WO2021003393A1 - Méthode, composition et appareil de traitement des maux de tête - Google Patents

Méthode, composition et appareil de traitement des maux de tête Download PDF

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Publication number
WO2021003393A1
WO2021003393A1 PCT/US2020/040700 US2020040700W WO2021003393A1 WO 2021003393 A1 WO2021003393 A1 WO 2021003393A1 US 2020040700 W US2020040700 W US 2020040700W WO 2021003393 A1 WO2021003393 A1 WO 2021003393A1
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WIPO (PCT)
Prior art keywords
patient
pressure
cavity
headache
eye
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PCT/US2020/040700
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English (en)
Inventor
John Berdahl
Gary BERMAN
Enrico Brambilla
Original Assignee
Equinox Ophthalmic, Inc.
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Publication date
Priority claimed from PCT/US2019/055515 external-priority patent/WO2020077032A1/fr
Application filed by Equinox Ophthalmic, Inc. filed Critical Equinox Ophthalmic, Inc.
Publication of WO2021003393A1 publication Critical patent/WO2021003393A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
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    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
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    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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    • A61K31/4704—2-Quinolinones, e.g. carbostyril
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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Definitions

  • Headache is a multi-factorial condition that afflicts millions of patients worldwide.
  • Existing treatments for headache are primarily pharmacologic in nature, but these treatments are not appropriate for all patients and can have various disadvantages and side-effects.
  • patients find that therapeutically effective dosages can result in unexpectable drowsiness, fatigue, weight gain, dry mouth, depressing or cognitive effects— even at minimum effective dosages.
  • commonly utilized headache medication is contraindicated.
  • triptans may not be suitable for patients with cerebrovascular or cardiovascular disease
  • serotonin antagonists like pizotifen can be contraindicated in patients with glaucoma
  • ergotamines can be contraindicated in pregnancy
  • amitriptyline and topiramate can be contraindicated in patients with glaucoma
  • antiemetics can cause akathisia and dystonia.
  • headaches There is a need for additional treatments for headaches.
  • Liu U.S. Patent No. 7,122,013 mentions a device for massaging eyes.
  • Lin U.S. Patent No. 7,637,878 mentions an eye massaging device.
  • Lin U.S. Publication No. 20180042805 mentions an eye massager to massage acupuncture points.
  • the present disclosure relates, among other things, to methods, drug compositions, devices, and systems for treating, inhibiting, or preventing headaches by adjusting a physiological parameter of the eye.
  • the present disclosure relates to a method of treating, inhibiting, or preventing headache by use of a drug composition, a device, a physical manipulation, or a combination thereof, that modifies a physiological parameter of the eye, which can include intraocular pressure (IOP), cerebrospinal fluid pressure (CSFP), translaminar pressure difference (TPD), aqueous humor production, aqueous humor outflow, or any combination thereof.
  • IOP intraocular pressure
  • CSFP cerebrospinal fluid pressure
  • TPD translaminar pressure difference
  • aqueous humor production aqueous humor outflow, or any combination thereof.
  • the one or more drugs can be other than vitamins, vitamin A, a B vitamin, vitamin C, vitamin D, vitamin E, beta- carotene, zinc, lutein, folate, a therapeutic gas, carbon dioxide (CO2), oxygen (O2), nitric oxide (NO), ozone (O3) , nitrogen (N), helium (He), hydrocarbons, fluorocarbons, perfluorocarbons, sulfur hexafluoride, cannabinoids, tetrahydrocannabinol (THC), and cannabidiol (CBD).
  • CO2 carbon dioxide
  • O2 oxygen
  • NO nitric oxide
  • O3 ozone
  • nitrogen (N) nitrogen
  • He helium
  • hydrocarbons fluorocarbons, perfluorocarbons, sulfur hexafluoride
  • cannabinoids tetrahydrocannabinol (THC), and cannabidiol (CBD).
  • the present disclosure provides a method of treating headache in a patient suffering therefrom, the method involving, in any order or
  • a pharmaceutical composition comprising one or more drug in an amount effective to modulate a physiologic characteristic of the patient eye, and applying an apparatus over the patient eye to provide a cavity and adjusting pressure in the cavity to a target cavity pressure.
  • the present disclosure also provides a method of treating headache in a patient suffering therefrom, the method involving, in any order or
  • a pharmaceutical composition comprising one or more drug to modulate a physiologic characteristic of the eye, performing a physical manipulation to modulate a physiologic characteristic of the eye, or both; and applying an apparatus over the patient eye to provide a cavity and adjusting the pressure in the cavity to a target cavity pressure to apply force on the patient.
  • the present disclosure further provides a method of treating headache in a patient suffering therefrom, the method involving, administering a pharmaceutical composition comprising one or more drug that modulates aqueous humor production, aqueous humor outflow, intraocular pressure (IOP), translaminar pressure difference (TPD), or any combination thereof, in an amount effective to treat headache.
  • a pharmaceutical composition comprising one or more drug that modulates aqueous humor production, aqueous humor outflow, intraocular pressure (IOP), translaminar pressure difference (TPD), or any combination thereof, in an amount effective to treat headache.
  • the present disclosure yet further provides a method of treating headache in a patient suffering therefrom, the method involving adjusting a physiologic characteristic of the eye to provide an intraocular pressure (IOP) at a target headache relief IOP (THR-IOP) level in the patient, or to provide a translaminar pressure difference (TPD) at a target headache relief TPD (THF- TPD) level, or both.
  • IOP intraocular pressure
  • TPD translaminar pressure difference
  • the patient suffers from headache, but does not suffer from glaucoma or a symptom attributed to glaucoma.
  • the pharmaceutical composition is administered in an amount that is below the minimum therapeutically-effective dosage for treating symptoms other than headache, below the minimum therapeutically-effective dosage for treating symptoms of an ophthalmic disorder, below the minimum therapeutically- effective dosage for treating headache absent applying the presently described device, below the minimum therapeutically-effective dosage for treating glaucoma absent applying the presently described device, or any combination thereof.
  • the present disclosure provides a pharmaceutical composition for use in treating headache in a patient suffering therefrom.
  • the pharmaceutical composition can contain one or more drug that modulate a physiologic characteristic of the patient eye, for example a drug that modulates aqueous humor production, aqueous humor outflow, intraocular pressure (I OP), translaminar pressure difference (TPD), or any combination thereof.
  • I OP intraocular pressure
  • TPD translaminar pressure difference
  • the present disclosure provides a device involving a covering that is sized and shaped to fit over a patient eye to provide a cavity between the cover and the patient.
  • the cavity can retain a non-ambient cavity pressure.
  • the cavity can be pressurized to provide an external force against a portion of the patient, such as one or more patient eye, a facial nerve, or a cranial nerve.
  • Headache can be treated by use of the presently described device to modify eye physiology, by use of drugs that modify eye physiology, or by concomitant use of both together.
  • Combined use of drug composition and device permits adjustment of physiological parameters of the eye that cannot be achieved by use of either drug or device, alone.
  • combined use of drug composition and device permits use of active components at lower dosages and frequency.
  • combined use of the drug composition and device can treat headache in a patient at subtherapeutic amounts, i.e., use of the drug components at amounts below labeled amounts indicated on existing drug labels for beating headache or other diseases.
  • the use of the drug composition, or combination of drug composition and device involves use of active components not previously described for beating headache.
  • the present disclosure represents a surprising new use of various drugs and drug classes for treating headache.
  • FIG. 1 shows a first example method to relieve headache, or a symptom arising therefrom.
  • FIG. 2 shows a second example method to relieve headache, or a symptom arising therefrom.
  • FIG. 3 shows a third example method to relieve headache, or a symptom arising therefrom.
  • FIG. 4 shows a fourth example method to affect a change in a headache, such a change in a headache symptom.
  • FIG. 5 shows an example of an apparatus to conbol an environment over a patient eye.
  • FIG. 6 shows an illustration of acupressure points on facial tissue.
  • FIG. 7A and 7B show an example of a protuberance and a recess located on the patient interface surface.
  • FIG. 8 shows an example of the cover including an anterior plate.
  • FIG. 9 shows an example of the cover including a posterior plate.
  • FIG. 10 shows an illustration of posterior acupressure points on a patient.
  • FIG. 11 shows an example of an apparatus that can control an eye environment over a patient eye, such as at least one of a left eye environment over the left patient eye or a right eye environment over the right patient eye.
  • FIG. 12 shows an example of an apparatus that can independently control a left eye environment over a left eye of a patient and a right eye environment over a right eye of the patient, such as with a single pressure source.
  • FIG. 13 shows an example method for using the apparatus to adjust patient perception of an indication of a headache symptom.
  • FIG. 14 shows an example block diagram of an example computing machine that can be used as control circuitry.
  • the present disclosure provides a method a method of treating, inhibiting, or preventing headache by use of a drug composition, a device, a physical manipulation, or any combination thereof, by adjusting a physiological parameter of the eye.
  • the method can involve use of one or more of drug composition, a device, or a physical manipulation that modifies a physiological parameter of the eye, such as intraocular pressure (IOP), cerebrospinal fluid pressure (CSFP), translaminar pressure difference (TPD), aqueous humor production, aqueous humor outflow, or any combination thereof.
  • IOP intraocular pressure
  • CSFP cerebrospinal fluid pressure
  • TPD translaminar pressure difference
  • aqueous humor production e.g., by applying pressure with the hands, or surgically manipulating the eye of the patient.
  • Physical manipulation does not refer to modulation of the eye by use of a drug composition or the presently described device.
  • the method can relate to use of a combination of two or more of drug composition, a device, or a physical manipulation that modifies a physiological parameter of the eye, which, taken together, are sufficient to treat headache in the patient.
  • the method can involve contemporaneously administering a pharmaceutical composition comprising one or more drug to modulate a physiologic characteristic of the eye, performing a physical manipulation to modulate a physiologic characteristic of the eye, applying an apparatus over the patient eye to provide a cavity and adjusting the pressure in the cavity to a target cavity pressure to apply force on the patient, or any combination thereof.
  • the method can relate to use of a combination of drug composition, device, and physical manipulation, which, taken together, are sufficient to treat the headache.
  • the method can involve, in any order or simultaneously, administering a pharmaceutical composition comprising one or more drug in an amount effective to modulate a physiologic characteristic of the patient eye, and applying an apparatus over the patient eye to provide a cavity and adjusting pressure in the cavity to a target cavity pressure.
  • Treating the patient can also involve one or more of administering the presently described pharmaceutical composition, applying the presently described apparatus, or physically manipulating the eye.
  • the present disclosure provides a method of treating, inhibiting, or preventing headache in a patient suffering therefrom, involving adjusting a physiologic characteristic of the eye to provide an intraocular pressure (IOP) at a target headache relief IOP (THR-IOP) level in the patient, or to provide a translaminar pressure difference (TPD) at a target headache relief TPD (THF-TPD) level, or both.
  • IOP intraocular pressure
  • TPD translaminar pressure difference
  • the present disclosure provides a method of treating, inhibiting, or preventing headache by administering a pharmaceutical composition comprising one or more drug that modulates aqueous humor production, aqueous humor outflow, intraocular pressure (IOP), translaminar pressure difference (TPD), or any combination thereof, in an amount effective to treat headache.
  • a pharmaceutical composition comprising one or more drug that modulates aqueous humor production, aqueous humor outflow, intraocular pressure (IOP), translaminar pressure difference (TPD), or any combination thereof, in an amount effective to treat headache.
  • IOP intraocular pressure
  • TPD translaminar pressure difference
  • the patient does not suffer from a symptom of glaucoma, or the pharmaceutical composition is administered in an amount that is below the minimum therapeutically-effective dosage for treating symptoms other than headache.
  • compositions, physical manipulations, apparatus, device, and systems described herein can be provided to a patient suffering from headache, to relieve headache or a symptom arising therefrom.
  • a headache can be caused by one or more pathophysiologies and can include primary headaches, such as a migraine headache, a sinus headache, a tension headache, a cluster headache, an exertional headache, a hypnic headache, and secondary headaches, such as a headache due to overuse of medication, a sinus headache, a caffeine-related headache, a head-injury headache, a menstrual headache, and a hangover headache.
  • a headache symptom can include patient perception or a physical manifestation of a headache, such as including pain, nausea, vomiting, dizziness, vertigo, fatigue, blurred vision, sensitivity to radiation including radiation that cause manifestation of temperature, sound and light, and visual disturbances including an aura.
  • Headache can be described as pain perceived in at least one of the head or neck region of an individual which can be caused by a variety of conditions and triggering stimuli.
  • a primary goal of headache care can be adjustment or relief of an indication of a headache symptom as perceived by a patient.
  • a headache can include at least one of an acute headache condition, such as a headache that can persist for a period of time measured in seconds, minutes, or days, or a chronic headache condition, such as a headache that can persist for a period of time measured in days, weeks, months, or years.
  • headache can be a diagnosis of exclusion, in that it refers to an episode of perceived pain in at least one of the head or neck region that is not attributed to a non-headache disease, trauma, or disorder.
  • headache can refer to pain perceived in at least one of the head or neck region not primarily attributed to a non-headache disease, injury, or disorder, together with the presence of an additional symptom of headache.
  • Adjustment of the indication of a headache symptom can include relief from the headache symptom, such as a reduction in pain perceived by the patient due to the headache condition.
  • headache can refer to primary headaches, secondary headaches, migraine, tension-type headache, trigeminal autonomic cephalalgias, and subsets thereof, as defined in The International Classification of Headache Disorders, 3rd edition, Headache Classification Committee of the International Headache Society (IHS), Cephalalgia 2018, Vol. 38(1) 1-211, which is hereby incorporated by reference herewith in its entirety.
  • IHS International Headache Society
  • Examples of primary headache can include migraines, tension-type headache, trigeminal autonomic cephalalgias, thunderclap headache, or any combination thereof.
  • a secondary headache can refer to a headache that occurs for the first time in close temporal relation to another disorder known to cause headache, or fulfils other criteria for causation by that disorder, the new headache is coded as a secondary headache attributed to the causative disorder.
  • secondary headache can include headache attributed to trauma or injury to the head or neck, headache attributed to cranial or cervical vascular disorder, headache attributed to non-vascular cranial disorder, headache attributed to substance withdrawal, headache attributed to infection, headache attributed to disorder of homeostasis, headache attributed to disorder of facial, cranial, or cervical structure, headache attributed to psychiatric disorder, or any combination thereof.
  • a symptom of headache is a symptom which arises from headache, and is not better accounted for by another diagnosis, or better attributed to a non headache causative disorder or disease.
  • a symptom of a secondary headache can be distinguished from a non-headache symptom, when a non-headache symptom when the criteria of a headache is not met.
  • Various criteria of headache are set forth in The International Classification of Headache Disorders, 3rd edition, Headache Classification Committee of the International Headache Society (IHS), Cephalalgia 2018, Vol. 38(1) 1-211, which is hereby incorporated by reference herewith in its entirety.
  • a patient that has suffered trauma to the head can experience head pain, where the pain arises from trauma rather than headache, the pain is a non-headache symptom.
  • pain might be a symptom of the secondary headaches. That is, a symptom of headache is causally linked to the headache.
  • the symptom of headaches can include pain, nausea, photophobia, and phonophobia, or a combination thereof.
  • patients are asked to identify their most bothersome symptom of headache (MBS) in addition to pain. The identification can take place either before the attack is treated (e.g., at the baseline visit), or at the time of the attack, but before administration of the drug.
  • Various treatments described herein can treat relieve the patient of headache pain at 2 hours after treatment, can have alleviate a patient’s most bothersome symptom, or both.
  • the patient is relieved of headache pain and receives a meaningful benefit with respect to second symptom of headache.
  • the symptom can be the patient’s most bothersome symptom of headache in addition to pain.
  • Headache pain and associated symptoms can be measured by asking patients to self-report the current status of their headache pain and associated symptoms.
  • a binary scale present or absent can be used for pain or other associated symptoms.
  • the patient suffering from headache can have a diagnosis of headache.
  • the patient suffering from headache can have a diagnosis of migraine, tension headaches, or both.
  • the patient suffering from headache can have a diagnosis of migraine without aura, migraine with aura, cluster headache, frequent episodic tension-type headache, chronic tension-type headache, cervicogenic headache, or a combination thereof.
  • the patient suffering from headache can be suffering from primary headache, secondary headache, or both.
  • the patient suffering from headache can be suffering from migraine without aura (MO).
  • a patient is suffering from migraine without aura (MO) if the patient has met the following criteria: at least five headache attacks lasting 4 - 72 hours (untreated or unsuccessfully treated), which has at least two of the four following characteristics: (1) Unilateral location, (2) Pulsating quality, (3) Moderate or severe intensity (inhibits or prohibits daily activities), or (4) Aggravated by walking stairs or similar routine physical activity.
  • the patient suffering from migraine without aura (MO) has experienced, during headache, at least one of the two following symptoms: (1) Phonophobia and photophobia, and (2) Nausea and/or vomiting.
  • the patient suffering from headache can be suffering from migraine with aura (MA).
  • a patient is suffering from migraine without aura (MO) if the patient has met the following criteria: (A) at least two attacks fulfilling criteria B and C; (B) One or more of the following fully reversible aura symptoms: (1) Visual, (2) Sensory, (3) speech and/or language, (4) Motor, (5) Brainstem, or (6) Retinal; (C) at least three of the following six characteristics: (1) at least one aura symptom spreads gradually over a period greater than or equal to 5 minutes, (2) two or more aura symptoms occur in succession, (3) each individual aura symptom lasts 5-60 minutes, (4) at least one aura symptom is unilateral, (5) at least one aura symptom is positive, (6) the aura is accompanied, or followed within 60 minutes, by headache.
  • the patient suffering from headache can be suffering from cluster headache.
  • a patient is suffering from cluster headache if the patient has met the following criteria: (A) at least five attacks fulfilling criteria B-D, (B) severe or very severe unilateral orbital, supraorbital and/or temporal pain lasting 15-180 minutes (when untreated), (C) Either or both of the following: (1) at least one of the following symptoms or signs, ipsilateral to the headache: a) conjunctival injection and/or lacrimation b) nasal congestion and/or rhinorrhoea c) eyelid oedema d) forehead and facial sweating e) miosis and/or ptosis, or (2) a sense of restlessness or agitation; and (D) occurring with a frequency between one every other day and eight per day.
  • the patient suffering from headache can be suffering from infrequent episodic tension-type headache.
  • a patient is suffering from infrequent episodic tension-type headache if the patient has met the following criteria: (A) at least 10 episodes of headache occurring on ⁇ 1 day/month on average ( ⁇ 12 days/year) and fulfilling criteria (B)-(D); (B) lasting from 30 minutes to seven days; (C) at least two of the following four characteristics: (1) bilateral location, (2) pressing or tightening (non-pulsating) quality, (3) mild or moderate intensity, or (4) not aggravated by routine physical activity such as walking or climbing stairs; and (D) both of the following: (1) no nausea or vomiting, or (2) no more than one of photophobia or phonophobia.
  • the patient suffering from headache can be suffering from frequent episodic tension-type headache.
  • a patient is suffering from frequent episodic tension-type headache if the patient has met the following criteria: (A) at least 10 episodes of headache occurring on 1-14 days/month on average for >3 months (greater than or equal to 12 and less than 180 days/year) and fulfilling criteria B- D; (B) lasting from 30 minutes to seven days; (C) at least two of the following four characteristics: (1) bilateral location, (2) pressing or tightening (non pulsating) quality, (3) mild or moderate intensity, or (4) not aggravated by routine physical activity such as walking or climbing stairs; and (D) both of the following: (1) no nausea or vomiting, or (2) no more than one of photophobia or phonophobia.
  • the patient suffering from headache can be suffering from chronic tension-type headache.
  • a patient is suffering from chronic tension-type headache if the patient has met the following criteria: (A) headache occurring on 15 days/month on average for >3 months (greater than or equal to 180 days/year), fulfilling criteria B-D, (B) lasting hours to days, or unremitting, (C) at least two of the following four characteristics: (1) bilateral location, (2) pressing or tightening (non-pulsating) quality, (3) mild or moderate intensity, or (4) not aggravated by routine physical activity such as walking or climbing stairs, and (D) both of the following: (1) no more than one of photophobia, phonophobia or mild nausea, or (2) neither moderate or severe nausea nor vomiting.
  • the patient suffering from headache can be suffering from cervicogenic headache.
  • a patient is suffering from cervicogenic headache if the patient has experienced pain localized to the neck and occipital region, which may project to forehead, orbital region, temples, vertex or ears; and the pain is precipitated or aggravated by special neck movements or sustained postures; and, additionally, at least one of the following: 1. Resistance to or limitation of passive neck movements; 2. Changes in neck muscle contour, texture, tone or response to active and passive stretching and contraction; 3. Abnormal tenderness of neck muscles; and, further, radiological examination has revealed at least one of the following: 1. Movement abnormalities in flexion/extension; 2. Abnormal posture; and 3.
  • the presently described treatment can involve treating a patient that is actively suffering from one or more primary headache or secondary headache, or the patient has recurring headaches, or both.
  • the treated patient suffering from headache can be suffering from one or more of an active headache episode, imminently suffering from headache, a headache earlier in the day, recurring headache, chronic headache, have an expectation or likelihood of experiencing a future headache, or may have experienced a headache within the past 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 24 hours,
  • the patient may have experienced a headache within the past month and also experienced a headache earlier in the same day as the treatment.
  • the patient suffering from headache can be a human patient.
  • the presently described subject matter can treat, alleviate, or relieve headache in the patient suffering therefrom.
  • relief of headache or a symptom of headache can include the patient has“no headache pain” at various time points following treatment.
  • Treating” a symptom or disease can refer to alleviating or eliminating that symptom or disease in a patient.“Alleviating” a symptom, can refer to reducing the severity of the symptom, or the frequency with which such a symptom is experienced by a subject, or both.
  • the subject matter of the present disclosure can involve alleviating a symptom of headache.
  • “Alleviating” a disease can refer to reducing the severity at which the subject suffers from the disease, or the frequency which the subject suffers from the disease, or both. Severity can include duration of the disease or symptom.
  • Severity can also refer to related disease classifications that have differing severity. For example, moderate vs severe glaucoma.
  • Preventing a symptom or disease can refer to one or more of reducing the risk of the symptom or disease occurring, or recurring; stopping an expected symptom or disease from occurring, or recurring; or taking advance measures against a probable symptom or disease. Preventing can refer to taking action to decrease the chance of a patient becoming afflicted with a symptom or disease.
  • a “preventive” or “prophylactic” treatment can refer to a treatment administered to a subject who does not exhibit signs, or exhibits only early signs, of a disease or disorder.
  • the subject matter described herein can be prophylactic or non prophylactic.
  • a prophylactic or preventative treatment is administered for the purpose of decreasing the risk of developing pathology associated with developing the disease or disorder.
  • the patient suffers from headache, but does not suffer from glaucoma or a symptom attributed to glaucoma.
  • the pharmaceutical composition is administered in an amount that is below the minimum therapeutically-effective dosage for treating symptoms other than headache, below the minimum therapeutically-effective dosage for treating symptoms of an ophthalmic disorder, below the minimum therapeutically- effective dosage for treating headache absent applying the presently described device, below the minimum therapeutically-effective dosage for treating glaucoma absent applying the presently described device, or any combination thereof.
  • the patient can also be suffering from various other diseases or disorders, e.g., an ophthalmic disease or disorder, such as glaucoma.
  • an ophthalmic disease or disorder such as glaucoma.
  • the patient suffering from headache is not suffering from an ophthalmic disease or disorder.
  • the patient is not suffering from: elevated intraocular pressure associated with open-angle glaucoma or ocular hypertension; open-angle glaucoma; ocular hypertension; acute angle-closure glaucoma; postoperative elevated IOP; amblyopia; non- uveitic secondary types of glaucoma; and inflammation of the eye.
  • the patient suffering from headache is not suffering from an ophthalmic disease or disorder, or a surgical patient, in need of induction of miosis, cycloplegia, or reduction of intraocular pressure.
  • the patient suffering from headache is not suffering from one or more of reactive airway disease, chest pain, coronary heart disease, high blood pressure, myocardial infarction, ataxia, Alzheimer’s disease, chronic stable angina, centrencephalic epilepsies, drug-induced edema, congestive heart failure, primary hypokalemic periodic, primary hyperkalemic periodic, low blood pressure,
  • the patient suffering from headache is not diagnosed with glaucoma, ocular hypertension, open angle glaucoma, angle closure glaucoma, or a related disease or disorder.
  • Open-angle glaucoma primary is a chronic, progressive disease that most often presents with characteristic optic nerve (ON) damage, retinal nerve fiber layer (NFL) defects, and subsequent visual field (VF) loss.
  • OAG occurs primarily in adults and is generally bilateral, but not always symmetrical, in its presentation.
  • IOP intraocular pressure
  • 21 mm Hg is considered the upper limit of statistically normal IOP
  • at least one-sixth of patients with open angle glaucoma have IOP levels below 21 mm Hg, which is considered statistically normal in the 95th percentile range.
  • some whose IOP levels are statistically abnormal have no evidence of ON damage or loss of vision function, a condition known as ocular hypertension (OH).
  • Open-angle glaucoma in which the IOP is below a certain level, typically 21 mm Hg is known as normal tension glaucoma (NTG). Historically, this has also been referred to as "low tension glaucoma" (LTG).
  • Open-angle glaucoma can also be secondary, e.g., caused by any of a variety of substances that mechanically block the outflow of aqueous through the trabecular meshwork, resulting in elevated IOP. These substances include pigment, exfoliation material, and red blood cells. Secondary open-angle glaucoma can also result from alterations in the structure and function of the trabecular meshwork, due to insults such as trauma, inflammation, and ischemia. Angle-closure glaucoma is a form of glaucoma characterized by narrowing or closure of the anterior chamber angle. The normal anterior chamber angle provides drainage for the aqueous humor, the fluid that fills the eyeball.
  • Patient selection can include a patient contacting a medical professional, such the patient can initiate contact with a medical professional to engage in at least one of the screening, diagnosis, or treatment of a headache.
  • selection can include a medical professional identifying a patient, such as the patient can be contacted or otherwise invited by the medical professional to engage in at least one of the screening, diagnosis, or treatment of a headache.
  • Identification by a medical professional can include identification based upon a screening criterion, such as a criterion to identify an“at-risk” patient from a population for examination by the medical professional.
  • a screening criterion can include a patient screening criterion (or criterion particular to an individual patient), such as a physiological parameter of the patient including age, body weight, stress level, or a genetic marker.
  • a screening criterion can include an environmental screening criterion (or criterion particular to a patient’s living environment), such as residence location of the patient, patient vocation, or potential exposure to a substance identified with initiation of a headache.
  • the present disclosure provides a method of treating headache in a patient suffering therefrom, the method involving adjusting a physiologic characteristic of the eye, for example by providing an intraocular pressure (IOP) at a target headache relief IOP (THR-IOP) level in the patient, or to provide a translaminar pressure difference (TPD) at a target headache relief TPD (THF- TPD) level, or both.
  • IOP intraocular pressure
  • TPD translaminar pressure difference
  • various aspects of the methods, drug compositions, devices, and systems described herein can treat headache by adjusting a physiologic characteristic of one or more of a patient’s eyes.
  • the physiologic characteristic of the patient’s eye can be quantitatively or qualitatively evaluated before treatment, during treatment, after treatment, or any combination thereof.
  • therapeutic effect can thus be controlled by the practitioner, or patient, administering the treatment based on a non-subjective physiologic response.
  • the therapeutic action is determined based on the patient’ s perception of relief from headache or a symptom arising therefrom.
  • the physiologic characteristic of the eye can be intraocular pressure (IOP), aqueous humor production, aqueous humor outflow, cerebrospinal fluid pressure (CSFP) in the retrobulbar space of the patient eye, translaminar pressure difference (TPD) across the lamina cribrosa of the patient eye, blood flow to the eye, nerve access to the eye, pupil size, size of ciliary body, and permeability of trabecular meshwork.
  • the physiologic characteristic can be intraocular pressure (IOP), aqueous humor production, aqueous humor outflow, or any combination thereof.
  • the physiologic characteristic can be cerebrospinal fluid pressure (CSFP) in the retrobulbar space of the patient eye, translaminar pressure difference (TPD) across the lamina cribrosa of the patient eye, or both.
  • CSFP cerebrospinal fluid pressure
  • TPD translaminar pressure difference
  • the physiologic characteristic of the eye is indirectly adjusted by modifying blood pressure, blood vessels, or cerebrospinal fluid pressure, including systemically.
  • the physiologic characteristic can be blood flow to the eye, nerve access to the eye, or pupil size.
  • Production of aqueous humor can occur in the patient eye, such as by a ciliary body located in the intraocular space of the patient eye.
  • the ciliary body can secrete aqueous humor from the ciliary epithelium and can fill the anterior chamber and the posterior chamber of the eye (collectively, the anterior and posterior chambers can define the intraocular space of the patient eye), such as to maintain the patient eye in a generally spherical shape.
  • Aqueous humor secretions such as the rate of ciliary secretion into the intraocular space of the eye and the rate of secretion outflow from the eye, can affect the intraocular pressure (IOP) within the patient eye.
  • IOP intraocular pressure
  • the rate of aqueous humor secretion from the ciliary epithelium can be adjusted, such as increased or decreased, by a drug.
  • Ciliary production of aqueous humor can be affected by the use of drugs to block sympathetic nerve endings in the ciliary epithelium.
  • at least one of a beta-blocker, an alpha-2 adrenergic agonist, a carbonic anhydrase inhibitor, or a cannabinoid can be administered, such as to affect the rate of aqueous humor secretion.
  • a b-adrenergic antagonist (or beta-blocker, such as an ocular beta- blocker) can be used to affect a change in the secretion of aqueous humor, such as to decrease secretion of aqueous humor.
  • An ocular beta-blocker can include at least one of a non-selective beta-blocker, such as carteolol, levobunolol, metipranolol, timolol maleate, and timolol hemihydrate, or a selective beta- blocker including betaxolol.
  • An alpha-2 adrenergic agonist can be used to affect a change in secretion of aqueous humor, such as to decrease secretion of aqueous humor.
  • An alpha-2 adrenergic agonist can include at least one of apraclonidine or brimonidine.
  • a carbonic anhydrase inhibitor can be used to affect a change in secretion of aqueous humor, such as to decrease secretion of aqueous humor.
  • a CAI can include at least one of dor zol amide or brinzolamide.
  • a cannabinoid can be used to affect a change in secretion of aqueous humor, such as to decrease secretion of aqueous humor through
  • a cannabinoid can include at least one of A9-Tetrahydrocannabinol (THC), cannabidiol (CBD), or an endocannabinoid including 2-arachidonoylglycero (2- AG) and anandamide (AEA).
  • THC A9-Tetrahydrocannabinol
  • CBD cannabidiol
  • AEA 2-arachidonoylglycero
  • the rate of aqueous humor flow can be adjusted, such as increased or decreased, by a drug.
