BR112018008893B1 - OPTICAL PHARMACEUTICAL COMPOSITION - Google Patents

Abstract

METHOD FOR TREATMENT OR ASSESSMENT OF SYMPTOMS IN AN INDIVIDUAL WITH A DISEASE ASSOCIATED WITH A PARTICULAR CRANIAL NERVE, AND OPTICAL PHARMACEUTICAL COMPOSITION. Methods for treating a variety of diseases that include performing auricular anesthesia of various cranial nerves. A pharmaceutical composition is administered to an ear canal of a subject in need of such treatment, the composition including an analgesic and/or at least one anesthetic. Useful compositions on the methods taught are also provided.

Description

[0001] This application claims the benefit and priority of Patent Application US14/931,581, filed on November 3, 2015, by Thomas M. Crews. Patent Application US14/931,581 is a continuation in part of International Application PCT/US2014/036855, filed on May 5, 2014, which claims priority to Provisional Application US61/819,023, filed on May 3, 2013, the content of which Each of these is incorporated herein by reference in full. The specification, figures and full disclosure of Provisional Application US61/819,023, PCT/US2014/036855 and Patent Application US14/931,581 are incorporated herein by specific reference for all purposes.

[0002] All patents, patent applications and publications cited in this document are hereby incorporated in their entirety by reference. The disclosures of these publications in their entirety are incorporated herein by reference into this application. in order to more fully describe the state of the art, as known to those skilled in the art, as of the date of the invention described and claimed herein.

[0003] This patent disclosure contains material that is subject to copyright protection. The copyright owner has no objection to facsimile reproduction of any patent document or patent disclosure as it appears in patent deposits or records of the U.S. Patent and Trademark Office, but otherwise reserves any and all copyright rights.

FIELD OF INVENTION

[0004] The present disclosure relates to methods for treating a variety of diseases by performing auricular anesthesia of the fifth cranial nerve (trigeminal nerve), the seventh cranial nerve (facial nerve), the ninth cranial nerve (glossopharyngeal nerve) and the tenth nerve cranial (vagus nerve).

BASICS OF THE INVENTION

[0005] Sympathetic presynaptic nerve cell bodies are located in the lateral horn of the T1-L2 spinal cord segments. Sympathetic postsynaptic cell bodies are in ganglia, sympathetic chain ganglia, or prevertebral ganglia. Sympathetic presynaptic fibers reach the sympathetic chain through the communicating white rami and either synapse at the level where they enter, ascend or descend to the synapse, or leave the sympathetic trunk unsynapsed as a splanchnic nerve to go to a presynaptic ganglion. vertebral. Sympathetic postsynaptic fibers may enter spinal nerves through gray rami communicantes to be distributed with dorsal and ventral primary rami, may form perivascular plexuses to be distributed with blood vessels, or may travel directly to the target organ. The sympathetic nervous system provides sympathetic innervation to essentially every part of the body.

[0006] The presynaptic parasympathetic cell bodies are located in the brain stem and in the lateral horns of the S2, S3 and S4 segments and leave the CNS in the cranial nerves III, VII, IX and X, and in the pelvic splanchnic nerves that arise from the ventral primary branches spinal nerves S2, S3 and S4. Parasympathetic postsynaptic cell bodies are located in four pairs of ganglia in the head (associated with cranial nerves III, VII, and IX) and otherwise in microscopic ganglia on or in the wall of the target organ. The distribution of the parasympathetic nervous system is more limited than the sympathetic nervous system, with cranial nerves III, VII and IX supplying the smooth muscles and glands of the head, the vagus nerve supplying the visceral organs up to the left colic flexure and the pelvic splanchnics. supplying the descending and sigmoid colon, the rectum and the pelvic viscera. With the exception of the external genitalia, the parasympathetic nervous system does not reach the body wall.

[0007] The autonomic nervous system allows vertebrate species to work daily without having to think about the mechanics of their organs. Hearts beat, intestines digest, blood vessels change diameter, and vertebrates adapt appropriately to any situation, all without us having to think about it.

SUMMARY OF THE INVENTION

[0008] The invention provides methods for treating a variety of diseases comprising performing topical auricular anesthesia of the external auditory canal for the purpose of anesthesia of cranial nerves 5, 7, 9, 10, 11 and 12, together with the parasympathetic nervous system, the sympathetic nervous system. In one embodiment, the invention provides auricular anesthesia of the autonomic nervous system. In one embodiment, auricular anesthesia is performed on the trigeminal nerve, facial nerve, glossopharyngeal nerve, vagus nerve, accessory nerve, hypoglossal nerves, or a combination thereof. The invention further provides for the modulation of the general somatic nervous system and the general visceral nervous system by administering an optical pharmaceutical composition comprising one or more anesthetics (such as lidocaine and/or tetracaine) in solution with a pharmaceutical carrier (such as an excipient). glycerin and with or without epinephrine. In some embodiments, the optical pharmaceutical composition further comprises an analgesic, such as a pyrazolone derivative. In some embodiments, the pyrazolone derivative is antipyrene. The invention provides methods for treating a variety of diseases which comprise performing auricular anesthesia of the sympathetic nervous system via the vagus nerve to the sympathetic plexus. The invention also provides methods for treating pain from any variety of diseases described herein by performing auricular anesthesia of the vagus nerve directly and the sympathetic nerve indirectly thereby blocking general somatic afferent signals and general visceral afferent signals. The invention further provides methods for blocking pain from a variety of diseases comprising performing auricular anesthesia of the vagus nerve with resultant anesthesia to the thalamic nuclei resulting in modulation of general visceral afferent pain and general somatic afferent pain. In various embodiments, the disease is a neurology and psychiatry related affliction, an ear-nose-throat (ENT) related affliction, a GU related affliction, a gastrointestinal (GI) tract related affliction, a heart related affliction, distress related to lung disease or distress related to metabolism.

[0009] In various embodiments, the present invention provides a safe and non-invasive procedure by which to treat a number of human diseases and their symptoms, which are associated with the fifth cranial nerve (trigeminal nerve), the seventh cranial nerve (trigeminal nerve), the facial), ninth cranial nerve (glossopharyngeal nerve) and the tenth cranial nerve (vagus nerve). The present disclosure provides a method for interrupting the normal physiological function of the nerve that does not depend on an invasive and expensive surgical procedure. The disclosed methods are capable of “blocking” the transduction of afferent and efferent signals from being transmitted through the trigeminal, facial, glossopharyngeal or vagus nerves. Such blockage of signal transduction in the nerve is achieved by a topical auricular anesthesia procedure, in which a pharmaceutical composition is administered to a subject's ear canal. It is the cutaneous auricular anesthesia of these nerves and their particular proximity and relationship with their respective ganglia that allows their modulation in function. It is this modulation of function that results in modulation of the expression of specific disease processes.

[0010] In one embodiment, the present disclosure provides a method for treating symptoms of a disease, which comprises topically administering to a subject's ear canal a pharmaceutical composition, comprising: (i) an analgesic and (ii) an anesthetic. In one embodiment, the analgesic is at least one pyrazolone derivative selected from the group consisting of ampyrone, dipyrone, antipyrine, aminopyrine and propyphenazone. In a preferred embodiment, the analgesic is antipyrine. In one embodiment, the anesthetic is at least one selected from the group consisting of benzocaine, chloroprocaine, cocaine, cyclometocaine, dimethocaine, larocaine, piperocaine, propoxycaine, procaine, novocaine, proparacaine, tetracaine, amethocaine, articaine, bupivacaine, cinchocaine, dibucaine, etidocaine , levobupivacaine, lidocaine, lidocaine, mepivacaine, prilocaine, ropivacaine, trimecaine and pharmaceutically acceptable derivatives thereof. In a preferred embodiment, the anesthetic is benzocaine.

[0011] One aspect of the invention provides an optical pharmaceutical composition, comprising: (i) at least one analgesic comprising a pyrazolone derivative. In other aspects of the invention, the optical pharmaceutical composition further comprises (ii) at least one anesthetic comprising Formula I: where R1 comprises: wherein R2 comprises H, CH3, Cl, , or wherein R3 comprises H or NH2; wherein R4 comprises H, NH2, CH3, wherein R5 comprises H; and wherein R6 comprises H or CH3. One aspect of the invention further provides an optical pharmaceutical composition comprising at least 2 anesthetic compounds having Formula I as described herein. For example, the optical pharmaceutical composition may comprise tetracaine anesthetics (

[0012] One aspect of the invention provides a method for treating or ameliorating symptoms in a subject with a disease associated with a particular cranial nerve, wherein the disease is an affliction related to neurology and psychiatry, an affliction related to the ear-nose-throat ( ENT), GU related distress, gastrointestinal (GI) related distress, heart related distress, lung disease related distress or metabolism related distress, the method comprising administering to an ear canal of a subject in need of such treatment, an effective amount of a pharmaceutical composition, comprising: (i) at least one analgesic comprising a pyrazolone derivative, and (ii) at least one anesthetic comprising Formula I, and wherein said pharmaceutical composition is administered to the ear canal of the subject in a concentration sufficient to physiologically alter the activity of the subject's particular cranial nerve as compared to the physiological activity of that particular cranial nerve in a subject who did not administer the pharmaceutical composition. One aspect of the invention is a method for treating or ameliorating symptoms in a subject with a disease associated with a particular cranial nerve, wherein the disease is a neurology and psychiatry related affliction, ear-nose-throat (ENT) related affliction, an GU-related affliction, a gastrointestinal (GI) related affliction, a heart-related affliction, a pulmonary disease-related affliction, or a metabolism-related affliction, administering to an ear canal of a subject in need of such treatment an effective amount of an optical pharmaceutical composition, wherein the pharmaceutical composition comprises at least 2 anesthetic compounds having Formula I as described herein. For example, the optical pharmaceutical composition may comprise tetracaine anesthetics (

[0013] In one embodiment, R1 of Formula I comprises comprises H or CH3; wherein R3 comprises H; where R4 comprises wherein R5 comprises H; and wherein R6 comprises H or CH3. In one embodiment, R1 of Formula I comprises wherein R2 comprises H or CH3; wherein R3 comprises H; wherein R4 comprises H, NH2or wherein R5 comprises H; and wherein R6 comprises H or CH3.

[0014]

[0015] In one embodiment, the analgesic is at least one pyrazolone derivative selected from the group consisting of ampyrone, dipyrone, antipyrine, aminopyrine and propyphenazone. In a preferred embodiment, the analgesic anesthetic is antipyrine. Numa comprises benzocaine ( chloroprocaine ( cocaine cyclomethocaine dimethocaine also known as larocaine), Piperocaine propoxycaine procaine also known as novocaine), proparacaine ( also referred to as proxymetacaine), tetracaine ( also referred to asamethocaine), articaine ( bupivacaine ( cinchocaine also referred to as dibucaine), etidocaine levobupivacaine lidocaine ( also known as lidocaine and xylocaine), mepivacaine ( prilocaine ( ropivacaine farmocaine trimecaine ( a combination of the anesthetics listed herein, or pharmaceutically acceptable derivatives thereof. In another embodiment, the anesthetic is not benzocaine. In one embodiment, the anesthetic is lidocaine. In one embodiment, the anesthetic is tetracaine. In one embodiment, the anesthetic is tetracaine and lidocaine.

[0016] In one embodiment, the invention is directed to a method for treating or ameliorating symptoms in a subject with a disease associated with a particular cranial nerve where auricular anesthesia is performed on the trigeminal nerve (cranial nerve 5), facial nerve (cranial nerve 7), glossopharyngeal nerve (cranial nerve 9), vagus nerve (cranial nerve 10), spinal accessory nerve (cranial nerve 11), the hypoglossal nerve (cranial nerve 12), or a combination thereof.

