WO2007110220A1 - UTILISATION DE 4,9-ANHYDROTÉTRODOTOXINE POUR LE TRAITEMENT DE MALADIES LIÉES À LA SOUS-UNITÉ α DES CANAUX SODIQUES DÉPENDANTS D'UN POTENTIEL D'ACTION NAV 1.6 - Google Patents

UTILISATION DE 4,9-ANHYDROTÉTRODOTOXINE POUR LE TRAITEMENT DE MALADIES LIÉES À LA SOUS-UNITÉ α DES CANAUX SODIQUES DÉPENDANTS D'UN POTENTIEL D'ACTION NAV 1.6 Download PDF

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WO2007110220A1
WO2007110220A1 PCT/EP2007/002661 EP2007002661W WO2007110220A1 WO 2007110220 A1 WO2007110220 A1 WO 2007110220A1 EP 2007002661 W EP2007002661 W EP 2007002661W WO 2007110220 A1 WO2007110220 A1 WO 2007110220A1
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sodium channel
tetrodotoxin
anhydro
subunit
voltage
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PCT/EP2007/002661
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English (en)
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Helmut H. Buschmann
Jose Miguel Vela Hernandez
Wolfgang Screibmayer
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Wex Pharmaceuticals Inc.
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Priority claimed from EP06384004A external-priority patent/EP1844782A1/fr
Priority claimed from EP06384005A external-priority patent/EP1844783A1/fr
Application filed by Wex Pharmaceuticals Inc. filed Critical Wex Pharmaceuticals Inc.
Publication of WO2007110220A1 publication Critical patent/WO2007110220A1/fr

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    • 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
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
    • 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
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention refers to the use of 4,9-anhydro-tetrodotoxin for the treatment of diseases related to the voltage-gated sodium channel ⁇ subunit Na v 1.6.
  • Voltage-gated sodium channels are encoded by a family of ten structurally-related genes that are expressed in spatially and temporally distinct patterns, mainly in excitable tissues. They underlie electrical signaling in nerve and muscle. It has long been known that sodium channel blockers are anaesthetics as well as powerful analgesics when delivered at low concentrations. In addition, there are indications that sodium channel blockers may also be useful in the treatment of cardiac arrhythmias, epilepsy, neurodegeneration, affective disorders and schizophrenia (Wood and Boorman, 2005). As more information is available about the subtypes of sodium channels and their distribution, new therapeutic opportunities are suggested.
  • the voltage-gated sodium channel ⁇ subunit Na v 1.6 is quite specifically involved in a number of diseases or symptoms. These include pathophysiologal symptoms of the injured nervous system such as demyelination, and neuroinflammatory disorders, where 4,9-anhydro TTX thus could have a direct neuroprotective effect on axons, and would thus also cover multiple sclerosis and (experimental) autoimmune encephalitis (EAE).
  • diseases or symptoms related to the voltage-gated sodium channel ⁇ subunit Na v 1.6 also include movement disorders including tremor, ataxia, dystonia and paralysis, where 4,9-anhydro TTX thus could inhibit hyperactivity affecting the CNS (Le. epilepsy) and locomotor apparatus.
  • neuropathic pain or neuropathic pain-related hyperalgesia and allodynia are also falling under this group.
  • multiple sclerosis is a very severe disease where treatment is far from satisfying and thus it was an underlying object of this to identify drug for the treatment of diseases related to the voltage-gated sodium channel ⁇ subunit NaJ .6, especially multiple sclerosis.
  • 4,9-anhydro-tetrodotoxin is a selective blocker of the voltage-gated sodium channel ⁇ subunit Na v 1.6.
  • the present invention relates to the use of 4,9-anhydro-tetrodotoxin, optionally in the form of its racemate, pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any suitable mixing ratio; in neutral form, in the form of an acid or base or in form of a salt, especially a physiologically acceptable salt, or in form of a solvate, especially a hydrate for the production of a medicament for the treatment of a disease/symptom related to the voltage-gated sodium channel ⁇ subunit Na v 1.6.
  • 4,9-anhydro-tetrodotoxin is inhibiting the neuronal Na v 1.6 in a nanomolar range and all the other subtypes either not or only in a micromolar range.
  • Disease/Symptom related to the voltage-gated sodium channel ⁇ subunit Na v 1.6 are defined as a disease/symptom in which the voltage-gated sodium channel ⁇ subunit Na v 1.6 can act in a protective or ameliorating way. Specifically the following diseases or symptoms are included:
  • hyperactivity affecting the locomotor apparatus • hyperactivity affecting the locomotor apparatus • movement disorders o tremor, o ataxia, o dystonia o paralysis,
  • neuropathic pain o neuropathic pain-related hyperalgesia o neuropathic pain-related allodynia o or diabetic neuropathy • neuropathic pain o neuropathic pain-related hyperalgesia o neuropathic pain-related allodynia o or diabetic neuropathy.
  • 4,9 anhydro-TTX could have a direct neuroprotective effect on axons and thus another preferred aspect of the invention is use of 4,9-anhydro-tetrodotoxin, optionally in the form of its racemate, pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any suitable mixing ratio; in neutral form, in the form of an acid or base or in form of a salt, especially a physiologically acceptable salt, or in form of a solvate, especially a hydrate for the production of a medicament for the a neuroprotective effect.
  • salt is to be understood as meaning any form of the active compound according to the invention in which this compound assumes an ionic form or is charged and - if applicable - is also coupled with a counter-ion (a cation or anion).
  • a counter-ion a cation or anion
  • complexes of the active compound with other molecules and ions in particular complexes which are complexed via ionic interactions.
  • this includes the acetate, mono- trifluoracetate, acetate ester salt, citrate, formate, picrate, hydrobromide, monohydrobromide, monohydrochloride or hydrochloride.
  • physiologically acceptable salt in the context of this invention is understood as meaning a “salt” (as defined above) of at least one of the compounds according to the invention which are physiologically tolerated by humans and/or mammals.
  • solvate according to this invention is to be understood as meaning any form of the active compound according to the invention which has another molecule (most likely a polar solvent) attached to it via non-covalent bonding. Examples of solvates include hydrates and alcoholates, e.g. methanolate.
  • treatment means administration of a compound or formulation according to the invention to prevent, ameliorate or eliminate one or more symptoms associated with (diseases related to) the voltage-gated sodium channel ⁇ subunit Na v 1.6.
  • to treat or “treatment” according to this invention include the treatment of symptoms associated with (diseases related to) the voltage-gated sodium channel ⁇ subunit Na v 1.6., the prevention or the prophylaxis of the symptoms of associated with (diseases related to) the voltage-gated sodium channel ⁇ subunit
  • the 4,9-anhydro-TTX or the pharmaceutical compositions comprising it may be administered, in unit dosage form, intestinally, enterally, parenterally or topically, orally, subcutaneously, intranasally, by inhalation, by oral absorption, intravenously, intramuscularly, percutaneously, intraperitoneally, rectally, intravaginally, transdermal ⁇ , sublingually, buccally, orally transmucosally.
  • Administrative dosage forms may include the following: tablets, capsules, dragees, lozenges, patches, pastilles, gels, pastes, drops, aerosols, pills, powders, liquors, suspensions, emulsions, granules, ointments, creams, suppositories, freeze-dried injections, injectable compositions, in food supplements, nutritional and food bars, syrups, drinks, liquids, cordials etc, which could be regular preparation, delayed- released preparation, controlled-released preparation and various micro-granule delivery system, in food supplements, nutritional and food bars, syrups, drinks, liquids, cordials.
  • various carriers known in the art may be used, e.g.
