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Definitions

• the invention relates to compositions of ion channel activators and methods of preparation, formulation, and the medical use of these compositions.
• compositions that include activators of ion channels may be useful to treat the above-mentioned conditions.
• the composition is formulated for modified release (e.g., delayed release, extended release, or rapid release) of said ion channel activator (e.g. , TRPVl channel activator, TRPA1 channel activator, ASIC channel activator, or combination thereof).
• said pharmaceutically acceptable excipient comprises an agent for modified release (e.g., delayed release, extended release, or rapid release) of an ion channel activator (e.g. , a TRPVl channel activator, a TRPA1 channel activator, an ASIC channel activator, or combination thereof), such that, when orally administered to a subject, the ion channel activator (e.g.
• the agent for modified release (e.g., delayed release, extended release, or rapid release) is selected from the group consisting of: hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, carboxymethyl cellulose, and mixtures thereof.
• the capsaicinoid is capsaicin.
• the TRPV1 channel activator is present from about 0.001% to about 10% (w/w) or from about 0.001% to about 10% (v/v).
• the TRPA1 channel activator is present from about 0.001% to about 10% (w/w) or from about 0.001% to about 10% (v/v).
• the composition is a liquid or a solid. In some embodiments, the composition is formulated as a liquid. In some embodiments, the liquid is selected from the group consisting of emulsions, microemulsions, solutions, suspensions, syrups (e.g., syrup concentrates), linctuses, drops, sprays, and elixirs. In some embodiments, the composition is formulated as a solid. In some embodiments, the solid is selected from the group consisting of tablets, capsules, powders, crystals, pastes, gels, lozenges (e.g., liquid filled lozenges), gums, candies, chews, foodstuffs, dissolving strips, films, and semi-solid formulations. In some embodiments, said solid is a tablet or capsule. In some embodiments, said capsule is a hard or soft capsule.
• the invention features a composition formulated for oral
• the composition comprising an ion channel activator (e.g., a TRPVl channel activator, a TRPA1 channel activator, an ASIC channel activator, or
• the TRPVl channel activator is a capsaicinoid, a capsinoid, oleoylethanolamide, N-oleoyldopamine, 3-methyl-N-oleoyldopamine, oleamide, capsiate, a 1 -monoacylglycerol having C18 and C20 unsaturated and C8-C12 saturated fatty acid, a 2- monoacylglycerol having C18 and C20 unsaturated fatty acids, miogadial, miogatrial, polygodial, a terpenoid with an alpha,beta-unsaturated 1,4-dialdehyde moiety, sanshool, evodiamine, acesulfame-K, cyclamate, CuS0 4 , ZnS0 4 , FeS0 4 , arvanil, anandamide, N- arachidonoyl-dopamine, flufenamic acid dopamide,
• the composition comprising an ion channel activator (e.g., a TRPV1 channel activator, a TRPA1 channel activator, an ASIC channel activator, or
• the composition comprises a liquid formulation (e.g., an emulsion, microemulsion, solution, suspension, syrup (e.g., syrup concentrate), linctus, drop, or elixir) and an effective amount of the liquid formulation is at least about 1 mL, about 2 mL, about 4 mL, about 6 mL, about 8 mL, about 10 mL, about 12 mL, about 14 mL, about 16 mL, about 18 mL, about 20 mL, about 22.5 mL, about 25 mL, or more. In some embodiments, an effective amount of the liquid formulation is between about 1 mL and 10 mL. In some embodiments, an effective amount of the liquid formulation is between about 5 mL and 10 mL. In some embodiments, an effective amount of the liquid formulation is between about 10 mL and 25 mL.
• a liquid formulation e.g., an emulsion, microemulsion, solution, suspension, syrup (e.g
• an effective amount of the liquid formulation is between about 25 mL and 100 mL. In some embodiments, an effective amount of the liquid formulation is between about 50 mL and 500 mL. In some embodiments, an effective amount of the liquid formulation is between about 100 mL and 1000 mL.
• said method comprises orally administering to a subject a composition comprising an ion channel activator (e.g. , a TRPVl channel activator, a TRPAl channel activator, an ASIC channel activator, or combination thereof) and a plurality of pharmaceutically acceptable excipients.
• an ion channel activator e.g. , a TRPVl channel activator, a TRPAl channel activator, an ASIC channel activator, or combination thereof
• said painful muscle contraction is a muscle contraction of the head or neck.