[0017] The diseases that are treatable by the disclosed methodology are numerous and described here. Any disease that is associated with an organ or body tissue that is innervated by the particular nerve could potentially be treated by current methods. Particular mention of the following diseases treatable by current methods is made: asthma, neurogenic cough, globus hystericus, spasmodic dysphonia, gastroesophageal reflux disease and obesity. The present methods are also suitable for the treatment of post-tonsillectomy or post-adenoidectomy pharyngeal pain, or oropharyngeal pain.

[0018] In one embodiment, the disease is a neurology and psychiatry related affliction, an ear-nose-throat (ENT) related affliction, a GU related affliction, a gastrointestinal (GI) related affliction, a heart related affliction, distress related to lung disease or distress related to metabolism. In one embodiment, the neurology- and psychiatry-related affliction is at least one selected from the group consisting of: chronic fatigue syndrome, fibromyalgia, epilepsy, Obsessive Compulsive Disorder, panic attack, Post-traumatic Stress Disorder, Tourette's Syndrome, Focal Dystonia, Tic Doloreaux, Bulimia, Anxiety, Depression, Restless Leg Syndrome, Lack of autonomy, Familial Intentional Tremor, Migraine Pain, Autism Spectrum Disorder, Anxiety, Headache, insomnia, Reticular Activating System (RAS) dysregulation ), Multiple Sclerosis, Peripheral Neuropathy, Apraxia, Neck and Shoulder Pain, Parkinson's Disease, General Somatic Afferent Pain, General Visceral, Afferent pain, opioid withdrawal, Dysarthria, ADHD, non-specific hand tremor, Stuttering, Cerebral Palsy , Raynaud's phenomenon and excessive sweating. In one embodiment, General Somatic Afferent Pain comprises Neuromuscular Pain of the neck, back, arms, legs or shoulders; Joint Pain; sciatic pain; Arthritis pain pain; Herpes zoster pain; Reflex Sympathetic Dystrophy Pain; or a combination thereof. In one embodiment, an opioid withdrawal symptom comprises Generalized Pain, Muscle Aches, Nausea, Vomiting, Sweating, Diarrhea or a combination thereof. In one embodiment, the ear-nose-throat (ENT) related affliction is at least one selected from the group consisting of: Palatal Myoclonus, Post Tonsillectomy Pain, Pharyngeal Pain, Laryngeal Pain, Neurogenic Cough, Globus Hystericus, Spasmodic Dysphonia, Snoring, Allergic Rhinitis, Chronic Sinusitis, Chronic Nasal Congestion, Allergic Conjunctivitis, Sneezing, Hiccups, Rhinitis, Tinnitus, Dysphagia, Earache, Neck Pain, Dry Eye Syndrome, Trigeminal Neuralgia Pain and Temporomandibular Joint Pain. In one embodiment, the Gastroenterology/Urology (GU)-related distress is at least one selected from the group consisting of: bladder spasm, dysmenorrhea, pelvic pain, premature birth, interstitial cystitis, prostatitis, eclampsia, pre-eclampsia, HELLP syndrome , cystitis, kidney pain, enuresis, dysuria, dyspareunia, encopresis, menstruation with heavy flow, frequent urination, Prolonged Vaginal Bleeding and decreased renal blood flow. In one embodiment, the gastrointestinal (GI) related distress is at least one selected from the group consisting of: irritable bowel syndrome (IBS), ulcerative colitis, acid reflux, gastritis, gastroenteritis, hyperemesis gravidarum, pediatric colic, hepatorenal syndrome, suppression appetite, gallbladder pain, chronic constipation, chronic diarrhea and pancreatitis. In one embodiment, the heart-related affliction is at least one selected from the group consisting of: Paroxysmal (Lone) Atrial Fibrillation (Vagal), Orthostatic (Neurogenic) Hypotension, Reflexive Asystolic Syncope, Postural Orthostatic Tachycardia Syndrome (POTS), Vasovagal Reflex , cough resulting from heart surgery, heart block, Atrial Contractions, Tachycardia and Congestive Heart Failure. In one embodiment, the lung disease-related affliction is at least one selected from the group consisting of: asthma, chronic obstructive pulmonary disease (COPD), bronchitis, cystic fibrosis, and bronchospasm. In one embodiment, the metabolism-related affliction is at least one selected from the group consisting of: hypertension, diabetes, septic shock, neurogenic shock, hyperglycemia, and hypercholesterolemia.

[0019] In still other modalities, diseases treatable by the disclosed methodology include, but are not limited to: heart disease, paroxysmal (solitary) atrial fibrillation (vagal), reflex systolic syncope, postural orthostatic tachycardia syndrome (POTS), excessive craving for vomiting, esophageal dysphagia, vomiting, nausea, odynophagia, esophageal pain, esophageal neuralgia, gastritis, dyspepsia, gallbladder disease, cholecystitis pain, abdominal pain, esophageal motility disorder or esophageal dysmotility, spastic colon, pancreas pain or spasms, pediatric colic, rectal spasms and pain, bladder spasm (overactive bladder), interstitial cystitis, dysmenorrhea, preterm labor, pelvic pain, chronic pelvic pain, chronic prostatitis pain, eclampsia, preeclampsia, HELLP syndrome, cystitis pain , irritable bowel syndrome, Cohn's disease, ulcerative colitis, reflux disease, gastritis, gastroenteritis symptoms, hyperemesis gravidarum, pediatric colic, hepatorenal syndrome, appetite suppression, gallbladder pain, inflammation of the esophagus, inflammation of the stomach, inflammation of the colon, (pain from kidney stone, infection or tumor), enuresis, dysuria, dyspareunia, encopresis, periods of heavy flow, frequent urination, prolonged vaginal bleeding, inhibited erections, prevention of premature ejaculation, inhibit excessive sweating, spasms ureteral, menstrual cramps, uterine spasms, ovarian pain and spasms, fallopian pain and spasms, pediatric asthma, adult asthma, chronic obstructive pulmonary disease (COPD), mucus in the bronchi, acute bronchitis, asthmatic bronchitis, chronic bronchitis, bronchospasm, fibrosis cystic, lung inflammation, emphysema, pleuritic chest pain, intercostal muscle pain, nerve pain, bronchospasm secondary to intubation and extubation, angina pectoris, cardiac vagal block, vasovagal reflex block, bradycardia, hypotension, orthostatic hypotension, hypertension, diabetes , shock, septic shock, reduction in blood sugar, inflammation of the pancreas, syncope secondary to vagal or cardiac reasons, vasovagal syncope, bradyarrhythmias, vasodilation of the skin, neuralgia, laryngospasm, acute laryngitis, pain in the larynx, post-extubation and intubation laryngospasms, palatal myoclonus, post-tonsillectomy pain, snoring, allergic rhinitis, vasomotor rhinitis, inflammatory polyposis (nasal), chronic sinusitis, chronic nasal congestion, allergic conjunctivitis, sneezing, hiccups, rhinitis, tinnitus, dysphagia, croup, chronic fatigue syndrome, fibromyalgia (chronic), epilepsy, obsessive compulsive disorder, panic attacks, post-traumatic stress disorder, Tourette syndrome, focal dystonia, tic pain, bulimia, anxiety, depression, restless legs syndrome, dysautonomia, familial intentional tremor, migraine, autism spectrum, anxiety, headaches, insomnia or sleep disorders, multiple sclerosis, reticular activating system modulation, peripheral neuropathy, apraxia, neck and shoulder pain, and Parkinson's disease.

[0020] Thus, the present method generally applies to the treatment of any disease, illness or bodily condition that may benefit from “blocking” particular nerve function. That is, any condition that would benefit from the nerve's impaired ability to transmit neurological signals is encompassed by the disclosed method.

[0021] In the methods disclosed herein, the pharmaceutical composition is administered to the ear canal of a subject in a concentration sufficient to physiologically alter the activity of the subject's nerve, as compared to the physiological activity of a nerve in a subject not administered the pharmaceutical composition. Thus, the present pharmaceutical composition used in a method as disclosed is capable of destroying the natural ability of the nerve to transmit neurological signals along its length. These signals, both afferent and efferent, are blocked or hindered by current methods.

[0022] The amount of analgesic present in the pharmaceutical composition comprises about: 1 to 100 mg per mL, 10 to 100 mg per mL, 20 to 100 mg per mL, 30 to 100 mg per mL, 40 to 100 mg per mL , 50 to 100 mg per mL, 60 to 100 mg per mL, 70 to 100 mg per mL, 80 to 100 mg per mL, 90 to 100 mg per mL, or 100 mg per mL. In some embodiments, the amount of analgesic present is about 50 to 60 mg per mL, or about 54 mg per mL, or about 50 to 55 mg per mL, or about 55 to 60 mg per mL.

[0023] The amount of anesthetic present in the pharmaceutical composition comprises of about: 1 to 100 mg per mL, 10 to 100 mg per mL, 20 to 100 mg per mL, 30 to 100 mg per mL, 40 to 100 mg per mL , 50 to 100 mg per mL, 60 to 100 mg per mL, 70 to 100 mg per mL, 80 to 100 mg per mL, 90 to 100 mg per mL, or 100 mg per mL. In some embodiments, the amount of anesthetic present is about 1 to 20 mg per mL, or about 1 to 15 mg per mL, or about 5 to 15 mg per mL, or about 10 to 20 mg per mL. or about 10 to 15 mg per ml, or about 14 mg per ml.

[0024] The total amount of pharmaceutical composition administered to a patient during a dosage may comprise from about: 0.001 to 0.01 mL of solution, or 0.01 to 0.1 mL of solution, or 0.1 to 0. 5 mL of solution, or 0.1 to 1 mL of solution, or 1 to 1.5 mL of solution, or 1.5 to 2 mL of solution, or 2 to 5 mL of solution or 5 to 10 mL of solution. Administration may include the use of a “dropper” bottle that applies “drops” of solution to the patient's ear canal during a typical dosage. Such administration may comprise 1 mL « 15-20 drops, 0.5 mL « 10 drops, 0.25 mL « 5 drops.

[0025] As used herein, unless expressly specified otherwise, all numbers such as those expressing values, ranges, quantities or percentages may be read as if preceded by the word "about", even if the term does not expressly appears. Any numerical range mentioned herein is intended to include all subranges therein. Plural encompasses singular and vice versa; for example, the singular forms “a”, “a” and “the” include plural referents unless expressly and unambiguously limited to one referent.

[0026] In certain embodiments, the subject treated by the present methods does not have an ear infection. Furthermore, in certain embodiments, the subject treated by the present methods does not have an ear pain or is not experiencing ear pain.

[0027] In particular aspects, the present method is used in patients with ear infections. That is, the present methods, in certain embodiments, are specifically used in patients with an infection of the external auditory canal, with otalgia or with a middle ear infection, whether or not associated with purulence. Certain embodiments specifically utilize the methods in subjects experiencing an earache or acute ear pain. In these embodiments, a first step of the method may comprise an ear examination by an attending physician to ensure that a patient has an ear infection or is experiencing ear pain, or has a hole in the eardrum. It may consist of redness, middle ear effusion or swelling of the external canal tissues or distortion of the eardrum. In some aspects, after verifying that the patient does indeed have an ear infection, whether in the eardrum, ear canal, or middle ear, topical anesthesia in the form of antipyrene/benzocaine dissolved in an excipient can be inserted into the ear canal at a form of ear drops to reduce ear pain. This can also be done with lidocaine and tetracaine in a similar glycerin excipient, with or without the presence of epinephrine. What is contraindicated is the use of any topical anesthetic in the ear canal in the presence of an ear tube or pressure equalization tube or an active perforation in progress.

[0028] The disclosed pharmaceutical compositions used in the present methods may comprise additional components such as: antibiotics, vasoconstrictors, glycerin and acetic acid.

