Botulinum toxin for use in treatment

Abstract

To provide botulinum toxins for use in treatment of ASD (autism) in a patient in need of treatment.SOLUTION: The treatment comprises administering a botulinum toxin to the patient by subcutaneous / intradermal injection. The administration to an adult comprises injecting 2-4 units to a trigeminal nerve and / or the vicinity thereof, 2-4 units to a cervical nerve and / or the vicinity thereof lateral to the patient's spine, 2-4 units to a thoracic nerve and / or the vicinity thereof lateral to the patient's spine, 2-4 units to a lumbar nerve and / or the vicinity thereof lateral to the patient's spine, and / or 2-4 units to a sacral nerve and / or the vicinity thereof lateral to the patient's spine, where the total dosage of the botulinum toxin in an adult who weighs about 150 pounds is less than or equal to about 50 units, and the total dosage is adjusted for the age, weight or a combination thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] [Priority claim] This application is a joint venture of the US Provisional Patent Application No. 2019 / 10 / 18 entitled "Drug therapy for treating autism using botulinum toxin". U.S. application Ser. No. 16 / 657,933, entitled "Treatment of Inflammatory Bowel Disease," currently issued on July 28, 2020. No. 10,722,552 B1, which is hereby incorporated by reference in its entirety. Claim priority.

[0002] [Technical field] The present invention relates to a method for treating dry eye syndrome (DES), ASD (autism), opioid tolerance, vestibular Neuropsychiatric and / or neurological disorders, such as, but not limited to, dizziness, and tinnitus The present invention relates to methods for diagnosing and treating (including alleviating and / or preventing) disorders. [Background technology]

[0003] Botulinum toxins bind to synaptosomal neuroassociated protein 25 ("SNAP25") and and / or synaptobrevin (also called vesicle-associated membrane protein ("VAMP")) Botulinum toxins types A, C, and E are distinct. Although the effect is the same - the protein is destroyed, Botulinum types B, D, F, and G The toxin cleaves VAMP present on the cytoplasmic surface of synaptic vesicles. Two important locations in the body are the terminals of motor neurons (muscles) and astrocytes and glial cells. These three cell types surround the sensory neurons. , which forms part of the blood-brain barrier. In motor neurons, acetylcholine is required to fire them. Vesicles of phosphorus move through the cell membrane at the synapse between the motor nerve and the muscle fiber from the inside of the motor neuron. Acetylcholine is released into the synapse, and the activated receptors of the muscle fiber contract the synapse. In sensory nerves, when the nerve is damaged by physical or mental injury, the three aforementioned structural cells produce large amounts of substance P, calcitonin gene-related peptide (CGRP), and glutamate internally, which is moved to the cell membrane by vesicles, where SNAP25 and / or VAMP move it through the cell membrane and release it into the cerebrospinal fluid surrounding the neuron. There it binds to the receptors of the sensory nerve and causes a nerve excitatory effect. It also diffuses into the cerebrospinal fluid (CSF) and can affect other sensory nerves and hyperactivate them, which is a process called central sensitization.

[0004] In muscles and sensory nerves, the mechanism that cleaves the aforementioned SNAP25 and / or VAMP causes the only known clinical effect of Clostridium botulinum. It paralyzes the muscle for 3 to 4 months until the cell grows new proteins. This effect has been used for decades in hyperactive bladder (cervical dystonia, blepharospasm, tic, Parkinson's disease, cerebral palsy, etc.), facial wrinkles , excessive sweating, and overactive bladder.

[0005] In the aforementioned sensory nerves, it is used for migraine and depression. The effect of blocking SNAP25 and / or VAMP in glial cells, satellite cells , and astrocytes acts for 5 to 9 months until these cells grow new proteins. The important part of this is , that the effect of the aforementioned Clostridium botulinum does not destroy the cell, and acetylcholine (muscle) in sensory nerves or the normal production or effect of substance P, CGRP, or glutamate is stopped This is. Due to these facts, a great advantage is brought compared to monoclonal antibodies that eliminate all glutamate, CGRP, and substance P. Side effects become tragic. Receptor antagonists also have problems. They are not site-specific. They block glutamate, substance P, and CGRP in any case. Too little glutamate, substance P, and CGRP is as much of a problem as too much. In regions where glutamate, substance P, and CGRP are very high, it is difficult to adjust the oral or in vivo dose to obtain the correct reduction without excessive reduction in the region of normal levels.

[0006] By cleavage of SNAP 25 and / or VAMP, a small amount of botulinum toxin is injected into specific muscles to calm the overreaction or, if desired, paralyze temporarily. Also, when injected subcutaneously near unmyelinated sensory nerves, it can reduce or stop the overproduction of sensory nerve excitatory compounds without affecting the production and function of normal glutamate, substance P, and CGRP. However, botulinum toxin is known to be very deadly. It is the most toxic poison known. One molecule of botulinum toxin destroys one protein molecule of SNAP25 and / or VAMP. It is very useful in small amounts. Manufacturing, storage, and injection need to be done with knowledge and care.

[0007] Especially the sensory effect (stopping the overproduction of glutamate, substance P, and CGRP ​​​​​​​​​​​​The mechanism of this is as follows: Almost all nerves in the human body are made up of a membrane called myelin. The nerves are surrounded by a protective coating that protects the nerves and makes nerve conduction faster. Turinum toxin has difficulty penetrating myelin. Just below the skin are unmyelinated C-fibers and There are several sensory pain nerves called sarcoma nerves. Research has shown that botulinum toxin binds to these axons. They penetrate and diffuse down the axons to the cell bodies into the CSF, where they reach glial cells, satellite cells, and astrocytes. It may affect SNAP25 and / or VAMP in blastocytes. The enzyme disrupts SNAP25 and / or VAMP, resulting in normal glutamate and substance P, and the nerve injury response without affecting CGRP production, use, or receptors. Prevents the release of excess substance P, CGRP, and glutamate, which are involved in the mechanism An example of a normal nerve mechanism going wrong is nerve infection by the varicella zoster virus. The infection damages the nerve but does not kill it or cause sensation (numbness). This leads to a surge in the production of glutamate, substance P, and CGRP. It causes the pain and hypersensitivity commonly known as shingles. The infection is controlled within 2-3 months. Sometimes, however, the nerve heals and the overproduction of neuroexcitatory chemicals returns to normal. For unknown reasons, the overproduction does not return to normal but remains elevated, causing severe chronic pain and Chronically overstimulated neurons, depending on where they are, are This can cause a lot of problems. These neuroexcitatory chemicals travel up the spinal cord and into the cerebrospinal fluid (CSF). They can travel to the brain, where they can affect neurons. This process is called central sensitization. Depending on where it is produced and where it travels, it can cause chronic pain, headaches, dizziness, and other symptoms. i. Photosensitivity to light, tactile hypersensitivity, cold intolerance, overactive bladder, depression, anxiety neurosis, flushing uback, mental fog, vasoconstriction of the extremities, sleep disorders, and perhaps death and malformation of the developing neural structures in children with ASD (autism), among others conditions or diseases not limited to these can be caused.

SUMMARY OF THE INVENTION

[0008] Some embodiments of the claimed invention relate to botulinum toxin for use in the treatment of the dry eye syndrome group in patients in need of treatment. The treatment includes administering the botulinum toxin to the patient. The botulinum toxin can be administered by subcutaneous / intradermal injection. The subcutaneous / intradermal injection can be administered to the trigeminal nerve of the patient and / or its periphery. The trigeminal nerve is selected from the group consisting of the oculomotor nerve, maxillary nerve, mandibular nerve, supraorbital nerve, superior laryngeal nerve, infraorbital nerve, lacrimal nerve, nasal ciliary nerve, superior alveolar nerve, buccal nerve, lingual nerve, inferior alveolar nerve, mental nerve, auriculotemporal nerve, lesser occipital nerve, greater occipital nerve, and combinations thereof. The subcutaneous / intradermal injection can be administered to the cervical nerve of the patient and / or its periphery. The cervical nerve is selected from the group consisting of c-2 nerve, c-3 nerve, c-4 nerve, c-5 nerve, c-6 nerve, c -7 nerve, c-8 nerve, and combinations thereof. In some embodiments, the subcutaneous / intradermal injection can be administered to the trigeminal nerve and cervical nerve of the patient and / or their periphery. Preferably, the administration to adults is 2 to 4 units to the oculomotor nerve (bilateral), maxillary nerve, and / or mandibular nerve of the trigeminal nerve, and / or its periphery, and / or to the c-2 to c-3, c-4 to c of the cervical nerve about 1 inch outside the spinal cord (bilateral). embodiments, the subcutaneous / intradermal injection can be administered to the trigeminal nerve and cervical nerve of the patient and / or their periphery. Preferably, the administration to adults is 2 to 4 units to the oculomotor nerve (bilateral), maxillary nerve, and / or mandibular nerve of the trigeminal nerve, and / or its periphery, and / or to the c-2 to c-3, c-4 to c of the cervical nerve about 1 inch outside the spinal cord (bilateral). ​​​​​​​-6 and / or to c-7 to c-8, and / or 2 to 4 units to its periphery including. In some embodiments, for each injection site, the described number of botulinum toxin units (i.e., 2 to 4 units) are given either over a period of time (e.g., separately at intervals) in a single hour or in multiple doses. Administration to infants from about 1 year to 5 years of age is adjusted according to age and body weight. In some preferred embodiments, the botulinum toxin is selected from the group consisting of botulinum toxin type A, botulinum toxin type B, botulinum toxin type C, botulinum toxin type D, E type botulinum toxin, type F botulinum toxin, type G botulinum toxin, fragments thereof, their hybrids, their chimeras, and combinations thereof. The botulinum toxin can be used together with other regulatory agents or chemicals. In further embodiments the total dose of botulinum toxin for an adult weighing about 150 pounds is between about 2 units and about 1 50 units. The dose of botulinum toxin for adults or children is adjusted according to age, weight, or a combination thereof.

[0009] Some embodiments of the claimed invention relate to botulinum toxin for use in the treatment of ASD (autism ) in patients in need of treatment. The treatment includes administering the botulinum toxin to the patient. The botulinum toxin can be administered by subcutaneous / intradermal injection . The subcutaneous / intradermal injection can be administered to the trigeminal nerve of the patient and / or its periphery . The trigeminal nerve can be the ophthalmic nerve, maxillary nerve, mandibular nerve, supraorbital nerve, superior laryngeal nerve, infraorbital nerve, lacrimal nerve, nasal ciliary nerve, superior alveolar nerve, buccal nerve, lingual nerve, inferior alveolar nerve, mental nerve, auricular Selected from the group consisting of the intermediate cranial nerve, the lesser occipital nerve, the greater occipital nerve, and combinations thereof. The subcutaneous / intradermal injection can be administered to and / or around the cervical nerves of the patient. The cervical nerves are selected from the group consisting of the c-2 nerve, the c-3 nerve, the c-4 nerve, the c-5 nerve, the c-6 nerve, the c-7 nerve, the c-8 nerve, and combinations thereof. In some embodiments, the subcutaneous / intradermal injection can be administered to and / or around the trigeminal nerve, the thoracic nerves, the lumbar nerves, and the sacral nerves of the patient. In some other embodiments, the trigeminal nerve, cervical nerves, thoracic nerves, lumbar nerves, and sacral nerves of the patient. Preferably, administration to an adult is by subcutaneous / intradermal injection of 2 to 4 units to the ophthalmic nerve, maxillary nerve, and / or mandibular nerve of the trigeminal nerve (bilateral), and / or around it, and 2 to 4 units to the c-2 to c-3, c-4 to c-6, and / or c-7 to c-8 of the cervical nerves about 1 inch outside the spinal cord (bilateral), and / or around it, 2 to 4 units to the t-2 to t-3, t-5 to t-6, t-7 to t-9, and / or t-10 to t-12 of the thoracic nerves about 1 inch outside the spinal cord, and / or around it, 2 to 4 units to the l-1 to l-2, l-2 to l-3, and / or l-4 to l-5 of the lumbar nerves about 1 inch outside the spinal cord, and / or around it, and 2 to 4 units to the s-1 to s-2, s-3 to s-4, and / or s-4 to s-5 of the sacral nerves about 1 inch outside the spinal cord (bilateral), and / or around it, including. In some embodiments, for each injection site, the stated number of units of botulinum toxin (i.e., 2 to 4 units) is given either at a single time or in multiple doses over a period of time (e.g., separately). Administration to infants from about 1 year to 5 years of age is based on age and ​​​​​​​​​​​​​​ In some desirable embodiments, the botulinum toxin Botulinum toxin types A, B, C, and D Botulinum toxin type E, botulinum toxin type F, botulinum toxin type G, fragments thereof, and hybrids thereof, chimeras thereof, and combinations thereof. In a further embodiment, the total dose of botulinum toxin for an adult weighing about 150 pounds is The dosage ranges from about 2 units to about 150 units. Amounts are adjusted for age, weight, or a combination. Infants or young children - From about 1 to 5 years of age, it is used to prevent or minimize damage to the developing brain; Reduces symptoms in older children and adults with autism spectrum disorder (ASD) or is used to eliminate