  • dilutent and resorbent such as starch, dextrin, calcium sulfate, kaolin, microcrystalline cellulose, aluminium silicate, etc; wetting agent and adhesives such as water, glycerin, polyethylene glycol, ethanol, propanol, starch mucilage, dextrin, syrup, honey, glucose solution, acacia, gelatin, carboxymethylcellulose sodium, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc; disintegrating agent, such as dried starch, alginate, agar powder, laminaran, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol aliphatic ester, lauryl sodium sulfate, methylcellulose, ethylcellulose, lactose, sucrose, maltose, mannitol, fructose, various disaccharides and polysaccharides etc; disintegration inhibiting agent, such as sucrose, tristearin
  • the tablet may be further formulated into coated tablet, e.g. sugar-coated tablet, film-coated tablet, enteric-coated tablet, or double-layer tablet and multi-layer tablet.
  • various carriers known in the art may be used, e.g. dilutent and resorbent, such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, polyvinylpyrrolidone, kaolin, talc, etc; adhesives, such as acacia, bassora gum, gelatin, ethanol, honey, liquid sugar, rice paste or flour paste, etc; disintegrating agent, such as agar powder, dried starch, alginate, lauryl sodium sulfate, methylcellulose, ethylcellulose.
  • various carriers known in the art may be used, e.g. polyethylene, lecithin, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glyceride, etc.
  • capsule it may be prepared by mixing said sodium channel blockers as active ingredient with the above mentioned carriers, followed by placing the mixture into a hard gelatin capsule or soft capsule.
  • said sodium channel blockers may be applied in the following dosage forms: microcapsules, suspension in an aqueous phase, hard capsule, or injection.
  • injection such as liquor, emulsion, freeze-dried injection, and suspension, all the dilutents common in the art may be used, e.g.
  • a suitable amount of sodium chloride, glucose or glycerin may be added into the preparation, as well as regular cosolvent, buffer, pH adjusting agent, etc.
  • coloring agent, antiseptic, perfume, correctives, food sweetening agent or other materials may be added to the pharmaceutical preparation if necessary.
  • a formulation or pharmaceutical composition according to the invention contains the active ingredient, 4,9-anhydro-TTX as well as optionally at least one auxiliary material and/or additive and/or optionally another active ingredient.
  • auxiliary material and/or additive can be specifically selected from conserving agents, emulsifiers and/or carriers for parenteral application.
  • the selection of these auxiliary materials and/or additives and of the amounts to be used depends upon how the pharmaceutical composition is to be applied. Examples include here especially parenteral like intravenous subcutaneous or intramuscular application formulations but which could also be used for other administration routes.
  • the 4,9-anhydro-TTX may be administered in a schedule of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty or more doses per day, alone or in combination with other medications, over range of time periods including but not limited to periods of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, sixteen, eighteen, twenty, twenty four, thirty, or more days; or over a period of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, sixteen, eighteen, twenty, twenty four, thirty, thirty six, forty eight, sixty, seventy two, eighty four or more months.
  • the maximum daily dose of 4,9-anhydro-TTX sodium channel blocker may be up to about 10 ⁇ g, up to about 50 ⁇ g, up to about 100 ⁇ g, up to about 144 ⁇ g, up to about 150 ⁇ g, up to about 300 ⁇ g, up to about 500 ⁇ g, up to about 750 ⁇ g, up to about 1000 ⁇ g, up to about 1250 ⁇ g, up to about 1500 ⁇ g, up to about 1750 ⁇ g, up to about 2000 ⁇ g or more.
  • the sodium channel blocker may be administered in an amount ranging between 5 and 4000 ⁇ g/day, or in ranges between 10 and 2000 ⁇ g/day, 10 and 1000 ⁇ g a day, 10 and 750 ⁇ g a day, 10 and 500 ⁇ g a day, 10 and 400 ⁇ g a day, 10 and 300 ⁇ g a day, 10 and 200 ⁇ g a day, or 10 and 100 ⁇ g/day.
  • the daily applied dose may be from about 10 to about 160 ⁇ g, about 10 to about 140 ⁇ g, about 10 to about 120 ⁇ g, about 10 to aboutlOO ⁇ g, _about 10 to about 90 ⁇ g, about 10 to about 80 ⁇ g, about 10 to about 70 ⁇ g, about 10 to about 60 ⁇ g, about 10 to about 50 ⁇ g, about 10 to about 40 ⁇ g, about 10 to about 30 ⁇ g, or 1 to 20 ⁇ g.
  • the daily dosage of 4,9-anhydro-TTX may be about 0.1 to about 40 ⁇ g per kilogram of body weight, about 1 to about 35 ⁇ g per kilogram of body weight, about 5 to about 30 ⁇ g per kilogram of body weight, about 10 to about 30 ⁇ g per kilogram of body weight, about 15 to about 30 ⁇ g per kilogram of body weight, about 10 to about 35 ⁇ g per kilogram of body weight, or about 20 to about 40 ⁇ g per kilogram of body weight.
  • the unit dose may be within a range of about 5 ⁇ g to about 2000 ⁇ g and may be about 5 to aboutiO ⁇ g, about 10 to about 15 ⁇ g, about 15 to about 20 ⁇ g, about 20 to about 25 ⁇ g, about 25 to about 30 ⁇ g, about 30 to about 40 ⁇ g, about 40 ⁇ g to about 50 ⁇ g, about 50 ⁇ g to about 75 ⁇ g, about 75 to about100 ⁇ g, about 100 to about 150 ⁇ g, about 150 to about 200 ⁇ g, about 200 to about 250 ⁇ g, about 250 to about 500 ⁇ g, about 500 to about1000 ⁇ g, about 1000 to about 1500 ⁇ g or about 1500 to about 2000 ⁇ g or more than 2000 ⁇ g.
  • the dose administered is between 10 and 4000 ⁇ g/day of 4,9- anhydro-tetrodotoxin, its derivatives or its analogues, especially the dose of 4,9- anhydro-tetrodotoxin administered is normally between 10 and 4000 ⁇ g/day or - given the likely twice per day treatment - between 5 to 2000 ⁇ g each given dose, sometimes preferably between 250 and 1000 ⁇ g each given dose, sometimes preferably between 25 and 50 ⁇ g each given dose depending on the route of administration.
  • the effectiveness of a course of treatment of one, two, three, four, five or more doses or one, two or three days may last for up to about five, ten, fifteen, twenty, twenty five or thirty.
  • dosing is only performed once every day or once every two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, sixteen, eighteen, twenty, twenty four, thirty or more days.
  • the dosage of 4,9-anhydro-TTX depends on a variety of factors, including the nature and severity of the diseases, the sex, age, weight and individual reaction of the subject, the particular compound employed, the route and frequency of administration, etc. 4,9-anhydro-TTX or the pharmaceutical compositions comprising it may be administered in single or divided dosage form, e.g. one to four doses per day. Those skilled in the art will readily understand and implement the changes to the treatment methods exemplified herein that are necessary or desirable to reflect varied therapeutic requirements.
  • a substance named as an "active ingredient” will have a purity of at least 97%.
  • a formulation said to have "500 ⁇ g of 4,9-anhydro-TTX as the active ingredient” may contain as much as 15 ⁇ g of an impurity.
  • the disease/symptom related to the voltage-gated sodium channel ⁇ subunit Na v 1.6 is selected from
  • pathophysiologal symptoms of the injured nervous system demyelination, neuroinflammatory disorders, multiple sclerosis, (experimental) autoimmune encephalitis (EAE), hyperactivity affecting the CNS, epilepsy, hyperactivity affecting the locomotor apparatus, movement disorders, tremor, ataxia, dystonia, paralysis, neuropathic pain, neuropathic pain-related hyperalgesia or neuropathic pain-related allodynia or diabetic neuropathy.
