JP2019504824A - Botulinum toxin for primary mood and emotional disorders by using neurotransmitters - Google Patents

Abstract

  The present invention provides methods comprising the administration of neurotoxins to treat primary mood and emotional disorders, including depressive disorders, anxiety, and sleep disorders, and CNS disorders.

Description

  This application consists of four US provisional applications 60 / 690,162 filed June 14, 2005, US provisional application 60 / 693,771 filed June 27, 2005, September 9, 2005. US Patent Provisional Application No. 60 / 721,060 filed on 28th of May, US Provisional Application No. 60 / 738,981 filed on 23rd November 2005 Claims the benefit of U.S. Patent Application No. 14 / 464,740 filed on August 21, 2014, claiming priority of U.S. Patent Application No. 11 / 447,984, all of which are The entirety of which is incorporated herein by reference.

  The present invention relates to the treatment by neurotoxins of primary mood and emotional disorders, including depression, anxiety, and sleep disorders, and other CNS disorders. The present invention is for selecting patients to be administered botulinum and for selecting an appropriate anatomical site in the extracranial region in close proximity to the target brain and CNS range where the neurotransmitter expression is abnormal Handles the use of neurotransmitter imaging of the brain and central nervous system cross-sections. This method enables the diffusion of botulinum toxin across the blood-brain barrier and the anatomical surface-brain barrier to deliver botulinum safely and effectively to the central nervous system and to block neurotransmitter function. is there.

  Depression is one of the most common and prevalent forms of psychosis that affects individuals regardless of age and gender (Non-Patent Document 1, Non-Patent Document 2, Non-Patent Document 3). The lifetime risk of major depression is generally about 12% for men and about 25% for women (Non-Patent Document 4). In addition, about 5-10% of all patients in the primary care environment show major depression, but about 3-5% of patients have been diagnosed with dysthymia (Non-Patent Document 5). However, in the situation of inpatients, 10-14% of all patients have been diagnosed with major depression (Non-Patent Document 6). Major depression, in particular, is repetitive and is particularly debilitating and harmful. The recurrence rate for patients with major depression is approximately 40% two years after the first episode. The occurrence of recurrence increases to approximately 75% within a period of 5 years after diagnosis of the second major depressive episode (Non-Patent Document 7).

  Depressive disorders are most commonly treated with three major classes of compounds: 1) monoamine oxidase inhibitors, 2) heterocyclic antidepressants, and 3) selective serotonin reuptake inhibitors (SSRIs). It is. Known and currently prescribed antidepressants are side by side with so many side effects. Monoamine oxidase inhibitors were the first antidepressant class used clinically. Monoamine oxidase inhibitors, including isocarboxazide, pheneizine, and tranylcypromine, inhibit phenylethylamine metabolism and catabolism of dopamine, serotonin, and norepinephrine. Monoamine oxidase inhibitors are now a first-line antidepressant as a result of a wide range of side effects including numerous dietary restrictions, hypertension, headaches, myoclonic attacks, insomnia, and gastrointestinal complications associated with the use of monoamine oxidase inhibitors. Is not used. Tricyclic antidepressants, including imipramine, desipramine, nortrypline, amitrypline, doxepin, and protrypline, have a variety of anticholinergic side effects, somnolence, orthostatic hypotension, cardiac arrhythmia Cause weight gain. Although generally milder than monoamine oxidase inhibitors and tricyclic antidepressants, SSRIs also cause numerous side effects. For example, SSRIs including fluoxetine, paroxetine, fluvoxamine, sertraline, and citalopram are associated with gastrointestinal disorders, irritability, agitation, and insomnia.

  In addition to the numerous side effects associated with traditional antidepressant medications, these treatments are also characterized by minimal effectiveness. Some studies on the effectiveness of antidepressant therapy for major depression have concluded that the response rate associated with acute disease treatment or maintenance therapy is 50-60% (Non-Patent Document 8). ). The average absolute response rate of antidepressant versus placebo is about 20-25% (Non-Patent Document 9). Therefore, new antidepressant therapy is now being sought.

  Given the numerous adverse side effects and sometimes minimal effectiveness of so many antidepressant therapies, depressive and sleep disorders do not cause side effects associated with the treatment of depression and / or sleep disorders There is a great need for improved pharmaceuticals that effectively treat. The present invention provides a composition comprising a botulinum toxin neurotoxin for treating depression and / or sleep disorders as well as other CNS disorders.

  It has traditionally been thought that the effects of pharmaceuticals based on botulinum toxin for medical use act on peripheral motor nerves and possibly sensory nerves. Such action of such drugs has been used to explain most of the beneficial effects on various indications including movement disorders, pain syndromes, autonomic syndromes, and spastic disorders. To date, the inventors have made clinical observations that show involvement of the central nervous system and cannot be explained by peripheral effects. Effects on the central nervous system are observed even when botulinum toxin is administered to the scalp, face, or neck region, including administration by any form of injection except intracranial injection. Such observations include improvement of dawn with periocular injection, improvement of sleep patterns and relief of insomnia, improvement of anxiety that does not balance with problems corrected by physical / muscular defects, problems caused by physical / muscular defects Improvement of depression commensurate with, and effects on dysmenorrhea symptoms and potential effects on gonadotropin hormones or other pituitary hormones.

  In addition, botulinum toxin has been shown to have an effect on neurotransmission within the central nervous system when the drug is injected directly into the brain parenchyma. Changes include decreased electrode depolarization, glutamate release, GABA staining, and decreased SNAP-25 cleavage in a period consistent with the botulinum toxin effect. Parenchymal brain injection has been associated with reduced seizure activity in the cerebral hemisphere when the seizure-inducing scarring is caused by caustic injection. Direct injection into the brain is induced bleeding, scarring, neuronal loss and difficulty in placement, potential and risk associated with infection (meningitis), and disadvantages related to the required delivery mechanism Because of this, it is impractical and in fact is not expected to be practiced routinely by skilled physicians in the treatment of seizure disorders. Direct injection into the CNS is very impractical due to such complications associated with open intracranial procedures. In this specification, a botulinum toxin-based pharmaceutical that allows penetration into the central nervous system with improved convenience and safety, with fewer or reduced adverse effects related to direct delivery System (by administration and method of injection not explicitly including transcranial, intrathecal, or intraspinal injection) is disclosed.

  The present inventors have surprisingly and unexpectedly discovered criteria for selecting subjects to treat pain syndromes using botulinum toxin. The present invention provides a method for identifying a subject with increased responsiveness to treatment of pain with a botulinum toxin. Specifically, the inventors have found that atopic diseases are associated with various pain syndromes, and that the presence of atopic diseases and the sensory trick phenomenon of pain relief by tactile stimulation is a botulinum toxin. We found that it seems to be a predictive value in predicting pain response to.

  Examples of the application of botulinum toxin to the treatment of facial muscle pain include initially cervical to treat tension headache, bruxism, temporal mandibular joint syndrome, lower back pain, and acoustic neuroma (retrocranial fossa brain tumor) Post-operative pain after surgical incision was included. The application of botulinum toxin to the treatment of migraine has become widespread after contemporaneous observation that migraines relieved after the facial wrinkle was eliminated by botulinum toxin in the forehead.

  Multiple case reports suggest that botulinum toxin is effective in treating tension and migraine and various forms of facial muscle pain syndrome. Despite this recommendation, a controlled study using a small number of patients in the study group did not demonstrate the effectiveness of botulinum toxin for the treatment of myofascial and other forms of pain (10). ). In control studies, it was attributed to the small sample size and relatively low power that botulinum toxin was ineffective in treating various pain syndromes. It is believed that the need for a larger number of patients and further multicenter studies is essential in order to obtain stronger evidence of efficacy.

  Efforts were made to conduct a larger study in light of a case report suggesting that botulinum toxin is indeed effective in treating migraine pain syndrome. The first multicenter controlled study, sponsored by Allergan Pharmaceutical Company, one of the largest suppliers of botulinum toxin A (BOTOX ™), was a general migraine (defined by International Headache Classification-1988). This suggests that botulinum toxin is effective in preventing repeated occurrences of botulinum. However, the statistical significance of these results was uncertain, inconsistent between treatment groups, and showed an unexplained reverse dose response curve (Non-Patent Document 11).

  Migraine, tension headache, myofascial pain in the head, and chronic atypical facial headache are primary headache disorders (not associated with structural pathology in the head or secondary to another disease process It represents a headache that is not a thing). Treatment of these conditions is associated with a very high placebo response rate (as high as 35%) and requires a large number of patients to detect significant differences between the test and control groups in clinical trials. The use of selection criteria (introduction criteria) to identify more responsive patient populations increases the response rate for subjects in the treatment group of the control study, resulting in a controlled study with a smaller test sample It is possible to establish therapeutic efficacy in More importantly, for any condition, selection criteria (diagnostic criteria) are the basis for accurate and effective pharmaceutical therapy. Parameters that identify patients who are more likely to respond to a given treatment 1) Prioritize within treatment when there are multiple treatment options 2) Avoid treatments that are unlikely to be successful And 3) It is possible to promote informed consent from patients while examining the risk-benefit ratio. Effective selection criteria will help researchers better understand the mechanism of action based on clinical evidence.

Gainotti et al. (2001) J. Neural Neurosurg. Psychiatr. 71: 258-261 Wong et al. (2001) Nature Rev. Neurosci. 2: 343-351 Nestler et al. (2002) Neuron 34: 13-25 Kessler et al. (1994) Arch. Gen. Psychiatry 51: 8 Barrett et al. (1988) Arch. Gen. Psychiatry 45: 1100 Blackburn et al. (1997) Br. J. Psychiatry 171: 328 Solomon et al. (2000) Am. J. Psychiatry 157: 229 Schulberg et al. (1998) Arch. Gen. Psychiatry 55: 1121 Williams et al. (2000) Ann. Intern. Med. 132: 743 Wheeler et al. (1998) A randomized, double-blind, prospective pilot study of botulinum toxin injection for refractory, unilateral, cervicothoracic, paraspinal, myofascial pain syndrome. Spine 23 (15): 1662-6 Silberstein et al. (2000) Botulinum toxin type A as a migraine preventive treatment. Headache 40 (6): 445-50

  The present invention is directed to treating patients suffering from various pain syndromes including, but not limited to, myofascial pain, myotonic headache, and chronic postoperative wound syndrome to treat pain syndromes involving the head and neck. A method of selection based on retrospective and prospective analysis in the application of botulinum toxins.

  The present invention provides a method for the treatment of depression, anxiety and sleep disorders comprising the administration of a pharmaceutical composition comprising a neurotoxin.

  The present invention provides a method for treating depression, comprising the steps of: a) identifying a subject having a depressive disorder or identifying a subject having one or more symptoms of depressive disorder; and b) botulinum in the subject. Administering an effective amount of the composition comprising a toxin and a pharmaceutically acceptable carrier.

  The present invention also provides a method for treating anxiety, comprising a) identifying a subject having an anxiety disorder, or identifying a subject having at least one symptom of anxiety disorder, and b) including a botulinum toxin in the subject. Administering an effective amount of the composition comprising a pharmaceutically acceptable carrier.

  The present invention is also a method for treating sleep disorders, comprising: a) identifying a subject having sleep disorder or identifying a subject exhibiting at least one symptom of sleep disorder; and b) botulinum toxin in the subject. And an effective amount of the composition comprising a pharmaceutically acceptable carrier.

