WO2003053336A2 - Methods for the treatment of peripheral neural and vascular ailments - Google Patents

Methods for the treatment of peripheral neural and vascular ailments Download PDF

Info

Publication number
WO2003053336A2
WO2003053336A2 PCT/US2002/035654 US0235654W WO03053336A2 WO 2003053336 A2 WO2003053336 A2 WO 2003053336A2 US 0235654 W US0235654 W US 0235654W WO 03053336 A2 WO03053336 A2 WO 03053336A2
Authority
WO
WIPO (PCT)
Prior art keywords
composition
skin
flavonoid
quercetin
pharmaceutically acceptable
Prior art date
Application number
PCT/US2002/035654
Other languages
French (fr)
Other versions
WO2003053336A3 (en
Inventor
Richard A. Rosenbloom
Original Assignee
The Quigley Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/US2001/049297 external-priority patent/WO2002049575A2/en
Application filed by The Quigley Corporation filed Critical The Quigley Corporation
Priority to EP02789474A priority Critical patent/EP1455778A4/en
Priority to MXPA04006039A priority patent/MXPA04006039A/en
Priority to IL16250502A priority patent/IL162505A0/en
Priority to AU2002352501A priority patent/AU2002352501B2/en
Priority to JP2003554096A priority patent/JP2005518381A/en
Priority to CA002470603A priority patent/CA2470603A1/en
Priority to NZ533439A priority patent/NZ533439A/en
Publication of WO2003053336A2 publication Critical patent/WO2003053336A2/en
Publication of WO2003053336A3 publication Critical patent/WO2003053336A3/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/82—Theaceae (Tea family), e.g. camellia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/35—Ketones, e.g. benzophenone
    • A61K8/355—Quinones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/42—Amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4913—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
    • A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4986—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with sulfur as the only hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/60—Sugars; Derivatives thereof
    • A61K8/602—Glycosides, e.g. rutin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/67—Vitamins
    • A61K8/671—Vitamin A; Derivatives thereof, e.g. ester of vitamin A acid, ester of retinol, retinol, retinal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/67—Vitamins
    • A61K8/676—Ascorbic acid, i.e. vitamin C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/67—Vitamins
    • A61K8/678—Tocopherol, i.e. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9771—Ginkgophyta, e.g. Ginkgoaceae [Ginkgo family]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9789—Magnoliopsida [dicotyledons]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/52—Stabilizers
    • A61K2800/522—Antioxidants; Radical scavengers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth

Definitions

  • the present invention relates to compositions and methods for the treatment of peripheral neural and vascular ailments.
  • a flavonoid is administered to a patient suffering from a peripheral neural or vascular ailment.
  • peripheral neuropathies and “small fiber neuropathies” are used interchangeably herein to refer to a set of conditions characterized by functional changes or pathological changes, or both, in the small, unmyelinated nerve fibers of the peripheral nervous system.
  • diabetic neuropathy is not included among the peripheral small fiber neuropathies.
  • Peripheral or small fiber neuropathies may be caused by any of about a hundred identified factors that can produce nerve damage. The cause may be metabolic, for example hypertriglyceridemia or pellagra.
  • Toxic exposures may also cause small fiber neuropathies, for example those resulting from alcoholism, excessive doses of vitamin B 6 , exposure to toxic metals such as thallium, or exposure to certain chemotherapeutic agents, such as vinca alkaloids.
  • Certain congenital conditions including amyloidosis, an- ⁇ -lipoproteinemia (Tangier's), and - galactosidase (Fabry's), are known to cause small fiber neuropathies.
  • Small fiber neuropathies may result from infections such as leprosy, or diseases such as AIDS, herpes simplex, herpes zoster (shingles), cytomegalovirus, hepatitis B and C, Lyme disease, autoimmune diseases, Fabry disease, diphtheria, vasculitis, and porphyria.
  • infections such as leprosy, or diseases such as AIDS, herpes simplex, herpes zoster (shingles), cytomegalovirus, hepatitis B and C, Lyme disease, autoimmune diseases, Fabry disease, diphtheria, vasculitis, and porphyria.
  • AIDS herpes simplex
  • herpes zoster cytomegalovirus
  • hepatitis B and C Lyme disease
  • autoimmune diseases Fabry disease
  • diphtheria diphtheria
  • vasculitis and porphyria
  • peripheral neuropathies Patients afflicted with peripheral neuropathies have pain in their extremities. The pain may at first be perceived as a tingling sensation in the fingers or toes. Decreased sensitivity to heat or cold is also a common early symptom. Frequently, however, a physical examination will show that the patient's reflexes, strength, sensory levels, and electrophysiology are normal. This has historically complicated the diagnosis of peripheral neuropathies, or led to underdiagnosis, especially in the early stages of the neuropathies. Recent technology, however, including skin biopsies and measurement of the density of different nerve fiber types in the epidermis, has improved the likelihood of detecting peripheral neuropathies.
  • Small fiber or peripheral neuropathies tend to progress by spreading upward, and patients may develop intense pain and/or a burning sensation that can be so severe as to be debilitating.
  • Other symptoms of these neuropathies include cold hands or feet, cramps, muscle weakness and/or atrophy, eventual loss of perception of pressure, pain and/or temperature, neuropathic ulcers, lack of sweating, dry eyes, dry mouth, impotence, and restless leg syndrome.
  • treatment of the underlying cause may also reverse or alleviate small fiber neuropathies.
  • treatment consists of reducing the symptoms of the neuropathies, typically by administering medications known to decrease pain from neuropathy and related conditions. These medications include tricyclic antidepressants, anticonvulsants, opioid medications, and local anesthetics applied to the painful area.
  • An afflicted patient may also undergo physical and occupational therapy to improve mobility and function.
  • peripheral neuropathies do not vary due to their underlying causes.
  • a neuropathy caused by exposure to chemotherapeutic agents may present symptoms almost identical to those of a neuriopathy caused by Lyme disease.
  • diabetic neuropathy is a fairly common long-term complication of diabetes mellitus that shares many of the symptoms of peripheral neuropathies.
  • the cause of diabetic neuropathy is believed to be a chronic systemic excess of the glucose metabolite sorbitol.
  • treating the underlying cause of diabetic neuropathy that is, improving glycemic control, will often prevent the symptoms from worsening.
  • Diabetic neuropathy is also known to be reversible, if good glycemic control is instituted while the condition is in its early stages.
  • Peripheral Neuropathies can also impair circulation in the affected area. Impaired circulation can adversely affect the appearance of the skin. Adverse effects on the appearance of the skin caused by radiation injury can include, for example, redness, discoloration, dryness of the skin.
  • "Peripheral vascular diseases” are diseases of the blood vessels outside the heart that lead to restriction or blockage of the blood vessels. Atherosclerosis, when it affects the extremities rather than the coronary arteries, is an example of a peripheral vascular disease. Peripheral vascular diseases may also be long-term complications of other diseases, such as Raynaud's disease, Raynaud's phenomenon, hypertension, or Buerger's disease (thromboangitis obliterans).
  • peripheral vascular disease An early symptom of peripheral vascular disease includes pain upon exercising that is relieved by rest. These diseases are progressive, however, and patients may also experience numbness, muscle weakness or pain, loss of hair on the affected extremities, cyanosis, weak or absent pulse in the affected extremities, gait abnormalities, pain when resting, skin ulcers, and, eventually gangrene. Impaired circulation caused by peripheral vascular disease can also adversely affect the appearance of the skin. Adverse effects on the appearance of the skin caused by radiation injury can include, for example, redness, discoloration, dryness of the skin. In general, an agent that promotes or induces angiogenesis, or one that at least partially clears blocked or restricted vessels, or one that will facilitate peripheral circulation by other means, i.e. by decreasing cellular adhesion, will be effective to treat peripheral vascular diseases.
  • rnicrocirculation is also a long-term complication of diabetes.
  • a therapy that is effective for peripheral vascular diseases will also be effective to counter decreased rnicrocirculation caused by diabetes.
  • a clinically effective treatment of peripheral vascular ailments there remains a need for a clinically effective treatment of peripheral vascular ailments.
  • the present invention provides a method for the treatment of peripheral neural and vascular ailments by administering a composition including a therapeutically effective amount of a flavonoid having antioxidant properties, and, optionally, an acceptable carrier.
  • the invention in another embodiment, relates to a composition for treating peripheral neural and vascular ailments.
  • the composition comprises a therapeutically effective amount of a mixture of a flavonoid having antioxidant properties, a therapeutically effective amount of a non-flavonoid antioxidant compound, and, optionally, an acceptable carrier.
  • compositions and methods of the invention provide significant, effective relief of symptoms of peripheral neural and vascular ailments, as well as partial recovery of lost rnicrocirculation or neurological function in some cases. Surprisingly, the efficacy of the invention is not dependent on the underlying causes of the peripheral neural and vascular ailments.
  • the composition used in the method of the invention when administered in a therapeutically effective amount to treat peripheral neural and vascular ailments, does not cause severe side effects.
  • the topical compositions and methods of the invention also treat adverse effects on the appearance of the skin caused by peripheral neuropathies and/or peripheral vascular disease. These cosmetic benefits are obtained in patients having such disorders. Adverse effects on the appearance of the skin include, for example, redness, discoloration, dryness.
  • the invention treats or cosmetically improves the appearance of persons having peripheral or neural vascular ailments by, for example, reducing or preventing redness of skin, reducing or preventing discoloration of skin, beautifying skin, improving appearance of skin, promoting attractiveness of skin, cleansing skin, removing dead or damaged skin or skin cells from skin and moisturizing skin.
  • compositions and methods of the invention also provide nutritional and/or dietary benefits. These nutritional or dietary cosmetic benefits are obtained in patients having peripheral neuropathies and/or peripheral vascular disease. Such nutritional or dietary effects are also intended to be included within the meaning of "treating ailments.”
  • the invention offers dietary or nutritional benefits in supporting and/or maintaining neural, vascular and muscular health, maintains sensory integrity, i.e. sensations of hot and cold, and supports the maintenance of skin health.