  • EAE autoimmune encephalitis
  • neuropathic pain is disclaimed from the diseases/symptoms related to the voltage-gated sodium channel ⁇ subunit Na v 1.6. In an embodiment pain is disclaimed from the diseases/symptoms related to the voltage-gated sodium channel ⁇ subunit Na v 1.6.
  • central-nervously derived neuropathic pain is disclaimed from the diseases/symptoms related to the voltage-gated sodium channel ⁇ subunit Na v 1.6.
  • this disclaimer also includes central-nervously derived neuropathic pain which is allodynia and/or hyperalgesia.
  • peripheral-nervously derived neuropathic pain is disclaimed from the diseases/symptoms related to the voltage-gated sodium channel ⁇ subunit Na v 1.6.
  • this disclaimer also includes peripheral-nervously derived neuropathic pain which is allodynia and/or hyperalgesia.
  • non-cancer derived neuropathic pain is disclaimed from the diseases/symptoms related to the voltage-gated sodium channel ⁇ subunit NaJ .6. Otionally this disclaimer also includes non-cancer derived neuropathic pain which is allodynia and/or hyperalgesia.
  • the disease/symptom related to the voltage-gated sodium channel ⁇ subunit NaJ .6 is selected from pathophysiologal symptoms of the injured nervous system, especially demyelination and/or neuroinflammatory disorders, more especially multiple sclerosis and (experimental) autoimmune encephalitis (EAE).
  • pathophysiologal symptoms of the injured nervous system especially demyelination and/or neuroinflammatory disorders, more especially multiple sclerosis and (experimental) autoimmune encephalitis (EAE).
  • the disease/symptom related to the voltage-gated sodium channel ⁇ subunit NaJ .6 is selected from
  • hyperactivity affecting the CNS especially epilepsy, and/or hyperactivity affecting the locomotor apparatus, especially movement disorders, more especially tremor, ataxia, dystonia or paralysis.
  • the disease/symptom related to the voltage-gated sodium channel ⁇ subunit NaJ .6 is selected from
  • neuropathic pain neuropathic pain-related hyperalgesia or neuropathic pain-related allodynia or diabetic neuropathy.
  • Demyelination and neuroinflammation Changes in the expression of sodium channels occur in demyelinated axons in multiple esclerosis (MS), with Na v 1.6 confined to nodes of Ranvier in controls but with diffuse distribution along extensive regions of demyelinated axons within acute MS plaques (Craner et al., 2004a). Na v 1.6 is also known to accumulate along degenerating axons in demyelinated regions of the CNS in mice with experimental autoimmune encephalitis (EAE) 1 an experimental model of MS (Craner et al., 2004b).
  • EAE experimental autoimmune encephalitis
  • Nav1.6 is known to produce a persistent sodium current and the NaVCa 2+ exchanger can be driven by persistent sodium current to import damaging levels of calcium into axons (Craner et al., 2004a,b).
  • sodium channels contribute to activation of microglia and macrophages in EAE and acute MS lesions.
  • a robust increase of sodium channel Na v 1.6 expression has been found in activated microglia and macrophages in EAE and MS.
  • Treatment with the sodium channel blocker phenytoin ameliorates the inflammatory cell infiltrate in EAE by 75% and TTX reduces the phagocytic function of activated rat microglia by 40%.
  • Microglia from med mice, which lack Na v 1.6 channels show a 65% reduction in phagocytic capacity compared with microglia from wildtype mice.
  • endogenous Schwann cells can remyelinate demyelinated spinal cord axons and establish and maintain nodes of Ranvier on central axons for over one year, and these nodes exhibit an apparently normal distribution of sodium channels, with Na v 1.6 the predominant subtype of sodium channel present at such nodes at all stages of their development (Black et al., 2006).
  • Na v 1.6 is abundantly expressed in spinal cord, dorsal root ganglia (DRG) and peripheral nerve, key anatomic elements involved in pain transmission (Caldwell et al., 2000; Krzemien et al., 2000; Dietrich et al., 1998). Localization of NaJ .6 in presynaptic terminals in the spinal cord, as well as at the nodes of Ranvier in peripheral nerves suggest its involvement in sensory (nociceptive) processing, since it was found in all types of DRG neurons as well as in the superficial laminae of the spinal dorsal horn (Tzoumaka et al., 2000).
  • Na v 1.6 channels produce both fast transient currents and smaller persistent currents that are generated closer to resting potential. Because these persistent currents can contribute to intrinsic burst activity, the upregulation of Na v 1.6 channels would be expected to contribute to hyperexcitability in diabetic neurons and thus to neuropathic pain-related hyperalgesia and allodynia (Craner et al., 2002).
  • Na v 1.6 is the major sodium channel isoform at nodes of Ranvier in myelinated axons and it is distributed along unmyelinated C-fibers of sensory neurons.
  • mitogen-activated protein kinases are expressed by neurons in some painful conditions and are activated after injury, for example, after sciatic nerve transection and inflammation.
  • CNS neurons express both Na v 1.6 and p38 MAPK.
  • spinal nerve ligation causes activation of p38 MAPK in microglia of the spinal cord, a cell type in which NaJ .6 is expressed (Craner et al., 2005).
  • Hyperactivity Movement disorders including tremor, ataxia, dystonia and paralysis have been observed in mice with mutations of the SCN8A gene coding Na v 1.6 (Smith and Goldin, 1999; Meisler et al., 2001 ).
  • the mouse mutant medJ contains a splice site mutation in the neuronal sodium channel SCN8A that results in a very low level of expression of Nav1.6 (Sprunger et al., 1999) and this results in severe motor disturbances accompanied by delayed maturation of nodes of Ranvier, slowed nerve conduction velocity, reduced muscle mass and reduction of brain metabolic activity (Kearney et al., 2002; Hamann et al., 2003).
  • inhibition of Na v 1.6-mediated currents could inhibit hyperactivity affecting the CNS (Le. epilepsy) and locomotor apparatus.
  • One of the big advantages of the use according to the invention is the reduction of side effects.
  • At least nine different voltage-gated sodium channels have been identified in mammals. Their involvement on particular functions depends on their specific tissue or cellular distributions.
  • the main advantage of using subtype-specific sodium channel blockers comes from the possibility to restrict the inhibitory effects on electrical excitability to particular organs, tissues and cells expressing the targeted channel. This allows the possibility to therapeutically modulate particular functions involving electrical transmission through the specific targeted channel, without affecting other functions involving other channels and thus reducing side effects.
  • cardiac side effects are not expected by 4,9-anhydro-TTX as the Nav1.5 sodium channel expressed by cardiac muscle (Lei et al., 2004) is not affected.
  • Respect to TTX that blocks Na v 1.1 , Na v 1.2, Na v 1.3, Na v 1.4, Na v 1.6 and Na v 1.7 (but not NaJ .5, Na v 1.8 and Na v 1.9), selective blocking of Na v 1.6 by 4,9-anhydro-TTX is expected to be devoid of side effects dependent on direct actions on skeletal musculature as the skeletal muscle-specific Na v 1.4 channel (Hudson et al., 1995) is not affected.
  • the SCN8A gene encodes the voltage-gated sodium channel Na v 1.6, which is widely expressed in neurons of the CNS and PNS.