  • Trabecular outflow can be defined as the flow of aqueous humor from the intraocular space to Schlemm’s canal through the trabecular network of the patient eye.
  • Drugs can be used to affect the trabecular network, such as to reduce flow resistance of aqueous humor from the intraocular space.
  • at least one of a muscarinic agonist, a muscarinic blocker, a rho or rho-associated protein kinase, or an adenosine A1 agonist can be administered, such as to affect the rate of trabecular outflow from a patient eye.
  • a muscarinic agonist such as an M3 agonist, can bind to a receptor in the ciliary muscle, such as to cause contraction of the muscle and displacement of the scleral spur to widen the spaces in the trabecular meshwork to facilitate aqueous humor flow from the patient eye.
  • a muscarinic agonist can include at least one of pilocarpine, carbamylcholine, or aceclidine.
  • a muscarinic blocker such as a cycloplegic medication
  • a cycloplegic medication can include at least one of an atropine, cyclopentolate, homatropine, scopolamine, or tropicamide.
  • a rho or rho-associated protein kinase can affect cell morphology and cell interactions in the eye. Inhibition of the rho-associated protein kinase (or ROCK) pathway can facilitate aqueous humor flow from the patient eye.
  • a rho kinase inhibitor can include at least one of fasudil, ripasudil, and netarsudil,
  • An adenosine A1 receptor agonist can reduce cell volume, such as trabecular meshwork cell volume, and increase the expression of matrix metalloproteinases, such as to facilitate aqueous humor flow from the patient eye.
  • An adenosine A1 receptor agonist can include at least one of 2-Chloro- N(6)-cyclopentyladenosine, N6-Cyclopentyladenosine, or N(6)- cyclohexyladenosine.
  • the rate of aqueous humor flow can be adjusted, such as increased or decreased, by a drug.
  • Uveoscleral outflow can be defined as the flow of aqueous humor from the intraocular space to the lymphatic system through any path from the patient eye other than the trabecular network.
  • aqueous humor flow that exits the intraocular space through the sclera or the nerves and vessels that penetrate the sclera can be considered uveoscleral outflow.
  • a prostaglandin analogue can be administered, such as to affect the rate of uveoscleral outflow from a patient eye.
  • a prostaglandin analog can bind to a prostaglandin receptor, such as to regulate matrix metalloproteinases and remodel extracellular matrices to facility aqueous humor flow via an uveoscleral path.
  • a prostaglandin analogue such as a prostaglandin receptor inhibitor, can include at least one of bimatoprost, travoprost, or latanaprost.
  • Aqueous humor such as the rate of aqueous humor secretion and aqueous humor outflow from the intraocular space, can be simultaneously adjusted, such as upon introduction of a drug.
  • a drug including a ROCK/NET inhibitor can include a substance that can operate to adjust one or more physiological characteristics of the patient eye, such as inhibiting rho kinase operation to adjust the rate of aqueous humor flow from the patient eye (ROCK) and inhibiting a norepinephrine transporter (NET) to adjust the rate of aqueous humor secretion from the ciliary body.
  • a ROCK/NET inhibitor can include a drug sold under the tradename RHOPRESSA by Aerie Pharmaceuticals, Inc.
  • IOP Intraocular Pressure
  • the IOP in the patient eye can be adjusted, such increased or decreased, by administering of a drug, performing a physical manipulation of the eye, or by using the presently described device.
  • Adjustment of IOP in the patient eye can include a change in an indication of IOP including an IOP level, such as a change from a first IOP level to a second IOP level different from the first IOP level.
  • An adjustment in IOP level can include an increase in IOP level, such as changing from a first IOP level to a second IOP level greater than the first IOP level.
  • An adjustment in IOP level can include a decrease in IOP level, such as changing from a first IOP level to a second IOP level less than the first IOP level.
  • Adjusting IOP can include administering an amount of drug sufficient to adjust IOP.
  • a drug can include a substance that can affect a change in the physiology of an organ, such as the physiology of the patient eye.
  • An adjustment in IOP can be realized by affecting a change to a physiological characteristic of the patient eye, such as the rate or amount of aqueous humor secretions in the patient eye, the rate or amount of aqueous humor flow from the intraocular space of the patient eye to the surrounding environment, or both.
  • IOP can be reduced by reducing aqueous humor production, increasing aqueous humor outflow, or both.
  • IOP can be increased by increasing aqueous humor production, reducing aqueous humor outflow, or both.
  • IOP may be controlled by balancing an increase of aqueous humor production with an increase of aqueous humor outflow, or by balancing a decrease of aqueous humor production with a decrease of aqueous humor outflow.
  • IOP is controlled by use of a device, which can increase or decrease IOP, in combination with use of a drug, which can increase or decrease IOP.
  • a b-adrenergic antagonist (or beta-blocker, such as an ocular beta- blocker), alpha-2 adrenergic agonist, carbonic anhydrase inhibitor (CAI), cannabinoid, or any combination thereof, can be used to adjust IOP.
  • IOP can be decreased by modifying the rate or amount of secretion of aqueous humor, such as by decreasing the rate or amount secretion of aqueous humor.
  • IOP can be affected by the use of drugs to block sympathetic nerve endings in the ciliary epithelium.
  • Examples of an ocular beta-blocker can include at least one of a non-selective beta-blocker, such as carteolol, levobunolol, metipranolol, timolol maleate, and timolol hemihydrate, or a selective beta- blocker including betaxolol.
  • An alpha-2 adrenergic agonist can include at least one of apraclonidine or brimonidine.
  • a CAI can include at least one of dorzol amide or brinzolamide.
  • a cannabinoid can include at least one of D9- Tetrahydrocannabinol (THC), cannabidiol (CBD), or an endocannabinoid including 2-arachidonoylglycero (2-AG) and anandamide (AEA).
  • THC D9- Tetrahydrocannabinol
  • CBD cannabidiol
  • AEA 2-arachidonoylglycero
  • AEA 2-arachidonoylglycero
  • a muscarinic agonist, a muscarinic blocker, a rho or rho-associated protein kinase, an adenosine A1 agonist, or any combination thereof can also be administered to adjust IOP.
  • IOP can be decreased by modifying the rate or amount of aqueous humor outflow, such as by decreasing the rate or amount aqueous humor outflow.
  • a muscarinic agonist, such as an M3 agonist can bind to a receptor in the ciliary muscle, such as to cause contraction of the muscle and displacement of the scleral spur to adjust IOP, which can include reducing IOP.
  • a muscarinic agonist can include at least one of pilocarpine, carbamylcholine, or aceclidine.
  • a muscarinic blocker such as a cycloplegic medication, can cause paralysis and contraction of the ciliary muscle, such as to exert stress on the trabecular meshwork to adjust IOP, for example, by reducing it.
  • a cycloplegic medication can include at least one of an atropine,
  • a rho or rho- associated protein kinase can adjust IOP by modifying cell morphology and cell interactions in the eye. Inhibition of the rho-associated protein kinase (or ROCK) pathway can adjust IOP, which can include reducing IOP.
  • a rho kinase inhibitor can include at least one of fasudil, ripasudil, and netarsudil.
  • An adenosine A1 receptor agonist can adjust IOP by facilitating aqueous humor flow from the patient eye.
  • An adenosine A1 receptor agonist can include at least one of 2- Chloro-N(6)-cyclopentyladenosine, N6-Cyclopentyladenosine, or N(6)- cyclohexyladenosine.
  • a prostaglandin, or analogue thereof can adjust also IOP.
  • I OP can be decreased by modifying the rate or amount of aqueous humor outflow, such as by decreasing the rate or amount aqueous humor outflow.
  • a prostaglandin analog can bind to a prostaglandin receptor, such as to regulate matrix metalloproteinases and remodel extracellular matrices to increase aqueous humor flow via an uveoscleral path thus reducing IOP.
  • a prostaglandin analogue such as a prostaglandin receptor inhibitor, can include at least one of bimatoprost, travoprost, or latanaprost.
  • Aqueous humor such as the rate of aqueous humor secretion and aqueous humor outflow from the intraocular space, can also be simultaneously adjusted by use of a combination of drugs or a drug having a combination of effects.
  • a ROCK/NET inhibitor can include a substance that can operate to adjust one or more physiological characteristics of the patient eye, such as inhibiting rho kinase operation to adjust the rate of aqueous humor flow from the patient eye (ROCK) and inhibiting a norepinephrine transporter (NET) to adjust the rate of aqueous humor secretion from the ciliary body.
  • a ROCK/NET inhibitor can include a drug sold under the tradename RHOPRESSA by Aerie Pharmaceuticals, Inc.
  • adjustment of IOP in the patient eye can include administering an amount of drug, applying the presently described apparatus, or performing a physical manipulation of the patient’s eye, sufficient to adjust IOP, such as to improve a headache symptom.
  • Improvement of a headache symptom can include an adjustment of IOP level in the patient eye, such as quantified by a patient assessment scale.
  • an improvement in a headache symptom can include adjustment of a first IOP level in the patient eye with a concomitant pain scale assessment value of“7” on a scale of 1 to 10, to a second IOP level with a pain scale assessment value of less than 7 on a scale of 1 to 10.
  • One or more of administering an amount of drug, applying the presently described apparatus, or performing a physical manipulation can be performed in an amount sufficient to adjust IOP to a target headache relief IOP (THR-IOP) level.
  • a THR-IOP level can include an IOP level that can be perceived by the patient to result in a desired improvement in the headache symptom, such as a target pain scale assessment value.
  • a first IOP level such as a first IOP level in the patient eye with a concomitant pain scale assessment value of 7 on a scale of 1 to 10
  • a second IOP level such as a THR- IOP level that results in a target (e.g., desired) pain scale assessment value of 3 on a scale of 1 to 10.
  • a THR-IOP level can include a change in IOP level, such as from a first IOP level to a lower second IOP level where the change in IOP level can be of at least one of 1 mmHg, 2 mmHg, 3 mmHg, 4 mmHg, 5 mmHg, 6 mmHg, 7 mmHg, 8 mmHg, 9 mmHg, 10 mmHg, 11 mmHg, 12 mmHg, 13 mmHg, 14 mmHg, 15 mmHg, 16 mmHg, 17 mmHg, 18 mmHg, 19 mmHg, or 20 mmHg.
  • the pharmaceutical composition, apparatus, physical manipulation, or combination thereof is provided in an amount effective to reduce IOP by about 1 mmHg to about 20 mmHg.
  • the pharmaceutical composition, apparatus, physical manipulation, or combination thereof is provided in an amount effective to establish in the patient eye an IOP of about 5 mmHg to 30 mmHg, about 8 mmHg to about 21 mmHg, or about 10 mmHg to about 20 mmHg.
  • the IOP can be adjusted to about 5 mmHg, 6 mmHg, 7 mmHg, 8 mmHg, 9 mmHg, 10 mmHg, 11 mmHg, 12 mmHg, 13 mmHg, 14 mmHg, 15 mmHg, 16 mmHg, 17 mmHg, 18 mmHg, 19 mmHg, 20 mmHg, 21 mmHg, 22 mmHg, 23 mmHg, 24 mmHg, 25 mmHg, 26 mmHg, 27 mmHg, 28 mmHg, 29 mmHg, or about 30 mmHg.
  • the combination of the pharmaceutical composition and the apparatus, together provide an IOP of about 5 mmHg to 30 mmHg, about 8 mmHg to about 21 mmHg, or about 10 mmHg to about 20 mmHg.
  • the IOP can be adjusted to about 5 mmHg, 6 mmHg, 7 mmHg, 8 mmHg, 9 mmHg, 10 mmHg, 11 mmHg, 12 mmHg, 13 mmHg, 14 mmHg, 15 mmHg, 16 mmHg, 17 mmHg, 18 mmHg, 19 mmHg, 20 mmHg, 21 mmHg, 22 mmHg, 23 mmHg, 24 mmHg, 25 mmHg, 26 mmHg, 27 mmHg, 28 mmHg, 29 mmHg, or about 30 mmHg.
  • one of the pharmaceutical composition, the apparatus, or the physical manipulation is, individually, provided in an amount effective to provide an IOP of 22 mmHg to about 42 mmHg.
  • the composition can be administered in an amount effective to provide an IOP of 22 mmHg to about 42 mmHg absent application of the apparatus.
  • the patient suffering from headache has an IOP of about 5 mmHg to 30 mmHg, about 8 mmHg to about 21 mmHg, about 10 mmHg to about 20 mmHg, less than 22 mmHg, less than 30 mmHg, less than 35 mmHg, or less than 50 mmHg.
  • the patient suffering from headache has an IOP of 21 mmHg or greater, 22 mmHg or greater, 25 mmHg or greater, 30 mmHg or greater, 35 mmHg or greater, 40 mmHg or greater, or 50 mmHg or greater.
  • Administering an amount of drug sufficient to adjust IOP can include a delivery method for introducing the drug into the patient.
  • a drug delivery method can include at least one of localized delivery or systemic delivery.
  • Localized delivery can include delivery of a drug to a specified portion of the patient, such as the drug can be applied to a specified tissue of the patient and at least partly biotransformed by the tissue.
  • Examples of localized drug delivery can include topical and transcutaneous delivery modalities.
  • Systemic delivery can include delivery of a drug to all tissues of the patient, such as by introduction of the drug into the blood stream of the patient. Examples of system drug delivery can include oral delivery, delivery by inhalation, sublingual delivery, and intravenous delivery.
  • Administering an amount of drug sufficient to adjust IOP can include dosing considerations, such as the amount of drug delivered during the process of administration.
  • Drug dosing can be quantified by the amount of drug delivered to the patient, such as the total dosing delivered.
  • Drug dosing can be quantified by the dose timing, such as the number of doses and the amount of drug prescribed for delivery during a duration of time. In an example, dose timing can be defined as the amount of drug and number of doses delivered over the course of a 24-hour period (e.g., a patient prescription for a administration of a first drug might read“25 mg of first drug 3 times per day”).
  • Drug dosing can be quantified by the delivery method for introducing the drug into the patient, such as localized delivery or systemic delivery.
  • Concentration of the drug can vary depending on the delivery method utilized, such as due to the ability of the drug to be absorbed by the patient or permeate tissue to be treated.
  • An adjustment in IOP can include performing a surgical procedure on the eye of the patient.
  • Performing a surgical procedure can include implanting a shunt, such as an ocular shunt, in the patient eye.
  • the ocular shunt can adjust IOP in the patient eye, such as by providing a low-resistance fluid path between the intraocular space of the patient eye and an organ or bodily structure of the patient external to the eye including episcleral blood vessels.
  • aqueous humor can flow from the intraocular space to the external bodily structure through the shunt, such as to reduce IOP in the patient eye.
  • a bodily fluid including lymph can flow from the external bodily structure to the intraocular space, such as to increase IOP in the patient eye.
  • the ocular shunt can adjust IOP in the patient eye, such as by providing a low-resistance fluid path between the intraocular space of the patient eye and the dural sheath, such as the dural sheath associated with the patient eye.
  • the dural sheath associated with the patient eye protects the optic nerve and can include a volume between the optic nerve and an inner surface of the dural sheath, such as the subarachnoid space, filled with cerebrospinal fluid.
  • CSFP cerebrospinal fluid pressure
  • aqueous humor can flow from the intraocular space to the subarachnoid space through the shunt, such as to reduce IOP in the patient eye.
  • IOP is less than the CSFP
  • cerebrospinal fluid can flow from the subarachnoid space to the intraocular space, such as to increase IOP in the patient eye.
  • Performing a surgical procedure can include modifying a bodily structure within the patient, such as the patient eye.
  • the surgical procedure can enhance the function of the existing bodily structure, such as by reducing the resistance to aqueous humor outflow from the intraocular space.
  • the surgical procedure can include at least one of a trabeculectomy surgery, laser surgery, such as argon laser trabeculoplasty (ALT) surgery and laser peripheral iridotomy (LPI) surgery, transscleral photocoagulation, or cycloablation surgery.
  • ALT argon laser trabeculoplasty
  • LPI laser peripheral iridotomy
  • FIG. 1 shows one example method 100 to affect a change in a headache, such a change in a headache symptom.
  • a patient can be selected, such as a patient with a headache symptom.
  • intraocular pressure (IOP) in a patient eye can be adjusted, such as to relieve a headache symptom.
  • IOP intraocular pressure
  • Production and absorption of cerebrospinal fluid can occur in the patient, such as production by the choroid plexuses and absorption by the arachnoid granulations located in the patient brain.
  • the choroid plexuses can secrete cerebrospinal fluid and can fill the subarachnoid space and the ventricles, cisterns, and sulci (collectively, the ventricular system around and inside the brain and spinal cord), such as to cushion the brain from injury.
  • Cerebrospinal fluid secretions such as the rate of cerebrospinal fluid secretion into the ventricular system and the rate of absorption by the arachnoid granulations, can affect the cerebrospinal fluid pressure (CSFP) within the patient.
  • CSFP cerebrospinal fluid pressure
  • Adjustment of CSFP in the patient can include a change in an indication of CSFP including a CSFP level, such as a change from a first CSFP level to a second CSFP level different from the first CSFP level.
  • An adjustment in CSFP level can include an increase in CSFP level, such as changing from a first CSFP level to a second CSFP level greater than the first CSFP level.
  • An adjustment in CSFP level can include a decrease in CSFP level, such as changing from a first CSFP level to a second CSFP level less than the first CSFP level.
  • An adjustment in CSFP can include administering an amount of drug sufficient to adjust CSFP.
  • An adjustment in CSFP can be realized by affecting a change to a physiological characteristic of the patient, such as at least one of the rate of cerebrospinal fluid secretion in the patient, the rate of cerebrospinal fluid absorption, or the vessel resistance to cerebrospinal fluid flow including a change in vessel resistance due to vasoconstriction or vasodilation of the vessels transporting cerebrospinal fluid.
  • the rate of cerebrospinal fluid secretion from the choroid plexuses can be adjusted, such as increased or decreased, by a drug. Adjusting the rate of secretion can increase CSFP, such as due to increased secretions, or decrease CSFP, such as due to decreased secretions.
  • a carbonic anhydrase inhibitor (CAI) can be used to affect a change in the secretion of cerebrospinal fluid, such as to decrease secretion of cerebrospinal fluid.
  • a CAI can include at least one of acetazolamide, methazolamide, or furosemide.
  • CSFP is measured based on systemic CSFP and in various aspects CSFP is based on the calculated CSFP in the retrobulbar space of the patient eye.
  • the resistance of cerebrospinal fluid flow in a vessel can be adjusted, such as increased or decreased, by a drug. Adjusting vessel resistance can increase CSFP, such as through administering a drug to effect vasoconstriction of cerebrospinal fluid vessels, or decrease CSFP, such as through administering a drug to effect vasodilation of cerebrospinal fluid vessels.
  • a hyperosmotic agent including a hypertonic saline can act as a diuretic, such as to adjust CSFP in the patient.
  • mannitol can act as a diuretic to reduce CSFP, such as by reducing cerebral parenchymal cell water, and as an agent to expand plasma volume and decrease cerebrospinal fluid viscosity, such as to decrease CSFP by autoregulatory vasoconstriction.
  • a hyperosmotic agent can include at least one of glycerine, isosorbide, or mannitol.
  • An adjustment in CSFP can include performing a surgical procedure on the patient.
  • Performing a surgical procedure can include implanting a shunt, such as to reduce CSFP by diverting a portion of cerebrospinal fluid from the ventricular system to another portion of the patient body.
  • An implanted shunt can include at least one of a lumboperitoneal shunt (LPS), a vertirculoperitoneal shunt (VPS), or a dural venous sinus stent including a lateral venous sinus stent.
  • LPS lumboperitoneal shunt
  • VPN vertirculoperitoneal shunt
  • dural venous sinus stent including a lateral venous sinus stent.
  • Performing a surgical procedure can include performing an optic nerve sheath fenestration (ONSF), such as to reduce CSFP by releasing a portion of cerebrospinal fluid from the ventricular system into the patient body for reabsorption.
  • Performing a surgical procedure can include performing a bariatric surgery, such as to reduce CSFP for treatment of idiopathic intercranial hypertension.
  • ONSF optic nerve sheath fenestration
  • Performing a surgical procedure can include performing a bariatric surgery, such as to reduce CSFP for treatment of idiopathic intercranial hypertension.
  • the pharmaceutical composition, apparatus, physical manipulation, or combination thereof is performed in an amount effective to reduce CSFP by about 1 mmHg to about 20 mmHg.
  • the pharmaceutical composition, apparatus, physical manipulation, or combination thereof is provided in an amount effective to establish in the patient eye a CSFP of about 4 mmHg to 15 mmHg, about 5 mmHg to about 13 mmHg, or about 8 mmHg to about 10 mmHg.
  • the IOP can be adjusted to about 5 mmHg, 6 mmHg, 7 mmHg, 8 mmHg, 9 mmHg, 10 mmHg, 11 mmHg, 12 mmHg, 13 mmHg, 14 mmHg, or about 15 mmHg.
  • the combination of the pharmaceutical composition and the apparatus, together provide a CSFP of about 5 mmHg to 30 mmHg, about 8 mmHg to about 21 mmHg, or about 10 mmHg to about 20 mmHg.
  • the CSFP in the retrobulbar space of the patient eye can be adjusted to about 5 mmHg, 6 mmHg, 7 mmHg, 8 mmHg, 9 mmHg, 10 mmHg,
  • the patient suffering from headache has a CSFP of about 90% to about 110% of an estimated CSFP value calculated by 0.44 x Body Mass Index [kg/m 2 ] + 0.16 x Diastolic Blood Pressure [mmHg]- 0.18 x Age [Years] - 1.91.
  • the patient suffering from headache can have a healthy or normal CSFP, prior to treatment with one or more, or all, of the pharmaceutical composition, apparatus, or physical manipulation of the eye.
  • the patient suffering from headache has a CSFP of less than 90% or greater than 110% of an estimated CSFP value calculated by 0.44 x Body Mass Index [kg/m 2 ] + 0.16 x Diastolic Blood Pressure [mmHg]- 0.18 x Age [Years] - 1.91.
  • the patient suffering from headache can have an unhealthy or abnormal CSFP, prior to treatment with one or more, or all, of the pharmaceutical composition, apparatus, or physical manipulation of the eye.
  • FIG. 2 shows one example method 200 to affect a change in a headache, such a change in a headache symptom.
  • a patient can be selected, such as a patient with a headache symptom.
  • cerebrospinal fluid pressure (CSFP) in a patient can be adjusted, such as to relieve a headache symptom.
  • CSFP cerebrospinal fluid pressure
  • TPD Translaminar Pressure Differential
  • Translaminar pressure describes the pressure differential across the lamina cribrosa.
  • the translaminar pressure difference can be defined as the difference between intraocular pressure in the patient eye and cerebrospinal fluid pressure in the patient body.
  • Translaminar pressure gradient is related to TPD and can be defined as the difference between IOP and CSFP per unit thickness of the lamina cribrosa.
  • An indication of TPD can indicate the physiological health of the patient eye, such as the presence or absence of an eye condition.
  • a physiologically normal eye such as a patient eye in the absence of an eye condition, can be characterized by a normal TPD level, such as normal TPD level in a range of at least one of about -6 mmHg to about 6 mmHg or about -4 mmHg to about 4 mmHg.
  • a non-normal eye such as a patient eye experiencing an eye condition including glaucoma
  • a TPD level that falls outside the range of normal TPD level, such as the TPD level can be less than about -6 mmHg or greater than about 6 mmHg for a normal TPD range defined as about -6 mmHg to about 6 mmHg, or the TPD level can be less than about -4 mmHg or greater than about 4 mmHg for a normal TPD range defined as about -4 mmHg to about 4 mmHg.
  • Adjustment of TPD in the patient can include a change in an indication of TPD including a TPD level, such as a change from a first TPD level to a second TPD level different from the first TPD level.
  • An adjustment in TPD level can include an increase in TPD level, such as changing from a first TPD level to a second TPD level greater than the first TPD level.
  • An adjustment in TPD level can include a decrease in TPD level, such as changing from a first TPD level to a second TPD level less than the first TPD level.
  • an increase in TPD level can be affected by adjusting at least one of an indication of IOP or an indication of CSFP, such as using the methods to adjust the indications of IOP and CSFP as described above.
  • the pharmaceutical composition, apparatus, physical manipulation, or combination thereof is performed in an amount effective to reduce TPD by about 1 mmHg to about 20 mmHg.
  • the pharmaceutical composition, apparatus, physical manipulation, or combination thereof is performed in an amount effective to reduce TPD by about 1 mmHg to about 20 mmHg.
  • TPD TPD of about 1 mmHg to 15 mmHg, about 1 mmHg to about 10 mmHg, about 1.5 mmHg to about 10 mmHg, about 1.5 mmHg to about 6 mmHg, about 0 mmHg to about 6 mmHg, about 0 mmHg to about 3 mmHg, or about 0 mmHg to about 15 mmHg, as absolute values.
  • the TPD can be adjusted to about 1.5 mmHg, 2 mmHg, 3 mmHg, 4 mmHg, 5 mmHg, 6 mmHg, 7 mmHg, 8 mmHg, 9 mmHg, or about 10 mmHg.
  • the combination of the pharmaceutical composition and the apparatus, together provide a TPD of about 1 mmHg to about 10 mmHg, about 1.5 mmHg to about 10 mmHg, or about 0 mmHg to about 15 mmHg, as absolute values.
  • the TPD can be based on the estimated value of the CSFP in the retrobulbar space of the patient eye, or can be based on the CSFP provided by lumbar puncture.
  • the patient suffering from headache has a TPD of about 90% to about 110% of an estimated TPD value calculated by IOP [mmHg] - 0.44 x Body Mass Index [kg/m 2 ] + 0.16 x Diastolic Blood Pressure [mmHg] - 0.18 x Age [Years] - 1.91.
  • the patient suffering from headache can have a healthy or normal TPD, prior to treatment with one or more, or all, of the pharmaceutical composition, apparatus, or physical manipulation of the eye.
  • the patient suffering from headache has a TPD of less than 90% or greater than 110% of an estimated TPD value calculated by IOP [mmHg] - 0.44 x Body Mass Index [kg/m 2 ] + 0.16 x Diastolic Blood Pressure [mmHg] - 0.18 x Age [Years] - 1.91.
  • the patient suffering from headache can have an unhealthy or abnormal TPD, prior to treatment with one or more, or all, of the pharmaceutical composition, apparatus, or physical manipulation of the eye.
  • the method can also involve other techniques that can be used to modify TPD, or measure TPD, in a patient are set forth in Ningli Wang et al., Intraocular and Intracranial Pressure Gradient in Glaucoma, Springer, 2019, which is hereby incorporated by reference herewith in its entirety
  • FIG. 3 shows one example method 300 of treating a headache or symptom attributed to headache.
  • TPD translaminar pressure difference
  • the method can involve adjusting blood pressure to the eye, or vasomotor adjustment of blood vessels to the eye.
  • a vasospasm such as caused by altered cerebral vasomotor reactivity, can lead to a patient headache.
  • a patient suffering from vasospastic syndrome or primary vascular dysregulation (PVD) can suffer from cold hands, low blood pressure, myocardial ischemia, and migraine.
  • Ocular PVD can be associated with glaucomatous optic neuropathy and compromised autoregulation in the eye, such as to sensitize the eye to changes in IOP including sensitization to an increase in IOP or systemic blood pressure including a sensitization to a decrease in blood pressure.
  • Adjustment of ocular vasospasm can include a change in an indication of OV including an OV level, such as a change from a first OV level to a second OV level different from the first OV level.
  • An OV level can include an indication of vessel diameter, such as a change in vessel diameter.
  • An adjustment in OV level can include an increase in OV level, such as changing from a first OV level to a second OV level greater than the first OV level.
  • An adjustment in OV level can include a decrease in OV level, such as changing from a first OV level to a second OV level less than the first OV level.
  • an adjustment in OV level can be affected by administering a drug, such as a muscle relaxant, in proximity to the vessel experiencing OV, such as through a topical medication applied to a cornea of the patient including an eye drop medication.
  • a muscle relaxant can include at least one of a natural muscle relaxant, such as arnica oil, cannabis oil, or an essential oil including peppermint or lemongrass oil, a non-steroidal anti-inflammatory drug (NSAIDs), or a smooth muscle relaxant, such as papaverine.
  • FIG. 4 shows a one example method 400 to treat a headache.
  • ocular vasospasm in a patient can be adjusted, such as to relieve a headache or symptom attributed to headache.
  • the present disclosure provides a pharmaceutical composition for use in the treatment of a patient suffering from headache, alone or in combination with another the apparatus described herein.
  • the pharmaceutical composition comprises one or more active agent, or drug, that modifies a physiologic characteristic of the patient eye, together with a pharmaceutically-acceptable carrier.
  • the present disclosure also provides one or more active agent, and compositions thereof, which may be used for manufacture of a medicament for the treatment of a patient suffering from headache.
  • the medicament is for use together with the presently described apparatus, for the treat for the treatment of a patient suffering from headache.
  • a drug in the composition can be in the range of from
  • the amount of drug administered to the patient can range from about 0.005 mg to 500 mg.
  • the amount of drug administered to the patient can range from about 0.0001 mg to about 10 mg/kg of patient body weight, e.g., from about 0.01 to about 50 mg/kg of body weight per day, such as 0.001 mg to about 10 mg per kilogram body weight of the recipient per day, can be in the range of 0.05 to 100 mg/kg/day, and can be in the range of 1 to 50 mg/kg/day.
  • the concentration of the drugs in the composition can be, for example, from about 0.0001% to about 25% (w/v), about 0.001% to about 1% (w/v), or about 0.001% to about 0.1% (w/v).
  • concentration in a semi-solid or solid composition such as a gel or a powder will be about 0.01% to about 5% (by weight).
  • the one or more drug may be administered in a form together with a pharmaceutically-accepted carrier, or in the form of the compound per se, and/or in the form of a salt, polymorph, ester, amide, prodrug, derivative, or the like, provided the salt, polymorph, ester, amide, prodrug or derivative is suitable pharmacologically.
  • salts, esters, amides, prodrugs and other derivatives of the active agents may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by J. March, Advanced Organic Chemistry: Reactions,
  • the active agent may be incorporated into the present compositions either as the racemate or in enantiomerically enriched form.
  • the one or more drug can be encapsulated into microcapsules, microspheres, microparticles, microfibers, reinforcing fibers and the like to facilitate mixing and achieving controlled, extended, delayed and/or sustained release and combined other agents or drugs.
  • active agent are sufficiently basic or acidic to form acid or base salts
  • use of the compounds as salts may be appropriate.
  • acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, a-ketoglutarate, and a-glycerophosphate.
  • Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
  • compositions comprising an active agent disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent or excipient are provided.
  • the pharmaceutical dosage forms suitable for ocular use, injection, or as drops can include sterile aqueous solutions or dispersions or can be in the form of sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile solutions or dispersions, optionally encapsulated in liposomes.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be useful to include isotonic agents, for example, sugars, buffers or sodium chloride.