[0010] Some embodiments of the claimed invention provide a method for treating narcotic intolerance in patients in need of treatment. The present invention relates to a botulinum toxin for use in treating sexual dysfunction, said treatment comprising administering a botulinum toxin to a subject. The botulinum toxin is administered by subcutaneous / intradermal injection. The subcutaneous / intradermal injection is administered to and / or around the trigeminal nerve of the patient. The trigeminal nerve may be the ophthalmic nerve, the maxillary nerve, the mandibular nerve, the supraorbital nerve, the supratracheal nerve, the orbital nerve, Inferior nerve, lacrimal nerve, nasal ciliary nerve, superior alveolar nerve, buccal nerve, lingual nerve, inferior alveolar nerve, mental nerve, Selected from the group consisting of the auriculotemporal nerve, the lesser occipital nerve, the greater occipital nerve, and combinations thereof The subcutaneous / intradermal injection is administered to and / or around the patient's cervical nerve. Obtained. The cervical nerves are selected from the group consisting of c-2 nerve, c-3 nerve, c-4 nerve, c-5 nerve, c-6 nerve, c-7 nerve, c-8 nerve and combinations thereof. In some embodiments, the subcutaneous / intradermal injection can be administered to and / or around the trigeminal nerve, thoracic nerve, lumbar nerve, and sacral nerve of the patient. In some other embodiments, the trigeminal nerve, cervical nerve, thoracic nerve, lumbar nerve, sacral nerve of the patient. Preferably, the administration to adults is by subcutaneous / intradermal injection to the ophthalmic nerve, maxillary nerve, and / or mandibular nerve of the trigeminal nerve (bilateral), and to and / or around it, 2-4 units, to the cervical nerves of about 1 inch outside the spinal cord (bilateral) of c-2 to c-3, c-4 to c-6, and / or c-7 to c-8, and to and / or around it, 2-4 units, to the thoracic nerves of about 1 inch outside the spinal cord of t-2 to t-3, t-5 to t-6, t-7 to t-9, and / or t-10 to t-12, and to and / or around it, 2-4 units, to the lumbar nerves of about 1 inch outside the spinal cord of l-1 to l-2, l-2 to l -3, and / or l-4 to l-5, and to and / or around it, 2-4 units, and / or, to the sacral nerves of about 1 inch outside the spinal cord (bilateral) of s-1 to s-2, s-3 to s-4, and / or s-4 to s-5, and to and / or around it, 2-4 units, including. In some embodiments, for each injection site, the described number of botulinum toxin units (i.e., 2-4 units) are given either at a single time or in multiple times over a period of time (e.g., separately). The dosage for 0-5 years old needs to be adjusted according to age and weight. In some preferred embodiments, the botulinum toxin is botulinum toxin type A, botulinum toxin type B, botulinum toxin type C, botulinum toxin type D toxin, etc. Toxins, botulinum toxin type E, botulinum toxin type F, and botulinum toxin type G, their fragments, their hybrids, their chimeras, and combinations thereof. Selected from the group consisting of. In a further embodiment, the total dose of botulinum toxin for an adult weighing about 150 pounds is between about 2 units and about 150 units. The dose of botulinum toxin for adults or children is adjusted according to age, weight, or a combination thereof.

[0011] Some embodiments of the claimed invention relate to botulinum toxin for use in the treatment of vestibular vertigo in a patient in need of treatment. Said treatment comprises administering the botulinum toxin to said patient. Said botulinum toxin can be administered by subcutaneous / intradermal injection. Said subcutaneous / intradermal injection can be administered to and / or around the trigeminal nerve of said patient. Said trigeminal nerve is selected from the group consisting of the ophthalmic nerve, maxillary nerve, mandibular nerve, supraorbital nerve, superior petrosal nerve, infraorbital nerve, lacrimal nerve, nasal ciliary nerve, superior alveolar nerve, buccal nerve, lingual nerve, inferior alveolar nerve, mental nerve, auriculotemporal nerve, lesser occipital nerve, greater occipital nerve, and combinations thereof. Said subcutaneous / intradermal injection can be administered to and / or around the cervical nerve of said patient. Said cervical nerve is selected from the group consisting of c-2 nerve, c-3 nerve, c-4 nerve, c-5 nerve, c-6 nerve, c-7 nerve, c-8 nerve, and combinations thereof. In some embodiments said subcutaneous / intradermal injection can be administered to and / or around the trigeminal nerve and cervical nerve of said patient. Preferably, the administration to an adult is 2 to 4 units to and / or around the ophthalmic nerve, maxillary nerve, Or about 1 inch lateral (on both sides) of the spinal cord, the cervical nerves c-2 to c-3, c-4 to c-6, and and / or 2-4 units to c-7 to c-8 and / or their surroundings. In some embodiments, for each injection site, a recited number of botulinum toxins (i.e., 2-4 credits) may be given once or multiple times over a period of time (e.g., for interference with motor function or are given separately at different times to avoid causing muscle paralysis. Dosing for children aged 1 to 5 years is adjusted according to age and weight. In embodiments, the botulinum toxin is a botulinum toxin type A, a botulinum toxin type B, a botulinum toxin type C, Botulinum toxin, botulinum toxin type D, botulinum toxin type E, botulinum toxin type F, and Botulinum toxin type G, fragments thereof, hybrids thereof, chimeras thereof, and In a further embodiment, the subject is selected from the group consisting of a human subject weighing about 150 kg or more and combinations thereof. The total dose of botulinum toxin per pound for an adult ranges from about 2 units to about 150 units. or the dosage of botulinum toxin for children depends on age, weight, or a combination of these. is adjusted according to the

[0012] Some embodiments of the claimed invention are directed to treating tinnitus in a patient in need of such treatment. The present invention relates to a botulinum toxin for use in treating a patient with botulinum toxin. The botulinum toxin may be administered by subcutaneous / intradermal injection. The subcutaneous / intradermal injection may be administered at and / or around the patient's trigeminal nerve. The trigeminal nerve includes the ophthalmic nerve, maxillary nerve, mandibular nerve, supraorbital nerve, supracochlear nerve, infraorbital nerve, Lacrimal nerve, nasal ciliary nerve, superior alveolar nerve, buccal nerve, lingual nerve, inferior alveolar nerve, mental nerve, auricular side Selected from the group consisting of the cranial nerves, the lesser occipital nerve, the greater occipital nerve, and combinations thereof . The subcutaneous / intradermal injection can be administered to and / or around the cervical nerves of the patient. The cervical nerves are selected from the group consisting of the c-2 nerve, the c-3 nerve, the c-4 nerve, the c-5 nerve, the c-6 nerve, the c-7 nerve, the c-8 nerve, and combinations thereof. In some embodiments , the subcutaneous / intradermal injection can be administered to and / or around the trigeminal nerve and the cervical nerves of the patient . Preferably, administration to an adult is 2 to 4 units to and / or around the ophthalmic nerve, the maxillary nerve, and / or the mandibular nerve of the trigeminal nerve (bilateral), and / or 2 to 4 units to and / or around the cervical nerves c-2 to c-3, c-4 to c-6, and / or c-7 to c-8, about 1 inch outside the spinal cord (bilateral). In some embodiments, for each injection site, the stated number of units of botulinum toxin ( i.e., 2 to 4 units) is given either singly or in multiple doses over a period of time (e.g., separately). Administration to infants from about 1 year to 5 years of age is adjusted according to age and weight . In some preferred embodiments, the botulinum toxin is selected from the group consisting of botulinum toxin type A, botulinum toxin type B, botulinum toxin type C, botulinum toxin type D, botulinum toxin type E, botulinum toxin type F, and botulinum toxin type G, fragments thereof, hybrids thereof, chimeras thereof, and combinations thereof . In a further embodiment, the total dose of botulinum toxin for an adult weighing about 150 pounds is between about 2 units and about 150 units. The dosage of botulinum toxin for adults or children is adjusted according to age, weight, or a combination thereof . . . In a further embodiment, the total dose of botulinum toxin for an adult weighing about 150 pounds is between about 2 units and about 150 units. The dosage of botulinum toxin for adults or children is adjusted according to age, weight, or a combination thereof

[0013] Some embodiments of the claimed invention provide a method for treating anxiety and / or malnutrition in patients in need of treatment. The present invention relates to a botulinum toxin for use in treating a patient suffering from a neurodegenerative disease, such as a neurodegenerative disorder, a neurodegenerative disorder, or a depression. Diagnosing anxiety and / or depression by symptoms and blood glutamate levels; The symptoms include sleep, appetite, energy levels, and the like. , changes in concentration, daily behavior or self-esteem, thoughts of suicide, or any combination thereof. The diagnosis of anxiety and / or depression is due to a physical injury to the patient. A psychological evaluation and medical testing may be required to determine whether the symptoms are due to a mental or physical condition. In some embodiments, the diagnosis further includes psychoanalysis. The treatment may include providing psychological treatment to the patient if the patient has experienced psychological injury or trauma. In some other embodiments, the diagnosis may further include providing a health The treatment includes providing medical treatment to the patient when the patient suffers a medical injury. After administration of the botulinum toxin, all symptoms are relieved. If symptoms are not alleviated, the patient may be administered an antidepressant. to the patient. The botulinum toxin is administered by subcutaneous / intradermal injection. The subcutaneous / intradermal injection may be administered to and / or around the trigeminal nerve of the patient. The trigeminal nerve may be any of the following: ophthalmic nerve, maxillary nerve, mandibular nerve, supraorbital nerve, supratracheal nerve, ophthalmic nerve, Infrafossa nerve, lacrimal nerve, nasal ciliary nerve, superior alveolar nerve, buccal nerve, lingual nerve, inferior alveolar nerve, mental nerve , auriculotemporal nerve, lesser occipital nerve, greater occipital nerve, and combinations thereof. is selected. The subcutaneous / intradermal injection can be administered at and / or around the cervical nerves of the patient. The cervical nerves are selected from the group consisting of c-2 nerve, c-3 nerve, c-4 nerve, c-5 nerve, c-6 nerve, c-7 nerve, c-8 nerve, and combinations thereof. In some embodiments, the subcutaneous / intradermal injection can be administered at and / or around the trigeminal nerve, thoracic nerve, lumbar nerve, and sacral nerve of the patient. In some other embodiments, the trigeminal nerve, cervical nerve, thoracic nerve, lumbar nerve, sacral nerve of the patient. Preferably, the administration to adults is by subcutaneous / intradermal injection, 2 to 4 units to the ophthalmic nerve, maxillary nerve, and / or mandibular nerve of the trigeminal nerve (bilateral), and / or around it, and / or 2 to 4 units to the c-2 to c-3, c-4 to c-6, and / or c-7 to c-8 of the cervical nerves about 1 inch outside the spinal cord (bilateral), and / or around it, 2 to 4 units to the t-2 to t-3, t-5 to t-6, t-7 to t-9, and / or t-10 to t-12 of the thoracic nerves about 1 inch outside the spinal cord, and / or around it, 2 to 4 units to the l-1 to l-2, l-2 to l-3, and / or l-4 to l-5 of the lumbar nerves about 1 inch outside the spinal cord, and / or around it, 2 to 4 units, and / or to the s-1 to s-2, s-3 to s-4, and / or s-4 to s-5 of the sacral nerves about 1 inch outside the spinal cord (bilateral), and / or around it, 2 to 4 units, including. In some embodiments, for each injection site, the described number of botulinum toxin units (i.e., 2 to 4 units) are given either once or multiple times over a period of time. The administration to infants from about 1 year to 5 years old is adjusted according to age and weight. The botulinum toxin is type A botulinum toxin, type B botulinum toxin, type C botulinum toxin, For each injection site, the described number of botulinum toxin units (i.e., 2 to 4 units) is given either once or multiple times over a period of time. The administration to infants from about 1 year to 5 years old is adjusted according to age and weight. The botulinum toxin is type A botulinum toxin, type B botulinum toxin, type C botulinum toxin, type C botulinum toxin, Linus toxin, botulinum toxin type D, botulinum toxin type E, botulinum toxin type F, botulinum toxin type G Linus toxin, fragments thereof, hybrids thereof, chimeras thereof, and combinations thereof selected from the group consisting of. In a further embodiment, the total dosage of botulinum toxin for an adult weighing about 150 pounds is between about 2 units and about 150 units. The dosage of botulinum toxin for adults or children is adjusted according to age, weight, or a combination thereof .

Mode for Carrying Out the Invention

[0014] [Detailed Description of the Invention] Furthermore, in connection with this, before describing at least a preferred embodiment of the present invention in more detail it should be understood that the present invention is not limited in its application to the details of construction and the arrangement of components described in the following description. Embodiments beyond those described herein are contemplated and it will be understood by those skilled in the art that the embodiments can be implemented and carried out in a plurality of different ways. Also, the terms used herein are for the purpose of description and should not be regarded as a limiting element. It should be understood that unless otherwise defined, the terms used herein refer to what would be understood by a person of ordinary skill in the art based on the contextual use of such terms in this specification .

