Botulinum toxins for use in therapy

Abstract

To provide a botulinum toxin for treating neuropsychiatric disorders and / or neurological disorders.SOLUTION: Provided is a botulinum toxin for use in the treatment of ASD (autism) in a patient in need thereof. Said treatment comprises administration of botulinum toxin to said patient by subcutaneous / intradermal injection. Administration to adults comprises injecting 2-4 units into and / or around the trigeminal nerve, 2-4 units into and / or around the cervical nerve outside the patient's spine, 2-4 units into and / or around the thoracic nerve outside the patient's spine, 2-4 units into and / or around the lumbar nerve outside the patient's spine, and / or 2-4 units into and / or around the sacral nerve outside the patient's spine. The total dosage of botulinum toxin for an adult human weighing about 150 pounds is no more than about 50 units, adjusted for age, weight, or a combination thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] [Priority claim] This application claims priority to U.S. Application No. 16 / 657,933, entitled "Treatment of Autism Using Botulinum Toxin," filed October 18, 2019, now U.S. Patent No. 10,722,552 B1, which issued July 28, 2020, and is incorporated by reference in its entirety.

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

[0003] Botulinum toxins cleave and destroy proteins called synaptosomal nerve-associated protein 25 (SNAP25) and / or synaptobrevin (also known as vesicle-associated membrane protein (VAMP)). Botulinum toxin types A, C, and E cleave SNAP25 at different locations, but the effect is the same—the protein is destroyed and inactive until the cell produces a new one. Botulinum toxin types B, D, F, and G cleave VAMP, which is present on the cytoplasmic surface of synaptic vesicles. Two key locations in the body where they are found are the terminals of motor neurons (muscles) and the cell membranes of astrocytes, glial cells, and satellite cells. These three cell types surround sensory neurons and form part of the blood-brain barrier. In motor neurons, to fire them, acetylcholine vesicles travel from inside the motor neuron through the cell membrane at the synapse between the motor neuron and muscle fiber. Acetylcholine is released into the synapse, and activated receptors in muscle fibers cause synaptic contraction. In sensory neurons, when the nerve is damaged by physical or psychological injury, the three structural cells mentioned above internally produce large amounts of substance P, calcitonin gene-related peptide (CGRP), and glutamate, which are transported to the cell membrane by vesicles. There, SNAP25 and / or VAMP transport them through the cell membrane and release them into the cerebrospinal fluid surrounding the neuron. There, they bind to receptors in the sensory nerve, causing neuroexcitation. They can also diffuse into the cerebrospinal fluid (CSF) and affect other sensory neurons, causing hyperactivity, a process known as central sensitization.

[0004] This mechanism of cleaving SNAP25 and / or VAMP in muscles and sensory nerves is responsible for botulinum's only known clinical effect: it paralyzes muscles for 3-4 months while the cells grow new proteins. This effect has been used for decades to treat overactive bladder (cervical dystonia, blepharospasm, tics, Parkinson's disease, cerebral palsy, etc.), facial wrinkles, excessive sweating, and overactive bladder.

[0005] In sensory neurons, it has been used to treat migraines and depression. Blocking SNAP25 and / or VAMP in glial cells, satellite cells, and astrocytes works for 5 to 9 months until these cells grow new proteins. An important part of this is that the botulinum effect does not destroy cells and does not stop the normal production or effects of acetylcholine (muscle), substance P, CGRP, or glutamate in sensory neurons. These facts give it a major advantage over monoclonal antibodies, which eliminate all glutamate, CGRP, and substance P. The side effects are devastating. Receptor antagonists also have problems. They are not site-specific. They block glutamate, substance P, and CGRP at all sites. Too little glutamate, substance P, and CGRP can be just as problematic as too much. It is difficult to adjust oral or in vivo doses to obtain the correct reduction in areas where glutamate, substance P, and CGRP are very high, without excessive reduction in areas where levels are normal.

[0006] By cleaving SNAP25 and / or VAMP, small amounts of botulinum toxin can be injected into specific muscles to calm overreactions or, if desired, temporarily paralyze them. Alternatively, when injected subcutaneously near unmyelinated sensory nerves, it can reduce or stop the overproduction of sensory excitatory compounds without affecting normal glutamate, substance P, and CGRP production and function. However, botulinum toxin is known to be extremely deadly. It is the most toxic poison known. One molecule of botulinum toxin destroys one protein molecule of SNAP25 and / or VAMP. Small amounts are highly effective. It must be manufactured, stored, and injected with knowledge and care.

[0007] Specifically, the mechanism of its sensory effect (stopping the overproduction of glutamate, substance P, and CGRP) is as follows: Nearly all nerves in the human body are surrounded by a protective coating called myelin, which protects the nerves and allows nerve conduction to occur more quickly. Botulinum toxin has difficulty penetrating myelin. Just beneath the skin are several sensory pain nerves called unmyelinated C fibers. Research has shown that botulinum toxin penetrates these axons, diffuses down the axons to the cell bodies, and then penetrates the CSF, where it can affect SNAP25 and / or VAMP in glial cells, satellite cells, and astrocytes. Botulinum toxin then disrupts SNAP25 and / or VAMP, preventing the release of excess substance P, CGRP, and glutamate involved in the nerve injury response mechanism without affecting normal glutamate, substance P, and CGRP production, use, or receptors. An example of a failure of normal nerve mechanisms is infection of a nerve by the varicella-zoster virus. The infection damages the nerves but does not kill them or cause sensation (numbness). This causes a surge in the production of glutamate, substance P, and CGRP, which causes the familiar pain and hypersensitivity associated with shingles. Over two to three months, the infection is contained, the nerves heal, and the overproduction of neuroexcitatory chemicals returns to normal. However, sometimes, for unknown reasons, the overproduction does not return to normal but remains elevated, resulting in persistent severe chronic pain and hypersensitivity. Chronically overstimulated neurons can cause a number of problems, depending on their location. These neuroexcitatory chemicals travel up the spinal cord in the cerebrospinal fluid 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 conditions or illnesses such as, but not limited to, chronic pain, headaches, dizziness, sensitivity to light, sensitivity to touch, intolerance to cold, overactive bladder, depression, anxiety, flashbacks, mental fog, vasoconstriction in the extremities, sleep disorders, and possibly death and malformation of developing neural structures in children with ASD (autism). Summary of the Invention

[0008] Some embodiments of the claimed invention relate to a botulinum toxin for use in treating dry eye syndrome in a patient in need thereof. The treatment comprises administering the botulinum toxin to the patient. The botulinum toxin may be administered by subcutaneous / intradermal injection. The subcutaneous / intradermal injection may be administered to and / or around the patient's trigeminal nerve. The trigeminal nerve may be selected from the group consisting of the ophthalmic nerve, maxillary nerve, mandibular nerve, supraorbital nerve, supratracheal 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 may be administered to and / or around the patient's cervical nerve. The cervical nerve may be 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. In some embodiments, the subcutaneous / intradermal injections may be administered to and / or around the patient's trigeminal and cervical nerves. Preferably, adult administration includes 2-4 units into and / or around the ophthalmic, maxillary, and / or mandibular nerves of the trigeminal nerve (both sides), and / or 2-4 units into 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 lateral to the spinal cord (both sides). In some embodiments, for each injection site, the indicated number of units of botulinum toxin (i.e., 2-4 units) are given either at a single time or multiple times over a period of time (e.g., spaced apart). Administration for children between about 1 and 5 years of age is adjusted for age and weight. In some desirable embodiments, the botulinum toxin is selected from the group consisting of botulinum toxin types A, B, C, D, E, F, G, fragments thereof, hybrids thereof, chimeras thereof, and combinations thereof. The botulinum toxin may be used in conjunction with other modulating agents or chemicals. In a further embodiment, the total dose of botulinum toxin for an adult weighing approximately 150 pounds is between about 2 units and about 150 units.The dosage of botulinum toxin for an adult or child is adjusted for age, weight, or a combination thereof.