• said painful muscle contraction is associated with tension headache, cluster headache, or migraine headache.
• the invention features a method of treating tactile sensitivity in a subject in need thereof, said method comprising orally administering to said subject a
• the invention features a method of treating a dystonia in a subject in need thereof, said method comprising orally administering to said subject a composition comprising an effective amount of an ion channel activator (e.g. , a TRPVl channel activator, a TRPAl channel activator, an ASIC channel activator, or combination thereof) and a ion channel activator (e.g. , a TRPVl channel activator, a TRPAl channel activator, an ASIC channel activator, or combination thereof) and a ion channel activator (e.g. , a TRPVl channel activator, a TRPAl channel activator, an ASIC channel activator, or combination thereof) and a ion channel activator (e.g. , a TRPVl channel activator, a TRPAl channel activator, an ASIC channel activator, or combination thereof) and a ion channel activator (e.g. , a TRPVl channel activator, a TRPAl
• said method comprises orally administering to a subject a composition comprising an ion channel activator (e.g. , a TRPVl channel activator, a TRPAl channel activator, an ASIC channel activator, or combination thereof) and a plurality of pharmaceutically acceptable excipients.
• an ion channel activator e.g. , a TRPVl channel activator, a TRPAl channel activator, an ASIC channel activator, or combination thereof
• said PNS condition is selected from the group consisting of: cramp fasciculation syndrome, Isaacs' Syndrome or neuromyotonia (NMT), peripheral neuropathy, carpal tunnel syndrome, and Epstein-Barr virus (EBV) infection.
• the capsaicinoid is capsaicin.
• the TRPVl channel activator is present from about 0.001% to about 10% (w/w) or from about 0.001% to about 10% (v/v).
• said solid is a tablet or capsule. In some embodiments, said capsule is a hard or soft capsule.
• the TRPA1 channel activator is allyl
• the TRPA1 channel activator is present from about 0.001% to about 10% (w/w) or from about 0.001% to about 10% (v/v).
• the ASIC channel activator comprises acetic acid, phosphoric acid, citric acid, malic acid, succinic acid, lactic acid, tartaric acid, fumaric acid, or ascorbic acid. In some embodiments, the ASIC channel activator is present from about 0.001% to about 10% (w/w) or from about 0.001% to about 10% (v/v).
• said muscle contraction is not induced by applied electrical stimulation.
• said test comprises: a) administering the test aliquot of the composition to said subject; b) inducing, e.g. , by application of electrical stimulation, e.g. , percutaneous stimulation or surface stimulation, a test muscle contraction; and c) evaluating the effect of administering the test aliquot of the composition on test muscle contraction.
• step a is performed before step b. In some embodiments, step a is performed after step b.
• said test comprises: a) administering the test aliquot of the composition to said subject; b) inducing, e.g. , by application of electrical stimulation, e.g. , percutaneous stimulation or surface stimulation, a test muscle contraction; and c) evaluating the effect of administering the composition on test muscle contraction, e.g. , by evaluating the electrical activity of said test muscle, e.g. , by EMG.
• electrical stimulation e.g. , percutaneous stimulation or surface stimulation
• step b is performed before step c.
• steps b and c are performed within a preselected time of one another, e.g. , they are performed sufficiently close in time that step b will modulate step c.
• said test muscle contraction comprises a contraction in a muscle of the foot, e.g. , the flexor hallucis brevis muscle.
• a decrease in the value from step f compared to the value from step e is indicative of efficacy in alleviating said test muscle contraction.
• said test aliquot of the composition comprises an ion channel activator (e.g. , a TRPVl channel activator, a TRPAl channel activator, an ASIC channel activator, or combination thereof), and a plurality of pharmaceutically acceptable excipients.
• an ion channel activator e.g. , a TRPVl channel activator, a TRPAl channel activator, an ASIC channel activator, or combination thereof
• said capsule is a hard or soft capsule.
• Figure 1 is a series of graphs from 6 sensory neurons isolated from the trigeminal ganglia of rats that illustrate their activation by the capsicum, cinnamon, and ginger extracts that were used in the human experiments.
• Directly acquiring a value or physical entity includes performing a process that includes a physical change in a physical substance or the use of a machine or device. Exemplary changes include applying a current to, or measuring a current from, the muscle of a subject. Directly acquiring a value includes performing a process that uses a machine or device, e.g. , a device to induce a cramp or a device to measure a parameter related to a cramp.