[0015] Based on the contextual use of such terms, the meaning of the terms used in this specification refers to what would be understood by a person of ordinary skill in the art such that the meaning of the terms as understood by a person of ordinary skill in the art takes precedence over any definition of such terms in any particular dictionary in any different way, and it is intended that the meaning of the terms used in this specification be different in any way from the definition of such terms in any particular dictionary and the meaning of the terms understood by a person of ordinary skill in the art is given priority .

[0016] As used herein, the term "about" means approximately or nearly and, in the context of a numerical value or range described in this specification, means ± 10% of the recited or claimed numerical value or range. As used herein, the term "about" means approximately or nearly and, in the context of a numerical value or range described in this specification, means ± 10% of the recited or claimed numerical value or range. 10% of the recited or claimed numerical value or range.

[0017] The term "treating" includes partially or completely delaying, alleviating, reducing, or reversing symptoms associated with one or more disorders or conditions and / or alleviating, reducing, or blocking one or more causes of the disorder or condition. Treatment according to the claimed invention can be prophylactic treatment, preventive treatment, remission of treatment, or improvement of treatment. The term "treating" includes partially or completely delaying, alleviating, reducing, or reversing symptoms associated with one or more disorders or conditions and / or alleviating, reducing, or blocking one or more causes of the disorder or condition. Treatment according to the claimed invention can be prophylactic treatment, preventive treatment, remission of treatment, or improvement of treatment. The term "treating" includes partially or completely delaying, alleviating, reducing, or reversing symptoms associated with one or more disorders or conditions and / or alleviating, reducing, or blocking one or more causes of the disorder or condition. Treatment according to the claimed invention can be prophylactic treatment, preventive treatment, remission of treatment, or improvement of treatment. The term "treating" includes partially or completely delaying, alleviating, reducing, or reversing symptoms associated with one or more disorders or conditions and / or alleviating, reducing, or blocking one or more causes of the disorder or condition. Treatment according to the claimed invention can be prophylactic treatment, preventive treatment, remission of treatment, or improvement of treatment.

[0018] The term "therapeutically effective amount" or "therapeutically effective dosage" refers to the amount of a composition, compound, treatment, or treatment process that is sufficient to effect such treatment of a disorder or disease when administered to an individual for treating the disorder or disease. The "therapeutically effective amount" varies depending on the composition, the compound, the treatment, the treatment process, the disorder or disease of the individual being treated, and its severity, age, weight, etc. The term "therapeutically effective amount" or "therapeutically effective dosage" refers to the amount of a composition, compound, treatment, or treatment process that is sufficient to effect such treatment of a disorder or disease when administered to an individual for treating the disorder or disease. The "therapeutically effective amount" varies depending on the composition, the compound, the treatment, the treatment process, the disorder or disease of the individual being treated, and its severity, age, weight, etc. The term "therapeutically effective amount" or "therapeutically effective dosage" refers to the amount of a composition, compound, treatment, or treatment process that is sufficient to effect such treatment of a disorder or disease when administered to an individual for treating the disorder or disease. The "therapeutically effective amount" varies depending on the composition, the compound, the treatment, the treatment process, the disorder or disease of the individual being treated, and its severity, age, weight, etc. The term "therapeutically effective amount" or "therapeutically effective dosage" refers to the amount of a composition, compound, treatment, or treatment process that is sufficient to effect such treatment of a disorder or disease when administered to an individual for treating the disorder or disease. The "therapeutically effective amount" varies depending on the composition, the compound, the treatment, the treatment process, the disorder or disease of the individual being treated, and its severity, age, weight, etc. The term "therapeutically effective amount" or "therapeutically effective dosage" refers to the amount of a composition, compound, treatment, or treatment process that is sufficient to effect such treatment of a disorder or disease when administered to an individual for treating the disorder or disease. The "therapeutically effective amount" varies depending on the composition, the compound, the treatment, the treatment process, the disorder or disease of the individual being treated, and its severity, age, weight, etc.

[0019] The term "unit" refers to the amount of botulinum toxin required to kill 50% of a group of female Swiss Webster mice weighing 18 - 20 gm that have received an intraperitoneal injection. The term "unit" refers to the amount of botulinum toxin required to kill 50% of a group of female Swiss Webster mice weighing 18 - 20 gm that have received an intraperitoneal injection.

[0020] The term "periphery of the nerve" refers to any location of the dermatome involved with the nerve.

[0021] In accordance with the principles of the present invention, the use of botulinum toxin for treating various conditions or diseases is provided. When administered subcutaneously, botulinum toxin, although at a low dose, has a therapeutic effect and is When administered subcutaneously, botulinum toxin, although at a low dose, has a therapeutic effect and is It penetrates into the axons of the C fibers of the nerves of the spinal cord, diffuses and migrates to the ganglia, and can prevent the overproduction of excitatory substances such as glutamate, substance P, and CGRP. For adults, administration of botulinum toxin is by subcutaneous or intradermal injection, 2 to 4 units to the trigeminal nerve

[0022] and / or around it, 2 to 4 units to the cervical nerves outside the spine of the patient, and / or around it, 2 to 4 units to the thoracic nerves outside the spine of the patient, and / or around it 2 to 4 units to the lumbar nerves outside the spine of the patient, and / or around it 2 to 4 units, and / or to the sacral nerves outside the spine of the patient, and / or around it 2 to 4 units, including injecting. Each subcutaneous injection preferably does not cause significant or negligible paralysis or interference with motor function in the muscles of the injection area, and is at a dosage level that provides the described therapeutic use for the nerves, which is called low-dose treatment. The low-dose treatment can be, for example, a therapeutic approach of botulinum toxin without being injected for the purpose of paralyzing muscles, and is low enough to provide treatment using subcutaneous injection. In some examples of embodiments of the present invention, higher dosages are also contemplated. For an adult weighing about 150 pounds, the total dosage of botulinum toxin is between about 2 units and about 150 units. The dosage of botulinum toxin for adults or children is adjusted according to age, weight, or a combination thereof. The botulinum toxin is type A botulinum toxin, type B botulinum toxin, type C botulinum toxin, type D botulinum toxin, type E botulinum toxin, type F botulinum toxin, type G botulinum toxin, their fragments, their hybrids, their chimeras 、or combinations thereof. Each type of said botulinum toxin may exhibit different effects in the treatment of a condition or disease but one unit of botulinum toxin required is the amount of botulinum toxin that kills 50% of a group of 18 - 20 gm female Swiss-Webster mice that have received an intraperitoneal injection . It refers to the amount of botulinum toxin required for

[0023] Treatment of dry eye syndrome Dry eye syndrome (DES), also known as keratoconjunctivitis sicca (KCS), is a condition that occurs when the eyes do not produce enough tears, when tears evaporate rapidly, or when the eyes do not produce the correct type of tears or tear film . The tear film is something that spreads over the eyes when blinking and is composed of three layers: an inner mucus-like layer, a middle aqueous layer, and an outer oil layer . The inner mucin layer nourishes the cornea and helps tears adhere to the surface of the eye. Much of the mucin is secreted by special goblet cells in the conjunctival epithelium . The middle aqueous or water layer helps prevent infection and wash away particles . Most of the aqueous humor is secreted from the lacrimal gland. The outer oil or lipid layer, most of which is secreted from the meibomian glands, seals the membrane to reduce the evaporation of natural tears . DES can cause damage and discomfort to the surface of the eye and is characterized by inflammation and gland dysfunction . The causes of this condition vary widely and include environmental conditions, inflammatory diseases, hormonal imbalances, systemic disorders (such as diabetes, lupus, rheumatoid arthritis, Sjogren's syndrome, etc.), ophthalmic surgery, and drug allergies . This application focuses on some of these causes that have specific solutions . 95% of patients who have undergone refractive ophthalmic surgery experience postoperative DES . One month after the surgery .

[0024] . Subsequently, 60% of the patients still suffer from DES. The majority of patients improve after 6 to 12 months, but 30% are seeing an ophthalmologist due to chronic dry eye. 9% of patients who have undergone cataract ophthalmic surgery develop chronic dry eye, and 60% develop it initially.

[0025] Incision of the cornea of the eye in these types of surgeries results in the severance of the branches of the long ciliary nerves, which are the ocular branches of the trigeminal nerve. These nerves supply the sensory innervation of the cornea. The greater petrosal nerve, which is a branch of the facial nerve, supplies the innervation of the lacrimal gland. In this area, there are many anastomoses (interconnections) between the facial nerve and the trigeminal nerve. According to a certain study, non-surgically induced DES is more common in people with neuropathic conditions such as migraine and fibromyalgia.

[0026] As mentioned above, when sensory nerves are damaged, in this case by surgical incision, excessive glutamic acid, substance P, and calcitonin gene-related peptide (CGRP) are produced. Transection and damage of the corneal sensory nerves stimulate the overproduction of these substances and cause corneal hypersensitivity. This stimulation affects the lacrimal gland by suppressing tear production and causing pain and hypersensitivity, as in the example of herpes zoster mentioned above. The long ciliary nerves become hypersensitive to the produced glutamic acid, substance P, and CGRP and cause pain. Dryness further stimulates and produces different tear layers due to the effects of glutamic acid, substance P, and CGRP on the gland. The overproduction of glutamic acid, substance P, and CGRP slows down as the eye heals and eventually normalizes. However, in some people, this overproduction does not return to normal over time and nerves result in a consistent chronic overproduction of excitatory chemicals, causing chronic dry eye syndrome to develop.

[0027] In people with chronic neuropathic symptoms such as migraine, fibromyalgia, and postherpetic facial pain syndrome, excessive glutamate, substance P, and CGRP can result from the chronic overproduction of these chemicals spreading from other sensory nerves by a process called central sensitization. This sensitization affects the long ciliary nerves and facial nerves that innervate the lacrimal gland, goblet cells, and Meibomian glands. Excessive nerve excitation from other nerves affects the cornea and lacrimal gland in the same way as surgical injury, creating a state of chronic overstimulation of the nerves involved. To diagnose DES, blood glutamate levels can be checked during regular doctor visits.

[0028] Physical symptoms can also be checked. These include, but are not limited to, a) a stinging, burning, or scratchy sensation in the eyes, b) stringy mucus in or around the eyes, c) mild allergies, d) eye redness, e) a foreign body sensation in the eyes, f) difficulty wearing contact lenses, g) difficulty driving at night, h) watery eyes, and i) blurry vision or eye fatigue.

[0029] If a patient is diagnosed with experiencing DES after an eye surgery such as refractive surgery or cataract surgery, to evaluate the blood concentrations of substance P, CGRP, and glutamate, and / or related symptoms and blood tests to prevent or alleviate them, they are The toxin is administered subcutaneously or by other injections that allow the botulinum toxin to reach unmyelinated sensory C fibers (e.g., intradermal injection, etc.). The botulinum toxin injection can be administered to and / or around the trigeminal nerve and / or cervical nerve of the patient . As the trigeminal nerve, the ophthalmic nerve, maxillary nerve, mandibular nerve, supraorbital nerve, superior laryngeal nerve, infraorbital nerve, lacrimal gland nerve, nasal ciliary nerve, superior alveolar nerve, buccal nerve, lingual nerve, inferior alveolar nerve, mental nerve, auriculotemporal nerve, lesser occipital nerve, greater occipital nerve, or a combination thereof may be mentioned, but is not limited thereto . As the cervical nerve, the c-2 nerve, c-3 nerve, c-4 nerve, c-5 nerve, c-6 nerve, c-7 nerve, c-8 nerve, and combinations thereof may be mentioned but is not limited thereto. For example, 2 to 4 units can be administered to and / or around the ophthalmic nerve, maxillary nerve, and / or mandibular nerve of the trigeminal nerve (bilateral), and / or 2 to 4 units can be administered to and / or around the c-2 to c-3, c-4 to c-6, and / or c-7 to c-8 of the cervical nerve 1 inch outside the spine (bilateral). In the trigeminal nerve and cervical nerve, due to significant crossover, bilateral injections are necessary even if it is a dry eye syndrome in one eye. These are adult dosages . The dosage for 0 to 5 years old needs to be adjusted according to age and weight . .

[0030] Botulinum toxin is administered to lower the levels of substance P, CGRP, and glutamate and usually begins to act about 3 days later . It usually takes about 1 to 2 weeks for the botulinum toxin to reach its high effectiveness . The botulinum toxin gradually decreases, and a blood test When an increase in substance P, glutamate, or CGRP is shown, the symptoms recur. and begin, and more botulinum toxin can be administered to counteract this effect. If the level / symptom does not normalize, one of the glutamate antagonists can be administered in small amounts, if further desirable, to lower the glutamate level without causing side effects.