  • Sterile solutions can be prepared by incorporating the active agent in the desired amount in the appropriate solvent with various of the other ingredients enumerated above followed by, for example, filter sterilization.
  • typical methods of preparation are vacuum drying and the freeze-drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • the composition can be formulated with a buffer.
  • the buffer can be citrate, phosphate, tris-HCl, borate, or other buffer systems suitable for ophthalmic use.
  • the composition is formulated to a pH of about 4.5 to about 7.5, about 4.75 to about 7.4, about 7 to about 7.4, where suitable.
  • a pH of about 7.4 can be suitable of ophthalmic drops.
  • the solution is at a lower pH, such as about 4.5 to about 5.
  • the solution is isotonic.
  • the solution can have a tonicity corresponding to that of an about 0.5% to about 1.8% solution of sodium chloride.
  • the pharmaceutical composition can contain one or more active agent.
  • the one or more active agent can be a glaucoma drug, a mydriatic drug, a miotic drug, a cycloplegic, beta-blocker, an alpha-2 adrenergic agonist, a carbonic anhydrase inhibitor, a cannabinoid, a ROCK/NET inhibitor, a muscarinic agonist, a muscarinic blocker, a rho or rho-associated protein kinase, an adenosine A1 agonist, a prostaglandin receptor inhibitor, a hyperosmotic agent, a muscle relaxant, or any combination thereof.
  • the drug can be a drug that modifies a physiologic characteristic of the eye other than a glaucoma drug, a mydriatic drug, a miotic drug, a cycloplegic, beta-blocker, an alpha-2 adrenergic agonist, a carbonic anhydrase inhibitor, a cannabinoid, a ROCK/NET inhibitor, a muscarinic agonist, a muscarinic blocker, a rho or rho-associated protein kinase, an adenosine A1 agonist, a prostaglandin receptor inhibitor, a hyperosmotic agent, a muscle relaxant, or any combination thereof.
  • the drug can be a compound that is a glaucoma drug and a carbonic anhydrase inhibitor, but is not a muscarinic agonist.
  • the drug can be a mydriatic drug, a miotic drug, or a cycloplegic, and other than a glaucoma drug, hyperosmotic agent, or a muscle relaxant.
  • the drug can be a miotic, which are agents that cause contraction of the pupil of the eye, such as pilocarpine, carbamoylcholine, physostigmine, echothiophate, and acetylcholine.
  • miotic are agents that cause contraction of the pupil of the eye, such as pilocarpine, carbamoylcholine, physostigmine, echothiophate, and acetylcholine.
  • the drug can be a drug that is a glaucoma medication, such as an alpha agonist, beta-blocker, prostogrlandin, rock inhibitor, or carbonic anhydrase inhibitor.
  • glaucoma medications include dipivefrin, brimonidine, epinephrine, levobunolol, carteolol, metipranolol, timolol, betaxolol, travoprost, bimatoprost, unoprostone, tafluprost, latanoprostene bunod, netarsudil, methazolamide, acetazolamide, dorzolamide, brinzolamide, and diclofenamide.
  • the glaucoma medication is administered to the patient in an amount less than the
  • the drug can also a dilation agent, such as phenylephrine or tropicamide, or a cycloplegic, such as cyclopentolate, atropine, or homatropine.
  • a dilation agent such as phenylephrine or tropicamide
  • a cycloplegic such as cyclopentolate, atropine, or homatropine.
  • the pharmaceutical composition can comprise a drug that increases outflow of the aqueous humor, decreases aqueous humor secretion from the ciliary gland, or decreases intraocular pressure (IOP).
  • IOP intraocular pressure
  • the pharmaceutical composition can comprise a drug in an amount effective to modulate ciliary production of aqueous humor, such as decrease aqueous humor secretion or increase aqueous humor secretion.
  • composition can contain a beta-blocker, an alpha-2 adrenergic agonist, a carbonic anhydrase inhibitor, a cannabinoid, or any combination thereof.
  • the pharmaceutical composition can comprise a drug in an amount effective to modulate trabecular or uveoscleral outflow of aqueous humor in the patient eye.
  • a drug in an amount effective to modulate trabecular or uveoscleral outflow of aqueous humor in the patient eye.
  • Such composition can contain a muscarinic agonist, a muscarinic blocker, a rho kinase inhibitor, an adenosine A1 receptor agonist, a prostaglandin analogue, or any combination thereof.
  • the pharmaceutical composition can comprise a drug in an amount effective to modulate cerebrospinal fluid pressure (CSFP) in the retrobulbar space of the patient eye, translaminar pressure difference (TPD) across the lamina cribrosa of the patient eye, or both.
  • CSFP cerebrospinal fluid pressure
  • TPD translaminar pressure difference
  • Such composition can contain a carbonic anhydrase inhibitor, a hyperosmotic agent, a muscle relaxant selected from papaverine, arnica oil, cannabis oil, peppermint oil, lemongrass oil, a non steroidal anti-inflammatory drug (NSAIDs), or any combination thereof
  • Beta-blockers can include carteolol, levobunolol, metipranolol, timolol maleate, timolol hemihydrate, betaxolol, and other oxypropanolamines.
  • the beta-blocker can be present in the pharmaceutical composition in an amount effective to modify a physiologic characteristic of the eye.
  • a dose of the pharmaceutical composition can contain about 0.1 mg to about 100 mg of a beta-blocker.
  • the pharmaceutical composition is a liquid, such as an aqueous solution
  • the beta-blocker is present at amount from about 0.05% (w/v) to about 5% (w/v) of the composition, about 0.05% (w/v) to about 0.20% (w/v) of the composition, about 0.01% (w/v) to about 0.10% (w/v) of the composition, about 0.25% (w/v) to about 1% (w/v) of the composition, or about 0.05% (w/v) to about 0.5% (w/v) of the composition.
  • the composition can be a solution comprising about 0.1 %, 0.2%, 0.3%, 0.4%, 0.5%, or about 1% (w/v) carteolol; about 0.025%, 0.05%, 0.1%, or about 0.25% to about 0.5 (w/v) levobunolol; about 0.03%, 0.06%, 0.12%, or about 0.3% (w/v) metipranolol; about 0.01%, 0.025%, 0.05%, 0.1%, or about 0.25% to about 0.5 (w/v) timolol maleate; about 0.01%, 0.025%, 0.05%, 0.1%, or about 0.25% to about 0.5 (w/v) betaxolol.
  • the composition can be less than about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or less than 1 % (w/v) carteolol; less than 0.25% (w/v) levobunolol; less than about 0.03%, 0.06%, 0.12%, or less than 0.3% (w/v) metipranolol; less than about 0.01 %, 0.025%, 0.05%, 0.1%, or less than 0.25% (w/v) timolol maleate; less than about 0.01%, 0.025%, 0.05%, 0.1%, or less than 0.25% (w/v) betaxolol.
  • the composition can be less than about 0.5% (w/v) carteolol; less than about 0.12% (w/v) levobunolol; less than about 0.15% (w/v) metipranolol; less than about 0.12% (w/v) timolol maleate; or less than about 0.12% (w/v) betaxolol.
  • Alpha-2 adrenergic agonists can include apraclonidine, brimonidine, and other 2-imidazoline adrenergic agonists.
  • the composition can be a solution comprising about 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or about 1% (w/v) apraclonidine; or about 0.01%, 0.025%, 0.05%, 0.1%, 0.2%, or about 0.25% (w/v) brimonidine.
  • the composition can be a solution comprising less than about 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or less than 1 % (w/v) apraclonidine; or less than about 0.01%, 0.025%, 0.05%, 0.1%, 0.2%, or less than 0.25% (w/v) brimonidine.
  • Carbonic anhydrase inhibitors can include dorzolamide, brinzolamide, other 2-sulfonamidothiophene carbonic anhydrase inhibitors, acetazolamide, methazolamide, furosemide, and other thiadiazole carbonic anhydrase inhibitors.
  • the composition can be a solution comprising about or at least 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1.0%, or about 2% (w/v) dorzolamide; about or at least 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1.0%, or about 2% (w/v) brinzolamide; or about or at least 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1.0%, or about 2% (w/v) furosemide.
  • the composition can be a solution comprising less than about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1.0%, or less than about 2% (w/v) dorzolamide; less than about 0.1 %, 0.2%, 0.3%, 0.4%, 0.5%, 1.0%, or less than about 2% (w/v) brinzolamide; or less than about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1.0%, or less than about 2% (w/v) furosemide.
  • Cannabinoids can include D9 -Tetrahydrocannabinol (THC), cannabidiol (CBD), endocannabinoids, 2-arachidonoylglycero (2 -AG), anandamide (AEA), and other ligands of CB1 and CB2 receptors.
  • THC cannabidiol
  • CBD cannabidiol
  • endocannabinoids 2-arachidonoylglycero (2 -AG), anandamide (AEA), and other ligands of CB1 and CB2 receptors.
  • the composition can be a solution comprising about or at least 0.1%, 0.2%,
  • the composition can be a solution comprising less than about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1.0%, or less than about 2% (w/v) THC, CBD, 2-AG, or AEA.
  • Muscarinic agonists can include pilocarpine, carbamylcholine, aceclidine, and other muscarine and acetylcholine analogues.
  • the composition can be a solution comprising about or at least 0.01%, 0.02%,
  • the composition can be a solution comprising less than about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 2%, 3%, or less than about 4%, (w/v) pilocarpine; or less than about 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1 %, 2%, 3%, or less than about 4%, (w/v) carbamylcholine.
  • Muscarinic blockers can include atropine, cyclopentolate, homatropine, scopolamine, tropicamide, and other related compounds.
  • the composition can be a solution comprising about or at least 0.01%, 0.02%,
  • the composition can be a solution comprising less than about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 2%, 3%, or less than about 4%, (w/v) atropine; less than about 0.01 %, 0.02%, 0.03%, 0.04%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, or less than about 2% (w/v) cyclopentolate; less than about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, or less than about 2% (w/v) homatropine; less than about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.1%, 0.2%, or less than about 0.25% scopolamine; or less than about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%,
  • Rho kinase inhibitors can include fasudil, ripasudil, netarsudil, or other rho kinase inhibitors including those formulated together with prostaglandins.
  • the composition can be a solution comprising about or at least 0.0001%, 0.001%, 0.005%, 0.01%, or about 0.02% netarsudil (w/v); about or at least 0.0001%, 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.1%, 0.2%, 0.3%, or about 0.4% ripasudil (w/v); or about or at least 0.0001%,
  • the composition can be less than about 0.0001%, 0.001%, 0.005%, 0.01%, or less than about 0.02% netarsudil (w/v); less than 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.1%, 0.2%, 0.3%, or less than about 0.4%, ripasudil (w/v); or less than about 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.1%, 0.2%, 0.3%, or less than about 0.4%, fasudil (w/v).
  • Adenosine A1 receptor agonists can include 2-Chloro-N(6)- cyclopentyladenosine, N(6)-cyclopentyladenosine, N(6)-cyclohexyladenosine, and other adenosine analogues that are selective to the A1 receptor.
  • Prostaglandins can include prostaglandin, bimatoprost, travoprost, latanoprost, and other analogues of the same.
  • the composition can be a solution comprising about or at least 0.0001%, 0.0003%, 0.0005%, 0.001%, 0.003%, 0.005%, 0.01%, or about 0.03% bimatoprost (w/v); about or at least 0.0001%, 0.0003%, 0.0005%, 0.001%, 0.003%, or about 0.004% travoprost (w/v); about or at least 0.0001%, 0.0003%, 0.0005%, 0.001%, 0.003%, or about 0.005% latanoprost (w/v).
  • the composition can be less than about 0.0001%, 0.0003%, 0.0005%, 0.001%, 0.003%, 0.005%, 0.01%, or less than about 0.03% bimatoprost (w/v); less than about 0.0001%, 0.0003%, 0.0005%, 0.001%, 0.003%, or less than about 0.004% travoprost (w/v); less than about 0.0001%, 0.0003%, 0.0005%, 0.001 %, 0.003%, or less than about 0.005% latanoprost (w/v).
  • the method can involve administering a prostaglandin at in a range of about 30 micrograms per milliliter (pg/mL) to about 70 pg/mL, or about 40 micrograms per milliliter (pg/mL) to about 60 pg/mL.
  • Hyperosmotic agents can include glycerine, isosorbide, and mannitol.
  • hyperosmotic agents can be present in the pharmaceutical composition in amounts effective to reduce IOP.
  • the hyperosmotic agent can be present in the pharmaceutical composition at a concentration of about 10 g/L to about 300 g/L or about 50 g/L to about 200 g/L.
  • the pharmaceutical composition can have an hyperosmotic agent at an amount effective to provide an osmolarity of about 100 mOsmol/L to about 1500 mOsmol/L, or about 270 mOsmol/L to about 1100 mOsmol/L, about 100, about 150, about 270, about 550, about 820, or about 1100 mOsmol/L.
  • the hyperosmotic agent is formulated as a solution for intravenous injection.
  • Muscle relaxants can include papaverine, arnica oil, cannabis oil, peppermint oil, lemongrass oil, and non-steroidal anti-inflammatory drugs (NSAIDs).
  • the NSAID can be aspirin, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen; ketorolac (ketoralac), meclofenamate, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or any combination of the NSAIDs.
  • the NSAID can be aspirin, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen; ketorolac (ketoral
  • the drug that modifies a physiologic characteristic of the eye is other than a muscle relaxant, NSAID, acetaminophen, essential oil, natural extract, cannabis oil, or plant-derived oil.
  • the NSAID or acetaminophen is at a dosage less than 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or less than 100 mg.
  • the muscle relaxant, NSAID, acetaminophen, essential oil, natural extract, cannabis oil, or plant-derived oil is administered to the patient at an amount less than the minimum therapeutically effective amount for treating pain relief or headache in a patient absent the apparatus.
  • the dosages and formulations for various active agents can be the same as, or other than, those set forth in the latest edition of the Prescribes’ Digital Reference, available on the world wide web at pdr.net, which is hereby incorporated by reference herewith in its entirety.
  • pharmaceutical composition can be an ophthalmic solution comprising about 1% (w/v) carteolol; about 0.25% to about 0.5 (w/v) levobunolol; about 0.3% (w/v) metipranolol; about 0.25% to about 0.5 (w/v) timolol maleate; about 0.25% to about 0.5 (w/v) betaxolol; about 0.5% to about 1.0 (w/v) apraclonidine; about 0.025% to about 0.33% (w/v) brimonidine; about 2% (w/v) dorzolamide; about 1% (w/v) brinzolamide; about 1% to about 2% (w/v) pilocarpine; about 1.5% to about 3% (w/v) carbamylcholine; about 1% (w/v) atropine; about 0.5% to about 2% (w/v) cyclopen tolate; about 0.5% to about 1.0 (w/v)
  • the pharmaceutical composition can be an ophthalmic solution comprising one or more of less than 1% (w/v) carteolol; less than 0.25% (w/v) levobunolol; less than 0.3% (w/v) metipranolol; less than 0.25% (w/v) timolol maleate; less than 0.25% (w/v) betaxolol; less than 0.5% (w/v) apraclonidine; less than 0.025% (w/v) brimonidine; less than 2% (w/v) dorzolamide; less than 1% (w/v) brinzolamide; less than 1 % (w/v) pilocarpine; less than 1.5% (w/v)
  • carbamylcholine less than 1% (w/v) atropine; less than 0.5% (w/v)
  • cyclopentolate less than 0.5% (w/v) tropicamide; less than 0.01% (w/v) bimatoprost; less than 0.004% (w/v) travoprost; less than 0.005% (w/v) latanoprost; or less than 0.2% (w/v) glycerin.
  • the pharmaceutical compositions include one or more active agents and a pharmaceutically acceptable excipient which can be a carrier or a diluent.
  • the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which can be in the form of an ampoule, capsule, sachet, paper, or other container.
  • a carrier which can be in the form of an ampoule, capsule, sachet, paper, or other container.
  • the active compound When the active compound is mixed with a carrier, or when the carrier serves as a diluent, it can be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid carrier, for example contained in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the composition can comprise a excipient, carrier, or diluent other than a solvent, water, or buffer solution.
  • compositions containing a compound can be prepared by conventional techniques, e.g. as described in Remington: The Science and Practice of Pharmacy, 19th Ed., 1995, which is hereby incorporated by reference herewith in its entirety.
  • compositions can appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
  • the formulations can be mixed with auxiliary agents which do not deleteriously react with active agent.
  • auxiliary agents which do not deleteriously react with active agent.
  • Such additives can include wetting agents, emulsifying and suspending agents, salt for influencing osmotic pressure, buffers and/or coloring substances preserving agents, sweetening agents or flavoring agents.
  • the compositions can also be sterilized if desired.
  • the pharmaceutical composition is an ophthalmic formulation suitable for application to the eye as drops, injection to the eye, or topically to the eye.
  • the composition can include various additional ingredients suitable for ophthalmic use such as tonicity agents, phospholipid carriers, buffers, surfactants, stabilizing polymer, preservatives, co-solvents viscosity building agents, surfactant, stabilizing polymers, wetting agents, emulsifying agents, lubricating agents, antioxidants, mucoadhesive agents, dispersing agents, or any combination thereof.
  • Tonicity agents can include, for example, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, simple sugars such as dextrose, fructose, galactose, and/or simply polyols such as the sugar alcohols mannitol, sorbitol, xylitol, lactitol, isomalt, maltitol, and hydrogenated starch hydrolysates may be added to the composition to approximate physiological tonicity in amounts effective to provide a suitable ophthalmic osmolality, such as about 150-450 mOsm, about 250-350 mOsm, or about 290 mOsm).
  • a tonicity agents can be about 2 to about 4% w/w.
  • Surfactants can include, for example, polysorbate, poloxamer, polyosyl 40 stearate, polyoxyl castor oil, tyloxapol, triton, sorbitan monolaurate, tritonX114, and tyloxapol.
  • Phospholipid carriers can include, for example, Visine Pure Tears®, Visine Tears Natural Tears Formula® (Johnson & Johnson) Tears Naturale®, Tears Naturale II®, Tears Naturale Free®, Bion Tears® (Alcon Laboratories, Inc. Forth Worth, Tex.), Refresh Tears®, Refresh Endura®, Refresh Plus® (Allergan Inc.).
  • Example mu coadhesives include cross-linked polyacrylic acids.
  • Suitable ophthalmic excipients and compounding methods are set forth in Alghamdi et al., Extemporaneous Ophthalmic Preparations, Springer, 2020, American Society of Hospital Pharmacists. ASHP technical assistance bulletin on pharmacy-prepared ophthalmic products. Am J Hosp Pharm. 1993; 50: 1462- 3, and P. Baranowski et al., Ophthalmic Drug Dosage Forms: Characterisation and Research Methods, each of which are hereby incorporated by reference herewith in their entirety.
  • the one or more drugs are not a triptan or a serotonin agonist.
  • the pharmaceutical composition can be free of a triptan or a serotonin agonist.
  • a triptan or a serotonin agonist include sumatriptan, rizatriptan, naratriptan, eletriptan, donitriptan, almotriptan, frovatriptan, avitriptan, and zolmitriptan.
  • the one or more drugs are not a CRGP (calcitonin gene -related peptide) inhibitor.
  • the pharmaceutical composition can be free of a CRGP (calcitonin gene-related peptide) inhibitor.
  • a triptan or a serotonin agonist include erenumab, fremanezumab, galcanezumab, eptinezumab, olcegepant, rimegepant, telcagepant, and ubrogepant.
  • the one or more drugs are not a general antagonist, such as NSAIDS or a general agonist beta-blocker.
  • the pharmaceutical composition can be free of a general antagonist, such as NSAIDS or a general agonist beta-blocker.
  • the pharmaceutical composition can be free of aspirin, ibuprofen, naproxen sodium, flurbiprofen, diclofenac potassium, indomethacin, or diclofenac potassium.
  • the one or more drugs are not a beta-blocker, such as propranolol, timolol, atenolol, or nadolol.
  • the pharmaceutical composition can be free of a beta-blocker, such as propranolol, timolol, atenolol, or nadolol.
  • the one or more drugs are not antiepileptics, antidepressants, nerve blocks, non-steroidal analgesics, opioids,
  • the pharmaceutical composition can be free of antidepressants, nerve blocks, non-steroidal analgesics, opioids, neuromodulators, or neurotoxic protein such as botulinum toxin.
  • composition can be administered to a patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes j 00169] It will be appreciated that composition can be administered using various kinds of delivery systems and media. For example, the composition can be administered as a sterile liquid composition administered to the eye as drops, administered to the eye as an injection, intravenously administered, or administered orally. Administration can be performed by a medical practitioner or by the patient themselves. Furthermore, the composition described herein can be administered in combination with other therapeutic agents, physical manipulations of the patient, application of an apparatus to the patient, and other kinds of treatments.
  • the active compound may also be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. These preparations can contain a preservative to prevent the growth of microorganisms.
  • Example preservatives can include benzalkonium chloride, chlorobutanol, benzododecinium bromide, methyl paraben, propyl paraben, phenylethyl alcohol, edentate disodium, sorbic acid, polyquaternium-1 , and thimerosal.
  • the route of administration can be any route which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment.
  • the composition can be administered systemically or locally, including by direct administration to the eye.
  • the composition can be directly injected into the eye or topically applied to the eye as an emulsion or solution.
  • the pharmaceutical composition is administered by a route other than via the working fluid of the apparatus, via the cavity of the apparatus, or both.
  • the pharmaceutical composition can be administered by a route other than as a therapeutic gas, mist, or fog.
  • pharmaceutical composition can be administered be separate from the device.
  • the pharmaceutical composition is not a working fluid of the apparatus, working gas of the apparatus, or working liquid of the apparatus.
  • the pharmaceutical composition does not apply external physical pressure to the eye of the patient.
  • the pharmaceutical composition is not in gas, mist, or fog form. In various embodiments, the pharmaceutical composition is not nebulized prior to administration. In various embodiments, the pharmaceutical composition can be administered separately from the apparatus, for example before, after, or by directly administering the composition to the patient without the administration being mediated by the apparatus or contained within the apparatus cavity.
  • Dosage forms can be administered daily, or more than once a day, such as twice or thrice daily. Alternatively, dosage forms can be administered less frequently than daily, such as every other day, or weekly, if found to be advisable by a prescribing physician.
  • the composition is administered as drops to the eye.
  • the composition can be administered as a single drop, two drops, three drops, or about 1 to about 5 drops.
  • Standard droplet size is about 0.05 ml, but the composition can also be administered as approximately a droplet having a volume of about 0.01 ml, 0.02 ml, 0.03 ml, 0.04 ml, 0.05 ml, 0.06 ml, 0.07 ml, 0.08 ml, 0.09 ml, or about 0.1 ml.
  • An“agonist” of a substance can refer to a composition of matter which, when administered enhances or extends a biological activity attributable to the referenced target cite, e.g., a receptor, or a referenced endogenous ligand.
  • An“antagonist” of a substance can refer to a composition of matter which, when administered inhibits a biological activity attributable to the referenced target cite, e.g., a receptor, or a referenced endogenous ligand.
  • An“analog”, or“analogue,” of a chemical compound can refer to a compound that, by way of example, resembles another in structure but is not necessarily an isomer.
  • An analog can include a derivative, which is a chemical compound that may be produced from another compound of similar structure in one or more steps, as in replacement of H by an alkyl, acyl, or amino group.
  • an“effective amount” or“therapeutically effective amount” can refer to an amount sufficient to produce a referenced effect, for example an effective amount for alleviating symptoms of a headache is sufficient to reduce the severity of the symptom, or the frequency with which such a symptom is experienced by a subject, or both.
  • a therapeutically effective amount to treat a symptom of glaucoma is the amount for alleviating symptoms of a headache is sufficient to reduce the severity of the symptom, or the frequency with which a glaucoma symptom is experienced by a subject, or both.
  • a given compound can have different effective amounts for different referenced effects. For example, the amount of a compound effective to treat headache when administered together with application of an apparatus can be less than the amount effective to treat glaucoma.
  • a therapeutically effective amount of a compound can also refer to the amount of compound which is sufficient to provide a target beneficial effect to the subject with respect to the intended indication for which the subject is treated. That is, therapeutically effective amount can differ based on indication. In some examples, such amounts can correspond to the dosage identified on a label (e.g., an FDA- approved label) for a given indication of an approved drug. In some examples, a therapeutically effective amount of a given treatment to treat headache can differ from patient to patient, but can be arrived at by monitoring a patient’s symptoms of headache to ascertain the amount that is effective to provide relief for a given patient.
  • a label e.g., an FDA- approved label
  • “Applying” or“administering” a pharmaceutical composition can refer to administration of a active agent by any number of routes and means including, but not limited to, topical, topical administration to the eye, drops to the eye, injection into the eye, oral, buccal, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, vaginal, ophthalmic, pulmonary, or rectal means.
  • modulate refers to adjusting the level of an activity, function, process, or physiologic characteristic.
  • the term can refer to inhibiting, or stimulating, or both.
  • the term can refer to increasing, or decrease, or both.
  • modulating can be reducing.
  • a pharmaceutically acceptable carrier can include standard
  • a phosphate buffered saline solution such as water, emulsions such as an oil/water or water/oil emulsion, and various types of wetting agents.
  • emulsions such as an oil/water or water/oil emulsion
  • wetting agents various types of wetting agents.
  • the term also encompasses any of the agents approved by a regulatory agency of the US Federal government or listed in the US
  • a pharmaceutical carrier refers to non-solvent or non-aqueous solution
  • the present disclosure provides a treatment that can involve use of an apparatus, device, or system to directly or indirectly modulate a physiological characteristic of the patient eye.
  • FIG. 5 shows an example of an apparatus 100, such as to stimulate patient tissue to adjust a headache symptom experienced by a patient, such as through control of an eye environment over a patient eye.
  • Stimulation of patient tissue can include at least one of the absorption of one or more therapeutic components into patient tissue, such as through adjustment of fluid composition in the eye environment, or the application of force to patient tissue, such as through adjustment of non-ambient pressure associated with the eye
  • the patient tissue can include any tissues of the patient affected by the eye environment, such as an anterior surface of the patient eye or patient skin exposed to the eye environment.
  • the apparatus 100 can include a cover 110, a fluid regulator 120, a sensor.
  • the cover 110 can be sized and shaped to surround the patient eye and be spaced from the eye, such as without contacting the eye including the anterior surface of the eye.
  • the cover 110 can be sized and shaped to surround and cover both patient eyes, such as the left eye and the right eye of a patient.
  • the cover 110 can include a mask, such as a cover 110 similar in shape and function to a diving or snorkeling mask that can cover both the left eye and the right eye of the patient.
  • the cover 110 can include a lens portion 182 to allow a patient to see outward through the cover 110 or to allow observation of the eye, such as exterior structures of the eye including the cornea or intraocular structures of the eye including the retina, inward through the cover 110.
  • the lens portion 182 can serve as a corrective lens for the patient, such as to correct an astigmatism of the eye.
  • the lens portion 182 can include a lens blank, such as an A8 lens blank, that can be shaped as a prescription lens for the patient, such as to correct for refractive error in the eye.
  • the lens portion 182 can include a replaceable lens portion 182, such as a first lens portion in the apparatus 100 can be interchanged with a second lens portion, such as to change the lens magnification presented to the patient.
  • lens magnification can be selected to allow for examination of the intraocular space of the eye including assessment of the retina and the choroid, such as for at least one of diagnostic or treatment purposes.
  • the lens magnification can be selected to enhance the examination of the eye, such as to focus the lens portion 182 to enhance visualization of a portion of the eye.
  • the inner surface of the lens portion 182 can be treated, such as with an anti-fog coating to prevent condensation from obscuring the view of the patient.
  • the lens portion 182 can be configured to control ambient light entering the cavity 112, such as to adjust or relieve a headache symptom.
  • the lens portion 182 can include tinting, such as an auto-tinting lens to reduce the intensity of light to adjust or relieve the headache symptom.
  • the cover 110 can define an enclosed cavity 112, such as when the cover 110 is placed over the eye and against the patient.
  • a peripheral edge of the cover 110 placed over the eye can contact at least a portion of patient tissue proximal to the eye socket, such as to form the cavity 112.
  • the cavity 112 can define an enclosed cavity 112 over both eyes, such as when the cover 110 includes a mask located over the left and right patient eyes.
  • the cavity 112 can include a spatial volume, such as the spatial volume defined between an inner surface 188 of the cover 110, and patient tissue, such as including an anterior surface of the patient eye.
  • the cavity 112 can contain a working fluid, such as a liquid or gaseous fluid, that can form at least part of an eye environment in contact with the patient tissue, such as including the anterior surface of the patient eye.
  • the cover 110 can include a first port 114.
  • the first post 114 can be located in a surface of the cover 110, such as the first port 114 can extend from an outer surface 187 of the cover 110 to an inner surface 188 of the cover 110, to allow access to the eye environment in the cavity 112.
  • the first port 114 can include a septum, such as a flexible septum located over the first port 114 to isolate the cavity 112 from the surrounding environment.
  • the flexible septum can maintain a gauge pressure in the cavity 112, such as at least one of a positive or negative gauge pressure.
  • the flexible septum can include a resealable septum, such as a septum formed from a self-healing material including a self-sealing polymer material that can allow the insertion and withdrawal of instruments through the septum into the cavity 112 while maintaining a gauge pressure in the cavity 112.
  • a resealable septum can allow a hypodermic needle to be inserted and withdrawn through the resealable septum while maintaining a gauge pressure (e.g. a positive or negative gauge pressure) in the cavity 112.
  • the resealable septum can allow for a hypodermic needle to be placed in proximity of the eye, such as to place a therapeutic fluid in contact with the eye, while maintaining a gauge pressure in the cavity 112.
  • the flexible septum can include a measurement septum, such as a septum to allow a sensor, such as the sensor 130, to sense an indication of the eye environment in the cavity 112 without contacting the eye environment.
  • a pressure sensor can be in contact with the measurement septum covering the first port 114 of the cover 110, such as to sense an indication of working fluid pressure in the cavity 112 through the measurement septum.
  • the cover 110 can include a second port 116, such as extending from an outer surface 187 of the cover 110 to an inner surface 188 of the cover 110.
  • the second port 116 can place the cavity 112 in communication with the pressure source 150, such as with a conduit 117.
  • the apparatus 100 can include a cavity check valve 189.
  • the cavity check valve 189 can be located on the apparatus 100 in communication with the cavity 112, such as on at least one of the cover 110 including any surface of the cover 110, the conduit 117, the control circuitry 140, or the pressure source 150.
  • the cavity check valve 189 can be located in proximity to, such as in, on, or over, the first port 114.
  • the cavity check valve 189 can limit fluid pressure, such as in the cavity 112.