  • derivatives refers to structurally similar compounds that exhibit a common activity (e.g., antioxidant) and contain at least one significant, common structural element with the compound from which it is derived, which common structural element provides the common activity.
  • therapeutically effective amount refers to a nontoxic amount of a compound which is sufficient to provide the desired therapy to counteract small fiber neuropathies or peripheral vascular diseases.
  • a therapeutic amount may, for example, reduce pain, reverse sensory fiber loss or demyelination, promote angiogenesis, increase rnicrocirculation, or increase sensory perception.
  • the exact amount required may vary, depending on the species, age, and general condition of the patient, the nature of the complications, the particular combination of compounds, the mode of administration, and the like.
  • the term “therapeutically” is intended to encompass beneficial cosmetic effects and effects of improved nutrition as well as medical effects.
  • compositions used in the method of the present invention include at least one flavonoid.
  • Flavonoids are small organic compounds having a phenyl benzopyrone structure. They are found in the leaves, fruits, seeds, stems, or flowers of all vascular plants. Citrus fruits are a prominent source of flavonoids, over 4000 of which have been identified as deriving from plant sources. On average, the daily Western diet contains about one gram of mixed flavonoids.
  • flavonoids include, without limitation, flavonones, flavonols, anthocyanidins, proanthocyanidins, procyanidolic oligomers, biflavans, polyphenols, rutinosides, hydroxyethylrutinosides, and leucoanthocyanins.
  • Suitable flavonoids for use in the present invention include those that do not induce significant, adverse side effects when administered to a mammal in a therapeutically effective amount, and that do not react with any of the other ingredients of the composition used in the present invention to cause a substantial loss of activity of one or more compounds of the composition.
  • Preferred flavonoids are obtained from natural sources. However, derivatives of such compounds may also be suitable for use in the present invention. Preferred flavonoids may be administered to humans without significant, adverse side effects when used in therapeutically effective amounts.
  • the selection of the flavonoid(s) included in the composition may be determined by factors such as toxicity, bioavailability, solubility or dispersability, and the like.
  • flavonoids suitable for use in the present invention include, without limitation, (-)-epigallocatechin; (-)-epigallocatechin-gallate; 1,2,3,6-tetra-o- gallyol- ⁇ -d-glucose; 2'-o-acetylacetoside; 3,3',4-tri-o-methyl-ellagic acid; 6,3',4'- trihydroxy-5,7,8-trimethoxyflavone; 6-hydroxy-luteolin; 6-hydroxykaempferol-3,6- dimethyl ether; 7-o-acetyl-8-epi-loganic acid; acacetin; acetoside; acetyl trisulfate quercetin; amentoflavone; apigenin; apiin; astragalin; avicularin; axillarin; baicalein; brazilin; brevifolin carboxylic acid; caryophyllene; catechin; chrysin;
  • Preferred flavonoids are those that also have strong antioxidant properties.
  • preferred flavonoids include, without limitation, (-)-epigallocatechin-3- gallate, catechin, rutin, quercetin, quercitrin, myricetin, kaempferol, myrecetrin luteolin, morin, fisetin, silymarin, apigenin, hesperitin, hesperidin, citrin, gossypetin, chrysin, oligomeric proanthocyanidins, biacalein, curcumin, gallic acid, epicatechin, dihydroquercetin, ginkgo flavone glycosides, ginkgo heterosides, silibin, silydianin silychristine, galangin, monoHER, diHER, triHER, tetraHER, naringenin, naringin, taxifolin, diosmin, phloretin, phloridzin, cyani
  • flavonoids include, without limitation, quercetin, quercitrin, myricetin, rutin, kaempferol and myrecetrin. These compounds exhibit good antioxidant properties in combination with relatively low toxicity.
  • flavonoids and flavonoid derivatives may provide additional beneficial effects in the composition of the present invention.
  • quercetin acts as a chelator for transition metals.
  • Flavonoids are also believed to possess anti- inflammatory activity and to assist in the stabilization of cell membranes, both activities that promote the treatment of small fiber neuropathies. Quercetin is also believed to have anticlastogenic properties.
  • some flavonoids and flavonoid derivatives act as radical scavengers, reducing the concentration of hydroxyl radicals, for example, and thereby further enhancing the antioxidant effect of the composition used in the present invention.
  • Suitable non-flavonoid antioxidants for use in the present invention include those that exhibit antioxidant activity without causing any severe adverse side affects when administered in a therapeutically effective amount, and that do not react with any of the other ingredients of the composition used in the present invention to cause a substantial loss of activity of one or more compounds.
  • Preferred antioxidants include those that occur naturally in the human body and materials obtained from plants or animals, or derivatives of such compounds.
  • Preferred non-flavonoid antioxidants include, without limitation, ascorbyl palmitate, ascorbic acid (vitamin C), vitamin A, vitamin E and its pharmaceutically acceptable esters (including but not limited to the acetate), ⁇ -lipoic acid, especially DL- ⁇ -lipoic acid, coenzyme Q10, glutathione (GSH), galangin, gingkolides, tocotrienols, carotenoids, cyanidin, curcuminoids, and derivatives thereof which exhibit antioxidant activity. More preferably, mixtures of two or more antioxidants are employed in the composition used in the present invention. Derivatives of one or more of these compounds that exhibit antioxidant activity when administered in the compositions of the present invention may also be employed.
  • the antioxidants may also be used in the form of their pharmaceutically acceptable salts. The salts may be preferred in some cases, for example to increase solubility or dispersability, or to reduce adverse side effects.
  • the antioxidant used in the composition of the present invention may comprise one or more antioxidant enzymes.
  • the antioxidant enzymes useful in the present invention are those capable of scavenging radicals, of promoting radical scavengers or preventing radical formation.
  • One or more of these antioxidant enzymes may act synergistically with one or more of the other antioxidants in the composition to scavenge free radicals more effectively and thereby aid in the prevention of cell damage in the skin.
  • the antioxidant enzyme used in the present invention is capable of abso ⁇ tion through the skin.
  • Preferred antioxidant enzymes for use in the present invention include superoxide dismutase, catalase, glutathione peroxidase, methionine reductase, and the like.
  • both quercetin and an antioxidant are included in the composition of the present invention.
  • This combination of quercetin and an antioxidant results in an enhanced anti-oxidative effect.
  • the antioxidant may be a flavonoid or a non-flavonoid.
  • compositions used in the present invention may also be included in the composition of the present invention to provide additional benefits, such as absorbability when applied topically, free radical scavenging, transition metal chelation, nitric oxide stabilization, analgesia, and anti-inflammatory activity. Some of these properties may have a beneficial effect on the pain of other related disorders such as fibromyalgia.
  • Additional materials that may optionally be included in the compositions used in the present invention include inositol and other B-complex vitamins.
  • Some preferred compositions used in the invention also contain vitamin D , a vitamin D 3 analog, a compound that may be converted or metabolized into vitamin D 3 in the human body, or a metabolite of vitamin D 3 .
  • Vitamin D 3 also known as cholecalciferol
  • Vitamin D 3 may be further converted into another vitamin D intermediate, 25-hydroxycholecalciferol, in the liver by rnitochondrial hydroxylase, in the presence of NADPH, and molecular oxygen.
  • vitamin D 3 When a more active form of vitamin D 3 is required, 25-hydroxycholecalciferol is transported to the kidney where a new hydrolase enzyme is synthesized. This enzyme introduces another hydroxyl group at position 1, and the bioactive form of vitamin D 3 , calcitriol, is produced.
  • An exemplary vitamin D 3 analog is 1(S), 3(R)-dihydroxy-20(R)-(l-ethoxy-5- ethyl-5-hydroxy-2-heptyn-l-yl)-9, 10-seco-pregna-5(Z), 7(E), 10 (19)-triene.
  • An exemplary vitamin D 3 metabolite is 1, 25-dihydroxyvitamin D 3 .
  • Pharmaceutically acceptable salts of vitamin D 3 and its derivatives and metabolites may be employed in the methods of the present invention.
  • Vitamin D 3 is particularly preferred for use in the present invention.
  • a dispersant may be necessary to facilitate the formulation of the vitamin D 3 or related compound. Suitable dispersants are well known to persons skilled in the art.
  • Corn oil is one dispersant that is well suited for vitamin D 3 and related compounds. Also advantageously, corn oil is a natural product. The corn oil is used in an amount sufficient to disperse the vitamin D 3 or related compound.
  • compositions used in the present invention may provide one or more of the following localized or systemic beneficial effects to a patient when administered in therapeutically effective amounts: relief of pain, burning, tingling, electrical sensations and/or hyperalgesia; increased rnicrocirculation; nitric oxide stabilization; promotion of healing of skin ulcers and lesions; protein kinase C inhibition; decreased oxidative stress; anti-inflammatory activity; blockage of the formation of leukotrienes; stabilization of cell membranes; and promotion of the synthesis of nerve growth factor.
  • compositions in accordance with the invention can provide additional effects of improving the appearance of the skin. Skin appearance may be adversely affected by peripheral neuropathies, including diabetic neuropathy, and/or peripheral vascular disease, or by other causes unrelated to the peripheral neuropathies and/or peripheral vascular disease being treated.
  • peripheral neuropathies including diabetic neuropathy, and/or peripheral vascular disease, or by other causes unrelated to the peripheral neuropathies and/or peripheral vascular disease being treated.
  • One or more of the following beneficial properties may be realized when compositions of the invention are topically applied in an effective amount: reducing or preventing redness of skin, reducing or preventing discoloration of skin, beautifying skin, improving appearance of skin, promoting attractiveness of skin, cleansing skin, removing dead or damaged skin or skin cells from skin and moisturizing skin.
  • an effective treatment might cause the degeneration of peripheral nerves to slow or to stop.
  • an effective treatment might induce healing or regeneration of the damaged nerves.
  • An effective treatment might also cause the generation of new nerves to replace the damaged nerves. It is therefore expected that effective treatments for small fiber neuropathies will be applicable to other diseases or conditions affecting peripheral nerves.
  • a method of regenerating nerves is beneficial to treat any patient suffering from nerve damage, for example, a skin graft patient or a victim of a nerve-severing trauma.