[0029] Pharmaceutical compositions may comprise any pharmaceutically acceptable carrier or adjuvant and may be formulated as: solutions, foams, gels, creams, pastes, lotions, emulsions and combinations of the aforementioned.

[0030] The pharmaceutical composition can be administered once a day, twice a day, three times a day, four times a day, five times a day, six times a day, seven times a day, eight times a day, nine times a day, 10 to 20 times a day, or even continuously throughout the day as needed. Furthermore, in certain embodiments, the pharmaceutical composition is administered at the onset of an asthma attack. In other embodiments, the pharmaceutical composition is administered to a person who is hungry. Some aspects of the methods involve administering the pharmaceutical composition when a patient experiences pain in his or her pharyngeal region. Certain embodiments contemplate not using the taught compositions on patients who suffer from ear pain, or who have an ear infection, or ear swelling associated with an ear infection. In these embodiments, the disclosed method of treating diseases associated with the vagus nerve can be immediately interrupted or stopped by a patient developing ear pain.

[0031] A specifically preferred disease to be treated by the disclosed method is pharyngeal or oropharyngeal pain associated with a postoperative tonsillectomy or postoperative adenoidectomy. These modalities treat the pain that patients feel after the aforementioned surgical procedures. In these embodiments, the pharmaceutical composition is applied to the ear canal of a subject who has had a tonsillectomy or adenoidectomy within: the preceding 168 hours (or 7 days), the preceding 48 hours, the preceding 24 hours, the preceding 12 hours, the preceding 4 hours, or immediately after the operation, before administering the pharmaceutical composition. Thus, the present method involves doctors prescribing the disclosed procedure and pharmaceutical composition for patients to use immediately after feeling pain in the pharyngeal or oropharyngeal regions post-surgery.

[0032] Another particularly preferred disease, or disease, to be treated by the disclosed method is asthma. In certain embodiments, acute asthma attacks are treated by the present methods. These embodiments involve administering the pharmaceutical composition to the ear canal of a subject who is currently experiencing an acute asthma attack. Furthermore, these modalities may comprise treating a subject who has suffered an asthma attack within the last 48, 24, 12, 6 or 1 hours. Thus, the methods described herein can be used in conjunction with standard bronchodilators and corticosteroids for the treatment and management of a patient's asthma. The methods may be suitable for use in asthma patients who experience a peak expiratory flow (PEF) of 50 to 79% of the patient's normal peak flow readings, i.e., “the yellow zone” as classified by the American Lung Association. . The methods are also suitable for use in patients with peak expiratory flow less than 50% of the patient's normal peak flow reading, i.e., "the red zone." The methods may be used in conjunction with a rescue inhaler when a patient experiences a severe asthma attack. Accordingly, in some embodiments, the present pharmaceutical composition is a component of a kit, wherein said kit comprises a rescue inhaler and a pharmaceutical composition comprising antipyrine and benzocaine. The kit is intended to be kept with a patient who is at risk of having a severe asthma attack. Furthermore, in some embodiments, the pharmaceutical composition is part of an emergency first aid kit that is kept in school classrooms, for example. In these embodiments, teachers can utilize the present pharmaceutical composition in times of emergency, such as when a student suffers a severe asthma attack, but there is not yet a rescue inhaler readily available.

[0033] The present methods are also suitable for use in the treatment of chronic asthma. In these embodiments, patients use the disclosed compositions as taught in the present disclosure to prevent the onset of an acute asthma attack. In these methods, chronic asthma is managed by continuous use of current methods. Thus, in certain embodiments, patients with asthma are administered the pharmaceutical compositions disclosed herein prior to the onset of an asthma attack. For example, certain embodiments of the present methods are effective in controlling asthma in patients who participate in sports. Patients suffering from asthma often experience a decreased ability to breathe after physical exertion, which in some cases can lead to a severe asthma attack that requires the use of an inhaler. The present methods permit treatment of a subject's ear canal with a pharmaceutical composition comprising antipyrine and benzocaine before the subject engages in the practice of a sport. Therefore, the present methods may be an effective therapy for the patient to use before engaging in physical activity in order to reduce the likelihood of having an asthma attack.

[0034] Another particularly preferred condition, or disease, to be treated by the disclosed method is obesity. The present methods treat obesity by providing a mechanism to suppress the patient's appetite. By suppressing a patient's appetite, current methods provide another tool for the doctor to utilize in managing a patient's weight. Thus, obesity can be treated by administering the pharmaceutical composition taught to the ear canal of a subject. In some embodiments, subjects are treated with the taught pharmaceutical composition whenever the subjects experience a feeling of hunger. Furthermore, some embodiments administer the disclosed pharmaceutical compositions to the subject's ear canal immediately before a meal is ingested, or 10 to 60 minutes before a meal is ingested, or 20 to 60 minutes before a meal is ingested, or 30 to 60 minutes before a meal is eaten or at the same time as food consumption. Thus, in some aspects, the present method of auricular vagus nerve anesthesia is used on a patient within one hour before the patient ingests any food. This way, the patient's appetite is satiated and less food will be consumed. Furthermore, some embodiments administer the disclosed pharmaceutical compositions to the subject's ear canal in the morning, preferably before the subject eats breakfast, thereby providing an effective appetite suppressant that lasts at least until lunch.

[0035] In some embodiments, the present pharmaceutical compositions and treatment methodology are part of a comprehensive weight loss program that involves not only utilizing the pharmaceutical composition to curb the patient's appetite, but may also include a specific diet and regimen. of exercises.

[0036] In some aspects, a person applying the topical pharmaceutical composition to a patient's ear canal must have good light in order to obtain a superficial view of the patient's ear in order to check for any gross obstruction, i.e. , wax, skin, infection, purulence or swelling. The person can gently pull the pinna outward and upward to straighten the ear canal. Ear drops comprising the taught pharmaceutical composition that have been previously heated and are quite viscous should be applied to the posterior or rear wall of the lateral opening of the ear. The drops should be applied very slowly and deliberately, one drop at a time, allowing each drop to slowly migrate through the ear canal. The patient's head must be supported on a flat, soft surface for optimal application. The back wall of the canal and eardrum has a large portion of the vagus nerve fibers, and thus punctual application to this area is desired. In some respects, children under the age of 10 will need 4 to 8 drops per ear, while adults and children over the age of 12 generally need 6 to 10 drops for anesthesia. In some embodiments, the drops are always followed by a cotton ball in the lateral ear canal for about an hour to ensure the medication remains in the ear canal to provide the necessary topical anesthesia to the vagus nerve. After an hour, the cotton can be removed.

[0037] The administration of a pharmaceutical composition to the patient's ear canal for the purpose of auricular anesthesia of the vagus nerve to treat a disease affected by physiological alteration of the vagus nerve is referred to in some embodiments as “Crews Maneuver.” The Crews Maneuver of using the ear canal as a conduit to anesthetize the vagus nerve does not suffer from the disadvantages present in the technique.

[0038] These and other features, aspects and advantages of the embodiments of the present disclosure will be better understood in relation to the description, claims and accompanying drawings explained below.

BRIEF DESCRIPTION OF THE FIGURES

[0039] This patent or application filing contains at least one drawing executed in color. Copies of such patent or patent application publication with color drawings will be provided by the Office upon request and payment of the required fee.

[0040] FIG. 1 is an illustration of the complex anatomy of the vagus nerve. The auricular branch is observed.

[0041] FIG. 2 is an illustration of the complex anatomy of the vagus nerve showing innervation from the parasympathetic division on one side of the body.

[0042] FIG. 3 is an illustration of the anatomy of the facial nerve.

[0043] FIG. 4 is an illustration of the anatomy of the trigeminal nerve.

[0044] FIG. 5 is an illustration of the anatomy of the glossopharyngeal nerve.

[0045] FIG. 6 is an illustration of the glossopharyngeal nerve.

[0046] FIG. 7 is an illustration of the inside of a human ear. The ear canal is observed.

[0047] FIG. 8 is an illustration of the nerves of the esophagus.

[0048] FIG. 9 is an illustration of the C-3, 5, 7, and 10 cranial nerves.

[0049] FIG. 10 is an illustration of the distribution of the hypoglossal nerve (cranial nerve 12).

[0050] FIG. 11 is an illustration of the anatomy of nerve innervations.

[0051] FIG. 12 is an illustration of the anatomy of the nerve innervations of the sympathetic (red) and parasympathetic (blue) systems.

[0052] FIG. 13 is an illustration of the anatomy of the nerve innervations of the sympathetic (blue) and parasympathetic (red) systems.

[0053] FIG. 14 is an illustration of the anatomy of nerve innervations and preganglionic and ganglionic neurons.

[0054] FIG. 15 is an illustration of the anatomy of somatic (orange) and visceral (blue) motor fibers.

[0055] FIG. 16 is an illustration of the anatomy of nerve innervations and preganglionic and ganglionic neurons.

[0056] FIG. 17 is an illustration of the anatomy of nerve innervations.

[0057] FIG. 18 is a map of cranial nerves in horses (top), canines (bottom) and felines (continued page).

[0058] FIG. 19 is an illustration of brains from several vertebrate species.

DETAILED DESCRIPTION OF THE INVENTION

[0059] Detailed descriptions of one or more preferred embodiments are provided here. It is to be understood, however, that the present disclosure may be incorporated in various forms. Therefore, specific details disclosed herein should not be construed as limiting, but rather as a basis for the claims and as a representative basis for teaching one skilled in the art to employ the present disclosure in any appropriate manner.

[0060] As used herein, the term "about" is used herein to mean approximately, more or less, around, or in the region of. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the bonds above or below the established numerical values. In general, the term “about” is used here to modify a numerical value above and below the stated value by a 20 percent variation up or down (higher or lower).

[0061] An “effective amount”, “sufficient amount” or “therapeutically effective amount”, as used herein, is an amount of a compound that is sufficient to effect beneficial or desired results, including clinical results. As such, the effective amount may be sufficient, for example, to reduce or ameliorate the severity and/or duration of an affliction or condition, or one or more symptoms thereof, prevent the advancement of conditions related to an affliction or condition, prevent the recurrence, development or onset of one or more symptoms associated with an affliction or condition or potentiate or otherwise improve the prophylactic or therapeutic effect(s) of another therapy. An effective amount also includes the amount of the compound that substantially avoids or attenuates undesirable side effects.

[0062] As used herein and as well understood in the art, “treatment” is an approach to obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical outcomes may include, but are not limited to, relief or improvement of one or more symptoms or conditions, lessening of the extent of the disease, a stabilized (i.e., not worsening) state of the disease, preventing the spread of the disease , delaying or slowing the progression of the disease, improvement or palliation of the disease state and remission (partial or total), detectable or undetectable. “Treatment” can also mean prolonging survival, compared to the expected survival if not receiving treatment.

[0063] The term “in need thereof” refers to the need for symptomatic or asymptomatic relief from a condition such as, for example, cancer or a neurodegenerative disease. The subject in need thereof may or may not be being treated for conditions related to, for example, cancer or a neurodegenerative disease.

[0064] The term "carrier" refers to a diluent, adjuvant, excipient or vehicle with which a compound is administered. Non-limiting examples of such pharmaceutical carriers include liquids such as water and oils, including those of animal, vegetable, petroleum or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Pharmaceutical carriers can also be saline, gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. Additionally, auxiliary agents, stabilizers, thickeners, lubricants and colorants can be used. Other examples of suitable pharmaceutical carriers are described in Remington: The Science and Practice of Pharmacy, 21st Edition (University of the Sciences in Philadelphia, ed., Lippincott Williams & Wilkins 2005); and Handbook of Pharmaceutical Excipients, 7th Edition (Raymond Rowe et al., ed., Pharmaceutical Press 2012); each incorporated herein by reference in its entirety.