  • the cavity check valve 189 can be used as a safety valve, such as to ensure that pressure in the cavity 112 will not exceed a cavity pressure level that could damage the patient eye.
  • the cavity check valve 189 can limit pressure in the cavity 112, such as to a target cavity pressure level.
  • the cavity check valve 189 can include a cracking pressure, such as a characteristic of the cavity check valve 189 that can control initiation of fluid flow through the valve.
  • the cracking pressure can describe an inlet pressure level of the cavity check valve 189, such as an inlet pressure level at which a fluid can initiate flow through the cavity check valve 189.
  • Fluid pressure in the cavity 112 can be limited to the target cavity pressure level, such as by selecting or setting the cracking pressure of the cavity check valve 189 to equal the target cavity pressure level.
  • the cavity check valve 189 can assume a closed state, such as to prevent the flow of fluid from the cavity 112 to the surrounding atmosphere.
  • the cavity check valve 189 can assume an open state, such as to allow a flow of fluid from the cavity 112 to the surrounding atmosphere.
  • the cavity check valve 189 can include a passive cavity check valve, such as a flapper valve or a poppet valve.
  • the cracking pressure of the passive cavity check valve can be adjusted, such as by changing the dimensions of the passive cavity check valve or components of the passive cavity check valve.
  • the cracking pressure of a flapper cavity check valve can be adjusted, such as by changing at least one of the flapper check valve dimensions (e.g., length, width, thickness), the flapper check valve constituent material (e.g. type of material, durometer of material, single or multi-ply material, stiffness of valve), or the flapper check valve hinge.
  • the cracking pressure of a poppet cavity check valve can be adjusted, such as by changing at least one of the poppet valve dimensions (e.g., spring stiffness, poppet diameter).
  • Headaches can be triggered by a variety of stimuli, such as changes in at least one of barometric pressure, medications, sleep patterns, hormonal composition, stress (such as including everyday aggravation experienced by a person), or sensory stimuli.
  • a source of light such as a point source of light including direct light, a diffuse source of light including ambient light, or incident light including reflected light, can trigger or proliferate a headache symptom in the patient.
  • light can be defined as transmitted energy that can be sensed by the patient eye, such as at least one of infrared energy (ranging in frequency from about 300 gigahertz to about 30 terahertz), visible light energy (ranging in frequency from about 300 terahertz to about 750 terahertz), or ultraviolet energy (ranging in frequency from about 750 terahertz to about 30 petahertz).
  • infrared energy ranging in frequency from about 300 gigahertz to about 30 terahertz
  • visible light energy ranging in frequency from about 300 terahertz to about 750 terahertz
  • ultraviolet energy ranging in frequency from about 750 terahertz to about 30 petahertz.
  • a light source can be characterized by an objective measure, such as a characteristic of the light source that can be sensed and quantified with a measurement instrument.
  • an objective measure can include an indication of light intensity, such as sensed by a light meter or photometer, an indication of wavelength spectrum, such as sensed by an optical wavelength meter, or an indication of strobing frequency including the number of on-off cycles (where one on-off cycle can be perceived as a“flash” of light) experienced during a period of time.
  • the cover 110 can adjust a characteristic of light received by the patient, such as to optically filter or otherwise modify a characteristic of light passing through the cover 110 and received by the patient eye.
  • An optical filter can include a material, such as one or more materials located in proximity to the cover 110, configured to modify a characteristic of light.
  • An optical filter can include a lens, such as an optical filter lens, configured to modify a characteristic of light, such as a characteristic of light passing through the optical filter lens.
  • An optical filter lens can include the cover 110, such as the cover 110 to which a treatment has been applied, or a lens separate from the cover 110, such as a lens that can be located in proximity to the cover 110.
  • a lens separate from the cover 110 can include a lens with a“clip-on” device, such as a mechanical clip or magnetic clip device including a first magnet with a positive polarization located on the lens and a second magnet with a negative polarization located on the apparatus 100 including the cover 110, to secure the lens in proximity to the cover 110.
  • a lens separate from the cover 110 can include an adhesive cover or a cling cover, such as a material configured as a membrane that can be located on a surface of the cover 110 and retained against the cover 110, such as with an adhesive located between the membrane and the cover 110 or by electrostatic charge between the membrane and the cover 110.
  • an adhesive cover or a cling cover such as a material configured as a membrane that can be located on a surface of the cover 110 and retained against the cover 110, such as with an adhesive located between the membrane and the cover 110 or by electrostatic charge between the membrane and the cover 110.
  • An optical filter lens can be configured to reduce the intensity of light passing through the optical filter lens, such as to reduce the intensity of incident light received by the patient eye.
  • the optical filter lens can reduce transmission of light received by the patient eye, such as through the cover 110, by a percentage, such as a percent fraction of the light impinging on the cover 110.
  • the optical filter lens can reduce transmission of light through the cover 110 by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% of light impinging on the cover 110.
  • the optical filter lens can reduce transmission of light through the cover 110 by 100%, such as to completely block the transmission of light through the cover 110.
  • An optical filter lens for broad frequency reduction of light intensity can include a tinted lens, such as a lens treated with at least one of a soluble organic dye or a metal oxide pigment.
  • Tinted lens can include a surface treatment, such as a tinting material that can be applied to at least a part of a surface of the optical filter lens, or be integrated through the bulk of optical filter lens, such as at least a portion of the bulk of the optical filter lens.
  • Tinted lens can be configured to filter a narrow frequency range of light, such as to mitigate a specific health issue or headache trigger.
  • a tinted lens can include a yellow- tinted lens, such as a lens to which a tinting process or tinting chemicals have been applied, configured to filter HEV light from the light received by the patient eye.
  • HEV light can be defined as light or radiated energy in a range of about 600 terahertz to about 700 terahertz.
  • An optical filter lens for general reduction of light intensity can include an iris lens, such as an optical filter lens with an iris.
  • the iris lens can include a fixed diameter iris, such as an optical filter lens that can be attached to or integrated with the cover 110 with a fixed iris opening smaller than the cover 110.
  • the iris lens can include an adjustable diameter iris, such as an optical filter lens than can be attached to or integrated with the cover 110 with an iris mechanism configured to allow a user to adjust the iris diameter.
  • An optical filter lens for general reduction of light intensity can include a“smart” lens, such as a lens utilizing“smart glass” or“switchable glass” to filter light through the cover 110.
  • Smart glass can include a chromic material, such as at least one of an electrochromic, photochromic, thermochromic, suspended-particle, micro-blind, or polymer-dispersed liquid crystal (PDLC) material.
  • PDLC polymer-dispersed liquid crystal
  • Other materials can include materials using ferro-electric mechanical polarization, light sensitive glazing, and single target direct current (DC) magnetron sputtering, such as including deposition of a magnesium-nickel (MgNi) compound on at least a part of a surface of the optical filter lens.
  • DC direct current
  • An optical filter lens for general reduction of light intensity can include a polarizing lens, such as a lens with a beam-splitting polarizer including at least one of a Fresnel reflection polarizer, a birefringent polarizer, a thin film polarizer, or a wire-grid polarizer.
  • An optical filter lens can include one or more polarizing lens, such as a first polarizing lens and a second polarizing lens configured to allow the second polarizing lens to be repeatedly locatable with respect to the first polarizing lens.
  • the first polar lens can be located in proximity to the cover 110, such as integrated into the cover 110 to form a portion of the cover 110
  • the second polar lens can be located in proximity to the first polar lens, such as adjacent to at least a portion of a surface of the first polar lens.
  • the second polarizing lens can be moved relative to the first polarizing lens, such as rotated about an axis perpendicular to both the first and second polarizing lenses, to form an adjustable optical filter lens, such as to allow a user wearing the cover 110 to adjust the intensity of light received by the user eye.
  • An optical filter lens for restricted frequency reduction of light intensity can include a photochromatic lens, such as a lens treated with at least one of a pyridobenzoxazine chemical or compound, a naphthopyran chemical or compound including an indenonaphthopyran, or a halide chemical or compound including a silver halide.
  • Photochomatic lens can include a surface treatment, such as a photochromatic material can be applied to the surface of the optical filter lens, or be integrated through at least a portion of the bulk of the optical filter lens.
  • a silver halide including silver chloride can be embedded into or applied to a surface of the cover 110, such as to form an optical filter lens to filter ultraviolet light including UV-A light (wavelength range of about 315 nanometers to about 400 nanometers) from light received by the patient eye.
  • UV-A light wavelength range of about 315 nanometers to about 400 nanometers
  • FIG. 6 shows an illustration of acupressure points on facial tissue.
  • Facial acupressure pressure points can include at least one of Seal Place (GV24.5), Eyes Bright (Bl), Harmony Bone (TW22), Yang White (GB14), Drilling bamboo (B2), Silk Bamboo Lollow (TW23), Hearing Meeting (GB 1), Receive Tears (ST1), Four Whites (S2), Welcome Perfume (LI20), Cheekbone (SI18), Middle of Person (GV26), Facial Beauty (ST3), Earth Granary (ST4), or Grain Bone (LI 19).
  • the facial acupressure pressure points can by symmetrical, such as bilaterally symmetrical about a centerline of the face, such as a centerline including at least one of a centerline extending vertically between the eyes and the nostrils of the face or a centerline connecting to acupressure points, such as the labeled points GV24.5 and GV26.
  • the acupressure ETD can be configured to locate the protuberance 191 over a facial acupressure point and contact pressure applied to the facial acupressure point, such as by adjustment of non-ambient pressure in the cavity 112, to stimulate patient tissue.
  • FIG. 7A and 7B show an example of a protuberance 191 and a recess 192, such as located on the patient interface surface 119A.
  • the protuberance 191 can include a feature, such as one or more features, that can be adjusted, such as to improve effectiveness of the acupressure ETD.
  • the protuberance 191 can assume a generally circular shape, such as shown in FIG. 7A, or any non-circular shape.
  • the protuberance 191 can assume a generally biaxially symmetric cross section, such as shown in FIG. 7B, or any non-symmetric cross section.
  • the height of the protuberance 191 can vary the level of force applied to the patient tissue.
  • the height of the protuberance 191 can be defined as the distance from a reference surface, such as the patient interface surface 119A, to the maximum excursion of the protuberance 191 from the reference surface.
  • the protuberance height can include a range of height, such as at least one of a range from about 0 mm to about 2 mm, a range from about 2 mm to about 5 mm, a range from about 5 mm to about 7.5 mm, or a range of greater than about 7.5 mm.
  • the protuberance 191 can include a needle, such as an acupuncture needle.
  • the recess 192 can include a feature, such as one or more features, that can be adjusted, such as to improve effectiveness of the acupressure ETD.
  • the recess 192 can assume a generally circular shape, such as shown in FIG. 7A, or any non-circular shape.
  • the recess 192 can assume a generally biaxially symmetric cross section, such as shown in FIG. 7B, or any non-symmetric cross section.
  • the depth of the recess 192 can vary the level of force applied to the patient tissue.
  • the depth of the recess 192 can be defined as the distance from a reference surface, such as the patient interface surface 119A, to the maximum excursion of the recess 192 from the reference surface.
  • the recess 192 depth can include a range of depth, such as at least one of a range from about 0 mm to about 2 mm, a range from about 2 mm to about 5 mm, a range from about 5 mm to about 7.5 mm, or a range of greater than about 7.5 mm.
  • the acupressure ETD can include a portion formed as an integral part of the patient interface surface 119A.
  • the protuberance 191 or the recess 192 can be incorporated as a feature into the mold or die used to form the patient interface surface 119A.
  • the acupressure ETD can include a component separate from the patient interface surface 119A.
  • the protuberance 191 can include a molded protuberance component that can adhere to the patient interface surface 119 A, such as a molded protuberance component that can be bonded to a location on the patient interface surface 119A to precisely position the protuberance component with respect to an acupressure pressure point on the patient tissue.
  • the protuberance 191 can in include a molded protuberance component that can be located over the acupressure pressure point on the patient tissue and then bonded to the patient interface surface 119A upon locating the cover 1 10 over the eye of the patient.
  • the acupressure ETD can include a flange cover, such as a flange cover configured overlay the patient interface surface 119A.
  • a flange cover can include any structure that can be located between the patient interface surface 119A and the patient.
  • the flange cover can include a base structure, such as a sheet-like material with an adhesive on one or both sides of the sheet-like material, to overlay at least a portion of the patient interface surface 119A, and a protuberance structure including a protuberance 191, connected to the base structure.
  • the flange cover can be configured to overlay the patient interface surface 119 A, such as to position the protuberance for contact with the patient tissue when the cover 110 is located against the patient.
  • the flange cover can be adjusted with respect to the patient interface surface 119 A, such as to relocate the protuberance structure from a first position to a second position different from the first position to better align the protuberance structure with a location on the patient tissue, such as an acupressure pressure point on the patient.
  • the ETD can include a sonic ETD, such as a device attached to or in proximity of the cover 110, to generate energy in the sonic frequency range for transmission to the patient to stimulate patient tissue.
  • the sonic frequency range can include a frequency range from about 2 Hertz (Hz) to about 20 kilohertz (kHz).
  • the ETD can include an electromagnetic (or EM) ETD, such as a device attached to or in proximity of the cover 110, to generate energy in the EM frequency range for transmission to the patient to stimulate patient tissue.
  • the EM frequency range can include a radio frequency range including a frequency range from about 20 kHz to about 300 megahertz (MHz).
  • the EM frequency range can include a microwave frequency range including a frequency range from about 300 MHz to about 300 gigahertz (GHz).
  • the EM frequency range can include an infrared frequency range including a frequency range from about 300 GHz to about 430 tetrahertz (THz).
  • the EM frequency range can include a visible light frequency range including a frequency range from about 430 THz to about 750 THz.
  • the EM frequency range can include an ultraviolet frequency range including a frequency range from about 750 THz to about 3 petahertz (PHz).
  • an EM ETD can include a visible light ETD, such as a device capable of transmitting radiation in the visible light frequency range from the visible light ETD into the patient eye, such as to stimulate ocular patient tissue including retinal tissue to increase ocular blood flow including macular blood flow.
  • the visible light ETD can generate pulses of visible light (or pulsed light), such as to stimulate the ocular tissue.
  • the frequency of the pulsed light can vary in a range, such as in a frequency range of at least one of about 0.25 Hz to about 500 Hz, about 2 Hz to about 100 Hz, about 10 Hz to about 70 Hz, or from about 20 Hz to about 50 Hz.
  • FIG. 8 shows an example of the cover 110 including an anterior plate 193.
  • the anterior plate 193 can include an extension of the cover 110 configured to cover at least a portion of patient tissue proximal to an anterior portion of the skull.
  • the anterior portion of the skull can include a bone of the skull such as at least a portion of one of a frontal bone, a parietal bone, a temporal bone, a sphenoid bone, an ethmoid bone, a nasal bone, a lacrimal bone, a zygomatic bone, a maxilla bone, or a mandible bone.
  • the anterior plate 193 can be coupled to and work in combination with the cover 110, such as to adjust patient perception of an indication of a headache symptom to treat, inhibit, or prevent the headache symptom.
  • the anterior plate 193 can be affixed to the cover 110, such as the anterior plate 193 and the cover 110 can form a single component of the apparatus 100.
  • the anterior plate 193 can be removably secured to the cover 110, such as the anterior plate 193 and the cover 110 can be attached to each other to form a single component of the apparatus 100 or removably detached one from the other to form two components.
  • the distance between the anterior plate 193 and the patient tissue can be adjusted, such as by adjusting non-ambient pressure in the cavity 112.
  • increasing the level of vacuum (e.g., increasing applied negative pressure) or decreasing the level of positive pressure in the cavity 112 can cause the anterior plate 193 to be drawn closer to the patient tissue, such as to decrease the distance between the anterior plate 193 and the patient tissue.
  • the level of vacuum can be increased such as to cause the anterior plate 193 to contact the patient tissue.
  • decreasing the level of vacuum (e.g., decreasing applied negative pressure) or increasing applied positive pressure in the cavity 112 can cause the anterior place 193 to be located further from the patient tissue, such as to increase the distance between the anterior plate 193 and the patient tissue.
  • the anterior plate 193 can include an anterior plate harness 194, such as a device capable of locating and retaining the anterior plate 193 over the patient tissue.
  • the anterior plate harness 194 can include a tether, such as a retention device including a strap, attached to the anterior plate 193 and configured to locate the anterior plate 193 on the patient over the patient tissue.
  • the anterior plate harness 194 can include a tensioner, in
  • the tensioner can include any device configured to create or retain tension in a tether or similar tether-like device, such as at least one of a winch mechanism, a belt tensioning device, a drawstring-style device, a come-along device, or an adjustable coupler, such as a turnbuckle.
  • the tensioner can include a sensor 130, such as a tension sensor to sense tension force in the tether.
  • the tensioner can be manually adjusted, such as a user can manipulate the tensioner to increase or decrease tension in the tether.
  • the tensioner can be remotely adjusted, such as with a tensioner actuator connected to the tensioner to increase or decrease tension in the tether.
  • the tensioner actuator can include any force-generating device, such as a pneumatic actuator, a hydraulic actuator, or an electric actuator including an electric motor.
  • the tensioner actuator can be in communication with the control circuitry 140, such as to adjust tension in the tether by adjusting the tensioner actuator based on a tension feedback control circuit.
  • the anterior plate 193 can contact at least a portion of patient tissue proximal to the anterior portion of the skull, such as to stimulate the patient tissue.
  • Patient tissue proximal to the anterior portion of the skull can include tissue covering the skull, such as including epidermis, dermis, hypodermis, and one or more structures residing within the tissue, such as including a blood vessel and a cranial nerve.
  • the cranial nerve can include any nerve located in proximity to the anterior portion of the skull, such as at least one of a trigeminal nerve or a facial nerve.
  • Patient tissue proximate to the anterior portion of the skull can include tissue in proximity to at least a portion of the interior of the skull, such as the meninges including a portion of dura mater, arachnoid mater, or pia mater, and other tissues associated with the meninges, such as including an interior blood vessel or interior cranial nerve.
  • the tether can encircle at least a portion of the patient head to locate the anterior plate 193 over the patient tissue and the tensioner can be adjusted, such as to cause the anterior plate 193 to contact the patient tissue.
  • the tensioner In bringing the anterior plate 193 into contact with patient tissue, the tensioner can be further adjusted, such as to generate plate contact pressure between the anterior plate 193 and the patient tissue.
  • the magnitude of the plate contact pressure can be adjusted, such as by at least one of adjusting tension in the tether with the tensioner or adjusting non-ambient pressure in the cavity 112.
  • the plate contact pressure generated by the anterior plate 193 against the patient tissue can stimulate the patient tissue to adjust a perceived patient headache symptom, such as to treat, inhibit, prevent the headache symptom.
  • the effect of the plate contact pressure to adjust the perceived patient headache symptom can be enhanced through additional stimulation of the patient tissue, such as with an energy transfer device (ETD).
  • ETD energy transfer device
  • the anterior plate 193 can include an ETD as described elsewhere in this application to stimulate patient tissue.
  • the ETD can include a protuberance 191, such as located between the anterior plate 193 and patient tissue.
  • the protuberance 191 can be positioned over and brought into contact with a facial acupressure point, such as to apply force to patient tissue.
  • the applied force can be varied, such as by adjusting at least one of the non-ambient pressure in the eye environment or the tensioner.
  • the ETD can attach to and removably detach from the anterior plate 193.
  • the anterior plate 193 can be constructed from a sheet material, such as a material formed in a sheet.
  • the sheet material can include a rigid sheet material, such as at least one of a thermoset material or a thermoplastic material.
  • the rigid sheet material can be conformed to the patient tissue, such as conformed to facial contours of the patient.
  • thermoplastic sheet material can conform to the patient tissue, such as facial contours of the patient covered by facial tissue, by heating the sheet to a temperature above a glass transition temperature of the sheet material and subsequently forming the sheet to the facial contours of the patient.
  • the anterior plate 193 can include a first anterior plate surface 193A (not shown), such as a surface of the anterior plate facing the patient tissue, and a second anterior plate surface 193B, such as a surface opposite the first anterior plate surface 193 A.
  • An anterior plate gasket 195 can be located around the periphery of the anterior plate 193, such as to create an anterior plate cavity between the first anterior plate surface 193A (not shown) and the patient tissue.
  • the anterior plate gasket 195 can create an air-tight interface between the first anterior plate surface 193 A (not shown) and patient tissue proximate to the anterior portion of the skull, such as to support a gauge pressure in the anterior plate cavity, such as an anterior plate cavity pressure.
  • Application of at least one of a positive gauge pressure or a negative gauge pressure, such as with the pressure source 150 can generate a force on the patient tissue exposed to the gauge pressure in the anterior plate cavity, such as to stimulate the patient tissue to adjust an indication of a headache symptom to treat, inhibit, or prevent the headache symptom.
  • the sheet material can include a flexible sheet material, such as at least one of an elastomer or a polymer including high-density polyethylene.
  • the flexible sheet material can conform to patient tissue, such as facial contours of the patient tissue, and can adhere to the patient tissue, such as due to at least one of the nature of flexible sheet material, processing of the flexible sheet material, or by locating an adhesive between the flexible sheet material and the patient tissue.
  • the flexible sheet material can incorporate an ETD, such as to locate and retain the ETD against the anterior patient tissue.
  • the ETD can be embedded in the flexible sheet material for placement against the anterior patient tissue or the ETD can be placed against the anterior patient tissue and covered by the flexible sheet material, such as to locate and retain the ETD against the anterior patient tissue.
  • a flex sheet cavity can be formed between the flexible sheet material and the patient tissue.
  • the flex sheet cavity can be formed by adhering at least a portion of the flexible sheet material to the patient tissue and preventing the remaining portion of the flexible sheet material from adhering to the patient tissue.
  • the periphery of the flexible sheet material can be adhered to the patient tissue and the flexible sheet material not forming the periphery can be prevented from adhering to the patient tissue, such as to form a“pouch” or flex sheet cavity between the flexible sheet material and the patient tissue.
  • the flex sheet cavity can be in communication with the pressure source 150 and configured to retain gauge pressure against the patient tissue, such as to generate a force due to gauge pressure on the patient tissue exposed to the gauge pressure and stimulate the patient tissue.
  • an inflatable pillow in communication with the pressure source 150 and configured to retain gauge pressure can be located in the flex sheet cavity, such as to generate a force reacted by the patient tissue to stimulate the patient tissue.
  • FIG. 9 shows an example of the cover 110 including a posterior plate 196.
  • the cover 110 can include the posterior plate 196, such as a component configured to cover at least a portion of patient tissue proximal to a posterior portion of the skull.
  • the posterior portion of the skull can include a bone of the skull such as at least a portion of at least one of a parietal bone, a frontal bone, an occipital bone, or a temporal bone.
  • the posterior plate 196 can contact at least a portion of patient tissue proximal to the posterior portion of the skull, such as to stimulate the patient tissue.
  • Patient tissue proximate to the posterior portion of the skull can include tissue covering the skull including epidermis, dermis, hypodermis, and one or more structures residing within the tissue including a blood vessel and a cranial nerve.
  • the cranial nerve can include any nerve located in proximity to the posterior portion of the skull, such as an occipital nerve.
  • Patient tissue proximate to the posterior portion of the skull can include tissue in proximity to at least a portion of the interior of the skull, such as the meninges including a portion of dura mater, arachnoid mater, or pia mater, and other tissues associated with the meninges including an interior blood vessel or interior cranial nerve.
  • the posterior plate 196 can be coupled to and work with the cover 110, such as with a posterior plate tether 198, to adjust patient perception of an indication of a headache symptom to treat, inhibit, such as a device capable of locating and retaining the posterior plate 196 in contact with the patient tissue.
  • the posterior plate tether 198 can include at least one of a rigid posterior plate tether or a flexible posterior plate tether.
  • the rigid posterior plate tether can include adjustable headgear, such as including an adjustable harness, strip rachet headband, or similar devices to locate and secure the posterior plate 196 to the patient and can include a tensioner configured to draw the posterior plate into contact with the patient tissue.
  • the flexible posterior plate tether can include a strap, such as to locate the posterior plate 196 against the patient, and a tensioner, such as to draw the posterior plate 196 into contact with the patient.
  • FIG. 10 shows an illustration of posterior acupressure points on a patient.
  • Acupressure pressure points can include at least one of Wind Mansion (GV16), Crown Chakra (GV20), Window of Heaven (TW16), Heavenly Pillar (B10), or Shoulder Well (GB21).
  • a protuberance 191 can be located on the first posterior plate surface 196 A (not shown) over a posterior acupressure point and contact pressure applied to the posterior acupressure point, such as by adjustment of tension in the posterior plate tether 198, to stimulate patient tissue.
  • the posterior plate 196 can include an ETD that can operate to transfer energy to the patient, such as through contact with the patient tissue, such as to stimulate a posterior acupressure point.
  • An ETD can include at least one of a temperature ETD, a vibration ETD, an acupuncture ETD, an electrostimulation ETD, an acupressure ETD, a sonic ETD, or an EM ETD.
  • the ETD can include a protuberance 191, such as located between the posterior plate 196 and patient tissue.
  • the protuberance 191 can be positioned over and brought into contact with a posterior acupressure point to apply force to patient tissue.
  • the applied force can be varied, such as by adjusting at least one of the non-ambient pressure in the eye environment or the tensioner.
  • the ETD can attach to and removably detach from the posterior plate 193.
  • the posterior plate 196 can be constructed from a sheet material.
  • the sheet material can include a rigid sheet material, such as at least one of a thermoset material or a thermoplastic material.
  • the rigid sheet material can be conformed to the patient tissue, such as conformed to posterior cranial contours of the patient.
  • the rigid thermoplastic sheet material can conform to the patient tissue by heating the sheet to a temperature above a glass transition temperature of the material and subsequently forming the sheet to the posterior cranial contours of the patient.
  • the posterior plate 196 can include a first posterior plate surface 196A (not shown), such as a surface of the posterior plate facing the patient tissue, and a second posterior plate surface 196B, such as a surface opposite the first posterior plate surface 196 A (not shown) .
  • a posterior plate gasket 197 can be located around the periphery of the posterior plate 196, such as to create a posterior plate cavity between the first posterior plate surface 196A (not shown) and the patient tissue.
  • the posterior plate gasket 197 can create an air-tight interface between the first posterior plate surface 196 A (not shown) and patient tissue proximate to the posterior portion of the skull, such as to support a posterior plate cavity pressure in the posterior plate cavity.
  • Application of at least one of a positive gauge pressure or a negative gauge pressure, such as with the pressure source 150, can generate a force on the patient tissue exposed to the gauge pressure, such as to stimulate the patient tissue to adjust an indication of an indication of a headache symptom including to treat, inhibit, or prevent the headache symptom.
  • the sheet material can include a flexible sheet material, such as at least one of an elastomer or a polymer including a high-density polyethylene.
  • the flexible sheet material can conform to patient tissue, such as posterior cranial contours of the patient tissue, and can adhere to the patient tissue, such as due to the nature of flexible sheet material, processing of the flexible sheet material, or by locating an adhesive between the flexible sheet material and the patient tissue.
  • the flexible sheet material can incorporate an ETD, such as to locate and retain the ETD against the posterior patient tissue.
  • the ETD can be embedded in the flexible sheet material for placement against the posterior patient tissue or the ETD can be placed against the posterior patient tissue and covered by the flexible sheet material.
  • the flexible sheet material can form a flex sheet cavity, such as described elsewhere in this application, between the flex sheet material and patient tissue proximal to the posterior portion of the skull.
  • An inflatable pillow such as described elsewhere in this application, can be located in the flex sheet cavity, such as to generate a force reacted by the patient tissue to stimulate the patient tissue.
  • the inflatable pillow can be in communication with the pressure source 150.
  • the fluid regulator 120 can regulate the flow of fluid between two reservoirs, such as the fluid flow between the cavity 112 and a fluid source 170, such as a pressurized gas cylinder.
  • the fluid regulator 120 can include a regulator valve, such as to regulate flow rates between the first and second reservoirs.
  • the regulator valve can include a passive valve, such as a check valve that closes as pressure exceeds a critical value.
  • a fluid regulator 120 with a check valve can be located between the cover 110 and a fluid source 170, such as if the pressure of the fluid source 170 exceeds a critical value, such as a pressure that can cause damage to a patient eye, the check valve can close to isolate pressure of the fluid source 170 from the patient eye, such as to protect the patient eye from excessive force.
  • the regulator valve can include an active valve, such as an electrically-modulated valve including a servo valve, or a proportional valve, such as a piezo-actuated proportional valve.
  • the regulator valve can receive a control signal, such as from the control circuitry 140, to modulate the position of the electrically-modulated spool with respect to the valve body, such as to regulate fluid flow through the electrically-modulated valve.
  • the fluid regulator 120 can attach to a fluid source 170, such as to regulate the flow of fluid from the fluid source 170 to the cavity 112.
  • the fluid source 170 can include a fluid vessel, such as a storage container of pressurized gaseous fluid.
  • the fluid source 170 can include a generator device, such as a device that concentrates or distills a constituent fluid from another fluid.
  • a generator device can include a concentrator, such as an oxygen concentrator or a carbon dioxide concentrator.
  • a generator device can include an atomizer, such as an ultrasonic humidifier or an aerosolizer, to transform a liquid therapeutic fluid, such as a miscible solution or colloidal suspension, into a gaseous working fluid, such as a therapeutic mist or fog.
  • an atomizer such as an ultrasonic humidifier or an aerosolizer
  • the fluid regulator 120 can communicate with apparatus 100, such as the fluid regulator 120 can communicate with the cavity 112.
  • the fluid regulator 120 can be connected to the cover 110, such as with the conduit 117 in direct communication with the cover 110 through the second port 116.
  • the fluid regulator 120 can be connected to the conduit 117 in communication with the cover 110 by a tube connector 118, such as a Y- connector.
  • the fluid regulator 120 can be connected to the control circuitry 140, such as to receive a control signal from the control circuitry 140 to adjust the position of a servo valve.
  • the sensor 130 can sense an indication of the eye environment in the cavity 112, such as at least one of an indication of a characteristic of the working fluid in the cavity 112 or an indication of a physiological parameter of the patient.
  • the sensor 130 can include sensor circuitry, such as sensor circuitry to receive an indication of a physical parameter sensed by the sensor 130 and process the received indication, such as into an indication including an electrical signal suitable to be received by at least one of the control circuitry 140 or the pressure source 150.
  • the sensor 130 can be located in proximity to the apparatus 100, such as in communication with the cavity 112 or at least partially attached to the patient.
  • the sensor 130 can be separate from the apparatus 100.
  • the sensor 130 can include a handheld pressure gauge, such as to be pressed against a measurement septum located over the port 114 to sense an indication of working fluid pressure in the cavity 112.
  • the sensor 130 can be in fluidic communication with the cavity 112, such as the sensor 130 can be located in the cavity 112 or on the control circuitry 140 in fluidic communication with the cavity 112.