  • many flavonoids are potent aldose reductase inhibitors. It has been shown that the oral administration of aldose reductase inhibitors increases the diameter of peripheral nerve bundles. Thus, it is expected that the methods of the present invention extend to the generation and regeneration of nerves.
  • the underlying cause of diabetic neuropathy is specifically known to be distinct from the other causes of small fiber neuropathies, the symptoms and pathologies are shared. It is therefore expected that an effective treatment for small fiber neuropathies will arrest, reverse, or alleviate certain symptoms of diabetic neuropathy. It has also been found that for treatment of diabetic neuropathy, the optional component, vitamin D 3 or a derivative or metabolite thereof, may be excluded from the composition and the composition will still provide a beneficial effect, provided the composition includes other suitable components. Flavonoids promote rnicrocirculation and therefore can also be used to treat peripheral vascular diseases. For example, the flavonoid quercetin supports vascular functioning in general, and therefore is an effective treatment for peripheral vascular diseases.
  • rnicrocirculation is believed to be caused at least in part by oxidative stress resulting from an excess of free radicals.
  • Quercetin an example of a flavonoid with antioxidant properties, is therefore an effective treatment for this condition.
  • the chelating properties of flavonoids such as quercetin contribute to its effectiveness.
  • the overabundance of sorbitol in the bloodstream of diabetic patients attracts metal ions, which are sequestered by chelation.
  • compositions used in the present invention are preferably formulated with an acceptable carrier.
  • the non-carrier ingredients may be combined with the carrier materials to produce a particular dosage form, or be customized for a particular treatment regimen.
  • the amount of each ingredient may vary depending on such factors as the particular mode of administration, the activity of the particular compounds employed, the age, bodyweight, general health, sex, and diet of the patient, time of administration, rate of excretion, the combination of compounds, or the severity of the illness, among other potential factors.
  • a standard reference text on pharmaceutical formulations Remington's Pharmaceutical Sciences, 18 th Ed., Mack Publishing Co. 1990, is inco ⁇ orated herein by reference in its entirety.
  • composition refers to stable mixtures, compositions, and formulations, respectively. Preferred mixtures, compositions, and formulations are stable over a period of at least about three months.
  • the composition may be administered via several routes, including, without limitation, topically, orally, via an implanted reservoir, or by inhalation.
  • the composition is administered orally.
  • An oral composition for use in the invention may be administered one to six times daily, or as needed to relieve pain and other symptoms of the small fiber neuropathies.
  • the composition when administered orally, is administered two to four times daily, as needed for pain.
  • a sufficient amount should be administered to provide one or more of the beneficial effects of the compositions described above.
  • the method initially treats acute symptoms but may be continued indefinitely to relieve pain, prevent symptoms from returning and possibly restore some nerve and/or skin function.
  • the oral compositions and methods of the invention also function as dietary or nutritional supplements.
  • oral compositions and methods can maintain and/or support neural health, maintain and/or support vascular health and circulation, maintain and/or support muscular health, maintain sensory integrit, i.e. sensations of hot and cold, and support the health of the skin.
  • compositions used in the present invention may be orally administered in any acceptable dosage form including, but not limited to, capsules, tablets, lozenges, troches, hard candies, powders, sprays, elixirs, syrups, and suspensions or solutions.
  • Suitable acceptable carriers for tablets include lactose and corn starch, for example.
  • Lubricating agents may also be added to the tablets, including, for example, magnesium stearate, sodium lauryl sulfate and talc. Tablets may also contain excipients such as sodium citrate, calcium carbonate and calcium phosphate.
  • Disintegrants such as starch, alginic acid and complex silicates, may also be employed. Tablets may also include binding agents such as polyvinylpyrrolidone, gelatin and gum acacia.
  • composition used in the invention may be administered in capsule form, with or without diluents.
  • diluents for capsules include, without limitation, lactose and dried cornstarch.
  • solid compositions similar to those of the tablets described above may be administered in soft and hard gelatin capsules.
  • compositions used in the invention may be administered orally as encapsulated or unencapsulated suspensions, and they may comprise emulsifying and/or suspending agents such as are well known to those of skill in the art.
  • Ancillary ingredients such as sweeteners, flavorants, coloring agents, dyes, and diluents such as water, ethanol, propylene glycol, glycerin and various combinations thereof may also be included in the oral formulations.
  • compositions used in the present invention may also be administered by nasal aerosol or by inhalation.
  • Appropriate formulations may be prepared using well- known techniques.
  • suitable carriers include, for example, saline and/or other conventional solubilizing or dispersing agents, optionally formulated with one or more preservatives, abso ⁇ tion promoters to enhance bioavailability, and/or fluorocarbons.
  • the composition is applied topically to an area of the skin in the vicinity of tissue that suffers from small fiber neuropathy in order to relieve pain and other symptoms of the small fiber neuropathy.
  • Such areas typically include the patients' extremities, such as the fingers, toes, hands and feet, where neuropathy is often most pervasive.
  • a suitable amount of the topical composition of the invention is applied one to six times daily, as needed. More preferably, the topical composition is applied two to four times daily, as needed. Also preferably, a sufficient amount of the topical composition is applied to cover the afflicted area with a thin layer of the composition and the composition is rubbed into the skin until little or no residue remains on the skin.
  • the treatment is almost immediately effective to alleviate acute symptoms, and may be continued, for a predetermined period or indefinitely, to relieve pain, prevent the return of symptoms of small fiber neuropathies, and possibly restore some nerve and/or skin function.
  • a topical formulation of the composition used in the invention preferably includes an acceptable topical carrier.
  • Many acceptable topical carriers are known to those of skill in the art.
  • the compounds in the composition may be dissolved, dispersed and/or suspended in the topical carrier.
  • hydrophilic ointment bases are known to persons skilled in the art.
  • Exemplary hydrophilic ointment bases suitable for use in the present invention are non-U.S.P. hydrophilic ointment bases such as those made by Fougera, Inc., a division of Altana, Inc. of Melville, NY.
  • Sufficient hydrophilic ointment base is employed to act as a carrier for the compounds of the composition.
  • the hydrophilic ointment base will make up more than 80% of the total composition and more preferably 80-90% of the composition is the hydrophilic ointment base.
  • the hydrophilic ointment base functions as a carrier and preferably enhances penetration of the compounds into the skin.
  • One preferred topical carrier comprises hydroxymethyl cellulose.
  • Another preferred acceptable carrier includes a solution of an acrylic copolymer in a non- aqueous solvent system.
  • the non-aqueous solvent system preferably contains a polyethylene glycol such as, for example, methoxy polyethylene glycol 550 (MPEG).
  • MPEG methoxy polyethylene glycol 550
  • One preferred MPEG is Sentry Carbowax MPEG 550 (Dow Co ⁇ ., Midland, MI), which is suitable for use in foods, pharmaceuticals, and cosmetics.
  • the acrylic copolymer is preferably present in a concentration range of 3-6% by weight of solution. Also preferably, the acrylic copolymer has a molecular weight of more than 20,000.
  • the acrylic copolymer has a molecular weight of more than 100,000, to substantially prevent abso ⁇ tion of the acrylic copolymer by the human body through the skin.
  • the acceptable topical carrier independently provides benefits to the patient.
  • the topical carrier may comprise panthenol or a panthenol derivative.
  • the panthenol derivatives useful in the present invention include at least D-panthenol, DL-panthenol, and mixtures thereof. Panthenol provides skin moisturizing properties, acts as a quick, deep penetrating component of the carrier, helps deliver the compounds through the skin to the area to be treated, and may impart a healing effect to damaged tissue.
  • panthenol or panthenol derivative preferably ranges from 0.25 to 10 weight percent, more preferably from 0.5 to 5 weight percent, and, still more preferably, from 1 to 2 weight percent, based on the total weight of the topical composition.
  • the topical carrier of the present invention may employ other penetrants in addition to panthenol or as an alternative to panthenol.
  • Exemplary penetrants include ethanol, oleic acid, sodium lauryl sulfate, isopropyl myristate, glycerol monooleate, caprylic/capric triglyceride, Crodamol GTC/C, glyceryl tricaprylate/caprate, Miglyol 810, Miglyol 812, MCT oil, Neobee M5, Nesatol, oleum neutrale, oleum vegetable whatsoever, thin vegetable oil, light mineral oil, stearyl alcohol and lanolin mixed with suitable vegetable oils or with soft paraffin. These penetrants may have an emollient effect and facilitate the abso ⁇ tion of ingredients of the topical composition of the present invention into the skin.
  • the topical carrier of the present invention contains at least a hydrophilic ointment base, panthenol or a panthenol derivative, and one or more dispersants, if needed to disperse an insoluble or partially insoluble compounds in the carrier.
  • the topical carrier of the present invention may also include additional ingredients well known to persons skilled in the art, such as other carrier materials, other moisturizers, humectants, emollients, radiation blocking compounds, particularly UV-blockers, as well as other suitable materials that do not have a significant adverse effect on the activity of the topical composition in the amount used.
  • a preferred additional ingredient for inclusion in the carrier is sodium acid phosphate, a moisturizer.
  • the topical composition of the present invention is preferably made by cold compounding, when one or more of the compounds employed in the topical composition are known to be sensitive to heat. Thus, in some cases, the stability or activity of the composition may be detrimentally affected as a result of other formulation methods.
  • a sufficient amount of the topical carrier is used, to provide a substantially homogeneous cream or ointment. It may be necessary to dissolve, disperse or suspend one or more of the ingredients prior to formulation in order to ensure substantially homogeneous distribution of one or more of the ingredients in the composition.
  • dosages may vary with the manner of formulating the compounds.
  • the components of the composition which include the flavonoid and the optional antioxidant, will make up from 0.5-90% by weight of the total composition to provide the desired daily dosage.
  • the body weight dosages herein, when not normalized, are based on a patient having a body weight of 70 kg.
  • the appropriate unit dosage may be determined by dividing the daily dosage by the number of unit doses per day.