[0009] Some embodiments of the claimed invention relate to a botulinum toxin for use in treating autism spectrum disorder (ASD) in a patient in need thereof. The treatment comprises administering a botulinum toxin to the patient. The botulinum toxin may be administered by subcutaneous / intradermal injection. The subcutaneous / intradermal injection may be administered to and / or around the patient's trigeminal nerve. The trigeminal nerve may be selected from the group consisting of the ophthalmic nerve, maxillary nerve, mandibular nerve, supraorbital nerve, supratracheal 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 may be administered to and / or around the patient's cervical nerve. The cervical nerve may be 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. In some embodiments, the subcutaneous / intradermal injection may be administered to and / or around the patient's trigeminal, thoracic, lumbar, and sacral nerves. In some other embodiments, the patient's trigeminal, cervical, thoracic, lumbar, and sacral nerves. Preferably, adult administration comprises subcutaneous / intradermal injection of 2-4 units into and / or around the ophthalmic, maxillary, and / or mandibular nerves of the trigeminal nerve (both sides); 2-4 units into 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 lateral to the spinal cord (both sides); 2-4 units into and / or around the thoracic nerves t-2 to t-3, t-5 to t-6, t-7 to t-9, and t-10 about 1 inch lateral to the spinal cord. and / or 2-4 units into and / or around t-10 to t-12, 2-4 units into and / or around l-1 to l-2, l-2 to l-3, and / or l-4 to l-5 of the lumbar nerves about 1 inch lateral to the spinal cord, and / or 2-4 units into and / or around s-1 to s-2, s-3 to s-4, and / or s-4 to s-5 of the sacral nerves about 1 inch lateral to the spinal cord (on both sides). In some embodiments, for each injection site, the stated number of units of botulinum toxin (i.e., 2-4 units) are given either at a single time or multiple times (e.g., spaced apart) over a period of time.Dosage for infants between about 1 and 5 years of age is adjusted for age and weight. In some desirable embodiments, the botulinum toxin is selected from the group consisting of botulinum toxin types A, B, C, D, E, F, and G, fragments thereof, hybrids thereof, chimeras thereof, and combinations thereof. In further embodiments, 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 for age, weight, or a combination thereof. In infants or toddlers between about 1 and 5 years of age, it is used to prevent or minimize damage to the developing brain; in older children and adults with autism spectrum disorder (ASD), it is used to reduce or eliminate symptoms.

[0010] Some embodiments of the claimed invention relate to a botulinum toxin for use in treating narcotic tolerance in a patient in need thereof. The treatment comprises administering the botulinum toxin to the patient. The botulinum toxin may be administered by subcutaneous / intradermal injection. The subcutaneous / intradermal injection may be administered to and / or around the patient's trigeminal nerve. The trigeminal nerve may be selected from the group consisting of the ophthalmic nerve, maxillary nerve, mandibular nerve, supraorbital nerve, supratracheal 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 may be administered to and / or around the patient's cervical nerve. The cervical nerve may be 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. In some embodiments, the subcutaneous / intradermal injection may be administered to and / or around the patient's trigeminal, thoracic, lumbar, and sacral nerves. In some other embodiments, the patient's trigeminal, cervical, thoracic, lumbar, and sacral nerves. Preferably, adult administration comprises subcutaneous / intradermal injection of 2-4 units into and / or around the ophthalmic, maxillary, and / or mandibular nerves of the trigeminal nerve (both sides); 2-4 units into 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 lateral to the spinal cord (both sides); 2-4 units into and / or around the thoracic nerves t-2 to t-3, t-5 to t-6, t-7 to t-9, and t-10 about 1 inch lateral to the spinal cord. and / or 2-4 units into and / or around t-10 to t-12, 2-4 units into and / or around l-1 to l-2, l-2 to l-3, and / or l-4 to l-5 of the lumbar nerves about 1 inch lateral to the spinal cord, and / or 2-4 units into and / or around s-1 to s-2, s-3 to s-4, and / or s-4 to s-5 of the sacral nerves about 1 inch lateral to the spinal cord (on both sides). In some embodiments, for each injection site, the stated number of units of botulinum toxin (i.e., 2-4 units) are given either at a single time or multiple times (e.g., spaced apart) over a period of time.The dosage for children aged 0-5 years should be adjusted for age and weight. In some desirable embodiments, the botulinum toxin is selected from the group consisting of botulinum toxin types A, B, C, D, E, F, and G, fragments thereof, hybrids thereof, chimeras thereof, and combinations thereof. In further embodiments, the total dosage of botulinum toxin for an adult weighing approximately 150 pounds is between about 2 units and about 150 units. The dosage of botulinum toxin for adults or children is adjusted for age, weight, or a combination thereof.

[0011] Some embodiments of the claimed invention relate to a botulinum toxin for use in treating vestibular vertigo in a patient in need thereof. The treatment comprises administering a botulinum toxin to the patient. The botulinum toxin may be administered by subcutaneous / intradermal injection. The subcutaneous / intradermal injection may be administered to and / or around the patient's trigeminal nerve. The trigeminal nerve may be selected from the group consisting of 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, auriculotemporal nerve, lesser occipital nerve, greater occipital nerve, and combinations thereof. The subcutaneous / intradermal injection may be administered to and / or around the patient's cervical nerve. The cervical nerve may be 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. In some embodiments, the subcutaneous / intradermal injections may be administered to and / or around the patient's trigeminal and cervical nerves. Preferably, adult administration includes 2-4 units into and / or around the ophthalmic, maxillary, and / or mandibular nerves of the trigeminal nerve (both sides), and / or 2-4 units into 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 lateral to the spinal cord (both sides). In some embodiments, for each injection site, the indicated number of botulinum toxin (i.e., 2-4 units) is given one or more times over a period of time (e.g., separately in time to avoid interfering with motor function or causing muscle paralysis). Administration for children approximately 1-5 years of age is adjusted for age and weight. In some desirable embodiments, the botulinum toxin is selected from the group consisting of botulinum toxin types A, B, C, D, E, F, and G, fragments thereof, hybrids thereof, chimeras thereof, and combinations thereof. In further embodiments, the total dose of botulinum toxin for an adult weighing approximately 150 pounds is between about 2 units and about 150 units.The dosage of botulinum toxin for an adult or child is adjusted for age, weight, or a combination thereof.

[0012] Some embodiments of the claimed invention relate to a botulinum toxin for use in treating tinnitus in a patient in need thereof. The treatment comprises administering the botulinum toxin to the patient. The botulinum toxin may be administered by subcutaneous / intradermal injection. The subcutaneous / intradermal injection may be administered to and / or around the patient's trigeminal nerve. The trigeminal nerve may be selected from the group consisting of 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, auriculotemporal nerve, lesser occipital nerve, greater occipital nerve, and combinations thereof. The subcutaneous / intradermal injection may be administered to and / or around the patient's cervical nerve. The cervical nerve may be 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. In some embodiments, the subcutaneous / intradermal injections may be administered to and / or around the patient's trigeminal and cervical nerves. Preferably, adult administration includes 2-4 units into and / or around the ophthalmic, maxillary, and / or mandibular nerves of the trigeminal nerve (both sides), and / or 2-4 units into 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 lateral to the spinal cord (both sides). In some embodiments, for each injection site, the indicated number of units of botulinum toxin (i.e., 2-4 units) are given either at a single time or multiple times over a period of time (e.g., spaced apart). Administration for children between about 1 and 5 years of age is adjusted for age and weight. In some desirable embodiments, the botulinum toxin is selected from the group consisting of botulinum toxin types A, B, C, D, E, F, and G, fragments thereof, hybrids thereof, chimeras thereof, and combinations thereof. In further embodiments, the total dose of botulinum toxin for an adult weighing approximately 150 pounds is between about 2 units and about 150 units. The dose of botulinum toxin for an adult or child is adjusted for age, weight, or a combination thereof.

