD nor 7-OH-CBD have agonist activity at 5-HT3 receptors (Figures 1C and 1D).
    [0074] [0074] None of the compounds interacted with the 5-HT receptor>% x (as shown in Figure 2B). Conclusions
    [0075] [0075] In clinical trials in humans with epilepsy, CBD concentrations of up to 330 ng / mL were reached in plasma, which is equivalent to a molar concentration of - 1IuM. The clinical use of CBD leads to the production of 7-OH-CBD, which reaches concentrations of -50% of those achieved by CBD (that is, -0.5SuM).
    [0076] [0076] Taken together, these affinity linkage and clinical exposure data demonstrate that the clinical use of CBD will produce enough CBD and 7-OH-CBD to engage and act on the 5-HT 3 receptor.
    [0077] [0077] The drug (+/-) - fenfluramine, and its human metabolites, (+/-) - nor-fenfluramine, bind and activate several different subtypes of human SHT2 receptors (Rothman et al., 2000), including 5 -HT> 2a, 5-HTog and 5-HTx in clinically relevant exposures. The interaction of these compounds with the 5-HT> 3 receptor causes cardiovascular side effects (heart valve disease) observed in the clinical use of fenfluramine and was the reason it was withdrawn from the clinical use originally licensed for weight loss (Rothman and Baumann, 2009 ).
    [0078] [0078] Fenfluramine is currently under investigation as a treatment for rare epilepsies (Dravet's syndrome and Lennox-Gastaut syndrome). CBD also has beneficial therapeutic effects on these same epilepsies. There is evidence that the efficacy of fenfluramine in epilepsy stems from its interaction with the 5-HT> xc receptor (Sourbron et al., 2016). However, some adverse cardiovascular effects have been reported in patients with epilepsy treated with fenfluramine. In addition, the risk of developing cardiovascular side effects associated with the use of fenfluramine increases with the dose and duration of treatment (Schoonjans et al., 2017). Patients with the epilepsies described above develop their first symptoms in the early years of childhood and require lifelong drug treatment.
    [0079] [0079] Co-administration of CBD with a 5-HT receptor agonist, such as fenfluramine, would reduce or prevent the risk of heart valve disease associated with 5-HT receptor agonism> 3xg. This is due to the CBD's ability to block 5-HT> x6 receptors, preventing agonists such as fenfluramine from activating receptors.
    [0080] [0080] Furthermore, coadministration of CBD with pharmaceutical agents such as fenfluramine would not adversely affect its beneficial effects on therapeutic targets, such as epileptic seizures, as we have shown that CBD does not act on 5-HTxc receptors through which it is proposed that fenfluramine exerts its effects on epileptic seizures. EXAMPLE 2: COMBINATION OF CANABIDIOL WITH PHENFLURAMINE PRODUCES SYNERGIC REDUCTION IN CRISES EPILEPTICS
    [0081] [0081] The following example describes the data produced from a combination of the cannabinoid CBD with the amphetamine derivative fenfluramine in a mouse model of epileptic seizures. Isobologographic analysis was performed to determine whether this combination could produce a synergistic reduction in epileptic seizures. Materials and methods
    [0082] [0082] The study was carried out in two phases. First, (Experiment A), a dose-dependent anticonvulsant effect of purified botanical CBD and fenfluramine (FEN) was demonstrated alone. Second, (Experiment B), drug interactions (DDI) and anticonvulsant activities for CBD / FEN in combination were determined.
    [0083] [0083] Experiment A was performed using 160 male C57BI6 mice, weighing between 20.1 to 30.1 g, and Experiment B was performed using 126 male CS57BI6 mice, weighing between 19.2 to 26.1 g, purchased from a licensed breeder (Charles River, UK). There were no significant differences in animal weight between groups or between exposures.
    [0084] [0084] Untreated mice (naive) were acclimated to the procedure room in their cages, with food and water available ad libitum. The animals were housed in groups of 2 to 5, in standard cages in a light-dark cycle of 12 hours / 12 hours. All animals were marked on the tail, weighed and randomly assigned to a vehicle or treatment group at the beginning of the studies. ANTIEPILEPTIC DRUGS (FAE)
    [0085] [0085] The following drugs were used in this study: Purified botanical CBD provided by GW Research Ltd., fenfluramine hydrochloride (FEN) purchased from Sigma Merck. The control vehicle used was 1: 1: 18 (5% ethanol, 5% Kolliphor EL, 90% saline). CBD and FEN were dissolved in the same control vehicle for comparison.