  • the at least one flavonoid of the present invention is administered in a safe and effective amount. Every pound of a preferred topical composition of the present invention preferably includes about 1 to about 150 grams of one or more flavonoids, about 0.1 to about 50 grams of non-flavonoid antioxidants, and other suitable ingredients such as topical carriers. Preferably, the flavonoid is used in an amount of about 2 to about 100 grams per pound of the composition. More preferably, the flavonoid is employed in an amount of about to about 10-50 grams per pound of the composition, and, still more preferably, about 15 to about 40 grams per pound of the composition.
  • the ratio of the amount of that compound to the amount of the flavonoid employed in the compositions of the present invention is from about 200 IU per gram of antioxidant to about 3 million IU per gram of flavonoid. More preferably, the composition contains about 1800 IU to about 1 million IU of nerve growth factor synthesis promoter per gram of flavonoid, and, still more preferably, about 5000 IU to about 200,000 IU of nerve growth factor synthesis promoter per gram of flavonoid.
  • the composition includes both vitamins A and D 3 , they are preferably formulated together in a corn oil dispersion.
  • each cubic centimeter (cc) or milliliter (mL) of the corn oil dispersion contains about 500,000 to about 2,000,000 IU of vitamin A and about 50,000 to about 200,000 IU of vitamin D 3 .
  • every milliliter of the corn oil contains about 800,000 to about 1,200,000 IU of vitamin A and about 80,000 IU to about 120,000 IU of vitamin D 3 .
  • the composition used in the invention contains about 1,000,000 IU and about 100,000 IU of vitamins A and D 3 , respectively.
  • an amount of about 6 to about 14.3 IU per kg of body weight of the patient for each administration More preferably, an amount of about 8 to about 14.3 IU per kg body weight of the patient, ' and, still more preferably, an amount of about 10 to about 13 IU is employed per kg of body weight of the patient, is administered.
  • the flavonoid is preferably used in an amount that provides substantially the same level of activity as a daily dose of about 13 to about 22 mg/kg bodyweight of quercetin. More preferably, the flavonoid is administered in an amount that provides substantially the same level of activity as a daily dose of about 17.2 to about 21.4 mg/ kg bodyweight of quercetin, and, still more preferably, an amount that provides substantially the same level of activity as a daily dose of about 18 to about 21 mg/kg bodyweight of quercetin.
  • about 11 to about 29 mg/kg bodyweight/day of ascorbyl palmitate may be administered. More preferably, about 14.3 to about 28.6 mg/kg bodyweight/day is administered.
  • the daily dosage is preferably about 4 to about 12 IU per kg bodyweight. More preferably, the daily dosage is about 5.7 to about 11.4 IU per kg bodyweight. Still more preferably, the daily dosage of mixed tocopherols is about 6 to about 10 IU per kg bodyweight.
  • an amount is administered that provides an equivalent effect as the above-described amounts of mixed tocopherols.
  • the daily dosage is preferably about 170 to about 360 IU per kg bodyweight per day. More preferably, the dosage is about 214.3 to about 357.1 IU per kg bodyweight per day. Still more preferably, the dosage is about 220 to about 340 IU per kg bodyweight per day.
  • Every pound of a preferred topical composition of the present invention preferably includes about 2 to about 50 grams of one or more flavonoids, about 1 to about 50 grams of non-flavonoid antioxidants, as well as other suitable ingredients such as topical carriers.
  • the witch hazel extract may be used in an amount of about 2.5 - 40 cc, more preferably of about 5 - 30 cc, and most preferably of about 10 - 20 cc per pound of topical base.
  • the glycerine humectant may be used in an amount of about 2-20 cc, more preferably of about 3.5 - 15 cc, and most preferably of about 5 - 10 cc per pound of topical base.
  • the apricot kernel oil may be used in an amount of about 0.5 - 5 cc, more preferably of about 0.5 - 4 cc, and most preferably of about 1 - 3 cc per pound of topical base.
  • the AJIDEWNL-50 NaPCA (50% aqueous solution) may be used in an amount of about 15 - 45 cc, more preferably of about 20 - 40 cc, and most preferably of about 25 - 35 cc per pound of topical base.
  • a more preferred topical composition of the invention can be made using the following ingredients: about 25 to about 35 cc of a 50% aqueous solution of AJIDEWNL-50 NaPCA (50% aqueous solution) moisturizing agent, about 5 to about 10 cc of D- or DL-panthenol, and about 10 to about 50 grams of quercetin powder.
  • hydrophilic ointment base As is well known in the art, larger amounts of one or more components, e.g. an antioxidant, can be employed while reducing the amount of another component of the same type or having a similar type of activity.
  • one or more components e.g. an antioxidant
  • about lOg/kg bodyweight of quercetin is used.
  • about 5g/kg bodyweight to about 25g/kg bodyweight, more preferably about 5g/kg bodyweight, of rutin are added to the composition.
  • about lOg to about 50g/kg bodyweight, more preferably about lOg/kg bodyweight, of glutathione are added to the composition.
  • compositions are substantially free of cinnamic acid derivatives of the formula:
  • groups X, Y and R independently of one another, can be chosen from the group consisting of H and branched or unbranched alkyl having 1-18 carbon atoms, acids thereof, and physiologically tolerated salts thereof.
  • EXAMPLE 1 A topical composition including a mixture of an hydrophilic ointment base, sodium acid phosphate moisturizing agent, and DL-panthenol, formulated together as the acceptable carrier, and further including quercetin was prepared by cold compounding.
  • the formulation of the composition is given in Table 1.
  • the formulation may optionally be supplemented with coenzyme Q10 (500mg) and may optionally contain another antioxidant,.
  • the composition was prepared by first placing the hydrophilic ointment base in a stainless steel bowl and mixing briskly until the ointment became creamy. The sodium acid phosphate, panthenol, quercetin, and other anti-oxidant, if any, were next added in that order. After each ingredient was added, mixing was continued until no traces of dry ingredients were visible and a substantially homogeneous mixture was obtained. The final color was a consistent yellow and the cream had the consistency of cake frosting. The mixture was stored in a sterile container. All containers and tools that contact the composition during mixing must also be sterilized with, for example, zephiran chloride, a bleach solution, or betadine.
  • This composition can be topically administered, under the supervision of a physician, to patients diagnosed with small fiber neuropathies.
  • the topical composition may be applied, for example, twice daily in the morning and afternoon, or up to six times daily, as needed for pain relief, over a period of a few days. Treated patients are predicted to experience positive results that will last up to a day or two after treatment is discontinued.
  • Examples 2 through 7 Other combinations of compounds suitable for use in the methods of the invention are set forth in Examples 2 through 7.
  • the compounds may be combined with about lib of hydrophilic ointment base for topical administration.
  • EXAMPLE 2 A topical composition was formulated using the ingredients listed in Table 2 below.
  • the composition of Table 2 was topically administered three times per day over a period of 4 weeks to 24 patients suffering from diabetic neuropathy in at least one foot as a result of having Type 1 or Type 2 diabetes mellitus in a placebo- controlled, double blind proof of concept study conducted in France. 12 patients received a placebo consisting of the composition of Table 2 except that the ascorbyl palmitate and quercetin dihydrate were left out. Eligible patients were screened using the Michigan Neuropathy Screening Instrument (MNSI), Feldman, E ., et al, "A Practical Two-Step Quantitative Clinical and Elecfrophysiological Assessment for the Diagnosis and Staging of Diabetic Neuropathy," Diabetes Care, 19 , pp. 1281-1289.
  • MNSI Michigan Neuropathy Screening Instrument
  • Feldman E ., et al, "A Practical Two-Step Quantitative Clinical and Elecfrophysiological Assessment for the Diagnosis and Staging of Diabetic Neuropathy," Diabetes Care, 19 , pp. 1281-1289.
  • the results of the test were positive.
  • the formulation produced a significant decrease of diabetic peripheral neuropathy pain and discomfort, and an improvement in the appearance and texture of the skin, including reduced dryness.
  • a similar formulation without ascorbyl palmitate was also effective on diabetic skin and aging skin, as well as providing relief from the discomfort of diabetic peripheral neuropathy and small fiber peripheral neuropathy.
  • Vitamin E acetate lcc
  • Vitamin E acetate lcc
  • Vitamin E acetate lcc

Abstract

Compositions and methods for the treatment of peripheral neural and vascular ailments are disclosed. The method comprises administering a flavonoid compound with antioxidant properties, optionally formulated in a pharmaceutically acceptable carrier. This compound or combination of compounds provides significant, effective relief of the symptoms of peripheral neural or vascular ailments. In addition, the compositions, when used according to the methods of the present invention, do not exhibit the severe side effects of many prior art compositions proposed for treatment of these ailments.

Description

METHODS FOR THE TREATMENT OF PERIPHERAL NEURAL AND VASCULAR AILMENTS
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to compositions and methods for the treatment of peripheral neural and vascular ailments. In the methods of the present invention, a flavonoid is administered to a patient suffering from a peripheral neural or vascular ailment.
2. Brief Description of the Prior Art The phrases "peripheral neuropathies" and "small fiber neuropathies" are used interchangeably herein to refer to a set of conditions characterized by functional changes or pathological changes, or both, in the small, unmyelinated nerve fibers of the peripheral nervous system. For the purpose of this application, diabetic neuropathy is not included among the peripheral small fiber neuropathies. Peripheral or small fiber neuropathies may be caused by any of about a hundred identified factors that can produce nerve damage. The cause may be metabolic, for example hypertriglyceridemia or pellagra. ' Toxic exposures may also cause small fiber neuropathies, for example those resulting from alcoholism, excessive doses of vitamin B6, exposure to toxic metals such as thallium, or exposure to certain chemotherapeutic agents, such as vinca alkaloids. Certain congenital conditions, including amyloidosis, an-α-lipoproteinemia (Tangier's), and - galactosidase (Fabry's), are known to cause small fiber neuropathies. Small fiber neuropathies may result from infections such as leprosy, or diseases such as AIDS, herpes simplex, herpes zoster (shingles), cytomegalovirus, hepatitis B and C, Lyme disease, autoimmune diseases, Fabry disease, diphtheria, vasculitis, and porphyria. In approximately 15% of cases, the cause of the small fiber neuropathy cannot be determined. The neuropathy is then referred to as idiopathic.