  The present invention is also a method for treating circadian rhythm disorders, comprising a) identifying a subject having a circadian rhythm disorder, and b) the subject comprising a botulinum toxin and a pharmaceutically acceptable carrier. Administering an effective amount of the composition.

  The present invention also provides a method for delivering a botulinum toxin across the blood brain barrier comprising the steps of: a) identifying a subject having at least one neuropsychiatric disorder; b) Administering a composition comprising an acceptable carrier in an amount sufficient to deliver the neurotoxin across the blood brain barrier.

  The present invention also provides a method for delivering a botulinum toxin across the blood brain barrier comprising the steps of: a) identifying a subject having at least one neuropsychiatric disorder; b) Administering a composition comprising an acceptable carrier in an amount sufficient to deliver the neurotoxin across the blood brain barrier, wherein the administration of the neurotoxin results in at least one neurotransmission. A method is provided wherein a substance is blocked. In a preferred embodiment, the neurotransmitter is acetylcholine.

  The present invention is also a method for treating an anxiety disorder comprising: a) identifying a subject having at least one anxiety disorder, or identifying a subject having one or more symptoms of an anxiety disorder; b) Administering to the subject a composition comprising a neurotoxin and a pharmaceutically acceptable carrier, wherein the composition comprises the blood brain barrier in an amount sufficient to reduce cholinergic neuronal transmission. A therapeutic method is provided that is delivered across.

  The invention is also a method for treating sleep disorders, comprising a) identifying a subject having at least one sleep disorder, or identifying a subject having one or more symptoms of sleep disorder; and b) Administering to the subject a composition comprising a neurotoxin and a pharmaceutically acceptable carrier, wherein the composition comprises the blood brain barrier in an amount sufficient to reduce cholinergic neuronal transmission. A therapeutic method is provided that is delivered across. In a preferred embodiment, the composition reduces choline acetyltransferase activity. In another preferred embodiment, the composition reduces acetylcholine synthesis. In another preferred embodiment, the sleep disorder is insomnia. In another preferred embodiment, the sleep disorder is narcolepsy, restless leg syndrome, or sleep apnea.

  The present invention is also a method of treating circadian rhythm disorders, a) identifying a subject having at least one circadian rhythm disorder, or identifying a subject having one or more symptoms of circadian rhythm disorder B) administering to said subject a composition comprising a neurotoxin and a pharmaceutically acceptable carrier, said composition comprising an amount sufficient to reduce cholinergic neuronal transmission A therapeutic method is provided that is delivered across the blood brain barrier. In a preferred embodiment, the composition reduces choline acetyltransferase activity. In another preferred embodiment, the composition reduces acetylcholine synthesis.

  The present invention is also a method of treating depressive disorder comprising: a) identifying a subject having at least one depressive disorder, or identifying a subject having one or more symptoms of depressive disorder; and b) Administering to the subject a composition comprising a neurotoxin and a pharmaceutically acceptable carrier, wherein the composition comprises the blood brain barrier in an amount sufficient to reduce cholinergic neuronal transmission. A therapeutic method is provided that is delivered across. In a preferred embodiment, the composition reduces choline acetyltransferase activity. In another preferred embodiment, the composition reduces acetylcholine synthesis.

  The present invention is a method for selecting a subject to be treated for pain using a botulinum toxin, and identifies a subject suffering from a condition selected from the group consisting of pain syndrome and depression, anxiety disorder, and sleep disorder Identifying a subject having a condition selected from the group consisting of pain syndrome and depressive disorder, anxiety disorder, and sleep disorder is predictive of increased responsiveness to treatment of pain with botulinum toxin Provide a method. In a preferred embodiment, the pain syndrome is facial muscle pain, migraine, postoperative wound pain, sinusitis-related headache, myotonic headache, posttraumatic headache, cluster headache, temporal mandibular joint syndrome, fibromyalgia Any one or a combination of pain syndromes selected from the group consisting of: atypical facial pain, post-incisional wound pain, cervical radiculopathy, and whiplash.

  In another embodiment of the invention, the subject suffering from a condition selected from the group consisting of depression disorder, anxiety disorder, and sleep disorder has a history of each of depression disorder, anxiety disorder, or sleep disorder It was identified by confirming that.

  The present invention is also a method for identifying subjects with increased responsiveness to treatment of pain disorders using botulinum toxin, comprising screening a population of subjects for pain disorders as well as depression disorders, anxiety disorders, and sleep. Identifying a subject afflicted with a condition selected from the group consisting of disorders, wherein the identification of a subject having a condition selected from the group consisting of pain syndrome and depression disorder, anxiety disorder, and sleep disorder is botulinum Methods are provided that are predictive of increased responsiveness to treatment of pain with toxins. In a preferred embodiment, the pain syndrome is facial muscle pain, migraine, postoperative wound pain, sinusitis-related headache, myotonic headache, posttraumatic headache, cluster headache, temporal mandibular joint syndrome, fibromyalgia Any one or a combination of pain syndromes selected from the group consisting of: atypical facial pain, post-incisional wound pain, cervical radiculopathy, and whiplash.

  The present invention includes the steps of identifying or diagnosing pain syndrome, diagnosing or deriving a history of a condition selected from the group consisting of depression disorder, anxiety disorder, and sleep disorder, and identifying the identified pain syndrome as botulinum toxin. Categorizing as having increased responsiveness to treatment with. In one embodiment, the pain syndrome is identified according to the International Headache Classification System (The International Headache Society (IHS)).

  The present invention relates to a method for selecting a patient for the treatment of human headache disorder using a medicine mainly comprising botulinum toxin, wherein the patient suffers from depressive disorder, anxiety disorder, obsessive-compulsive behavior, or sleep disorder. A method comprising the steps of diagnosing a headache pattern that occurs in the method and administering a therapeutically effective amount of a botulinum toxin. In one embodiment, the headache disorder is associated with migraine, tension headache, complex tension migraine, myofascial headache, sinus headache, headache associated with temporal mandibular joint syndrome, fibromyalgia Headache or headache associated with neuralgia.

  The present invention is also a method for selecting a patient for the treatment of human facial pain disorder using a medicine mainly composed of botulinum toxin, which suffers from depression, anxiety disorder, obsessive-compulsive behavior, or sleep disorder. A method comprising: diagnosing a facial pain disorder occurring in a patient, and administering a therapeutically effective amount of a botulinum toxin. In one embodiment, the facial pain disorder is trigeminal neuralgia, the facial pain disorder is associated with bruxism, or the facial pain disorder is postoperative chronic surgical wound pain.

  The composition of the present invention comprises a botulinum toxin and a pharmaceutically acceptable carrier. In a preferred embodiment, the botulinum toxin is immunotype A, B, C, D, E, F, or G. In a more preferred embodiment, the botulinum toxin is a type A botulinum toxin from the Hall strain Clostridium botulinum.

  The methods of the present invention preferably include transcutaneous, percutaneous, subcutaneous, intraperitoneal, transdermal, intramuscular, and intraosseous, but intracranial, transcranial Intrathecal or intraspinal injection or administration may be performed by administering the botulinum toxin composition by injection not explicitly including. In one embodiment, there are at least two injection sites. In another embodiment, the injection is multipolar. The botulinum toxin is preferably administered elsewhere such as the forehead, scalp, or neck, or periocular area, and other facial areas that enhance venous drainage from the site of administration to the central nervous system (CNS). it can. In another embodiment, the botulinum toxin may be administered to the soft tissue outside the neural skull. In another embodiment, the botulinum toxin may be administered at a location that maximizes uptake by portal pituitary drainage.

Examples of compounds and formulations that can be used in the present invention include botulinum toxins stabilized with proteins such as serum albumin or hyaluronidase. In a preferred embodiment, the serum albumin or hyaluronidase is recombinant. In another embodiment, serum albumin is present at a concentration of greater than 500 μg per ₅₀ units of 100 botulinum toxin. The botulinum toxin pharmaceutical may be further stabilized with a stabilizing monosaccharide or polysaccharide (eg, sucrose, lactose, or trehalose). The botulinum toxin is preferably a single component neurotoxin having a molecular weight of 150,000 daltons that does not contain a botulinum toxin complex protein. The compositions disclosed herein also include nanoemulsions based on polyethylene glycol polymers, vegetable fats, and any nanoemulsion in which one or more monounsaturated or polyunsaturated oils are used. May include. In a preferred embodiment, the botulinum toxin composition used in the methods of the present invention is formulated such that penetration of the botulinum toxin into and through the skin is enhanced.

  Recent advances in pharmaceutical technology have focused on enhancing delivery systems such as transdermal or transcutaneous delivery systems. Such a system would be more convenient and associated with less pain. Problems associated with such systems include inadequate material penetration through the epidermis and dermis. Hyaluronidase improves penetration.

  A pharmaceutical composition comprising botulinum neurotoxin, hyaluronidase, and sugar (monosaccharide and oligosaccharide) is suitable for the method of the present invention. A botulinum toxin pharmaceutical formulation suitable for use in the method of the present invention preferably does not contain any human blood or recombinant blood product and is stabilized in air-dried or lyophilized form. The pH is preferably between pH 3.0 and 7.4, and the preparation can be used as an injection, transdermal or topical agent. Botulinum toxin pharmaceutical formulations suitable for use in the methods of the present invention include injections, needle-free delivery systems, and methods that require disruptive techniques such as electroporation, sonication, high pressure air gas flow injection, or in the form of microneedles. Can be delivered. Microneedles are generally 150-600 microns. Furthermore, a botulinum toxin pharmaceutical formulation suitable for use in the method of the present invention may further comprise a polycationic protein.

  Currently, hyaluronidase is available in several specific activities. For example, sheep-based materials may have a specific activity greater than 1,500 mg or greater than 1.5 mcg. Typically, 75-300 U is used for injections such as those performed using peribulbar anesthesia for intraocular surgery. This would correspond to about 100-450 mg by mass of enzyme protein sufficient to act as a stabilizing excipient.

  Previous studies have shown that protein excipients such as human serum albumin can stabilize botulinum toxin. Test studies conducted have demonstrated that hyaluronidase also stabilizes botulinum toxin at the same level as observed for human serum albumin.

The compositions disclosed herein may be such that the dosage is formulated to a concentration suitable for administration as an eye drop that promotes transconjunctival penetration for the treatment of ocular surface disease. The compositions disclosed herein may be such that the LD ₅₀ units range from 1.25 U to 3,000 units for type A botulinum toxin. The composition disclosed herein may be such that the LD ₅₀ unit is in the range of 1.25 to 20,000 U for B-type botulinum. The compositions disclosed herein may be such that the formulation is delivered as an aerosol to the nasal cavity or oral cavity to facilitate intracranial delivery of pharmaceuticals based on botulinum toxin. The compositions disclosed herein may be such that the formulation is delivered as an aerosol to the ear canal to facilitate intracranial delivery of a botulinum based pharmaceutical product.

  The present invention relates to a drug mainly composed of botulinum toxin, at least when compared with an untreated subject by any injection or topical application method except intracranial, transcranial, intrathecal, or intraspinal injection. A method of delivering to a central nervous system of a subject in a therapeutically effective amount sufficient to reduce one central nervous system neurotransmitter is provided. In a preferred embodiment, the at least one central nervous system neurotransmitter is glutamate, norepinephrine, or acetylcholine. In a more preferred embodiment, the at least one central nervous system neurotransmitter is glutamate. In another embodiment, the method of the present invention reduces at least one central nervous system neurotransmitter when compared to an untreated subject, resulting in insomnia, sleep disorders, anxiety disorders, depression disorders, dysmenorrhea At least one symptom of appetite or eating disorder or seizure disorder is sufficiently reduced. In a preferred embodiment, the seizure disorder is a general, focal movement, or complex partial seizure disorder.