[0013] Some embodiments of the claimed invention relate to a botulinum toxin for use in treating anxiety and / or depression in a patient in need of such treatment. The treatment includes diagnosing anxiety and / or depression based on the patient's symptoms and blood glutamate levels; and administering a botulinum toxin to the patient. The symptoms are selected from the group consisting of changes in sleep, appetite, energy levels, concentration, daily activities or self-esteem, thoughts of suicide, and combinations thereof. Psychological evaluation and medical testing can be used to determine whether a diagnosis of anxiety and / or depression is due to the patient's physical injury or psychological condition. In some embodiments, the diagnosis further includes psychoanalysis. The treatment can further include providing psychological treatment to the patient if the patient has experienced a psychological injury or trauma. In some other embodiments, the diagnosis further includes a medical examination. The treatment can further include providing medical treatment to the patient if the patient has suffered a medical injury. If all symptoms are not alleviated after administration of botulinum toxin, the patient may be administered an antidepressant. The treatment includes administering botulinum toxin to the patient. The botulinum toxin may be administered by subcutaneous / intradermal injection. The subcutaneous / intradermal injection may be administered to and / or around the patient's trigeminal nerve. The trigeminal nerve may be selected from the group consisting of the ophthalmic nerve, maxillary nerve, mandibular nerve, supraorbital nerve, supratracheal 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 may be administered to and / or around the patient's cervical nerve. The cervical nerve may be 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. In some embodiments, the subcutaneous / intradermal injection may be administered to and / or around the patient's trigeminal, thoracic, lumbar, and sacral nerves, hi some other embodiments, the patient's trigeminal, cervical, thoracic, lumbar, and sacral nerves.Preferably, adult administration consists of subcutaneous / intradermal injection of 2-4 units into and / or around the ophthalmic, maxillary, and / or mandibular nerves of the trigeminal nerve (both sides), 2-4 units into and / or around 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 lateral to the spinal cord (both sides), 2-4 units into and / or around the t-2 to t-3, t-5 to t-6, t-7 to t-9, and thoracic nerves about 1 inch lateral to the spinal cord. In some embodiments, the number of units of botulinum toxin administered per injection site is 2-4 units into and / or around T-10 to T-12, 2-4 units into and / or around L-1 to L-2, L-2 to L-3, and / or L-4 to L-5 of the lumbar nerves about 1 inch lateral to the spinal cord, and / or 2-4 units into and / or around S-1 to S-2, S-3 to S-4, and / or S-4 to S-5 of the sacral nerves about 1 inch lateral to the spinal cord (on both sides). In some embodiments, for each injection site, the stated number of units of botulinum toxin (i.e., 2-4 units) are given either single or multiple times over a period of time. For infants between about 1 and 5 years of age, dosing is adjusted for age and weight. The botulinum toxin is selected from the group consisting of botulinum toxin types A, B, C, D, E, F, G, fragments thereof, hybrids thereof, chimeras thereof, and combinations thereof. In a further embodiment, the total dose of botulinum toxin for an adult weighing approximately 150 pounds is between about 2 units and about 150 units. The dose of botulinum toxin for an adult or child is adjusted for age, weight, or a combination thereof. DETAILED DESCRIPTION OF THE INVENTION

[0014] [Detailed Description of the Invention] Further in this regard, before describing at least preferred embodiments of the invention in more detail, it is to be understood that the invention is not limited in its application to the details of construction and the arrangement of components set forth in the following description. It will be understood by those skilled in the art that embodiments beyond those described herein are contemplated and that the embodiments can be practiced and carried out in a number of different ways. It is also to be understood that the terminology used herein is for the purpose of description and should not be regarded as limiting.

[0015] Unless otherwise defined, terms used herein refer to what one of ordinary skill in the art would understand such terms to mean based on the contextual use of such terms herein. To the extent that the meaning of a term used herein as understood by one of ordinary skill in the art based on the contextual use of such terms differs in any way from any particular dictionary definition of such term, the meaning of the term as understood by one of ordinary skill in the art is intended to control.

[0016] As used herein, the term "about" means approximately or approximately, and in the context of a numerical value or range set forth herein, means ±10% of the stated or claimed numerical value or range.

[0017] The term "treating" includes partially or completely delaying, alleviating, relieving, or reversing symptoms associated with one or more disorders or conditions, and / or alleviating, mitigating, or blocking one or more causes of the disorder or condition. Treatment according to the claimed invention may be preventative treatment, prophylactic treatment, ameliorative treatment, or ameliorative treatment.

[0018] The term "therapeutically effective amount" or "therapeutically effective dosage" refers to the amount of a composition, compound, therapy, or treatment process that, when administered to an individual for treating a disorder or disease, is sufficient to effect such treatment for the disorder or disease. The "therapeutically effective amount" will vary depending on the composition, compound, therapy, or 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 18-20 gm female Swiss-Webster mice injected intraperitoneally.

[0020] The term "around a nerve" refers to any location in the dermatome that is involved with said nerve.

[0021] In accordance with the principles of the present invention, there is provided the use of botulinum toxin to treat various conditions or diseases. When administered subcutaneously, low doses of botulinum toxin, while therapeutically effective, can penetrate the axons of C-fibers in unmyelinated nerves, diffuse and travel to the ganglia, and block the overproduction of neuroexcitatory substances such as glutamate, substance P, and CGRP.

[0022] For adults, administration of botulinum toxin includes subcutaneous or intradermal injection of 2-4 units into and / or around the trigeminal nerve, 2-4 units into and / or around the cervical nerve outside the patient's spine, 2-4 units into and / or around the thoracic nerve outside the patient's spine, 2-4 units into and / or around the lumbar nerve outside the patient's spine, and / or 2-4 units into and / or around the sacral nerve outside the patient's spine. Each subcutaneous injection is preferably at a dosage level that provides the described therapeutic use for the nerve without causing significant or measurable paralysis or disruption of motor function in the muscles in the injection area, referred to as low-dose therapy. Such low-dose therapy is sufficiently low to provide therapy using subcutaneous injections without injecting muscles with the intent to paralyze them, which could be a therapeutic approach for botulinum toxin, for example. Higher dosages are also contemplated in some exemplary embodiments of the present invention. The total dose of botulinum toxin for an adult weighing approximately 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. The botulinum toxin includes botulinum toxin types A, B, C, D, E, F, G, fragments thereof, hybrids thereof, chimeras thereof, or combinations thereof. While each type of botulinum toxin may be differently effective in treating a condition or disease, one unit of botulinum toxin required refers to the amount of botulinum toxin required to kill 50% of a group of 18-20 gm female Swiss-Webster mice injected intraperitoneally.

[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 tear film. The tear film, which spreads across the eye when you blink, is composed of three layers: an inner mucus-like layer, a middle aqueous layer, and an outer oily layer. The inner mucin layer nourishes the cornea and helps tears adhere to the eye's surface. Much of the mucin is secreted by specialized goblet cells in the conjunctival epithelium. The middle aqueous or watery layer helps prevent infection and wash away particles. Most aqueous humor is secreted by the lacrimal gland. The outer oily or lipid layer, mostly secreted by the meibomian gland, seals the film to reduce natural tear evaporation. DES is characterized by inflammation and glandular dysfunction, which can cause damage and discomfort to the ocular surface. 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), ocular surgery, and drug hypersensitivity. This application focuses on some of these causes, which have the potential for specific solutions.

[0024] 95% of patients who undergo LASIK eye surgery experience postoperative DES. One month after surgery, 60% of patients still have DES. The majority of patients improve after 6-12 months, but 30% continue to visit their ophthalmologist for chronic dry eye. 9% of patients who undergo cataract eye surgery will develop chronic dry eye, and 60% will develop it initially.

[0025] The incision in the cornea of ​​the eye in these types of surgeries results in the severing of branches of the long ciliary nerve, a branch of the ophthalmic division of the trigeminal nerve. These nerves supply sensory innervation of the cornea. The greater petrosal nerve, a branch of the facial nerve, supplies innervation of the lacrimal gland. There are many anastomoses (interconnections) between the facial nerve and the trigeminal nerve in this area. Research has shown that non-surgically induced DES is much more common in people with neuropathic conditions such as migraines and fibromyalgia.

[0026] As previously mentioned, damage to sensory nerves, in this case due to surgical incision, stimulates the overproduction of glutamate, substance P, and calcitonin gene-related peptide (CGRP). Cutting and damage to corneal sensory nerves stimulates the overproduction of these substances, causing corneal hypersensitivity. This stimulation impacts the lacrimal gland by suppressing tear production, resulting in pain and hypersensitivity, as in the case of shingles. The long ciliary nerves become hypersensitive due to the glutamate, substance P, and CGRP produced, causing pain. Dryness further stimulates the gland to produce a different tear film due to the effects of glutamate, substance P, and CGRP on the gland. Overproduction of glutamate, substance P, and CGRP slows and eventually normalizes as the eye heals. However, in some people, this overproduction does not return to normal over time, resulting in consistent, chronic overproduction of neuroexcitatory chemicals and chronic dry eye syndrome.

[0027] In individuals with chronic neuropathic conditions such as migraine, fibromyalgia, and postherpetic facial pain syndrome, excess glutamate, substance P, and CGRP may result from chronic overproduction of these chemicals that spreads from other sensory nerves through a process called central sensitization. This sensitization affects the long ciliary nerve and facial nerve, which innervate the lacrimal gland, goblet cells, and meibomian glands. Excessive nerve excitation from other nerves can affect the cornea and lacrimal gland in a manner similar to surgical injury, resulting in a state of chronic overstimulation of the involved nerves.