    [0086] [0086] The animals were medicated (10 ml / kg) i.p. at 60 minutes for CBD and 30 minutes for pretreatment times with FENS5, before MES and before plasma and brain sampling immediately after the MES test.
    [0087] [0087] For Experiment A, in addition to the vehicle group, five dose groups were used for each active treatment. Here, doses were selected based on known ED50 and NOAELs for all drugs and were: CBD-BOT [10, 30, 50, 70 and 100 mg / kg] and FEN [1,2,3,5e mg / kg ]. The number of animals in each of these groups was 10 (n = 10) and 160 in total.
    [0088] [0088] For Experiment B, in addition to the vehicle group, three dose groups were used for each of the treatments. Here, doses were selected based on the analysis of data obtained in Experiment A according to the methods described for determining isobologographic interactions. The doses as a CBD / FEN combination were [20.9 / 2.5, 13.6 / 3.9 and 28.3 / 1.2 mg / kg]. The number of animals in each of these groups was 10 (n = 10) and with individual doses of CBD, FEN and VPA n = 190 in total. MAXIMUM ELECTROCHOCK-INDUCED CONVULSION TEST (MONTH)
    [0089] [0089] The electroconvulsions were produced by applying a fixed current intensity of 30 mA (duration of 0.2 s) supplied via corneal electrodes. These parameters were previously validated to safely produce tonic epileptic seizures of extension of the hind limbs in 100% of the control animals. The mice were individually evaluated for the production of epileptic seizures, determined by the presence or absence of tonic extension of the posterior limbs after the application of current.
    [0090] [0090] The data were collected by an observer who was unaware of the treatment received by each animal. The data were expressed as the total number of animals that presented and did not present extension of the hind limbs from which the percentage of inhibition of the epileptic seizure was derived versus the relevant vehicle group. ISOBOLOGICAL ANALYSIS OF DDI
    [0091] [0091] Isobologographic analysis is considered the gold standard for assessing DDI; determination of equivalent doses of FAE and the classification of DDI as synergistic (supra-additive), additive or antagonist (sub-additive) in preclinical studies. Isobolograms are determined for the desired and adverse effects of DDI, ideally to find synergistic combinations for the desired effect and antagonistic for the adverse effect.
    [0092] [0092] The protective activities of CBD and FEN administered in isolation were evaluated and expressed as effective doses (EDso; mg / kg based on the administered dose) and effective exposures (EEso; uM based on the bioanalysis of brain samples) in which EXs, o is defined as the dose or brain exposure necessary to protect 50% of mice from tonic epileptic seizures induced by MES. CBD / FEN combinations were evaluated at three fixed ratios (1: 3, 1: 1 and 3: 1) based on an EEs, derived from an assumption of linearly additive effects of EEs of the two drugs in combination.
    [0093] [0093] For the three CBD / FEN fixed ratio combinations (1: 3, 1: 1 and 3: 1), the calculations were based on Loewe's additivity equation, as follows; x / EEso (CBD) + y / EEso (FEN) = 1; where x = the exposure of the CBD and y = the exposure in which the CBD, when co-administered with FEN, should theoretically have the desired / additive effect of 50%. Subsequently, doses of CBD and FEN corresponding to 50% of the respective EEs, were used for the CBD / FEN 1: 1 ratio. Similarly, dose proportions were calculated for CBD / FEN ratios 1: 3 and 3: 1 based on the theoretical additive
    [0094] [0094] All statistical tests were performed on GraphPad Prism v7.0 (GraphPad Software, San Diego, CA, USA). Any differences between individual treatment groups and vehicle-treated controls were assessed using the two-tailed Fisher's Exact Probability Test (p <0.05 considered significant).
    [0095] [0095] The percentage of protection of animals against epileptic seizures induced by MES was plotted against doses of FAE alone (CBD or FEN) from Experiment A as log-probit linear regression analysis to derive ED50 and EESO0. For log-probit analysis, it is standard practice to select 4 doses with effects ranging from 16% to 84% to determine effective doses for subsequent isobiological analysis.
    [0096] [0096] Loewe's additivity equation was used to determine the EEso fractions in the three 1: 3, 1: 1 and 3: 1 ratios for each of the CBD / FEN combinations. The graphs were plotted in Prism, for CBD and FEN to determine the ratios versus these exposures to determine the actual doses for the combination study (Experiment B).