[0031] Generally, a therapeutically effective dose or amount can be between 1 and 150 units depending on body weight. The dose for an adult weighing about 150 pounds is about 50 - 150 units. Children over about 5 years old with halted brain formation can adjust the dose according to their body weight. For example, for infants (about 1 - 5 years old), the dose can be about 1 - 30 units.

[0032] Treatment of Autism Autism is a developmental disorder characterized by difficulties in social interaction, communication, and restricted repetitive behaviors. Parents usually notice signs during the first 2 - 3 years of their child's life. Some children with autism reach the milestones of development expected at a normal pace before deteriorating, but these signs often develop gradually. The cause is unknown but is thought to be related to a combination of genetic and environmental factors. Risk factors during pregnancy include specific infections such as measles, as well as toxins such as valproic acid, alcohol, cocaine, pesticides, and air pollutants. The debate includes other proposed environmental causes, such as the disproven vaccine hypothesis. Autism affects brain information processing by altering how neurons and their synapses connect and organize. The mechanism is not fully understood. The DSM - 5, Autism, and Less severe conditions, including Asperger's syndrome and pervasive developmental disorder not otherwise specified (PDD-NOS) is associated with the diagnosis of autism spectrum disorder (ASD).

[0033] As noted above, the exact cause of ASD (autism) is unknown. Genetic abnormalities are not seen in about 90% of cases. Gene mutations have been found in the remaining 10%, and almost all of these are related to glutamate receptors or the metabolism of glutamate. There is no animal model for autism; it is a condition unique to humans. This is because, in terms of neural capabilities, there is a lack of formation or damage to parts of the brain that are only seen in the human brain during development. Up to about 1.5 to 5 years of age, these special structures and the complex neural networks around and between them are organized and grow. Neurons connect in a complex mesh-like pattern. Special thin and tapered neurons (VEN) are involved in empathy, guilt, confusion, etc., and are a high-functioning structure unique to humans and great apes. The VEN are located in the insular cortex, corpus callosum, prefrontal cortex, and anterior cingulate cortex, and the cortical neural columns (mini-columns) support parallel processing. A large number of synapses are interconnected between the neural structures and both sides of the brain (corpus callosum). This development, organization, and interconnection enable complex social cognition, language, abstract thinking, planning, practical and educational abilities, inference, and deception. The high degree of reorganization of the human brain has given us these abilities and many of the abilities that define us as human. However, it comes at a cost. Neurodegenerative diseases such as schizophrenia, autism, and Alzheimer's disease. These disorders are as unique to humans as high brain functions. The specific causes of these problems are currently unknown. pattern. Special thin and tapered neurons (VEN) are involved in empathy, guilt, confusion, etc., and are a high-functioning structure unique to humans and great apes. The VEN are located in the insular cortex, corpus callosum, prefrontal cortex, and anterior cingulate cortex, and the cortical neural columns (mini-columns) support parallel processing. A large number of synapses are interconnected between the neural structures and both sides of the brain (corpus callosum). pattern. Special thin and tapered neurons (VEN) are involved in empathy, guilt, confusion, etc., and are a high-functioning structure unique to humans and great apes. The VEN are located in the insular cortex, corpus callosum, prefrontal cortex, and anterior cingulate cortex, and the cortical neural columns (mini-columns) support parallel processing. A large number of synapses are interconnected between the neural structures and both sides of the brain (corpus callosum). pattern. Special thin and tapered neurons (VEN) are involved in empathy, guilt, confusion, etc., and are a high-functioning structure unique to humans and great apes. The VEN are located in the insular cortex, corpus callosum, prefrontal cortex, and anterior cingulate cortex, and the cortical neural columns (mini-columns) support parallel processing. A large number of synapses are interconnected between the neural structures and both sides of the brain (corpus callosum). pattern. Special thin and tapered neurons (VEN) are involved in empathy, guilt, confusion, etc., and are a high-functioning structure unique to humans and great apes. The VEN are located in the insular cortex, corpus callosum, prefrontal cortex, and anterior cingulate cortex, and the cortical neural columns (mini-columns) support parallel processing. A large number of synapses are interconnected between the neural structures and both sides of the brain (corpus callosum). pattern. Special thin and tapered neurons (VEN) are involved in empathy, guilt, confusion, etc., and are a high-functioning structure unique to humans and great apes. The VEN are located in the insular cortex, corpus callosum, prefrontal cortex, and anterior cingulate cortex, and the cortical neural columns (mini-columns) support parallel processing. A large number of synapses are interconnected between the neural structures and both sides of the brain (corpus callosum). This development, organization, and interconnection enable complex social cognition, language, abstract thinking, planning, practical and educational abilities, inference, and deception. The high degree of reorganization of the human brain has given us these abilities and many of the abilities that define us as human. However, it comes at a cost. Neurodegenerative diseases such as schizophrenia, autism, and Alzheimer's disease. These disorders are as unique to humans as high brain functions. The specific causes of these problems are currently unknown. pattern. Special thin and tapered neurons (VEN) are involved in empathy, guilt, confusion, etc., and are a high-functioning structure unique to humans and great apes. The VEN are located in the insular cortex, corpus callosum, prefrontal cortex, and anterior cingulate cortex, and the cortical neural columns (mini-columns) support parallel processing. A large number of synapses are interconnected between the neural structures and both sides of the brain (corpus callosum). diseases such as schizophrenia, autism, and Alzheimer's disease. These disorders are as unique to humans as high brain functions. The specific causes of these problems are currently unknown. diseases such as schizophrenia, autism, and Alzheimer's disease. These disorders are as unique to humans as high brain functions. The specific causes of these problems are currently unknown. The specific causes of these problems are currently unknown.

[0034] All neurons operate essentially by the same mechanism. When they are stimulated up to a certain threshold, they fire and send an electrochemical signal up the axon to the cell body. The body regulates this with proteins, chemicals, and substances - these are called ligands. When they are stimulated up to a certain threshold, they fire and send an electrochemical signal up the axon to the cell body. The body regulates this with proteins, chemicals, and substances - these are called ligands. When they are stimulated up to a certain threshold, they fire and send an electrochemical signal up the axon to the cell body. The body regulates this with proteins, chemicals, and substances - these are called ligands.

[0035] One of the main theories is that there is an excessive concentration of the excitatory neurotransmitter glutamate in the developing brains and cerebrospinal fluid (CSF) of these suffering children. According to research, it has been shown by elevated levels in the brains, CSF, and blood of children with autism. There is a correlation between high levels of glutamate and more severe autism symptoms. This is thought to cause a condition called excitotoxicity while the high levels are growing and interconnecting between 1.5 and 5 years of age. This can damage the developing interconnected neurons. The age of onset of high levels of glutamate, the degree above normal levels, the genetic susceptibility to it, and the brain regions affected can cause the wide range of symptoms present in autism. One of the main theories is that there is an excessive concentration of the excitatory neurotransmitter glutamate in the developing brains and cerebrospinal fluid (CSF) of these suffering children. According to research, it has been shown by elevated levels in the brains, CSF, and blood of children with autism. There is a correlation between high levels of glutamate and more severe autism symptoms. This is thought to cause a condition called excitotoxicity while the high levels are growing and interconnecting between 1.5 and 5 years of age. This can damage the developing interconnected neurons. The age of onset of high levels of glutamate, the degree above normal levels, the genetic susceptibility to it, and the brain regions affected can cause the wide range of symptoms present in autism. One of the main theories is that there is an excessive concentration of the excitatory neurotransmitter glutamate in the developing brains and cerebrospinal fluid (CSF) of these suffering children. According to research, it has been shown by elevated levels in the brains, CSF, and blood of children with autism. There is a correlation between high levels of glutamate and more severe autism symptoms. This is thought to cause a condition called excitotoxicity while the high levels are growing and interconnecting between 1.5 and 5 years of age. This can damage the developing interconnected neurons. The age of onset of high levels of glutamate, the degree above normal levels, the genetic susceptibility to it, and the brain regions affected can cause the wide range of symptoms present in autism. One of the main theories is that there is an excessive concentration of the excitatory neurotransmitter glutamate in the developing brains and cerebrospinal fluid (CSF) of these suffering children. According to research, it has been shown by elevated levels in the brains, CSF, and blood of children with autism. There is a correlation between high levels of glutamate and more severe autism symptoms. This is thought to cause a condition called excitotoxicity while the high levels are growing and interconnecting between 1.5 and 5 years of age. This can damage the developing interconnected neurons. The age of onset of high levels of glutamate, the degree above normal levels, the genetic susceptibility to it, and the brain regions affected can cause the wide range of symptoms present in autism. One of the main theories is that there is an excessive concentration of the excitatory neurotransmitter glutamate in the developing brains and cerebrospinal fluid (CSF) of these suffering children. According to research, it has been shown by elevated levels in the brains, CSF, and blood of children with autism. There is a correlation between high levels of glutamate and more severe autism symptoms. This is thought to cause a condition called excitotoxicity while the high levels are growing and interconnecting between 1.5 and 5 years of age. This can damage the developing interconnected neurons. The age of onset of high levels of glutamate, the degree above normal levels, the genetic susceptibility to it, and the brain regions affected can cause the wide range of symptoms present in autism. One of the main theories is that there is an excessive concentration of the excitatory neurotransmitter glutamate in the developing brains and cerebrospinal fluid (CSF) of these suffering children. According to research, it has been shown by elevated levels in the brains, CSF, and blood of children with autism. There is a correlation between high levels of glutamate and more severe autism symptoms. This is thought to cause a condition called excitotoxicity while the high levels are growing and interconnecting between 1.5 and 5 years of age. This can damage the developing interconnected neurons. The age of onset of high levels of glutamate, the degree above normal levels, the genetic susceptibility to it, and the brain regions affected can cause the wide range of symptoms present in autism. One of the main theories is that there is an excessive concentration of the excitatory neurotransmitter glutamate in the developing brains and cerebrospinal fluid (CSF) of these suffering children. According to research, it has been shown by elevated levels in the brains, CSF, and blood of children with autism. There is a correlation between high levels of glutamate and more severe autism symptoms. This is thought to cause a condition called excitotoxicity while the high levels are growing and interconnecting between 1.5 and 5 years of age. This can damage the developing interconnected neurons. The age of onset of high levels of glutamate, the degree above normal levels, the genetic susceptibility to it, and the brain regions affected can cause the wide range of symptoms present in autism. One of the main theories is that there is an excessive concentration of the excitatory neurotransmitter glutamate in the developing brains and cerebrospinal fluid (CSF) of these suffering children. According to research, it has been shown by elevated levels in the brains, CSF, and blood of children with autism. There is a correlation between high levels of glutamate and more severe autism symptoms. This is thought to cause a condition called excitotoxicity while the high levels are growing and interconnecting between 1.5 and 5 years of age. This can damage the developing interconnected neurons. The age of onset of high levels of glutamate, the degree above normal levels, the genetic susceptibility to it, and the brain regions affected can cause the wide range of symptoms present in autism. One of the main theories is that there is an excessive concentration of the excitatory neurotransmitter glutamate in the developing brains and cerebrospinal fluid (CSF) of these suffering children. According to research, it has been shown by elevated levels in the brains, CSF, and blood of children with autism. There is a correlation between high levels of glutamate and more severe autism symptoms. This is thought to cause a condition called excitotoxicity while the high levels are growing and interconnecting between 1.5 and 5 years of age. This can damage the developing interconnected neurons. The age of onset of high levels of glutamate, the degree above normal levels, the genetic susceptibility to it, and the brain regions affected can cause the wide range of symptoms present in autism.

[0036] Substances that fire neurons with less stimulation are called "excitatory". Substances that make neurons require more stimulation to fire are called "inhibitory". Examples of excitatory neurotransmitters are nicotine, cocaine, methamphetamine, epinephrine, and glutamate. Substances that fire neurons with less stimulation are called "excitatory". Substances that make neurons require more stimulation to fire are called "inhibitory". Examples of excitatory neurotransmitters are nicotine, cocaine, methamphetamine, epinephrine, and glutamate. Substances that fire neurons with less stimulation are called "excitatory". Substances that make neurons require more stimulation to fire are called "inhibitory". Examples of excitatory neurotransmitters are nicotine, cocaine, methamphetamine, epinephrine, and glutamate. Examples of inhibitory neurotransmitters are serotonin, gamma-aminobutyric acid (GABA), anesthetics, and other drugs such as Lyrica (for nerve pain) and barium (antianxiety / sedative). If neurons are overly inhibited, it can cause drowsiness and death. In contrast, if there is an excess of excitatory compounds, Examples of inhibitory neurotransmitters are serotonin, gamma-aminobutyric acid (GABA), anesthetics, and other drugs such as Lyrica (for nerve pain) and barium (antianxiety / sedative). If neurons are overly inhibited, it can cause drowsiness and death. In contrast, if there is an excess of excitatory compounds, Examples of inhibitory neurotransmitters are serotonin, gamma-aminobutyric acid (GABA), anesthetics, and other drugs such as Lyrica (for nerve pain) and barium (antianxiety / sedative). If neurons are overly inhibited, it can cause drowsiness and death. In contrast, if there is an excess of excitatory compounds, The firing of nerves is too fast, and pain, sleep deprivation, photosensitivity, cell death, seizures, etc. may occur (the symptoms vary depending on the function of specific nerves).