[0028] To diagnose DES, blood glutamate levels may be checked during routine doctor visits. Physical symptoms may also be checked, including, but not limited to, a) a stinging, burning, or scratchy sensation in the eye, b) stringy mucus in or around the eye, c) slight sensitivity, d) bloodshot eyes, e) foreign body sensation in the eye, f) difficulty wearing contact lenses, g) difficulty driving at night, h) watery eyes, and i) blurred vision or eye strain.

[0029] If a patient is diagnosed with DES after eye surgery, such as LASIK or cataract surgery, botulinum toxin can be administered subcutaneously or via other injections (e.g., intradermal injections) that allow the toxin to reach unmyelinated sensory C-fibers to prevent or alleviate associated symptoms and / or blood tests to assess blood levels of substance P, CGRP, and glutamate. The botulinum toxin injection can be administered to and / or around the patient's trigeminal and / or cervical nerves. The trigeminal nerves can include, but are not limited to, the ophthalmic nerve, maxillary nerve, mandibular nerve, supraorbital nerve, supratracheal 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. The cervical nerves may include, but are not limited to, the c-2, c-3, c-4, c-5, c-6, c-7, c-8, and combinations thereof. For example, 2-4 units may be administered to and / or around the ophthalmic, maxillary, and / or mandibular nerves of the trigeminal nerve (bilaterally), and / or 2-4 units may 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 nerves one inch lateral to the spine (bilaterally). Because there is significant crossover between the trigeminal and cervical nerves, bilateral injections are necessary even in cases of dry eye syndrome in one eye. These dosages are for adults. Dosages for children 0-5 years old should be adjusted for age and weight.

[0030] Botulinum toxin is administered to lower levels of substance P, CGRP, and glutamate, typically beginning to work after about three days. It usually takes about one to two weeks for botulinum toxin to reach its peak effectiveness. As the botulinum toxin gradually decreases and blood tests show elevated levels of substance P, glutamate, or CGRP, the symptoms begin to return, and more botulinum toxin may be administered to counteract this effect. If levels / symptoms do not normalize, a small dose of one of the glutamate antagonists may be administered, if desired, to further lower glutamate levels without causing side effects.

[0031] Generally, a therapeutically effective dose or amount can be between 1 and 150 units depending on body weight. For an adult weighing approximately 150 pounds, the dose is approximately 50 to 150 units. For children over the age of approximately 5 years, whose brains have stopped forming, the dose can be adjusted based on body weight. For example, for infants (approximately 1 to 5 years old), the dose can be approximately 1 to 30 units.

[0032] Treatment of autism Autism is a developmental disorder characterized by difficulties with social interaction and communication, and restricted, repetitive behaviors. Parents usually notice signs during the first two to three years of a child's life. While some children with autism reach expected developmental milestones at a normal pace before worsening, 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 certain infections, such as measles, and toxins, including valproic acid, alcohol, cocaine, pesticides, and air pollutants. Debate includes other proposed environmental causes, such as the disproven vaccine hypothesis. Autism affects information processing in the brain by altering how neurons and their synapses connect and organize. The mechanisms underlying this are not fully understood. According to the DSM-5, autism, as well as less severe conditions, including Asperger's syndrome and pervasive developmental disorder not otherwise specified (PDD-NOS), are associated with the diagnosis of autism spectrum disorder (ASD).

[0033] As mentioned above, the exact cause of ASD (autism) is unknown. Approximately 90% of cases show no genetic abnormalities. Genetic mutations have been found in the remaining 10%. Almost all of these are related to glutamate receptors or the way glutamate is metabolized. There are no animal models of autism; it is a condition exclusive to humans. This is due to the lack of formation or damage to parts of the developing brain that are unique to humans in terms of neural capacities. From approximately 1.5 to 5 years of age, these specialized structures and complex neural networks around and between them are organized and growing. Neurons connect in complex mesh-like patterns. Specialized thin, tapered neurons (VENs) are highly functional structures found only in humans and great apes, involved in empathy, guilt, and embarrassment. The VENs are located in the insular cortex, corpus callosum, prefrontal cortex, and anterior cingulate cortex, and cortical neural columns (minicolumns) support parallel processing. Numerous synapses interconnect neural structures to both sides of the brain (corpus callosum). This development, organization, and interconnection enables complex social cognition, language, abstract thinking, planning, practical and educational abilities, reasoning, and deception. The sophisticated reorganization of the human brain has given us these and many other abilities that define us as human. However, it has come at a cost: neurodegenerative disorders such as schizophrenia, autism, and Alzheimer's disease. These disorders, like advanced brain functions, are uniquely human. The specific causes of these problems are currently unknown.

[0034] All neurons operate by essentially the same mechanism: when they are stimulated to a certain threshold, they fire, sending electrochemical signals up the axon to the cell body. The body regulates this with proteins, chemicals, and substances—these are called ligands.

[0035] One leading theory is that these afflicted children have excessive concentrations of the neuroexcitatory substance glutamate in their developing brains and cerebrospinal fluid (CSF). Research has shown this to be the case, with elevated levels in the brain, 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 neuroexcitotoxicity, which occurs during development and interconnection of developing structures between the ages of 1.5 and 5 years. This can damage interconnected neurons during development. The age of onset of elevated glutamate levels, the degree of above-normal levels, genetic susceptibility to it, and the brain regions affected may account for the wide range of symptoms present in autism.

[0036] Substances that cause a nerve to fire with less stimulation are called "excitatory." Substances that make a nerve fire require more stimulation to fire and are called "inhibitory." Examples of neuroexcitatory substances are nicotine, cocaine, methamphetamine, epinephrine, and glutamate. Examples of neuroinhibitory substances are serotonin, gamma-aminobutyric acid (GABA), opioids, and other drugs such as Lyrica (for nerve pain) and Valium (anxiety / sedative). Too much inhibition of a nerve can cause drowsiness and death. In contrast, too much excitatory compound can cause a nerve to fire too quickly, resulting in pain, sleep deprivation, photosensitivity, cell death, seizures, etc. (Symptoms vary depending on the function of the specific nerve.)

[0037] Doctors have attempted to eliminate these high levels of glutamate in the brains of children with autism by blocking its production or disabling glutamate receptors. This has been unsuccessful because glutamate is the most prevalent neurotransmitter in the brain (approximately 60%) and medications have significant side effects. The problem is the origin of the excess glutamate. An even greater challenge is how to remove it without affecting normal glutamate levels in neurons and their normal function. Excess glutamate in the blood, CSF, and brains of children with autism is expected to result from children who are born with or develop migraine, fibromyalgia, or related neuropathic conditions between the ages of 1.5 and 5, when the brain's highly functional structures are forming. Glutamate levels in the brain, blood, and CSF are elevated in adults with migraine, fibromyalgia, and neuropathic conditions. The physical symptoms that can be observed in young children with ASD are similar to those of fibromyalgia, migraines, and neuropathic conditions—light sensitivity, dilated pupils, sensitivity to loud noises, sleep disturbances, hyperactivity, sensitivity to touch, depression, and anxiety.

[0038] In migraine and fibromyalgia, glutamate overproduction is thought to originate in the neuronal structural cells surrounding neurons: glial cells, satellite cells, and astrocytes. The mechanism is that substance P, CGRP (calcitonin gene-related peptide), and glutamate are produced intracellularly by the ribosomes of these cells, packaged in vesicles, and transported to the plasma membrane. Special proteins called SNAP25 and / or VAMP transport them across the plasma membrane and release them into the CSF. They then act as ligands to neurons, causing them to fire with less stimulation (neuronal excitation). The only other place in the human body where SNAP25 and / or VAMP are known to act is at the neuromuscular junction of muscle cells, where they release vesicles containing acetylcholine into the neuromuscular junction, causing muscle contraction. In normal intracellular production of glutamate, substance P, and CGRP, they are used within the neuron and are not released into the CSF by SNAP25 and / or VAMP.

[0039] In particular, excess glutamate, substance P, and CGRP in the brain disrupt, damage, or cause malformations of developing higher-order structures. Subcutaneous botulinum toxin injections or other injections (e.g., intradermal injections) that deliver botulinum toxin to unmyelinated sensory C-fibers have been shown to successfully reduce glutamate levels in adult patients with migraine, fibromyalgia, and other neuropathic conditions.