  • the senor 130 can be at least partially attached to the patient, such as to a surface of the eye including an anterior surface of the eye or patient tissue covering the skull including tissue over the frontal, parietal, sphenoid, temporal, zygomatic, maxillary, occipital, and mandibular bones.
  • the sensor 130 can include an
  • electroretinography device such as part of which can include an electrode attached to patient tissue to sense an indication of electrical activity in the patient including electrical activity associated with a pattern electroretinography (or PERG) test.
  • PERG pattern electroretinography
  • the sensor 130 can be in electrical communication with the apparatus, such as at least one of the control circuitry 140 or the pressure source 150.
  • the sensor 130 can provide at least one of continuous or periodic (e.g. intermittent) sensing of the working fluid, such as for monitoring an indication of the eye environment with the sensor 130, or an indication of the physiological parameter associated with the patient, such as IOP or CSFP.
  • the sensor 130 can include an IOP sensor, such as a device to sense an indication of an intraocular pressure (IOP) level in the eye.
  • the IOP sensor can include at least one of an invasive IOP sensor, such as an IOP sensor implantable in an intraocular space of the eye to sense IOP including a sensor from Implandata Ophthalmic Products GmbH (Hannover, Germany) offered for sale under the trademark EYEMATE® or a non-invasive IOP sensor, such as an IOP sensor to sense IOP without implantation into the body including a contact lens-based sensor from Sensimed AG (Lausanne, Switzerland) offered for sale under the trademark SENSIMED TRIGGERFISH®.
  • an invasive IOP sensor such as an IOP sensor implantable in an intraocular space of the eye to sense IOP including a sensor from Implandata Ophthalmic Products GmbH (Hannover, Germany) offered for sale under the trademark EYEMATE®
  • a non-invasive IOP sensor such as an IOP sensor to sense IOP without implantation into
  • the IOP sensor can include at least one of a continuous IOP sensor, such as an IOP sensor capable of continuous sensing of IOP level in the patient eye, or a periodic IOP sensor, such as an IOP sensor that capable of sensing IOP level in the patient eye at periodic or aperiodic intervals.
  • a periodic IOP sensor can include a tonometer, such as a handheld tonometer designed for patient self-monitoring of IOP.
  • the data sensed by the IOP sensor can be received by the control circuitry 140, such as to facilitate use of the apparatus 100.
  • the sensor 130 can include a cardiac sensor, such as to detect an indication of cardiac activity in a patient.
  • An indication of cardiac activity can include at least one of an indication of systemic blood pressure, such as an indication of systolic and an indication of diastolic blood pressure, or an indication of heart rate.
  • the cardiac sensor can include a blood pressure (BP) sensor, such as a device to sense an indication of blood pressure level including systemic blood pressure level, in the patient.
  • BP blood pressure
  • the BP sensor can include at least one of an invasive BP sensor, such as a BP sensor implantable within the patient, and a non-invasive BP sensor, such as a BP sensor that can sense BP without implantation within the patient body.
  • the sensor 130 can include a working fluid flow sensor, such as a device to sense an indication of working fluid flow including at least one of volumetric flow rate or mass flow rate into or out of the cavity 112.
  • the sensor 130 can include a humidity sensor, such as a device to sense an indication of the relative humidity of the working fluid in the cavity 112.
  • the sensor 130 can include a thermometer, such as a device to sense an indication of the temperature of the working fluid in the cavity 112.
  • the sensor 130 can include a working fluid flow sensor, such as a device to sense an indication of working fluid flow including at least one of volumetric flow rate or mass flow rate into or out of the cavity 112.
  • the sensor 130 can include a humidity sensor, such as a device to sense an indication of the relative humidity of the working fluid in the cavity 112.
  • the sensor 130 can include a thermometer, such as a device to sense an indication of the temperature of the working fluid in the cavity 112.
  • the sensor 130 can include a thermometer
  • displacement sensor such as a device to sense an indication of displacement including an optical coherence tomography device configured to sense displacement of structures associated with the patient eye.
  • the sensor 130 can include a pressure sensor, such as a device to sense an indication of working fluid pressure in the cavity 112.
  • the pressure sensor can be located in proximity to the cavity 112, such as in communication with the cavity 112.
  • the pressure sensor can include a cavity pressure sensor, such as a pressure sensor located in the cavity 112.
  • Static cavity pressure level in the cavity 112 such as the pressure level sensed by the pressure sensor when the pressure source 150 is not adjusting working fluid pressure in the cavity 112, can be the same at any location in the cavity 112.
  • Dynamic cavity pressure level such as the pressure level sensed by the pressure sensor when the pressure source 150 is adjusting working fluid pressure in the cavity 112, can vary depending on the location of the pressure sensor in communication with the cavity 112.
  • the sensor 130 can include a pressure sensor in combination with another indication, such as an indication of the operating state of the pressure source 150, to estimate a static cavity pressure level in the cavity 112.
  • the pressure sensor such as a pressure-flow sensor including a sensor that can measure both working fluid pressure (static and dynamic) and working fluid flow at a measurement location, can be located in proximity to the pressure source 150, such as an inlet port or an outlet port of the pressure source 150, to sense an indication of dynamic pressure at the pressure sensor location and include circuitry, such as sensor circuitry to receive an indication of the operation state of the pressure source 150 including an indication of flow rate (e.g., pump speed can be proportional to flow rate).
  • flow rate e.g., pump speed can be proportional to flow rate
  • the pressure -flow sensor can process at least one of the indication of dynamic pressure or the indication of flow rate, such as to form a control signal that can be received by the pressure source 150 to achieve a static cavity pressure level, such as a target pressure level, in the cavity 112.
  • the control signal can be based on a relationship between the indication of dynamic pressure and the indication flow rate, such as a relationship between pressure and flow including the relationship described by a p-Q (e.g., pressure-flow) chart that can account for the operating characteristics of the pressure source 150.
  • the pressure sensor can be located in proximity to the pressure source 150.
  • the control circuitry 140 can be configured to receive an indication of dynamic pressure from the pressure sensor and an indication of the operation state of the pressure source 150 including an indication of pump speed.
  • the control circuitry 140 can process at least one of the indication of dynamic pressure or the indication of pressure source 150 operation state, such as to form a control signal that can be received by the pressure source 150 to achieve a static cavity pressure level, such as a target pressure level, in the cavity 112.
  • the sensor 130 can include a concentration sensor or a working fluid composition sensor, such as a device to sense an indication of a chemical constituent in the working fluid.
  • the concentration sensor can be configured to sense an indication of the working fluid, such as a constituent in the working fluid.
  • the constituent in the working fluid such as the constituent in the working fluid delivered to the cavity 112, can include a therapeutic fluid.
  • the working fluid composition sensor can sense a therapeutic fluid, such as at least one of (CO2), oxygen (O2), nitric oxide (NO), ozone (O3), nitrogen, helium (He), hydrocarbons including fluorocarbons and perfluorocarbons, sulfur hexafluoride, cannabinoids including
  • THC tetrahydrocannabinol
  • CBD cannabidiol
  • the sensor 130 can include a biomarker sensor, such as a device to sense an indication of a biomarker including a chemical constituent.
  • a chemical constituent in the working fluid can include a biomarker, such as a biomarker emitted by the patient eye or sensed within the patient eye.
  • a biomarker can suggest a physiological state of the eye, such as a state of distress where medical intervention can be desired.
  • the biomarker sensor can include a ketone, such as can be detected with a volatile gas sensor including a quartz crystal nanobalance (QCN) sensor, glucose, such as can be detected with an optical glucose sensor including an OCT imaging system, oxygen levels, such as can be detected with a non-in vasive optical oxygen sensor, dissolved salts, such as can be detected with a salinity sensor, and vascular endothelial growth factor (or VEGF), such as can be detected with an aptamer-based sensor including the sensor and methods described in the publication“Flexible FET-Type VEGF Aptasensor Based on Nitrogen-Doped Graphene Converted from Conducting Polymer”, by Kwon, et at., ACS Nano, Vol.6, #2, pages 1486-1493, published February 2012, and incorporated herein by reference in its entirety.
  • QCN quartz crystal nanobalance
  • a biomarker can include at least one of an enzyme, such as matrix metallopeptidase 9 (MPP-9), that can be detected with an enzyme sensor or a protein, such as brain-derived neurotrophic factor (BDNF), that can be detected with a protein sensor.
  • an enzyme such as matrix metallopeptidase 9 (MPP-9)
  • MPP-9 matrix metallopeptidase 9
  • BDNF brain-derived neurotrophic factor
  • the sensor 130 can include a biosensor, such as a sensor configured to sense an indication of a physiological parameter associated with a patient.
  • a physiological parameter can include an indication of a physiological process associated with the patient, such as a process associated with a patient eye or process associated with physiological activity of the patient eye.
  • a physiological parameter can include at least one of an indication of intraocular pressure (IOP) in the patient eye, such as an IOP level, an indication of cerebrospinal fluid pressure (CSFP) associated with the patient, such as a CSFP level, an indication of cardiac activity, such as at least one of systemic blood pressure or heart rate.
  • IOP intraocular pressure
  • CSFP cerebrospinal fluid pressure
  • a physiological parameter can include an indication of retinal activity, such as measured by an electroretinography device including a pattern electroretinography (or PERG) device.
  • the sensor 130 can include an imaging sensor to sense an indication of the eye, such as an intraocular portion of the eye.
  • the imaging sensor can be located in proximity to the eye, such as attached to apparatus 100 including the cover 110 or exist separately from the apparatus including as a stand-alone device.
  • the imaging sensor can include a camera, such as a single image capture camera or a multi-image capture camera including a video camera, such as the one or more captured images can be transferred to the apparatus 100 for image processing.
  • the imaging sensor can include an optical coherence tomography (OCT) device.
  • OCT optical coherence tomography
  • the sensor 130 can include a blood flow sensor, such as an ocular blood flow sensor.
  • the blood flow sensor can include an invasive blood flow sensor ocular imaging system, such as a blood flow sensor and imaging system that involves at least a part component of the system to be inserted into the patient.
  • an invasive blood flow sensor an invasive ocular imaging system can include a fluorescein angiography system.
  • the blood flow sensor can include a non-invasive ocular blood flow sensor, such as a blood flow sensor that does not require insertion into the patient.
  • the non-invasive ocular blood flow sensor ocular imaging system can include a system to sense an indication of ocular blood flow from a patient or circuitry to process information from the patient to yield an indication of ocular blood flow.
  • the non-invasive ocular blood flow sensor ocular imaging system can include an ocular energy source, such as to radiate illuminate a tissue including ocular tissue with energy to elicit a response from the tissue that can be sensed with a sensor.
  • the ocular tissue can be illuminated with electromagnetic (EM) energy generated by the ocular energy source, such as EM energy in a frequency range from about 3 hertz (Hz) to about 300 exahertz (EHz).
  • EM electromagnetic
  • an ocular energy source can include a diffuse light source, such as generated by a light bulb, and a collimated light source, such as generated by a laser diode.
  • the non-invasive ocular blood flow sensor ocular imaging system can include an ocular blood flow sensor, such as to sense energy radiated from ocular tissue including energy elicited from the ocular tissue by illuminating the ocular tissue with an energy source.
  • An ocular blood flow sensor can be configured to sense EM energy, such as EM energy in a frequency range from about 3 hertz (Hz) to about 300 exahertz (EHz).
  • the ocular blood flow sensor can include an ultrasonic sensor, such as an ultrasonic sensor configured to sense EM energy in a frequency range from about 3 Hz to about 300 gigahertz (GHz) including a frequency range from about 20 kilohertz (kHz) to about 400 kHz and a frequency range of about 1 megahertz (MHz) to about 18 MHz.
  • an ultrasonic sensor such as an ultrasonic sensor configured to sense EM energy in a frequency range from about 3 Hz to about 300 gigahertz (GHz) including a frequency range from about 20 kilohertz (kHz) to about 400 kHz and a frequency range of about 1 megahertz (MHz) to about 18 MHz.
  • GHz gigahertz
  • kHz kilohertz
  • MHz megahertz
  • the ocular blood flow sensor can include a charge coupled device (CCD) sensor such as including a complementary metal-oxide- semiconductor (CMOS) sensor.
  • CCD charge coupled device
  • CMOS complementary metal-oxide- semiconductor
  • the CCD sensor can be configured to sense EM energy in a frequency range, such as at least one of a range from about 300 GHz to about 300 exahertz or EHz including a frequency range from about 300 GHz to about 400 tetrahertz or THz (infrared radiation, corresponding to wavelengths of about 1,000 micrometers to about 750 nanometers or nm), a frequency range from about 400 THz to about 800 THz (visible light, corresponding to wavelengths of about 750 nm to about 375 nm), and a frequency range from about 800 THz to about 30 petahertz or PHZ (ultraviolet radiation, corresponding to wavelengths of about 375 nm to about 10 nm).
  • the non-invasive ocular blood flow sensor ocular imaging system can include a color doppler imaging (CDI) system, such as a medical ultrasonic imaging system with at least one of an ocular energy source, such as an ultrasonic transducer, an ocular blood flow sensor, such as an ultrasonic receiver, or a combination of ocular energy source and ocular blood flow sensor, such as an ultrasonic transceiver.
  • CDI color doppler imaging
  • the CDI system can be configured with an energy source capable of generating EM energy at a frequency of about 6.5 MHz.
  • the non-invasive ocular blood flow sensor system ocular imaging can include a laser speckle flowgraphy (LSF) or laser speckle contrast imaging (LSCI) system.
  • LSF laser speckle flowgraphy
  • LSCI laser speckle contrast imaging
  • the LSF system can be configured with an energy source capable of generating EM energy at a frequency of about 361 THz (corresponding to a wavelength of about 830 nm).
  • the LSF system can include a system from Nidek Co., Ltd. (Aichi, Japan) offered for sale under the tradename LSFG-Retflow.
  • the non-invasive ocular blood flow sensor system can include a laser Doppler flowmeter (LDF), such as a confocal scanning laser Doppler flowmetry (CSLDF) system.
  • LDF laser Doppler flowmeter
  • CSLDF confocal scanning laser Doppler flowmetry
  • the LDF system can be configured with an energy source capable of generating EM energy at a frequency of about 384 THz (corresponding to a wavelength of about 780 nm).
  • the CSLDF system can include a system from Heidelberg Engineering GmbH (Heidelberg, Germany) offered for sale under the tradename Heidelberg Retina Flowmeter.
  • the non-in vasive ocular blood flow sensor system can include an ocular coherence tomography angiography (OCT A) system.
  • OCT ocular coherence tomography
  • the function of an ocular coherence tomography (OCT) system can be enhanced, such as by placing an OCTA module in communication with the OCT system.
  • An OCTA module can include control circuitry that can execute coded instructions to cause the OCT system to repeatedly scan a section of eye tissue, store each scan of eye tissue into memory, and process the stored scans to identify differences between scans, such as to generate an indication of ocular blood flow.
  • the OCTA system can include at least one of an OCT system from Heidelberg Engineering GmbH (Heidelberg, Germany) offered for sale under the tradename Spectralis or an OCTA module from Heidelberg Engineering GmbH (Heidelberg, Germany) offered for sale under the tradename Spectralis OCT Angiography Module.
  • the non-in vasive ocular blood flow sensor system can include a laser doppler velocimetry (LDV) system.
  • LDV laser doppler velocimetry
  • the LDV system can be configured with an energy source capable of generating EM energy at a frequency of about 444 THz (corresponding to a wavelength of about 675 nm).
  • the non-in vasive ocular blood flow sensor system can include a retinal vessel analyzer (RVA) system.
  • the RVA system can include a system that illuminates the eye vessel and senses at least one of a coefficient of light reflection or a coefficient of light absorption.
  • the non-invasive ocular blood flow sensor system can include a doppler optical coherence tomography (DOCT) system with a collimated light source, such as a collimated light source configured to illuminate ocular tissue and a CCD sensor configured to receive the collimated light reflected from the ocular tissue.
  • the DOCT system can be configured with an energy source capable of generating EM energy at a frequency of about 356 THz (corresponding to a wavelength of about 841 nm).
  • the DOCT system can include the DOCT system from Optovue, Inc (Fremont, CA) offered for sale under the tradename RTVue.
  • the non-in vasive ocular blood flow sensor system can include at least one of a retinal functional imager (RFI) system, a pulsatile ocular blood flow (POBF) system, a fundus pulsation amplitude (FPA) system, a fluorescein and Indocyanine Angiography (FA, ICG) system, a color doppler imaging (CDI) system, a retinal oximetry system, a magnetic resonance imaging (MRI) system, a magnetic resonance imaging (MRI) system, a blue light entoptoscopy) system, a frequency domain optical coherence tomography (FD-OCT) system, an angiography system, or a Split Spectrum Amplitude Decorrelation Angiography with Optical Coherence Tomography (SSADA-OCT) system.
  • RFI retinal functional imager
  • POBF pulsatile ocular blood flow
  • FPA fundus pulsation amplitude
  • FA, ICG fluorescein and Indocyanine Ang
  • the non-invasive ocular imaging system can include an
  • ERG electroretinography
  • VEP visual evoked potential
  • the ERG system can be configured with an energy source capable of generating EM energy at a frequency of about 440 THz (corresponding to a wavelength of about 680 nm or greater).
  • the ERG system can include a system from Diopsys, Inc. (Pine Brook, NJ) offered for sale under the tradename Diopsys Nova-ERG.
  • the ERG system can include a recording electrode, such as to sense an indication of electrical activity in the eye, including at least one of a neural and a non-neuronal cell in the retina, from stimulus applied to the eye including EM energy such as visible light.
  • the recording electrode can be used with an ERG system to measure an indication of electrical activity in the eye, such as a pattern electroretinography (PERG) test as an indication of ocular blood flow.
  • the recording electrode can include at least one of an electrode that can be in contact with the eye, such as an electrode attached to a contact lens and configured for contact with a surface of the eye, or an electrode in proximity to the eye, such as an electrode that can be located on the lower eye lid of an eye.
  • the non-invasive ocular imaging system can include a retinal functional imaging (RFI) system.
  • the RFI system can be configured with an energy source capable of generating EM energy at a frequency of about 547 THz (corresponding to a wavelength of about 548 nm).
  • the RFI system can include a system from Optical Imaging, Ltd. (Rehovot, Israel) offered for sale under the tradename RFI 3000.
  • the RFI system can be configured with an energy source capable of generating EM energy at a frequency of about 666 THz (corresponding to a wavelength of at least 450 nm).
  • the RFI system can include a system from OcuScience Inc. (Ann Arbor, MI) offered for sale under the tradename OcuMet Beacon.
  • the sensor 130 can include a force sensor, such as to sense force applied to patient tissue.
  • the force sensor can located on the cover 110, such as to sense applied force between the cover 110 and patient tissue, such as when the cover 110 is located over the patient eye.
  • the force sensor can be positioned at a specified location on the cover 110, such as to sense force applied to patient tissue at the location, or distributed around the peripheral edge of the cover 110, such as to sense force applied to patient tissue at any location around the periphery of the cover 110.
  • the force sensor can be positioned between at least one of the cover 110 and the seal 119 or the patient interface surface 119A and patient tissue.
  • the force sensor can be located on at least one of the anterior plate 193 or the posterior plate 196.
  • the force sensor can be configured to sense applied force between at least one of the anterior plate 193 and patient tissue or the posterior plate 196 and patient tissue, such as when at least one of the anterior plate 193 is located in contact with at least a portion of the anterior patient tissue or the posterior plate 196 is located over at least a portion of the posterior patient tissue.
  • the sensor 130 can include a patient response sensor, such as to receive input from a patient using the apparatus 100.
  • the patient response sensor can be in communication with the control circuitry 140, such as wired or wireless communication, to transfer data received from the patient to the control circuit 140 for at least one of data processing or data recording.
  • Patient input can include an indication of patient perception, such as effectiveness of an applied therapeutic regimen to adjust an indication of an indication of a headache symptom.
  • Patient input can include patient commands, such as with regards to operation of the apparatus 100.
  • the patient response sensor can adjust a parameter of the apparatus 100, such as an environmental parameter to increase or decrease the parameter, in response to patient input
  • the patient response sensor can include a device to collect patient input, such as at least one of a smart device running an app configured to receive patient input and in communication with the control circuitry 140 or a fob device, such as an electro/mechanical device in communication with the control circuitry 140.
  • the patient response sensor can include one or more selection buttons, such as to collect patient input.
  • the one or more selection buttons can allow a patient to communicate an indication of patient perception, such as in response to an applied therapeutic regimen, to the control circuitry 140.
  • the control circuitry 140 can facilitate and coordinate operation of the apparatus 100.
  • the control circuitry 140 can be coupled to, such as in communication with, at least one of the cover 110, such as an ETD associated with the cover 110, the fluid regulator 120, the sensor 130, the pressure source 150, the fluid source 170, or an adjunct device 160.
  • the control circuitry 140 can include a data interface.
  • the data interface can be configured to receive a signal, such as at least one of an indication of the eye environment sensed by the sensor 130.
  • the control circuitry 140 can process the received signal, such as into a processed signal, and transmit the processed signal to one or more components of the apparatus 100.
  • the data interface can be configured to transmit a signal, such as at least one of a remote data storage device or other computing machine 1400 remote from the apparatus 100 for subsequent data processing and data analysis.
  • the control circuitry 140 can be in communication with the fluid regulator 120, such as to adjust the position of the regulator valve to control the working fluid composition.
  • the control circuitry 140 can be in communication with the sensor 130, such as to receive and process an indication of the eye environment including sensed data from the sensor 130.
  • the control circuitry 140 can be in communication with the pressure source 150, such as to generate a pressure source control signal to adjust at least one of working fluid pressure or working fluid flow in the apparatus 100.
  • the control circuitry 140 can provide a communication interface, such as to allow for a user to operate and interact with the apparatus 100.
  • the communication interface can include a graphical user interface (or GUI), such as communicate information to the user including information on the apparatus 100 (e.g., readout of sensed indications, fault status, etc) or receive information from the user.
  • Information received from the user can include at least one of information to manage basic functionality of the apparatus 100, such as cycling the power to the apparatus 100, or an indication of user preference, such as operational parameters including target levels to define therapeutic protocols and safety parameter such as maximum and minimum limits.
  • the communication interface can receive a safety pressure level, such as at least one of a maximum or minimum pressure level in the cavity 112 selected by the user to prevent damage to the patient eye, adjusting the working fluid pressure delivered to the cavity 112, or setting a target pressure level in the cavity 112.
  • a safety pressure level such as at least one of a maximum or minimum pressure level in the cavity 112 selected by the user to prevent damage to the patient eye, adjusting the working fluid pressure delivered to the cavity 112, or setting a target pressure level in the cavity 112.
  • the control circuitry 140 can include a digital signal processing (DSP) circuit, such as to receive and record an indication including an indication of the eye environment sensed by the sensor 130, such as at least one of an DSP circuit, such as to receive and record an indication including an indication of the eye environment sensed by the sensor 130, such as at least one of an DSP circuit, such as to receive and record an indication including an indication of the eye environment sensed by the sensor 130, such as at least one of an indication of the eye environment sensed by the sensor 130, such as at least one of an indication of the eye environment sensed by the sensor 130, such as at least one of an indication of the eye environment sensed by the sensor 130, such as at least one of an DSP circuit, such as to receive and record an indication including an indication of the eye environment sensed by the sensor 130, such as at least one of an DSP circuit, such as to receive and record an indication including an indication of the eye environment sensed by the sensor 130, such as at least one of an DSP circuit, such as to receive and record an indication including an indication of the eye
  • the indication of the eye environment can be monitored and recorded by the control circuitry 140 for a duration, such as for a period of seconds, minutes, hours, days, years, or for the lifetime of the patient.
  • the control circuitry 140 can include a processing unit, such as a programmable central processing unit (CPU).
  • the CPU can be configured to execute instructions to implement methods of using the apparatus 100, such as to treat, inhibit, prevent, or adjust an indication of an indication of a headache symptom experienced by a patient.
  • the CPU can be a component of a computing machine, such as a computing machine 1400.
  • the CPU can be configured as a control circuit, such as a feedback control circuit.
  • the feedback control circuit can receive information, such as at least one of an indication sensed by the sensor 130, an indication of user preference from the communication interface, or an indication of a processed signal including a signal processed by the CPU.
  • the CPU can process the received information, such as to form a control signal, such as including at least one of a pressure source control signal or a tensioner control signal.
  • the pressure source control signal can be based on an indication of cavity pressure, such as pressure in the cavity 112, to achieve a target pressure level in the cavity 112.
  • the pressure feedback control circuit can receive an indication of working fluid pressure in the cavity 112, such as an indication of cavity pressure level sensed by the sensor 130 including a pressure sensor in communication with the cavity 112.
  • the pressure feedback control circuit can process the received indication of pressure level to form a control signal, such as a control signal to adjust the pressure source 150 to achieve the target pressure level in the cavity 112.
  • the CPU can be configured as a pressure feedback control circuit, such as to generate a control signal for the pressure source 150 (e.g., a pressure source control signal) to adjust pressure level in the cavity 112.
  • the pressure level in the cavity 112 can be adjusted toward a target cavity pressure level, such as a headache target cavity pressure level selected to adjust patient perception of pain due to a headache symptom, including relief of patient pain.
  • the pressure source control signal can be based on an indication sensed by a sensor 130, such as the difference between an indication sensed by a sensor 130 and the target cavity pressure level.
  • the CPU can be configured as a blood flow pressure feedback control circuit, such as to generate a blood flow pressure feedback control signal to adjust pressure level in the cavity 110 to vary ocular blood flow based on an indication of ocular blood flow.
  • the indication of ocular blood flow can be sensed with the sensor 130, such as a blood flow sensor.
  • the pressure level in the cavity can be adjusted toward a blood flow target cavity pressure level, such as the blood flow target cavity pressure level to adjust patient perception of pain due to a headache symptom, including relief of patient pain.
  • the blood flow target cavity pressure level can be selected to minimize patient perception of pain.
  • the CPU can be configured as an applied force pressure feedback control circuit, such as to generate an applied force pressure feedback control signal to adjust pressure level in the cavity 110 to vary force applied to patient tissue, such as based on an indication of applied force between the cover 110 and patient tissue.
  • the indication of applied force can be sensed with the sensor 130, such as a force sensor.
  • the pressure level in the cavity can be adjusted toward an applied force target cavity pressure level, such as the applied force target cavity pressure level to adjust patient perception of pain due to a headache symptom, including relief of patient pain due to the headache symptom.
  • the applied force target cavity pressure level can be selected to minimize patient perception of pain.
  • the CPU can be configured as a tensioner feedback control circuit, such as to generate a tensioner control signal to adjust tension level in a harness or tether of the apparatus 100.
  • the tensioner control signal can be based on an indication of applied force, such as between the anterior plate 193 and anterior patient tissue, such as with a force sensor located between the anterior plate and anterior patient tissue.
  • the tensioner control signal can be based on an indication of applied force, such as between the posterior plate 193 and posterior patient tissue, such as with a force sensor located between the posterior plate and posterior patient tissue.
  • the tension in the harness or tether can be adjusted toward an applied plate force target tensioner level, such as the tension level to adjust patient perception of pain due to a headache symptom, including relief of patient pain due to the headache symptom.
  • the applied plate force target tensioner level can be selected to minimize patient perception of pain.
  • the control circuitry 140 can include sweep circuitry, such as function-specific circuitry integrated into the control circuitry 140 or instructions implemented on the CPU.
  • the sweep circuity can be configured to adjust non ambient pressure applied to the cavity 112, such as by generating a control signal to adjust the pressure source 150 to apply a pressure level to the cavity 112, such as in a specified pattern.
  • a pressure range can be defined by a first pressure level and a second pressure level, such as where the second pressure level is greater than the first pressure level.
  • the sweep circuitry can be configured to perform a sweep test, such as to sequentially vary non-ambient pressure level applied to the cavity 112 over a pressure range. Sequential variation of non-ambient pressure can include sequentially increasing non-ambient pressure level over the pressure range, such as from the first pressure level to the second pressure level. Sequential variation of non-ambient pressure can include sequentially decreasing non-ambient pressure level over the pressure range, such as from the second pressure level to the first pressure level.
  • a patient such as a patient experiencing a headache symptom, can perform the sweep test and respond to each sweep pressure, such as by logging a response through the patient input sensor. Patient response to the sweep test can identify one or more target cavity pressures, such as a target cavity pressure that can relieve a headache symptom in the patient.
  • the sweep circuitry can be configured to define a target cavity pressure level, such as to adjust patient perception of an indication of a headache symptom to treat, inhibit, or prevent the headache symptom.
  • the target cavity pressure level such as the headache target cavity pressure value, can include a pressure level in the cavity 112, such as selected to adjust the patient perception associated with the headache symptom, such as to minimize patient perception of pain associated with the headache symptom.
  • the apparatus 100 can operate to identify or define a target cavity pressure level, such as a target cavity pressure level to adjust patient perception of an indication of a headache symptom to treat, inhibit, or prevent the headache symptom.
  • the apparatus 100 can include a sensor 130, such as the patient response sensor, configured to receive patient input, such as patient perception of pain associated with an indication of a headache symptom as the non-ambient pressure in the cavity 112 is varied in the pressure range.
  • the target cavity pressure value can be defined as the non-ambient pressure level applied to the cavity 112 that can minimize patient perception of pain associated with the headache symptom.
  • Processing the received indication of pressure can include calculating an indication, such as calculating an indication of the difference between the indication of cavity pressure level and an indication of user preference, including a cavity pressure setpoint level received from the communication interface to form an indication of a cavity pressure difference value.
  • Processing the received indication can include generating a control signal based on the indication of cavity pressure difference value with a proportional-integral-derivative (PID) control algorithm running on the CPU to adjust the pressure source 150.
  • PID proportional-integral-derivative
  • Generating a control signal can include generating a control signal to minimize the difference between the received indication of pressure level and the cavity pressure setpoint level.
  • the CPU can be configured as a concentration feedback control circuit, such as to generate a regulator control signal to adjust a chemical constituent level in the cavity 112.
  • the regulator control signal can be based on an indication of a chemical constituent associated with the working fluid, such as an indication of nitric oxide (NO) concentration, to achieve a target NO concentration level in the working fluid.
  • the concentration feedback control circuit can receive an indication of NO concentration level in the working fluid, such as an indication of NO level sensed by the senor 130 including a concentration sensor configured to sense NO.
  • the concentration feedback control circuit can process the received indication of NO level to form a control signal, such as a control signal to adjust the regulator 120 to achieve the target NO concentration level in the cavity 112.
  • Processing the received indication of NO concentration can include calculating the difference between the indication of NO concentration and an indication of user preference, including a NO setpoint level received from the communication interface, to form a NO difference value.
  • Processing the received indication can include generating a control signal based on the NO difference value.
  • Processing the received indication can include generating a control signal based on the NO difference value with a proportional-integral-derivative (PID) control algorithm running on the CPU to adjust the regulator 120.