[0065] The terms “animal”, “subject” and “patient”, as used herein, include all members of the animal kingdom, including, but not limited to, mammals, animals (e.g., cats, dogs, horses, swine , etc.) and humans.

[0066] Autonomic nervous system.

[0067] The autonomic nervous system is divided into sympathetic and parasympathetic components. The sympathetic nervous system prepares the body for stress and is called the "fight or flight" system. The parasympathetic system prepares the body for rest and is called the "rest and digest" or "vegetative" system.

[0068] The sympathetic nervous system is one of the two main divisions of the autonomic nervous system; the other being the parasympathetic nervous system. The sympathetic nervous system can be modulated or significantly affected by the use of ear anesthesia in the external auditory canal. Auricular anesthesia for the external auditory canal can modulate the vagus and glossopharyngeal nerves, which have direct connections to the sympathetic chain or nervous system Figure 12, Figure 13; See also Figure 1 and Figure 5). The primary process of the sympathetic nervous system is to stimulate the body's fight or fight response. However, it is constantly active on a basic level to maintain homeostasis. It works as a complement in close conjunction with the parasympathetic nervous system through direct neural communication.

[0069] There are two types of neurons involved in the transmission of any signal through the sympathetic nervous system: preganglionic or postganglionic. The shorter preganglionic neurons originate in the thoracolumbar region of the spinal cord (levels T1 to L2 specifically) to travel to a ganglion, often one of the paravertebral ganglia, where they synapse with a postganglionic neuron. From there, the long postganglionic neuron extends across most of the body. Sympathetic nerves arise from near the middle of the spinal cord in the intermediolateral nucleus of the lateral gray spine, beginning in the first thoracic vertebrae of the spinal column and are believed to extend to the second or third lumbar vertebrae. The axons of these nerves leave the spinal cord through the anterior root. They pass near the sensory ganglion of the spinal cord and enter the anterior rami of the spinal nerves. However, unlike somatic innervation, they quickly separate through white branch connectors that connect to paravertebral or prevertebral ganglia that extend along the spinal column. Presynaptic nerves or axons that terminate in either the paravertebral ganglia or the prevertebral ganglia. In all cases, the axon enters the paravertebral ganglia at the level of the spinal nerve of origin. After that, it can synapse in this ganglion, ascend to a higher one, or descend to a more inferior paravertebral ganglion and synapse there, or it can descend to a pre-vertebral ganglion and synapse with the postsynaptic cell. The postsynaptic cell continues to innervate the target and the effector, i.e., the gland, smooth muscle, etc. Notable exceptions are the innervation pathways of the suprarenal adrenal medulla. In this case, presynaptic neurons pass through the paravertebral ganglia to the prevertebral ganglia and then synapse directly with the adrenal tissue. Auricular anesthesia of the vagus nerve can send signals to the paravertebral ganglia and affect neural transmission and thus affect sympathetic outflow to various organs, muscles, blood vessels, glands, skin and nerves, affecting disease processes.

[0070] The sympathetic nervous system is involved in hundreds of disease processes, including the following: chronic fatigue syndrome, fibromyalgia, post-traumatic stress disorder, restless leg, anxiety, dysautonomia, hand tremors, migraines, and muscle diseases , such as multiple sclerosis, cerebral palsy and Parkinson's disease. Other diseases such as peripheral neuropathies, arthritis, reflex sympathetic dystrophy, muscle pain, sweating, orthostatic hypotension, postural orthostatic tachycardia syndrome, vasovagal reflex, cardiac arrhythmias, hypertension, diabetes, high blood sugar levels, high cholesterol, irritable bowel disease , irritable bowel syndrome, chronic constipation, ulcerative colitis, eclampsia, preeclampsia, HELLP syndrome, premature ejaculation, supraventricular tachycardia, and congestive heart failure can all be affected by an overactive sympathetic nervous system. Modulation of this system can be accomplished through direct modulation of the parasympathetic nervous system through the auricular branch of the vagus nerve and the glossopharyngeal nerve and its intimate connections with the superior cervical sympathetic ganglion with its connections with the rest of the sympathetic nervous system, please see outstanding figures. It should also be noted that the functions of the sympathetic nervous system also include dilation of the pupils, increased dryness of the eyes, increased dryness of the nose and mouth, increased heart rate and force of contraction, dilation of the bronchi, dilation of skeletal muscles , dilation of blood vessels going to the brain, decreased blood flow to the kidney, decreased blood flow to the gastrointestinal tract, increased activation of sweat glands inhibiting peristalsis, increased renin levels, increased cholesterol levels and triglycerides, increasing blood pressure levels and promoting ignition for ejaculation.

[0071] The present invention provides a method for treating or ameliorating symptoms in a subject with a disease associated with a particular cranial nerve, wherein the disease is a neurology- and psychiatry-related affliction, ear-nose-throat (ENT)-related affliction , GU-related distress, gastrointestinal (GI)-related distress, heart-related distress, lung disease-related distress, or metabolism-related distress. In one embodiment, the disease is a neurology and psychiatry related affliction, an ear-nose-throat (ENT) related affliction, a GU related affliction, a gastrointestinal (GI) related affliction, a heart related affliction, a lung disease or metabolism-related affliction. In one embodiment, the neurology- and psychiatry-related affliction is at least one selected from the group consisting of: chronic fatigue syndrome, fibromyalgia, epilepsy, Obsessive Compulsive Disorder, panic attack, Post-traumatic Stress Disorder, Tourette's Syndrome, Focal Dystonia, Tic Doloreaux, Bulimia, Anxiety, Depression, Restless Leg Syndrome, Lack of autonomy, Familial Intentional Tremor, Migraine Pain, Autism Spectrum Disorder, Anxiety, Headache, insomnia, Reticular Activating System (RAS) dysregulation ), Multiple Sclerosis, Peripheral Neuropathy, Apraxia, Neck and Shoulder Pain, Parkinson's Disease, General Somatic Afferent Pain, General Visceral, Afferent pain, opioid withdrawal, Dysarthria, ADHD, non-specific hand tremor, Stuttering, Cerebral Palsy , Raynaud's phenomenon and excessive sweating. In one embodiment, General Somatic Afferent Pain comprises Neuromuscular Pain of the neck, back, arms, legs or shoulders; Joint Pain; sciatic pain; Arthritis pain pain; Herpes zoster pain; Reflex Sympathetic Dystrophy Pain; or a combination thereof. In one embodiment, an opioid withdrawal symptom comprises Generalized Pain, Muscle Aches, Nausea, Vomiting, Sweating, Diarrhea or a combination thereof. In one embodiment, the ear-nose-throat (ENT) related affliction is at least one selected from the group consisting of: Palatal Myoclonus, Post Tonsillectomy Pain, Pharyngeal Pain, Laryngeal Pain, Neurogenic Cough, Globus Hystericus, Spasmodic Dysphonia, Snoring, Allergic Rhinitis, Chronic Sinusitis, Chronic Nasal Congestion, Allergic Conjunctivitis, Sneezing, Hiccups, Rhinitis, Tinnitus, Dysphagia, Earache, Neck Pain, Dry Eye Syndrome, Trigeminal Neuralgia Pain and Temporomandibular Joint Pain. In one embodiment, the Gastroenterology/Urology (GU) related affliction is at least one selected from the group consisting of: bladder spasm, dysmenorrhea, pelvic pain, premature birth, interstitial cystitis, prostatitis, eclampsia, pre-eclampsia, HELLP syndrome , cystitis, kidney pain, enuresis, dysuria, dyspareunia, encopresis, menstruation with heavy flow, frequent urination, Prolonged Vaginal Bleeding and decreased renal blood flow. In one embodiment, the gastrointestinal (GI) related affliction is at least one selected from the group consisting of: irritable bowel syndrome (IBS), ulcerative colitis, acid reflux, gastritis, gastroenteritis, hyperemesis gravidarum, pediatric colic, hepatorenal syndrome , appetite suppression, gallbladder pain, chronic constipation, chronic diarrhea and pancreatitis. In one embodiment, the heart-related affliction is at least one selected from the group consisting of: Paroxysmal (Lone) Atrial Fibrillation (Vagal), Orthostatic (Neurogenic) Hypotension, Reflexive Asystolic Syncope, Postural Orthostatic Tachycardia Syndrome (POTS), Vasovagal Reflex , cough resulting from heart surgery, heart block, Atrial Contractions, Tachycardia and Congestive Heart Failure. In one embodiment, the lung disease-related affliction is at least one selected from the group consisting of: asthma, chronic obstructive pulmonary disease (COPD), bronchitis, cystic fibrosis, and bronchospasm. In one embodiment, the metabolism-related affliction is at least one selected from the group consisting of: hypertension, diabetes, septic shock, neurogenic shock, hyperglycemia, and hypercholesterolemia.

[0072] Visceral fibers and general afferents conduct sensory impulses, generally pain and reflex sensations from the viscera, glands and blood vessels to the central nervous system. They are considered part of the visceral nervous system and not the autonomic nervous system. However, unlike the efferent fibers of the autonomic nervous system, afferent fibers are not classified as sympathetic or parasympathetic. General visceral afferents create referred pain to activate general somatic afferent fibers, where the two meet in the posterior horn of the spinal cord. Cranial nerves that contain general visceral afferent fibers include the facial nerve, glossopharyngeal nerve, and vagus nerve, all of which innervate the external auditory canal. Visceral afferent referred pain can be modulated by auricular anesthesia to these cranial nerves, as they provide sensory innervation to specific areas of the external auditory canal. Topical anesthesia for these areas can modulate the body's general visceral afferent signals back to the central nervous system.

[0073] General somatic afferent fibers (GSA or somatic sensory nerves) afferent fibers arrive from cells in the spinal ganglia and are found in all spinal nerves, except occasionally the first cervical, and conduct impulses of pain, touch and surface temperature of the body through the posterior roots of the spinal cord and impulses from the muscle sense, tendon sense and common sense from deeper structures. General somatic afferent fibers travel through the sympathetic chain to the spinal nerve, dorsal root ganglion, dorsal root, and spinal cord. It can travel down the spinal cord toward the central nervous system to the thalamic level and then to the brain, where it can become involved in a reflex arc involving visceral, motor, and somatic nerves, which also travel from the ventral root back through the spinal cord. sympathetic to your respectful organs. FIGS. 12-13. It is not known at this time whether paravertebral and prevertebral sympathetic nervous system modulation modulates pain at the ganglion or thalamic level at this time. Without being limited by theory, general somatic afferent pain and general visceral afferent pain can be modulated through auricular anesthesia applied topically to the external canal modulating the vagus nerve and its connections with the sympathetic nervous system.

[0074] The anatomy of vertebrates has many common anatomical and physiological neurological aspects. There is no reason to preclude the use of topical anesthesia or auricular modulation of the external auditory canal for the purpose of disease modulation via the cranial nerves and sympathetic nervous system in other vertebrate species such as primates, felines, canines, bovines, and rodent species. Without being limited by theory, other vertebrate species may also benefit from treating specific cranial nerve-associated diseases through auricular modulation of the autonomic nervous system. The method comprises topically administering to an ear canal of a vertebrate subject a pharmaceutical composition comprising: i. an analgesic and/or ii. an anesthetic for the external ear canal.

[0075] Cranial nerves.

[0076] The vagus nerve, also known as cranial nerve X, is the tenth of twelve pairs of cranial nerves and is the longest of the cranial nerves. As the medulla leaves between the medullary pyramid and the inferior cerebellar peduncle, it extends through the jugular foramen and passes into the carotid sheath between the internal carotid artery and the internal jugular vein, below the head, to the neck, chest and abdomen where contributes to the innervation of the viscera. The anatomy of the vagus nerve is illustrated in FIGS. 1 and 2.