[0040] From birth, children can be tested for elevated blood levels of substance P, CGRP, and glutamate during routine checkups. If these levels are higher than normal and they exhibit physical symptoms and fail to meet developmental milestones, then subcutaneous or other injections (e.g., intradermal) that deliver botulinum toxin to unmyelinated sensory C-fibers can reduce excess glutamate and restore a normal developmental environment in the brain. The injected botulinum toxin reduces or stops the overproduction of glutamate, substance P, and CGRP, and the neuroexcitatory effects that occur in fibromyalgia, migraine, and other neuropathic conditions.

[0041] To diagnose ASD, blood glutamate levels may be checked during regular doctor visits beginning in infancy. Physicians also need to ensure that brain development milestones are met. Physical symptoms are virtually identical in migraines, fibromyalgia, depression, ASD, and other neuropathic disorders, including: a) light sensitivity (dilated pupils), b) sensitivity to loud noises, c) hyperactivity, d) sensitivity to touch (tight clothing, being hugged, etc.), and e) stomach problems, such as IBS, of unknown cause.

[0042] If a patient is diagnosed with autism, they may be given a subcutaneous or other injection (e.g., intradermal injection) that allows the botulinum toxin to reach unmyelinated sensory C-fibers to prevent or alleviate associated symptoms and / or blood tests to assess blood levels of substance P, CGRP, and glutamate. Developmental milestones and neuropathic symptoms, as well as glutamate levels, are then monitored periodically. Monitoring glutamate levels is particularly important for infants, as their developmental milestones and neuropathic symptoms are difficult to assess due to their age. This treatment therefore allows the physician to know when botulinum toxin needs to be re-administered. The botulinum toxin injection may be administered to and / or around the patient's trigeminal, cervical, thoracic, lumbar, and / or sacral nerves. Botulinum toxin injections into all of the above nerves are also considered within the scope of the present invention. The trigeminal nerve may include, but is not limited to, 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, auriculotemporal nerve, lesser occipital nerve, greater occipital nerve, or a combination thereof. The cervical nerve may include, but is 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 a combination thereof.For example, 2-4 units to and / or around the ophthalmic, maxillary, and / or mandibular nerves of the trigeminal nerve (both sides); 2-4 units to and / or around c-2 to c-3, c-4 to c-6, and / or c-7 to c-8 of the cervical nerves about 1 inch lateral to the spinal cord (both sides); 2-4 units to and / or around t-2 to t-3, t-5 to t-6, t-7 to t-9, and / or t-10 to t-11 of the thoracic nerves about 1 inch lateral to the spinal cord. The following dosages may be administered: 2-4 units into and / or around the lumbar nerves l-1 to l-2, l-2 to l-3, and / or l-4 to l-5, approximately 1 inch lateral to the spinal cord; and / or 2-4 units into and / or around the sacral nerves s-1 to s-2, s-3 to s-4, and / or s-4 to s-5, approximately 1 inch lateral to the spinal cord (both sides). In one embodiment, three injections of 2 units each distributed along both sides of the neck in the trigeminal region, and one injection of 2 units each divided into subcutaneous ocular, maxillary, and mandibular regions on each side. These are adult dosages. Dosages for children 0-5 years should be adjusted for age and weight.

[0043] Botulinum toxin is administered to lower substance P, CGRP, and glutamate levels. It is typically administered about 1 / 2 to 1 inch from the spinal cord for all spinal injections, and begins to work after about three days. Many independent studies have used it in the forearm or calf, where it takes about two weeks to begin working. When administered near the dorsal root ganglion, it typically takes three to five days and one to two weeks to reach full effectiveness. This is due to the short distance it must diffuse up the axon to the cell body. Blood glutamate levels can be monitored to ensure normal decline, and physical symptoms can be monitored to ensure normalization (charted developmental milestones). As the botulinum toxin gradually decreases, if blood tests show increased substance P, glutamate, or CGRP levels and / or symptoms begin to recur, more botulinum toxin can be administered to counteract these effects. If levels / symptoms do not normalize, one of the glutamate antagonists above can be administered in small doses to lower glutamate levels without causing side effects, if desired.

[0044] Typically, the therapeutically effective dose or amount can be between 1 and 150 units, depending on body weight. For an adult weighing approximately 150 pounds, the dose is approximately 50 to 150 units. For children over the age of approximately 5 years, whose brains have stopped forming, the dose can be adjusted based on body weight. For example, for young children (approximately 1 to 5 years old), the dose can be approximately 1 to 30 units. While this is an estimate, the maximum dose that has been safely used since the 1990s to control severe muscle spasms in infants and young children with cerebral palsy is 30 units.

[0045] Treating narcotic tolerance One theory behind tolerance is that opioids inhibit neuronal firing by acting on opioid receptors, resulting in a decrease in sensory pain. When various functional nerves are inhibited, opioids can cause other symptoms, such as drowsiness, constipation, lethargy, euphoria, shallow breathing, and forgetfulness. In response to system-wide inhibition and the suppression of neuronal firing, sensory nerves produce neuroexcitatory substances (substance P, CGRP, and glutamate) to balance the opioid-induced inhibition of firing and the nervous system. After the production of excitatory chemicals increases and the body returns to a more normal neurological state, the opioid is no longer effective, requiring the patient to take more and more opioid to achieve a similar effect. This results in increased production of excitatory chemicals, creating a vicious cycle in which the patient takes more and more of the opioid to alleviate mental or physical pain or maintain the euphoric feeling they desire.

[0046] Chronic opioid use, due to the tolerance mechanisms described above, leads to increased use of the drug in an attempt to achieve the same desired effect as previously achieved with less of the drug. This results in the body's massive overproduction of neuroexcitatory chemicals in its fight to return to a state of normal neuronal function. When a person runs out of the drug, cannot obtain it, or stops taking it, the extreme neuronal inhibition (depression) of the body's neuronal firing suddenly disappears. The continued massive overproduction of neuroexcitatory chemicals caused by the drug tolerance effect leads to withdrawal symptoms such as alternating sweating and chills, diarrhea, nausea, rhinorrhea, trembling, tachycardia, uncontrollable yawning, tearing, sneezing, dilated pupils, restlessness, depression, migraines, anxiety, and pain.

[0047] If a patient must take opioids for an extended period of time, botulinum toxin may be administered to prevent tolerance, and blood tests may be performed to assess basal blood levels of substance P, CGRP, and glutamate. This allows physicians to test for elevated glutamate levels and clinical symptoms to determine whether tolerance is developing. A novel approach to treating chronic pain involves: Baseline glutamate levels are obtained when opioids are first administered; a regular dose of opioid is given to control pain and botulinum toxin in all sensory nerve areas; and then, symptoms of tolerance and glutamate levels are monitored periodically. This allows physicians to know when botulinum toxin needs to be re-administered. Glutamate testing allows physicians to determine if patients are lying about their tolerance or if they are lying to obtain or sell more drugs for euphoria. Subcutaneous botulinum toxin injections, or other injections (e.g., intradermal injections) that deliver botulinum toxin to unmyelinated sensory C-fibers, can be administered to and / or around the patient's trigeminal, cervical, thoracic, lumbar, and / or sacral nerves. Botulinum toxin injections into all of the above nerves are also considered within the scope of the present invention. The trigeminal nerves may include, but are not limited to, the ophthalmic nerve, maxillary nerve, mandibular nerve, supraorbital nerve, supratracheal 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. The cervical nerves may include, but are not limited to, the C-2, C-3, C-4, C-5, C-6, C-7, C-8 nerves, and combinations thereof.For example, 2-4 units to and / or around the ophthalmic, maxillary, and / or mandibular nerves of the trigeminal nerve (both sides); 2-4 units to and / or around c-2 to c-3, c-4 to c-6, and / or c-7 to c-8 of the cervical nerves about 1 inch lateral to the spinal cord (both sides); 2-4 units to and / or around t-2 to t-3, t-5 to t-6, t-7 to t-9, and / or t-10 to t-11 of the thoracic nerves about 1 inch lateral to the spinal cord. 2-4 units may be administered to and / or around the lumbar nerves l-1 to l-2, l-2 to l-3, and / or l-4 to l-5 about 1 inch lateral to the spinal cord; and / or 2-4 units to and / or around the sacral nerves s-1 to s-2, s-3 to s-4, and / or s-4 to s-5 about 1 inch lateral to the spinal cord (both sides). These are adult dosages. Dosage for ages 0-5 should be adjusted for age and weight.