  Glutamate is a neurotransmitter that exhibits endogenous neurotoxic activity found in several neurodegenerative diseases and disorders, vascular accidents such as stroke, and seizure disorders. For example, subjects with mild to moderate dementia and almost certainly Alzheimer's disease have been shown to exhibit elevated levels of glutamate in the central nervous system. Elevated glutamate in the central nervous system reflects an increase in glutamatergic activity in early stages of Alzheimer's disease. The progressive neuronal loss observed in Alzheimer's disease and other neurodegenerative disorders and diseases correlates with increased glutamate and increased excitotoxicity associated with increased levels of this neurotransmitter.

  The present invention relates to a method for reducing glutamate levels in the central nervous system, brain, or parts of the brain, wherein the botulinum toxin pharmaceutical is any one other than intracranial, transcranial, intrathecal, or intrathecal injection. Administering to a subject in an amount sufficient to reduce glutamate levels in the central nervous system, brain, or portions of the brain relative to an untreated subject by injection or topical application of .

  The present invention relates to neuronal loss in the central nervous system, brain, or parts of the brain, by botulinum toxin pharmaceuticals by any injection or topical application, except intracranial, transcranial, intrathecal, or intraspinal injection. Is provided to a subject in an amount sufficient to reduce relative to an untreated subject.

  The invention also provides a therapeutically effective amount of a botulinum toxin-based pharmaceutical agent sufficient to reduce at least one central nervous system neurotransmitter when compared to an untreated subject by nasal sinus injection. A method of delivering to a central nervous system of a subject is provided. In a preferred embodiment, the at least one central nervous system neurotransmitter is glutamate, norepinephrine, or acetylcholine. In a more preferred embodiment, the at least one central nervous system neurotransmitter is glutamate. In another embodiment, the method of the present invention reduces at least one central nervous system neurotransmitter when compared to an untreated subject, resulting in insomnia, sleep disorders, anxiety disorders, depression disorders, dysmenorrhea Or at least one symptom of seizure disorder is sufficiently reduced. In a preferred embodiment, the seizure disorder is a general, focal movement, or complex partial seizure disorder.

  The present invention also relates to a drug mainly composed of botulinum toxin when compared with an untreated subject by any injection or topical application method except intracranial, transcranial, intrathecal, or intraspinal injection, Methods are provided for delivery to a central nervous system of a subject in a therapeutically effective amount sufficient to reduce at least one central nervous system neurotransmitter. In a preferred embodiment, the at least one central nervous system neurotransmitter is glutamate, norepinephrine, or acetylcholine. In a more preferred embodiment, the at least one central nervous system neurotransmitter is glutamate. In another embodiment, the method of the invention reduces at least one central nervous system neurotransmitter when compared to an untreated subject, such as mental retardation, schizophrenia, Huntington's chorea, or Alzheimer's disease. The related upset behavior is sufficiently reduced.

  The present invention also relates to a drug mainly composed of botulinum toxin when compared with an untreated subject by any injection or topical application method except intracranial, transcranial, intrathecal, or intraspinal injection, Methods are provided for delivery to a central nervous system of a subject in a therapeutically effective amount sufficient to reduce at least one central nervous system neurotransmitter. In a preferred embodiment, the at least one central nervous system neurotransmitter is glutamate, norepinephrine, or acetylcholine. In a more preferred embodiment, the at least one central nervous system neurotransmitter is glutamate. In another embodiment, the method of the present invention reduces at least one central nervous system neurotransmitter when compared to an untreated subject, and sufficiently reduces at least one symptom of a neurodegenerative disease associated with inflammation. It is reduced.

  The invention also provides for treating any one of the disorders, diseases or conditions disclosed herein, including depression disorder, anxiety disorder, sleep disorder, circadian rhythm disorder, neuropsychiatric disorder, Alzheimer's disease, and the like. And the use of a botulinum toxin or a botulinum toxin composition of the present invention in the manufacture of a medicament for treating pain, such as various headaches, associated with pain syndrome.

It is a figure which shows that the glutamate receptor activity in the new striatum of a botulinum toxin treatment mouse | mouth reduced compared with the non-treatment mouse | mouth. It is a figure which shows the graphic technique which locates the bias position of glutamic acid. It is a figure which shows the range over the frontal cortex and temporal cortex where the expression of excessive glutamic acid is shown. FIG. 5 shows that regions of the brain are analyzed locally for a range of excessive GABA neurotransmission, and an extracranial injection strategy is targeted to such a range of treatments.

A. Definitions As used herein, “administration” of a composition includes, but is not limited to, oral, nasal, transcutaneous, percutaneous, subcutaneous, intraperitoneal, transdermal. Means any route of administration including intramuscular and intraosseous, and specifically excludes administration by any method except intracranial, transcranial, intrathecal, or intrathecal injection.

  As used herein, a “botulinum toxin” is isolated from a strain of Clostridium botulinum that includes various immunotypes such as A, B, C1, C2, C3, D, E, F, and G. It means protein toxins and their complexes.

  As used herein, “depressive disorder” means major depression, dysthymia, and atypical depression or specifically designated depression.

  As used herein, an “effective amount” is an amount sufficient to reduce one or more symptoms associated with depression, anxiety, or sleep disorders, or any of the disorders described herein. It is.

  As used herein, the term “pharmaceutically acceptable carrier” refers to a chemical composition that can be combined with the active ingredients and then used to administer the active ingredients to the subject. Means. “Pharmaceutically acceptable carrier” also includes, but is not limited to, excipients, surfactants, dispersants, inert diluents, granulating and disintegrating agents, binders, lubricants, sweeteners, Perfumes, colorants, preservatives, physiologically degradable compositions such as gelatin, aqueous media and solvents, oil media and solvents, suspending agents, dispersing or wetting agents, emulsifiers, demulcents, buffers, salts , Thickeners, fillers, emulsifiers, antioxidants, antibiotics, antifungal agents, stabilizers, and one or more of pharmaceutically acceptable polymers or hydrophobic materials. Other “additional ingredients” that may be included in the pharmaceutical compositions of the present invention are known in the art and are described, for example, in Genaro, ed., 1985, Remington's Pharmaceutical Sciences, incorporated herein by reference. Mack Publishing Co., Easton, Pa.

  As used herein, “increased responsiveness” refers to all subjects (responsive and non-responsive to botulinum toxin) of subjects that are responsive to pain treatment with botulinum toxin. Refers to an increase in the ratio.

  As used herein, “response ratio” refers to the ratio of a subject responsive to pain treatment with botulinum toxin to the total subject (responsive and non-responsive to botulinum toxin). Point to.

  As used herein, the term “screening a population” means a retrospective review and analysis of a subject's medical history, or confirmation of a particular diagnosis that exists simultaneously.

  Formulations of the pharmaceutical compositions described herein can be prepared by any method known or later developed in the field of pharmacology. In general, such methods of preparation involve associating the active ingredient with a carrier or one or more other accessory ingredients and then shaping the product into the desired single or multiple dosage units, if necessary or desired. Or packaging.

  Although the description of the pharmaceutical composition presented herein is primarily directed to pharmaceutical compositions suitable for ethical administration to humans, such compositions are generally administered to all types of animals. It will be understood by those skilled in the art that this is suitable. Modifications to make a pharmaceutical composition suitable for administration to humans suitable for administration to various animals are well understood, and a normal veterinary physicist would consider such modifications to be made. It can be designed and implemented with just ordinary experimentation. Subjects contemplated for administration of the pharmaceutical compositions of the present invention include, but are not limited to, humans and other primates, and other mammals.

  The relative amounts of active ingredient, pharmaceutically acceptable carrier, and any additional ingredients in the pharmaceutical composition of the present invention can be further determined depending on the individuality, size, and condition of the subject being treated. It depends on the route of administration. By way of example, the composition may comprise between 0.1% and 100% (w / w) active ingredient. In addition to the active ingredient, the pharmaceutical composition of the present invention may further comprise one or more additional pharmaceutically active agents. Additional agents specifically contemplated include antiemetics and scavengers such as cyanide and cyanate scavengers. Controlled or sustained release formulations of the pharmaceutical compositions of the invention may be made using conventional techniques.

  As used herein, the term “physiologically acceptable” ester or salt is compatible with any other component of the pharmaceutical composition and is not harmful to the subject to which the composition is to be administered. Mean active ingredient in ester or salt form.

B. Depressive disorders Depressive disorders include the diagnosis of major depression, dysthymia, and atypical depression or specifically designated depression ("minor depression"). Various subgroups of depressive disorder are categorized and defined by the Diagnostic and Statistical Manual of Mental Disorders 4th Edition (DSM-IV) (American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4.sup.th Ed., Primary Care Version (DSM-IV-PC). American Psychiatric Association Press, Washington, DC 1995). According to DSM-IV, for the diagnosis of “major depression”, during the diagnosis period, the patient has the following nine symptoms: 1) most of the day is depressed (the most severe in the morning), 2) Significant reduction in interest or pleasure in almost all activities (anxiety), 3) significant weight loss or increase, 4) insomnia or hypersomnia, 5) psychomotor agitation or delay, 6) fatigue and energy Need to demonstrate at least 5 of 7) diminished, 7) guilt and worthlessness, 8) poor concentration and indecision, and 9) repetitive thinking about death or suicide. To support the diagnosis of major depression, depressed mood or loss of interest (analgesia) must become one of the five observed symptoms. In contrast, diagnosis of the most common form of depression, “atypical depression” or “specially unspecified depression” (also called “minor depression”), has two to four depressive symptoms. It must be present daily or almost daily for at least 2 weeks. Dysthymia is a weak, chronic mood disorder that lasts for more than two years and is characterized by anorexia, low self-esteem, and weak energy. Seasonal affective disorder is considered a form of major depression characterized by seasonal changes.

  Depressive disorders do not include normal emotional responses, normal grief responses, or reactions secondary to organic causes such as physical disease or drug exposure. As used herein, depressive disorder refers to a primary disorder of mood and sleep patterns and does not refer to secondary or reactive disorders. Such reactive disorders include hyperhidrosis, spastic torticollis, migraine headache, tension headache, various pain syndromes, Fangguan emergency, blepharospasm, strabismus, inflammatory local and systemic diseases, postoperative pain syndrome Secondary to other medical disorders, such as hemifacial spasm, cancer, myocardial infarction, stroke, degenerative neurological disease, or any other physical disorder that causes an emotional response.

C. Anxiety Anxiety is a group of disorders characterized by several psychosomatic symptoms that cannot be clearly explained. Anxiety, fear of impairing self-control, fear of “crazy”, fear of waiting for death, imminent danger, or embarrassment are among the most common mental symptoms. Common physical symptoms include dizziness, lethargy, chest pain, abdominal pain, nausea, increased heart rate, or diarrhea. Chronic anxiety, also called generalized anxiety disorder, manifests itself as indefinite anxiety, fear, and negative thinking lasting for at least six months. Chronic anxiety often results in excessive anxiety, headache, and nausea in daily activities. Sleep disturbance or early arousal, depression, tension, muscle pain, and fatigue can all be associated with chronic anxiety.