  • Na v 1.6 is abundant at the axon initial segment and is the major sodium channel isoform at nodes of Ranvier (Caldwell et al., 2000). It is present in the soma of small sensory neurons in dorsal root ganglion (DRG) and along their myelinated and unmyelinated fibers within the sciatic nerve (Caldwell et al., 2000; Krzemien et al., 2000; Tzoumaka et al., 2000).
  • Na v 1.6 has been shown to accumulate along degenerating axons in demyelinated regions of the CNS in mice with experimental autoimmune encephalitis (EAE) and in patients with multiple sclerosis (MS) (Craner et al., 2004a,b). Additionally, Na v 1.6 has been shown to be significantly upregulated in activated microglia and macrophages in EAE and in acute MS lesions (Craner et al., 2005). Thus, Na v 1.6 appears to play an important role in normal axonal conduction and may significantly contribute to the pathophysiology of the injured nervous system. (Wittmack et al., 2005).
  • Na v 1.6 channels produce a persistent current in addition to fast activating and inactivating TTX-sensitive currents (Herzog et al., 2003).
  • the rapidly activating and inactivating Na v 1.6 current is characterized by fast recovery from inactivation and this appears to poise Na v 1.6 for high-frequency firing of myelinated fibers that do not, however, fire in response to sustained slow depolarizations.
  • Nodes of Ranvier are the axonal regions without myelin and glial cell wrapping, which are essential for the efficient conduction of action potentials.
  • Na v 1.6 is the predominant isoform at the nodes of Ranvier in both sensory and motor neurons of the adult CNS and PNS (Caldwell et al., 2000).
  • Na v 1.6 shows use-dependent potentiation during a rapid train of depolarizations. Rapid stimulation accelerated a slow phase of activation in the Na v 1.6 channel that had fast inactivation removed, resulting in faster channel activation. As repetitive depolarizations accelerated the activation kinetics of NaJ .6 and this channels is thus more resistant to inactivation that other channels, Na v 1.6 might be specialized to more faithfully propagate high-frequency firing at nodes of Ranvier compared to other sodium channels (Zhou and Goldin, 2004).
  • Resurgent sodium currents are an unusual type of sodium current that reactivate during mild repolarizations following depolarization to positive potentials and may be critical in determining the firing patterns of neurons. While classic sodium channel tail currents activate instantaneously and decay rapidly, resurgent currents show much slower kinetics.
  • Na v 1.6 currents activate and inactivate during depolarization, as well as reactivate during repolarization from positive potentials, producing a "resurgent" current.
  • This reopening of channels not only generates inward current after each action potential, but also permits rapid recovery from inactivation.
  • DRG neurons particularly large diameter DRG neurons, posses Na v 1.6 channels and it is known that these neurons show channels that open transiently during recovery from inactivation, generating a resurgent sodium current that flows immediately following action potentials.
  • Voltage-gated sodium channel Nav1.6 is modulated by p38 mitogen-activated protein kinase. J Neurosci. 2005 25:6621-30. o Zhou W, Goldin AL. Use-dependent potentiation of the Nav1.6 sodium channel. Biophys J. 2004 87(6):3862-72. o Craner MJ, Damarjian TG, Liu S, Hains BC, Lo AC, Black JA, Newcombe J,
  • anhydro-tetrodotoxin is used in an amount of 0.1 to 5.0 ⁇ g/kg per dose, especially between 0.1 to 1.5 ⁇ g/kg per dose
  • anhydro-tetrodotoxin is used in an amount between 10 ⁇ g/day and 4 mg/day, especially between 20 and 100 ⁇ g/day.
  • the 4,9- anhydro-tetrodotoxin is isolated from a biological source, preferably from fish, especially puffer fish.
  • the 4,9- anhydro-tetrodotoxin is synthetic.
  • this invention is especially also a method of treatment of a patient or a mammal, including men, suffering from a disease related to the voltage-gated sodium channel ⁇ subunit Na v 1.6 using 4,9-anhydro-TTX, optionally in the form of its racemate, pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any suitable ratio; in neutral form, in the form of an acid or base or in form of a salt, especially a physiologically acceptable salt, or in form of a solvate, especially a hydrate,.
  • 4,9-anhydro-tetrodotoxin is used in an amount between 10 ⁇ g/day and 4 mg/day, especially in a dose of 0.1-1 ⁇ g/kg, is isolated from a biological source, preferably from fish, especially puffer fish, or is synthesized/synthetic.
  • a sodium channel blocker including especially tetrodotoxin and/or its derivatives, optionally in the form of its racemate, pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any suitable mixing ratio; in neutral form, in the form of an acid or base or in form of a salt, especially a physiologically acceptable salt, or in form of a solvate, especially a hydrate for the production of a medicament for the treatment of a disease/symptom related to the voltage-gated sodium channel ⁇ subunit Na v 1.6.
  • Disease/Symptom related to the voltage-gated sodium channel ⁇ subunit Na v 1.6 are defined as a disease/symptom in which the voltage-gated sodium channel ⁇ subunit Na v 1.6 can act in a protective or ameliorating way. Specifically the following diseases or symptoms are included:
  • neuropathic pain o neuropathic pain-related hyperalgesia o neuropathic pain-related allodynia o or diabetic neuropathy • neuropathic pain o neuropathic pain-related hyperalgesia o neuropathic pain-related allodynia o or diabetic neuropathy.
  • the disease/symptom related to the voltage-gated sodium channel ⁇ subunit Na v 1.6 is selected from
  • pathophysiologal symptoms of the injured nervous system demyelination, neuroinflammatory disorders, multiple sclerosis, (experimental) autoimmune encephalitis (EAE), hyperactivity affecting the CNS, epilepsy, hyperactivity affecting the locomotor apparatus, movement disorders, tremor, ataxia, dystonia, paralysis, neuropathic pain, neuropathic pain-related hyperalgesia, neuropathic pain-related allodynia, or diabetic neuropathy.
  • EAE autoimmune encephalitis
  • neuropathic pain is disclaimed from the diseases/symptoms related to the voltage-gated sodium channel ⁇ subunit Na v 1.6.
  • pain is disclaimed from the diseases/symptoms related to the voltage-gated sodium channel ⁇ subunit Na v 1.6.
  • central-nervously derived neuropathic pain is disclaimed from the diseases/symptoms related to the voltage-gated sodium channel ⁇ subunit Na v 1.6.
  • this disclaimer also includes central-nervously derived neuropathic pain which is allodynia and/or hyperalgesia.
  • peripheral-nervously derived neuropathic pain is disclaimed from the diseases/symptoms related to the voltage-gated sodium channel ⁇ subunit Na v 1.6.
  • this disclaimer also includes peripheral-nervously derived neuropathic pain which is allodynia and/or hyperalgesia.
  • non-cancer derived neuropathic pain is disclaimed from the diseases/symptoms related to the voltage-gated sodium channel ⁇ subunit Na v 1.6. Otionally this disclaimer also includes non-cancer derived neuropathic pain which is allodynia and/or hyperalgesia.
  • the disease/symptom related to the voltage-gated sodium channel ⁇ subunit Na v 1.6 is selected from pathophysiologal symptoms of the injured nervous system, especially demyelination and/or neuroinflammatory disorders, more especially multiple sclerosis and (experimental) autoimmune encephalitis (E ⁇ AE).
  • the disease/symptom related to the voltage-gated sodium channel ⁇ subunit Na v 1.6 is selected from
  • hyperactivity affecting the CNS especially epilepsy, and/or hyperactivity affecting the locomotor apparatus, especially movement disorders, more especially tremor, ataxia, dystonia or paralysis.