[0048] Botulinum toxin is administered to maintain substance P, CGRP, and glutamate levels, usually beginning to work after about three days. It usually takes about one to two weeks for botulinum toxin to reach its full effectiveness. Blood glutamate levels can be monitored to ensure they remain normal, as can physical symptoms to ensure they remain normal. If levels / symptoms do not normalize, a small dose of one of the glutamate antagonists can be administered, if desired, to lower glutamate levels without causing side effects.

[0049] Typically, a therapeutically effective dose or amount can be between 1 and 150 units, depending on body weight. For an adult weighing approximately 150 pounds, the dose is approximately 50 to 150 units. For children over the age of approximately 5 years, whose brains have stopped forming, the dose can be adjusted based on body weight. For example, for young children (approximately 1 to 5 years old), the dose can be approximately 1 to 30 units. Although this is an estimate, the maximum dose that has been safely used since the 1990s to control severe muscle spasms in infants and young children with cerebral palsy is 30 units.

[0050] Treatment for vestibular vertigo Dizziness is a symptom of several health conditions that can be described as vertigo, disorientation, or an abnormal or false sense of movement. It can be associated with other symptoms such as nausea, sweating, headache, and difficulty walking, and is usually worse when standing or moving the head.

[0051] There are many suspected causes of dizziness, including Meniere's disease, labyrinthitis, benign paroxysmal positional vertigo (BPPV), and other less likely causes such as brain tumors or brain injury, stroke, migraine, toxin exposure, and uneven pressure in the middle ear. While not wishing to be bound by theory, it has been suggested that one cause may be chronic overproduction of the neurostimulators glutamate, substance P, and calcitonin gene-related peptide (GCRP) from localized damage to the vestibular nerve or from central sensitization effects caused by depression, migraine, fibromyalgia, or other neuropathic conditions. This results in a state of chronic hypersensitivity to damaged and undamaged neurons (vestibular vertigo).

[0052] There are several known causes of dizziness, one of which may be related to migraine. One widely accepted theory about the cause of migraine is the chronic or periodic overproduction of neuroexcitatory substances. Excessive production of glutamate, substance P, and GCRP occurs by neural structural cells (glia, satellite cells, and astrocytes). These cause hyperexcitability and hypersensitivity of the vestibular nerve, which then fires with minimal stimulation, resulting in dizziness. As explained in the previous paragraph, subcutaneous injections of botulinum toxin or other injections (e.g., intradermal injections) that allow botulinum toxin to reach unmyelinated sensory C-fibers can be used to effectively suppress the overproduction of these substances for extended periods.

[0053] The problem is that the vestibular nerve is a cranial nerve and has no superficial sensory exposure. It runs 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 side to side or turning too quickly. The purpose of this is that if the head moves too quickly, there is too much visual information to process, resulting in a pixelated image like on a television. Of course, this system can be voluntarily overridden by moving the head quickly if necessary, but while moving quickly, vision is not as clear.

[0054] Using this interconnection of the visual tracking system, it is believed that botulinum toxin can be injected subcutaneously or by other injections, which will allow it to reach the unmyelinated sensory C-fibers to reach the cervical and trigeminal nerves and the vestibular nerve and ganglion to subside their hypersensitivity.

[0055] The usual causes of dizziness will be identified and, if present, treated, but tests If negative, especially in conjunction with other migraines, depression, and fibromyalgia, as well as other neuropathic conditions, symptoms such as headaches, light sensitivity, sensitivity to touch in the head, ears, or neck or cervical area, depression, anxiety, and / or sleep disorders, a blood glutamate test may be performed to see if it is elevated.

[0056] If a patient is diagnosed with vestibular vertigo, a botulinum toxin can be injected subcutaneously or by other means (e.g., intradermal) to deliver the botulinum toxin to unmyelinated sensory C-fibers to prevent or alleviate associated symptoms. Blood tests can be performed, if desired, to assess blood levels of substance P, CGRP, and glutamate. The botulinum toxin injection can be administered to and / or around the trigeminal and / or cervical nerves. Botulinum toxin injections into all of the above nerves are also considered within the scope of the present invention. The trigeminal nerve can include, but is not limited to, 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, auriculotemporal nerve, lesser occipital nerve, greater occipital nerve, or a combination thereof. The cervical nerves may include, but are not limited to, the C-2, C-3, C-4, C-5, C-6, C-7, C-8 nerves, and combinations thereof. For example, 2-4 units may be administered to and / or around the ophthalmic, maxillary, and / or mandibular nerves of the trigeminal nerve (bilaterally), and / or 2-4 units may be administered to and / or around the C-2 to C-3, C-4 to C-6, and / or C-7 to C-8 cervical nerves approximately 1 inch lateral to the spine (bilaterally). Because the trigeminal and cervical nerves cross significantly from side to side, bilateral injections are necessary even if the dizziness is in one ear. These dosages are for adults. Dosages for children 0-5 years old should be adjusted for age and weight.

[0057] Botulinum toxin is administered to lower substance P, CGRP, and glutamate levels, usually beginning to work after about three days. It usually takes about one to two weeks for botulinum toxin to reach its full effectiveness. Blood glutamate levels can be monitored to ensure they decrease to normal, and physical symptoms can be monitored to ensure normalization. As botulinum toxin gradually decreases and blood tests show increased substance P, glutamate, or CGRP, the symptoms begin to recur, and more botulinum toxin can be administered to counteract this effect. If levels / symptoms do not normalize, a small dose of one of the glutamate antagonists can be administered, if desired, to lower glutamate levels without causing side effects.

[0058] Typically, the therapeutically effective dose or amount can be between 1 and 150 units depending on body weight. For an adult weighing approximately 150 pounds, the dose is about 50 to 150 units. For children over the age of about 5 years, whose brains have stopped forming, the dose can be adjusted based on body weight. For example, for toddlers (about 1 to 5 years old), the dose can be about 1 to 30 units.

[0059] Tinnitus treatment Tinnitus is defined as a sound heard in the absence of external sound. Patients often describe tinnitus as "ringing in the ears," but may also hear clicking, hissing, roaring, or, more rarely, indistinct voices or music. Patients may describe what they hear as loud or soft, high-pitched or low-pitched, and may experience it in one or both ears. Tinnitus usually begins gradually, but can be more sudden, depending on the cause. In some cases, tinnitus can become severe, cause depression or anxiety, and interfere with concentration.

[0060] Tinnitus is not a disease in itself, but a symptom that can result 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, brain damage, heart or vascular disease, Meniere's disease, psychological stress, certain medications, or excessive earwax production. It is commonly seen in patients suffering from depression, and a diagnosis of the cause of the symptom is usually based on the patient's description.

[0061] If neurons in the ear are damaged or destroyed, the ability to hear should be diminished or even completely lost. Therefore, it seems counterintuitive that patients with damaged or destroyed neurons in the ear would experience constant or even increased sound volume. While not wishing to be bound by theory, tinnitus may result from the overproduction of substance P, glutamate, and CGRP (calcitonin gene-related peptide), which are produced after damage to sensory neurons. These neuroexcitatory chemicals cause the remaining cochlear neurons to become hypersensitive, firing with little or no stimulation.

[0062] For botulinum toxin to be effective, it must be injected near the unmyelinated subcutaneous C fibers. The problem is that the cochlear nerve is a cranial nerve that emerges directly from the brain and enters the ear without any superficial exposure. How do we reach the cochlear ganglion with botulinum toxin? Animals have a sound localization system that allows them to determine the direction and distance of sounds. Extreme examples are bats, which can fly in the dark and catch insects in the air at night while flying, and whales and porpoises, which use underwater (sonar) sensors. This system requires input from the cervical nerves C1-C3 and the trigeminal and facial nerves. These nerves move the neck, face, and ears, positioning them and enabling the ear to identify the origin of sound. For this system to function, it has branches that connect (anastomose) with the cochlear and vestibular nerves. These have superficial C fibers that allow botulinum toxin to be injected and reach the cochlear nerve. The botulinum toxin can be injected into them, travel to the cochlear ganglion, and reduce the chronic nerve excitation that is one of the causes of tinnitus. This has been shown clinically by subcutaneous injection of the botulinum toxin or other injections (e.g., intradermal injections) that allow the botulinum toxin to reach unmyelinated sensory C-fibers, where it reduces or eliminates this cause of tinnitus.

[0063] To diagnose tinnitus, blood glutamate levels and physical symptoms may be checked during regular doctor visits, including, but not limited to, intermittent or continuous noises in the ears, such as ringing, roaring, buzzing, hissing, or whistling.