  Acute anxiety, or panic disorder, attacks as a sudden attack or fear with symptoms that may resemble heart attacks, such as palpitations, chest pain, and dizziness. Fear of shortness of breath, upset stomach, chills, cold sweat, hot flashes, or unreasonable death, in combination with these symptoms, can cause terrible experiences for individuals experiencing them. Excessive levels of norepinephrine appear to increase the breathing and pulse rate of those experiencing panic attacks. Post-traumatic stress disorder is also classified as an anxiety disorder and can be caused by anyone who experiences or witnesses an event that is deeply brutal. Some symptoms of post-traumatic stress disorder may be anger, depression, emotional paralysis, flashback, nightmares, and a tendency to be surprised.

  Obsessive compulsive disorder, which is a phobia, or irrational fear, and a tendency to repeated or uncontrollable behavior, is also classified along with anxiety disorders. These may be present at the same time so that many individuals with obsessive-compulsive disorder are a phobia for bacilli or lack of cleanliness and may overwash their hands or bathtub.

  Anxiety disorders do not include normal emotional responses, normal responses to stress, or reactions secondary to organic causes such as physical disease or drug exposure.

D. Sleep disorders Circadian rhythm refers to a cycle of approximately 24 hours caused by an organism. Most physiological systems show circadian changes. The systems with the most significant changes are the sleep-wake cycle, thermoregulation, and endocrine system. Circadian rhythm disturbances can be categorized into two main groups: transient disorders (eg, jet lag, work, social responsibility, and sleep schedule changes due to disease) and chronic disorders. The most common chronic disorders are late sleep phase syndrome (DSPS), advanced sleep phase syndrome (ASPS), and irregular sleep-wake cycles. Katzenberg et al. Propose a genetic correlation (ie, clock polymorphism) of circadian rhythm patterns. DSPS is characterized by a state of falling asleep at a socially accepted time and being unable to wake up indefinitely (more than 6 months). When these patients fall asleep, they can maintain their sleep and have normal total sleep time. (In contrast, patients with insomnia have a shorter total sleep time than normal due to difficulty in initiating or maintaining sleep.) ASPS starts early night sleep (6: 00-9: 00) And an early morning awakening time, generally 3:00 AM to 5:00 AM. ASPS is much less frequent than DSPS and is most commonly seen in older adults and depressed individuals.

  The suprachiasmatic nucleus (SCN), which is the neural basis of circadian rhythm, is located on the anterior ventral part of the hypothalamus and has been confirmed to be a substrate that generates circadian activity. SCN lesions result in a loss of circadian rhythm in sleep-wake cycle, activity-rest cycle, skin temperature, and corticosteroid secretion. There are other pacemakers that are not located in the SCN. For example, deep body temperature rhythms persist despite bilateral resection of SCN. In addition, self-running studies provide evidence for multiple circadian oscillators. Under free-running conditions, the circadian rhythm may be divided into independent components.

  The SCN is the site of the parent circadian clock in mammals. The SCN clock is mainly tuned by the light / dark cycle. Light information is transmitted from the retina directly to the SCN by the retinal hypothalamic fibers. The SCN also receives other projections such as cholinergic fibers from the forebrain basal ganglia. Cholinergic afferents and transmission have been shown to be involved in the regulation of light-induced circadian rhythms (Erhardt et al. 2004 The Neuroanantomy of the Circadian Rhythm).

  In the United States, DSPS is common. Approximately 7-10% of patients complaining of insomnia are diagnosed with circadian rhythm disorders, most often DSPS. DSPS patients have a normal total sleep time, and DSPS patients adjust their lifestyle to fit their sleep schedule and do not seek medical treatment, so the prevalence of DSPS Is probably higher than insomnia. In adolescence, the prevalence is approximately 7%. In contrast, ASPS is probably very rare. However, age-related phase advance is common in older people who tend to go to bed early and get up early.

  The diagnosis of circadian rhythm disorders is mainly based on a detailed social, physical and neurological history. The distinction of a transient disorder from a chronic disorder and a primary disorder from a secondary disorder affects the direction of evaluation and treatment planning. As with all medical and psychiatric backgrounds, the nature of complaints should be addressed first. In the case of insomnia, it is important to distinguish individuals who have difficulty starting sleep from individuals who have difficulty maintaining sleep, individuals who are severely disturbed during the day, and those who complain that sleep does not promote recovery.

  Disorders associated with various sleep disorders include narcolepsy, weakness attacks, restless leg syndrome, and sleep apnea. Anxiety disorders do not include normal emotional responses, normal responses to stress, or reactions secondary to organic causes such as physical disease or drug exposure.

E. CNS Disorders The present invention also provides a central system for treating various CNS disorders using pharmaceuticals based on botulinum toxin that are injected transdermally or by any of the routes of administration disclosed herein. A method for inducing a nervous system inhibitory effect is disclosed. The present inventors have found that botulinum toxin exerts a CNS inhibitory effect in rats injected subcutaneously into the scalp. Injections may include intracranial and intraspinal injections or administration, although not directly into the skull or brain, or may be specifically excluded. Subcutaneous administration of botulinum toxin is assumed to cross the blood / brain barrier. The present invention includes seizures, anxiety, agitation, mania, bipolar disorder, generalized seizures, mental retardation, delirium, hyperactivity syndrome, attention deficit disorder (ADD), dementia, Huntington's disease, Alzheimer's disease, Parkinson's disease, psychosis, Methods of using the botulinum toxin-based pharmaceuticals disclosed herein for treating schizophrenia, insomnia, and other CNS disorders are provided.

In certain embodiments, the botulinum toxin-based pharmaceuticals disclosed herein are used at various dosage levels that induce general atrophy effects in the CNS. This effect is useful in the treatment of various CNS disorders. We have found that rats injected with high doses of botulinum toxin (ie, LD ₅₀ or near dose) show dilation or enlargement of the lateral ventricle in the brain. The control does not show such an effect, but the treated animal shows a significant effect. Generalized brain atrophy is an indicator of biological activity at the neurotransmitter level that is induced by subcutaneous administration of botulinum toxin. Evidence is consistent with an inhibitory effect in the hypothalamus of treated animals. This may also have a direct effect on the release of hormones such as thyroid releasing factor, gonadotropin releasing factor.

  All books, papers, patents, or other publications and references are incorporated herein by reference in their entirety. Reference to any compound herein includes the racemate as well as the single enantiomer.

Further evidence of transcranial movement of botulinum toxin injection from extracranial soft tissue injection in the head and neck region (see animal studies)
Botulinum toxin has been shown to cause brain atrophy by being diffused directly into the brain on the basis of morphological changes due to high-dose extracranial head injection in animals. Neurotransmission and changes in vital neurotransmitters such as glutamate, norepinephrine, acetylcholine were significantly altered at doses approaching lethal levels. The scientific basis for the effect on neurotransmission was studied using several important neurotransmitters. GABA receptor (see FIG. 1) was monitored. In 20-30 gram mouse brain structures, surprisingly, GABA receptors have decreased strength and expression over controls as glutamate receptors decreased in neurons after extracranial injection of botulinum toxin. It was. Such receptors are thought to be critical in balancing neurotransmission against glutamate and its expression. The discovery that GABA receptors are also blocked is closely related to understanding the CNS effects of botulinum toxin. Certain GABA receptor blockers, such as benzodiazepines, include many treatments for anxiety, generalized anxiety disorder, anorexia associated with anxiety, obsessive-compulsive personality characteristics, obsessive-compulsive behavior, self-cutting behavior, and post-traumatic stress It has been confirmed to be effective in the treatment of various diseases. Usually, anesthesiologists use such drugs to treat pain and agitation before the painful medical experience to relieve the pain experience. Such drugs are also used in mood and emotional disorders as mentioned herein. Blocking GABA transmission has the opposite effect as blocking glutamate neurotransmitter receptors. Botulinum toxin not only affects glutamate neurotransmission, but also appears to have an effect on GABA transmission. All of these together are critical for the modulating and stabilizing effects on mood and emotional disorders of botulinum toxin extracranial injection.

Botulinum toxin for the treatment of central hypertension Excessive glutamate expression is associated with excessive norepinephrine transmission in the brain and the pathogenesis of central hypertension. Central hypertension is a form of hypertension caused by abnormalities in central nervous system neurotransmitters, resulting in increased sympathetic outflow from the brain and brainstem structure. Norepinephrine release triggered by glutamic acid has been documented in the literature. In the past, there have been studies using antagonists of N-methyl-D-aspartate (NMDA) and glutamate receptors in the modulation of central hypertension. It has been strongly suggested that NMDA and glutamate receptors, as well as other forms of glutamate receptors, may have a modulating effect on central sympathetic tone and hypertension.

The transfer of botulinum toxin to the brain for central hypertension to block the related metabotropic glutamate and / or NMDA receptors is a concept derived from multiple effects on the central nervous system of botulinum toxin It is. The mechanism is
1. 1. Direct effect on anxiety 2. Direct effects on central nervous system sympathetic outflow 3. Direct effect on sleep promotion and insomnia relief Includes direct effects on the circadian cycle such as regulation and governance of the angiotensin-renin aldosterone system.

We are an example of a patient who has been injected with botulinum toxin around the face and eyes, with improved mood and emotion, improved depression, and reduced anxiety associated with lower blood pressure. I'm watching. The change in sensitivity to light in certain patients suggests circadian effects that affect the angiotensin renin cycle. Such observations
1. Identifying pharmacological techniques, i.e. patients with central or resistant hypertension using the drug;
2. Botulinum toxin is injected into the soft tissue outside the neural skull in such a way as to enhance the diffusion of the botulinum toxin to the areas of the basal ganglia and the locus coeruleus, the bridge, the midbrain, and the central nervous system including the thalamus Steps can be used to treat troublesome, hypertensive patients. The caudate nucleus is also a target for botulinum toxin diffusion and can be a target using extracranial injection. The target is in the central nervous system, more specifically in the area of autonomic output that the brainstem governs.

  The exact mechanism by which this is done and at least one neurotransmitter is blocked is important in the treatment of central hypertension. Such central hypertension may occur in response to brain disease or may be idiopathic and may be one of the components of essential hypertension. Essential hypertension is a target for treatment with botulinum toxin. This means hypertension that is not secondary to kidney disease, brain disease, or other secondary forms of hypertension.

  Upregulation of NMDA receptor activity may also have an effect on the hypothalamus. The sleep disorder accompanied by abnormalities of the circadian clock taught in advance is also a form mediated by hypertension. Botulinum toxin is thought to be useful in the treatment of circadian rhythm disorders, and it has long been thought that hypertension improves when targeting the hypothalamus.

  These findings show that the inventor has used his experience of injecting botulinum toxin for 30 years, and that patients over the age of 61 who have repeatedly received botulinum toxin are followed in the 2007 US census This is an effect that was discovered after confirming that it seemed to live longer than the old one, which is consistent with the previous idea called The Centurion Effect.

The relationship between mood, emotions, anxiety, and hypertension As previously taught, botulinum toxin is found in depression (major depression, obsessive-compulsive personality traits, anxiety disorders including posttraumatic stress, and generalized floating anxiety and various forms of It is effective for mood and emotional disorders consisting of anxiety neuroses and sleep disorders including various forms of insomnia. In this specification:
1. Treating mood and emotional problems, especially anxiety, anxiety neuroses, or sleep disorders following high blood pressure;
2. Injecting the botulinum toxin into the soft tissue outside the neural skull so that the botulinum toxin diffuses into the central nervous system brain parenchyma and affects at least one neurotransmitter in the brain;
3. Identifying patients with central hypertension,
4). A method for treating hypertension using a multi-faceted, multi-technical technique is described that includes assessing outcomes that result in improved systolic and diastolic blood pressure.