Patients afflicted with peripheral neuropathies have pain in their extremities. The pain may at first be perceived as a tingling sensation in the fingers or toes. Decreased sensitivity to heat or cold is also a common early symptom. Frequently, however, a physical examination will show that the patient's reflexes, strength, sensory levels, and electrophysiology are normal. This has historically complicated the diagnosis of peripheral neuropathies, or led to underdiagnosis, especially in the early stages of the neuropathies. Recent technology, however, including skin biopsies and measurement of the density of different nerve fiber types in the epidermis, has improved the likelihood of detecting peripheral neuropathies.
Small fiber or peripheral neuropathies tend to progress by spreading upward, and patients may develop intense pain and/or a burning sensation that can be so severe as to be debilitating. Other symptoms of these neuropathies include cold hands or feet, cramps, muscle weakness and/or atrophy, eventual loss of perception of pressure, pain and/or temperature, neuropathic ulcers, lack of sweating, dry eyes, dry mouth, impotence, and restless leg syndrome.
In some cases, treatment of the underlying cause may also reverse or alleviate small fiber neuropathies. When the underlying cause is unidentifiable or otherwise untreatable, however, treatment consists of reducing the symptoms of the neuropathies, typically by administering medications known to decrease pain from neuropathy and related conditions. These medications include tricyclic antidepressants, anticonvulsants, opioid medications, and local anesthetics applied to the painful area. An afflicted patient may also undergo physical and occupational therapy to improve mobility and function.
Often, the symptoms of peripheral neuropathies do not vary due to their underlying causes. For example, a neuropathy caused by exposure to chemotherapeutic agents may present symptoms almost identical to those of a neuriopathy caused by Lyme disease. As a further example, diabetic neuropathy, is a fairly common long-term complication of diabetes mellitus that shares many of the symptoms of peripheral neuropathies. The cause of diabetic neuropathy, however, is believed to be a chronic systemic excess of the glucose metabolite sorbitol. Further, treating the underlying cause of diabetic neuropathy, that is, improving glycemic control, will often prevent the symptoms from worsening. Diabetic neuropathy is also known to be reversible, if good glycemic control is instituted while the condition is in its early stages.
Peripheral Neuropathies, including diabetic neuropathies, can also impair circulation in the affected area. Impaired circulation can adversely affect the appearance of the skin. Adverse effects on the appearance of the skin caused by radiation injury can include, for example, redness, discoloration, dryness of the skin. "Peripheral vascular diseases" are diseases of the blood vessels outside the heart that lead to restriction or blockage of the blood vessels. Atherosclerosis, when it affects the extremities rather than the coronary arteries, is an example of a peripheral vascular disease. Peripheral vascular diseases may also be long-term complications of other diseases, such as Raynaud's disease, Raynaud's phenomenon, hypertension, or Buerger's disease (thromboangitis obliterans).
An early symptom of peripheral vascular disease includes pain upon exercising that is relieved by rest. These diseases are progressive, however, and patients may also experience numbness, muscle weakness or pain, loss of hair on the affected extremities, cyanosis, weak or absent pulse in the affected extremities, gait abnormalities, pain when resting, skin ulcers, and, eventually gangrene. Impaired circulation caused by peripheral vascular disease can also adversely affect the appearance of the skin. Adverse effects on the appearance of the skin caused by radiation injury can include, for example, redness, discoloration, dryness of the skin. In general, an agent that promotes or induces angiogenesis, or one that at least partially clears blocked or restricted vessels, or one that will facilitate peripheral circulation by other means, i.e. by decreasing cellular adhesion, will be effective to treat peripheral vascular diseases.
Decreased rnicrocirculation is also a long-term complication of diabetes. In general, a therapy that is effective for peripheral vascular diseases will also be effective to counter decreased rnicrocirculation caused by diabetes. There remains a need for a treatment for small fiber neuropathies that is clinically effective when the underlying cause of the neuropathy is unknown. A need also remains for an effective treatment for small fiber neuropathies that does not suffer from the disadvantage of causing severe side effects. In addition, there remains a need for a clinically effective treatment of peripheral vascular ailments.
Accordingly, it is an object of certain embodiments of the present invention to provide a method that is effective for the treatment of small fiber neuropathies and peripheral vascular ailments. It is another object of certain embodiments of the present invention to provide a method for the treatment of small fiber neuropathies or peripheral vascular ailments by administering a composition that does not cause severe side effects in the patient.
It is another object of certain embodiments of the present invention to provide a composition for the treatment of peripheral neuropathies or peripheral vascular ailments.
These and other objects of the present invention will be apparent from the summary and detailed descriptions of the invention that follow.
SUMMARY OF THE INVENTION The present invention provides a method for the treatment of peripheral neural and vascular ailments by administering a composition including a therapeutically effective amount of a flavonoid having antioxidant properties, and, optionally, an acceptable carrier.
In another embodiment, the invention relates to a composition for treating peripheral neural and vascular ailments. The composition comprises a therapeutically effective amount of a mixture of a flavonoid having antioxidant properties, a therapeutically effective amount of a non-flavonoid antioxidant compound, and, optionally, an acceptable carrier. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The compositions and methods of the invention provide significant, effective relief of symptoms of peripheral neural and vascular ailments, as well as partial recovery of lost rnicrocirculation or neurological function in some cases. Surprisingly, the efficacy of the invention is not dependent on the underlying causes of the peripheral neural and vascular ailments. In addition, the composition used in the method of the invention, when administered in a therapeutically effective amount to treat peripheral neural and vascular ailments, does not cause severe side effects. The topical compositions and methods of the invention also treat adverse effects on the appearance of the skin caused by peripheral neuropathies and/or peripheral vascular disease. These cosmetic benefits are obtained in patients having such disorders. Adverse effects on the appearance of the skin include, for example, redness, discoloration, dryness. Such cosmetic effects are intended to be included within the meaning of "treating ailments," although the effects relate to the appearance of skin in people using the composition and methods, Thus, the invention treats or cosmetically improves the appearance of persons having peripheral or neural vascular ailments by, for example, reducing or preventing redness of skin, reducing or preventing discoloration of skin, beautifying skin, improving appearance of skin, promoting attractiveness of skin, cleansing skin, removing dead or damaged skin or skin cells from skin and moisturizing skin.
The oral compositions and methods of the invention also provide nutritional and/or dietary benefits. These nutritional or dietary cosmetic benefits are obtained in patients having peripheral neuropathies and/or peripheral vascular disease. Such nutritional or dietary effects are also intended to be included within the meaning of "treating ailments." Thus, the invention offers dietary or nutritional benefits in supporting and/or maintaining neural, vascular and muscular health, maintains sensory integrity, i.e. sensations of hot and cold, and supports the maintenance of skin health.
The term "derivatives," as used herein, refers to structurally similar compounds that exhibit a common activity (e.g., antioxidant) and contain at least one significant, common structural element with the compound from which it is derived, which common structural element provides the common activity.
The expression "therapeutically effective amount," as used herein, refers to a nontoxic amount of a compound which is sufficient to provide the desired therapy to counteract small fiber neuropathies or peripheral vascular diseases. A therapeutic amount may, for example, reduce pain, reverse sensory fiber loss or demyelination, promote angiogenesis, increase rnicrocirculation, or increase sensory perception. The exact amount required may vary, depending on the species, age, and general condition of the patient, the nature of the complications, the particular combination of compounds, the mode of administration, and the like. The term "therapeutically" is intended to encompass beneficial cosmetic effects and effects of improved nutrition as well as medical effects.
The compositions used in the method of the present invention include at least one flavonoid. Flavonoids are small organic compounds having a phenyl benzopyrone structure. They are found in the leaves, fruits, seeds, stems, or flowers of all vascular plants. Citrus fruits are a prominent source of flavonoids, over 4000 of which have been identified as deriving from plant sources. On average, the daily Western diet contains about one gram of mixed flavonoids.
Examples of flavonoids include, without limitation, flavonones, flavonols, anthocyanidins, proanthocyanidins, procyanidolic oligomers, biflavans, polyphenols, rutinosides, hydroxyethylrutinosides, and leucoanthocyanins.
Suitable flavonoids for use in the present invention include those that do not induce significant, adverse side effects when administered to a mammal in a therapeutically effective amount, and that do not react with any of the other ingredients of the composition used in the present invention to cause a substantial loss of activity of one or more compounds of the composition. Preferred flavonoids are obtained from natural sources. However, derivatives of such compounds may also be suitable for use in the present invention. Preferred flavonoids may be administered to humans without significant, adverse side effects when used in therapeutically effective amounts. The selection of the flavonoid(s) included in the composition may be determined by factors such as toxicity, bioavailability, solubility or dispersability, and the like. Examples of flavonoids suitable for use in the present invention include, without limitation, (-)-epigallocatechin; (-)-epigallocatechin-gallate; 1,2,3,6-tetra-o- gallyol-β-d-glucose; 2'-o-acetylacetoside; 3,3',4-tri-o-methyl-ellagic acid; 6,3',4'- trihydroxy-5,7,8-trimethoxyflavone; 6-hydroxy-luteolin; 6-hydroxykaempferol-3,6- dimethyl ether; 7-o-acetyl-8-epi-loganic acid; acacetin; acetoside; acetyl trisulfate quercetin; amentoflavone; apigenin; apiin; astragalin; avicularin; axillarin; baicalein; brazilin; brevifolin carboxylic acid; caryophyllene; catechin; chrysin; chrysin-5,7- dihydroxyflavone; chrysoeriol; chrysosplenol; chrysosplenoside-a; chrysosplenoside- d; cosmosiin; δ-cadinene; curcumin; cyanidin; dihydroquercetin; dimethylmussaenoside; diacerylcirsimaritin; diosmin; diosmetin; dosmetin; ellagic acid; ebinin; epicatechin; ethyl brevifolin carboxylate; flavocannibiside; flavosativaside; galangin; gallic acid; genistein; ginkgo flavone glycosides; ginkgo heterosides; gossypetin; gossypetin-8-glucoside; haematoxylin; hesperidine; hispiduloside; hyperin; indole; iridine; isoliquiritigenin; isoliquiritin; isoquercitrin; jionoside; juglanin; kaempferol; kaempferol-3-rhamnoside; kaempferol-3- neohesperidoside; kolaviron; licuraside; linariin; linarin; lonicerin; luteolin; luteolin- 7-glucoside; luteolin-7-glucoronide; macrocarpal-a; macrocaφal-b; macrocarpal-d; macrocaφal-g; maniflavone; morin; methyl scutellarein; monoHER, diHER, triHER, tetraHER, myricetin; naringenin; naringin; nelumboside; nepetin; nepetrin; nerolidol; oligomeric proanthocyanidins; oxyayanin-a; pectolinarigenin; pectolinarin; pelargonidin; phloretin, phloridzin, polyphenols, including green tea polyphenols; quercetagetin; quercetin; quercimertrin; quercitrin; quercitryl-2" acetate; reynoutrin; rhamnetin; rhoifolin; rutin; scutellarein; sideritoflavone; silibin; silydianin; silychristine; silymarin; sophoricoside; sorbarin; spiraeoside; taxufolin; trifolin; vitexin; and wogonin, and the pharmaceutically acceptable salts ; solvates; and derivatives of these compounds.