[0064] If a patient is diagnosed with tinnitus, they may receive a subcutaneous or other injection (e.g., intradermal injection) of botulinum toxin that reaches unmyelinated sensory C-fibers to prevent or alleviate associated symptoms and / or blood tests to assess blood levels of substance P, CGRP, and glutamate. The botulinum toxin injection may be administered to and / or around the patient's trigeminal and / or cervical nerves. Botulinum toxin injections into all of the above nerves are also considered within the scope of the present invention. The trigeminal nerve may include, but is not limited to, the ophthalmic nerve, maxillary nerve, mandibular nerve, supraorbital nerve, supratracheal 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. The cervical nerves may include, but are not limited to, the c-2, c-3, c-4, c-5, c-6, c-7, c-8 nerves, and combinations thereof. For example, 2-4 units may be administered to and / or around the ophthalmic, maxillary, and / or mandibular nerves of the trigeminal nerve (bilaterally), and / or 2-4 units may be administered to and / or around the c-2 to c-3, c-4 to c-6, and / or c-7 to c-8 cervical nerves approximately 1 inch lateral to the spine (bilaterally). Because of significant crossing of the trigeminal and cervical nerves, bilateral injections are necessary even if the tinnitus is in one ear. These dosages are for adults. Dosages for children 0-5 years old should be adjusted for age and weight.

[0065] Botulinum toxin is administered to lower substance P, CGRP, and glutamate levels, usually beginning to work after about three days. It usually takes about one to two weeks for botulinum toxin to reach its full effectiveness. Blood glutamate levels can be monitored to ensure they decrease to normal, and physical symptoms can be monitored to ensure they normalize. If botulinum toxin gradually decreases and blood tests show an increase in substance P, glutamate, or CGRP, the symptoms may begin to recur and more botulinum toxin can be administered to counteract this effect. If levels / symptoms do not normalize, a small dose of one of the glutamate antagonists can be administered, if desired, to lower glutamate levels without causing side effects.

[0066] Typically, a therapeutically effective dose or amount can be between 1 and 150 units depending on body weight. For an adult weighing approximately 150 pounds, the dose is about 50 to 150 units. For children over the age of about 5 years, whose brains have stopped forming, the dose can be adjusted based on body weight. For example, for toddlers (approximately 1 to 5 years old), the dose can be about 1 to 30 units.

[0067] Novel clinical treatments for the symptoms and causes of anxiety and / or depression Subcutaneous botulinum toxin or other injections (e.g., intradermal injections) that deliver botulinum toxin to unmyelinated sensory C-fibers can halt or minimize symptoms of depression and / or anxiety. Without wishing to be bound by any particular theory, depression and / or anxiety are believed to be associated with increased glutamate levels. These increased glutamate levels can be caused by either psychological or medical injury. Botulinum toxin is initially administered to alleviate or halt the symptoms, and an appropriate specialist, such as a physician, can then conduct a psychoanalysis or physical examination to assess the cause of the patient's elevated glutamate levels. If the psychoanalysis reveals that the patient has suffered a psychological injury, appropriate psychotherapy can be provided to help the patient cope with the injury. If the patient is found to have sustained an injury after the examination, treatment is administered to prevent the increase in glutamate levels. Physical symptoms can also be monitored. These include, but are not limited to, changes in sleep, appetite, energy levels, concentration, daily activities or self-esteem, or thoughts of suicide.

[0068] If a patient is diagnosed with depression and / or anxiety, blood tests can be performed to assess blood levels of botulinum toxin and / or substance P, CGRP, and glutamate to reduce or eliminate symptoms of anxiety and / or depression. The botulinum toxin injection can be administered to and / or around the patient's trigeminal, cervical, thoracic, lumbar, and / or sacral nerves. Botulinum toxin injections into all of the above nerves are also considered within the scope of the present invention. The trigeminal nerve can include, but is not limited to, the ophthalmic nerve, maxillary nerve, mandibular nerve, supraorbital nerve, supratracheal 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. The cervical nerves may include, but are not limited to, the c-2, c-3, c-4, c-5, c-6, c-7, c-8 nerves, and combinations thereof. For example, 2-4 units of the trigeminal nerve (both sides) to and / or around the ophthalmic, maxillary, and / or mandibular nerves, 2-4 units of the cervical nerves c-2 to c-3, c-4 to c-6, and / or c-7 to c-8 about 1 inch lateral to the spinal cord (both sides), and 2-4 units of the thoracic nerves t-2 to t-3, t-5 to t-6, t-7 to t-9, and / or t-10 to t-11 about 1 inch lateral to the spinal cord. 2-4 units may be administered to and / or around the lumbar nerves l-1 to l-2, l-2 to l-3, and / or l-4 to l-5 about 1 inch lateral to the spinal cord; and / or 2-4 units to and / or around the sacral nerves s-1 to s-2, s-3 to s-4, and / or s-4 to s-5 about 1 inch lateral to the spinal cord (both sides). These are adult dosages. Dosage for ages 0-5 should be adjusted for age and weight.

[0069] Botulinum toxin is administered to lower substance P, CGRP, and glutamate levels, usually beginning to work after about three days. It usually takes about one to two weeks for botulinum toxin to reach its peak effectiveness. Blood glutamate levels can be monitored to ensure normal levels are reduced, as can physical symptoms to ensure normalization. Normal blood glutamate levels can range from 40 to 60 μM. Alternatively, normal blood glutamate levels can be a level that would be reasonably perceived by one of skill in the art. As botulinum toxin gradually decreases and blood tests show increased substance P, glutamate, or CGRP, the symptoms begin to recur, and more botulinum toxin can be administered to counteract this effect. If levels / symptoms do not normalize, small doses of either glutamate antagonists or antidepressants can be administered to reduce glutamate levels without causing side effects. If they cannot be cured, the botulinum toxin is continued indefinitely to minimize or eliminate symptoms.

[0070] Typically, the dosage can be 1 to 150 units depending on body weight. For an adult weighing about 150 pounds, the dosage is about 50 to 150 units. For children over about 5 years of age, whose brains have stopped forming, the dosage can be adjusted based on body weight.

[0071] The botulinum toxin for use according to the claimed invention may 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 may be combined with a pharmaceutically acceptable excipient, stabilizer, and / or carrier, such as albumin. The lyophilized material may be reconstituted with saline or water to produce a solution or composition containing the botulinum toxin for administration to the patient.

[0072] Preferably, the botulinum neurotoxin is administered peripherally by administering it to or near the nerve, or to the nerve branch or its ganglionic nucleus. This administration method allows the botulinum neurotoxin to be administered to or affect selected intracranial target tissues. The administration method, as described above, includes injection of a solution or composition containing the botulinum neurotoxin, and implantation of a controlled-release system that controllably releases the botulinum neurotoxin into the target trigeminal nerve tissue. Such a sustained-release system reduces the need for repeated injections. The diffusion of the botulinum toxin's biological activity within tissues can be gradual, as shown by the dose function. (Jankovic J., et al., Therapy With Botulinum Toxin, Marcel Dekker, Inc., (1994), page 150). Thus, controlling the diffusion of the botulinum toxin can reduce potentially undesirable side effects that may affect the patient's cognitive abilities. For example, the botulinum neurotoxin can be administered so that it primarily affects the nervous system believed to be involved in the selected neuropsychiatric disorder, without adversely affecting other nervous systems.

[0073] Furthermore, the botulinum neurotoxin may be administered to the patient in combination with a solution or composition that locally lowers the pH of the target tissue environment. For example, a solution containing hydrochloric acid may be used to locally and temporarily lower the pH of the target tissue environment to promote neurotoxin translocation across cell membranes. A decrease in local pH may be desirable when the composition contains a fragment of a botulinum neurotoxin that may not have a functional targeting moiety (e.g., a portion of the toxin that binds to a neurotoxin receptor) and / or a translocation domain. By way of example and not limitation, a fragment of a botulinum toxin containing the toxin's proteolytic domain may be administered to the patient in combination with an agent that lowers the local pH of the target tissue. Without wishing to be bound by theory, it is believed that the lower pH promotes translocation of the proteolytic domain across cell membranes, allowing the neurotoxin fragment to exert its toxic effects within the cell. Because the pH of the target tissue is only temporarily lowered, neuronal and / or glial damage is reduced.