  • the disease/symptom related to the voltage-gated sodium channel ⁇ subunit Na v 1.6 is selected from neuropathic pain, neuropathic pain-related hyperalgesia, neuropathic pain-related allodynia, or diabetic neuropath.
  • the sodium channel blockers such as TTX or STX, their analogues/derivatives or the pharmaceutical compositions comprising them, may be administered, in unit dosage form, intestinally, enterally, parenterally or topically, orally, subcutaneously, intranasally, by inhalation, by oral absorption, intravenously, intramuscularly, percutaneously, intraperitoneally, rectally, intravaginally, transdermal ⁇ , sublingually, buccally, orally transmucosally.
  • Administrative dosage forms may include the following: tablets, capsules, dragees, lozenges, patches, pastilles, gels, pastes, drops, aerosols, pills, powders, liquors, suspensions, emulsions, granules, ointments, creams, suppositories, freeze-dried injections, injectable compositions, in food supplements, nutritional and food bars, syrups, drinks, liquids, cordials etc, which could be regular preparation, delayed- released preparation, controlled-released preparation and various micro-granule delivery system, in food supplements, nutritional and food bars, syrups, drinks, liquids, cordials.
  • various carriers known in the art may be used, e.g.
  • dilutent and resorbent such as starch, dextrin, calcium sulfate, kaolin, microcrystalline cellulose, aluminium silicate, etc; wetting agent and adhesives such as water, glycerin, polyethylene glycol, ethanol, propanol, starch mucilage, dextrin, syrup, honey, glucose solution, acacia, gelatin, carboxymethylcellulose sodium, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc; disintegrating agent, such as dried starch, alginate, agar powder, laminaran, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol aliphatic ester, lauryl sodium sulfate, methylcellulose, ethylcellulose, lactose, sucrose, maltose, mannitol, fructose, various disaccharides and polysaccharides etc; disintegration inhibiting agent, such as sucrose, tristearin
  • the tablet may be further formulated into coated tablet, e.g. sugar-coated tablet, film-coated tablet, enteric-coated tablet, or double-layer tablet and multi-layer tablet.
  • various carriers known in the art may be used, e.g. dilutent and resorbent, such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, polyvinylpyrrolidone, kaolin, talc, etc; adhesives, such as acacia, bassora gum, gelatin, ethanol, honey, liquid sugar, rice paste or flour paste, etc; disintegrating agent, such as agar powder, dried starch, alginate, lauryl sodium sulfate, methylcellulose, ethylcellulose.
  • various carriers known in the art may be used, e.g. polyethylene, lecithin, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glyceride, etc.
  • capsule it may be prepared by mixing said sodium channel blockers as active ingredient with the above mentioned carriers, followed by placing the mixture into a hard gelatin capsule or soft capsule.
  • said sodium channel blockers may be applied in the following dosage forms: microcapsules, suspension in an aqueous phase, hard capsule, or injection.
  • injection such as liquor, emulsion, freeze-dried injection, and suspension, all the dilutents common in the art may be used, e.g.
  • sorbitol aliphatic ester water, ethanol, polyethylene glycol, propylene glycol, oxyethylated isostearyl alcohol, polyoxidated isostearyl alcohol, polyoxyethylene sorbitol aliphatic ester, etc.
  • a suitable amount of sodium chloride, glucose or glycerin may be added into the preparation, as well as regular cosolvent, buffer, pH adjusting agent, etc.
  • coloring agent, antiseptic, perfume, correctives, food sweetening agent or other materials may be added to the pharmaceutical preparation if necessary.
  • a formulation or pharmaceutical composition according to the invention contains the active ingredient (TTX, its derivatives and/or its analogues) as well as optionally at least one auxiliary material and/or additive and/or optionally another active ingredient.
  • auxiliary material and/or additive can be specifically selected from conserving agents, emulsifiers and/or carriers for parenteral application.
  • the selection of these auxiliary materials and/or additives and of the amounts to be used depends upon how the pharmaceutical composition is to be applied. Examples include here especially parenteral like intravenous subcutaneous or intramuscular application formulations but which could also be used for other administration routes.
  • routes of administration of tetrodotoxin its derivatives and its analogues can include intramuscular injection, intraveneous injection, subcutaneous injection, sublingual, bucal, patch through skin, oral ingestion, implantable osmotic pump, collagen implants, aerosols or suppository.
  • the sodium channel blockers such as TTX or STX, their analogues/derivatives may be administered in a schedule of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty or more doses per day, alone or in combination with other medications, over range of time periods including but not limited to periods of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, sixteen, eighteen, twenty, twenty four, thirty, or more days; or over a period of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, sixteen, eighteen, twenty, twenty four, thirty, or more days; or over a period of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, sixteen, eighteen, twenty, twenty four, thirty, thirty six, forty eight,
  • the sodium channel blockers such as TTX or STX, their analogues/derivatives may be a voltage-gated sodium channel blocker and may bind to a SS1 or SS2 ⁇ subunit of a sodium channel.
  • the maximum daily dose of sodium channel blocker may be up to about 10 ⁇ g, up to about 50 ⁇ g, up to about 100 ⁇ g, up to about 144 ⁇ g, up to about 150 ⁇ g, up to about 300 ⁇ g, up to about 500 ⁇ g, up to about 750 ⁇ g, up to about 1000 ⁇ g, up to about 1250 ⁇ g, up to about 1500 ⁇ g, up to about 1750 ⁇ g, up to about 2000 ⁇ g or more.
  • the sodium channel blocker may be administered in an amount ranging between 5 and 4000 ⁇ g/day, or in ranges between 10 and 2000 ⁇ g/day, 10 and 1000 ⁇ g a day, 10 and 750 ⁇ g a day, 10 and 500 ⁇ g a day, 10 and 400 ⁇ g a day, 10 and 300 ⁇ g a day, 10 and 200 ⁇ g a day, or 10 and 100 ⁇ g/day.
  • the daily applied dose may be from about 10 to about 160 ⁇ g, about 10 to about 140 ⁇ g, about 10 to about 120 ⁇ g, about 10 to aboutlOO ⁇ g,
  • the daily dosage of the sodium channel blocker may be about 0.1 to about 40 ⁇ g per kilogram of body weight, about 1 to about 35 ⁇ g per kilogram of body weight, about 5 to about 30 ⁇ g per kilogram of body weight, about 10 to about 30 ⁇ g per kilogram of body weight, about 15 to about 30 ⁇ g per kilogram of body weight, about 10 to about 35 ⁇ g per kilogram of body weight, or about 20 to about 40 ⁇ g per kilogram of body weight.
  • the unit dose may be within a range of about 5 ⁇ g to about 2000 ⁇ g and may be about 5 to aboutiO ⁇ g, about 10 to about 15 ⁇ g, about 15 to about 20 ⁇ g, about 20 to about 25 ⁇ g, about 25 to about 30 ⁇ g, about 30 to about 40 ⁇ g, about 40 ⁇ g to about 50 ⁇ g, about 50 ⁇ g to about 75 ⁇ g, about 75 to aboutiOO ⁇ g, about 100 to about 150 ⁇ g, about 150 to about 200 ⁇ g, about 200 to about 250 ⁇ g, about 250 to about 500 ⁇ g, about 500 to about1000 ⁇ g, about 1000 to about 1500 ⁇ g or about 1500 to about 2000 ⁇ g or more than 2000 ⁇ g.
  • the dose administered is between 10 and 4000 ⁇ g/day of tetrodotoxin, its derivatives or its analogues, especially the dose of tetrodotoxin administered is normally between 10 and 4000 ⁇ g/day or - given the likely twice per day treatment - between 5 to 2000 ⁇ g each given dose, sometimes preferably between 250 and 1000 ⁇ g each given dose, sometimes preferably between 25 and 50 ⁇ g each given dose depending on the route of administration.