  What is described herein also includes diagnosing central hypertension. Central hypertension can be diagnosed by identifying an abnormality in at least one neurotransmitter. The neurotransmitter is norepinephrine, glutamate, glutamate receptor, NMDA receptor, norepinephrine receptor and norepinephrine neurotransmitter, and acetylcholine receptor and acetylcholine neurotransmitter, more particularly glutamate neurotransmitter or NMDA receptor It may be a glutamate receptor including the body.

In light of these findings, scanning methods can include spectral MRI scans, PET scans, or any other form of imaging scan that assay for neurotransmitter abnormalities. The technique is
1. 1. Diagnose hypertension. It will diagnose whether hypertension is refractory to conventional therapies such as the use of beta blockers, ACE inhibitors, ACE receptor inhibitors, calcium channel blockers, or diuretics. If such drugs are not valid or effective, it can be assumed that there is central hypertension. In addition, and more particularly, it becomes possible to diagnose whether a neurotransmitter abnormality is abnormal at the level of the brain, brainstem (including diencephalon, midbrain, pons, or medulla oblongata). Such abnormalities may include imaging glutamate receptors, glutamate neurotransmission, or any other form of neurotransmitter transmission. If a diagnosis of central hypertension has been made, a smaller dose corresponding to a distance closer to the critical abnormal area in the brain, more preferably such that the soft tissue is injected outside the neural skull A botulinum toxin type A dose of 2.0-3,000 LD50 units in a single or multi-point injection strategy such that the botulinum toxin has a sufficient chance of spreading into the area using To alleviate the shortcomings. Such doses can most preferably be less than 800 units of type A toxin, more preferably less than 400 units of type A toxin, and most preferably less than 200 units of type A toxin. The purpose is to cause diffusion to the central nervous system across the neural skull, blood-brain barrier, and to have an effect on neurotransmitters so that hypertension can be treated. It is essential to understand that hypertension is central hypertension and not caused by other forms of hypertension, including renovascular hypertension. Essential idiopathic hypertension may be a combination of central hypertension and possible abnormalities of renal function. This is also the proposed target of the present invention.

Targeted Glutamate Receptor Neurotransmitter Related Diseases Glutamate is an important neurotransmitter and constitutes about 40-50% of all synaptic transmission occurring in the human brain and spinal cord. Glutamate is an important neurotransmitter that has been identified to be associated with cell death and neurotoxicity, particularly at high levels. At high levels, glutamate neurotransmission is associated with ion influx into neurons that lead to cell death associated with NMDA and glutamate receptors. A great deal of effort has been made to use glutamate receptor blockers to treat multiple central nervous system disorders. Ketamine has been associated with the treatment of depression by blocking glutamate receptors and thus relieving depression. Several efforts have been made to use glutamate receptor blockade in some central nervous system disease processes. Attempts have been made to use glutamate receptor blockers as post-stroke neuroprotective agents. This approach has so far been unsuccessful due to multiple side effects with some test drugs acting as glutamate receptor blockers. Treatment of some central nervous system disorders requires safe and effective glutamate receptor blockers with low toxicity. The unique properties of botulinum toxin's ability to travel through the blood-brain barrier to the central nervous system, effectively down-regulate both glutamate receptors, and block glutamate neurotransmission by other mechanisms are several A clear advance in the treatment of central nervous system diseases. The established high safety profile of botulinum toxin highlights the applicability in many clinical situations seeking neuroprotection as described herein.

  These central nervous system diseases are major depression, bipolar disease, bipolar depression, bipolar mania, mania, schizophrenia, psychosis, dementia, Alzheimer's disease, Huntington's disease, Parkinson's disease, obsessive-compulsive personality traits, relapse Epilepsy, forms of anorexia, systemic lupus erythematosus involving the central nervous system, autoimmune central nervous system disorders involving glutamate, head injury, head trauma, brain contusion, cerebral aneurysm rupture, hydrocephalus Or mood or emotional diseases or disorders including any other central nervous system disease with tissue disruption.

  It is important that glutamate can be imaged by spectral MRI, PET scan, or any other method. For the administration of botulinum toxin administered to protect against neurotoxicity associated with neurotransmitters by various methods and techniques that demonstrate high levels of glutamate or any other neurotransmitter in the course of the disease An excellent opportunity is given.

  Described herein is a method for treating and preventing the progression of central nervous system disease comprising administration of botulinum toxin in the extracranial portion of the head. This extracranial part contains the scalp, face, periocular region, head and neck region, mandibular region, periarticular region or nasal sinus, nasal cavity, sinus, bone structure, in order to achieve sufficient diffusion of botulinum toxin into the brain. And the oropharynx. Inherent in the present invention is to cause the direct diffusion of botulinum toxin into the brain and block one important neurotransmitter. Others have previously taught to block botulinum toxins from crossing the blood brain barrier. The present description describes the opposite and novel finding that botulinum toxin can enter the brain and show a direct effect on neurotransmitters. More specifically, neurotransmitters include glutamate, acetylcholine, glycine, and GABA, which can affect the expression of appropriate receptors and disable toxic neurotransmitters from causing cell death. .

This method
1. Checking the state of the central nervous system;
2. Applied to extracranial soft tissue to diffuse botulinum toxin into the brain, thereby blocking at least one neurotransmitter in the brain, thus improving symptoms of central nervous system disease or attenuating its progression Step to
4). Assessing the result of the injection by neuroimaging and clinical history and physical examination;
5). Repeatedly applying botulinum toxin and monitoring the effects so that progression of central nervous system disease does not occur.

  Again, central nervous system diseases are neurodegenerative, cerebrovascular, and traumatic. Protection can be done at the level of cranial nerves. Neuroprotection can function with respect to viral or bacterial infections, or brain bleeding.

In summary, the present invention
1. Assessing neurotransmitter abnormalities that have been imaged to identify central nervous system disorders,
2. Applying botulinum toxin in the extracranial soft tissue of the head and neck,
3. It can be stated that the improvement of the symptoms caused by the central nervous system disease is evaluated, or that the progression rate of the central nervous system disease is slowed down.

Dosing Again, the dosing is 2.5 to 3000 units. The medication can be placed in multiple locations. Selective administration to the brain is possible by injecting over the targeted brain area. For example, when targeting the brain stem and midbrain, periocular injection will be preferred. Not only can sinus injections be given, this region can also be given nasal sinus injections. If the target is towards the temporal lobe, an injection can be given over the area around the temporal bone ear. If the target is in the occipital lobe, make injections under the neck, over the large occipital foramen, or over the occipital bone so that diffusion can be achieved through the interdisc vein in that part of the head Can do. It should be noted that venous drainage into the brain is often done in soft tissue within the extracranial circulation, but this mechanism may not be limited to this invasion route. A small amount of toxin can be diffused directly through soft tissue and even bone. A guidance map showing venous drainage in the extracranial region of the head and neck is shown in FIG.

  Injections should be repeated at 3-4 month intervals as needed for disease progression to improve overall symptoms. At the same time, image processing for a neurotransmitter may be performed. Specifically, the neurotransmitter may be selected from glutamate, acetylcholine, GABA, glycine, or norepinephrine.

  The relative proportion of neurotransmitters can be assessed using different image processing techniques and can be matched diagnostically to both the botulinum toxin effect and the pathogenesis of the targeted disease.

  The present application of the present invention should be considered to correspond in detail with the enabling diagnosis and associated neurotransmitter abnormalities. Mood and emotional disorders include major depression, bipolar disorder, minor depression, reactive depression, schizophrenia, seasonal emotional disorder, generalized anxiety disorder, anxiety neurosis with subdivision, post-traumatic stress syndrome It is a general term. In addition, anxiety-related anorexia, anorexia nervosa, psychosis, obsessive-compulsive personality traits; all forms of recurrent epilepsy, including generalized seizures, complex partial seizures, focal seizures; and any that occur in the central nervous system Toxic metabolic disorders can be targets for local neurotransmitter abnormalities.

Preferential injection strategies Currently, it is known that there is botulinum penetration and diffusion affecting brain neurotransmitters, so that certain parts of the brain can receive preferential medication for botulinum toxins. It is possible to change the injection strategy. Preferential medication in different regions of the brain is staged in different regions within the soft tissue outside the neural skull so that the diffusion gradient is optimized for the region of the brain where central nerve transmission is targeted. Use of an amount of botulinum toxin. This is due to, for example, the anatomical drainage pattern of the venous structures in this range and the proximity of adjacent areas, and the periocular region is expected to diffuse into the midbrain, frontal lobe, and thalamus regions. Is higher, and the supraorbital area means the most likely. Treatment of the temporal lobe area will include injection on the temporal bone. Cerebellar injections will include injections on the occipital fossa and the posterior occipital bone overlying the cerebellum. Injection into the upper cervical spinal cord will include injection on the paraspinal bone processes, the spinous processes lying on the spinal cord.

  This selective injection is anatomically controlled based on delivery and can also be optimized by medication. As mentioned earlier, due to the significance of extracranial injection, this injection has limited side effects and limited damage to the vital structures of the central nervous system, such as the cortex and brain structure. Applicable to The present invention does not teach direct injection into the brain by any of these techniques. In order to enhance the injection, small screw conduits are used in the critical area of the neural skull, which can allow more significant diffusion if necessary and can have an effect beyond that in a given area. Adjuvant therapy can be included.

A unique finding about what is taught herein is that central nerve transmission can be controlled by injection of botulinum toxin outside the neural skull by injection in soft tissue. As the inventor has previously taught for other patents, the diffusion of botulinum toxin is a dose-dependent phenomenon. The accessibility to the affected brain tissue by injection into the soft structure outside the neural skull provides a new approach to the central nervous system that was not previously correctly recognized. With advances in neurotransmitter imaging, this form of the invention and injection strategy has become a novel tool for dosing, administration, and disease targeting. Such diseases may include neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, seizure disorders, recurrent seizure disorders with injury, mood and emotional disorders, and damage from cerebrovascular obstruction. Limiting the damage of cerebrovascular occlusion also limits the excretion of vital neurotransmitters. More particularly, the neurotransmitter can include glutamate-related activity at the glutamate or central synapse level. Therefore, in the present specification, in carrying out the present invention,
1. Identifying areas of the brain with a limited range of neurotransmitter diseases and activity by image processing studies;
2. Applying the botulinum toxin in close proximity to this area by direct injection or by other forms of transdermal delivery systems as taught elsewhere in this disclosure;
3. Assaying the clinical benefit of such injection strategies,
4). It is taught to repeat the scanning system or scan to ensure that excessive neurotransmitter activity is adequately suppressed. Repeated injections over many years are expected.