    [0097] [0097] DDI using these three fixed dose ratios of CBD / FEN was assessed using CalcuSyn v2.11 (Biosoft). Calcusyn determines the median potency of the drug alone (Dm) which inhibits the system by 50% and the coefficient m means the form of the dose-effect relationship, where m = 1,> 1 and <l indicate dose-effect curves hyperbolic, sigmoidal and flat sigmoidal. The combination index (CI) equation below quantitatively defines DDI as synergy (IC <]), additivity (IC = 1) or antagonism (IC> 1) cre Pr, OD: OD ã OD): DJ: DJ): DA - = fA (DaJdfsA-fal "where DI and D2 are doses of drugs 1 and 2, fa is the fraction affected by D (percentage inhibition / 100), Dm is the dose with a median effect and Dx is the dose needed to inhibit the system at x%. In addition, CalcuSyn was also used to generate isobolograms normalized for DDI with non-constant dose ratio and dose reduction index (DRI) for specific effects. DRI expresses dose reduction by multiples of each drug in a synergistic combination at a given level of effect compared to single administration. RESULTS EXPERIMENT A: PERCENTAGE INHIBITION OF ACTIVITY ELECTROCONVULSIVANT BY SINGLE FAE
    [0098] [0098] Both CBD and FEN showed dose-dependent anticonvulsant effects on the incidence of convulsions induced by maximum electroshock when compared to the vehicle. Protocol analysis revealed statistically significant anticonvulsant effects (p <0.05) from 50 to 100 mg / kg for CBD and 10 mg / kg for FEN (Figure 3). DOSAGE SELECTION OF CBD / FEN AND CBD / VPA FOR ANALYSIS ISOBOLOGICAL
    [0099] [0099] Based on the EEs values, derived for CBD and FEN, the three fixed ratios (1: 3, 1: 1 and 3: 1) were calculated using Loewe's additivity equation (CBD / FEN: 1.6 / 29.7, 3.2 / 19.8 and 4.8 / 9.9 µM). Dose versus average brain exposure plots were used to calculate CBD / FEN doses for isobologographic analysis using linear equations. The doses of the CBD / FEN ratio were 20.9 / 2.5, 13.6 / 3.9 and 28.3 / 1.2 mg / kg. EXPERIMENT B: PERCENTAGE INHIBITION OF ELECTROCONVULSIONS BY CBD / FEN COMBINATION
    [00100] [00100] CBD or FEN alone did not have a significant effect on the incidence of maximum electroshock-induced seizures (MES) when compared to the vehicle at any of the doses tested, which was consistent with the low dose effects in the previous study (Experiment A) .
    [00101] [00101] In contrast, CBD plus FEN (p <0.01) produced significant anticonvulsant effects when compared to the vehicle in two (CBD / FEN) of the tested dose ratio combinations (Figure 4). ISOBOLOGICAL ANALYSIS OF DDI BASED ON DOSES OF CBD / FEN
    [00102] [00102] The three fixed ratios of CBD / FEN 1: 3, 1: 1 and 3: 1 corresponded to theoretically additive EEso values that, when adjusted to the dose, reflect ratios of 1: 2.3 (EDs; s + ADD ), 1: 1 (EDso + ADD), and 3: 1 (EDa1s + ADD). As such, there is enough difference between dose and exposure ratios to reveal different effects.
    [00103] [00103] Median effect curves for potencies derived from doses of CBD and FEN (Dr or EDso) of 33.2 mg / kg and 4.9 mg / kg. At the same time, the m-values of the dose-effect curves for CBD and FEN were also derived and 2.6 + 0.5 and 2.6 + 0.7 were found, where m> 1 indicates a sigmoidal dose-effect relationship. The isobologram of the normalized dose (Figure 5) and the CI (Table 5) revealed synergy for CBD / FEN in the ratios of 1: 2 and 1: 1. Table 5. Combination index (CI) values for doses of CBD / FEN mg / kg) mg / kg) Ratio (theoretical ED)
    [00104] [00104] Dose reduction index (DRI) calculations report CBD dose reduction by 5.690 times and FEN by 2.921 times when administered in combination for a 90% anticonvulsant effect compared to the administration of any drug alone (Table 6). Table 6. Dose reduction index (DRI) values for CBD / FEN DRI effect)
    [00105] [00105] These data indicate that the combination of CBD with fenfluramine for various reasons produced a synergistic reduction in epileptic seizures and, as such, could be a useful treatment option in difficult-to-treat childhood epilepsy syndromes, such as Dravet's syndrome or Lennox-Gastaut syndrome.
    [00106] [00106] The maximum electroshock-induced seizure test (MES) is widely used to assess the anticonvulsant efficacy of standard antiepileptic drugs (FAE). CBD and FEN showed dose-dependent anticonvulsant effects on the MES when administered alone, where significant decreases (p <0.05) in the incidence of epileptic seizures versus vehicle were seen in 50 to 100 mg / kg for CBD and 10 mg / kg for FEN .