  • the effectiveness of a course of treatment of one, two, three, four, five or more doses or one, two or three days may last for up to about five, ten, fifteen, twenty, twenty five or thirty.
  • dosing is only performed once every day or once every two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, sixteen, eighteen, twenty, twenty four, thirty or more days.
  • the dosage of said sodium channel blocker such as TTX or STX, their analogues/derivatives depends on a variety of factors, including the nature and severity of the diseases, the sex, age, weight and individual reaction of the subject, the particular compound employed, the route and frequency of administration, etc.
  • Said sodium channel blockers such as TTX or STX, their analogues/derivatives or the pharmaceutical compositions comprising them may be administered in single or divided dosage form, e.g. one to four doses per day.
  • a substance named as an "active ingredient” will have a purity of at least 97%.
  • a formulation said to have "500 ⁇ g of TTX as the active ingredient” may contain as much as 15 ⁇ g of anhydrotetrodotoxin as an impurity.
  • a formulation said to have "500 ⁇ g of TTX and 500 ⁇ g of anhydrotetrodotoxin as active ingredients” will contain at least 485 ⁇ g of TTX and 485 ⁇ g of anhydrotetrodotoxin, but may contain as much as 30 ⁇ g of other substances as impurities of the active ingredients.
  • substances named as other components of a formulation are not included when the purity of the active ingredient is considered.
  • analogues as used in this application is defined here as meaning a chemical compound that is a derivative of a compound which has similar biochemical activity to that compound.
  • “Analogues” of TTX bind to the same site on the alpha subunit of sodium channels as does TTX.
  • derivatives as used in this application is defined here as meaning a chemical compound having undergone a chemical derivation such as substitution or addition of a further chemical group to change (for pharmaceutical use) any of its physico-chemical properties, such as solubility or bioavailability.
  • Derivatives include so-called prodrugs, e.g. ester and ether derivatives of an active compound that yield the active compound per se after administration to a subject.
  • sodium channel blockers or “sodium channel blocking compounds” in the sense of this invention thus encompass any chemicals that bind selectively to the to the voltage-gated sodium channel ⁇ subunit Na v 1.6 and thereby deactivate the sodium channel.
  • Particularly tetrodotoxin is found to possess similar pharmaceutical activity (US 6,407,088, hereby incorporated by reference).
  • Tetrodotoxin also known as Ti Qu Duo Xin
  • Ti Qu Duo Xin is an alkaloid found in puffer fish (Tetradontiae).
  • the chemical name is Octahydro-12-(Hydroxymethyl)-2-imino-5, 9, 7, 10a-dimethano- 10aH-[1 , 3]dioxocino[6,5-d]pyrimidine-4,7, 10,11 ,12-pentol with a molecular formula CnH 17 N 3 O 8 and a Molecular weight of 319.27. It is a potent non-protein neurotoxin and an indispensable tool for the study of neurobiology and physiology.
  • Tetrodotoxin is a marine organic toxin which is mainly found in testicles, ovaries, eggs, livers, spleens, eyeballs, and blood of puffer fish as well as in diverse animal species, including goby fish, newt, frogs and the blue ringed octopus and even in marine alga.
  • TTX is a marine organic toxin which is mainly found in testicles, ovaries, eggs, livers, spleens, eyeballs, and blood of puffer fish as well as in diverse animal species, including goby fish, newt, frogs and the blue ringed octopus and even in marine alga.
  • Several processes for producing TTX are known.
  • TTX is extracted from marine organisms (e.g.
  • Tetrodotoxin is a well known compound described for example in WO02/22129 as systemically acting as analgesic.
  • tetrodotoxin derivatives of tetrodotoxin
  • derivatives of tetrodotoxin are including but are not limited to anhydro-tetrodotoxin, tetrodaminotoxin, methoxytetrodotoxin, ethoxytetrodotoxin, deoxytetrodotoxin and tetrodonic acid, 6 epi-tetrodotoxin, 11 -deoxytetrodotoxin as well as the hemilactal type TTX derivatives (e.g.
  • 6-ep/-TTX lactone
  • 11-cteoxy-TTX lactone
  • 11-nor-TTX-6(S)-ol lactone
  • 11- ⁇ or-TTX-6( R)-Ol lactone
  • 11-/7or-TTX-6,6-diol lactone
  • 5-cteoxy-TTX 5, 11 -dideoxy-TTX
  • 4-ep/-5, 11 -didroxy-TTX 1 -hydroxy-5, 11 -dideoxy-TTX, 5,6,11- trideoxy-TTX and 4-ep/-5,6 F 11-f/7cteoxy-TTX
  • 4,9-anhydro type TTX analogs e.g., 4,9-anhydro-6-epi-TTX, A.Q-anhydroA ⁇ -deoxy-UX, 4,9-anhydro-TTX-8-O- hemisuccinate, 4,9-an/?yc/ro-TTX-11-O-hemisuccinate
  • TTX derivatives possess only 1/8 to 1/40 of the toxicity of TTX in mice, based upon bioassay in mice. It has been observed that these derivatives produce joint action, and do not interact adversely.
  • TTX derivatives include novel TTX derivatives isolated from various organisms, as well as those that are partially or totally chemically synthesized (see e.g., Yotsu, M. et al. Agric. Biol. Chem., 53(3):893-895 (1989)).
  • Derivatives and analogues of TTX may include compounds having the general formula I
  • R 2 and R 5 can be selected from the group consisting of H, OH, OAC, respectively;
  • R 1 call be H, or an alkyl with C 1 -C 4 , OH, OR, OC(O)R 1 , NH 2 , NHR", NR 11 R'", among them R can be an alkyl with C 1 -C 6 , R' can be an alkyl with C 1 -C 3 , and R", R 1 " can be an alkyl with C 1 -C 4 , respectively;
  • R 4 when R 3 is OH or OC(O)R and R is an alkyl with C 1 -C 3 , R 4 can be selected from the group consisting of:
  • NAP is 4-triazo-2-nitrobenzoic amide, indicated as formula (a);
  • AAG is 2-triazo-O-aminobenzoic amide, indicated as formular (b);
  • NMAG is O-methylaminobenzoic amide, indicated as formula (c);
  • ANT is O-aminobenzoic amide, indicated as formula (d);
  • amino hydrogenated quinazoline compounds and derivatives thereof are compounds having following general formula II,
  • R 1 can be selected from the group consisting of OH, an alkyl or a oxyalkyl with C 1 -C 4 , NH 2 , NHR", NR 11 R 1 ", among them R" and R" 1 can be an alkyl with C 1 -C 4 .
  • amino hydrogenated quiniazoline compounds and derivatives thereof are compounds having following general formula III
  • amino hydrogenated quinazoline and their derivatives are compounds having following general formula IV,
  • R 4 can be selected from the group consisting of:
  • the more preferred compounds are:
  • the derivatives/analogues of tetrodotoxin comprise tetrodotoxin, anhydro- tetrodotoxin, tetrodaminotoxin, methoxytetrodotoxin, ethoxytetrodotoxin, deoxytetrodotoxin, epi-tetrodotoxin and tetrodonic acid, more preferably the derivatives/analogues of tetrodotoxin a consisting of tetrodotoxin, anhydro- tetrodotoxin, tetrodaminotoxin, methoxytetrodotoxin, ethoxytetrodotoxin, deoxytetrodotoxin, epi-tetrodotoxin (4- and 6-epi-tetrodotoxin) and tetrodonic acid.