Brain areas targeted using botulinum toxin and a unique injection strategy Botulinum toxin diffuses directly through the venous drainage system or other conduits into the neural skull and can cross the blood-brain barrier, thus preventing glutamate neurotransmission. It is possible to target brain regions with abnormally high levels. This technique provides a unique way to modify dosing and local brain neurotransmission that has not been previously described and can be applied to the various central nervous system disorders described herein . Among the recent technological advances in brain imaging, various neurotransmitter imaging can be realized by studies using PET scanning (positron emission tomography) and spectral MRI (magnetic resonance imaging). . Other methods are also envisaged. These advances have led to many mood and emotional disorders (major depression, bipolar disease, mania, schizophrenia, Parkinson's disease, Alzheimer's disease, anxiety, post trauma, stroke, cerebral hemorrhage, circadian rhythm disorders (sleep disorders) Various mediators in characterizing and understanding the mechanisms of hypertension, insomnia, hypersomnia, sleep apnea), anxiety disorders, post-traumatic stress syndrome, chronic anxiety, anorexia disorder, and anorexia) This is useful for starting to evaluate the contribution of defects. Such image processing methods not only characterize neurotransmission abnormalities, but can also enable the geographical location of the central nervous system region where neurotransmission is abnormal. Such a localization method allows for the administration of extracranial injections to maximize the penetration of the botulinum toxin-based formulation through the blood-brain barrier into the neural skull, and the targeted area of the drug is When taking the drug, drug application is not desirable, facial expression disorder, drooping, eyelids can not be closed, head movement is dull, flowing saliva, eyebrows drooping, paralytic hallux, facial asymmetry, Causes side effects such as facial palsy, double vision, obscure language, difficulty swallowing, upper airway dysfunction, aspiration, melancholy facial appearance, or other side effects associated with overdose of muscle tissue in the head and neck region Detailed plans are obtained regarding minimizing penetration away from the muscle, peripheral, and central nervous range.

  Neurotransmitter abnormality characterization can be applied to the aforementioned diagnostic entities to further characterize the nature of the disorder.

  The characterization will be done not only by the neurotransmitter type, but also by the specific brain region where the abnormal neurotransmitter activity is occurring. For example, if anomalous activity of neurotransmitter X is found in brain region Y, injection of botulinum toxin into the soft tissue outside the neurocranium is preferential to region Y in order to block neurotransmitter X. It can be adapted to target proper penetration and diffusion.

Region Y is
Diencephalon (rostral brainstem, caudate nucleus, thalamus, lens nucleus), midbrain, pons, medulla, any one of the times in the right or left hemisphere, hypothalamus, pituitary gland, fronto-temporal temporal lobe, It may be any one or combination of the spinal cord and occipital lobe or any other central nervous system part.

  The neurotransmitter X may be glutamic acid, acetylcholine, gamma aminobenzoic acid (GABA), norepinephrine, glycine, serotonin, or dopamine, more particularly any one or combination of glutamic acid, acetylcholine GABA, or norepinephrine. is there.

  Injections are maximized for diffusion and central nervous system delivery by either transcranial delivery by infiltration with venous drainage (orbital vein, facial vein, interdiscal vein), or any other blood brain barrier component , Anywhere outside the neural skull. Distance analysis from the injection site can be easily categorized by computer measurements on the imaged anatomy using MR or CT imaging.

  Central nervous system diseases include major depression, bipolar disease, bipolar depression, bipolar mania, mania, schizophrenia, psychosis, dementia, Alzheimer's disease, Huntington's disease, Parkinson's disease, obsessive-compulsive personality trait, recurrent Autoimmune central nervous system diseases involving glutamate such as epilepsy, systemic lupus erythematosus involving the central nervous system, head injury, head trauma, brain contusion, cerebral aneurysm rupture, hydrocephalus, or disruption of nervous tissue Includes mood and emotional diseases or disorders, including any other central nervous system disease involved.

  Inherent to the present invention, glutamate can be imaged using spectral MRI, PET scans, or any other mechanism that indicates higher levels of glutamate or any other neurotransmitter. The idea is that such neurotransmitters are also associated with toxic effects on neurons.

  Also, in this specification, the progression of any central nervous system disease is achieved by administering botulinum toxin in the extracranial portion of the head and blocking neurotoxic neurotransmitters using extracranial botulinum toxin. A method of treating, slowing or preventing the progression of a central nervous system disease, including, preventing, slowing, slowing or even preventing is described.

  The injection site includes a scalp, face, periocular region, head and neck region, mandibular region, periarticular region or nasal sinus, nasal cavity, sinus, bone, in order to achieve sufficient diffusion of botulinum toxin to selected regions in the brain. And the oropharynx. The process of determining the location is by analyzing the area of the brain that has shown abnormalities in neurotransmission by the techniques described above and selecting the extracranial region of the head and neck that allows maximum delivery. Inherent in the present invention is that it causes botulinum toxin to diffuse directly into the brain via the transcranial passage (without direct brain injection) and to block one important neurotransmitter. All others have previously taught to block botulinum toxins from crossing the blood brain barrier. In this specification, the opposite of the prevailing view, and that botulinum toxin can enter the brain within hours to days after injection and show a direct effect on neurotransmitters by extracranial injection. Describe new findings. More specifically, neurotransmitters include glutamate, acetylcholine, glycine, GABA, and botulinum toxins affect the expression of appropriate receptors, rendering toxic neurotransmitters ineffective in causing cell death. can do.

The method includes the following.
1. To confirm the state of the central nervous system (diagnostic entity) by diagnosis. Identifying brain regions that have been determined to have abnormal neurotransmitters for selective diagnosis.
2. Applying botulinum toxin to extracranial soft tissue in an amount sufficient to diffuse into the targeted brain region, or in certain situations, diffusely throughout the brain.
3. Block at least one neurotransmitter in the brain, thus improving the symptoms of the disease or reducing its progression.
4). Evaluate injection results by neuroimaging and clinical evaluation of signs and symptoms. Neuroimaging may have been used previously to establish the location of injection or the nature or subtype of the diagnostic entity being treated.
5). Repeat the application of botulinum toxin and monitor the effect so that progression of central nervous system disease does not occur.

A table representing the means of access to neurotransmission:
The following is a table of access for botulinum toxin injections to access various brain areas with associated diagnostic conditions for which targeted administration is contemplated. This table is for approximations and examples. The neuroimaging process for each individual with impaired neurotransmission will need to be evaluated prior to application.

  More specific injections can be given on individual occasions, or in areas where very specific focal areas of the brain can be treated by extracranial injection. For example, if a focal motion seizure originates from the frontal cortex of the left cerebral hemisphere, to achieve an intracranial injection in this region to administer directly without causing an effect on the adjacent region Can do.

  The above table is only an example and may be expanded based on conventional anatomy as described in Grant's atlas of Anatomy and Gray's Anatomy and Functional neuroanatomy textbooks. In clinical practice, localization can be achieved by using neuroimaging research, especially spectral MRI and PET scans, or any other form of localization technology that confirms that the condition is localized in the brain. Done optimally. For generalized brain or spinal cord conditions, a diffusion injection strategy can be used and tailored to produce a more general effect on the brain.

Further finishing of the injection strategy Since it has been established that botulinum penetrates the brain and as a result has an effect on neurotransmitters, the injection strategy ensures that certain parts of the brain receive preferential medication for botulinum toxin. It is possible to change. Preferential medication in different regions of the brain is staged in different regions within the soft tissue outside the neural skull so that the diffusion gradient is optimized for the region of the brain where central nerve transmission is targeted. Use of an amount of botulinum toxin. This is because, for example, the anatomical drainage pattern to the brain of venous structures in this area, as well as the proximity of the adjacent area, injection into the periocular region is the midbrain, frontal lobe, and thalamus region Means more likely to spread to the range. Treatment of the temporal lobe range will include injection of soft tissue over the temporal bone. Cerebellar injections will include injections on the occipital fossa and the posterior occipital bone overlying the cerebellum. Injection into the upper cervical spinal cord will include injection over the paraspinous process, the spinous process lying on the spinal cord.

  This selective injection is anatomically controlled based on delivery and can also be optimized by medication. As mentioned earlier, due to the significance of extracranial injection, this injection has limited side effects and limited damage to the vital structures of the central nervous system, such as the cortex and brain structure. Applicable to The present invention does not teach direct injection into the brain by any of these techniques.

  Include adjunctive therapies that use small screw conduits in the critical area of the neural skull that can allow more pronounced diffusion if necessary to have an effect beyond that in a given area to enhance injection It is possible.

Implantable conduit pins to enhance transcranial diffusion:
Transcranial diffusion is required for delivery of botulinum toxin to the brain structure across the bone and blood brain barrier, thus minimizing invasiveness and without requiring any major neurosurgical procedures. There are methods available to enhance this process. These methods enhance the direct penetration or diffusion application of botulinum toxin to the brain parenchyma through the neural skull cap, three layers of meninges (dura mater, arachnoid and pia mater) at the targeted location Includes device implantation. For example, a titanium pin with an open conduit can create a self-drilling screw and place it outside, in the middle, or in some cases on the inner tablet. Such implants reinforce the natural conduit found in the bony cranium around the vein and allow more toxins to penetrate if injections are made on such implants. Such a device may be made of any biocompatible material (titanium, ceramic, plastic, plastic) that is biocompatible. Such devices can be left in place even when future injections are not required.

  By using conduits to help central nervous system penetration, brain neurotoxin levels using lower doses without causing excessive weakness outside the central nervous system due to diffusion of neuromuscular effects Can be made higher.

Localized effects in dementia and other forms of neurodegeneration:
A unique finding about what is taught herein is that central nerve transmission can be controlled by injection of botulinum toxin outside the neural skull by injection in soft tissue. As previously taught in the patent cited as a reference, botulinum toxin diffusion is a dose-dependent phenomenon, and the accessibility to the affected brain tissue by injection into the soft structure outside the neural skull is: This provides a new access to the central nervous system that was not correctly recognized before or was directly implemented before. With advances in neurotransmitter imaging, this form of the invention and injection strategy has become a novel tool for dosing and disease targeting, as previously taught. Such diseases can include neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, seizure disorders, recurrent seizure disorders with injury, mood and emotional disorders, and damage from cerebrovascular obstruction. Limiting damage to cerebrovascular occlusion also limits critical neurotransmitters involved in neuronal cell damage. More particularly, the neurotransmitter can include glutamate-related activity at the glutamate or central synapse level. Therefore, in the present specification, in carrying out the present invention,
1. Identifying areas of the brain that have a limited range of neurotransmitter diseases and activity,
2. Applying the botulinum toxin in close proximity to this area by direct injection or by other forms of transdermal delivery systems as taught elsewhere in this disclosure;
3. Assaying the clinical benefit of such injection strategies,
4). It is taught to repeat the scanning system or scan to ensure that excessive neurotransmitter activity is adequately suppressed.

Insomnia Insomnia has been previously pointed out to be associated with certain problems with circadian rhythm function. The circadian rhythm functions of both sleep, blood pressure regulation in the general circulation, and cortisol secretion are, to some extent, interrelated with the central nervous system circadian system.

From a medical point of view, the disorder of insomnia has been associated with disturbances in blood pressure control. Sleep disorders may be associated with high blood pressure in certain treatment-resistant hypertensive patient populations. In these populations, botulinum toxin can be used in the form of extracranial soft tissue injections to affect the central nervous system so that the neurotoxin can alleviate sleep disorders and thus alleviate hypertension. . The mechanisms by which botulinum toxin can affect hypertension are the following:
1. 1. Improve sleep disorders 2. Improve anxiety. 3. Improve major depression It affects glutamate central nervous system neurotransmission so that the circadian clock and circadian rhythm are better maintained.

The combined effect requires that the botulinum toxin moves from the extracranial injection location through the nerve cranium and affects at least one neurotransmitter. The neurotransmitter is most likely to be glutamate, but may be norepinephrine, acetylcholine, or other forms of neurotransmitter. Diffusion to the brain is critical in how the present invention works. In particular, the present invention does not work by affecting sensory nerves, exerting effects on sensory nerve adaptation, or limiting either form of neuromuscular effects to cause weakness. The following points should be taken into account when implementing the present invention.
1. Diagnosis of hypertension that is resistant to conventional use or primary hypertension without prior treatment,
2. Diagnosis of accompanying sleep problems,
3. Administration of botulinum toxin to treat sleep disorders and thereby regulate hypertension,
4). Monitor hypertension using standard monitors and procedures.