  • Generating a control signal can include generating a control signal to minimize the difference between the received indication of NO concentration and the NO setpoint level.
  • PID proportional-integral-derivative
  • the control circuitry 140 can include a power source 152, such as to supply electrical energy to the apparatus 100.
  • the power source 152 can include a battery, such as a lithium ion battery, and a transformer, such as to receive power from a wall outlet for use in the apparatus 100 at a specified voltage and current.
  • the control circuitry 140 can include a heating element, such as a heating element in communication with the therapeutic fluid including a heating element located on a surface of or in proximity to the cover 110 including an inner surface 188 of the cover 110, or the fluid regulator 120, to increase the temperature of the therapeutic fluid.
  • the pressure source 150 can generate a volumetric flow of working fluid in the apparatus 100, such as to move working fluid from the pressure source 150 to the cavity 112 or to move working fluid from the cavity 112 to at least one of the pressure source 150 or to the surrounding environment.
  • the pressure source 150 can be configured to apply non-ambient pressure to the cavity 112, such as to adjust an indication of fluid pressure including an indication of pressure level in the cavity 112, from a first pressure level to a second pressure level different from the first pressure level.
  • a non-ambient pressure can include a pressure in the cavity 112 different from an ambient pressure, such as an ambient pressure surrounding the apparatus 100.
  • a non-ambient pressure can include at least one of a positive non ambient pressure, such as where the cavity pressure can be greater than the surrounding atmosphere, or a negative non-ambient pressure, such as where the cavity pressure can be less than the surrounding atmosphere.
  • the pressure source 150 can include a pump, such as a pump that can generate at least one of a positive gauge pressure or a negative gauge pressure.
  • the pressure source 150 can include an electrically-powered pressure source, such as a pump including a displacement pump or a centrifugal pump.
  • the pressure source 150 can include a diaphragm pump, such as a diaphragm vacuum pump.
  • the pressure source 150 can include a manually- powered pressure source, such as a hand pump including a bellows-style pump.
  • the pressure source 150 can be integrated into a component of the apparatus 100, such as the cover 110.
  • the pressure source 150 can include a source of pressure, such as a pressurized gas cylinder or a source of pressurized fluid separate from the apparatus 100 that can be used to adjust working fluid pressure in the cavity 112.
  • the pressure source 150 can include a source of pressure used in combination with a supplementary device to adjust pressure in the cavity.
  • the pressure source 150 can include a venturi-type pump, such as a venturi jet pump, in communication with the source of pressure to adjust fluid pressure in the cavity 112.
  • the pressure source 150 can be characterized by physical characteristics, such as a relationship between physical characteristics.
  • a useful measure for comparing the performance of several sources of flow includes a volume-pressure characteristic, such as the relationship between the volume of working fluid flow from a source of flow and the pressure, such as static pressure, created due to the fluid flow.
  • the pressure source 150 can be characterized by a volume-pressure characteristic, such as a p-Q chart.
  • the pressure source 150 can generate a pressure in the cavity 112, such as to adjust pressure in the cavity 112 to move towards or achieve a target cavity pressure in the cavity 112.
  • the target cavity pressure can include the cavity pressure to adjust patient perception of an indication of a headache symptom, such as a headache target cavity pressure.
  • the adjunct device 160 can apply energy to stimulate patient tissue, such as in combination with the apparatus 100, such as to affect a patient headache symptom.
  • the adjunct device 160 can apply energy at a level, such as a headache target energy level, in combination with the apparatus 100, such as to minimize perceived patient pain associated with a headache symptom.
  • the adjunct device 160 can include a neuromodulation device, such as an electrical stimulation neuromodulation device.
  • An electrical neuromodulation stimulation device can include a transcutaneous electrical nerve stimulation (TENS) device.
  • TENS device can include a power supply, such as to generate electrical stimulation energy, and an electrode, such as to transmit energy from the power supply to a patient.
  • the TENS device can include a facial nerve stimulator, such as a device to stimulate a supraorbital (or trigeminal) nerve.
  • the facial nerve stimulator can include a device from CEFALY-Technology (Liege, Belgium) offered for sale under at least one of the tradenames Cefaly ACUTE, Cefaly DUAL, or Cefaly PREVENT.
  • the TENS device can include a cranial nerve stimulator, such as a device to stimulate at least one of a vagus nerve or a nerve originating at the trigeminal nerve nuclei.
  • the vagus nerve stimulator can include a device from electroCore (Basking Ridge, New Jersey) offered for sale under at least one of the trademarks GAMMACORE®, GAMMACORE SAPPHIRE®, or
  • the TENS device can include a peripheral nerve stimulator, such as a device to stimulate at least one of a peripheral or a non-cranial nerve in the patient.
  • the peripheral nerve stimulator can include a device from Theranica Bio-Electronics Ltd. (Netanya, Israel) offered for sale under the trademark NERIVIO MIGRA®.
  • An electrical neuromodulation stimulation device can include an implantable electrode device.
  • An implantable electrode device can include a power supply, such as to generate electrical stimulation energy, and an implantable electrode, such as to transmit energy from the power supply to a patient.
  • the implantable electrode device can include an occipital nerve stimulator, such as a device to stimulate an occipital nerve in the patient.
  • the implantable electrode device can include a spinal cord stimulator, such as a device to stimulate a spinal nerve including a dorsal column in the patient.
  • the implantable electrode device can include a sphenopalatine ganglion stimulator, such as a device to stimulate the sphenopalatine ganglion.
  • the implantable electrode device can include a deep brain stimulator, such as a device to stimulate the ventral tegmental area.
  • An electrical neuromodulation stimulation device can include a magnetic stimulation device.
  • a magnetic stimulation device can include a power supply, such as to generate electrical stimulation energy, and a coil, such as to transmit energy from the power supply to a patient in the form of a magnetic field.
  • the magnetic stimulation device can include a transcranial magnetic stimulator (TMS) including a repetitive transcranial magnetic stimulator (rTMS), such as a device to stimulate at least a portion of the patient brain to affect a patient headache symptom.
  • TMS transcranial magnetic stimulator
  • rTMS repetitive transcranial magnetic stimulator
  • the magnetic stimulation device can include a single-pulse TMS (sTMS), such as a device to stimulate at least a portion of the patient brain to affect a patient headache symptom with a single pulse of magnetic energy.
  • the sTMS can include a device from eNeura (Baltimore, MD) offered for sale under the trademark sTMS miniTM.
  • the adjunct device 160 can include a pharmacological (or pharma) drug delivery device, such as for localized or systemic delivery of a drug to a patient to enhance the effect of therapies described elsewhere in this application including stimulation of patient tissue with the apparatus 100.
  • a pharmacological (or pharma) drug delivery device such as for localized or systemic delivery of a drug to a patient to enhance the effect of therapies described elsewhere in this application including stimulation of patient tissue with the apparatus 100.
  • the pharma drug delivery device can include a timer or other notification device, such as to alert or remind a patient to administer a medication orally.
  • a timer or other notification device such as to alert or remind a patient to administer a medication orally.
  • acute headaches can be treated with the apparatus 100 adjusting applied non-ambient cavity pressure toward a target cavity pressure value and administration of a fast-acting headache relief drug, such as to adjust patient perception of the headache symptom to treat, inhibit, or prevent the headache symptom.
  • the pharma drug delivery device can include an infusion pump, such as to titrate a medication over an extended period of time.
  • chronic headaches can be treated with the apparatus 100 adjusting applied non-ambient cavity pressure toward a target cavity pressure value and administration of a headache relief drug in the form of at least one of an orally-ingested, timed- release drug or titrated infusion with an infusion pump, such as to adjust patient perception of the headache symptom to treat, inhibit, or prevent the headache symptom.
  • a headache relief drug can include medications configured to adjust patient perception of an indication of a headache symptom.
  • a headache relief drug can encompass many types of medications, such as antiepileptics, antidepressants, nerve blocks, non-steroidal analgesics, opioids,
  • a headache relief drug can include one or more classes of medications, such as general antagonists, triptans, and CRGP inhibitors.
  • a general antagonist can be used in the treatment of migraine -type headaches.
  • a general antagonist can include any receptor antagonist that can be effective in inhibiting or preventing a headache, such as at least one of a NS AID (nonsteroidal anti-inflammatory drug) and a beta blocker.
  • a NSAID can include at least one of aspirin, ibuprofen, naproxen sodium, flurbiprofen, diclofenac potassium, indomethacin, or diclofenac potassium.
  • a beta blocker can include at least one of propranolol, timolol, atenolol, or nadolol.
  • a triptan can be used in the treatment of migraine-type and cluster- type headaches.
  • a triptan can include a serotonin agonist, such as to cause constriction in blood vessels with 5-HT-1B and 5-HT-1D receptors.
  • a triptan can include at least one of sumatriptan, rizatriptan, naratriptan, eletriptan, donitriptan, almotriptan, frovatriptan, avitriptan, or zolmitriptan.
  • a CRGP (calcitonin gene-related peptide) inhibitor can be used in the treatment of migraine -type headaches.
  • a CRGP inhibitor can include at least one of a monoclonal antibody or a CGRP antagonist, such as to block the CGRP receptor of nerve cells.
  • a CRGP inhibitor can include at least one of erenumab, fremanezumab, galcanezumab, eptinezumab, olcegepant, rimegepant, telcagepant, or ubrogepant.
  • the target cavity pressure can include the cavity pressure to affect a treatment of the patient eye, such as a cavity pressure prescribed by a medical professional to treat, inhibit, or prevent an eye condition.
  • pressure in the cavity 112 can be adjusted with the pressure source 150 toward a target cavity pressure, such as a target cavity pressure to affect an indication of a physiological parameter of the patient eye including an indication of IOP level in the patient eye that can be sensed by a sensor 130 including a biosensor configured to sense an indication of IOP.
  • Treatment of the patient eye can be affected by the pressure source 150, such as by adjusting the pressure source to achieve a target cavity pressure in the cavity 112 to affect a desired indication of IOP level in the patient eye.
  • the target cavity pressure can include a headache target cavity pressure, such as a pressure applied to the cavity 112 to adjust patient perception of an indication of a headache symptom, such as to treat, inhibit, or prevent the headache symptom.
  • the headache target cavity pressure value can include a pressure level in the cavity 112 selected to minimize patient perception of pain associated with the headache symptom. The pressure level selected to minimize pain can be determined, such as by performing a headache sweep test with the apparatus 100 located on a patient.
  • a headache target cavity pressure value can include cavity pressure level in a range of about 0 mmHg to about 100 mmHg, a cavity pressure level in a range of about 5 mmHg to about 40 mmHg, and a cavity pressure level in a range of about 10 mmHg to about 20 mmHg.
  • the cavity pressure level can be a negative gauge pressure.
  • the headache target cavity pressure can be in a range of about 0 mmHg to about 50 mmHg, about 1 mmHg to about 50 mmHg, about 5 mmHg to about 50 mmHg, about 5 mmHg to about 40 mmHg, about 8 mmHg to about 40 mmHg, about 10 mmHg to about 40 mmHg, about 15 mmHg to about 40 mmHg, about 20 mmHg to about 40 mmHg, about 25 mmHg to about 40 mmHg, about 30 mmHg to about 40 mmHg, about 1 mmHg to about 30 mmHg, about 5 mmHg to about 30 mmHg, about 8 mmHg to about 30 mmHg, about 10 mmHg to about 30 mmHg, about 15 mmHg to about 30 mmHg, about 20 mmHg to about 30 mmHg, about 25 mmHg to about 30 mmHg, about 30
  • the cavity pressure level can be a positive gauge pressure.
  • the headache target cavity pressure can be in a range of about 0 mmHg to about 50 mmHg, about 1 mmHg to about 50 mmHg, about 5 mmHg to about 50 mmHg, about 5 mmHg to about 40 mmHg, about 8 mmHg to about 40 mmHg, about 10 mmHg to about 40 mmHg, about 15 mmHg to about 40 mmHg, about 20 mmHg to about 40 mmHg, about 25 mmHg to about 40 mmHg, about 30 mmHg to about 40 mmHg, about 1 mmHg to about 30 mmHg, about 5 mmHg to about 30 mmHg, about 8 mmHg to about 30 mmHg, about 10 mmHg to about 30 mmHg, about 15 mmHg to about 30 mmHg, about 20 mmHg to about 30 .
  • FIG. 11 shows an example of an apparatus 1100 that can control an eye environment over a patient eye, such as at least one of a left eye environment over the left patient eye or a right eye environment over the right patient eye.
  • Controlling an eye environment can include at least one of establishing, adjusting, or maintaining an indication of the eye environment over the patient eye, such as an indication of working fluid cavity pressure in the cavity 112.
  • control of the left eye environment can be independent of the right eye environment and control of the right eye environment can be independent of the left eye environment.
  • the apparatus 1100 can include a left system 1102 with a left cover 110A sized and shaped to fit over a left eye of a patient to define a left cavity 112A between the left cover 110A and an anterior surface of the left eye.
  • the apparatus 1100 can include a right system 1104 with a right cover 110B sized and shaped to fit over the right eye of the patient to define a right cavity 112B between the right cover 110B and an anterior surface of the right eye.
  • the apparatus 1100 can include a bridge 1106, such as to locate the left system 1102 with respect to the right system 1104.
  • the left system 1102 can include at least one of the apparatus 100 and the right system 1104 can include at least one of the apparatus 100.
  • the apparatus 1100 can include system control circuitry 1140 to facilitate, coordinate, and control operation of the apparatus 1100.
  • the system control circuitry 1140 can be configured to receive and process an indication of the eye environment, such as at least one of an indication of the left eye environment, an indication of the right eye environment, or an indication of a relationship between the indication of the left eye environment and the indication of the right eye environment.
  • the system control circuitry 1140 can include at least one of left control circuitry 140A, such as left control circuitry 140A to facilitate, coordinate, and control operation of the left system 1102, or right control circuitry 140B, such as right control circuitry 140B to facilitate, coordinate, and control operation of the right system 1102.
  • the left control circuitry 140A can be configured to control operation of the left system 1102 independently of the right system 1104 and the right system 1104 can be configured to control operation of the right system 1104 independently of the left system 1102.
  • the left control circuitry 140 A can be capable of receiving and processing at least one of the indication of the left eye
  • the right control circuitry 140B can be capable of receiving and processing at least one of the indication of the right eye environment or the indication of the relationship between the left eye environment and the right eye environment.
  • the system control circuitry 1140 can include pressure source circuitry, such as pressure source circuitry configured to adjust operation of the pressure source based on at least one of the indication of the left eye
  • the pressure source circuitry can include at least one of left pressure source circuitry, such as coupled to the left control circuitry 140A, or right pressure source circuitry, such as coupled to the right control circuitry 140B.
  • the system control circuitry 1140 can be configured to facilitate, coordinate, and control operation of the apparatus 1100, such as in a parent-child control configuration.
  • a first control circuitry can receive and process an indication of the eye environment and a second control circuitry, in communication with the first control circuitry, can receive the processed indication from the first control circuitry and adjust operation of the apparatus 1100, such as at least one of the left system 1102 or the right system 1104.
  • the first control circuitry can include the left control circuitry 140A and the second control circuitry can include the right control circuitry 140B.
  • the first control circuitry can include the right control circuitry 140B and the second control circuitry can include the left control circuitry 140 A.
  • FIG. 12 shows an example of an apparatus 1200 that can control a left eye environment over a left eye of a patient and a right eye environment over a right eye of the patient, such as with a single pressure source.
  • the apparatus 1200 can be operated with a single control system, such as the eye environment in the left cavity 112A and the eye environment in the right cavity 112B can be controlled to have the same eye environment in each cavity.
  • the apparatus 1200 can be operated, such as cavity pressure in the left cavity 112A can be equal to, such as approximately equal to, cavity pressure in the right cavity 112B.
  • the apparatus 1200 can include a cavity valve 1290, such as at least one of a left cavity valve 1290A or a right cavity valve 1290B.
  • the apparatus 1200 can include a cavity reservoir 1292, such as at least one of a left cavity reservoir 1292A or a right cavity reservoir 1292B.
  • the apparatus 1200 can be operated with independent control of the eye environment, such as control of the left eye environment can be independent of control of the right eye environment and control of the right eye environment can be independent of the left eye environment.
  • the apparatus 1200 can be operated, such as cavity pressure in the left cavity 112A can be different from cavity pressure in the right cavity 112B, such as by appropriate control of the cavity valve 1290 and the cavity reservoir 1292.
  • the apparatus 1200 can include a cavity valve 1290, such as the cavity valve 1290 in communication with the cavity 112.
  • the cavity valve 1290 can be in communication with, such as coupled to, at least one of the sensor 130, the control circuitry 140, or the pressure source 150.
  • the cavity valve 1290 can include at least one of a left control valve 1290 A in
  • the cavity valve 1290 can control working fluid pressure in the cavity 112, such as to achieve a target cavity pressure in the cavity 112.
  • the left control valve 1290A can control working fluid pressure in the cavity 112 A
  • the right control valve 1290B can control working fluid pressure in the cavity 112B.
  • the apparatus 1200 can include a cavity reservoir 1292, such as the cavity reservoir 1292 in communication with the cavity 112.
  • the cavity reservoir 1292 can include at least one of a left cavity reservoir 1292 A and a right cavity reservoir 1292B.
  • the cavity reservoir 1292 can serve to adjust an indication of system elastance in the apparatus 1200, such as to improve the ability of the apparatus 1200 to achieve a target cavity pressure.
  • an indication of system elastance can be equivalent to an indication of component elastance and an indication of system compliance can be equivalent to an indication of component compliance.
  • a fluidic system with “high” elastance implies a fluidic system that can experience rapid pressure change as a function of volume change.
  • an active cavity valve can fail to achieve the target cavity pressure in an apparatus 1200 with high elastance, such as due to slow feedback response resulting in overshooting the target cavity pressure.
  • control of the apparatus 1200 can be improved, such as by reducing the rate of pressure change due to volume change to minimize feedback tracking error.
  • the cavity reservoir 1292 can include a supplementary volume, such as a volumetric space in communication with the cavity 112, including at least one of a fluidic accumulator or an expansion chamber.
  • a supplementary volume can be defined as any additional volume of the cavity 112, such as any component in fluidic communication with the cavity 112, beyond the minimum volume required to convey pressure to the patient eye.
  • the amount of supplementary volume in the cavity reservoir 1292 can be selected, such as to adjust the system elastance to change system lag and error when pressurizing the apparatus 1200.
  • Supplementary volume can be adjusted from a first supplementary volume level to a second supplementary volume.
  • the second supplementary volume level can be less than the first supplementary volume level, such as to increase system elastance.
  • system lag for the apparatus 1200 including pressure system lag
  • the second supplementary volume level can be greater than the first supplementary volume level, such as to reduce system elastance.
  • system lag for the apparatus 800 including pressure system lag, can be increased.
  • the cavity reservoir 1292 can include a compliant portion of the apparatus 1200, such as a compliant portion of the apparatus 1200 in communication with the cavity 112.
  • a compliant portion can include a portion of the apparatus 1200 in fluidic communication with the cavity 112, such as a portion of the apparatus 1200 that demonstrates a percentage variation in component compliance greater than the least compliant component of the cavity 112 or any component in fluidic communication with the cavity 112.
  • the percentage variation in component compliance can be in a range of at least one of about 1% to about 25%, about 25% to about 50%, about 50% to about 75%, or about 75% to about 100% as compared to the least compliant component of the system.
  • the compliant portion can include an elastic portion, such as a portion of the apparatus 1200 in communication with the cavity 112 that demonstrates a percentage variation in component compliance greater than the least compliant component of the system.
  • an elastic portion can include a membrane, such as the flexible septum as noted previously in this application.
  • FIG. 13 shows an example method 1300 for using the apparatus 100 to adjust patient perception of an indication of a headache symptom.
  • the control circuitry 140 can be configured to receive an indication from a user, such as an indication of a target cavity pressure level selected to minimize patient pain associated with a headache symptom, and process the received indication, such as to adjust the pressure level in the cavity 112 toward the indication of the target cavity pressure level received from the user.
  • the control circuitry 140 can adjust the cavity pressure from a first indication of cavity pressure to a second indication of cavity pressure, such as approximately equivalent to the target cavity pressure level, such as to minimize patient pain associated with the headache symptom.
  • non-ambient pressure can be applied to a cavity 112, such as defined by a cover 110 over the eye of a patient, such as where the patient has a history of experiencing the headache symptom.
  • Applying non ambient pressure to the cavity 112 can include changing pressure in the cavity 112, such as from an ambient pressure to a non-ambient pressure.
  • Applying non-ambient pressure can include applying an external force to the cover 110, such as to compress at least one of the seal 119 or patient tissue, such as to decrease the volume of the cavity 112, such as to increase gauge pressure in the cavity 112.
  • a positive pressure check valve such as in communication with the cavity 112, can release positive gauge pressure from the cavity 112, such as limited by the cracking pressure of the positive pressure check valve.
  • Applying non-ambient pressure can include releasing the external force from the cover 110, such as to allow the seal 119 or patient tissue to rebound, such as to decrease gauge pressure in the cavity 112.
  • Applying non ambient pressure can include regulating gauge pressure in the cavity 112, such as with a negative pressure check valve, such as with a cracking pressure selected to adjust non-ambient pressure in the cavity toward a target cavity pressure level.
  • Applying non-ambient pressure can include applying non-ambient pressure to the cavity 112 with a pressure source 150, such as toward a target cavity pressure level.
  • the non-ambient pressure applied to the cavity can be adjusted toward a target cavity pressure level, such as at least one of a headache target cavity pressure level or a force target cavity pressure level, to treat, inhibit, or prevent the headache symptom.
  • a target cavity pressure level such as at least one of a headache target cavity pressure level or a force target cavity pressure level
  • Adjusting the applied non-ambient pressure can include adjusting the cavity pressure toward an applied force target cavity pressure level.
  • the applied force target cavity pressure level can be received, such as from a user specifying an applied force target cavity pressure level through an interface in
  • Adjusting the applied non-ambient pressure can include specifying a target cavity headache pressure value, such as by communicating the target cavity headache pressure value to the control circuitry 140 including inputting the value through a GUI attached to the control circuitry 140. Adjusting the applied non-ambient pressure can include operating a feedback control loop, such as running on the control circuitry 140, to minimize an error between the target cavity headache pressure value and an indication of cavity pressure in the cavity 112.
  • cavity pressure can be sensed by a sensor 130, such as a pressure sensor located in communication with the cavity 112.
  • the applied force target cavity pressure level can be identified, such as by initiating a pressure sweep test with the sweep circuitry associated with the control circuitry 140 and collecting feedback from a user with a patient response sensor, such as from a user experiencing a headache symptom.
  • the control circuitry 140 can process the data received, such as to identify one or more sweep pressure levels that can bring relief to the user and store the identified sweep pressure levels as one or more applied force target cavity pressure levels.
  • the pressure sweep test can be conducted periodically, such as to update the applied force target cavity pressure levels.
  • an anterior plate 193 can be located in contact with patient tissue proximal to at least a portion of a patient trigeminal nerve.
  • the apparatus 100 can include an anterior plate 193, such as attached to the cover 110. Locating the anterior plate in contact with patient tissue can include locating the cover 110 of the apparatus 100 over the patient eye so that the anterior plate 193 can contact the patient tissue.
  • the anterior plate 193 can include an anterior plate harness 194.
  • Locating the anterior plate 193 can include tensioning the anterior plate harness 194, such as to generate plate contact pressure between the anterior plate 193 and the patient tissue.
  • Tensioning the anterior plate can include specifying an applied force target tensioner level, such as by communicating the applied force target tensioner level to the control circuitry 140 including inputting the level through a GUI attached to the control circuitry 140.
  • Adjusting the applied non-ambient pressure can include operating a feedback control loop, such as running on the control circuitry 140, to minimize an error between the applied force target tensioner level and an indication of tension in the anterior plate harness 194.
  • tension in the anterior plate harness 194 can be sensed by a sensor 130, such as a tension sensor in communication with the anterior plate harness 194.
  • force between the anterior plate 194 and the patient tissue can be sensed by a sensor 130, such as a force sensor located between the anterior plate 194 and the patient tissue.
  • Locating the anterior plate 193 can include adjusting non-ambient pressure in the cavity 112 toward a target cavity pressure, such as a non-ambient pressure in the cavity 112 adjusted toward a target cavity pressure to achieve a target plate contact pressure between the anterior plate 193 and the patient tissue proximal to the patient trigeminal nerve.
  • a posterior plate 196 can be located in contact with patient tissue proximal to at least a portion of a patient occipital nerve. Locating the posterior plate in contact with patient tissue can include locating the cover 110 of the apparatus 100 over the patient eye and adjusting the posterior plate tether 198 so that the posterior plate 196 can contact the patient tissue.
  • Locating the posterior plate 196 can include tensioning the posterior plate tether 198, such as to generate plate contact pressure between the posterior plate 196 and the patient tissue.
  • Tensioning the posterior plate can include specifying an applied force target tensioner level, such as by communicating the applied force target tensioner level to the control circuitry 140 including inputting the level through a GUI attached to the control circuitry 140.
  • Adjusting the applied non-ambient pressure can include operating a feedback control loop, such as running on the control circuitry 140, to minimize an error between the applied force target tensioner level and an indication of tension in the posterior plate tether 198.
  • tension in the posterior plate tether 198 can be sensed by a sensor 130, such as a tension sensor in communication with the posterior plate tether 198.
  • force between the posterior plate 196 and the patient tissue can be sensed by a sensor 130, such as a force sensor located between the posterior plate 196 and the patient tissue.
  • Locating the posterior plate 196 can include adjusting non-ambient pressure in the cavity 112 toward a target cavity pressure, such as a non-ambient pressure in the cavity 112 adjusted toward a target cavity pressure to achieve a target plate contact pressure between the posterior plate 196 and the patient tissue proximal to the patient occipital nerve.
  • a headache cover method can be formed from a sequence of steps, such as step 1310 and step 1320.
  • the headache cover method can be implemented, such as by performing step 1310 and step 1320, such as to treat, inhibit, or prevent a headache symptom.
  • An anterior plate method can be formed from a sequence of steps, such as step 1310, step 1320, and step 1330.
  • the anterior plate method can be implemented, such as by performing step 1310, step 1320, and step 1330, such as to treat, inhibit, or prevent a headache symptom.
  • a posterior plate method can be formed from a sequence of steps, such as step 1310, step 1320, and step 1340.
  • the posterior plate method can be implemented, such as by performing step 1310, step 1320, and step 1340, such as to treat, inhibit, or prevent a headache symptom.
  • a combined plate method can be formed from a sequence of steps, such as step 1310, step 1320, step 1330, and step 1340.
  • the combined plate method can be implemented, such as by performing a sequence of steps, such as at least one or more of step 1310, step 1320, step 1330, or step 1340
  • a sequence of steps can include step 1310, step 1320, step 1330, and step 1340.
  • Method examples described herein can be machine or computer- implemented at least in part. Some examples can include a computer-readable medium or machine-readable medium encoded with instructions operable to configure an electronic device to perform methods as described in the above examples.
  • An implementation of such methods can include code, such as microcode, assembly language code, a higher-level language code, or the like. Such code can include computer readable instructions for performing various methods. The code may form portions of computer program products. Further, in an example, the code can be tangibly stored on one or more volatile, non- transitory, or non-volatile tangible computer-readable media, such as during execution or at other times.
  • Examples of these tangible computer-readable media can include, but are not limited to, hard disks, removable magnetic disks, removable optical disks (e.g., compact disks and digital video disks), magnetic cassettes, memory cards or sticks, random access memories (RAMs), read only memories (ROMs), and the like.
  • FIG. 14 shows an example block diagram of an example computing machine 1400 that can be used as control circuitry 140. Methods can be implemented on the control circuitry 140.
  • the control circuitry 140 can include a computing machine 1400 upon which any one or more of the techniques or methods discussed herein can be performed.
  • the machine 1400 may be a local or remote computer, or processing node in an on-the-go (OTG) device such as a smartphone, tablet, or wearable device.
  • OOG on-the-go
  • the machine 1400 may operate as a standalone device or may be connected (e.g., networked) to other machines. In an example, the machine may be directly coupled or be integrated with the apparatus 100, such as any components of the apparatus 100.
  • machine 1400 may operate in the capacity of a server machine, a client machine, or both in server-client network environments.
  • the machine 1400 may act as a peer machine in peer-to-peer (P2P) (or other distributed) network environment.
  • P2P peer-to-peer
  • the machine 1400 may be a personal computer (PC), a tablet PC, a set-top box (STB), a personal digital assistant (PDA), a mobile telephone, a web appliance, a network router, switch or bridge, or any machine capable of executing instructions (sequential or otherwise) that specify actions to be taken by that machine.
  • the machine 1400 can include a purpose -designed circuit, such as a printed circuit board that can execute the functions and methods disclosed throughout this application.
  • machine can also be taken to include any collection of machines that individually or jointly execute a set (or multiple sets) of instructions to perform any one or more of the methodologies discussed herein, such as cloud computing, software as a service (SaaS), other computer cluster configurations.
  • cloud computing software as a service
  • SaaS software as a service
  • Examples, as described herein, may include, or may operate by, logic or a number of components, or mechanisms.
  • Circuitry can include a collection of circuits implemented in tangible entities that include hardware (e.g., simple circuits, gates, logic, etc.). Circuitry membership may be flexible over time and underlying hardware variability. Circuitries include members that may, alone or in combination, perform specified operations when operating. In an example, hardware of the circuitry may be immutably designed to carry out a specific operation (e.g., hardwired).
  • the hardware of the circuitry may include variably connected physical components (e.g., execution units, transistors, simple circuits, etc.) including a computer readable medium physically modified (e.g., magnetically, electrically, moveable placement of invariant massed particles, etc.) to encode instructions of the specific operation.
  • a computer readable medium physically modified (e.g., magnetically, electrically, moveable placement of invariant massed particles, etc.) to encode instructions of the specific operation.
  • the instructions enable embedded hardware (e.g., the execution units or a loading mechanism) to create members of the circuitry in hardware via the variable connections to carry out portions of the specific operation when in operation.
  • the computer readable medium is communicatively coupled to the other components of the circuitry when the device is operating.
  • any of the physical components may be used in more than one member of more than one circuitry.
  • execution units may be used in a first circuit of a first circuitry at one point in time and reused by a second circuit in the first circuitry, or by a third circuit in a second circuitry at a different time.
  • Machine 1400 can include a hardware processor 1402 (e.g., a central processing unit (CPU), a graphics processing unit (GPU), a hardware processor core, or any combination thereof), a main memory 1404 and a static memory 1406, some or all of which may communicate with each other via an interlink (e.g., bus) 1408.
  • the machine 1400 may further include a display unit 1410, an alphanumeric input device 1412 (e.g., a keyboard), and a user interface (UI) navigation device 1414 (e.g., a mouse).
  • the display unit 1410, input device 1412 and UI navigation device 1414 may be a touch screen display.