• compositions that can be reconstituted with a liquid (e.g. , powders, granules, or tablets that may be reconstituted with water), gels, semi-solids (e.g. , ice cream, pudding, or yogurt), frozen liquids (e.g. , ice pops), lozenges or hard candies, dissolving strips (e.g. , an edible strip containing pullulan and compositions of the invention), and chewing gums.
• a liquid e.g. , powders, granules, or tablets that may be reconstituted with water
• gels e.g. , semi-solids (e.g. , ice cream, pudding, or yogurt), frozen liquids (e.g. , ice pops), lozenges or hard candies, dissolving strips (e.g. , an edible strip containing pullulan and compositions of the invention), and chewing gums.
• Muscle cramp as used herein is a muscle cramp which is treated with the composition described herein. In embodiments it is not induced but rather arises spontaneously either from activity or underlying disease etiology, e.g. , athletic activity or night cramp.
• the muscle cramp comprises a cramp in a muscle other than the muscle of the test muscle cramp.
• the muscle cramp can be a contraction of a skeletal muscle or the smooth muscle.
• muscle cramps occur most frequently in the muscles of the foot, calf, front of the thigh (e.g. , quadricep), back of the thigh (e.g. , hamstring), hands, arms (e.g.
• Fasciculation refers to a small, local, involuntary muscle contraction and relaxation. Fasciculations are also commonly known as a “muscle twitch”.
• an effective amount of an agent is, for example, an amount sufficient to achieve an increase in TRPV1, TRPA1, and/or ASIC channel activity as compared to the response obtained without administration of the agent.
• the effective amount of active compound(s) used to practice the present invention can also be varied based on, for example, the age, and body weight, of the subject or the nature of the exercise.
• subject refers to a mammal, including, but not limited to, a human or non-human mammal, such as a bovine, equine, canine, ovine, or feline mammal.
• TRP channels are a family of ion channels that are generally expressed on the cell surface. Members of the TRP channel family share some structural similarity and are organized in sub-families, comprising TRPA, TRPC, TRPV, TRPM, TRPML, TRMPN, and TRPP. Each of these sub-families comprise subunit genes, which include, for example, TRPVl, TRPV2, TRPV4, TRPV3, TRPV5, TRPV6, TRPAl, TRPP3, TRPP2, TRPP5, TRPC4, TRPC5, TRPC1, TRPC3, TRPC7, TRPC6, TRPM1, TRPM3, TRPM6, TRPM7, TRPM4, TRPM5, TRPM2, TRPM8, TRPML1, TRPML3, and TRPML2.
• the compositions described herein may comprise at least one activator or agonist of any of the TRP channels.
• esterification at the exocyclic hydroxy group of the diterpene e.g. 20-homovanillyl-mezerein and 20-homovanillyl- 12-deoxyphorbol- 13 -phenyl acetate
• civamide N-[(4-hydroxy-3- methoxyphenyl)-methyl]-8-methyl-(Z)-6-nonemamide
• nuvanil capsavanil, olvaml, arvanil, and paivanil (N-palmitoyl - vaniliamide) .
• TRPVl channel activators for use in the compositions and methods described herein can also be identified using standard methodology, as described, for example, in U.S. Patent Application Publication No. 2003/0104085, which is hereby incorporated by reference.
• the TRPV1 channel activator may be present at a concentration range of about 20 mg to 500 mg per unit dosage (e.g., 23 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 420 mg, or 450 mg).
• Compounds that activate TRPA1 that may be used in the compositions of the present invention include, naturally occurring and non-naturally occurring compounds (e.g. , synthetic analogs and derivatives of naturally occurring compounds), including but not limited to those described below.
• TRPA1 activators of TRPA1 are described, for example, in Harteneck et al., Adv Exp Med Biol. 2011, 704:87-106; Viana et al. Expert Opin. Ther. Pat. 2009, 19(12): 1787-99; Bandell et al., Neuron, 2004, 41 (6): 840-857; McNamara et al., Proc. Natl. Acad. Sci. USA 2007, 104(33): 13525-13530; Trevisiani et al., Proc. Natl. Acad. Sci.