[0037] Doctors have tried to remove these high levels of glutamate in the brains of autistic children by blocking its production or disabling glutamate receptors. Glutamate is the most common neurotransmitter in the brain (about 60%), and this has not been successful because the side effects of the drugs are often severe. The problem is the origin of the excessive glutamate. A further problem is the method of removing it without affecting the normal glutamate levels and its normal function within neurons. Excessive glutamate in the blood, CSF, and brain of autistic children is expected to be caused by or present in children with related neurological disorder conditions such as migraine, fibromyalgia, or in children aged 1.5 - 5 years when the higher functional structures of the brain are being formed or are already developed. In adults with migraine, fibromyalgia, and neurological conditions, the glutamate levels in the brain, blood, and CSF are elevated. Physical symptoms that can be observed in young children with ASD (autism) are similar to the symptoms of fibromyalgia, migraine, and neurological conditions - photosensitivity, pupillary dilation, sensitivity to loud noises, sleep disturbances, hyperactivity, tactile sensitivity, depression, and anxiety.

[0038] In migraine and fibromyalgia, the cause of the excessive production of glutamate is thought to be the nerve structural cells that surround the neurons. These are glial cells, satellite cells, and astrocytes. The mechanism involves substance P, CGRP (calcitonin gene-related peptide). ​​​​​​​​​​​​​​​peptide), and glutamate are produced intracellularly by the ribosomes of these cells, The vesicles transport the proteins to the plasma membrane. and / or a special protein called VAMP transports it across the cell membrane and into the CSF. They then act as ligands to the nerves, causing less stimulation (neural excitation). ) to ignite them. The only other known location is the neuromuscular junction of muscle cells, where small molecules containing acetylcholine It releases vesicles into the neuromuscular junction, causing muscle contraction. It is used inside neurons in the production of stimulants P, and CGRP, which is essential for the production of SNA. Not released into the CS space by P25 and / or VAMP.

[0039] In particular, excess glutamate, substance P, and CGRP in the brain are essential for the development of higher Disrupt, damage, or cause malformation of structures. Subcutaneous botulinum toxin injection or Other injections (e.g., intradermal injections) that deliver botulinum toxin to unmyelinated sensory C-fibers are Glutamine in adult patients with cerebrovascular disease, migraine, fibromyalgia, and other neuropathic conditions It has been shown to lower acid levels to normal.

[0040] From birth, blood levels of substance P, CGRP, and glutamate were measured at regular checkups. Children can be screened to see if they have high blood pressure. If it is higher than normal and they have physical symptoms, If the child shows symptoms and does not meet developmental milestones, then treatment should be subcutaneous or botulinum toxin injection. Other injections (e.g., intradermal injections) that allow the neurotransmitter to reach unmyelinated sensory C-fibers can result in excess glutamate release. It can reduce glutamic acid and restore the normal developmental environment in the brain. The injected botulinum toxin reduces or halts the overproduction of glutamic acid, substance P, CGRP, and the excitatory effects on nerves that occur in fibromyalgia, migraine, and other neuropathic conditions.

[0041] To diagnose ASD (autism), blood glutamic acid levels can be checked in regular doctor visits starting from infancy. The doctor also needs to confirm that the developmental milestones of the brain have been achieved. Physical symptoms are substantially the same in migraine, fibromyalgia, depression, ASD (autism), and the following other neuropathic disorders: a) photosensitivity (dilated pupils), b) sensitivity to loud noises, c) hyperactivity, d) sensitivity to touch (tight clothes, being hugged, etc.), e) stomach problems such as idiopathic IBS. If a patient is diagnosed as experiencing autism, they are given botulinum toxin subcutaneously or by other injections (e.g., intradermal injection, etc.) that allow the botulinum toxin to reach unmyelinated sensory C fibers, which can prevent or alleviate the

[0042] related symptoms and / or blood tests to evaluate the blood levels of substance P, CGRP, and glutamic acid. Next, developmental milestones, neuropathic symptoms, and glutamic acid levels are monitored regularly. Due to age making it difficult to evaluate developmental milestones and neuropathic symptoms, monitoring glutamic acid levels is particularly important for infants. Thus, with this treatment, the doctor can know when it is necessary to re-administer the botulinum toxin. The botulinum toxin injection is administered to the trigeminal nerve, cervical nerves, thoracic nerves, lumbar nerves, and / or to the patient. Since it is difficult to evaluate developmental milestones and neuropathic symptoms due to age, monitoring glutamic acid levels is particularly important for infants. Therefore, with this treatment, the doctor can know when it is necessary to re-administer the botulinum toxin. The botulinum toxin injection is administered to the trigeminal nerve, cervical nerves, thoracic nerves, lumbar nerves, and / or or can be given to the sacral nerve and / or its periphery. Botulinum toxin injection to all of the above nerves is also considered to be within the scope of the claims of the present invention. As the trigeminal nerve, the ophthalmic nerve, maxillary nerve, mandibular nerve, supraorbital nerve, superior spiral nerve, infraorbital nerve, lacrimal nerve, nasal ciliary nerve, superior alveolar nerve, buccal nerve, lingual nerve, inferior alveolar nerve, mental nerve, auriculotemporal nerve, lesser occipital nerve, greater occipital nerve, or a combination thereof can be mentioned, but is not limited thereto. As the cervical nerve, c-2 nerve, c-3 nerve, c-4 nerve, c-5 nerve, c-6 nerve, c-7 nerve, c-8 nerve, and combinations thereof can be mentioned, but are not limited thereto. For example, 2 to 4 units to the ophthalmic nerve, maxillary nerve, and / or mandibular nerve of the trigeminal nerve (bilateral) and / or its periphery, c-2 to c-3, c-4 to c-6, and / or c-7 to c-8 of the cervical nerves about 1 inch outside the spinal cord (bilateral) and / or to its periphery, 2 to 4 units to t-2 to t-3, t-5 to t-6, t-7 to t-9, and / or t-10 to t-12 of the thoracic nerves about 1 inch outside the spinal cord and / or to its periphery, 2 to 4 units to l-1 to l-2, l-2 to l-3, and / or l-4 to l-5 of the lumbar nerves about 1 inch outside the spinal cord and / or to its periphery, and 2 to 4 units to s-1 to s-2, s-3 to s-4, and / or s-4 to s-5 of the sacral nerves about 1 inch outside the spinal cord (bilateral) and / or to its periphery can be administered. In one embodiment, three injections of 2 units each distributed along both sides of the neck of the trigeminal nerve, one injection of 2 units in a split of the subcutaneous eyes, maxilla, and mandible on both sides. These are adult dosages. The dosages for 0 to 5 years old must be adjusted according to age and weight. ​ There is a need.

[0043] Botulinum toxin is administered to lower the levels of substance P, CGRP, and glutamate and is usually administered at a position about 1 / 2 to 1 inch from the spinal cord in all spinal injections. When this is done, it begins to act about 3 days later. In many independent studies, it has been given in the forearm or calf and it takes about 2 weeks to start working. When given near the dorsal root ganglion ; it usually takes 3 - 5 days and 1 - 2 weeks to reach the peak of its effect. This is because the distance for the axon to diffuse to the cell body is short. The blood glutamate level can be monitored to confirm that the level has decreased to normal, and the physical symptoms can be similarly monitored to confirm normalization (graphical development milestones). When the botulinum toxin gradually decreases and an increase in substance P, glutamate, or CGRP is indicated by a blood test and / or when the symptoms begin to recur, more botulinum toxin can be administered to counteract this effect. If the level / symptom does not normalize, when desirable, a small amount of one of the glutamate antagonists can be administered to lower the glutamate level without causing side effects.

[0044] Usually, the therapeutically effective dose or amount can be between 1 and 150 units depending on body weight. The dose for an adult weighing about 150 pounds is about 50 - 150 units. Children over about 5 years old with arrested brain formation can have their dose adjusted according to body weight. For example, in the case of infants (about 1 - 5 years old), the dose can be about 1 - 30 units. This is an estimated value, but it has been safely used since the 1990s for infants and young children with cerebral palsy to suppress severe muscle spasms. ​​​​​​The maximum dose administered so far is 30 units.

[0045] Treatment of tolerance to narcotics One theory of the cause of tolerance is that narcotics act on opioid receptors to suppress neuronal firing and cause a decrease in sensory pain. Narcotics cause other symptoms such as drowsiness, constipation, lethargy, intoxication, shallow breathing, and amnesia when various functional nerves are suppressed. In response to the suppression of the entire system and neuronal firing, sensory nerves produce neuroexcitatory substances (substance P, CGRP, and glutamate) to balance the suppression of firing by narcotics and the suppression of the nervous system. After the production of excitability increases and the body returns to a more normal neurological state, the narcotics are no longer effective, so the patient needs to take more narcotics to obtain the same effect. As a result, the production of excitatory chemicals increases, a vicious cycle occurs, and the patient increasingly takes the narcotics they are dependent on to relieve mental and physical pain or to maintain the intoxication they seek.

[0046] Chronic use of narcotics causes an increase in the use of narcotics to obtain the same desirable effects previously achieved with less medication due to the above tolerance mechanism. This results in a huge overproduction of neuroexcitatory substances in the body's fight to return to a state of normal nerve function. When a person runs out of drugs, cannot obtain drugs, or stops taking them, the extreme suppression of neurons (depression) due to the firing of the body's neurons suddenly disappears. The continuous massive overproduction of neuroexcitatory substances caused by the narcotic use tolerance effect results in alternating sweating and chills, diarrhea, nausea, runny nose, tremors, rapid , sneezing, pupil dilation, restlessness, depression, migraine, anxiety, and withdrawal symptoms such as pain are caused.

[0047] If a patient must take a narcotic for a long period of time, botulinum toxin is administered to prevent tolerance, and a blood test can be performed to evaluate the baseline blood concentrations of substance P, CGRP, and glutamate. This allows the physician to test for elevated glutamate levels and clinical symptoms to determine whether tolerance has developed. A novel method for treating chronic pain is as follows. The baseline glutamate level is obtained when the narcotic is first administered. The normal dosage of the narcotic is given to control pain and botulinum toxin in all sensory nerve areas. Thereafter, the symptoms of tolerance and glutamate levels are monitored regularly. This allows the physician to know when it is necessary to re-administer botulinum toxin. The glutamate test allows the physician to determine whether the patient is telling the truth about tolerance symptoms or lying to obtain or sell more drugs for the sake of intoxication. Subcutaneous botulinum toxin injection, or other injections that allow botulinum toxin to reach unmyelinated sensory C fibers (e.g., intradermal injection, etc.), can be given to the trigeminal nerve, cervical nerves, thoracic nerves, lumbar nerves, and / or sacral nerves of the patient, and / or in the vicinity thereof. Botulinum toxin injection into all of the above nerves is also considered to be within the scope of the claims of the present invention. As the trigeminal nerve, the oculomotor nerve, maxillary nerve, mandibular nerve, supraorbital nerve, superior laryngeal nerve, infraorbital nerve, lacrimal nerve, nasal ciliary nerve, Examples may include, but are not limited to, the cervical nerves such as the c-2 nerve, c- -3 nerve, c-4 nerve, c-5 nerve, c-6 nerve, c-7 nerve, c-8 nerve, and combinations thereof, but are not limited thereto. For example, the trigeminal nerve (bilateral) to the ophthalmic nerve, maxillary nerve, and / or mandibular nerve, and / or to the vicinity thereof, 2-4 units, the cervical nerves about 1 inch outside the spinal cord (bilateral) to c-2 to c-3, c-4 to c-6, and / or c-7 to c-8, and / or to the vicinity thereof, 2-4 units, the thoracic nerves about 1 inch outside the spinal cord to t-2 to t-3, t-5 to t-6, t-7 to t-9, and / or t-10 to t-12, and / or to the vicinity thereof, 2-4 units, the lumbar nerves about 1 inch outside the spinal cord to l-1 to l-2, l-2 to l-3, and / or l-4 to l-5, and / or to the vicinity thereof, 2-4 units, and / or, the sacral nerves about 1 inch outside the spinal cord (bilateral) to s-1 to s-2, s-3 to s-4, and / or s-4 to s-5, and / or to the vicinity thereof, 2-4 units may be administered. These are for adult

[0048] dosages. The dosage for 0-5 year olds needs to be adjusted according to age and weight. Botulinum toxin is administered to maintain the levels of substance P, CGRP, and glutamic acid and usually begins to act about 3 days later. It usually takes about 1-2 weeks for botulinum toxin to reach its high efficacy. The blood glutamate level can be monitored to confirm that the level is maintained normally, and similarly, the physical , administering a small amount of one of the glutamate antagonists can reduce the glutamate level without causing side effects. It can be obtained.