    [00107] [00107] The DDD of CBD / FEN was analyzed based on the effects of dose response and response to brain exposure using three combined doses of CBD / FAE. Based on Loewe's additivity equation, they correspond to the CBD / FAE ratios of 1: 3, 1: 1 and 3: 1. The ICe theorem to the isobologographic analysis revealed CBD / FEN PD synergism in the ratio of 1: 3 and
    [00108] [00108] Taken together, the data from Example 1, which shows that CBD is able to prevent the side effects of valve disease produced by 5-HTx6 receptor agonists, and the data from Example 2, which demonstrate that a combination of CBD and the 5-HT receptor agonist> 25g and the amphetamine derivative fenfluramine provide a synergistic reduction in epileptic seizures, clearly demonstrating the highly therapeutic value of this combination.
    [00109] [00109] Furthermore, this combination would allow a reduction in the dose of CBD or the 5-HT5g receptor agonist, amphetamine or amphetamine derivative.
    Considering the known and harmful side effects demonstrated by the 5-HT> g receptor agonist, amphetamine or amphetamine derivatives, such as fenfluramine, reducing the therapeutic dose of this class of compounds would have great significance.
    权利要求:
    Claims (19)
    [1]
    1. Cannabidiol (CBD) in combination with a 5-HTx6 receptor agonist, an amphetamine or an amphetamine derivative, characterized by the fact that it is for use in the treatment of epilepsy.
    [2]
    2. CBD in combination with a 5-HT5g receptor agonist, an amphetamine or an amphetamine derivative for use according to claim 1, characterized by the fact that the combination is for use in preventing or reducing side effects associated with agonism of the 5-HT2B receptor.
    [3]
    3. CBD in combination with a 5-HT> 2g receptor agonist, an amphetamine or an amphetamine derivative for use according to claim | or 2, characterized by the fact that the 5-HT receptor agonist, amphetamine or amphetamine derivative is one or more of: guanfacine; 3 4-methylenedioxymethamphetamine (MDMA); methylenedioxyanphetamine (MDA); 2,5-dimethoxy-4-ethoxyamphetamine (MEM); pergolide; cabergoline; norphenfluramine; fenfluramine; chlorphentermine; aminorex; meta-chlorophenylpiperazine (nCPP); bromo-dragonfly; N, N-dimethyltryptamine (DMT); S-methoxy-N, N-dimethyltryptamine (S-MeO-DMT); lysergic acid diethylamide (LSD-25); psilocin; amphetamine; methamphetamine; ephedrine; cathinone; phentermine; - mephentermine; —Bupropion; methoxyphenamine; selegiline; amfepramone; n-fenfluramine; pyrovalerone; MDMA (ecstasy) and DOM (STP).
    [4]
    4. CBD in combination with a 5-HT> 3g receptor agonist, an amphetamine or an amphetamine derivative for use according to any of the preceding claims, characterized by the fact that the 5-HT2B receptor agonist, amphetamine or derivative amphetamine is norphenfluramine or fenfluramine.
    [5]
    5. Cannabidiol (CBD) in combination with a 5-HT56 receptor agonist, an amphetamine or an amphetamine derivative for use according to claim 2, characterized by the fact that the side effects that are prevented or reduced are heart valve diseases .
    [6]
    6. Cannabidiol (CBD) in combination with a 5-HT56 receptor agonist, an amphetamine or an amphetamine derivative for use according to any of the preceding claims, characterized by the fact that CBD is in the form of a highly purified extract cannabis that comprises at least 98% (w / w) CBD.
    [7]
    7. Cannabidiol (CBD) in combination with a 5-HT3g receptor agonist, an amphetamine or an amphetamine derivative for use according to any one of claims 1 to 5, characterized by the fact that CBD is present as a synthetic compound .
    [8]
    8. Cannabidiol (CBD) in combination with a 5-HT2B receptor agonist, an amphetamine or an amphetamine derivative for use according to any of the preceding claims, characterized by the fact that epilepsy is treatment-resistant epilepsy (TRE) .
    [9]
    9. Cannabidiol (CBD) in combination with a 5-HT2B receptor agonist, an amphetamine or an amphetamine derivative for use according to claim 8, characterized by the fact that treatment-resistant epilepsy is one of the following: Dravet; Epilepsy with myoclonic absence; Lennox-Gastaut syndrome, generalized epilepsy of unknown origin; CDKLS5 mutation; Aicardi syndrome; tuberous sclerosis complex; bilateral polymicrogyria; Dupl5q; SNAP25; febrile infection-related epilepsy syndrome (FIRES); benign rolandic epilepsy; juvenile myoclonic epilepsy; infantile spasm (West syndrome); and Landau-Kleffner syndrome.