• BAA bisandrographalide
• anandamide any of the compounds disclosed in WO
• a TRP channel agonist or activator may be present in a composition of the invention at a concentration range of about 0.001 % to 10% by weight by weight based on the total volume of the composition (e.g. , 0.001, 0.005, 0.01, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10%), though a TRP channel agonist or activator may be present in lower or higher concentrations.
• the acidulant may be present in a composition of the invention at a concentration range of about 0.001% to 10% by weight based on the total volume of the composition (e.g. , about 0.001, 0.005, 0.01, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10%), though the acidulant may be present in lower or higher concentrations.
• the composition of the present invention may have a viscosity greater than water (i.e., about 1.0 cP at 20°C), e.g., about 100, 200, 300, 400, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 6000, 7000, 8000, 9000 cP or more. If a consistency of corn syrup is desired, viscosities in the range of about 2500 cP are suitable. If a consistency of a soft gel or honey is desired, viscosities in the range of about 10000 cP to about 15000 cP are suitable. For puddinglike products, viscosities in the range of about 30000 cP to about 38000 cP are desirable.
• preservatives e.g., sorbic acid, benzoic acid, calcium sorbate, sodium sorbate, potassium sorbate, calcium benzoate, sodium benzoate, potassium benzoate, and mixtures thereof.
• the preservative is included at levels from about 0.0005% to about 0.5% (e.g., about 0.0005%, about 0.001%, about 0.005%, about 0.01%, about 0.05%, about 0.1%, or about 0.5%) by weight based on the total volume of the composition, though preservatives may be present in lower or higher concentrations.
• the powdered ingredients are mixed together with a binding agent, such as acacia or tragacanth, and are then made into a plastic mass by incorporation of any liquid drugs and addition of an inert liquid,
• a binding agent such as acacia or tragacanth
• the resulting mass is then rolled into spheres and coated with talc, gelatin, or sugar.
• Coatings of various types may be applied to the tablet to protect the ingredients from deterioration, to hide the taste of certain components, to control the release of the active components from the tablet, or to produce a more attractive tablet.
• a concentrated sucrose syrup containing suspended starch, calcium or magnesium carbonate, or other suitable substance is applied, each successive layer being dried before the application of the next. After the final layer is dried, it is highly polished to give an elegant finish.
• Sugar coatings provide both protection and a sweet taste.
• Film coatings can also be used, in which a very thin transparent film, usually a cellulose derivative, is applied. Enteric coating is designed to resist solution in the stomach and to dissolve in the more alkaline intestinal fluid.
• cellulose acetate phthalate cellacephate
• a compressed tablet is fed to a second machine where another layer is compressed around it.
• drugs normally incompatible may be formulated in the same tablet.
• Other solid dosages such as lozenges, candies, dragees, or pastilles disintegrate or dissolve in the mouth, slowly releasing the active ingredient (e.g. , any of the TRPVl, TRPAl, or ASIC channel activators described herein).
• the base usually consists of a mixture of sugar and gum or gelatin. Lozenges are generally manufactured by compression techniques, while pastilles are fabricated by fusion and the use of molds.
• Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups (e.g., syrup concentrates), linctuses, drops, and elixirs.
• active ingredient e.g.
• the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,
• polyvinylpyrrolidone Luvitol® BD 10 P (BASF), povidone and its derivatives; dextrin derivatives, polyethylene glycol, polypropylene glycol, marmitol and glycerin, and mono and diglycerides of essential oils, polyglycerin fatty acid esters, sucrose palmitic acid ester, pentaerytbritol ester of wood rosin (Pentalyn A®), and Eudagrits®. Crystallization inhibitors may range from about 0.1 to 10% w/w.
• the oils of the ion channel activators described herein may be administered orally as an oil.
• the core can for example, be made by conventional wet granulation or continuous granulation such as extrusion followed by compaction of the granulate into tablets.
• the core is then coated using appropriate technology, for example, by air-suspension using ethylcellulose and a hydrophi Sic excipient such as hydroxy! propyl cellulose (HPC).
• HPC hydroxy! propyl cellulose
• the ion channel activator e.g. , TRPV1 channel activator, TRPA1 channel activator, ASIC channel activator, or combination thereof
• the ion channel activator e.g. , TRPV1 channel activator, TRPA1 channel activator, ASIC channel activator, or combination thereof
• the ion channel activator e.g. , TRPV1 channel activator, TRPA1 channel activator, ASIC channel activator, or combinations thereof
• PLGA poly(lactic-co-glycolic acid)
• the ion channel activator (e.g. , TRPV1 channel activators, TRPA1 channel activators, ASIC channel activators, or combinations thereof) is administered through the oral cavity to achieve mucosal and transmucosal effects.