[0077] Upon exiting the jugular foramen, the vagus nerve forms the jugular ganglion and the nodose ganglion or the superior and inferior ganglion of the vagus. The jugular ganglion is joined by filaments from the petrosal ganglion of the glossopharyngeal nerve. The auricular branch of the vagus nerve also has connections from the jugular ganglion of ten and the petrosal ganglion of the glossopharyngeal nerve as it enters the mastoid canaliculus from the lateral wall of the jugular fossa. Brushing the temporal bone, the auricular branch of the vagus leaves the tympanomastoid fissure and divides into two branches; one joins the post-auricular nerve and the other is distributed to the skin on the back of the ear and the posterior external auditory canal.

[0078] The vagus nerve transmits sensory information about the state of the body's organs to the central nervous system. Approximately 80% of the nerve fibers of the vagus nerve are afferent, or sensory nerves, communicating the state of the viscera to the brain, while the remaining 20% are efferent, or functional, nerves.

[0079] The vagus nerve is responsible for regulating a number of bodily functions, including, but not limited to breathing, speaking, sweating, facilitating the opening of the larynx during breathing, monitoring and regulating the heartbeat, and digestion of food in the stomach , along with a number of other physiological functions.

[0080] Consequently, manipulation of the vagus nerve and subsequent alteration of its normal physiological function can have profound effects on a wide range of human diseases associated with regulation of the vagus nerve. However, the present procedures available in the art to alter the function of the vagus nerve are highly invasive. These current procedures often rely on implanting artificial mechanical devices into a patient's body. In addition to being highly invasive surgical procedures, these methods are very expensive.

[0081] For example, the United States Food and Drug Administration approved a procedure called vagus nerve stimulation (VNS) in the late 1990s for the treatment of partial-onset epilepsy. VNS is performed as a surgical procedure to install a pacemaker-like device in a subject suffering from epileptic seizures. The device, implanted within the patient's neck area, is used to send mild electrical impulses through the vagus nerve. The device is battery operated and has an electrical pulse generator. After it is implanted, plastic-insulated electrodes are run to the vagus nerve beneath the skin in the patient's neck. The pulse is set to operate alternately, turning on every few seconds and then turning off.

[0082] Researchers have also begun to investigate the possibility of using these pacemaker-like devices in the stomach of obese patients to block the function of the vagus nerve in order to suppress appetite. Again, these procedures are highly invasive and involve implanting artificial devices into a patient's body.

[0083] Some surgeons have performed vagotomy procedures to treat obesity. In these procedures, the surgeon completely cuts a patient's vagus nerve. Although these procedures have successfully allowed subjects to lose weight, it is evident that such an invasive and permanent surgical procedure is problematic for many patients.

[0084] Cranial nerve seven or the facial nerve is one of the twelve pairs of cranial nerves (see FIG. 3). It is so called because its main function is to provide motor innervation to the muscles of the face. Other innervated muscles are the platysma, the posterior belly of the digastric muscle and the stapedius muscle. The sensory and parasympathetic portion of the facial nerve travels in the intermediary nerve and supplies the following components: (1) taste to the anterior two-thirds of the tongue; (2) secretory and vasomotor fibers to the lacrimal gland, mucous glands of the nose and paranasal sinuses, mouth, and submandibular and sublingual salivary glands; and (3) cutaneous sensory impulses from the external auditory canal and dorsum regions of the ear. It is also believed that a parasympathetic impulse from the intermediate nerve, to the sphenopalatine ganglion, to the mucosa and submucosa of the nose and paranasal sinuses determines its venous capacity and the level of congestion.

[0085] The parasympathetic portion of the seventh cranial nerve has its origin in the nucleus salivatorius in the brain stem and enters the internal acoustic meatus, separate from the motor division of the facial nerve. Combines with the facial nerve proximal to the geniculate ganglion. The fibers leave the geniculate ganglion via the great superficial petrosal nerve and are joined by the great deep petrosal nerve to form the vidian nerve, or the nerve of the pterygoid canal, where together they advance to synapse in the sphenopalatine ganglion. There they provide parasympathetic innervation to the eye, nose, sinus, palate, pharynx, and salivary glands. The geniculate ganglion receives general somatic afferent fibers from the external auditory canal through the auricular branch of the vagus nerve and its connection with the seventh cranial nerve. General somatic sensory afferent fibers synapse in the geniculate ganglion.

[0086] The trigeminal nerve or fifth cranial nerve is the fifth of twelve pairs of cranial nerves and is the largest of all cranial nerves (see FIG. 4). It is the large sensory nerve of the skin of the face, scalp, ear canal, mucous membranes, and other internal structures of the head. It also has motor innervation functions for the chewing muscles and contains proprioceptive fibers. Furthermore, it carries sensory innervation of the brain's dura mater with its various branches. The fifth cranial nerve is quite extensive. The main sensory nucleus extends from the pons to the upper spinal cord. The nucleus receives its afferent fibers from the semilunar ganglion, also known as the trigeminal ganglion or gasserian ganglion. The trigeminal ganglion contains the cell bodies of sensory fibers for its three main divisions. It receives three major sensory divisions: the ophthalmic, maxillary and mandibular divisions. The sensory root fibers leave the ganglion posteriorly to pass their insertion into the pons.

[0087] The glossopharyngeal nerve, also known as the ninth cranial nerve, is the ninth of the twelve paracranial nerves that is known as the tympanic nerve and has both sensory and secretory fibers (see FIGS. 5 and 6). The nerve is a mixed sensory and motor nerve. The sensory component consists of somatic afferent fibers that transmit sensation to the mucous membranes of the pharynx and tonsillar region and posterior tongue. The superficial origin of the glossopharyngeal nerve from the brain stem is from three or four rootlets in the groove between the olive and inferior peduncles. It exits the skull through the jugular foramen and runs anteriorly between the internal carotid artery and the internal jugular vein. Upon exiting the jugular foramen, it forms a pair of ganglion swellings: the superior or jugular ganglion and the inferior or petrosal ganglion. The ganglion contains cell bodies of the nerve's sensory fibers. The ninth nerve communicates with the vagus nerve or the tenth cranial nerve, the facial nerve and the sympathetic ganglion. The glossopharyngeal nerve has five distinct general functions: (1) motor (special visceral efferent) supplies the stylopharyngeal muscle; (2) visceral motor (general visceral efferent) provides parasympathetic innervation of the parotid gland; (3) visceral sensory (general visceral afferent) carries visceral sensory information from the carotid sinus and carotid body; (4) general sensory (general somatic efferent) provides general sensory information from the skin of the outer ear, inner surface of the tympanic membrane, upper pharynx, and posterior one-third of the tongue; and (5) special sensory (special afferent) provides taste sensation from the posterior third of the tongue, including circumvallate papillae.

[0088] The accessory nerve or spinal accessory nerve is cranial nerve 11. The cranial nerve controls the sternocleidomastoid muscle and the trapezius muscle. The sternocleidomastoid muscle tilts and rotates the head while the trapezius muscle has several factors on the scapula, including shoulder elevation and arm abduction. Range of motion and strength testing in the neck and shoulders may be measured during a neurological exam to assess spinal accessory nerve function. Limited range of motion or low muscle strength indicates damage to the spinal accessory nerve. This can be the result of a variety of cranial nerve causes. The spinal accessory nerve exits the skull through a specialized hole or foramen. The nerve originates in most individuals from neurons located in the upper spinal cord. From there, the fibers enter the foramen magnum and run along the inner wall of the skull towards the jugular foramen through which it exits the skull with the glossopharyngeal (or 9th cranial nerve) and the vagus nerve (or the 10th cranial nerve). and the vagus nerve (or the tenth cranial nerve) due to a peculiar course, the spinal accessory nerve is notable for being the only cranial nerve to enter and exit the skull (Figure 1, Figure 2 and Figure 5). Once the nerve exits the jugular foramen, it crosses the internal jugular vein around the level of the posterior belly of the digastric muscle. It runs to innervate the trapezius and sternocleidomastoid muscles. The function of the spinal accessory nerve is the efferent or special visceral innervation and motor control function of the sternocleidomastoid and trapezius muscles. Abnormalities of the spinal accessory nerve can cause spasm of these two muscles, along with fasciculation and weakness or aberrations in head, neck, shoulder and arm movements and range of motion. The spinal accessory nerve is closely connected to the vagus nerve which is the superior and inferior ganglion of the vagus nerve. Auricular anesthesia of the vagus nerve directly modulates the electrical input and function of the spinal accessory nerve Figure 5).

[0089] The hypoglossal nerve is the 12th cranial nerve and innervates the muscles of the tongue. The nerve arises along with the other cranial nerves in the brain stem. The nerve exits the base of the skull in the posterior fossa through the hypoglossal canal. When leaving the skull, it detaches a small meningeal branch and takes a branch from the anterior branch of C1. It runs in close proximity to the vagus nerve and the spinal position of the accessory nerve and runs behind the vagus nerve and passes between the internal carotid artery and the internal jugular vein situated in the carotid sheath. It passes deep into the posterior belly of the digastric muscle in the submandibular region. It passes lateral to the hyoglossus muscle in the inferior laryngeal nerve to reach and innervate the tongue. It is closely involved in speech as it innervates the tongue. It innervates the intrinsic and extrinsic muscles of the tongue and is characterized as a general somatic efferent nerve type. It can be modulated by indirect modulation or anesthesia to the vagus nerve, which communicates directly with the hypoglossal nerve (see Figure 1 and Figure 5). The hypoglossal nerve is involved in speech, in addition to swallowing to clear the mouth of saliva and other involuntary activities completed by the tongue. Most roles are voluntary. Voluntary functions require conscious thought and nerve pathways occur in the corticobulbar region of the spinal cord. The nucleus of the hypoglossal nerve is supplied by the innervation of the reticular formation by which it is involved in various reflexive or automatic movements and in assisting the unconscious movement required when engaging in speech and articulation. Modulation of signals to the hypoglossal nerve via the 10th cranial nerve can have profound effects on improving articulation, speech, swallowing, and posterior fossa headaches.

[0090] Therefore, there is a great need in the medical community for methods of treating diseases associated with the vagus and other cranial nerves that do not depend on altering the function of the vagus nerve or other cranial nerves through invasive surgical procedures or artificial devices. Specifically, there is a great need in the art for procedures to alter the function of the vagus nerve and other cranial nerves that are non-invasive, safe, effective and economical.

[0091] Interrupting the Transduction of Neurological Signals Along Cranial Nerves.

[0092] The present invention provides methods of treating a variety of diseases described herein comprising performing auricular anesthesia (e.g., topical anesthesia) of the external auditory canal for the purpose of anesthesia of cranial nerves 5, 7, 9, 10, 11 and /or 12. The present invention also provides methods of treating a variety of diseases described herein comprising performing auricular anesthesia (e.g., topical anesthesia) of the sympathetic and/or parasympathetic nervous system. The present invention further provides methods of treating a variety of diseases described herein comprising performing auricular anesthesia of general visceral afferents, general somatic afferents, general visceral efferents and/or general efferents. In some embodiments, auricular anesthesia is performed on a variety of vertebrate species including, but not limited to, species such as humans, horses, cows, pigs, dogs, cats, etc. In some embodiments, auricular anesthesia is performed by administering a combination of lidocaine and tetracaine combined in solution with a glycerin excipient with and without epinephrine present. Antipyrine and benzocaine can also be used to conduct auricular anesthesia of the external auditory canal for the purpose of treating diseases (see examples here). Glycerin is a substance based on the usp of the excipient. Tetracaine can also be administered without epinephrine to achieve similar results. Other excipients will also be used to transport the topical anesthetic or topical analgesic. In one embodiment, the present disclosure provides a method for treating symptoms of a disease, which comprises topically administering to an ear canal of a subject a pharmaceutical composition comprising an anesthetic and another anesthetic. In some embodiments, an analgesic with an anesthetic may also be used. This would be a separate ear drop product in itself. In one embodiment, the analgesic is antipyrine, but may also consist of other known analgesics. In one embodiment, the anesthetic is at least one of a selected group consisting of an amide or an ester compound discussed herein.