  • the machine 1400 may additionally include a storage device (e.g., drive unit) 1416, a signal generation device 1418 (e.g., a speaker), a network interface device 1420, and one or more sensors 1421, such as a global positioning system (GPS) sensor, compass, accelerometer, or other sensor.
  • sensors 1421 such as including sensors 130, can include wearable, assistive device-based and environmental sensors, as described above.
  • the machine 1400 may include an output controller 1428, such as a serial (e.g., universal serial bus (USB), parallel, or other wired or wireless (e.g., infrared (IR), near field communication (NFC), etc.) connection to communicate or control one or more peripheral devices (e.g., a printer, card reader, etc.).
  • a serial e.g., universal serial bus (USB), parallel, or other wired or wireless (e.g., infrared (IR), near field communication (NFC), etc.) connection to communicate or control one or more peripheral devices (e.g., a printer, card reader, etc.).
  • USB universal serial bus
  • IR infrared
  • NFC near field communication
  • the storage device 1416 may include a machine readable medium 1422 on which is stored one or more sets of data structures or instructions 1424 (e.g., software) embodying or utilized by any one or more of the techniques or functions described herein.
  • the instructions 1424 may also reside, completely or at least partially, within the main memory 1404, within static memory 1406, or within the hardware processor 1402 during execution thereof by the machine 1400.
  • one or any combination of the hardware processor 1402, the main memory 1404, the static memory 1406, or the storage device 1416 may constitute machine readable media.
  • machine readable medium 1422 is illustrated as a single medium, the term “machine readable medium” may include a single medium or multiple media (e.g., a centralized or distributed database, or associated caches and servers) configured to store the one or more instructions 1424.
  • machine readable medium may include a single medium or multiple media (e.g., a centralized or distributed database, or associated caches and servers) configured to store the one or more instructions 1424.
  • machine readable medium may include any medium that is capable of storing, encoding, or carrying instructions for execution by the machine 1400 and that cause the machine 1400 to perform any one or more of the techniques of the present disclosure, or that is capable of storing, encoding or carrying data structures used by or associated with such instructions.
  • Non limiting machine readable medium examples may include solid-state memories, and optical and magnetic media.
  • a massed machine readable medium comprises a machine readable medium with a plurality of particles having invariant (e.g., rest) mass. Accordingly, massed machine -readable media are not transitory propagating signals.
  • Specific examples of massed machine readable media may include: non-volatile memory, such as semiconductor memory devices (e.g., Electrically Programmable Read-Only Memory
  • EEPROM electrically erasable programmable read-only memory
  • flash memory devices such as internal hard disks and removable disks; magneto-optical disks; and CD-ROM and DVD- ROM disks.
  • the instructions 1424 may further be transmitted or received over a communications network 1426 using a transmission medium via the network interface device 1420 utilizing any one of a number of transfer protocols (e.g., frame relay, internet protocol (IP), transmission control protocol (TCP), user datagram protocol (UDP), hypertext transfer protocol (HTTP), etc.).
  • transfer protocols e.g., frame relay, internet protocol (IP), transmission control protocol (TCP), user datagram protocol (UDP), hypertext transfer protocol (HTTP), etc.
  • Example communication networks may include a local area network (LAN), a wide area network (WAN), a packet data network (e.g., the Internet), mobile telephone networks (e.g., cellular networks), Plain Old Telephone (POTS) networks, and wireless data networks (e.g., Institute of Electrical and Electronics Engineers (IEEE) 802.11 family of standards known as Wi-Fi®, IEEE 802.16 family of standards known as WiMax®), IEEE 802.15.4 family of standards, peer-to-peer (P2P) networks, among others.
  • the network interface device 1420 may include one or more physical jacks (e.g., Ethernet, coaxial, or phone jacks) or one or more antennas to connect to the communications network 1426.
  • the network interface device 1420 may include a plurality of antennas to wirelessly communicate using at least one of single-input multiple-output (SIMO), multiple -input multiple -output (MIMO), or multiple-input single-output (MISO) techniques.
  • SIMO single-input multiple-output
  • MIMO multiple -input multiple -output
  • MISO multiple-input single-output
  • transmission medium shall be taken to include any intangible medium that is capable of storing, encoding or carrying instructions for execution by the machine 1400, and includes digital or analog communications signals or other intangible medium to facilitate communication of such software.
  • the present disclosure provides a treatment that can involve a combination of two or more of administering the presently described pharmaceutical composition, physically manipulating a physiological characteristic of the eye, or applying the presently described apparatus.
  • the pharmaceutical composition is for use together with the apparatus, device, or system, or the device is configured for use with the pharmaceutical composition.
  • the pharmaceutical composition can be delivered by way of the apparatus, device, or system; packaged together with the apparatus, device, or system; or can be provided with instructions directing its use with the apparatus, device, or system.
  • composition can be administered
  • “contemporaneous” or“contemporaneously” includes simultaneous and non-simultaneous acts, in which the effects of the act are coexistent.
  • contemporaneous administration of a drug and application of an apparatus can involve application of the apparatus during the period in which the drug is effective.
  • contemporaneous administration of a drug and application of an apparatus can involve administration of a drug to patient who has received a benefit of the apparatus during the period in which the benefit of the apparatus is imparted on the patient.
  • Contemporaneous use of a drug and an apparatus includes use of a drug prior to use of the apparatus, use of the apparatus prior to use of the drug, use of the drug and apparatus at the same time, or any combination thereof.
  • the composition is administered prior to application of the apparatus.
  • the composition can be administered about 1 to about 60 minutes prior to application of the apparatus.
  • the composition can be administered about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 120, 150, or about 180 minutes prior to application of the apparatus, or about 1 to about 3 hours prior to application of the apparatus, or about 1 to about 3 days prior to application of the apparatus.
  • the composition can be administered prior to application of the apparatus by a period of about 0.1, 0.5, 1.0, 1.5, 2.0, or 3.0 half-life of a drug in the composition.
  • the composition is administered after application of the apparatus.
  • the composition can be administered about 1 to about 60 minutes after initial application, or removal, of the apparatus.
  • the composition can be administered about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 120, 150, or about 180 minutes after initial application, or removal, of the apparatus, or about 1 to about 3 hours after initial application, or removal, of the apparatus, or about 1 to about 3 days after initial application, or removal, of the apparatus.
  • the composition is administered after setting a non-ambient cavity pressure with the apparatus.
  • the composition can be administered about 1 to about 60 minutes after setting a non ambient cavity pressure.
  • the composition can be administered about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 120, 150, or about 180 minutes setting a non-ambient cavity pressure, or about 1 to about 3 hours setting a non ambient cavity pressure, or about 1 to about 3 days setting a non-ambient cavity pressure.
  • the apparatus, or cavity pressure is applied to the eye for about or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 120, 150, or about or at least 180 minutes, or about or at least 1 hour, 2 hours, 3 hours, 4 hours, or overnight. For example, 5 to 30 minutes, or 1 to 2 hours.
  • the composition is administered at about the same time that the apparatus is applied to the patient.
  • the composition can be administered while the apparatus is applied to the patient, while the apparatus is operated, while the apparatus is subjecting a tissue of the patient to a force, while the patient is under the influence of an external force applied by the apparatus, while the apparatus is adjusting the IOP of the patient, or any combination thereof.
  • the composition can be administered to the patient once, twice, or more.
  • the composition can be administered to the patient before application of the apparatus, at about the same time as applying the apparatus, during operation of the apparatus, after operating the apparatus, after removing the apparatus from the patient, or any combination thereof.
  • the presently described method of treatment is more effective than use of the composition alone, physical manipulation of the eye alone, or the apparatus alone.
  • the combined treatment of administering the pharmaceutical composition and applying the apparatus can be more effective than either the composition, or the apparatus, alone.
  • the apparatus which provides a physical manipulation of the eye, provides a cooperative effective together with the drug composition. It is also surprising that various pharmaceutical compositions described herein can result in more effective functioning of the described apparatus, device, and system, to an extent that is more than additive based off the same amount of drug administered alone.
  • the amount of each active agent, when administered in combination with another compound, apparatus, device, system, or physical manipulation of the patient, may be different from when that active agent is administered alone.
  • an effective amount of a combination of active agent, or active agent and device can refer collectively to the combination as a whole, although the actual amounts of each active agent may vary.
  • the term“more effective” means that the selected effect is alleviated to a greater extent by one treatment relative to the second treatment to which it is being compared.
  • coadministration of apparatus and pharmaceutical composition on a diurnal schedule avoids undesirable effects such as sleepiness, dizziness, or nausea that can interfere with activity of a patient.
  • the diurnal cycle can include a daytime period, such as a patient active period of increased or continuous patient activity, and a nighttime period, such as a patient inactive period of decreased or intermittent patient activity.
  • the patient with a headache symptom can use the apparatus during the daytime, and take the pharmaceutical composition at nighttime, or use the apparatus during the nighttime, and take the pharmaceutical composition at daytime
  • the composition can also be packaged with instructions directing use of the composition with the apparatus.
  • Instructions or instructional material can refer to a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of the composition for a designated use.
  • the instructional material may be included in a kit.
  • the instructional material of the kit may, for example, be affixed to a container which contains the composition or be shipped together with a container which contains the composition. Alternatively, the instructional material may be shipped separately from the container with the intention that the instructional material and the composition be used cooperatively by the recipient.
  • Patients suffering from headache are treated with an ophthalmic modulator contemporaneously with applying the presently described apparatus to the eye and providing a target cavity pressure.
  • Pharmaceutical compositions containing an ophthalmic modulator which are active agents that modulate a physiologic characteristic of the eye, are provided in Table 1. Active agents are obtained from commercially-available sources at the specified concentration or obtained in pure drug substance form and compounded in sterile buffer solution. Control patients are not treated with any ophthalmic modulator, but can be provided a placebo or are treated with the apparatus, depending on the study parameters.
  • the apparatus corresponds to apparatus 100, which is depicted in FIG. 5
  • Example 1 Coadministration of Composition with Apparatus
  • Patients suffering from headache are treated with one or more of ophthalmic modulator composition 1-53 shortly after applying the presently described apparatus to the eye until patient reports initial relief.
  • the apparatus is adjusted to provide a negative gauge pressure in the apparatus cavity against the eye of -5 mmHg to -30 mmHg.
  • the patient is treated with the apparatus until the patient reports initial headache relief. Control patients are not treated with any ophthalmic modulator.
  • Example 2 Administration of Composition following Apparatus
  • Patients suffering from headache are treated with the presently described apparatus to the eye until patient reports initial relief.
  • the apparatus is adjusted to provide a negative gauge pressure in the apparatus cavity against the eye of -5 mmHg to -30 mmHg.
  • After removal of the apparatus from the patient and upon the patient’ s first report of headache recurrence, increased headache pain, or increased most burdensome associated symptom of headache, the patient is treated with one or more of ophthalmic modulator composition 1-53. Control patients are not treated with any ophthalmic modulator.
  • Patients that are treated with an ophthalmic modulator composition 1- 53 and the apparatus report a greater relief from headache, e.g., a longer period of reduced most bothersome symptom of headache, than is reported by the patients treated with the apparatus or composition alone.
  • Patients suffering from headache are treated with one or more of ophthalmic modulator composition 1-53.
  • the patient is treated with the presently described apparatus to the eye until patient reports initial relief.
  • the apparatus is adjusted to provide a negative gauge pressure in the apparatus cavity against the eye of -5 mmHg to -30 mmHg.
  • the patient is treated with the apparatus until the patient reports initial headache relief. Control patients are not treated with any ophthalmic modulator.
  • Patients that are treated with an ophthalmic modulator composition 1- 53 and the apparatus report relief from headache, e.g., relief of headache pain after 2 hours or relief from the patient’s most bothersome symptom of headache.
  • Example 5 - Administration of Subtherapeutic Dosages of Composition j 00396] Patients suffering from headache are treated with a subtherapeutic dosage of an ophthalmic modulator composition 1-53, with or without application of the presently described apparatus. The subtherapeutic dosage is less than a dosage listed in Table 1, e.g., a 10% dosage or half dosage.
  • the ophthalmic modulator is provided contemporaneously.
  • the apparatus is adjusted to provide a negative gauge pressure in the apparatus cavity against the eye of -5 mmHg to -30 mmHg.
  • the patient is treated with the apparatus until the patient reports initial headache relief. Control patients are not treated with any ophthalmic modulator.
  • Patients that are treated with a subtherapeutic dosage of an ophthalmic modulator composition 1-53 report relief from headache, and report greater relief from headache than is reported by the patients not treated with any ophthalmic modulator.
  • Example 6 Coadministration of Composition to Increase Blood Flow to Eye
  • Patients suffering from headache are treated with a dosage of an ophthalmic modulator composition 1-53 effective to increase blood flow to the eye.
  • Blood flow to the eye is measured with a pulsatile ocular blood flowmeter.
  • the apparatus is subsequently applied.
  • the apparatus is adjusted to provide a negative gauge pressure in the apparatus cavity against the eye of -5 mmHg to - 30 mmHg.
  • the patient is treated with the apparatus until the patient reports initial headache relief. In control patients, blood flow to the eye is not increased.
  • Patients suffering from headache are treated with a dosage of an ophthalmic modulator composition 1-53 effective to reduce IOP by about 1 to about 20 mmHg, which is measured with a tonometer.
  • the apparatus is subsequently applied.
  • the apparatus is adjusted to provide a negative gauge pressure in the apparatus cavity against the eye of -5 mmHg to -30 mmHg.
  • the patient is treated with the apparatus until the patient reports initial headache relief. In control patients, IOP is not decreased
  • Patients suffering from headache are treated with one or more of ophthalmic modulator composition 1-10 (e.g., a miotic) contemporaneously with applying the presently described apparatus to the eye until patient reports initial relief.
  • the apparatus is adjusted to provide a negative gauge pressure in the apparatus cavity against the eye of -5 mmHg to -30 mmHg.
  • the patient is treated with the apparatus until the patient reports initial headache relief. Control patients are not treated with any miotic.
  • Example 9 Coadministration of Composition with a Glaucoma Medication
  • Patients suffering from headache are treated with one or more of ophthalmic modulator composition 11-38 (e.g., a cycloplegic or mydriatic) contemporaneously with applying the presently described apparatus to the eye until patient reports initial relief.
  • the apparatus is adjusted to provide a negative gauge pressure in the apparatus cavity against the eye of -5 mmHg to -30 mmHg.
  • the patient is treated with the apparatus until the patient reports initial headache relief.
  • Control patients are not treated with any cycloplegic, dilation agent, or ocular muscle relaxant.
  • ophthalmic modulator composition 39-53 e.g., a cycloplegic or mydriatic
  • the apparatus is adjusted to provide a negative gauge pressure in the apparatus cavity against the eye of -5 mmHg to -30 mmHg.
  • the patient is treated with the apparatus until the patient reports initial headache relief.
  • Control patients are not treated with any cycloplegic, dilation agent, or ocular muscle relaxant.
  • Examples 1-8 are performed using an apparatus having light-blocking eye covers. Control patients use an apparatus having transparent eye covers.
  • Examples 1-8 are performed together with applying pressure on the supratrochlear nerve.
  • the terms“a” or“an” are used, as is common in patent documents, to include one or more than one, independent of any other instances or usages of“at least one” or“one or more.”
  • the term “or” is used to refer to a nonexclusive or, such that“A or B” includes“A but not B,”“B but not A,” and“A and B,” unless otherwise indicated.
  • Geometric terms such as“parallel”,“perpendicular”,“round”, or “square”, are not intended to require absolute mathematical precision, unless the context indicates otherwise. Instead, such geometric terms allow for variations due to manufacturing or equivalent functions. For example, if an element is described as“round” or“generally round,” a component that is not precisely circular (e.g., one that is slightly oblong or is a many-sided polygon) is still encompassed by this description.
  • the term“about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range.
  • the term“weight percent,”“weight %,”“wt %”“% by weight,” is understood to mean the weight of an ingredient relative to the total weight of all other ingredients of the referenced composition, including solvent where applicable.
  • the term“% (w/v)” or“weight/volume %” refers to a concentration of a component in a solution or other liquid composition, or intended for addition to such compositions, expressed as weight per volume where the weight and volume are of the same metric category, e.g., gram per liter, milligram per milliliter and the units for this designation of concentration is wt/v% or“% (w/v).” Volume is the amount of liquid present in the composition but does not include solids.
  • Aspect 1 provides a method of treating headache in a patient, the method comprising: administering a pharmaceutical composition comprising one or more drug in an amount effective to modulate a physiologic characteristic of an eye of the patient; and applying an apparatus over the patient eye to provide a cavity and adjusting pressure in the cavity to a target cavity pressure, wherein the one or more drugs are other than vitamins, a therapeutic gas, hydrocarbons, fluorocarbons, perfluorocarbons, sulfur hexafluoride, and cannabinoids, and the pharmaceutical composition and cavity pressure, together, are used to treat the headache.
  • Aspect 2 provides a method of treating headache in a patient, the method comprising: administering a pharmaceutical composition comprising one or more drug to modulate a physiologic characteristic of the eye, performing a physical manipulation to modulate a physiologic characteristic of the eye, or both; and applying an apparatus over the patient eye to provide a cavity and adjusting the pressure in the cavity to a target cavity pressure to apply force on the patient, wherein the one or more drugs are other than vitamins, a therapeutic gas, hydrocarbons, fluorocarbons, perfluorocarbons, sulfur hexafluoride, and cannabinoids, and the modulation and cavity pressure, together, are sufficient to treat the headache.
  • Aspect 3 provides a method of treating headache in a patient, the method comprising: administering a pharmaceutical composition comprising one or more drug that modulates aqueous humor production, aqueous humor outflow, intraocular pressure (IOP), translaminar pressure difference (TPD), or any combination thereof, in an amount effective to treat headache, wherein the one or more drugs are other than vitamins, a therapeutic gas, hydrocarbons, fluorocarbons, perfluorocarbons, sulfur hexafluoride, and cannabinoids; and the patient does not suffer from a symptom of glaucoma, or the pharmaceutical composition is administered in an amount that is below a minimum
  • Aspect 4 provides a method of treating headache comprising administering a pharmaceutical composition comprising one or more drug to modulate a physiologic characteristic of the eye to adjust intraocular pressure (IOP), adjust translaminar pressure difference (TPD), or both, to a target level in response to a headache symptom, wherein the one or more drugs are other than vitamins, a therapeutic gas, hydrocarbons, fluorocarbons, perfluorocarbons, sulfur hexafluoride, and cannabinoids
  • Aspect 5 provides the method of any one of Aspects 1-4, wherein the pharmaceutical composition is administered in an amount that is below the minimum therapeutically-effective amount for treating headache, or glaucoma, absent applying the apparatus.
  • Aspect 6 provides the method of any one of Aspects 1-5, wherein the one or more drug is present in the pharmaceutical composition in an amount that is below the minimum therapeutically-effective dosage for treating symptoms other than headache.
  • Aspect 7 provides the method of any one of Aspects 1-6, comprising administering the pharmaceutical composition to the patient eye that is concurrently under the influence of a cavity pressure applied by the apparatus to the patient eye.
  • Aspect 8 provides the method of any one of Aspects 1-7, wherein the pharmaceutical composition is administered before applying the apparatus.
  • Aspect 9 provides the method of any one of Aspects 1-8, wherein the pharmaceutical composition is administered subsequent to application of the apparatus.
  • Aspect 10 provides the method of any one of Aspects 1-9, wherein the patient is concomitantly suffering from one or more primary headache or secondary headache, the patient has recurring headaches, or both.
  • Aspect 11 provides the method of any one of Aspects 1-10, wherein the patient has been indicated to have glaucoma.
  • Aspect 12 provides the method of any one of Aspects 1-10, wherein the patient has not been indicated to have glaucoma.
  • Aspect 13 provides the method of any one of Aspects 1-12, wherein the physiologic characteristic includes intraocular pressure (I OP), aqueous humor production, aqueous humor outflow, or any combination thereof.
  • I OP intraocular pressure
  • aqueous humor production aqueous humor outflow, or any combination thereof.
  • Aspect 14 provides the method of any one of Aspects 1-13, wherein the physiologic characteristic includes cerebrospinal fluid pressure (CSFP), translaminar pressure difference (TPD) across the lamina cribrosa of the patient eye, or both.
  • CSFP cerebrospinal fluid pressure
  • TPD translaminar pressure difference
  • Aspect 15 provides the method of any one of Aspects 1-14, wherein the physiologic characteristic includes blood flow to the eye, nerve access to the eye, or pupil size.
  • Aspect 16 provides the method of any one of Aspects 1-15, wherein the pharmaceutical composition comprises a glaucoma drug, a mydriatic drug, a miotic drug, or any combination thereof.
  • Aspect 17 provides the method of any one of Aspects 1-16, wherein the pharmaceutical composition comprises one or more drug selected from a beta-blocker, an alpha-2 adrenergic agonist, a carbonic anhydrase inhibitor, a cannabinoid, a ROCK/NET inhibitor, a muscarinic agonist, a muscarinic blocker, a rho or rho-associated protein kinase, an adenosine A1 agonist, a prostaglandin receptor inhibitor, a hyperosmotic agent, a muscle relaxant, and any combination thereof.
  • a beta-blocker an alpha-2 adrenergic agonist
  • a carbonic anhydrase inhibitor a cannabinoid
  • a ROCK/NET inhibitor a muscarinic agonist
  • a muscarinic blocker a rho or rho-associated protein kinase
  • Aspect 18 provides the method of any one of Aspects 1-17, wherein the pharmaceutical composition comprises a drug that increases outflow of the aqueous humor, decreases aqueous humor secretion from the ciliary gland, or decreases intraocular pressure (IOP).
  • the pharmaceutical composition comprises a drug that increases outflow of the aqueous humor, decreases aqueous humor secretion from the ciliary gland, or decreases intraocular pressure (IOP).
  • Aspect 19 provides the method of any one of Aspects 1-18, wherein the pharmaceutical composition comprises a drug in an amount effective to modulate ciliary production of aqueous humor.
  • Aspect 20 provides the method of any one of Aspects 1-19, wherein the pharmaceutical composition comprises: a beta-blocker selected from carteolol, levobunolol, metipranolol, timolol maleate, and timolol hemihydrate, betaxolol; an alpha-2 adrenergic agonist selected from apraclonidine and brimonidine; a carbonic anhydrase inhibitor selected from dor .ol amide and brinzolamide; a cannabinoid selected from A9-Tetrahydrocannabinol (THC), cannabidiol (CBD), endocannabinoid including 2-arachidonoylglycero (2- AG) and anandamide (AEA); or any combination thereof.
  • a beta-blocker selected from carteolol, levobunolol, metipranolol, timolol maleate, and timolol
  • Aspect 21 provides the method of any one of Aspects 1-20, wherein the pharmaceutical composition comprises a drug in an amount effective to modulate trabecular or uveoscleral outflow of aqueous humor in the patient eye.
  • Aspect 22 provides the method of any one of Aspects 1-21, wherein the pharmaceutical composition comprises: a muscarinic agonist selected from pilocarpine, carbamylcholine, and aceclidine; a muscarinic blocker selected from atropine, cyclopentolate, homatropine, scopolamine, and tropicamide; a rho kinase inhibitor selected from fasudil, ripasudil, and netarsudil; an adenosine A1 receptor agonist selected from 2-Chloro-N(6)-cyclopentyladenosine, N(6)- cyclopentyladenosine, and N(6)-cyclohexyladenosine; a prostaglandin analogue selected from bimatoprost, travoprost, and latanoprost; or any combination thereof.
  • a muscarinic agonist selected from pilocarpine, carbamylcholine, and acecl
  • Aspect 23 provides the method of any one of Aspects 1-22, wherein the pharmaceutical composition comprises a drug in an amount effective to modulate cerebrospinal fluid pressure (CSFP) in the retrobulbar space of the patient eye, translaminar pressure difference (TPD) across the lamina cribrosa of the patient eye, or both.
  • CSFP cerebrospinal fluid pressure
  • TPD translaminar pressure difference
  • Aspect 24 provides the method of any one of Aspects 1-23, wherein the pharmaceutical composition comprises: a carbonic anhydrase inhibitor selected from acetazolamide, methazolamide, or furosemide; a hyperosmotic agent selected from glycerine, isosorbide, and mannitol; a muscle relaxant selected from arnica oil, cannabis oil, peppermint oil, lemongrass oil, a non steroidal anti-inflammatory drug (NSAIDs), or papaverine; or any combination thereof.
  • NSAIDs non steroidal anti-inflammatory drug
  • Aspect 25 provides the method of any one of Aspects 1-24, wherein pharmaceutical composition comprises about 1% (w/v) carteolol; about 0.25% to about 0.5 (w/v) levobunolol; about 0.3% (w/v) metipranolol; about 0.25% to about 0.5 (w/v) timolol maleate; about 0.25% to about 0.5 (w/v) betaxolol; about 0.5% to about 1.0 (w/v) apraclonidine; about 0.025% to about 0.33% (w/v) brimonidine; about 2% (w/v) dorzolamide; about 1% (w/v) brinzolamide; about 1% to about 2% (w/v) pilocarpine; about 1.5% to about 3% (w/v)
  • carbamylcholine about 1% (w/v) atropine; about 0.5% to about 2% (w/v) cyclopentolate; about 0.5% to about 1.0 (w/v) tropicamide; about 0.01% to about 0.03% (w/v) bimatoprost; about 0.004% (w/v) travoprost; about 0.005% (w/v) latanoprost; about 0.2% to about 2% (w/v) glycerin; or any combination thereof.
  • Aspect 26 provides the method of any one of Aspects 1-24, wherein pharmaceutical composition has, if present, less than 1% (w/v) carteolol; less than 0.25% (w/v) levobunolol; less than 0.3% (w/v) metipranolol; less than 0.25% (w/v) timolol maleate; less than 0.25% (w/v) betaxolol; less than 0.5% (w/v) apraclonidine; less than 0.025% (w/v) brimonidine; less than 2% (w/v) dorzolamide; less than 1% (w/v) brinzolamide; less than 1% (w/v) pilocarpine; less than 1.5% (w/v) carbamylcholine; less than 1% (w/v) atropine; less than 0.5% (w/v) cyclopentolate; less than 0.5% (w/v) tropicamide; less than 0.01 % (w) carteol
  • Aspect 27 provides the method of any one of Aspects 1-26, wherein the pharmaceutical composition is administered in an amount effective to reduce I OP by about 1 mmHg to about 20 mmHg.
  • Aspect 28 provides the method of any one of Aspects 1-27, wherein the pharmaceutical composition is administered in an amount effective to reduce the absolute difference in TDP by about 1 mmHg to about 20 mmHg.
  • Aspect 29 provides the method of any one of Aspects 1-28, wherein the pharmaceutical composition is administered in an amount effective to provide an IOP of about 22 mmHg to about 42 mmHg absent application of the apparatus.
  • Aspect 30 provides the method of any one of Aspects 1-29, wherein the pharmaceutical composition is administered in an amount effective to provide a translaminar pressure difference (TPD) across the lamina cribrosa of the patient eye of about less than -6 mmHg, or greater than about 6 mmHg, absent application of the apparatus.
  • TPD translaminar pressure difference
  • Aspect 31 provides the method of any one of Aspects 1-30, wherein the patient suffering from headache has an intraocular pressure (IOP) of about 8 mmHg to about 21 mmHg.
  • IOP intraocular pressure
  • Aspect 32 provides the method of any one of Aspects 1-30, wherein the patient suffering from headache has an intraocular pressure (IOP) of about 22 mmHg or greater.
  • IOP intraocular pressure
  • Aspect 33 provides the method of any one of Aspects 1-31, wherein the patient suffering from headache has a CSFP of about 90% to about 110% of an estimated CSFP value calculated by 0.44 x Body Mass Index [kg/m 2 ] + 0.16 x Diastolic Blood Pressure [mmHg]- 0.18 x Age [Years] - 1.91.
  • Aspect 34 provides the method of any one of Aspects 1-31, wherein the patient suffering from headache has a CSFP of less than 90% or greater than 110% of an estimated CSFP value calculated by 0.44 x Body Mass Index
  • Aspect 35 provides the method of any one of Aspects 1-32, wherein the patient suffering from headache has a TPD of about 90% to about 110% of an estimated TPD value calculated by IOP [mmHg] - 0.44 x Body Mass Index [kg/m 2 ] + 0.16 x Diastolic Blood Pressure [mmHg] - 0.18 x Age [Years] - 1.91.
  • Aspect 36 provides the method of any one of Aspects 1-32, wherein the patient suffering from headache has a TPD of less than 90% or greater than 110% of an estimated TPD value calculated by IOP [mmHg] - 0.44 x Body Mass Index [kg/m 2 ] + 0.16 x Diastolic Blood Pressure [mmHg] - 0.18 x Age [Years] - 1.91.
  • Aspect 37 provides the method of any one of Aspects 1-36, wherein the patient suffering from headache has a CSFP of about 5 mmHg to about 13 mmHg.
  • Aspect 38 provides the method of any one of Aspects 1-37, wherein the patient suffering from headache has a TPD of about 1.5 mmHg to about 10 mmHg.
  • Aspect 39 provides the method of any one of Aspects 1-38, wherein adjusting the pressure in the cavity comprises pressurizing the cavity to generate a positive force against the patient eye, depressurizing the cavity to generate a negative force against the patient, or both.
  • Aspect 40 provides the method of any one of Aspects 1-39, wherein the administering step and applying step, together, provide an IOP of about 8 mmHg to about 21 mmHg.
  • Aspect 41 provides the method of any one of Aspects 1-40, wherein the administering step and applying step, together, provide an TPD of about -6 mmHg to about 6 mmHg.
  • Aspect 42 provides the method of any one of Aspects 1-41, wherein the pressure in the cavity is adjusted to a positive pressure of about 5 mmHg to about 100 mmHg greater than ambient pressure, or a negative pressure of about 5 mmHg to about 100 mmHg less than ambient pressure.
  • Aspect 43 provides the method of any one of Aspects 1-42, wherein the pressure in the cavity is adjusted to an amount effective to reduce IOP by about 1 mmHg to about 20 mmHg.
  • Aspect 44 provides the method of any one of Aspects 1-43, wherein the pressure in the cavity is adjusted to an amount effective to an IOP of about 22 mmHg to about 42 mmHg absent administration of the pharmaceutical composition.
  • Aspect 46 provides the method of any one of Aspects 1-45, wherein the pharmaceutical composition is an ophthalmic formulation administered directly to the eye.
  • Aspect 47 provides the method of any one of Aspects 1-46, the method comprising: administering a pharmaceutical composition comprising one or more drug to modulate a physiologic characteristic of the eye, performing a physical manipulation to modulate a physiologic characteristic of the eye, or both; and applying an apparatus over the patient eye to provide a cavity and adjusting the pressure in the cavity to a target cavity pressure to apply force on the patient, wherein the modulation and cavity pressure, together, are sufficient to treat the headache.