• exemplary applications include buccal, nasal, intradermal, inhalational, topical, subcutaneous, sublingual, sublabial, and insufflation administrations.
• Compositions of the current invention may include a penetration enhancer to increase the bioavailability of the ion channel activator within the oral cavity.
• polyesters from lactic and/or glycolic acid e.g. poly(glycolic acid) and poly(L-lactic acid) (PLG/PLA microspheres).
• PLA/PLA microspheres polyesters from lactic and/or glycolic acid
• in situ forming depot systems such as thermoplastic pastes and gelling systems formed by solidification, by cooling, or due to the sol- gel transition, cross-linking systems and organogels formed by amphiphilic lipids.
• PNS Peripheral Nervous System
• compositions of the invention can be used to treat conditions affecting the peripheral nervous system (PNS). These conditions include: diseases, disorders, or injuries to the peripheral nervous system include but are not limited to: cramp fasciculation syndrome, Isaacs' Syndrome or neuromyotonia (NMT), peripheral neuropathy (e.g., diabetic neuropathy), carpal tunnel syndrome, or EBV infection.
• PNS peripheral nervous system
• diseases, disorders, or injuries to the peripheral nervous system include but are not limited to: cramp fasciculation syndrome, Isaacs' Syndrome or neuromyotonia (NMT), peripheral neuropathy (e.g., diabetic neuropathy), carpal tunnel syndrome, or EBV infection.
• compositions of the invention can be used to treat conditions affecting the central nervous system (CNS).
• CNS central nervous system
• central nervous system diseases and conditions including infections of the central nervous system such as encephalitis and poliomyelitis, early-onset neurological disorders including ADHD and autism, late-onset neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and essential tremor, autoimmune and inflammatory diseases such as multiple sclerosis and acute
• the subject has been diagnosed or identified as having multiple sclerosis.
• Multiple sclerosis is also known as disseminated sclerosis and encephalomyelitis disseminate.
• MS is an inflammatory disease in which the insulating sheaths of nerve cells in the brain and spinal cord are damaged, thereby disrupting the ability of the nervous system to communicate.
• the three main characteristics of MS are the formation of lesions in the central nervous system (also called plaques), inflammation, and the destruction of myelin sheaths of neurons. Symptoms of MS can include muscle spasms and muscle weakness.
• compositions and methods disclosed herein are suitable for treating or evaluating a subject that has an absence of a normal muscle contraction, such as a gait abnormality.
• Gait abnormalities are deviations from normal walking or unusual and
• erythematosus erythematosus, rheumatoid arthritis, scleroderma, Sjogren's syndrome, and mixed connective tissue disease.
• compositions of the invention are useful in treating various types of sarcoidosis including but not limited to: annular sarcoidosis, erythrodermic sarcoidosis, ichthyosiform sarcoidosis, hypopigmented sarcoidosis, Lofgren syndrome, lupus pernio, morpheaform sarcoidosis, mucosal sarcoidosis, neurosarcoidosis, papular sarcoid, scar sarcoid, subcutaneous sarcoidosis, systemic sarcoidosis, and ulcerative sarcoidosis.
• compositions of the present invention may also be useful for treating or reducing cough in a subject.
• Cough is a reflex that is often repetitive in nature and may aid in clearing the breathing passages from particles, irritants, secretions, and the like. Coughing may be voluntary or involuntary.
• Exemplary conditions related to cough include respiratory conditions (e.g., asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, pneumonia, cystic fibrosis, pleural cavity diseases, influenza, or a cold), exposure to allergens or chemical irritants, or inflammation.
• the composition of the present invention may be a cough suppressant.
• Comparison and analysis of the recordings of the first and second test cramp can indicate the efficacy of the test aliquot on reducing, alleviating, or preventing the cramp. Comparison and analysis of the recordings can also be used to classify subjects, or identify subjects for certain treatments for muscle cramps.
• Alpha motor neurons project from the brainstem and the spinal cord and innervate the muscles. Stimulation of the alpha motor neurons results in transmittal of an electrical signal to the muscles, generated from the movement of ions across the cell membrane. The electrical stimulation from the motor neurons causes muscle movement or contraction, e.g. , a muscle cramp or spasm. When the muscles are at rest, there is minimal or no electrical signal.