[0093] The tenth cranial nerve (vagus nerve) is associated with several bodily organs and alteration of its normal physiological function can have profound effects on a number of human diseases. That is, by “blocking” or “disturbing” or “numbing” the conduction of neurological signals in the particular nerve, it is possible to influence a series of organs that are innervated by that nerve. Consequently, blocking the transduction of signals transmitted along the nerve, whether these signals are afferent or efferent in nature, will alter the normal physiological response of various organs and tissues. This, in turn, can have profound implications in the treatment of a variety of diseases, or diseases that are associated with human organs and tissues that are innervated by the particular nerve.

[0094] Auricular anesthesia of the cutaneous portion of the seventh cranial nerve (facial nerve) takes signals back to the geniculate ganglion where parasympathetic fibers and sensory fibers are anesthetized, blocked or otherwise modulated. Anesthesia of the geniculate ganglion and its connection to the sphenopalatine ganglion serves to modulate or block the transduction of efferent signals through the facial nerve. This can profoundly affect disease processes such as, but not limited to, allergic rhinitis, vasomotor rhinitis, inflammatory nasal polyposis, chronic sinusitis, chronic nasal congestion, allergic conjunctivitis, sneezing and rhinitis in all forms.

[0095] The sensory aspect of the fifth cranial nerve (trigeminal nerve) deals with information from the dura mater, the mucous membranes of the eyes, the mucous membranes of the nose and nasal sinuses, the skin of the external tympanum of the ear canal. Auricular anesthesia of the ear canal skin then signals to the trigeminal ganglion via the auriculotemporal branch of the mandibular division of the trigeminal nerve. Modulation of afferent signals through the trigeminal ganglion has profound effects on multiple disease processes. Modulation of afferent signals from the dura mater, eye, nose and sinuses leads to the modulation of several pathological processes. Manipulation of dural signals that pass through the ophthalmic, maxillary, and mandibular divisions have profound effects in the treatment of headaches and migraines. Manipulation or modulation or blockade of afferent signals from the ophthalmic and maxillary divisions of the trigeminal nerve will result in modulated efferent signals from the motor division of the seventh cranial nerve dealing with allergic rhinitis, vasomotor rhinitis, all forms of rhinitis, inflammatory nasal polyposis, sinusitis chronic, chronic nasal congestion, allergic conjunctivitis and sneezing.

[0096] Auricular anesthesia of the cutaneous portion of the ninth cranial nerve (glossopharyngeal nerve) and its proximity to the petrosal ganglion and its connection with the seventh cranial nerve and the tenth cranial nerve can have a profound effect on certain pathological processes. Because of the neural connections between the glossopharyngeal nerve and those of the seventh and tenth cranial nerves, disease processes specific to these nerves can also be modulated. Specific diseases of the glossopharyngeal nerve that may be affected by topical auricular anesthesia include, but are not limited to, pharyngeal pain, post-tonsillectomy pain, sneezing, and parotid salivation.

[0097] Thus, various embodiments of the present invention comprise a method that blocks the transduction of efferent signals through the vagus, trigeminal, facial or glossopharyngeal nerves. Another modality of disclosure blocks afferent transduction of signals through the vagus, trigeminal, facial, or glossopharyngeal nerves. The present disclosure also provides a methodology by which both afferent and efferent signal transduction through the vagus, trigeminal, facial, or glossopharyngeal nerves are blocked.

[0098] In one embodiment, the invention provides a method for treating or ameliorating symptoms in a subject with a disease associated with a particular cranial nerve, wherein the disease is a neurology- and psychiatry-related affliction, ear-nose-related affliction. throat (ENT), GU related distress, gastrointestinal (GI) related distress, heart related distress, lung disease related distress or metabolism related distress, the method comprising administering to an ear canal of a subject in need of such treatment, an effective amount of a pharmaceutical composition, comprising: (i) at least one analgesic comprising a pyrazolone derivative, and (ii) at least one anesthetic comprising Formula I: where R1 comprises: wherein R2 comprises H, CH3, Cl, or wherein R3 comprises H or NH2; wherein R4 comprises H, NH2, CH3, ; wherein R5 comprises H; and wherein R6 comprises H or CH3, and wherein said pharmaceutical composition is administered to the subject's ear canal in a concentration sufficient to physiologically alter the activity of the subject's particular cranial nerve as compared to the physiological activity of that particular cranial nerve in a subject. not administered with the pharmaceutical composition. In one embodiment, the particular cranial nerve is the trigeminal nerve, the facial nerve, the glossopharyngeal nerve, the accessory nerve, the hypoglossal nerve, the vagus nerve, or a combination thereof.

[0099] Pharmaceutical Compositions.

[00100] The methods of the present disclosure utilize the application of a pharmaceutical composition to the ear canal of the subject in need of such treatment. The ear canal is illustrated in FIG. 7. The pharmaceutical compositions comprise an analgesic and an anesthetic.

[00101] The analgesic present in embodiments of the disclosure are pyrazolone derivatives (C3H4N2O). The molecular structure of 3-pyrazolone is as follows:

[00102] Derivatives of the isomeric form 5-pyrazolone are also covered by the disclosure.

[00103] Particular embodiments of the present methods use antipyrine as the pyrazolone derivative. Antipyrine (C11H12N2O) is also referred to as phenazone. The molecular structure of antipyrine is as follows:

[00104] In one embodiment, the pharmaceutical methods and compositions comprise at least one anesthetic comprising Formula I where R1 comprises: wherein R2 comprises H, CH3, Cl, or wherein R3 comprises H or NH2; where R4 comprises H, NH2, CH3 wherein R5 comprises H; and wherein R6 comprises H or CH3.

[00105] In another embodiment, R1 of Formula I comprises comprises H or CH3; wherein R3 comprises H; wherein R4 comprises H, NH2, wherein R5 comprises H; and wherein R6 comprises H or CH3.

[00106] In one embodiment, the anesthetic comprises or a combination thereof.

[00107] In one embodiment, the anesthetic comprises benzocaine ( ), chloroprocaine ( ), cocaine ( ), cyclomethocaine ( ) dimethocaine ( ; also known as larocaine), piperocaine ( ) propoxycaine ( ), procaine ( also known as novocaine), proparacaine ( ; also referred to as proxymetacaine), tetracaine ( ; also referred to as amethocaine), articaine ( ), bupivacaine ( ), cinchocaine ( ; also referred to as dibucaine), etidocaine ( ), levobupivacaine ( ), lidocaine ( ; also known as lidocaine and xylocaine), mepivacaine ( ), prilocaine ( ), ropivacaine ( ), farmocaine ( ) trimecaine ( ), a combination of the anesthetics listed here, or pharmaceutically acceptable derivatives thereof. In another embodiment, the anesthetic is not benzocaine.

[00108] In one embodiment, the anesthetic is lidocaine.

[00109] In one embodiment, the anesthetic is tetracaine.

[00110] In one embodiment, the anesthetic is tetracaine and lidocaine.

[00111] The anesthetics present in some embodiments of the disclosure are ester-based anesthetics. In a particular embodiment, the anesthetic is benzocaine (C9H11NO2), whose molecular formula is as follows: In another embodiment, the anesthetic is not benzocaine.

[00112] Other modalities of the method use amide-based anesthetics.

[00113] In a preferred embodiment of the present methods, the disclosed pharmaceutical compositions comprise antipyrine as an analgesic and benzocaine as an anesthetic.

[00114] In some embodiments, the disclosed pharmaceutical compositions comprise antipyrine as an analgesic and tetracaine and/or lidocaine as the anesthetic. In some embodiments, the disclosed pharmaceutical compositions comprise tetracaine and lidocaine as the anesthetic.

[00115] In one embodiment, the invention is directed to an optical pharmaceutical composition. In various embodiments, the optical pharmaceutical composition comprises (i) at least one analgesic comprising a pyrazolone derivative, and (ii) at least one anesthetic comprising Formula I: wherein R2 comprises H, CH3, Cl, or wherein R3 comprises H or NH2; wherein R4 comprises H, NH2, CH3, wherein R5 comprises H; and wherein R6 comprises H or CH3, and wherein the analgesic is present in the pharmaceutical composition at a concentration of about 50 to about 60 mg per mL, and wherein the anesthetic is present in the pharmaceutical composition at a concentration of about 10 to about 20 mg per mL.

[00116] In one embodiment, R1 of Formula I comprises wherein R2 comprises H or CH3; wherein R3 comprises H; wherein R4 comprises H, NH2or wherein R5 comprises H; and wherein R6 comprises H or CH3.

[00117] In some embodiments, the optical pharmaceutical composition further comprises an antibiotic, a vasoconstrictor, glycerin, epinephrine, acetic acid or a combination thereof. In some embodiments, the anesthetic comprises lidocaine, tetracaine, benzocaine, or a combination thereof. In some embodiments, the anesthetic is not benzocaine. In other embodiments, the anesthetic comprises lidocaine, tetracaine or a combination thereof.

[00118] In one embodiment, the pyrazolone derivative of the optical pharmaceutical composition comprises ampyrone, dipyrone, antipyrine, aminopyrine or propyphenazone. In some embodiments, the analgesic is antipyrine.

[00119] Pharmaceutical compositions can be formulated in various ways, including, but not limited to the following: solutions, foams, gels, creams, pastes, lotions, emulsions and combinations of the aforementioned.

[00120] Furthermore, the present disclosure contemplates that active ingredients of the pharmaceutical composition, such as antipyrine and benzocaine, can be infused into material that is then placed in a patient's ear canal. For example, cotton gauze material may be composed to contain the present pharmaceutical composition, said gauze providing a convenient application method for exposing the ear canal to the present pharmaceutical composition.

[00121] In one embodiment, an optical pharmaceutical composition is administered to an ear canal of a subject in need of such treatment, wherein the subject is a vertebrate species that includes, but is not limited to, a human, horse, cow, pig, dog, cat, etc. In some embodiments, the optical pharmaceutical composition comprises a topical anesthetic alone or in combination with other topical anesthetics with or without analgesics. In one embodiment, the analgesic is antipyrine. In another embodiment, the anesthetic is at least one selected from the group consisting of benzocaine, formacaine, cocaine and cyclometicaine. In other embodiments, the anesthetic comprises tetracaine and/or lidocaine. In some embodiments, the optical pharmaceutical composition further comprises the presence or absence of epinephrine, suspended in solution of various pharmaceutical carriers. The optical pharmaceutical composition is subsequently administered to the ear canal for the desired effect.

[00122] Anatomical Site of Application of the Pharmaceutical Composition

[00123] The invention provides methods for treating a variety of diseases comprising performing topical auricular anesthesia of the external auditory canal for the purpose of anesthesia of cranial nerves 5, 7, 9, 10, 11 and 12, together with anesthetizing the parasympathetic nervous system and /or the sympathetic nervous system. In one embodiment, the invention provides the treatment of a variety of diseases that comprises performing topical auricular anesthesia of the autonomic nervous system. In one embodiment, auricular anesthesia is performed on the trigeminal nerve (cranial nerve 5), facial nerve (cranial nerve 7), glossopharyngeal nerve (cranial nerve 9), vagus nerve (cranial nerve 10), spinal accessory nerve (cranial nerve 11) , the hypoglossal nerve (cranial nerve 12), or a combination thereof. The invention further provides for the modulation of the general somatic nervous system and the general visceral nervous system by administering an optical pharmaceutical composition comprising one or more anesthetics (such as lidocaine and/or tetracaine) in solution with a pharmaceutical carrier (such as an excipient). glycerin and with or without epinephrine. In some embodiments, the optical pharmaceutical composition further comprises an analgesic, such as a pyrazolone derivative. In some embodiments, the pyrazolone derivative is antipyrene.