  The above correctly recognizes the contribution of the central nervous system to idiopathic hypertension as well as other forms of hypertension.

  Sleep disorders are associated with a high incidence among minorities. Sleep disorders are more likely to occur in obesity and are more likely to occur in black populations by race composition. Such populations are also at higher risk of cardiovascular disease, so race and ethnicity are important in helping to predict the use of the invention described herein. In this situation, the assessment will need to be done in a high-risk population, such as African American racial selection with a much higher incidence of both sleep disorders and cardiovascular disorders. Such differences can be exploited to focus the implementation of the present invention on high risk populations. Furthermore, since the present invention is a technique administered by a physician and does not require any patient compliance, the present invention can be used in patients whose treatment of compliance is restricted.

  In these circumstances, the physician regularly administers toxin at doses of 2.5 to 3000 units of type A. Because patients do not have to apply medication daily at a specified time, the compliance factor is limited. A very long duration of botulinum toxin action of 12-16 weeks can be beneficial.

Administration in depression, unique attributes (major depression, bipolar depression, seasonal emotional disorder, posttraumatic stress syndrome)
The present teaching teaches the use of botulinum toxin for depressive disorders, particularly for major depressive disorder (MDD). Botulinum toxin can also be used for various other forms of depression, such as bipolar depression, post-traumatic stress syndrome, and seasonal affective disorder.

  Described herein is a method of administering botulinum toxin as an advantage in that it does not require daily patient compliance. This also limits the risk of suicide. In depression, administration is completely physician-driven and patients do not need to be exposed to large amounts of oral medication.

  In short, the risk of suicide with botulinum toxin administration is essentially zero. This is very advantageous in the treatment of depressed patients. This description describes not only the treatment of major depression, but also a method for treating major depression with a high suicide risk. In the practice of the present invention, a psychiatrist or physician assesses a patient's suicide risk based on the patient's past history, previous suicide attempts, and previous compliance with the use of drug applications. Botulinum toxin is recommended if the risk becomes clear. The inventive nature of this relies on the fact that the botulinum toxin is unilaterally given by the physician and does not require patient cooperation as far as medication or use is concerned. In this situation, this is an important advantage in practicality and is inventive in that it solves a major problem within psychiatric practice.

Hypertension, glutamate, and circadian disorders:
Blood pressure regulation is a major circadian function with circadian variation.

  Hypertension can be caused by abnormalities of the central nervous system function, and its treatment can be modulated by the use of drugs that act on the CNS, such as botulinum toxin preparations. Excessive sympathetic outflow from the autonomic CNS center is governed by circadian mechanisms that can have pathological consequences. Myocardial infarction is most commonly experienced in the morning because, in the morning, blood pressure and cardiovascular stimulation increase diurnally. Mitigating sympathetic nerve output by transcranial diffusion of botulinum toxin to the circadian clock mechanism in the hypothalamus can be useful in modulating blood pressure control.

  The hypothalamic periventricular nucleus (PVN) contributes to the development of hypertension in an experimental rat model. A population of neurons projects to sympathetic neurons in the spinal cord and cephalad ventral lateral bone marrow and regulates sympathetic outflow as well as vascular tone and blood pressure. Increased sympathetic nerve activity contributes to essential hypertension, such as the spontaneously hypertensive rat model. Glutamate is the major neurotransmitter in the paraventricular nucleus. Glutamate is the main neurotransmitter in the paraventricular nucleus, and increased glutamate input to presympathetic neurons has been shown to cause increased vasomotor tone and hypertension in a rat model. The paraventricular nucleus is a part of the circadian nervous system structure that receives significant input from the suprachiasmatic nucleus.

  Injections to extracranial structures to modulate glutamate neurotransmission in these areas that maximize flow to the hypothalamus (0074), basal ganglia, and pituitary vasculature are such as in the paraventricular nucleus. It is effective in regulating blood pressure by regulating and suppressing sympathetic nerve output from the region. Glutamate in these areas is associated with circadian rhythms (Castanada TR, Circadian Rhythms of dopamine, glutamate, and GABA in the striatum and nucleus accumbens in the awake rat, modulation by light J. Pineal Res. 2004 36 (3 ), 177-85).

  Therefore, the use of botulinum toxin in the frontal and extracranial areas to maximize venous drainage and transport of botulinum toxin into the brain area governing circadian rhythms uses one or more injections. It focuses on the treatment of central hypertension, and more particularly hypertension governed by circadian circadian variation. This form of hypertension disorder has been shown to be more dangerous with respect to the cardiovascular risk of myocardial infarction. This form of high blood pressure often eliminates evidence of blood pressure drop during sleep. Botulinum toxin effectively restores diurnal blood pressure fluctuations and relieves hypertension by treating circadian rhythm disorders. The dose may be as described herein.

Circadian rhythm disorders:
The circadian rhythm is under the influence of variations and expression of various neurotransmitters and related receptors. Various circadian rhythm disorders are due to perceptual light blockage (blindness), acquired disorders of neurotransmitters, and genetic abnormalities of enzymes, mechanical proteins, receptors, and other components of the molecular basis of neurotransmission. It can occur as a result of pathological fluctuations of neurotransmitters based.

  By changing circadian rhythm function, such as sleep disorder, attention deficit disorder, hypertension, cardiovascular stress due to central nervous system sympathetic outflow, appetite to regulate body weight and body fat mass, affective degenerative physiological dysfunction, etc. Several related disorders can be effectively treated. Emotional degenerative dysfunctions include diarrhea (convulsive colon disease) associated with anxiety and stress, hyperventilation, pervasive sweating, heartbeat-palpitations, asthma, increased pain, dizziness, chest discomfort, carelessness, forgetfulness, And fatigue.

  Improving sleep, sleep synchrony effectively helps many associated circadian functions and thus helps treat related dysfunctions. For example, improving sleep synchrony and associated blood pressure regulation may be associated with high blood pressure, coronary occlusion symptoms, asthma, functional abdominal pain, convulsive colon, ADD, and generalized non disruptive fatigue syndrome. Can be useful in treatment.

Improved sleep synchronization can ameliorate major depression, mania, bipolar disease, anxiety disorders, migraine-related disorders, chronic tension headache, back pain, or any other chronic pain disorder. By improving sleep,
1. Pain syndrome 2. Other mood and emotional disorders including major depression and anxiety syndrome as defined in DSM IV 3. General fatigue 4. Organic brain symptoms, dementia, memory, and cognition 5. Decreased energy and interest in daily life functions. Decreased concentration 7. Pathological changes in appetite 8. 8. Excitability and pathological agitation Repetitive thinking 10. The emotional component of essential hypertension can be effectively improved.

Use of Botulinum Toxin for Eating Disorders As previously described herein, botulinum toxin can be used to treat certain forms of eating disorders. These eating disorders include generalized anxiety, phobias, post-traumatic stress syndrome, and eating disorders associated with various forms of anorexia associated with depression. Anorexia nervosa is also an intended indication for botulinum toxin, when associated with an appropriate form of psychosocial, and mood and emotional disorders may also be targeted for treatment.

  Circadian rhythms have been implicated not only in maintaining blood pressure, sleep, and other forms of circadian rhythm function, but also in governing food intake. Glutamate neurotransmitters, as well as other forms of neurotransmitters, can be important for appetite development and anorexia. Described herein are methods for treating patients with certain forms of anorexia that may be associated with CNS abnormalities and neurotransmission. Again, application is by an extracranial injection strategy at commonly used doses, eg, 5-2000 units, more particularly 100-300 units, more particularly about 150-200 units.

  Such injections are given in single and multiple locations and are subcutaneous, subdermal, transdermal, intraosseous injection. Injections are directed to a critical area where diffusion governs appetite, and the toxin is administered locally so that the brain will encompass the hypothalamus and thalamus, the temporal area, and the brainstem and midbrain Can be applied by the method. This can be used in conjunction with other forms of anorexia therapy and can be useful in controlling anorexia, nausea, and appetite.

Down-regulation of opposing receptors:
In this specification, effects on glutamate and GABA, which are opposing neurotransmitters, are described. Dual activity by down-regulating receptor expression on central neurons is a very unique attribute in how botulinum toxins act in the central nervous system. Because glutamate is associated with neuronal hyperactivity and GABA is associated with neuronal repressors, botulinum toxin modulates both excitability and repression of neuronal bioactivity. Such effects may exhibit unique characteristics related to mood and emotion, including, but not limited to, experiencing anxiety in some ways and depression in others.
[Example]

  The following examples serve to further illustrate the invention and are not to be construed as limiting its scope in any way.

  A 78-year-old man who pointed to sleep disturbance and anxiety was initially diagnosed with blepharospasm. When botulinum toxin was administered by injection, the subject noted improved sleep and reduced anxiety.

  A 44-year-old bus driver was diagnosed with unilateral facial spasm and reported symptoms of anxiety. Botulinum toxin was administered by injection. The subject pointed out that he was able to deal with work-related stress and has been able to cope with less stress in difficult situations.

  A 72-year-old consultant who was diagnosed with unilateral facial spasm who reported sleep disturbance and anxiety was treated with a botulinum toxin administered by injection. Subject reported improved sleep, reduced anxiety, and less agitation.

  A 45-year-old woman was treated with botulinum toxin for cosmetic indications. The initial diagnosis was cosmetic crust. The subject noted that there were fewer symptoms of depression and less anxiety for 2 months.

  A 44-year-old woman diagnosed with severe tension headache and sleep disorder received botulinum toxin treatment by injection. Subjects noted that sleep patterns improved and less headaches up to 2 months after treatment.

  A 73-year-old man with idiopathic blepharospasm reported sleep disturbance and anxiety characterized by "nervous tension". Botulinum toxin was administered by injection. Subject noted that after injection, anxiety decreased and sleep improved. Symptom relief lasted 2-3 months and eventually recurred.

  A 43-year-old person with facial muscle pain and sleep problems received botulinum toxin treatment by injection. The subject noted that after injection, the sleep pattern became better and persisted for 3 months.

  A 42-year-old person was diagnosed with facial muscle pain, tension headache, and depression and was treated with botulinum toxin administered by injection. Subject noted that sleep pattern improved somewhat after toxin injection.

  The subject is a 54 year old person diagnosed with idiopathic blepharospasm and depression. Botulinum toxin was introduced by injection. The subject noted that there were fewer symptoms of depression after botulinum toxin injection.

  The subject is a 57-year-old doctor diagnosed with idiopathic blepharospasm. Botulinum toxin was introduced by injection. Subject noted euphoria, a sense of well-being, and improved mood after botulinum toxin injection.

  A 47-year-old woman with a history of cervical headache and frequent insomnia problems. Insomnia was characterized by difficulty in starting sleep, intermittent wakefulness, early morning wakefulness, and inability to maintain sleep. Injections were given at a number of locations along the area commonly used for treatment of spastic torticollis, as well as both anterior and posterior hairline. The dose ranged from 5 to 20 units per subcutaneous injection site with a total dose of 100 U. Within 3-5 days, improvement of insomnia occurred and lasted for 10-14 weeks. Improvements in each of the women's sleep disturbances occurred. The recurrence of sleep disorders occurred after 10-14 weeks.