[0049] Typically, a therapeutically effective dosage or amount can be between 1 and 150 units depending on body weight. The dosage for an adult weighing about 150 pounds is about 50 - 150 units. For children over about 5 years old where brain formation has stopped, the dosage can be adjusted according to body weight. For example, in the case of infants (about 1 - 5 years old), the dosage can be about 1 - 30 units. Although this is an estimated value, the maximum dosage that has been safely used since the 1990s for infants and young children with cerebral palsy to suppress severe muscle convulsions is 30 units. For children over about 5 years old, the dosage can be adjusted according to body weight. For example, in the case of infants (about 1 - 5 years old), the dosage can be about 1 - 30 units. This is an estimated value, but for infants and young children with cerebral palsy, the maximum dosage that has been safely used since the 1990s to suppress severe muscle convulsions is 30 units. For children over about 5 years old, the dosage can be adjusted according to body weight. For example, in the case of infants (about 1 - 5 years old), the dosage can be about 1 - 30 units. This is an estimated value, but for infants and young children with cerebral palsy, the maximum dosage that has been safely used since the 1990s to suppress severe muscle convulsions is 30 units. For children over about 5 years old, the dosage can be adjusted according to body weight. For example, in the case of infants (about 1 - 5 years old), the dosage can be about 1 - 30 units. This is an estimated value, but for infants and young children with cerebral palsy, the maximum dosage that has been safely used since the 1990s to suppress severe muscle convulsions is 30 units. For children over about 5 years old, the dosage can be adjusted according to body weight. For example, in the case of infants (about 1 - 5 years old), the dosage can be about 1 - 30 units. This is an estimated value, but for infants and young children with cerebral palsy, the maximum dosage that has been safely used since the 1990s to suppress severe muscle convulsions is 30 units.

[0050] Treatment of vestibular vertigo Vertigo can be described as rotational vertigo, loss of orientation, or abnormal or false kinesthetic sensations in several health conditions. It can be associated with other symptoms such as nausea, sweating, headache, difficulty walking, etc., and usually worsens when standing or moving the head. Vertigo can be described as rotational vertigo, loss of orientation, or abnormal or false kinesthetic sensations in several health conditions. It can be associated with other symptoms such as nausea, sweating, headache, difficulty walking, etc., and usually worsens when standing or moving the head. Vertigo can be described as rotational vertigo, loss of orientation, or abnormal or false kinesthetic sensations in several health conditions. It can be associated with other symptoms such as nausea, sweating, headache, difficulty walking, etc., and usually worsens when standing or moving the head.

[0051] There are many suspected causes of vertigo, such as Meniere's disease, otitis media, benign paroxysmal positional vertigo (BPPV), and other less likely causes such as brain tumors or brain injuries, stroke, migraine, toxin exposure, and uneven pressure in the middle ear. Without wishing to be bound by theory, it is suggested that one of the causes may be chronic overproduction of the neurotransmitters glutamate, substance P, and calcitonin gene-related peptide (GCRP) from local damage to the vestibular nerve or from central sensitization effects that develop due to depression, migraine, fibromyalgia, or other neuropathic conditions. This can lead to damaged neurons and There are many suspected causes of vertigo, such as Meniere's disease, otitis media, benign paroxysmal positional vertigo (BPPV), and other less likely causes such as brain tumors or brain injuries, stroke, migraine, toxin exposure, and uneven pressure in the middle ear. Without wishing to be bound by theory, it is suggested that one of the causes may be chronic overproduction of the neurotransmitters glutamate, substance P, and calcitonin gene-related peptide (GCRP) from local damage to the vestibular nerve or from central sensitization effects that develop due to depression, migraine, fibromyalgia, or other neuropathic conditions. This can lead to damaged neurons and There are many suspected causes of vertigo, such as Meniere's disease, otitis media, benign paroxysmal positional vertigo (BPPV), and other less likely causes such as brain tumors or brain injuries, stroke, migraine, toxin exposure, and uneven pressure in the middle ear. Without wishing to be bound by theory, it is suggested that one of the causes may be chronic overproduction of the neurotransmitters glutamate, substance P, and calcitonin gene-related peptide (GCRP) from local damage to the vestibular nerve or from central sensitization effects that develop due to depression, migraine, fibromyalgia, or other neuropathic conditions. This can lead to damaged neurons and There are many suspected causes of vertigo, such as Meniere's disease, otitis media, benign paroxysmal positional vertigo (BPPV), and other less likely causes such as brain tumors or brain injuries, stroke, migraine, toxin exposure, and uneven pressure in the middle ear. Without wishing to be bound by theory, it is suggested that one of the causes may be chronic overproduction of the neurotransmitters glutamate, substance P, and calcitonin gene-related peptide (GCRP) from local damage to the vestibular nerve or from central sensitization effects that develop due to depression, migraine, fibromyalgia, or other neuropathic conditions. This can lead to damaged neurons and There are many suspected causes of vertigo, such as Meniere's disease, otitis media, benign paroxysmal positional vertigo (BPPV), and other less likely causes such as brain tumors or brain injuries, stroke, migraine, toxin exposure, and uneven pressure in the middle ear. Without wishing to be bound by theory, it is suggested that one of the causes may be chronic overproduction of the neurotransmitters glutamate, substance P, and calcitonin gene-related peptide (GCRP) from local damage to the vestibular nerve or from central sensitization effects that develop due to depression, migraine, fibromyalgia, or other neuropathic conditions. This can lead to damaged neurons and There are many suspected causes of vertigo, such as Meniere's disease, otitis media, benign paroxysmal positional vertigo (BPPV), and other less likely causes such as brain tumors or brain injuries, stroke, migraine, toxin exposure, and uneven pressure in the middle ear. Without wishing to be bound by theory, it is suggested that one of the causes may be chronic overproduction of the neurotransmitters glutamate, substance P, and calcitonin gene-related peptide (GCRP) from local damage to the vestibular nerve or from central sensitization effects that develop due to depression, migraine, fibromyalgia, or other neuropathic conditions. This can lead to damaged neurons and There are many suspected causes of vertigo, such as Meniere's disease, otitis media, benign paroxysmal positional vertigo (BPPV), and other less likely causes such as brain tumors or brain injuries, stroke, migraine, toxin exposure, and uneven pressure in the middle ear. Without wishing to be bound by theory, it is suggested that one of the causes may be chronic overproduction of the neurotransmitters glutamate, substance P, and calcitonin gene-related peptide (GCRP) from local damage to the vestibular nerve or from central sensitization effects that develop due to depression, migraine, fibromyalgia, or other neuropathic conditions. This can lead to damaged neurons and Neurons that are not present (vestibular vertigo) enter a state of chronic hypersensitivity.

[0052] There are several known causes of vertigo, one of which may be related to migraine. Migraine One of the widely accepted theories about the cause of migraine is the chronic or periodic overproduction of excitatory substances. The overproduction of glutamate, substance P, and GCRP is caused by nerve structural cells (glia, satellite, and astrocytes). They cause hyperexcitation and hypersensitivity of the vestibular nerve, firing with minimal stimulation and causing symptoms of vertigo. As described in the above paragraph, subcutaneous injection of botulinum toxin or other injections (such as intradermal injection) that allow botulinum toxin to reach unmyelinated sensory C fibers can effectively suppress the overproduction of these substances for a long time. The problem is that the above-mentioned vestibular nerve is a cranial nerve and there is no exposure to superficial sensation. It

[0053] extends directly from the brain to the back of the inner ear. However, there are anastomotic connections between the cervical nerve, trigeminal nerve, and vestibular nerve. This is part of the visual tracking mechanism that prevents the head from moving left and right too quickly or rotating too fast. The purpose of this is that when the head movement is too fast, there is too much visual information to process, resulting in an image similar to pixelation on a TV. Of course this system can be spontaneously disabled by quickly moving the head as needed, but while moving quickly the visual field is not very clear. Using this interconnection of the visual tracking system, botulinum toxin reaches unmyelinated sensory C fibers

[0054] reaches the cervical and trigeminal nerves, reaches the vestibular nerve and ganglia, and relieves its hypersensitivity and reaches the vestibular nerve and ganglia to relieve its hypersensitivity It is considered that botulinum toxin can be injected by subcutaneous or other injections to cause sedation. It is conceivable.

[0055] The usual causes of dizziness are identified and, of course, treated if present, but tests are negative, especially other migraines, depression, and fibromyalgia, as well as headaches, mild reactions, head, ear , or sensitivity to touch in areas such as the neck or cervical region, depression, anxiety, and / or other neuropathic conditions such as sleep disorders, if accompanied by symptoms, a blood glutamate test can be performed to check if it is elevated.

[0056] If a patient is diagnosed with experiencing vestibular dizziness, to prevent or relieve related symptoms , botulinum toxin can be injected subcutaneously, or other injections (such as intradermal injections) can be performed so that the botulinum toxin reaches the unmyelinated sensory C fibers. If desired, blood tests can be performed to evaluate the blood concentrations of substance P, CGR P, and glutamate. The botulinum toxin injection can be given to the trigeminal nerve and / or the cervical nerve and / or around them. Botulinum toxin injections to all of the above nerves are also considered to be within the scope of the claims of the present invention and are contemplated. Examples of the trigeminal nerve include, but are not limited to, the ophthalmic nerve, maxillary nerve, mandibular nerve, supraorbital nerve, superior vestibular nerve, infraorbital nerve, lacrimal nerve, nasal ciliary nerve, superior alveolar nerve, buccal nerve, lingual nerve, inferior alveolar nerve, mental nerve, auriculotemporal nerve, lesser occipital nerve, greater occipital nerve, or combinations thereof. Examples of the cervical nerve include, but are not limited to, the c-2 nerve, c-3 nerve, c-4 nerve, c-5 nerve, c-6 nerve, c-7 nerve, c-8 nerve, and combinations thereof. For example, the ophthalmic nerve of the trigeminal nerve (bilateral), superior nerve, maxillary nerve, mandibular nerve, supraorbital nerve, superior vestibular nerve, infraorbital nerve, lacrimal nerve, nasal ciliary nerve, superior alveolar nerve, buccal nerve, lingual nerve, inferior alveolar nerve, mental nerve, auriculotemporal nerve, lesser occipital nerve, greater occipital nerve, or combinations thereof. Examples of the cervical nerve include, but are not limited to, the c-2 nerve, c-3 nerve, c-4 nerve, c-5 nerve, c-6 nerve, c-7 nerve, c-8 nerve, and combinations thereof. For example, the ophthalmic nerve of the trigeminal nerve (bilateral), superior nerve, maxillary nerve, mandibular nerve, supraorbital nerve, superior vestibular nerve, infraorbital nerve, lacrimal nerve, nasal ciliary nerve, superior alveolar nerve, buccal nerve, lingual nerve, inferior alveolar nerve, mental nerve, auriculotemporal nerve, lesser occipital nerve, greater occipital nerve, or combinations thereof. Examples of the cervical nerve include, but are not limited to, the c-2 nerve, c-3 nerve, c-4 nerve, c-5 nerve, c-6 nerve, c-7 nerve, c-8 nerve, and combinations thereof. For example, the ophthalmic nerve of the trigeminal nerve (bilateral), superior 2 to 4 units to and / or around the trigeminal nerve and / or the mandibular nerve, and / or to and / or around the c-2 to c-3, c-4 to c-6, and / or c-7 to c-8 cervical nerves about 1 inch outside (bilateral) of the spine can be administered. Since there is a significant cross between the trigeminal nerve and the cervical nerve on the left and right, even when the dizziness is in one ear the bilateral injection is necessary. These are adult dosages. The dosages for 0 to 5 years old need to be adjusted according to age and weight.

[0057] Botulinum toxin is administered to lower the levels of substance P, CGRP, and glutamate, and usually begins to act about 3 days later. It usually takes about 1 to 2 weeks for botulinum toxin to reach its high efficacy. The blood glutamate level can be monitored to confirm that the level decreases normally, and the physical symptoms can be monitored to confirm normalization. As the botulinum toxin gradually decreases and an increase in substance P, glutamate, or CGRP is shown in a blood test, the symptoms begin to recur, and more botulinum toxin can be administered to counter this effect. If the level / symptoms do not normalize, in a desirable case, a small amount of one of the glutamate antagonists can be administered to lower the glutamate level without causing side effects.

[0058] Usually, the therapeutically effective dosage or amount can be between 1 and 150 units depending on body weight. The dosage for an adult weighing about 150 pounds is about 50 to 150 units. Children over about 5 years old with halted brain formation can adjust the dosage according to body weight. For example, in the case of infants (about 1 to 5 years old), the dosage can be about 1 to 30 units. ​

[0059] Treatment of Tinnitus Tinnitus is defined as a sound that is heard when there is no external sound. Patients often express tinnitus as "ringing in the ears" ", but a clicking sound, a hissing sound, a roaring sound, or rarely an unclear voice or music may be heard. Patients can describe what they hear as loud or soft, high or low pitch, and can experience this in one or both ears. Tinnitus usually occurs gradually but can be more sudden depending on the cause. In some cases, tinnitus can become severe and cause depression or anxiety and interfere with concentration.