[00124] The present method contemplates the application of the disclosed pharmaceutical composition to a patient's ear canal. It has been found that the ear canal serves as a convenient point in the human anatomy to which the present pharmaceutical composition is applied and can interrupt neurological signals along the vagus or other cranial nerves. That is, by placing a pharmaceutical composition, as described herein, in a patient's ear canal, it has been found that the body will absorb the composition and that the vagus nerve or other cranial nerve will be "blocked" such that the normal physiological nerve function will be altered. The present methodology of using the ear canal as a channel to anesthetize the particular nerve does not suffer from the disadvantages present in the prior art.

[00125] The present methods of applying a pharmaceutical composition as described are non-invasive and do not represent the risks associated with surgical procedures. Furthermore, the present methods do not rely on the insertion of artificial devices into the patient's body. It is clear that the present methods represent a significant advance over the state of the art, since the disclosed non-invasive procedure is capable of altering the function of the vagus nerve or other cranial nerve without artificial devices or surgery. The present methods are also cost-effective and therefore provide access to treatment for the vast majority of a population.

[00126] The presently disclosed embodiments of a method of blocking signal transduction in the vagus nerve will now be further elaborated by reference to the following examples. In each of these examples, the disclosed method was able to successfully treat a human disease, or disease, that was associated with a particular cranial nerve. Without being limited by theory, the methods are also useful for treating a disease or illness associated with a particular cranial nerve in a variety of vertebrate species, including but not limited to horses, cows, pigs, dogs, cats, etc. . The conditions treated in the examples disclosed herein were capable of being controlled to a clinically effective degree by the disclosed method of performing auricular anesthesia on the vagus or other cranial nerve, or by performing auricular anesthesia of the autonomic nervous system, i.e., referred to as the "Crews Maneuver". In one embodiment, the disease is a neurology and psychiatry related affliction, an ear-nose-throat (ENT) related affliction, a GU related affliction, a gastrointestinal (GI) related affliction, a heart related affliction, a to lung disease or metabolism-related affliction. In one embodiment, the neurology- and psychiatry-related affliction is at least one selected from the group consisting of: chronic fatigue syndrome, fibromyalgia, epilepsy, Obsessive Compulsive Disorder, panic attack, Post-traumatic Stress Disorder, Tourette's Syndrome, Focal Dystonia, Tic Doloreaux, Bulimia, Anxiety, Depression, Restless Leg Syndrome, Lack of autonomy, Familial Intentional Tremor, Migraine Pain, Autism Spectrum Disorder, Anxiety, Headache, insomnia, Reticular Activating System (RAS) dysregulation ), Multiple Sclerosis, Peripheral Neuropathy, Apraxia, Neck and Shoulder Pain, Parkinson's Disease, General Somatic Afferent Pain, General Visceral, Afferent pain, opioid withdrawal, Dysarthria, ADHD, non-specific hand tremor, Stuttering, Cerebral Palsy , Raynaud's phenomenon and excessive sweating. In one embodiment, General Somatic Afferent Pain comprises Neuromuscular Pain of the neck, back, arms, legs or shoulders; Joint Pain; sciatic pain; Arthritis pain pain; Herpes zoster pain; Reflex Sympathetic Dystrophy Pain; or a combination thereof. In one embodiment, an opioid withdrawal symptom comprises Generalized Pain, Muscle Aches, Nausea, Vomiting, Sweating, Diarrhea or a combination thereof. In one embodiment, the ear-nose-throat (ENT) related affliction is at least one selected from the group consisting of: Palatal Myoclonus, Post Tonsillectomy Pain, Pharyngeal Pain, Laryngeal Pain, Neurogenic Cough, Globus Hystericus, Spasmodic Dysphonia, Snoring, Allergic Rhinitis, Chronic Sinusitis, Chronic Nasal Congestion, Allergic Conjunctivitis, Sneezing, Hiccups, Rhinitis, Tinnitus, Dysphagia, Earache, Neck Pain, Dry Eye Syndrome, Trigeminal Neuralgia Pain and Temporomandibular Joint Pain. In one embodiment, the Gastroenterology/Urology (GU) related affliction is at least one selected from the group consisting of: bladder spasm, dysmenorrhea, pelvic pain, premature birth, interstitial cystitis, prostatitis, eclampsia, pre-eclampsia, HELLP syndrome , cystitis, kidney pain, enuresis, dysuria, dyspareunia, encopresis, menstruation with heavy flow, frequent urination, Prolonged Vaginal Bleeding and decreased renal blood flow. In one embodiment, the gastrointestinal (GI) tract-related affliction is at least one selected from the group consisting of: irritable bowel syndrome (IBS), ulcerative colitis, acid reflux, gastritis, gastroenteritis, hyperemesis gravidarum, pediatric colic, hepatic syndrome -renal, appetite suppression, gallbladder pain, chronic constipation, chronic diarrhea and pancreatitis. In one embodiment, the heart-related affliction is at least one selected from the group consisting of: Paroxysmal (Lone) Atrial Fibrillation (Vagal), Orthostatic (Neurogenic) Hypotension, Reflexive Asystolic Syncope, Postural Orthostatic Tachycardia Syndrome (POTS), Vasovagal Reflex , cough resulting from heart surgery, heart block, Atrial Contractions, Tachycardia and Congestive Heart Failure. In one embodiment, the lung disease-related affliction is at least one selected from the group consisting of: asthma, chronic obstructive pulmonary disease (COPD), bronchitis, cystic fibrosis, and bronchospasm. In one embodiment, the metabolism-related affliction is at least one selected from the group consisting of: hypertension, diabetes, septic shock, neurogenic shock, hyperglycemia, and hypercholesterolemia. ***

[00127] Unless otherwise defined, all technical and scientific terms used in this document have the same meaning as commonly understood by a person skilled in the art to which this invention belongs. Exemplary methods and materials are described below although methods and materials similar or equivalent to those described herein may also be used in practicing or testing the present invention.

[00128] As will be apparent to one skilled in the art from a reading of this disclosure, embodiments of the present disclosure may be embodied in forms other than those specifically disclosed above. The particular embodiments described herein are therefore considered to be illustrative and not restrictive. Those skilled in the art will recognize, or be able to verify, using no more than routine experimentation, that numerous equivalents to the specific embodiments are described herein. The scope of the invention is as set out in the appended claims and their equivalents, rather than being limited to the examples contained in the previous description.

[00129] All publications and other references mentioned herein are incorporated by reference in their entirety, as if each individual publication or reference were specifically and individually indicated to be incorporated by reference. Publications and references cited here are not accepted as prior art.

EXAMPLES

[00130] Examples are provided below to facilitate a more complete understanding of the invention. The following examples illustrate exemplary ways of making and practicing the invention. However, the scope of the invention is not limited to the specific embodiments disclosed in these Examples, which are for illustration purposes only, as alternative methods may be used to obtain similar results.

[00131] Example 1: Treatment of post-tonsillectomy pharyngeal or oropharyngeal pain

[00132] Protocol

[00133] A test of a preferred embodiment of the present method was carried out to evaluate the effectiveness of the method for treating patients suffering from post-tonsillectomy pharyngeal or oropharyngeal pain.

[00134] 500 patients previously undergoing tonsillectomy were instructed to use six drops of a pharmaceutical composition composed of antipyrine («54.0 mg) and benzocaine («14.0 mg), in each ear three times a day, for a period of ten days after tonsillectomy.

[00135] Results

[00136] Of the 500 patients treated, 495 patients reported a significant reduction in pharyngeal and/or oropharyngeal pain.

[00137] Example 2: Treatment of post-adenoidectomy pharyngeal or oropharyngeal pain

[00138] Protocol

[00139] A test of a preferred embodiment of the present method was carried out to evaluate the effectiveness of the method for treating patients suffering from post-adenoidectomy pharyngeal or oropharyngeal pain.

[00140] 200 patients previously undergoing adenoidectomy were instructed to use six drops of a pharmaceutical composition composed of antipyrine («54.0 mg) and benzocaine («14.0mg), in each ear twice a day, for a period of seven days after adenoidectomy.

[00141] Results

[00142] Of the 200 patients treated, 200 patients reported a significant reduction in pharyngeal and/or oropharyngeal pain.

[00143] Example 3: Asthma treatment

[00144] Protocol

[00145] A test of a preferred embodiment of the present method was carried out to evaluate the effectiveness of the method for treating patients suffering from chronic asthma and acute asthmatic attack.

[00146] 10 patients with asthma were instructed to use six drops of a pharmaceutical composition containing antipyrine («54.0 mg) and benzocaine («14.0 mg), in each ear in the morning, for two months.

[00147] A patient suffering from an acute attack of severe asthma was also treated by immediately filling the patient's ear canal with the aforementioned pharmaceutical composition.

[00148] Results

[00149] Of the 10 patients treated, 10 patients reported a significant reduction in asthmatic attacks.

[00150] Furthermore, the patient suffering from the severe asthma attack experienced a dramatic increase in the amount of oxygen reaching his lungs within 60 minutes of treatment.

[00151] Example 4: Treatment of obesity (i.e., a method of appetite suppression)

[00152] Protocol

[00153] A test of a preferred embodiment of the present method was conducted to evaluate the effectiveness of the method for treating patients suffering from obesity.

[00154] 5 overweight patients were instructed to use six drops of a pharmaceutical composition comprising antipyrine («54.0 mg) and benzocaine («14.0 mg), in each ear in the morning, for an indefinite period of time .

[00155] Results

[00156] Of the 5 patients treated, all 5 patients reported a significant reduction in appetite while using the treatment. The significant reduction in appetite led to weight loss.

[00157] Example 5: Treatment of neurogenic cough

[00158] Protocol

[00159] A test of a preferred embodiment of the present method was conducted to evaluate the effectiveness of the method for treating patients suffering from neurogenic cough.

[00160] Four patients suffering from neurogenic cough were instructed to use six drops of a pharmaceutical composition comprising antipyrine (« 54.0 mg) and benzocaine (« 14.0 mg), in each ear twice a day, for a period seven days and only when necessary.

[00161] Results

[00162] Of the 4 patients treated, all 4 patients reported a significant reduction in coughing.

[00163] Example 6: Treatment of Globus Hystericus

[00164] Protocol

[00165] A test of a preferred embodiment of the present method was conducted to evaluate the effectiveness of the method for treating patients suffering from globus hystericus.

[00166] 2 patients suffering from globus hystericus were instructed to use six drops of a pharmaceutical composition comprising antipyrine (« 54.0 mg) and benzocaine (« 14.0 mg), in each ear once a day, for an indefinite period time as needed.

[00167] Results

[00168] Of the two patients treated, all two patients reported significant reduction in throat tightness.

[00169] Example 7: Treatment of spasmodic dysphonia

[00170] Protocol

[00171] A test of a preferred embodiment of the present method was conducted to evaluate the effectiveness of the method for treating patients suffering from spasmodic dysphonia.

[00172] One (1) patient suffering from spasmodic dysphonia was instructed to use six drops of a pharmaceutical composition comprising antipyrine (~54.0 mg) and benzocaine (~14.0 mg), in each ear once a day, over an indefinite period of time as needed.

[00173] Results

[00174] The patient reported a significant reduction in throat hoarseness and vocal cord spasm almost immediately after using the treatment.