  A 52-year-old woman received a botulinum injection to make the crusts (facial wrinkles) between the eyebrows inconspicuous. Additional injections were made at a number of locations along the hairline, and the woman also suffered from insomnia, which makes it difficult to initiate and maintain sleep. After botulinum toxin injection, sleep pattern improved and persisted for about 10-12 weeks. The total dose administered at multiple locations was 30 units.

  A 71 year old male with idiopathic blepharospasm received a 60 U injection divided along the periocular area and forehead. An improvement in sleep patterns, characterized by more continuous sleep, was observed after each injection. The benefit lasted about 3 months and was observed over 3 injection cycles. Upon raising the patient's attention, the patient associated the improvement with a botulinum toxin injection. When the patient felt it was time to repeat botulinum toxin injections, insomnia recurred.

A botulinum toxin composition comprising human serum albumin and nanoemulsion in various addition amounts and consisting of a single component neurotoxin molecule without accessory protein or complex protein is prepared from any of the immunotypes (A to G). . Nanoemulsions may contain polymers consisting of either polyethylene glycol, vegetable oils, vegetable oil derivatives, or monounsaturated or polyunsaturated oils. Permeability may be enhanced by changing the pH in the composition. Alternatively, botulinum toxin is prepared from immunotypes A to G consisting of a single component neurotoxin, without a nanoemulsion carrier, albumin, and an acidic pH of 1-6 units. A rodent model (20-30 gram mouse) commonly used for the investigation of neurodegenerative diseases was used to demonstrate the effect on the central nervous system from transcranial injection. Injection with botulinum toxin type A was given over the scalp area at a dose close to and approaching the LD ₅₀ for this animal. Surviving animals were necropsied and the brains were cut serially and histologically stained using standard Nissl methods. Substantial atrophy of the basal ganglia and periventricular cells was observed. Such changes are usually not seen in systemic disease without direct brain pathology. The neuropathological evaluation is that a direct inhibitory effect occurs in the central nervous system at high doses (close to the LD ₅₀ for animal models). At smaller therapeutic doses based on clinical knowledge about efficacy against insomnia, dysmenorrhea, depression, and anxiety, finer changes are expected and observed. In the experiments described herein, blocking of neurotransmission of excitatory neurotransmitters is usually shown to the extent that pathological changes occur in brain structures. The major central nervous system neurotransmitters that are blocked include glutamate, norepinephrine, and acetylcholine. The GABA effect is increased. SNAP-25 is observed to be cut across the targeted range.

A rodent model (20-30 gram mouse) commonly used for the investigation of neurodegenerative diseases was used to demonstrate the effect on the central nervous system from transcranial injection. Four botulinum toxin injections (total 0.8LD ₅₀ units) were given over the scalp area. Surviving animals were necropsied and the brains were cut serially and histologically stained using standard Nissl methods. Substantial atrophy of the basal ganglia and periventricular cells was observed. There was a substantial decrease in cholinergic neurons. A substantial decrease in the amount of choline acetyltransferase was observed. Smaller changes are expected at lower therapeutic doses based on clinical knowledge of efficacy against insomnia, dysmenorrhea, depression, and anxiety. In the experiments described herein, blocking of neurotransmission of excitatory neurotransmitters is usually shown to the extent that pathological changes occur in brain structures. The major central nervous system neurotransmitters that are blocked include glutamate, norepinephrine, and acetylcholine. The GABA effect is increased. SNAP-25 is observed to be cut across the targeted range.

A rodent model (20-30 gram mouse) commonly used for the investigation of neurodegenerative diseases was used to demonstrate the effect on the central nervous system from transcranial injection. Four botulinum toxin injections (total 0.8LD ₅₀ units) were given over the scalp area. Surviving animals were necropsied and the brains were cut serially and histologically stained using standard Nissl methods. Serially cut mouse tissue sections were stained for Nissl material using cresyl violet and immunostained for glutamate receptor activity. Sections were rinsed for 1 hour in Tween 20 supplemented TRIS buffered saline (TBS-T) containing 10% normal goat serum. The sections were then incubated overnight with 0.1% sodium azide and anti-GluR4 in TBS-T. Sections were rinsed 3 times in TBS-T and then incubated in TBS-T containing goat anti-mouse peroxidase conjugated secondary antibody for 2-3 hours to detect glutamate. The sections were then rinsed 3 times in TBS-T. Diaminobenzidine was used to visualize the antibody complex. To show antibody specificity and the background resulting from this detection assay, pre-absorption of excess target protein or exclusion of primary or secondary antibodies was utilized. Tissue sections were examined using a Nikon Eclipse E800 microscope equipped with a Spot RT digital camera. Photographs of tissue sections of new striatum in untreated mice (sham injection) and botulinum toxin treated mice (4 injections of BOTOX® totaling 0.8LD ₅₀ injected percutaneously over the scalp area) As shown in FIG.

  To further understand whether scientific evidence of transcranial movement of botulinum toxin into the brain parenchyma and brain structure is accumulated, the fusion of Alexa dye and botulinum toxin is used to describe the experimental rat model described herein. Put it in. This fusion preparation resulted from the same strain and culture used for the production type A toxin Hall strain commonly used as Botox ™ sold by Allergan Pharmaceuticals in the treatment of human diseases It was. The fusion of this botulinum toxin type A neurotoxin with Alexa dye was studied for the possibility of diffusion from the extracranial injection into the brain at 3, 6, 12, 24 hours, and 2 weeks. A series of 3-5 mice were analyzed for each period. At 6 hours, Alexa dye was found in the brain, and immunohistochemical analysis of the central nervous system structure was performed by examining brain slices and brain slices by immunofluorescence microscopy. At 3 hours, no such dye was observed, and no dye was observed thereafter. This was a pharmacokinetic experiment suggesting that the toxin and dye together moved from the extracranial injection to the brain.

  This finding, coupled with anatomical atrophic changes near lethal doses and changes in receptor expression of key brain neurotransmitters, causes botulinum toxin to migrate to the neurocranium and against at least one neurotransmitter. It clearly shows that it can show biological effects. Herein, a central nervous system that involves neurotransmitters important for practical use from this experimental model, i.e., mood and emotion disorders as described herein, is useful in the treatment of disorders involving mood and emotion. Describes the operation of system neurotransmission.

  In major depressive disorder, abnormalities in glutamate neurotransmission are confirmed in the basal ganglia and adjacent hemisphere compared to normal control comparison data. The symptoms of MDD are assessed according to the DSM IV criteria. The treatment plan uses anatomical parameters, calculates a dose-dependent diffusion strategy, and applies botulinum toxin in close proximity to the rostral basal ganglia where abnormal neurotransmitter activity has been confirmed To be built.

  Overlapping anatomical scans to match abnormal neurotransmitter activity (eg, glutamate neurotransmission, glutamate content, or glutamate receptor expression) so that the shortest distance from the neuroimaging study is extrapolated . Various doses of botulinum toxin are administered at single or multiple administration locations so that delivery is directed from the extracranial injection to the central nervous system and brain.

  44 years of major depression who is not responsive to serotonin reuptake inhibitors (Cymbalta ™) and tricyclic antidepressants and has been diagnosed with at least five DSM IV determinants of major depression Women were analyzed by PET scans set for glutamate neurotransmission and glutamate content using an appropriate computer-aided program, compared to control levels in non-depressive normal controls, and deviations were measured by graphic techniques, FIG. The position of the glutamic acid deviation in the image as shown in FIG. Deviations are indicated by arrows.

  Botulinum toxin type A is injected along the left peri eye area deep into the mucous membrane of the left nasal cavity and into the center of the face. Botulinum toxin dosing is 4 to 3000 units in total, but the dose is an extracranial anatomical area, dose, number of injections, and glutamate that correlates with significant biological effects in a number of dosing trial multiclinical studies Adjustments are made based on a predetermined nomogram determination of changes using images that reveal effects on neurotransmission. The dose is applied in such a way as to alleviate the adverse effects on facial facial muscles, so non-facial muscle regions are preferred. Facial muscles that contribute to cosmetic benefits are subjected to a higher degree of dose splitting, thus avoiding facial asymmetry or impaired aesthetics.

  Several weeks later, the effect on major depression will be evaluated. Repetitive injections are given at 6-14 week intervals. Various parameters such as hyaluronidase or polycation protein can be used in the injection strategy.

  A 67-year-old elderly man has memory and spatial disabilities. This man has been clinically diagnosed as having Alzheimer's disease. PET and spectral MRI scans have spread throughout the cerebral cortex but show a more pronounced increase in glutamate activity across the frontal and temporal regions. In order to limit neurotoxicity from glutamate in the generation with advanced Alzheimer's disease, multiple injections are given in the frontal and temporal regions. In FIG. 3, excessive glutamic acid expression is shown in the range (indicated by arrows) extending from the frontal cortex and temporal cortex. Botulinum is injected in the bone structure on the involved cerebral cortex to reduce glutamate activity, thus suppressing the symptoms of organic brain dysfunction and mitigating the progression of progressive dementia.

  Some patients are found to have excessive GABA neurotransmission based on neuroimaging studies. FIG. 4 shows that areas of the brain are analyzed locally for areas of excess GABA neurotransmission, and extracranial injection strategies cover these areas of treatment. Botulinum toxin, according to the animal studies presented herein, has shown inhibition of GABA neurotransmission and is given an effective dose ranging from 5 to 3000 U at single or multiple locations in the extracranial region.

Claims (20)

A method of treating a central nervous system disorder defined as having an abnormality of at least one brain neurotransmitter in at least one or more regions of the brain, comprising:
a. Injecting botulinum toxin into the extracranial area of the head or neck,
b. The extracranial region of the head and neck is in close proximity to one region of the brain so that abnormal neurotransmitter activity can be determined using PET scanning, functional magnetic resonance imaging, or brain scanning;
c. The botulinum toxin blocks neurotransmission involving at least one neurotransmitter,
The method of treatment comprising a method.   The treatment method according to claim 1, wherein the neurotransmitter is glutamic acid.   The treatment method according to claim 1, wherein the neurotransmitter is acetylcholine.   The treatment method according to claim 1, wherein the neurotransmitter is GABA.   The method according to claim 1, wherein the neurotransmitter is norepinephrine.   The method of claim 1, wherein the brain abnormality is associated with major depressive disorder.   The method of claim 1, wherein the brain abnormality is associated with bipolar disease.   The method according to claim 1, wherein the brain abnormality is associated with generalized anxiety disorder and post-traumatic stress syndrome.   2. The method of treatment according to claim 1, wherein the disorder is associated with seizures.   10. The method of treatment of claim 9, wherein the seizure includes focal movements and complex partial seizures.   The method of treatment according to claim 1, wherein the disorder is neurodegeneration characterized as Alzheimer's disease, Parkinson's disease, or Huntington's disease.   The treatment method according to claim 1, wherein the disorder is cerebrovascular accident.   The method of treatment according to claim 1, wherein the disorder is central hypertension.   14. The method of treatment according to claim 13, wherein the disorder comprises a central component of essential hypertension.   The treatment method according to claim 1, wherein the disorder is an appetite disorder that is obsessive-compulsive disorder.   The method according to claim 1, wherein the disorder is circadian rhythm disorder.   The treatment method according to claim 1, wherein the disorder is a sleep disorder.   The method of claim 1, wherein the disorder is a pain disorder characterized as migraine, tension headache, complex tension headache migraine, trigeminal neuralgia, myofascial pain, cluster headache, postoperative wound pain.   The method of treatment according to claim 1, wherein the disorder is schizophrenia.   The treatment method according to claim 1, wherein the disorder is seasonal emotional disorder.