• Activity of the alpha motor neurons can be modulated by signaling from primary sensory neurons, which are activated by sensory input. Stimulation of non-taste primary sensory neurons with nerve endings in the mouth, esophagus and stomach, e.g., through activation of specific ion channels, can induce cause upregulation of inhibitory signals to the alpha motor neurons. Through this mechanism of interneuronal negative feedback, activation of primary sensory neurons inhibit or prevents alpha motor neuron firing via inhibitory signaling, and thereby inhibits muscle contractions of muscle cramps or spasms.
• Electrodes The electrical activity of a muscle, e.g. , a test muscle, is recorded and detected by an electrode, or a lead.
• an electrode or a lead.
• the electrode used in the present invention is a surface electrode.
• a recording electrode is preferably placed over a test muscle, and a reference electrode is placed nearby, e.g. , within 2-6 inches of an active electrode.
• the reference electrode is placed on a synergistic muscle.
• a synergistic muscle is a muscle that aids or participates in movement with the test muscle but does not cramp with the test muscle when electrically induced.
• a series or an array of multiple recording electrodes is used.
• a linear array of 8 recording electrodes is applied on the test muscle, and optionally, a linear array of 4-8 recording electrodes is used on the synergistic muscle.
• a grid array of recording electrodes is applied on the target muscle, e.g. , a grid array of 6 x 5 electrodes is used.
• the appropriate stimulation frequency of electrical stimulation to induce a test muscle cramp may vary depending on the size or location of the muscle or the individual.
• the electrical stimulation can be at least 1 Hz, at least 2 Hz, at least 3 Hz, at least 4 Hz, at least 5 Hz, at least 6 Hz, at least 7 Hz, at least 8 Hz, at least 9 Hz, at least 10 Hz, at least 11 Hz, at least 12 Hz, at least 13 Hz, at least 14 Hz, at least 15 Hz, at least 20 Hz, at least 25 Hz, at least 30 Hz, at least 35 Hz, at least 40 Hz, at least 50 Hz, at least 60 Hz, at least 70 Hz, at least 80 Hz, at least 90 Hz, or at least 100 Hz.
• the parameters of electrical stimulation to be applied to the test muscle may be adjusted to decrease or increase the magnitude of the test muscle contraction to better recapitulate a muscle cramp, spasm, dystonia, or fasciculation.
• the frequency or intensity of electrical current applied to the test muscle may vary depending on the type of test muscle contraction desired, e.g. , the frequency of stimulation is increased to induce a test muscle cramp compared to a test muscle spasm.
• the electrical activity of a target muscle is detected and recorded by a recording electrode before, during, and after an induced cramp.
• the electrical activity is recorded and displayed as a profile or electromyogram.
• the profile contains the electrical activity before, during, and after the application of electrical stimulation to induce a muscle cramp.
• the profile contains the electrical activity during the application of electrical stimulation and after the application of electrical stimulation.
• the electrical activity is converted to root mean square (RMS) values and are displayed as a function of time.
• RMS root mean square
• the profile contains the average electrical activity detected from all of the recording electrodes as a function of time.
• the peak amplitude after cessation of the electrical stimulus can be compared between the reference and treatment profiles.
• a reduction in or absence of the peak amplitude in a treatment profile compared to a reference profile indicates that an electrically induced cramp has been reduced or prevented.
• the peak amplitude in a treatment profile may be at least 1%, 5%, 10%, 15,%, 20%, 25%, 30%, 35%, or 50% decreased compared to the peak amplitude of the reference profile.
• the duration of the test cramp can be compared between the reference and treatment profile.
• a decrease in or absence of the duration of the cramp indicates the reduction or prevention of the electrically induced cramp.
• the duration of the cramp may be at least 1%, 5%, 10%, 15,%, 20%, 25%, 30%, 35%, or 50% decreased compared to the duration of the cramp in the reference profile.
• the test comprises determining that a cramp can be induced in a subject by application of stimulus.
• the stimulus is percutaneous electrical stimulation or surface electrical stimulation.
• the magnitude of the parameters of the induced muscle cramp e.g., as determined from an EMG profile, identifies or classifies subjects with respect to selection of treatment regimens, or predicts the response of a subject to a specific treatment regimen.