[0060] Tinnitus is not a disease itself but a symptom that can arise from many underlying causes. Conditions that can cause tinnitus include ear infections, noise-induced hearing loss, Bell's palsy, brain tumors, neck injuries in the C1-C3 region of the neck, brain injuries, heart and blood vessel diseases, Meniere's disease, psychological stress, certain medications , or excessive production of earwax. This is often seen in patients suffering from depression, and the diagnosis of the cause of the symptoms is usually based on the patient's description. When the neurons in the ear are damaged or destroyed, the ability to hear should decrease or disappear completely. Therefore, it seems counterintuitive that patients with damaged or destroyed ear neurons experience even an increase in certain sounds or volume. Without being bound by theory but hoping not to be, tinnitus may be caused by the overproduction of substance P, glutamate, and CGRP (calcitonin

[0061] gene-related peptide). These are produced after damage to sensory neurons. These neuroexcitatory chemical substances cause a state of hypersensitivity in the remaining cochlear neurons and fire with little or no stimulation. It is reasonable to expect that patients with damaged or destroyed ear neurons should experience a decrease in hearing ability or even complete deafness. Therefore, it seems counterintuitive that patients with damaged or destroyed ear neurons experience even an increase in certain sounds or volume. Without being bound by theory but hoping not to be, tinnitus may be caused by the overproduction of substance P, glutamate, and CGRP (calcitonin gene-related peptide). These are produced after damage to sensory neurons. These neuroexcitatory chemical substances cause a state of hypersensitivity in the remaining cochlear neurons and fire with little or no stimulation. gene-related peptide). These are produced after damage to sensory neurons. These neuroexcitatory chemical substances cause a state of hypersensitivity in the remaining cochlear neurons and fire with little or no stimulation. after damage to sensory neurons. These neuroexcitatory chemical substances cause a state of hypersensitivity in the remaining cochlear neurons and fire with little or no stimulation. after damage to sensory neurons. These neuroexcitatory chemical substances cause a state of hypersensitivity in the remaining cochlear neurons and fire with little or no stimulation.

[0062] For botulinum toxin to be effective, it needs to be injected near the unmyelinated subcutaneous C fibers. The problem is that the cochlear nerve exits directly from the brain and is a cranial nerve that enters the ear without superficial exposure. How can we reach the cochlear ganglion with botulinum toxin? There is a system that locates the position of the sound of an animal so that the animal can determine the direction and distance of the sound. Extreme examples are bats that can fly in the dark and catch insects in the night sky during flight, as well as whales and dolphins that use healthy locations in the water (sonar). In this system, input from the cervical nerves c1 - c3, the trigeminal nerve, and the facial nerve is required. These nerves move the neck, face, and ears to position the ears so that the origin of the sound can be identified. To make this system function, it has branches that anastomose with the cochlear nerve and the vestibular nerve. They have superficial C fibers that allow botulinum toxin to be injected to reach the cochlear nerve. The botulinum toxin is injected into them, moves to the cochlear ganglion, and can reduce chronic nerve excitation, which is one of the causes of tinnitus. This has been clinically shown when botulinum toxin is injected subcutaneously or by other injections (such as intradermal injection, etc.) that allow the botulinum toxin to reach the unmyelinated sensory C fibers, where tinnitus is reduced or eliminated due to this cause. To diagnose tinnitus, the blood glutamate level and physical symptoms can be checked by a regular doctor's examination. Physical symptoms include, but are not limited to, intermittent or continuous noises in the ear such as tinnitus, roaring, booming, hissing, whistling, etc. For botulinum toxin to reach the cochlear ganglion, what should be done? There is a system that enables an animal to determine the direction and distance of a sound by identifying the position of the animal's sound. Extreme examples are bats that can fly in the dark and catch insects in the night sky during flight, as well as whales and dolphins that use healthy locations in the water (sonar). In this system, input from the cervical nerves c1 - c3, the trigeminal nerve, and the facial nerve is required. These nerves move the neck, face, and ears to position the ears so that the origin of the sound can be identified. To make this system function, it has branches that anastomose with the cochlear nerve and the vestibular nerve. They have superficial C fibers that allow botulinum toxin to be injected to reach the cochlear nerve. The botulinum toxin is injected into them and moves to the cochlear ganglion, and can reduce chronic nerve excitation, which is one of the causes of tinnitus. This has been clinically shown when botulinum toxin is injected subcutaneously or by other injections (such as intradermal injection, etc.) that allow the botulinum toxin to reach the unmyelinated sensory C fibers, where tinnitus is reduced or eliminated due to this cause.

[0063] To diagnose tinnitus, the blood glutamate level and physical symptoms can be checked by a regular doctor's examination. Physical symptoms include tinnitus, roaring, booming, hissing, whistling, etc., which are intermittent or continuous noises in the ear, but are not limited to these. ​​

[0064] If patients are diagnosed with tinnitus, they may be given botulinum toxin subcutaneously or compared with other injections (e.g., intradermal injections) that allow botulinum toxin to reach unmyelinated sensory C-fibers. and associated symptoms and / or substance P, CGRP, and glutamate. The botulinum toxin may prevent or mitigate the need for blood tests to assess blood levels of botulinum toxin. The bacteriotoxic injection is administered into and / or around the trigeminal and / or cervical nerves of the patient. Botulinum toxin injections into any of the above nerves are also included in the claimed invention. The trigeminal nerve includes the ophthalmic nerve, maxillary nerve, mandibular nerve, Supraorbital nerve, supratracheal nerve, infraorbital nerve, lacrimal nerve, nasal ciliary nerve, superior alveolar nerve, buccal nerve, tongue nerve, inferior alveolar nerve, mental nerve, auriculotemporal nerve, lesser occipital nerve, greater occipital nerve, or The cervical nerves may include, but are not limited to, the following combinations: c-2, Nerve, c-3 nerve, c-4 nerve, c-5 nerve, c-6 nerve, c-7 nerve, c-8 nerve, For example, the trigeminal nerve ( to and / or around the ophthalmic, maxillary, and / or mandibular nerves (both sides) 2-4 units of the cervical nerves c-2 to c-3, and / or about 1 inch lateral to the spine (on both sides) 3, c-4 to c-6, and / or c-7 to c-8, and / or their surrounding areas The trigeminal and cervical nerves have significant crossovers from side to side, so the dose can be 2 to 4 units. Therefore, even if the tinnitus is in one ear, bilateral injections are necessary. Dosage: For children 0-5 years old, the dosage should be adjusted according to age and weight.

[0065] Botulinum toxin reduces the levels of substance P, CGRP, and glutamate and is administered to do so, usually beginning to act about 3 days later. It usually takes about 1-2 weeks for botulinum toxin to reach its high efficacy. By monitoring the blood glutamate level to confirm that the level decreases to normal, and by monitoring the physical symptoms to confirm normalization can be achieved. As the botulinum toxin gradually decreases and an increase in substance P, glutamate, or CGRP is indicated by a blood test, the symptoms begin to recur, and more botulinum toxin can be administered to counteract this effect. If the levels / symptoms do not normalize, in a desirable case, one of the glutamate antagonists can be administered in a small amount to lower the glutamate level without causing side effects . Usually, a therapeutically effective dose or amount can be between 1 and 150 units depending on body weight. The dose for an adult weighing about 150 pounds is about 50-150 units. Children about 5 years old and older with halted brain formation can have their doses adjusted according to their body weight. For example, in the case of infants (about 1-5 years old ), the dose can be about 1-30 units.

[0066] Normally, a therapeutically effective dose or amount can be between 1 and 150 units depending on body weight. The dose for an adult weighing about 150 pounds is about 50-150 units. Children about 5 years old and older with halted brain formation can have their doses adjusted according to their body weight. For example, in the case of infants (about 1-5 years old ), the dose can be about 1-30 units.

[0067] New clinical treatments for the symptoms and causes of anxiety and / or depression Subcutaneous botulinum toxin or other injections that reach unmyelinated sensory C fibers with botulinum toxin (e.g., intradermal injection, etc.) can halt or minimize the symptoms of depression and / or anxiety. Without wishing to be bound by a particular theory, depression and / or anxiety are thought to be associated with an increase in glutamate levels . The glutamate level can increase due to either mental injury (trauma) or medical injury. Botulinum toxin helps with the symptoms ​ or initially administered to stop, and appropriate specialists such as physicians can perform psychoanalysis or health diagnosis to enable evaluation of the cause of the increased glutamate level in the patient. If it is found after psychoanalysis that the patient has suffered mental damage, appropriate psychotherapy can be provided to help the patient cope with the mental damage. If the patient is injured after examination, treatment is performed to prevent the increase in the glutamate value. Physical symptoms can also be checked. These include, but are not limited to, changes in sleep, appetite, energy level, concentration ability, daily behavior or self-esteem, or thoughts of suicide.

[0068] If the patient is diagnosed with depression and / or anxiety disorder, botulinum toxin and / or substance P, C GRP, and a blood test can be performed to evaluate the blood level of glutamate to reduce or eliminate the symptoms of anxiety disorder and / or depression. The botulinum toxin injection can be administered to the trigeminal nerve, cervical nerve, thoracic nerve, lumbar nerve, and / or sacral nerve of the patient, and / or around them. Botulinum toxin injection to all of the above nerves is also considered to be within the scope of the claims of the present invention. As the trigeminal nerve, the ophthalmic nerve, maxillary nerve, mandibular nerve, supraorbital nerve, superior tracheal nerve, infraorbital nerve, lacrimal nerve, nasal ciliary nerve, superior alveolar nerve, buccal nerve, lingual nerve, inferior alveolar nerve, mental nerve, auriculotemporal nerve, lesser occipital nerve, greater occipital nerve, or a combination thereof can be mentioned, but are not limited thereto. As the cervical nerve, the c-2 nerve, c-3 nerve, c-4 nerve, c-5 nerve, c-6 nerve, c-7 nerve, c-8 nerve, and combinations thereof can be mentioned, but are not limited thereto. thereto. is not limited. For example, the ophthalmic nerve, maxillary nerve, and / or mandibular nerve of the trigeminal nerve (bilateral) 2 - 4 units to and / or around the spinal cord, about 1 inch outside (bilateral) of the cervical nerves of the spinal cord to c - 2~c - 3, c - 4~c - 6, and / or c - 7~c - 8, and / or 2 - 4 units to and / or around the spinal cord to the t - 2~t - 3, t - 5~t - 6, t - 7~t - 9, and / or t - 10~t - 12 of the thoracic nerves about 1 inch outside the spinal cord, and / or 2 - 4 units to and / or around the spinal cord, to the l - 1~l - 2, l - 2~l - 3, and / or l - 4~l - 5 of the lumbar nerves about 1 inch outside the spinal cord, and / or 2 - 4 units to and / or around the spinal cord, to the s - 1~s - 2, s - 3~s - 4, and / or s - 4~s - 5 of the sacral nerves about 1 inch outside (bilateral) of the spinal cord, and / or 2 - 4 units to and / or around the spinal cord can be administered. These are adult dosages. The dosages for 0 - 5 years old need to be adjusted according to age and body weight. Botulinum toxin is administered to lower the levels of substance P, CGRP, and glutamate, and usually begins to act about 3 days later. It usually takes about 1 - 2 weeks for botulinum toxin to reach its high efficacy level. It is possible to monitor the blood glutamate level to confirm that the level decreases normally, and similarly monitor the physical symptoms to confirm normalization . The normal blood glutamate level can be in the range of 40 - 60 μM. Or, the normal blood glutamate level can be at a level that a person skilled in the art would reasonably perceive

[0069] Botulinum toxin gradually decreases, and substance P, glutamate, can be detected by blood test . . . . . . Or when an increase in CGRP is indicated, the symptoms begin to recur, and in order to counteract this effect more botulinum toxin can be administered. If the level / symptoms do not normalize, a small amount of either a glutamate antagonist or an antidepressant can be administered to lower glutamate levels without causing side effects. If they are not curable, botulinum toxin is continued to minimize or eliminate the symptoms indefinitely.

[0070] Typically, the dosage can be 1 to 150 units depending on body weight. The dosage for an adult weighing about 150 pounds is about 50 to 150 units. Children over about 5 years old in whom brain formation has stopped can have the dosage adjusted according to body weight.