Preferred flavonoids are those that also have strong antioxidant properties. Examples of preferred flavonoids include, without limitation, (-)-epigallocatechin-3- gallate, catechin, rutin, quercetin, quercitrin, myricetin, kaempferol, myrecetrin luteolin, morin, fisetin, silymarin, apigenin, hesperitin, hesperidin, citrin, gossypetin, chrysin, oligomeric proanthocyanidins, biacalein, curcumin, gallic acid, epicatechin, dihydroquercetin, ginkgo flavone glycosides, ginkgo heterosides, silibin, silydianin silychristine, galangin, monoHER, diHER, triHER, tetraHER, naringenin, naringin, taxifolin, diosmin, phloretin, phloridzin, cyanidin, pelargonidin and derivatives thereof, and the pharmaceutically acceptable salts of these compounds.
More preferred flavonoids include, without limitation, quercetin, quercitrin, myricetin, rutin, kaempferol and myrecetrin. These compounds exhibit good antioxidant properties in combination with relatively low toxicity. Advantageously, flavonoids and flavonoid derivatives may provide additional beneficial effects in the composition of the present invention. For example, quercetin acts as a chelator for transition metals. Flavonoids are also believed to possess anti- inflammatory activity and to assist in the stabilization of cell membranes, both activities that promote the treatment of small fiber neuropathies. Quercetin is also believed to have anticlastogenic properties. In addition, some flavonoids and flavonoid derivatives act as radical scavengers, reducing the concentration of hydroxyl radicals, for example, and thereby further enhancing the antioxidant effect of the composition used in the present invention.
Suitable non-flavonoid antioxidants for use in the present invention include those that exhibit antioxidant activity without causing any severe adverse side affects when administered in a therapeutically effective amount, and that do not react with any of the other ingredients of the composition used in the present invention to cause a substantial loss of activity of one or more compounds. Preferred antioxidants include those that occur naturally in the human body and materials obtained from plants or animals, or derivatives of such compounds.
Preferred non-flavonoid antioxidants include, without limitation, ascorbyl palmitate, ascorbic acid (vitamin C), vitamin A, vitamin E and its pharmaceutically acceptable esters (including but not limited to the acetate), α-lipoic acid, especially DL- α-lipoic acid, coenzyme Q10, glutathione (GSH), galangin, gingkolides, tocotrienols, carotenoids, cyanidin, curcuminoids, and derivatives thereof which exhibit antioxidant activity. More preferably, mixtures of two or more antioxidants are employed in the composition used in the present invention. Derivatives of one or more of these compounds that exhibit antioxidant activity when administered in the compositions of the present invention may also be employed. The antioxidants may also be used in the form of their pharmaceutically acceptable salts. The salts may be preferred in some cases, for example to increase solubility or dispersability, or to reduce adverse side effects.
In a preferred embodiment, the antioxidant used in the composition of the present invention may comprise one or more antioxidant enzymes. The antioxidant enzymes useful in the present invention are those capable of scavenging radicals, of promoting radical scavengers or preventing radical formation. One or more of these antioxidant enzymes may act synergistically with one or more of the other antioxidants in the composition to scavenge free radicals more effectively and thereby aid in the prevention of cell damage in the skin. In a more preferred embodiment, the antioxidant enzyme used in the present invention is capable of absoφtion through the skin. Preferred antioxidant enzymes for use in the present invention include superoxide dismutase, catalase, glutathione peroxidase, methionine reductase, and the like.
In a more preferred embodiment, both quercetin and an antioxidant are included in the composition of the present invention. This combination of quercetin and an antioxidant results in an enhanced anti-oxidative effect. The antioxidant may be a flavonoid or a non-flavonoid.
Other compounds may also be included in the composition of the present invention to provide additional benefits, such as absorbability when applied topically, free radical scavenging, transition metal chelation, nitric oxide stabilization, analgesia, and anti-inflammatory activity. Some of these properties may have a beneficial effect on the pain of other related disorders such as fibromyalgia. Additional materials that may optionally be included in the compositions used in the present invention include inositol and other B-complex vitamins. Some preferred compositions used in the invention also contain vitamin D , a vitamin D3 analog, a compound that may be converted or metabolized into vitamin D3 in the human body, or a metabolite of vitamin D3.
Vitamin D3, also known as cholecalciferol, may be further converted into another vitamin D intermediate, 25-hydroxycholecalciferol, in the liver by rnitochondrial hydroxylase, in the presence of NADPH, and molecular oxygen.
Figure imgf000011_0001
When a more active form of vitamin D3 is required, 25-hydroxycholecalciferol is transported to the kidney where a new hydrolase enzyme is synthesized. This enzyme introduces another hydroxyl group at position 1, and the bioactive form of vitamin D3, calcitriol, is produced.
Figure imgf000011_0002
Calcitriol
An exemplary vitamin D3 analog is 1(S), 3(R)-dihydroxy-20(R)-(l-ethoxy-5- ethyl-5-hydroxy-2-heptyn-l-yl)-9, 10-seco-pregna-5(Z), 7(E), 10 (19)-triene. An exemplary vitamin D3 metabolite is 1, 25-dihydroxyvitamin D3. Pharmaceutically acceptable salts of vitamin D3 and its derivatives and metabolites may be employed in the methods of the present invention. Vitamin D3 is particularly preferred for use in the present invention. A dispersant may be necessary to facilitate the formulation of the vitamin D3 or related compound. Suitable dispersants are well known to persons skilled in the art. Corn oil is one dispersant that is well suited for vitamin D3 and related compounds. Also advantageously, corn oil is a natural product. The corn oil is used in an amount sufficient to disperse the vitamin D3 or related compound.
The compositions used in the present invention may provide one or more of the following localized or systemic beneficial effects to a patient when administered in therapeutically effective amounts: relief of pain, burning, tingling, electrical sensations and/or hyperalgesia; increased rnicrocirculation; nitric oxide stabilization; promotion of healing of skin ulcers and lesions; protein kinase C inhibition; decreased oxidative stress; anti-inflammatory activity; blockage of the formation of leukotrienes; stabilization of cell membranes; and promotion of the synthesis of nerve growth factor.
Compositions in accordance with the invention can provide additional effects of improving the appearance of the skin. Skin appearance may be adversely affected by peripheral neuropathies, including diabetic neuropathy, and/or peripheral vascular disease, or by other causes unrelated to the peripheral neuropathies and/or peripheral vascular disease being treated. One or more of the following beneficial properties may be realized when compositions of the invention are topically applied in an effective amount: reducing or preventing redness of skin, reducing or preventing discoloration of skin, beautifying skin, improving appearance of skin, promoting attractiveness of skin, cleansing skin, removing dead or damaged skin or skin cells from skin and moisturizing skin.
Without wishing to be held to a particular theory, there are several physiological processes that might be affected by an effective treatment for small fiber neuropathies. For example, an effective treatment might cause the degeneration of peripheral nerves to slow or to stop. Alternatively, an effective treatment might induce healing or regeneration of the damaged nerves. An effective treatment might also cause the generation of new nerves to replace the damaged nerves. It is therefore expected that effective treatments for small fiber neuropathies will be applicable to other diseases or conditions affecting peripheral nerves. A method of regenerating nerves is beneficial to treat any patient suffering from nerve damage, for example, a skin graft patient or a victim of a nerve-severing trauma. In fact, many flavonoids are potent aldose reductase inhibitors. It has been shown that the oral administration of aldose reductase inhibitors increases the diameter of peripheral nerve bundles. Thus, it is expected that the methods of the present invention extend to the generation and regeneration of nerves.
Although the underlying cause of diabetic neuropathy is specifically known to be distinct from the other causes of small fiber neuropathies, the symptoms and pathologies are shared. It is therefore expected that an effective treatment for small fiber neuropathies will arrest, reverse, or alleviate certain symptoms of diabetic neuropathy. It has also been found that for treatment of diabetic neuropathy, the optional component, vitamin D3 or a derivative or metabolite thereof, may be excluded from the composition and the composition will still provide a beneficial effect, provided the composition includes other suitable components. Flavonoids promote rnicrocirculation and therefore can also be used to treat peripheral vascular diseases. For example, the flavonoid quercetin supports vascular functioning in general, and therefore is an effective treatment for peripheral vascular diseases. Decreased rnicrocirculation is believed to be caused at least in part by oxidative stress resulting from an excess of free radicals. Quercetin, an example of a flavonoid with antioxidant properties, is therefore an effective treatment for this condition. The chelating properties of flavonoids such as quercetin contribute to its effectiveness. The overabundance of sorbitol in the bloodstream of diabetic patients attracts metal ions, which are sequestered by chelation.