  • Aspect 48 provides the method of any one of Aspects 1-47, the method comprising administering a pharmaceutical composition comprising one or more drug that modulates aqueous humor production, aqueous humor outflow, intraocular pressure (IOP), translaminar pressure difference (TPD), or any combination thereof, in an amount effective to treat headache, wherein the patient does not suffer from a symptom of glaucoma, or the pharmaceutical composition is administered in an amount that is below the minimum therapeutically-effective dosage for treating symptoms other than headache.
  • a pharmaceutical composition comprising one or more drug that modulates aqueous humor production, aqueous humor outflow, intraocular pressure (IOP), translaminar pressure difference (TPD), or any combination thereof, in an amount effective to treat headache, wherein the patient does not suffer from a symptom of glaucoma, or the pharmaceutical composition is administered in an amount that is below the minimum therapeutically-effective dosage for treating symptoms other than headache.
  • Aspect 49 provides the method of any one of Aspects 1-45, the method comprising adjusting a physiologic characteristic of the eye to provide an intraocular pressure (IOP) at a target headache relief IOP (THR-IOP) level in the patient, or to provide a translaminar pressure difference (TPD) at a target headache relief TPD (THF-TPD) level, or both.
  • IOP intraocular pressure
  • TPD translaminar pressure difference
  • Aspect 50 provides a pharmaceutical composition, comprising one or more drug in an amount effective to modulate a physiologic characteristic of the patient eye, wherein the amount is sufficient to treat headache in a patient.
  • Aspect 51 provides the pharmaceutical composition of Aspect 50, wherein the one or more drug in the pharmaceutical composition are present in an amount that is below the minimum therapeutically-effective dosage for treating symptoms other than headache.
  • Aspect 52 provides the pharmaceutical composition of any one of Aspects 50-51 , wherein the pharmaceutical composition is administered in an amount that is below the minimum therapeutically-effective amount for treating headache, or glaucoma, absent applying an apparatus over the patient eye to provide a cavity and adjusting pressure in the cavity to a target cavity pressure.
  • Aspect 53 provides the pharmaceutical composition of any one of Aspects 50-52, wherein the pharmaceutical composition comprises a glaucoma drug, a mydriatic drug, a miotic drug, or any combination thereof.
  • Aspect 54 provides the pharmaceutical composition of any one of Aspects 50-53, wherein the pharmaceutical composition comprises one or more drug selected from a beta-blocker, an alpha-2 adrenergic agonist, a carbonic anhydrase inhibitor, a cannabinoid, a ROCK/NET inhibitor, a muscarinic agonist, a muscarinic blocker, a rho or rho-associated protein kinase, an adenosine A1 agonist, a prostaglandin receptor inhibitor, a hyperosmotic agent, a muscle relaxant, and any combination thereof.
  • a beta-blocker an alpha-2 adrenergic agonist
  • a carbonic anhydrase inhibitor a cannabinoid
  • ROCK/NET inhibitor a muscarinic agonist
  • a muscarinic blocker a rho or rho-associated protein kinase
  • Aspect 55 provides the pharmaceutical composition of any one of Aspects 50-54, wherein the pharmaceutical composition comprises a drug that increases outflow of the aqueous humor, decreases aqueous humor secretion from the ciliary gland, or decreases intraocular pressure (IOP).
  • the pharmaceutical composition comprises a drug that increases outflow of the aqueous humor, decreases aqueous humor secretion from the ciliary gland, or decreases intraocular pressure (IOP).
  • Aspect 56 provides the pharmaceutical composition of any one of Aspects 50-55, wherein the pharmaceutical composition comprises a drug in an amount effective to modulate ciliary production of aqueous humor.
  • Aspect 57 provides the pharmaceutical composition of any one of Aspects 50-56, wherein the pharmaceutical composition comprises: a beta- blocker selected from carteolol, levobunolol, metipranolol, timolol maleate, and timolol hemihydrate, betaxolol; an alpha-2 adrenergic agonist selected from apraclonidine and brimonidine; a carbonic anhydrase inhibitor selected from dorzol amide and brinzolamide; a cannabinoid selected from D9- Tetrahydrocannabinol (THC), cannabidiol (CBD), endocannabinoid including 2- arachidonoylglycero (2 -AG) and anandamide (AEA); or any combination thereof.
  • a beta- blocker selected from carteolol, levobunolol, metipranolol, timolol maleate, and timolol
  • Aspect 58 provides the pharmaceutical composition of any one of Aspects 50-57, wherein the pharmaceutical composition comprises a drug in an amount effective to modulate trabecular or uveoscleral outflow of aqueous humor in the patient eye.
  • Aspect 59 provides the pharmaceutical composition of any one of Aspects 50-58, wherein the pharmaceutical composition comprises: a muscarinic agonist selected from pilocarpine, carbamylcholine, and aceclidine; a muscarinic blocker selected from atropine, cyclopentolate, homatropine, scopolamine, and tropicamide; a rho kinase inhibitor selected from fasudil, ripasudil, and netarsudil; an adenosine A1 receptor agonist selected from 2-Chloro-N(6)- cyclopentyladenosine, N(6)-cyclopentyladenosine, and N(6)- cyclohexyladenosine; a prostaglandin analogue selected from bimatoprost, travoprost, and latanoprost; or any combination thereof
  • Aspect 60 provides the pharmaceutical composition of any one of Aspects 50-59, wherein the pharmaceutical composition comprises a drug in an amount effective to modulate cerebrospinal fluid pressure (CSFP) in the retrobulbar space of the patient eye, translaminar pressure difference (TPD) across the lamina cribrosa of the patient eye, or both.
  • CSFP cerebrospinal fluid pressure
  • TPD translaminar pressure difference
  • Aspect 61 provides the pharmaceutical composition of any one of Aspects 50-60, wherein the pharmaceutical composition comprises: a carbonic anhydrase inhibitor selected from acetazolamide, methazolamide, or furosemide; a hyperosmotic agent selected from glycerine, isosorbide, and mannitol; a muscle relaxant selected from arnica oil, cannabis oil, peppermint oil, lemongrass oil, a non-steroidal anti-inflammatory drug (NSAIDs), or papaverine; or any combination thereof.
  • NSAIDs non-steroidal anti-inflammatory drug
  • Aspect 62 provides the pharmaceutical composition of any one of Aspects 50-61, wherein the pharmaceutical composition is an ophthalmic solution comprising about 1% (w/v) carteolol; about 0.25% to about 0.5 (w/v) levobunolol; about 0.3% (w/v) metipranolol; about 0.25% to about 0.5 (w/v) timolol maleate; about 0.25% to about 0.5 (w/v) betaxolol; about 0.5% to about 1.0 (w/v) apraclonidine; about 0.025% to about 0.33% (w/v) brimonidine; about 2% (w/v) dorzolamide; about 1% (w/v) brinzolamide; about 1% to about 2% (w/v) pilocarpine; about 1.5% to about 3% (w/v) carbamylcholine; about 1% (w/v) atropine; about 0.5% to about 2% (w/v)
  • Aspect 63 provides the pharmaceutical composition of any one of Aspects 50-62, wherein pharmaceutical composition is an ophthalmic solution comprising one or more of less than 1% (w/v) carteolol; less than 0.25% (w/v) levobunolol; less than 0.3% (w/v) metipranolol; less than 0.25% (w/v) timolol maleate; less than 0.25% (w/v) betaxolol; less than 0.5% (w/v) apraclonidine; less than 0.025% (w/v) brimonidine; less than 2% (w/v) dorzolamide; less than 1% (w/v) brinzolamide; less than 1% (w/v) pilocarpine; less than 1.5% (w/v) carbamylcholine; less than 1% (w/v) atropine; less than 0.5% (w/v)
  • cyclopentolate less than 0.5% (w/v) tropicamide; less than 0.01% (w/v) bimatoprost; less than 0.004% (w/v) travoprost; less than 0.005% (w/v) latanoprost; or less than 0.2% (w/v) glycerin.
  • Aspect 64 provides the pharmaceutical composition of any one of Aspects 50-63, wherein the one or more drug is present in the pharmaceutical composition in an amount effective to reduce IOP by about 1 mmHg to about 20 mmHg.
  • Aspect 65 provides the pharmaceutical composition of any one of Aspects 50-64, wherein the one or more drug is present in the pharmaceutical composition in an amount effective to reduce the absolute difference in TDP by about 1 mmHg to about 20 mmHg.
  • Aspect 66 provides the pharmaceutical composition of any one of Aspects 50-65, wherein the one or more drug is present in the pharmaceutical composition in an amount effective to provide an IOP of about 22 mmHg to about 42 mmHg absent application of the apparatus.
  • Aspect 67 provides the pharmaceutical composition of any one of Aspects 50-66, wherein the one or more drug is present in the pharmaceutical composition in an amount effective to provide a translaminar pressure difference (TPD) across the lamina cribrosa of the patient eye of about less than -6 mmHg, or greater than about 6 mmHg, absent application of the apparatus.
  • TPD translaminar pressure difference
  • Aspect 68 provides an apparatus, or the method or pharmaceutical composition of any one of Aspects 1-67, wherein the apparatus includes a cover, sized and shaped to fit over a patient eye to define a cavity between the cover and the patient, the cover capable of applying and retaining a non-ambient cavity pressure in contact with the patient to treat, inhibit, or prevent the headache symptom.
  • Aspect 69 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-68, wherein the apparatus can include or use a positive pressure cavity check valve configured to release positive gauge pressure from the cavity and a negative pressure cavity check valve configured to regulate cavity pressure toward a target cavity pressure.
  • Aspect 70 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-69, wherein the apparatus can include or use an apparatus including a pressure source, in communication with the cavity, capable of applying non-ambient cavity pressure to the patient to treat, inhibit, or prevent the headache symptom.
  • a pressure source in communication with the cavity, capable of applying non-ambient cavity pressure to the patient to treat, inhibit, or prevent the headache symptom.
  • Aspect 71 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-70, wherein the apparatus can include or use control circuitry, in communication with the pressure source, the control circuitry configured to receive a target cavity pressure level to control the pressure source to adjust the cavity pressure toward the target cavity pressure level to treat, inhibit, or prevent the headache symptom.
  • Aspect 72 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-71, wherein the apparatus can include or use the target cavity pressure, wherein the target cavity pressure level includes a blood flow target cavity pressure level.
  • Aspect 73 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-72, wherein the apparatus can include or use an ocular blood flow sensor, in communication with the control circuitry, to sense an indication of ocular blood flow in the patient eye and wherein the control circuity includes blood flow pressure feedback control circuitry to adjust the cavity pressure toward the blood flow target cavity pressure level.
  • the apparatus can include or use an ocular blood flow sensor, in communication with the control circuitry, to sense an indication of ocular blood flow in the patient eye and wherein the control circuity includes blood flow pressure feedback control circuitry to adjust the cavity pressure toward the blood flow target cavity pressure level.
  • Aspect 74 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-73, wherein the apparatus can include an applied force target cavity pressure level.
  • Aspect 75 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-74, wherein the apparatus can include or use a force sensor, in communication with the control circuitry, to sense an indication of force applied by the cover to patient tissue and wherein the control circuity includes applied force pressure feedback control circuitry to adjust the cavity pressure toward the applied force target cavity pressure level.
  • Aspect 76 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-75, wherein the control circuitry includes sweep circuitry configured to sequentially vary non-ambient pressure level applied to the cavity in a pressure range to identify the target cavity pressure value, the pressure range defined by a first pressure level and a second pressure level, wherein the second pressure level is greater than the first pressure level j 00499]
  • Aspect 77 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-76, wherein the sweep circuitry is configured to sequentially vary non-ambient pressure from the first pressure level to the second pressure level.
  • Aspect 78 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-77, wherein the sweep circuitry is configured to sequentially vary non-ambient pressure from the second pressure level to the first pressure level.
  • Aspect 79 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-78, wherein the control circuitry includes patient input circuitry configured to receive an indication of an indication of a headache symptom from a patient.
  • Aspect 80 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-79, wherein the apparatus can include or use a patient input interface, in communication with the patient input circuitry, configured to receive the indication of the headache symptom from the patient.
  • Aspect 81 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1 -80, wherein the patient input interface includes a fob device in communication with the control circuitry.
  • Aspect 82 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-81, wherein the patient input interface includes an app running on a mobile device, the app in communication with the control circuitry.
  • Aspect 83 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1 -82, wherein the control circuitry includes memory circuitry configured to store an indication of activity associated with the apparatus for use in at least one of programming the apparatus or monitoring patient use of the apparatus.
  • Aspect 84 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-83, wherein the apparatus can include or use an anterior plate attached to the cover and configured to contact patient tissue proximal to at least a portion of an anterior portion of the skull including a patient trigeminal nerve.
  • Aspect 85 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1 -84, wherein the anterior plate is configured to apply pressure to the patient tissue, wherein the applied pressure is based upon non-ambient pressure applied to the cavity.
  • Aspect 86 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-85, wherein the control circuitry is configured to adjust the non-ambient pressure applied to the cavity toward a headache target cavity pressure.
  • Aspect 87 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-86, wherein the apparatus can include or use a posterior plate attached to the cover and configured to contact patient tissue proximal to at least a portion of a posterior portion of the skull including a patient occipital nerve.
  • Aspect 88 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-87, wherein the posterior plate is configured to apply pressure to the patient tissue, wherein the applied pressure is based upon non-ambient pressure applied to the cavity.
  • Aspect 89 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-88, wherein the apparatus can include or use a method of using an apparatus to treat, inhibit, or prevent an indication of a headache symptom experienced by a patient, the method including forming a cavity over a patient eye; and pressurizing the cavity to generate a force against the patient to treat, inhibit or prevent the indication of the headache symptom.
  • Aspect 90 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-89, wherein forming a cavity includes locating a cover over the patient eye and pressurizing the cavity includes, applying an external force to compress the cover against the patient, and releasing the external force to create a negative gauge pressure in the cavity.
  • Aspect 91 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1 -90, wherein the apparatus can include applying a non-ambient pressure to a cavity defined by a cover over the eye of the patient, wherein the patient has a history of experiencing the headache symptom; and adjusting the non-ambient pressure applied to the cavity toward a headache target cavity pressure level specified to treat, inhibit, or prevent the headache symptom.
  • Aspect 92 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-91, wherein the patient with a history of experiencing the headache symptom is experiencing the headache symptom.
  • Aspect 93 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1 -92, wherein the cover includes an anterior plate and the method comprises locating the anterior plate in contact with patient tissue proximal to at least a portion of a patient trigeminal nerve.
  • Aspect 94 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-93, wherein adjusting non-ambient pressure includes adjusting non-ambient pressure toward a headache target cavity pressure.
  • Aspect 95 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1 -94, wherein the cover includes a posterior plate and the method comprises locating the posterior plate in contact with patient tissue proximal to the occipital nerve.
  • Aspect 96 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-95, wherein adjusting non-ambient pressure includes adjusting non-ambient pressure toward a headache target cavity pressure.
  • Aspect 97 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-96, wherein the apparatus can include a cover sized and shaped to fit over an eye of the patient to define a cavity between the cover and an anterior surface of the eye, the cover including a patient interface surface with a protuberance located between the cover and the patient, the protuberance configured to apply a force to the patient to affect the headache symptom.
  • Aspect 98 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-97, wherein the apparatus can include a pressure source, in communication with the cavity, configured to apply non- ambient pressure to the cavity, wherein the protuberance force is variable based on the non-ambient pressure applied to the cavity
  • Aspect 99 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-98, wherein the protuberance includes at least one of a positive protuberance or a negative protuberance.
  • Aspect 100 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-99, wherein the protuberance includes the positive protuberance.
  • Aspect 101 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-100, wherein the protuberance includes the negative protuberance.
  • Aspect 102 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-101, wherein at least one of the positive protuberance or the negative protuberance is configured to be movable on the patient interface surface.
  • Aspect 103 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-102, wherein the patient interface surface is configured to vary the temperature of the patient interface surface.
  • Aspect 104 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-103, wherein the temperature can be varied by at least one of increasing the temperature of the patient interface surface or decreasing the temperature of the patient interface surface.
  • Aspect 105 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-104, wherein the patient interface surface is configured to transmit energy to the patient in a frequency range of about 10 Hz to about 100 kHz.
  • Aspect 106 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-105, wherein the apparatus can include or use an anterior plate attached to the cover and configured to contact patient tissue surrounding at least a portion of the trigeminal nerve.
  • Aspect 107 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-106, wherein the anterior plate is configured to apply contact pressure to tissue surrounding at least a portion of the trigeminal nerve.
  • Aspect 108 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-107, wherein the anterior plate is configured to vary the temperature of the anterior plate interface surface.
  • Aspect 109 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-108, wherein the anterior plate is configured to transmit energy to the patient in a frequency range of about 10 Hz to about 100 kHz.
  • Aspect 110 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-109, wherein the apparatus can include or use a posterior plate attached to the cover and configured to contact tissue surrounding at least a portion of the occipital nerve.
  • Aspect 111 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-110, wherein the posterior plate is configured to apply contact pressure to the patient tissue surrounding at least a portion of the occipital nerve.
  • Aspect 112 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-111, wherein the posterior plate is configured to transmit energy to the patient in a frequency range of about 10 Hz to about 100 kHz.
  • Aspect 113 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-112, wherein the apparatus can include locating a cover over a patient eye to form a cavity between the cover and an anterior surface of the patient eye, the cover including a patient interface surface with a protuberance between the cover and the patient, the protuberance configured to apply a protuberance force to the patient; and applying non ambient pressure to the cavity to vary the protuberance force to affect the headache symptom.
  • Aspect 114 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-113, wherein locating the cover includes adjusting the location of at least one of a positive protuberance or a negative protuberance on the patient interface surface.
  • Aspect 115 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-114, wherein the apparatus can include or use an anterior plate attached to the cover and locating the cover includes locating the anterior plate in contact with patient tissue surrounding at least a portion of the trigeminal nerve.
  • Aspect 116 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-115, wherein applying non-ambient pressure includes applying contact pressure to patient tissue surrounding at least a portion of the trigeminal nerve with the anterior plate.
  • Aspect 117 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-116, wherein the apparatus can include or use a posterior plate attached to the cover and locating the cover includes locating the posterior plate in contact with patient tissue surrounding at least a portion of the occipital nerve.
  • Aspect 118 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-117, wherein applying non-ambient pressure includes applying contact pressure to patient tissue surrounding at least a portion of the occipital nerve with the posterior plate.
  • Aspect 119 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-118, wherein the apparatus can include or use subject matter (such as an apparatus, a system, a device, a method, a means for performing acts, or a device readable medium including instructions that, when performed by the device, can cause the device to perform acts), such as an apparatus to affect a headache symptom in a patient, the apparatus including a cover sized and shaped to fit over an eye of the patient to define a cavity between the cover and an anterior surface of the eye; and control circuitry, configured to regulate a pressure source in communication with the cavity and an adjunct device in communication with the patient to affect the headache symptom.
  • subject matter such as an apparatus, a system, a device, a method, a means for performing acts, or a device readable medium including instructions that, when performed by the device, can cause the device to perform acts
  • the apparatus to affect a headache symptom in a patient the apparatus including a cover sized and shaped to fit over an eye of the patient to
  • Aspect 120 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-119, wherein the adjunct device includes at least one of a trigeminal energy transfer device, an occipital energy transfer device, or a peripheral nerve energy transfer device.
  • Aspect 121 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-120, wherein the adjunct device is the trigeminal energy transfer device with a patient interface surface located against tissue proximal to the patient trigeminal nerve.
  • Aspect 122 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-121, wherein the patient interface surface is configured to adjust temperature of the patient interface surface including at least one of increasing the temperature of the patient surface interface or decreasing the temperature of the patient surface interface.
  • Aspect 123 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-122, wherein the patient interface surface is configured to transmit energy to the patient in a frequency range of about 10 Hz to about 100 kHz.
  • Aspect 124 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-123, wherein the adjunct device is the occipital energy transfer device with a patient interface surface located against tissue proximal to the patient occipital nerve.
  • Aspect 125 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-124, wherein the patient interface surface is configured to adjust temperature of the patient interface surface including at least one of increasing the temperature of the patient surface interface or decreasing the temperature of the patient interface surface.
  • Aspect 126 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-125, wherein the frequency range is about 10 Hz to about 500 Hz.
  • Aspect 127 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-126, wherein the frequency range is about 500 Hz to about 10 kHz.
  • Aspect 128 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-127, wherein the adjunct device is the peripheral nerve energy transfer device with a patient interface surface located against tissue proximal to a peripheral nerve of the patient.
  • Aspect 129 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-128, wherein the apparatus can include or use a method of using an apparatus to affect a headache symptom, the apparatus including a cover sized and shaped to fit over an eye of a patient to define a cavity between the cover and an anterior surface of the eye and control circuitry to regulate a pressure source in communication with the cavity and an adjunct device in communication with the patient, the method including adjusting non ambient pressure in the cavity toward a headache target cavity pressure level with the pressure source to affect the headache symptom, and adjusting energy applied to the patient toward a headache target energy level with the adjunct device to further affect the headache symptom.
  • Aspect 130 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-129, wherein the adjunct device includes an anterior plate configured to contact patient tissue proximal to at least a portion of a patient trigeminal nerve and adjusting energy includes applying pressure to the patient tissue toward a trigeminal nerve headache target contact pressure with the anterior plate.
  • Aspect 131 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-130, wherein applying pressure to the patient to the patient tissue includes applying pressure based upon the non ambient pressure level in the cavity.
  • Aspect 132 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-131, wherein the adjunct device includes a posterior plate configured to contact patient tissue proximal to at least a portion of a patient occipital nerve and adjusting energy includes applying pressure to the patient tissue toward an occipital nerve headache-relief target contact pressure with the posterior plate.
  • Aspect 133 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-132, wherein applying pressure to the patient tissue includes applying pressure based upon the non-ambient pressure level in the cavity.
  • Aspect 134 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-133, wherein the adjunct device includes a peripheral energy transfer device configured to contact patient tissue proximal to at least a portion of a patient peripheral nerve and adjusting energy includes applying stimulation energy to the patient tissue toward a peripheral nerve headache target energy level with the peripheral energy transfer device j 00557]
  • Aspect 135 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-134, wherein the apparatus can include an energy transfer device configured to contact patient tissue proximal to at least a portion of a patient peripheral nerve and adjusting energy includes applying stimulation energy to the patient tissue toward a peripheral nerve headache target energy level with the peripheral energy transfer device.
  • Aspect 136 provides the apparatus, method, or pharmaceutical composition of any one of Aspects 1-135, for use in treating headache in a patient suffering therefrom.
  • Aspect 137 provides the pharmaceutical composition of any one of Aspects 50-67 for use in treating headache in a patient suffering therefrom.
  • Aspect 138 provides the pharmaceutical composition of any one of Aspect 50-67 for use with the apparatus, method, or pharmaceutical composition of any one of Aspects 1-135 to treat headache in a patient.
  • Aspect 139 provides the use of the pharmaceutical composition of any one of Aspect 50-67 for the manufacturing of a medicament or kit for treating headache.
  • Aspect 140 provides the use of the pharmaceutical composition of any one of Aspect 50-67 patient eye for the manufacturing of a medicament for treating headache.
  • Aspect 141 provides any one of Aspects 1-140, wherein the pharmaceutical composition and physical manipulation, when present, is provided to the patient separately from the apparatus.
  • Aspect 142 provides any one of Aspects 1-141, wherein the pharmaceutical composition and physical manipulation, when present, is provided to the patient before applying the apparatus, or after applying and then removing the apparatus.
  • Aspect 143 provides any one of Aspects 1-142, wherein the pharmaceutical composition is provided to the patient directly.
  • Aspect 144 provides any one of Aspects 1-143, wherein the pharmaceutical composition is provided to the patient orally.
  • Aspect 145 provides any one of Aspects 1-144, wherein the pharmaceutical composition is provided to the patient as eye drops dropped onto the eye.
  • Aspect 146 provides any one of Aspects 1-145, wherein the pharmaceutical composition is provided to the patient systemically.
  • Aspect 147 provides any one of Aspects 1-146, wherein the pharmaceutical composition is provided to the patient by injection intravenously, intramuscularly, intraarterially, or subcutaneously.
  • Aspect 148 provides any one of Aspects 1-147, wherein the pharmaceutical composition by a route other than via the working fluid of the apparatus, via the cavity of the apparatus, or both.
  • Aspect 149 provides any one of Aspects 1-148, wherein the pharmaceutical composition by a route other than as a therapeutic gas, mist, or fog.
  • Aspect 150 provides any one of Aspects 1-149, wherein the pharmaceutical composition is not a working fluid of the apparatus.
  • Aspect 151 provides any one of Aspects 1-150, wherein the one or more drugs are a glaucoma drug, a mydriatic drug, a miotic drug, a cycloplegic, beta-blocker, an alpha-2 adrenergic agonist, a carbonic anhydrase inhibitor, a ROCK/NET inhibitor, a muscarinic agonist, a muscarinic blocker, a rho or rho- associated protein kinase, an adenosine A1 agonist, a prostaglandin receptor inhibitor, a hyperosmotic agent, a muscle relaxant, or a combination thereof.
  • the one or more drugs are a glaucoma drug, a mydriatic drug, a miotic drug, a cycloplegic, beta-blocker, an alpha-2 adrenergic agonist, a carbonic anhydrase inhibitor, a ROCK/NET inhibitor, a
  • Aspect 152 provides any one of Aspects 1-151, wherein the one or more drugs are other than: vitamins, such as vitamin A, a B vitamin, vitamin C, vitamin D, vitamin E, beta-carotene, zinc, lutein, and folate; a therapeutic gas, such as carbon dioxide (CO2), oxygen (O2), nitric oxide (NO), ozone (O3), nitrogen (N), and helium (He); hydrocarbons; fluorocarbons; perfluorocarbons; sulfur hexafluoride; and cannabinoids, such as tetrahydrocannabinol (THC) and cannabidiol (CBD).
  • vitamins such as vitamin A, a B vitamin, vitamin C, vitamin D, vitamin E, beta-carotene, zinc, lutein, and folate
  • a therapeutic gas such as carbon dioxide (CO2), oxygen (O2), nitric oxide (NO), ozone (O3), nitrogen (N), and helium (He)
  • Aspect 153 provides any one of Aspects 1-152, wherein the pharmaceutical composition is free of vitamins, such as vitamin A, a B vitamin, vitamin C, vitamin D, vitamin E, beta-carotene, zinc, lutein, folate; a therapeutic gas, such as carbon dioxide (CO2), oxygen (O2), nitric oxide (NO), ozone (O3), nitrogen (N), and helium; hydrocarbons; fluorocarbons; perfluorocarbons; sulfur hexafluoride; and cannabinoids, such as tetrahydrocannabinol (THC) and cannabidiol (CBD).
  • vitamins such as vitamin A, a B vitamin, vitamin C, vitamin D, vitamin E, beta-carotene, zinc, lutein, folate
  • a therapeutic gas such as carbon dioxide (CO2), oxygen (O2), nitric oxide (NO), ozone (O3), nitrogen (N), and helium
  • hydrocarbons fluorocarbons; perflu
  • Aspect 154 provides any one of Aspects 1-153, wherein the pharmaceutical composition is substantially free of a therapeutically effective amount of a gaseous therapeutic fluid, such as carbon dioxide (C02), oxygen (02), nitric oxide (NO), ozone (03), nitrogen (N), helium (He), hydrocarbons including fluorocarbons and perfluorocarbons, and sulfur hexafluoride.
  • a gaseous therapeutic fluid such as carbon dioxide (C02), oxygen (02), nitric oxide (NO), ozone (03), nitrogen (N), helium (He), hydrocarbons including fluorocarbons and perfluorocarbons, and sulfur hexafluoride.
  • Aspect 155 provides any one of Aspects 1-154, wherein the pharmaceutical composition is substantially free of cannabinoids including tetrahydrocannabinol (THC) and cannabidiol (CBD).
  • cannabinoids including tetrahydrocannabinol (THC) and cannabidiol (CBD).
  • Aspect 156 provides any one of Aspects 1-155, wherein the one or more drugs are other than antiepileptics, antidepressants, nerve blocks, non steroidal analgesics, opioids, neuromodulators, neurotoxic protein, botulinum toxin, general antagonists, triptans, CRGP inhibitors, NSAIDs, and beta blockers.
  • the one or more drugs are other than antiepileptics, antidepressants, nerve blocks, non steroidal analgesics, opioids, neuromodulators, neurotoxic protein, botulinum toxin, general antagonists, triptans, CRGP inhibitors, NSAIDs, and beta blockers.
  • Aspect 157 provides any one of Aspects 1-156, wherein the pharmaceutical composition is free of one or more of antiepileptics, antidepressants, nerve blocks, non-steroidal analgesics, opioids,
  • neuromodulators neurotoxic protein, botulinum toxin, general antagonists, triptans, CRGP inhibitors, NSAIDs, and beta blockers.
  • Aspect 158 provides any one of Aspects 1-157, wherein the pharmaceutical composition is free of antiepileptics, antidepressants, nerve blocks, non-steroidal analgesics, opioids, neuromodulators, neurotoxic protein, botulinum toxin, general antagonists, triptans, CRGP inhibitors, NSAIDs, and beta blockers.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pain & Pain Management (AREA)
  • Neurology (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)

Abstract

L'invention concerne une méthode de traitement, d'inhibition ou de prévention des maux de tête chez un patient en utilisant une composition médicamenteuse, un appareil ou les deux. La composition médicamenteuse peut comprendre un ou plusieurs constituants qui modifient une caractéristique physiologique de l'œil, par exemple qui modifient l'humeur aqueuse. L'appareil peut comprendre un couvercle, dimensionné et façonné pour s'adapter sur un œil d'un patient pour délimiter une cavité entre le couvercle et une surface antérieure de l'œil lorsque le couvercle est situé sur l'œil du patient. Une pression de cavité non ambiante peut être appliquée dans la cavité vers une valeur de pression de cavité cible. La composition médicamenteuse peut être administrée simultanément à l'application de l'appareil pour traiter, inhiber ou prévenir un ou plusieurs symptômes du mal de tête.
PCT/US2020/040700 2019-07-03 2020-07-02 Méthode, composition et appareil de traitement des maux de tête WO2021003393A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201962870554P 2019-07-03 2019-07-03
US62/870,554 2019-07-03
PCT/US2019/055515 WO2020077032A1 (fr) 2018-10-10 2019-10-10 Appareil et méthodes de traitement de céphalées
USPCT/US2019/055515 2019-10-10

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WO2021003393A1 true WO2021003393A1 (fr) 2021-01-07

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US20140343041A1 (en) * 2013-03-15 2014-11-20 Ora, Inc. Topical Ophthalmic Formulations for the Treatment and Prevention of Migraine Headache
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US9408746B2 (en) * 2010-03-31 2016-08-09 Ocuject, Llc Device and method for intraocular drug delivery
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