  • Saxitoxin (STX) and its pharmacologically acceptable salts are species of 2,6- diamino -4-((aminocarbonyl)oxy) methyl-3a,4,8,9 -tetrahydro-1 H, 1OH- pyrrolo(1 ,2-c) purine -10,10-diol (3aS-(3a-a-a-4-a,10aR * )).
  • the molecular formula of Saxitoxin is Ci 0 H 17 N 7 O 4, it has a molecular weight of 299.3 and a general structure of:
  • Saxitoxin is readily soluble in water and can be dispersed in aerosols. It is toxic by ingestion and by inhalation, with inhalation leading to rapid respiratory collapse and death. Chemically, saxitoxin is stable, although it can be inactivated by treatment with strong alkali. It is naturally-occurring, produced by bacteria that grow in other organisms, including the dinoflagellates Gonyaulax catenella and G. tamarensis; which are consumed by the Alaskan butter clam Saxidomus giganteus and the California sea mussel, Mytilus californianeus. The toxin can be isolated from S. giganteus or M.
  • tetrodotoxin, saxitoxin, and their derivatives or analogues or metabolite can be optionally in the form of their racemate, pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any suitable ratio; in neutral form, in the form of an acid or base or in form of a salt, especially a physiologically acceptable salt, or in form of a solvate, especially a hydrate.
  • the sodium channel blockers such as TTX or STX, their analogues/derivatives or the pharmaceutical compositions comprising them, may be administered, in unit dosage form, intestinally, enterally, parenterally or topically, orally, subcutaneously, intranasally, by inhalation, by oral absorption, intravenously, intramuscularly, percutaneously, intraperitoneally, rectally, intravaginally, transdermally, sublingually, buccally, orally transmucosally.
  • Administrative dosage forms may include the following: tablets, capsules, dragees, lozenges, patches, pastilles, gels, pastes, drops, aerosols, pills, powders, liquors, suspensions, emulsions, granules, ointments, creams, suppositories, freeze-dried injections, injectable compositions, in food supplements, nutritional and food bars, syrups, drinks, liquids, cordials etc, which could be regular preparation, delayed- released preparation, controlled-released preparation and various micro-granule delivery system, in food supplements, nutritional and food bars, syrups, drinks, liquids, cordials.
  • various carriers known in the art may be used, e.g.
  • dilutent and resorbent such as starch, dextrin, calcium sulfate, kaolin, microcrystalline cellulose, aluminium silicate, etc; wetting agent and adhesives such as water, glycerin, polyethylene glycol, ethanol, propanol, starch mucilage, dextrin, syrup, honey, glucose solution, acacia, gelatin, carboxymethylcellulose sodium, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc; disintegrating agent, such as dried starch, alginate, agar powder, laminaran, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol aliphatic ester, lauryl sodium sulfate, methylcellulose, ethylcellulose, lactose, sucrose, maltose, mannitol, fructose, various disaccharides and polysaccharides etc; disintegration inhibiting agent, such as sucrose, tristearin
  • the tablet may be further formulated into coated tablet, e.g. sugar-coated tablet, film-coated tablet, enteric-coated tablet, or double-layer tablet and multi-layer tablet.
  • various carriers known in the art may be used, e.g. dilutent and resorbent, such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, polyvinylpyrrolidone, kaolin, talc, etc; adhesives, such as acacia, bassora gum, gelatin, ethanol, honey, liquid sugar, rice paste or flour paste, etc; disintegrating agent, such as agar powder, dried starch, alginate, lauryl sodium sulfate, methylcellulose, ethylcellulose.
  • various carriers known in the art may be used, e.g. polyethylene, lecithin, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glyceride, etc.
  • capsule it may be prepared by mixing said sodium channel blockers as active ingredient with the above mentioned carriers, followed by placing the mixture into a hard gelatin capsule or soft capsule.
  • said sodium channel blockers may be applied in the following dosage forms: microcapsules, suspension in an aqueous phase, hard capsule, or injection.
  • injection such as liquor, emulsion, freeze-dried injection, and suspension, all the dilutents common in the art may be used, e.g.
  • sorbitol aliphatic ester water, ethanol, polyethylene glycol, propylene glycol, oxyethylated isostearyl alcohol, polyoxidated isostearyl alcohol, polyoxyethylene sorbitol aliphatic ester, etc.
  • a suitable amount of sodium chloride, glucose or glycerin may be added into the preparation, as well as regular cosolvent, buffer, pH adjusting agent, etc.
  • coloring agent, antiseptic, perfume, correctives, food sweetening agent or other materials may be added to the pharmaceutical preparation if necessary.
  • a formulation or pharmaceutical composition according to the invention contains the active ingredient (TTX, its derivatives and/or its analogues) as well as optionally at least one auxiliary material and/or additive and/or optionally another active ingredient.
  • auxiliary material and/or additive can be specifically selected from conserving agents, emulsifiers and/or carriers for parenteral application.
  • the selection of these auxiliary materials and/or additives and of the amounts to be used depends upon how the pharmaceutical composition is to be applied. Examples include here especially parenteral like intravenous subcutaneous or intramuscular application formulations but which could also be used for other administration routes.
  • routes of administration of tetrodotoxin its derivatives and its analogues can include intramuscular injection, intraveneous injection, subcutaneous injection, sublingual, bucal, patch through skin, oral ingestion, implantable osmotic pump, collagen implants, aerosols or suppository.
  • the sodium channel blockers such as TTX or STX, their analogues/derivatives may be administered in a schedule of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty or more doses per day, alone or in combination with other medications, over range of time periods including but not limited to periods of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, sixteen, eighteen, twenty, twenty four, thirty, or more days; or over a period of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, sixteen, eighteen, twenty, twenty four, thirty, or more days; or over a period of one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, sixteen, eighteen, twenty, twenty four, thirty, thirty six, forty eight,
  • the sodium channel blockers such as TTX or STX, their analogues/derivatives may be a voltage-gated sodium channel blocker and may bind to a SS1 or SS2 ⁇ subunit of a sodium channel.
  • the maximum daily dose of sodium channel blocker may be up to about 10 ⁇ g, up to about 50 ⁇ g, up to about 100 ⁇ g, up to about 144 ⁇ g, up to about 150 ⁇ g, up to about 300 ⁇ g, up to about 500 ⁇ g, up to about 750 ⁇ g, up to about 1000 ⁇ g, up to about 1250 ⁇ g, up to about 1500 ⁇ g, up to about 1750 ⁇ g, up to about 2000 ⁇ g or more.
  • the sodium channel blocker may be administered in an amount ranging between 5 and 4000 ⁇ g/day, or in ranges between 10 and 2000 ⁇ g/day, 10 and 1000 ⁇ g a day, 10 and 750 ⁇ g a day, 10 and 500 ⁇ g a day, 10 and 400 ⁇ g a day, 10 and 300 ⁇ g a day, 10 and 200 ⁇ g a day, or 10 and 100 ⁇ g/day.
  • the daily applied dose may be from about 10 to about 160 ⁇ g, about 10 to about 140 ⁇ g, about 10 to about 120 ⁇ g, about 10 to aboutlOO ⁇ g,
  • the daily dosage of the sodium channel blocker may be about 0.1 to about 40 ⁇ g per kilogram of body weight, about 1 to about 35 ⁇ g per kilogram of body weight, about 5 to about 30 ⁇ g per kilogram of body weight, about 10 to about 30 ⁇ g per kilogram of body weight, about 15 to about 30 ⁇ g per kilogram of body weight, about 10 to about 35 ⁇ g per kilogram of body weight, or about 20 to about 40 ⁇ g per kilogram of body weight.