• additional therapeutic agent(s) may be administered with compositions of the present invention for, e.g. , the treatment of peripheral nervous system conditions (e.g., peripheral neuropathy), central nervous system conditions, muscle conditions and disorders (e.g., fibromyalgia, muscle spasms and cramps (e.g. , nocturnal cramps), painful muscle contractions (e.g., a muscle contraction of the head or neck), neuromuscular disorders (e.g., motor neuron disease) or dystonia (e.g., cervical dystonia, blepharospasm, back spasms, or leg cramps due to spinal stenosis)), connective tissue diseases (e.g.
• peripheral nervous system conditions e.g., peripheral neuropathy
• central nervous system conditions e.g., central nervous system conditions, muscle conditions and disorders (e.g., fibromyalgia, muscle spasms and cramps (e.g. , nocturnal cramps), painful muscle contractions (e.g.
• the candidate therapeutic agents are agents already known in the art for use for other conditions or disorders, e.g. , neuromuscular therapeutic agents.
• the additional therapeutic agent(s) can be administered as a separate formulation or may be combined with any of the compositions described herein.
• any of the compositions described herein can be used for the treatment of nocturnal (or night) cramps.
• the compositions can be used in
• Sleep aids that can be used in combination with the compositions and methods described herein include: antihistamines (e.g. , diphenhydramine and doxylamine); benzodiazepines (e.g. , estazolam (ProSom), flurazepam (Dalmane), quazepam (Doral), temazepam (Restoril), and triazolam (Halcion)); non-benzodiazepine sedative hypnotics (e.g. , eszopiclone (Lunesta), zalepon (Sonata), and Zolpidem (Ambien)); and melatonin receptor agonist hypnotics (e.g.
• antihistamines e.g. , diphenhydramine and doxylamine
• benzodiazepines e.g. , estazolam (ProSom), flurazepam (Dalmane), quazepam (Doral), temazepam (
• any of the compositions described herein can also be used in combination with a treatment for pain or a disorder relating to the oral cavity, such as oral lesions, canker sores, cold sores, thrush, gingivitis, leukoplakia, halitosis, or dry mouth.
• the composition can be used with or antibacterial or antiviral agents to treat or prevent tooth decay or carries.
• TRP-Stim The solution (“TRP-Stim”) administered to the volunteers contains: a base of a 1: 1 mixture of water and light karo syrup (for increased viscosity); 0.075% of a capsicum
• the active stimulation electrode is a 1.25" circular mesh -backed silver patch electrode (Bio-Flex manufactured by Lead-Lok) and is placed so as to produce contraction of the FHB with minimal stimulation amplitude.
• the stimulation reference electrode is a 2" square patch electrode (Bio-Flex manufactured by Lead-Lok) is placed on the opposite side of the foot, e.g., under the lateral malleous.
• Cramping is quantified by making EMG recordings from the belly of the FHB.
• Two external EMG recording electrodes (Vermed SilveRest) are placed along the belly of the FHB.
• the differential voltage relative to a third ground electrode placed at the ankle is amplified, digitized, and saved to computer using a 1-330-C2+ EMG unit with PhysioLab software (J&J Engineering, Poulsbo, WA).
• the raw wide -band EMG signal (10-400 Hz) is processed by being rectified and integrated to provide the area under the curve (RMS).
• the duration of cramp is quantified by the time required for the RMS EMG to return to an amplitude of 3 standard deviations above the baseline value. This will correlate well with duration of the cramp as observed by the return to the toe to resting position.
• Figure 1 shows graphs from six sensory neurons isolated from the trigeminal ganglia of rats, illustrating their activation by the capsicum, cinnamon, and ginger extracts that are used in the human experiments. Activation is quantified as an increase in intracellular free calcium, monitored by a fluorescent calcium indicator. Extracts are diluted into normal extracellular saline (Tyrode's solution) and are tested at lower concentrations than used in the beverage, taking account that concentrations present at nerve endings in mouth, esophagus, or stomach are expected to be lower than the beverage as a result of dilution into mucosa and interstitial fluid. All three extracts are capable of activating individual neurons when applied at concentrations 50- fold to 15,000-fold lower than used in the beverage.
• Figure 2 is a graph showing the effect of the TRP-Stim beverage on cramping of the flexor hallucis brevis of Subject A.

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• 2015
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