[0074] The botulinum toxin is selected from the group consisting of botulinum toxin types A, B, C, D, E, F, and G, fragments thereof, hybrids thereof, chimeras thereof, and combinations thereof. Because the mechanisms and cleavage sites of botulinum toxins differ, different types of botulinum toxins may have different potencies, dosages, or durations. The botulinum toxin may be used in combination with other modulators or chemical compounds. In a further embodiment, the therapeutically effective amount of botulinum toxin administered is between about 1 unit and about 150 units. [Example]

[0075] The claimed invention will now be explained in detail with reference to examples.

[0076] [Example 1] A 40-year-old female patient experienced the following neuropathic symptoms: chronic severe post-herpetic pain from c-7 to t-4 on the left side, chronic migraines, trigeminal neuralgia, tinnitus, chronic dry eye syndrome (DES) from LASIK surgery 4 years prior, sleep disturbances (waking after 3-4 hours of sleep and unable to fall back asleep), chronic fatigue, anxiety, depression, neck, shoulder, and upper back pain, and muscle spasms. The patient was taking the following medications: Tegretol for trigeminal neuralgia, gabapentin for shingles, and Lexapro for depression. These medications provided some relief of her symptoms, but not significantly. Next, she received botulinum toxin type A, all administered subcutaneously: 2-4 units in the ophthalmic, maxillary, and mandibular dermatomes of the trigeminal nerve (bilaterally); and 4 units in the c-2, c-4, c-6, t-2, t-4, and t-6 dermatomes approximately 1 inch lateral to the spine (bilaterally).

[0077] All of her symptoms began to subside by day 5 and were resolved by day 14, allowing the patient to discontinue all medications. All symptoms, including the dry eye syndrome, were resolved for approximately four 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, again disappeared.

[0078] [Example 2] A 25-year-old autistic female experienced moderate to severe autism. The subject was diagnosed with pervasive developmental disorder at age 2. She also had agenesis of the corpus callosum (ACC), attention deficit disorder (ADD), and obsessive-compulsive disorder (OCD). During her early life, she was prescribed Ritalin to help her stay focused. She also took Zoloft to control anxiety. She graduated from school as a special needs student in life skills classes by age 22. After years of taking medication and experiencing emotional highs and lows, her family decided to discontinue the medication. The subject's conversations were focused on expressing wants and / or needs, not conversation. Her last day of prescribed medication was December 27, 2018.

[0079] On July 17, 2019, she received multiple subcutaneous injections of botulinum toxin for trigeminal and cervical dermatitis: three 2-unit injections distributed along both sides of the neck in the cervical portion of the trigeminal nerve, and one 2-unit injection subcutaneously on each side in the ophthalmic, maxillary, and mandibular regions. The maximum total amount of botulinum toxin injected in this case was 2 units * 3 injections (cervical) * 2 (both sides) + 2 units * 3 injections (ophthalmic, maxillary, and mandibular regions of the trigeminal nerve, respectively) * 2 (both sides) = 24 units. No immediate changes were observed.

[0080] After about two weeks, she became more conversational and aware of her surroundings. She also no longer exhibited the mood swings she sometimes exhibited. She still exhibited some OCD moments, such as slamming the toilet seat cover, slamming doors, and slamming the refrigerator door. Her mother reported that there was definitely progress.

[0081] After another week, she began to sleep better. She also demonstrated more sociable behavior with appropriate responses to external circumstances. She was more verbal about her situation and acted independently and appropriately. She even recalled details of past events and held conversations.

[0082] Overall, she was much more in tune with her surroundings. She showed significant improvement in behavior, emotions, and language skills. She is now enjoying her life in a much more independent and autonomous way. The female patient in the case study weighed approximately 150 pounds. Dosage for an infant weighing approximately 25 pounds can be adjusted accordingly.

[0083] [Example 3] A 62-year-old female patient experienced severe, intractable vertigo. Her dizziness was so severe that she felt spinning and nauseous, so she spent most of her day lying down with as little head movement as possible. Riding in a car was extremely difficult for her; she had to stop periodically to vomit. She visited many doctors, tried many specialists, tried many medications, and even underwent surgery to vainly control it. She presented with severe nausea, dizziness, photosensitivity, and moderate sensitivity to light in the right ear / temple area and behind the ear. Her diagnosis was probable vestibular vertigo. Therefore, subcutaneous botulinum toxin was injected bilaterally into the ophthalmic, maxillary, and mandibular regions of the trigeminal nerve; 2 to 4 units in the C-2 to C-3 regions, 2 to 4 units in the C-4 to C-5 regions, and 2 to 4 units in the C-6 to C-7 regions.

[0084] Within two weeks, she reported that 95% of her dizziness and nausea symptoms had disappeared, and she was able to walk independently and ride in a car without symptoms. Some dizziness was still present if she moved her head back and forth very quickly. Botulinum toxin A usually lasts 3 to 4 months. She did not want it to return, so she received a new injection at about 2.5 months.

[0085] [Example 4] The patient is a 49-year-old man. He suffers from chronic, severe lumbar, sacral, and occasional cervical pain. He also has a protein S deficiency and takes Eloquis to combat the resulting blood clots. Protein S deficiency could be contributing to his chronic pain. He has been to numerous doctors for surgeries and steroid injections, only to find temporary relief. In February, one of his orthopedic surgeons told him that he was taking too many 6-Vicodin tablets daily and needed to stop taking them, otherwise he would become addicted. He did so, and for several weeks he experienced moderate to severe withdrawal pain. He stopped taking them for about a month, but then decided that the pain was having an excessive effect on him and began taking them three times a day. Initially, each tablet provided approximately 5–6 hours of pain relief, depending on whether he was physically active or not. After 6–8 weeks, the tablets' effectiveness began to decline. By July, they were only effective for 2–3 hours. On August 21, 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 in the central sacral region—a total of 60 units. Five days after the injections, he began to notice that the pain seemed to last longer. By the 10th day, they were lasting up to six hours.

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

Claims

1. 1. A botulinum toxin for use in treating autism spectrum disorder (ASD) in a patient in need thereof, wherein said botulinum toxin is administered to said patient, thereby treating the autism spectrum disorder (ASD); Administration to adults is by subcutaneous or intradermal injection. 2-4 units on and / or around the trigeminal nerve 2-4 units on and / or around the cervical nerves outside the patient's spine; 2-4 units in and / or around the thoracic nerve outside the patient's spine; 2-4 units in and / or around the lumbar nerves outside the patient's spine; and / or injecting 2-4 units into and / or around the sacral nerve outside the patient's spine; The total dose of botulinum toxin for an adult weighing approximately 150 pounds is approximately 50 units or less, The total dose of botulinum toxin administered to adults is adjusted for age, weight, or a combination thereof.

2. 2. The botulinum toxin of 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. 2. The botulinum toxin of claim 1, wherein the cervical nerve is 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.

4. 2. The botulinum toxin of claim 1, wherein the thoracic nerves include a t-2 nerve, a t-3 nerve, a t-5 nerve, a t-6 nerve, a t-7 nerve, a t-8 nerve, a t-9 nerve, a t-10 nerve, a t-11 nerve, a t-12 nerve, or a combination thereof.

5. 2. The botulinum toxin of claim 1, wherein the lumbar nerves include the I-1 nerve, the I-2 nerve, the I-3 nerve, the I-4 nerve, the I-5 nerve, or a combination thereof.

6. 2. The botulinum toxin of claim 1, wherein the sacral nerves include an s-1 nerve, an s-2 nerve, an s-3 nerve, an s-4 nerve, an s-5 nerve, or a combination thereof.

7. 2. The botulinum toxin of claim 1, which is selected from the group consisting of botulinum toxin types A, B, C, D, E, F, and G, fragments thereof, hybrids thereof, chimeras thereof, and combinations thereof.

8. 10. The botulinum toxin of claim 1, wherein each of the subcutaneous or intradermal injections is bilateral.

9. 10. The botulinum toxin of claim 1, wherein said treatment comprises treating autism spectrum disorder (ASD) by administering said botulinum toxin to said patient.

10. 10. The botulinum toxin of claim 1, wherein administration of the botulinum toxin prevents the onset of autism spectrum disorder (ASD) in children between about 1 and 5 years of age.

11. 10. The botulinum toxin of claim 1, wherein administration of the botulinum toxin reduces or eliminates symptoms of autism spectrum disorder (ASD) in children over the age of about 5 years and in adults whose brains have stopped forming.

12. 10. The botulinum toxin of claim 1, wherein the total dose of the botulinum toxin administered to children aged about 5 years and older and toddlers aged about 1 to 5 years is adjusted for age, weight, or a combination thereof.