  • the unit dose may be within a range of about 5 ⁇ g to about 2000 ⁇ g and may be about 5 to aboutiO ⁇ g, about 10 to about 15 ⁇ g, about 15 to about 20 ⁇ g, about 20 to about 25 ⁇ g, about 25 to about 30 ⁇ g, about 30 to about 40 ⁇ g, about 40 ⁇ g to about 50 ⁇ g, about 50 ⁇ g to about 75 ⁇ g, about 75 to aboutiOO ⁇ g, about 100 to about 150 ⁇ g, about 150 to about 200 ⁇ g, about 200 to about 250 ⁇ g, about 250 to about 500 ⁇ g, about 500 to about1000 ⁇ g, about 1000 to about 1500 ⁇ g or about 1500 to about 2000 ⁇ g or more than 2000 ⁇ g.
  • the dose administered is between 10 and 4000 ⁇ g/day of tetrodotoxin, its derivatives or its analogues, especially the dose of tetrodotoxin administered is normally between 10 and 4000 ⁇ g/day or - given the likely twice per day treatment - between 5 to 2000 ⁇ g each given dose, sometimes preferably between 250 and 1000 ⁇ g each given dose, sometimes preferably between 25 and 50 ⁇ g each given dose depending on the route of administration.
  • the effectiveness of a course of treatment of one, two, three, four, five or more doses or one, two or three days may last for up to about five, ten, fifteen, twenty, twenty five or thirty.
  • dosing is only performed once every day or once every two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, sixteen, eighteen, twenty, twenty four, thirty or more days.
  • the dosage of said sodium channel blocker such as TTX or STX, their analogues/derivatives depends on a variety of factors, including the nature and severity of the diseases, the sex, age, weight and individual reaction of the subject, the particular compound employed, the route and frequency of administration, etc.
  • Said sodium channel blockers such as TTX or STX, their analogues/derivatives or the pharmaceutical compositions comprising them may be administered in single or divided dosage form, e.g. one to four doses per day.
  • a substance named as an "active ingredient” will have a purity of at least 97%.
  • a formulation said to have "500 ⁇ g of TTX as the active ingredient” may contain as much as 15 ⁇ g of anhydrotetrodotoxin as an impurity.
  • a formulation said to have "500 ⁇ g of TTX and 500 ⁇ g of anhydrotetrodotoxin as active ingredients” will contain at least 485 ⁇ g of TTX and 485 ⁇ g of anhydrotetrodotoxin, but may contain as much as 30 ⁇ g of other substances as impurities of the active ingredients.
  • substances named as other components of a formulation are not included when the purity of the active ingredient is considered.
  • tetrodotoxin its derivative and/or one of its analogues is used in an amount between 10 ⁇ g/day and 4 mg/day.
  • the used tetrodotoxin, its derivative or its analogue is isolated from a biological source, preferably from fish, especially puffer fish.
  • the used tetrodotoxin, its derivative or its analogue is synthesized / synthetic.
  • the neuronal isoform Na v 1.6 exerts IC 50 1 S in the nanomolar range, while Na v 1.4 and Na v 1.5 are blocked by micomolar concentrations only.
  • TTX sensitive channels Na v 1.2, Na v 1.3, Na v 1.4, Na v 1.6 and Na v 1.7 and insensitive ones (Na v 1.5 and Na v 1.8).

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Abstract

La présente invention concerne l'utilisation de 4,9-anhydrotétrodotoxine pour le traitement de maladies liées à la sous-unité α des canaux sodiques dépendants d'un potentiel d'action Nav 1.6.
PCT/EP2007/002661 2006-03-27 2007-03-26 UTILISATION DE 4,9-ANHYDROTÉTRODOTOXINE POUR LE TRAITEMENT DE MALADIES LIÉES À LA SOUS-UNITÉ α DES CANAUX SODIQUES DÉPENDANTS D'UN POTENTIEL D'ACTION NAV 1.6 WO2007110220A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP06384005.2 2006-03-27
EP06384004A EP1844782A1 (fr) 2006-03-27 2006-03-27 4,9-Anhydro-Tetrodoxin pour le traitement des maladies liées à la subunitée Nav1.6 du canal sodique potentio-dépendant
EP06384005A EP1844783A1 (fr) 2006-03-27 2006-03-27 4,9-Anhydro-Tetrodoxin pour le traitement des maladies liées à la subunitée Nav1.6 du canal sodique potentio-dépendant
EP06384004.5 2006-03-27

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WO2007110220A1 true WO2007110220A1 (fr) 2007-10-04

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6407088B1 (en) * 2000-09-18 2002-06-18 Wex Medical Instrumentation Co., Ltd. Method of analgesia
US20020161013A1 (en) * 2001-04-25 2002-10-31 Wex Medical Intrumentation Co., Ltd. Method of local anesthesia and analgesia
WO2006032459A1 (fr) * 2004-09-22 2006-03-30 Laboratorios Del Dr. Esteve S.A. Tétrodotoxine et ses dérivés dans le traitement de la douleur neuropathique d’origine nerveuse périphérique
WO2006032481A1 (fr) * 2004-09-21 2006-03-30 Laboratorios Del Dr. Esteve S.A. Tétrodotoxine et dérivés de tétrodotoxine utilisés dans le traitement de douleurs neuropathiques prenant leur origine dans le système nerveux central

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6407088B1 (en) * 2000-09-18 2002-06-18 Wex Medical Instrumentation Co., Ltd. Method of analgesia
US20020161013A1 (en) * 2001-04-25 2002-10-31 Wex Medical Intrumentation Co., Ltd. Method of local anesthesia and analgesia
WO2006032481A1 (fr) * 2004-09-21 2006-03-30 Laboratorios Del Dr. Esteve S.A. Tétrodotoxine et dérivés de tétrodotoxine utilisés dans le traitement de douleurs neuropathiques prenant leur origine dans le système nerveux central
WO2006032459A1 (fr) * 2004-09-22 2006-03-30 Laboratorios Del Dr. Esteve S.A. Tétrodotoxine et ses dérivés dans le traitement de la douleur neuropathique d’origine nerveuse périphérique

Non-Patent Citations (4)

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Title
CRANER MATTHEW J ET AL: "Sodium channels contribute to microglia/macrophage activation and function in EAE and MS.", GLIA. 15 JAN 2005, vol. 49, no. 2, 15 January 2005 (2005-01-15), pages 220 - 229, XP009068644, ISSN: 0894-1491 *
DEVAUX JEROME J ET AL: "Altered ion channels in an animal model of Charcot-Marie-Tooth disease type IA", JOURNAL OF NEUROSCIENCE, vol. 25, no. 6, 9 February 2005 (2005-02-09), pages 1470 - 1480, XP002388268, ISSN: 0270-6474 *
HONG SHUANGSONG ET AL: "Early painful diabetic neuropathy is associated with differential changes in tetrodotoxin-sensitive and -resistant sodium channels in dorsal root ganglion neurons in the rat", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 279, no. 28, 9 July 2004 (2004-07-09), pages 29341 - 29350, XP002388284, ISSN: 0021-9258 *
KHALIQ Z M ET AL: "The contribution of resurgent sodium current to high-frequency firing in Purkinje neurons: An experimental and modeling study", JOURNAL OF NEUROSCIENCE 15 JUN 2003 UNITED STATES, vol. 23, no. 12, 15 June 2003 (2003-06-15), pages 4899 - 4912, XP002388285, ISSN: 0270-6474 *

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