The compositions used in the present invention are preferably formulated with an acceptable carrier. The non-carrier ingredients may be combined with the carrier materials to produce a particular dosage form, or be customized for a particular treatment regimen. Thus, the amount of each ingredient may vary depending on such factors as the particular mode of administration, the activity of the particular compounds employed, the age, bodyweight, general health, sex, and diet of the patient, time of administration, rate of excretion, the combination of compounds, or the severity of the illness, among other potential factors. A standard reference text on pharmaceutical formulations, Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co. 1990, is incoφorated herein by reference in its entirety.
It is well known in the art that the individual ingredients in formulated products may interact with each other. These interactions include, for example, chemical equilibria and other chemical or physical processes. These interactions may cause the original individual components of a formulated product to change over time. Such changes may be chemical or physical. For example, an acidic component may become deprotonated in a formulation that also contains a basic component. Alternatively, one or more components may precipitate or crystallize from a formulated product. Equilibria and other processes may be expected to increase in number and complexity with increasing numbers of components in a given formulation. Such equilibria and other processes may be either innocuous or deleterious to the activity of the formulated product. The term "stable" as used herein refers to the property of retaining at least a portion of the intended activity over a certain period of time.
The terms "mixture," "composition" and "formulation" as used herein refer to stable mixtures, compositions, and formulations, respectively. Preferred mixtures, compositions, and formulations are stable over a period of at least about three months. In the method of the present invention, the composition may be administered via several routes, including, without limitation, topically, orally, via an implanted reservoir, or by inhalation.
In a method of the invention, the composition is administered orally. An oral composition for use in the invention may be administered one to six times daily, or as needed to relieve pain and other symptoms of the small fiber neuropathies.
Preferably, when administered orally, the composition is administered two to four times daily, as needed for pain. A sufficient amount should be administered to provide one or more of the beneficial effects of the compositions described above. The method initially treats acute symptoms but may be continued indefinitely to relieve pain, prevent symptoms from returning and possibly restore some nerve and/or skin function. The oral compositions and methods of the invention also function as dietary or nutritional supplements. In this aspect of the invention, oral compositions and methods can maintain and/or support neural health, maintain and/or support vascular health and circulation, maintain and/or support muscular health, maintain sensory integrit, i.e. sensations of hot and cold, and support the health of the skin.
The oral compositions used in the present invention may be orally administered in any acceptable dosage form including, but not limited to, capsules, tablets, lozenges, troches, hard candies, powders, sprays, elixirs, syrups, and suspensions or solutions. Suitable acceptable carriers for tablets include lactose and corn starch, for example. Lubricating agents may also be added to the tablets, including, for example, magnesium stearate, sodium lauryl sulfate and talc. Tablets may also contain excipients such as sodium citrate, calcium carbonate and calcium phosphate. Disintegrants such as starch, alginic acid and complex silicates, may also be employed. Tablets may also include binding agents such as polyvinylpyrrolidone, gelatin and gum acacia.
The composition used in the invention may be administered in capsule form, with or without diluents. Useful diluents for capsules include, without limitation, lactose and dried cornstarch. In addition, solid compositions similar to those of the tablets described above may be administered in soft and hard gelatin capsules.
The compositions used in the invention may be administered orally as encapsulated or unencapsulated suspensions, and they may comprise emulsifying and/or suspending agents such as are well known to those of skill in the art. Ancillary ingredients such as sweeteners, flavorants, coloring agents, dyes, and diluents such as water, ethanol, propylene glycol, glycerin and various combinations thereof may also be included in the oral formulations.
The compositions used in the present invention may also be administered by nasal aerosol or by inhalation. Appropriate formulations may be prepared using well- known techniques. For this method of administration, suitable carriers include, for example, saline and/or other conventional solubilizing or dispersing agents, optionally formulated with one or more preservatives, absoφtion promoters to enhance bioavailability, and/or fluorocarbons.
In a preferred method of the present invention, the composition is applied topically to an area of the skin in the vicinity of tissue that suffers from small fiber neuropathy in order to relieve pain and other symptoms of the small fiber neuropathy.
Such areas typically include the patients' extremities, such as the fingers, toes, hands and feet, where neuropathy is often most pervasive.
Preferably, a suitable amount of the topical composition of the invention is applied one to six times daily, as needed. More preferably, the topical composition is applied two to four times daily, as needed. Also preferably, a sufficient amount of the topical composition is applied to cover the afflicted area with a thin layer of the composition and the composition is rubbed into the skin until little or no residue remains on the skin. The treatment is almost immediately effective to alleviate acute symptoms, and may be continued, for a predetermined period or indefinitely, to relieve pain, prevent the return of symptoms of small fiber neuropathies, and possibly restore some nerve and/or skin function.
A topical formulation of the composition used in the invention preferably includes an acceptable topical carrier. Many acceptable topical carriers are known to those of skill in the art. The compounds in the composition may be dissolved, dispersed and/or suspended in the topical carrier.
Suitable hydrophilic ointment bases are known to persons skilled in the art. Exemplary hydrophilic ointment bases suitable for use in the present invention are non-U.S.P. hydrophilic ointment bases such as those made by Fougera, Inc., a division of Altana, Inc. of Melville, NY. Sufficient hydrophilic ointment base is employed to act as a carrier for the compounds of the composition. Typically the hydrophilic ointment base will make up more than 80% of the total composition and more preferably 80-90% of the composition is the hydrophilic ointment base. The hydrophilic ointment base functions as a carrier and preferably enhances penetration of the compounds into the skin. One preferred topical carrier comprises hydroxymethyl cellulose. Another preferred acceptable carrier includes a solution of an acrylic copolymer in a non- aqueous solvent system. The non-aqueous solvent system preferably contains a polyethylene glycol such as, for example, methoxy polyethylene glycol 550 (MPEG). One preferred MPEG is Sentry Carbowax MPEG 550 (Dow Coφ., Midland, MI), which is suitable for use in foods, pharmaceuticals, and cosmetics. The acrylic copolymer is preferably present in a concentration range of 3-6% by weight of solution. Also preferably, the acrylic copolymer has a molecular weight of more than 20,000. More preferably, the acrylic copolymer has a molecular weight of more than 100,000, to substantially prevent absoφtion of the acrylic copolymer by the human body through the skin. Preferably, the acceptable topical carrier independently provides benefits to the patient. For example, the topical carrier may comprise panthenol or a panthenol derivative. The panthenol derivatives useful in the present invention include at least D-panthenol, DL-panthenol, and mixtures thereof. Panthenol provides skin moisturizing properties, acts as a quick, deep penetrating component of the carrier, helps deliver the compounds through the skin to the area to be treated, and may impart a healing effect to damaged tissue. The amount of panthenol or panthenol derivative preferably ranges from 0.25 to 10 weight percent, more preferably from 0.5 to 5 weight percent, and, still more preferably, from 1 to 2 weight percent, based on the total weight of the topical composition. The topical carrier of the present invention may employ other penetrants in addition to panthenol or as an alternative to panthenol. Exemplary penetrants include ethanol, oleic acid, sodium lauryl sulfate, isopropyl myristate, glycerol monooleate, caprylic/capric triglyceride, Crodamol GTC/C, glyceryl tricaprylate/caprate, Miglyol 810, Miglyol 812, MCT oil, Neobee M5, Nesatol, oleum neutrale, oleum vegetable tenue, thin vegetable oil, light mineral oil, stearyl alcohol and lanolin mixed with suitable vegetable oils or with soft paraffin. These penetrants may have an emollient effect and facilitate the absoφtion of ingredients of the topical composition of the present invention into the skin.
Preferably, the topical carrier of the present invention contains at least a hydrophilic ointment base, panthenol or a panthenol derivative, and one or more dispersants, if needed to disperse an insoluble or partially insoluble compounds in the carrier.
The topical carrier of the present invention may also include additional ingredients well known to persons skilled in the art, such as other carrier materials, other moisturizers, humectants, emollients, radiation blocking compounds, particularly UV-blockers, as well as other suitable materials that do not have a significant adverse effect on the activity of the topical composition in the amount used. A preferred additional ingredient for inclusion in the carrier is sodium acid phosphate, a moisturizer. The topical composition of the present invention is preferably made by cold compounding, when one or more of the compounds employed in the topical composition are known to be sensitive to heat. Thus, in some cases, the stability or activity of the composition may be detrimentally affected as a result of other formulation methods. Preferably, a sufficient amount of the topical carrier is used, to provide a substantially homogeneous cream or ointment. It may be necessary to dissolve, disperse or suspend one or more of the ingredients prior to formulation in order to ensure substantially homogeneous distribution of one or more of the ingredients in the composition.
As noted above, dosages may vary with the manner of formulating the compounds. In general, the components of the composition, which include the flavonoid and the optional antioxidant, will make up from 0.5-90% by weight of the total composition to provide the desired daily dosage. The body weight dosages herein, when not normalized, are based on a patient having a body weight of 70 kg. The appropriate unit dosage may be determined by dividing the daily dosage by the number of unit doses per day.
The at least one flavonoid of the present invention is administered in a safe and effective amount. Every pound of a preferred topical composition of the present invention preferably includes about 1 to about 150 grams of one or more flavonoids, about 0.1 to about 50 grams of non-flavonoid antioxidants, and other suitable ingredients such as topical carriers. Preferably, the flavonoid is used in an amount of about 2 to about 100 grams per pound of the composition. More preferably, the flavonoid is employed in an amount of about to about 10-50 grams per pound of the composition, and, still more preferably, about 15 to about 40 grams per pound of the composition. When vitamin D or a derivative or metabolite thereof is used in the composition, the ratio of the amount of that compound to the amount of the flavonoid employed in the compositions of the present invention is from about 200 IU per gram of antioxidant to about 3 million IU per gram of flavonoid. More preferably, the composition contains about 1800 IU to about 1 million IU of nerve growth factor synthesis promoter per gram of flavonoid, and, still more preferably, about 5000 IU to about 200,000 IU of nerve growth factor synthesis promoter per gram of flavonoid. When the composition includes both vitamins A and D3, they are preferably formulated together in a corn oil dispersion. Generally, each cubic centimeter (cc) or milliliter (mL) of the corn oil dispersion contains about 500,000 to about 2,000,000 IU of vitamin A and about 50,000 to about 200,000 IU of vitamin D3. Preferably, every milliliter of the corn oil contains about 800,000 to about 1,200,000 IU of vitamin A and about 80,000 IU to about 120,000 IU of vitamin D3. More preferably, the composition used in the invention contains about 1,000,000 IU and about 100,000 IU of vitamins A and D3, respectively. When a composition including vitamin D or derivative or metabolite of vitamin D3 is administered, the vitamin D3 or derivative or metabolite of vitamin D3 is used in a safe and effective amount. More preferably, an amount of about 6 to about 14.3 IU per kg of body weight of the patient for each administration. More preferably, an amount of about 8 to about 14.3 IU per kg body weight of the patient, ' and, still more preferably, an amount of about 10 to about 13 IU is employed per kg of body weight of the patient, is administered.