[00175] Example 8: Treatment of laryngeal pain

[00176] Protocol

[00177] A test of a preferred embodiment of the present method was conducted to evaluate the effectiveness of the method for treating patients suffering from laryngeal pain.

[00178] 2 patients suffering from laryngeal pain were instructed to use six drops of a pharmaceutical composition comprising antipyrine (« 54.0 mg) and benzocaine (« 14.0 mg), in each ear once a day, for an indefinite period time as needed.

[00179] Results

[00180] Of the two patients treated, all patients reported a significant reduction in laryngeal pain.

[00181] Example 9: Treatment of gastroesophageal reflux disease

[00182] Protocol

[00183] A test of a preferred embodiment of the present method was conducted to evaluate the effectiveness of the method for treating patients suffering from Gastroesophageal Reflux Disease (GERD).

[00184] 2 patients suffering from GERD were instructed to use six drops of a pharmaceutical composition comprising antipyrine (« 54.0 mg) and benzocaine (« 14.0 mg), in each ear once a day, for an indefinite period of time as needed.

[00185] Results

[00186] Of the two patients treated, all two patients reported significant reduction in acid reflux and heartburn.

[00187] The results of the aforementioned clinical experiments can be found below in Table 1.

[00188] Table 1. Clinical Experiments

[00189] Example 10: Treatment of diseases

[00190] Protocol

[00191] A test of an embodiment of the present method was performed to evaluate the effectiveness of the method for treating patients suffering from a disease associated with a particular cranial nerve, wherein the disease is an affliction related to neurology and psychiatry, ear-nose-throat (ENT) related affliction, a Gastroenterology/Urology (GU) related affliction, a gastrointestinal (GI) related affliction, heart related affliction, lung disease related affliction, or metabolism related affliction.

[00192] Patients suffering from neurology and psychiatry related affliction, an ear-nose-throat (ENT) related affliction, a GU related affliction, a gastrointestinal (GI) disease related affliction, a heart related affliction, an affliction related to lung disease or an affliction related to metabolism were instructed to utilize drops of a pharmaceutical composition comprising antipyrine (« 54.0 mg) and benzocaine (« 14.0 mg) (treatment protocol, Tmt Protocol "AB") or drops of a pharmaceutical composition comprising lidocaine («40.0 mg) and tetracaine («5.0 mg) (treatment protocol, LATTmt Protocol), in one or both ears, at least once a day (e.g. morning or evening), for a period of time as needed (Tmt Time). The LAT solution used in the tests includes 4% lidocaine, 0.5% tetracaine, 1/100. 000 of epinephrine and anhydrous glycerin. The AB solution used in the tests comprises 5.4% Antipyrine, 1.4% Benzocaine, Oxyquinoline Sulfate and Anhydrous Glycerin.

[00193] Table 2. Clinical experiences with afflictions related to neurology and psychiatry

[00194] Table 3. Clinical experiments with ear-nose-throat (ENT) related afflictions.

[00195] Table 4. Clinical experiments with gastroenterology/urology (GU)-related conditions

[00196] Table 5. Clinical experiments with afflictions related to gastrointestinal (GI) disease

[00197] Table 6. Clinical experiments with curacao-related afflictions

[00198] Table 6. Clinical experiments with afflictions related to lung disease

[00199] Table 7. Clinical experiments with metabolism-related afflictions

[00200] The diseases that are treatable by the disclosed methodology are numerous. Any disease that is associated with an organ or body tissue that is innervated by the particular nerve could potentially be treated by current methods. Particular mention of the following diseases treatable by current methods is made: asthma, neurogenic cough, globus hystericus, spasmodic dysphonia, gastroesophageal reflux disease and obesity. The present methods are also suitable for the treatment of post-tonsillectomy or post-adenoidectomy pharyngeal pain, or oropharyngeal pain.

[00201] In still other modalities, diseases treatable by the disclosed methodology include, but are not limited to: heart disease, paroxysmal (solitary) atrial fibrillation (vagal), reflex systolic syncope, postural orthostatic tachycardia syndrome (POTS), excessive craving for vomiting, esophageal dysphagia, vomiting, nausea, odynophagia, esophageal pain, esophageal neuralgia, gastritis, dyspepsia, gallbladder disease, cholecystitis pain, abdominal pain, esophageal motility disorder or esophageal dysmotility, spastic colon, pancreas pain or spasms, pediatric colic, rectal spasms and pain, bladder spasm (overactive bladder), interstitial cystitis, dysmenorrhea, preterm labor, pelvic pain, chronic pelvic pain, chronic prostatitis pain, eclampsia, preeclampsia, HELLP syndrome, cystitis pain , irritable bowel syndrome, Cohn's disease, ulcerative colitis, reflux disease, gastritis, gastroenteritis symptoms, hyperemesis gravidarum, pediatric colic, hepatorenal syndrome, appetite suppression, gallbladder pain, inflammation of the esophagus, inflammation of the stomach, inflammation of the colon, (pain from kidney stone, infection or tumor), enuresis, dysuria, dyspareunia, encopresis, periods of heavy flow, frequent urination, prolonged vaginal bleeding, inhibited erections, prevention of premature ejaculation, inhibit excessive sweating, spasms ureteral, menstrual cramps, uterine spasms, ovarian pain and spasms, fallopian pain and spasms, pediatric asthma, adult asthma, chronic obstructive pulmonary disease (COPD), mucus in the bronchi, acute bronchitis, asthmatic bronchitis, chronic bronchitis, bronchospasm, fibrosis cystic, lung inflammation, emphysema, pleuritic chest pain, intercostal muscle pain, nerve pain, bronchospasm secondary to intubation and extubation, angina pectoris, cardiac vagal block, vasovagal reflex block, bradycardia, hypotension, orthostatic hypotension, hypertension, diabetes , shock, septic shock, reduction in blood sugar, inflammation of the pancreas, syncope secondary to vagal or cardiac reasons, vasovagal syncope, bradyarrhythmias, vasodilation of the skin, neuralgia, laryngospasm, acute laryngitis, pain in the larynx, post-extubation and intubation laryngospasms, palatal myoclonus, post-tonsillectomy pain, snoring, allergic rhinitis, vasomotor rhinitis, inflammatory polyposis (nasal), chronic sinusitis, chronic nasal congestion, allergic conjunctivitis, sneezing, hiccups, rhinitis, tinnitus, dysphagia, croup, chronic fatigue syndrome, fibromyalgia (chronic), epilepsy, obsessive compulsive disorder, panic attacks, post-traumatic stress disorder, Tourette syndrome, focal dystonia, tic pain, bulimia, anxiety, depression, restless legs syndrome, dysautonomia, familial intentional tremor, migraine, autism spectrum, anxiety, headaches, insomnia, multiple sclerosis, reticular activating system modulation, peripheral neuropathy, apraxia, neck and shoulder pain, and Parkinson's disease.

[00202] In particular, improvement was reported in more than half of the patients treated in accordance with the above methods, where there were a minimum of 5 patients treated for symptoms or conditions associated with the following diseases or disorders, vasovagal reflex blockade, bronchitis chronic, asthmatic bronchitis, hypotension, hypertension, diabetes, bladder spasm, dysmenorrhea, pelvic pain, cystitis pain, enuresis, dysuria, dyspareunia, periods of heavy menstrual flow, frequent urination, spasmodic dysphonia, snoring, allergic rhinitis, vasomotor rhinitis, chronic sinusitis, chronic nasal congestion, allergic conjunctivitis, sneezing, hiccups, rhinitis, dysphagia, irritable bowel syndrome, gastritis, appetite suppression, chronic fatigue syndrome, fibromyalgia, anxiety, depression, restless legs syndrome, familial intentional tremor, migraines , autism spectrum, anxiety headaches, insomnia, sleep disorders, apraxia, and neck and shoulder pain. Similar positive results (i.e., positive results reported for all or more than half of all treated patients) have also been observed with other listed diseases or related diseases.

[00203] Although methods for treating various diseases associated with the vagus nerve and other cranial nerves have been described in the application in relation to various modalities, the scope of the methods is not intended to be limited to the particular modalities so disclosed. But, rather, the methods are intended to cover such alternatives, modifications and equivalents as may be included within the scope and spirit of the claims below.

EQUIVALENTS

[00204] Those skilled in the art will recognize, or be able to verify, using no more than routine experimentation, numerous equivalents to the specific substances and procedures described herein. Such equivalents are considered within the scope of this invention, and are covered by the following claims.

Claims (2)

1. OPTICAL PHARMACEUTICAL COMPOSITION, characterized by comprising an anesthetic lidocaine and tetracaine; wherein the anesthetic lidocaine and tetracaine is present in the pharmaceutical composition at a concentration of 2 to 20 mg per mL; wherein said optical pharmaceutical composition is a solution or a foam; wherein said optical pharmaceutical composition is intended to treat post-tonsillectomy pharyngeal or oropharyngeal pain, post-adenoidectomy pharyngeal or oropharyngeal pain, asthma, obesity, neurogenic cough, globus hystericus, spasmodic dysphonia, laryngeal pain, gastroesophageal reflux disease, chronic fatigue, fibromyalgia, epilepsy, Obsessive Compulsive Disorder, panic attack, Post-traumatic Stress Disorder, Tourette's Syndrome, Focal Dystonia, Tic Doloreaux, Bulimia, Anxiety, Depression, Restless Legs Syndrome, Lack of autonomy, Familial Intentional Tremor , Migraine Pain, Autism Spectrum Disorder, Anxiety, Headache, insomnia, Reticular Activating System (RAS) dysregulation, Multiple Sclerosis, Peripheral Neuropathy, Apraxia, Neck and Shoulder Pain, Parkinson's Disease, Somatic Afferent Pain General, General Visceral, Afferent pain, opioid withdrawal, Dysarthria, ADHD, non-specific hand tremor, Stuttering, Cerebral Palsy, Raynaud's phenomenon and excessive sweating, Palatal Myoclonus, Post Tonsillectomy Pain, Pharyngeal Pain, Laryngeal Pain, Neurogenic Cough, Globus Hystericus, Spasmodic Dysphonia, Snoring, Allergic Rhinitis, Chronic Sinusitis, Chronic Nasal Congestion, Allergic Conjunctivitis, Sneezing, Hiccups, Rhinitis, Tinnitus, Dysphagia, Earache, Neck Pain, Dry Eye Syndrome, Trigeminal Neuralgia Pain and Pain in Temporomandibular Joint, bladder spasm, dysmenorrhea, pelvic pain, premature birth, interstitial cystitis, prostatitis, eclampsia, pre-eclampsia, HELLP syndrome, cystitis, kidney pain, enuresis, dysuria, dyspareunia, encopresis, heavy flow menstruation, frequent urination , Prolonged Vaginal Bleeding, decreased renal blood flow, irritable bowel syndrome (IBS), ulcerative colitis, acid reflux, gastritis, gastroenteritis, hyperemesis gravidarum, pediatric colic, hepatorenal syndrome, appetite suppression, gallbladder pain, chronic constipation, chronic diarrhea, pancreatitis, Paroxysmal (Lone) Atrial Fibrillation (Vagal), Orthostatic (Neurogenic) Hypotension, Reflexive Asystolic Syncope, Postural Orthostatic Tachycardia Syndrome (POTS), Vasovagal Reflex, cough from cardiac surgery, heart block, Atrial Contractions, Tachycardia , Congestive Heart Failure, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, cystic fibrosis, bronchospasm, or hypertension, diabetes, septic shock, neurogenic shock, hyperglycemia and hypercholesterolemia, and wherein said pharmaceutical composition does not comprise an analgesic. 2. COMPOSITION, according to claim 1, characterized by further comprising an antibiotic, a vasoconstrictor, glycerin, epinephrine, acetic acid or a combination thereof.