    [10]
    10. Cannabidiol (CBD) in combination with a 5-HT36 receptor agonist, an amphetamine or an amphetamine derivative for use according to claim 6, characterized by the fact that the highly purified extract comprises less than 0.15% of THC.
    [11]
    11. Cannabidiol (CBD) in combination with a 5-HT2B receptor agonist, an amphetamine or an amphetamine derivative for use according to claim 6, characterized by the fact that the highly purified extract comprises up to 1% CBDV.
    [12]
    12. Cannabidiol (CBD) in combination with a 5-HT36 receptor agonist, an amphetamine or an amphetamine derivative for use according to any one of the preceding claims, characterized by the fact that the ratio of CBD to 5-receptor agonist HT2B, amphetamine or amphetamine derivative is between 20: 1 and 1:20.
    [13]
    13. Cannabidiol (CBD) in combination with a 5-HT> 26 receptor agonist, an amphetamine or an amphetamine derivative for use according to any of the preceding claims, characterized by the fact that the ratio of CBD to receptor agonist 5-HT2B, amphetamine or amphetamine derivative is between 10: 1 and 1:10.
    [14]
    14. Cannabidiol (CBD) in combination with a 5-HT56 receptor agonist, an amphetamine or an amphetamine derivative for use according to any of the preceding claims, characterized by the fact that the ratio of CBD to 5-receptor agonist HT> r, amphetamine or amphetamine derivative is between 3: 1 to 1: 3.
    [15]
    15. Cannabidiol (CBD) in combination with a 5-HT2 receptor agonist, an amphetamine or an amphetamine derivative for use according to any of the preceding claims, characterized by the fact that the ratio of CBD to agonist of the 5- HT> g, amphetamine or amphetamine derivative is between 2: 1 to 1: 2.
    [16]
    16. Cannabidiol (CBD) in combination with a 5-HT> 56 receptor agonist, an amphetamine or an amphetamine derivative for use according to any one of the preceding claims, characterized by the fact that the ratio of CBD to receptor agonist 5-HT> 3, amphetamine or amphetamine derivative is approximately 1: 1.
    [17]
    17. Cannabidiol (CBD) in combination with a 5-HT2B receptor agonist, an amphetamine or an amphetamine derivative for use according to any of the preceding claims, characterized by the fact that the CBD dose is between 5 and 50 mg / kg / day.
    [18]
    18. Cannabidiol (CBD) in combination with a 5-HT56 receptor agonist, an amphetamine or an amphetamine derivative for use according to any of the preceding claims, characterized in that the dose of a 5-HTx6 receptor agonist , amphetamine or amphetamine derivative is less than 0.01 and 1 mg / kg / day.
    [19]
    19. Method for treating epilepsy, characterized by the fact that it comprises administering cannabidiol (CBD) in combination with a 5-HT2B receptor agonist, an amphetamine or an amphetamine derivative to an individual.
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    同族专利:
    公开号 | 公开日
    IL273583D0|2020-05-31|
    KR20200060422A|2020-05-29|
    JP2020535198A|2020-12-03|
    EP3687576A1|2020-08-05|
    WO2019064031A1|2019-04-04|
    CA3076995A1|2019-04-04|
    RU2020114753A3|2021-10-29|
    GB201806481D0|2018-06-06|
    CN111201039A|2020-05-26|
    US20200237683A1|2020-07-30|
    AU2018341091A1|2020-04-23|
    GB201715919D0|2017-11-15|
    GB2568809A|2019-05-29|
    RU2020114753A|2021-10-29|
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    法律状态:
    2021-11-23| B350| Update of information on the portal [chapter 15.35 patent gazette]|
    优先权:
    申请号 | 申请日 | 专利标题
    GB1715919.5|2017-09-29|
    GBGB1715919.5A|GB201715919D0|2017-09-29|2017-09-29|use of cannabinoids in the treatment of epilepsy|
    GB1806481.6|2018-04-20|
    GBGB1806481.6A|GB201806481D0|2017-09-29|2018-04-20|Use of cannabinoids in the treatment of epilepsy|
    PCT/GB2018/052805|WO2019064031A1|2017-09-29|2018-10-01|Use of cannabidiol in combination with 5-ht2b receptor agonists or amphetamins in the treatment of epilepsy|
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