[0071] The botulinum toxin for use according to the claims of the present invention can be stored in a lyophilized vacuum-dried form, in a container under vacuum pressure, or as a stable liquid. Prior to lyophilization, the botulinum toxin can be combined with a pharmaceutically acceptable excipient, stabilizer, and / or a carrier such as albumin. The lyophilized material can be reconstituted with saline or water to produce a solution or composition containing

[0072] the botulinum toxin for administration to the patient. Preferably, the botulinum neurotoxin is peripherally administered by administering it to the aforementioned nerve or in the vicinity thereof, or to the aforementioned nerve branch or its ganglion nucleus. By this method of administration, the botulinum neurotoxin can be administered to a selected intracranial target tissue or can have an Including transplantation of the system. Such sustained release systems reduce the need for repeated injections. The spread of the biological activity of botulinum toxin within the tissue can be carried out stepwise as a function of the dose. Jankovic J., et al Therapy With Botu linum toxin, Marcel Dekker, Inc., (1994) , page 150. Thus, controlling the spread of botulinum toxin can reduce potentially undesirable side effects that can affect the cognitive ability of the patient. For example, the botulinum neurotoxin can be administered such that it primarily affects the nervous system thought to be involved in the selected neuropsychiatric disorder and does not have an adverse effect on other nervous systems. Furthermore, the botulinum neurotoxin can be administered to the patient in combination with a solution or composition that locally reduces the pH of the target tissue environment. For example, using a solution containing hydrochloric acid, locally and temporarily reducing the pH of the target tissue environment can promote the movement of the neurotoxin across the cell membrane. When the composition may not have a functional targeting moiety (e.g., a part of the toxin that binds to the neurotoxin receptor) and / or a translocation domain, a reduction in local pH may be desirable. By way of non-limiting example, a fragment of botulinum toxin containing the proteolytic domain of the toxin can be administered to the patient in combination with an agent that reduces the local pH of the target tissue. Without wishing to be bound by a particular theory, a lower pH is thought to promote the translocation of the proteolytic domain across the cell membrane, allowing the neurotoxin fragment to exert its toxic effect intracellularly. The pH of the target tissue is temporary.

[0073] Furthermore, the botulinum neurotoxin can be administered to the patient in combination with a solution or composition that locally reduces the pH of the target tissue environment. For example, using a solution containing hydrochloric acid, locally and temporarily reducing the pH of the target tissue environment can promote the movement of the neurotoxin across the cell membrane. When the composition may not have a functional targeting moiety (e.g., a part of the toxin that binds to the neurotoxin receptor) and / or a translocation domain, a reduction in local pH may be desirable. By way of non-limiting example, a fragment of botulinum toxin containing the proteolytic domain of the toxin can be administered to the patient in combination with an agent that reduces the local pH of the target tissue. Without wishing to be bound by a particular theory, a lower pH is thought to promote the translocation of the proteolytic domain across the cell membrane, allowing the neurotoxin fragment to exert its toxic effect intracellularly. The pH of the target tissue is temporary. For example, a fragment of botulinum toxin containing the proteolytic domain of the toxin can be administered to the patient in combination with an agent that reduces the local pH of the target tissue. Without wishing to be bound by a particular theory, a lower pH is thought to promote the translocation of the proteolytic domain across the cell membrane, allowing the neurotoxin fragment to exert its toxic effect intracellularly. The pH of the target tissue is temporary. membrane, allowing the neurotoxin fragment to exert its toxic effect intracellularly. The pH of the target tissue is temporary. ​Since it only decreases in a certain manner, damage to neurons and / or glia is reduced.

[0074] The botulinum toxin is selected from the group consisting of botulinum toxin type A, botulinum toxin type B, botulinum toxin type C, botulinum toxin type D, botulinum toxin type E, botulinum toxin type F, botulinum toxin type G, fragments thereof, hybrids thereof, chimeras thereof, and combinations thereof. Since the mechanisms and cleavage sites of botulinum toxins are different, the efficacy, dosage, or duration may vary depending on the type of botulinum toxin. The botulinum toxin can be used together with other regulators or chemicals. In a further embodiment, the therapeutically effective amount of botulinum toxin administered is between about 1 unit and about 150 units.

Examples

[0075] The claims of the present invention will be described in detail hereinafter with reference to examples.

[0076] [Example 1] A 40-year-old female patient experienced the following neuropathic symptoms: chronic severe post-herpetic neuralgia from c-7 to t-4 on the left side, chronic migraine, trigeminal neuralgia, tinnitus, chronic dry eye syndrome (DES) since a laser surgery 4 years ago, sleep disorder (waking up after sleeping for 3 - 4 hours and unable to fall back asleep), chronic fatigue, anxiety, depression, pain in the neck, shoulders, and upper back, and muscle spasms. The patient was taking the following medications: Tegretol for trigeminal neuralgia, gabapentin for herpes zoster, and Lexapro for depression. These medications somewhat alleviated her symptoms, but not significantly. Next, she was administered botulinum toxin type A, all by subcutaneous injection: at the ophthalmic, maxillary, and mandibular cutaneous segments of the trigeminal nerve (bilaterally). ​ 2 to 4 units; and 4 units at c-2, c-4, c-6, t-2, approximately 1 inch outside the spine (bilateral). , t-4, and t-6.

[0077] All of her symptoms began to resolve by the 5th day and were resolved by the 14th day, and the patient was able to discontinue all medications. All symptoms, including the dry eye syndrome, disappeared for approximately 4 months, at which point all symptoms, including the dry eye syndrome, began to recur. When she received botulinum toxin again, all of her symptoms, including her dry eye syndrome, disappeared again.

[0078] [Example 2] A 25-year-old autistic woman experienced moderate to severe ASD (autism spectrum disorder). The subject was diagnosed with pervasive developmental disorder at age 2. She also suffered from agenesis of the corpus callosum (ACC), attention deficit disorder (ADD), and obsessive-compulsive disorder (OCD). During her young life, she was prescribed Ritalin to help her stay focused. She also took Zoloft to control her anxiety. She graduated from school as a special education student in a life skills class until age 22. After taking medications for several years and experiencing mood swings of emotional outbursts, the family decided to stop the medications. The subject's conversations were not conversations but were related to expressing desires and / or needs. The last day of prescription medication was taken on December 27, 2018.

[0079] On July 17, 2019, she received multiple subcutaneous injections of botulinum toxin for trigeminal and cervical dermatitis: 2 units of injection distributed along both sides of the neck of the trigeminal nerve respectively. ​​​​​​​​​​​​​Three times, 2 units were injected once on both sides subcutaneously in the eye area, upper jaw area, and lower jaw area. In this case, the maximum total amount of botulinum toxin injected was 2 units * 3 injections (cervical vertebra) * 2 (both sides) + 2 units * 3 injections (in the eye, upper jaw, and lower jaw areas of the trigeminal nerve respectively) * 2 (both sides) = 24 units. No immediate changes were observed.

[0080] About two weeks later, she became more talkative and familiar with her surroundings. She also no longer showed the mood swings she sometimes displayed. She still showed some OCD moments, such as slamming the toilet seat cover shut, slamming the door shut, slamming the refrigerator door shut, etc. Her mother reported definite progress.

[0081] One week later, she began to sleep better. She also showed more positive social behavior through appropriate responses to the external environment. She spoke more verbally about her situation and acted appropriately independently. She recalled details of past events and even engaged in conversations.

[0082] Overall, she was quite harmonious with her surroundings. She showed significant improvement in behavior, emotions, and language abilities. Currently, she is enjoying her life in a much more independent and self - regulated way. The weight of the female patient in the case study was approximately 150 pounds. The dosage for an infant weighing about 25 pounds can be adjusted according to weight.

[0083] [Example 3] A 62 - year - old female patient experienced severe and refractory dizziness. Her dizziness symptoms were very severe, with severe rotation and nausea, so she spent most of the day with minimal head movement She spent lying down as little as possible. It was very difficult for her to get in the car. She had to stop regularly and vomit. She saw many doctors, tried many specialists, tried many medications, and even had surgery to try to control it uselessly. She presented with severe nausea, dizziness, photosensitivity, and moderate hypersensitivity, and touched the right ear / behind the earlobe area. Her diagnosis could have been vestibular vertigo. Therefore, subcutaneous botulinum toxin was injected - 2 - 4 units into the ophthalmic, maxillary, and mandibular regions of the trigeminal nerve on both sides; and 2 - 4 units in the c - 2 to c - 3 region, 2 - 4 units in the c - 4 to c - 5 region, and 2 - 4 units in the c - 6 to c - 7 region. Within two weeks, she reported that 95% of the symptoms of dizziness and nausea had disappeared, and the woman could walk on her own and get in the car without symptoms. When she moved her head very quickly back and forth, there was still some dizziness. The botulinum toxin A usually lasts for 3 - 4 months.

[0084] Since she did not want it to come back, she received a new injection in about 2.5 months. When she moved her head very quickly back and forth, there was still some dizziness. The botulinum toxin A usually lasts for 3 - 4 months. Since she did not want it to come back, she received a new injection in about 2.5 months.

[0085] [Example 4] The patient is a 49 - year - old man. He suffers from chronic severe lumbar, sacral, and sometimes cervical pain. He also has a deficiency of protein S and takes Eloquis due to the resulting blood clots. The deficiency of protein S can contribute to his chronic pain. He went to many doctors for surgery and steroid injections only for temporary relief of his pain. In February, one of his orthopedic surgeons said that the 6 - Vicodin he was taking daily was very ​​It was conveyed that, due to the large quantity, it was necessary to discontinue the medication, or else poisoning would occur. Therefore he did so, and for several weeks, he experienced moderate to severe withdrawal pain. He abstained for about a month, but then, judging that the pain was having an excessive impact on him, he began taking it three times a day. Initially, depending on whether physical activity was excessive or not, each tablet relieved the pain for about 5 - 6 hours. After 6 - 8 weeks, the effectiveness of the tablets began to decline. In July, they were only effective for 2 - 3 hours. On August 21st, he received subcutaneous botulinum toxin - 12 units in the trigeminal nerve, 12 units in the neck, 12 units in the chest, 12 units in the lumbar spine, and 12 units at the center of the sacrum, for a total of 60 units. On the 5th day after the injection, he began to notice that they seemed to last longer. By the 10th day, they had lasted for 6 hours.

[0086] Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as ordinarily understood by one of ordinary skill in the technical field to which this invention belongs. Therefore the scope of the embodiments of the invention in the claims should be determined by the appended claims and their legal equivalents.

Claims

Claim 1: A therapeutic agent containing botulinum toxin for use in the treatment of autism spectrum disorder (ASD) in a patient in need of treatment, wherein the botulinum toxin is administered to the patient, whereby the autism spectrum disorder (ASD) is treated. The administration to the patient is by subcutaneous injection or intradermal injection. 2 to 4 units are injected into the trigeminal nerve and / or its periphery. 2 to 4 units are injected into the cervical nerve outside the spine of the patient and / or its periphery. 2 to 4 units are injected into the thoracic nerve outside the spine of the patient and / or its periphery. 2 to 4 units are injected into the lumbar nerve outside the spine of the patient and / or its periphery. And / or 2 to 4 units are injected into the sacral nerve outside the spine of the patient and / or its periphery. The total dose of botulinum toxin for an adult weighing about 150 pounds is about 50 units or less. The total dose of botulinum toxin for an adult is adjusted according to body weight, and the total dose of botulinum toxin for children about 5 years old and above and infants about 1 to 5 years old is adjusted according to age, body weight, or a combination thereof. A therapeutic agent.

2. The therapeutic agent according to claim 1, wherein the trigeminal nerve is selected from the group consisting of the ophthalmic nerve, maxillary nerve, mandibular nerve, superior orbital nerve, superior trochlear nerve, infraorbital nerve, lacrimal nerve, nasal ciliary nerve, superior alveolar nerve, buccal nerve, lingual nerve, inferior alveolar nerve, mental nerve, auriculotemporal nerve, lesser occipital nerve, greater occipital nerve, and combinations thereof.

3. The therapeutic agent according to claim 1, wherein the cervical nerve is selected from the group consisting of the c-2 nerve, c-3 nerve, c-4 nerve, c-5 nerve, c-6 nerve, c-7 nerve, c-8 nerve, and combinations thereof.

4. The therapeutic agent according to claim 1, wherein the administration of the botulinum toxin alleviates or eliminates the symptoms of autism spectrum disorder (ASD) in children about 5 years old and above and adults in whom brain formation has stopped.

5. The therapeutic agent according to claim 1, wherein each of the subcutaneous injection or intradermal injection is bilateral.

6. The therapeutic agent according to claim 1, wherein the thoracic nerve includes the t-2 nerve, t-3 nerve, t-5 nerve, t-6 nerve, t-7 nerve, t-8 nerve, t-9 nerve, t-10 nerve, t-11 nerve, t-12 nerve, or combinations thereof.

7. The therapeutic agent according to claim 1, wherein the lumbar nerve includes the l-1 nerve, l-2 nerve, l-3 nerve, l-4 nerve, l-5 nerve, or a combination thereof.

8. The therapeutic agent according to claim 1, wherein the sacral nerve includes the s-1 nerve, s-2 nerve, s-3 nerve, s-4 nerve, s-5 nerve, or a combination thereof.