The flavonoid is preferably used in an amount that provides substantially the same level of activity as a daily dose of about 13 to about 22 mg/kg bodyweight of quercetin. More preferably, the flavonoid is administered in an amount that provides substantially the same level of activity as a daily dose of about 17.2 to about 21.4 mg/ kg bodyweight of quercetin, and, still more preferably, an amount that provides substantially the same level of activity as a daily dose of about 18 to about 21 mg/kg bodyweight of quercetin.
About 11 to about 29 mg/kg bodyweight/day of ascorbyl palmitate may be administered. More preferably, about 14.3 to about 28.6 mg/kg bodyweight/day is administered.
When vitamin E is administered in the form of mixed tocopherols, the daily dosage is preferably about 4 to about 12 IU per kg bodyweight. More preferably, the daily dosage is about 5.7 to about 11.4 IU per kg bodyweight. Still more preferably, the daily dosage of mixed tocopherols is about 6 to about 10 IU per kg bodyweight. When vitamin E is administered in another form, an amount is administered that provides an equivalent effect as the above-described amounts of mixed tocopherols. When vitamin A is administered, the daily dosage is preferably about 170 to about 360 IU per kg bodyweight per day. More preferably, the dosage is about 214.3 to about 357.1 IU per kg bodyweight per day. Still more preferably, the dosage is about 220 to about 340 IU per kg bodyweight per day.
Every pound of a preferred topical composition of the present invention preferably includes about 2 to about 50 grams of one or more flavonoids, about 1 to about 50 grams of non-flavonoid antioxidants, as well as other suitable ingredients such as topical carriers. The witch hazel extract may be used in an amount of about 2.5 - 40 cc, more preferably of about 5 - 30 cc, and most preferably of about 10 - 20 cc per pound of topical base. The glycerine humectant may be used in an amount of about 2-20 cc, more preferably of about 3.5 - 15 cc, and most preferably of about 5 - 10 cc per pound of topical base. The apricot kernel oil may be used in an amount of about 0.5 - 5 cc, more preferably of about 0.5 - 4 cc, and most preferably of about 1 - 3 cc per pound of topical base. The AJIDEWNL-50 NaPCA (50% aqueous solution) may be used in an amount of about 15 - 45 cc, more preferably of about 20 - 40 cc, and most preferably of about 25 - 35 cc per pound of topical base.
A more preferred topical composition of the invention can be made using the following ingredients: about 25 to about 35 cc of a 50% aqueous solution of AJIDEWNL-50 NaPCA (50% aqueous solution) moisturizing agent, about 5 to about 10 cc of D- or DL-panthenol, and about 10 to about 50 grams of quercetin powder.
The above amounts are appropriate for combination with one pound of hydrophilic ointment base. As is well known in the art, larger amounts of one or more components, e.g. an antioxidant, can be employed while reducing the amount of another component of the same type or having a similar type of activity.
In a preferred embodiment, about lOg/kg bodyweight of quercetin is used. In another preferred embodiment, about 5g/kg bodyweight to about 25g/kg bodyweight, more preferably about 5g/kg bodyweight, of rutin are added to the composition. In another preferred embodiment, about lOg to about 50g/kg bodyweight, more preferably about lOg/kg bodyweight, of glutathione are added to the composition.
In one embodiment of the present invention, the compositions are substantially free of cinnamic acid derivatives of the formula:
Figure imgf000021_0001
wherein the groups X, Y and R, independently of one another, can be chosen from the group consisting of H and branched or unbranched alkyl having 1-18 carbon atoms, acids thereof, and physiologically tolerated salts thereof.
The following examples are provided to describe the invention in further detail. These examples, which set forth a preferred mode presently contemplated for carrying out the invention, are intended to illustrate and not to limit the invention.
EXAMPLE 1 A topical composition including a mixture of an hydrophilic ointment base, sodium acid phosphate moisturizing agent, and DL-panthenol, formulated together as the acceptable carrier, and further including quercetin was prepared by cold compounding. The formulation of the composition is given in Table 1. The formulation may optionally be supplemented with coenzyme Q10 (500mg) and may optionally contain another antioxidant,.
The composition was prepared by first placing the hydrophilic ointment base in a stainless steel bowl and mixing briskly until the ointment became creamy. The sodium acid phosphate, panthenol, quercetin, and other anti-oxidant, if any, were next added in that order. After each ingredient was added, mixing was continued until no traces of dry ingredients were visible and a substantially homogeneous mixture was obtained. The final color was a consistent yellow and the cream had the consistency of cake frosting. The mixture was stored in a sterile container. All containers and tools that contact the composition during mixing must also be sterilized with, for example, zephiran chloride, a bleach solution, or betadine.
This composition can be topically administered, under the supervision of a physician, to patients diagnosed with small fiber neuropathies. The topical composition may be applied, for example, twice daily in the morning and afternoon, or up to six times daily, as needed for pain relief, over a period of a few days. Treated patients are predicted to experience positive results that will last up to a day or two after treatment is discontinued.
Table 1
Ingredient Amount
Hydrophilic ointment base lib
50%) aqueous solution of Sodium acid phosphate 25cc
DL-panthenol 5cc
Quercetin powder 10g-50g
Other Antioxidant 10g-50g
Other combinations of compounds suitable for use in the methods of the invention are set forth in Examples 2 through 7. The compounds may be combined with about lib of hydrophilic ointment base for topical administration. EXAMPLE 2 A topical composition was formulated using the ingredients listed in Table 2 below.
Table 2
Ingredient Amount White Petrolatum 5,760.0 g Stearyl Alcohol 4,030.0 g Isopropyl Palmitate 1,730.0 g Apricot Kernal Oil 140.5 g Vitamin A Palmitate and Vitamin D3 in corn oil dispersion 140.5 g
DL-α-tocopheryl acetate 47.7 g
Butylated Hydroxy Anisole 13.25 g
Methylparaben 5.83 g
Propylparaben 3.45 g
Sodium Lauryl Sulfate 230.6 g
Propylene Glycol 2,766.6 g
DL-Panthenol, 50% in water 304.8 g
Sodium L-Pyrrolidone Carboxyiic Acid (50% in water) 1,598.0 g
Purified Water 8,500.0 g
Glycerin 318.0 g
Ascorbyl Palmitate 100.7 g
Quercetin Dihydrate 204.1 g
Witch Hazel Extract 598.9 g
The composition of Table 2 was topically administered three times per day over a period of 4 weeks to 24 patients suffering from diabetic neuropathy in at least one foot as a result of having Type 1 or Type 2 diabetes mellitus in a placebo- controlled, double blind proof of concept study conducted in France. 12 patients received a placebo consisting of the composition of Table 2 except that the ascorbyl palmitate and quercetin dihydrate were left out. Eligible patients were screened using the Michigan Neuropathy Screening Instrument (MNSI), Feldman, E ., et al, "A Practical Two-Step Quantitative Clinical and Elecfrophysiological Assessment for the Diagnosis and Staging of Diabetic Neuropathy," Diabetes Care, 19 , pp. 1281-1289.
5.3 ml of the topical ointment was topically administered to the affected area three times per day. Treatment was assessed using both a detailed symptom assessment and a quality of life questionnaire.
The results of the test were positive. The formulation produced a significant decrease of diabetic peripheral neuropathy pain and discomfort, and an improvement in the appearance and texture of the skin, including reduced dryness. A similar formulation without ascorbyl palmitate was also effective on diabetic skin and aging skin, as well as providing relief from the discomfort of diabetic peripheral neuropathy and small fiber peripheral neuropathy.
EXAMPLE 3
Ingredient Amount
Hydrophilic ointment base lib
50%) aqueous solution of Sodium acid phosphate 25cc
DL-panthenol 5cc
Quercetin powder 10g-50g
Glutathione 10g-50g
EXAMPLE 4
Ingredient Amount
Hydrophilic ointment base lib
50%) aqueous solution of Sodium acid phosphate 25cc
DL-panthenol 5cc
Quercetin powder 10g-50g
Rutin 5g-25g EXAMPLE 5
Ingredient Amount
Ascorbyl Palmitate 2g
Hesperidine 2g
Rutin 20g
Vitamins A and D3 3cc
Vitamin E acetate lcc
DL Panthenol 50-L 5cc
10
EXAMPLE 6
Ingredient Amount
Ascorbyl Palmitate 2g
Ascorbyl glucosamine ig
15 Luteolin 15g
Vitamins A and D3 3cc
Vitamin E acetate lcc
DL-Panthenol 50-L 5cc
20 EXAMPLE 7
Ingredient Amount
Ascorbyl glucosamine 2g
Apigenin 15g
Vitamins A and D3 3cc
25 Vitamin E acetate lcc
DL Panthenol 50-L 5cc EXAMPLE 8
Ingredient Amount
Ascorbyl palmitate 2g
Gamma linolenic acid 10g
Rutin 15g
Vitamins A and D3 3cc
Vitamin E acetate lcc
DL Panthenol 50-L 5cc
Although the present invention has been described and exemplified in terms of certain preferred embodiments, other embodiments will be apparent to those skilled in the art. The invention is, therefore, not limited to the particular embodiments described and exemplified, but is capable of modification or variation. The full scope of the invention is delineated by the appended claims.

Claims

What is claimed is:
1. A method of treating peripheral neural and vascular ailments comprising the step of administering to a patient having a peripheral neural or vascular ailment a composition formulated from a therapeutically effective amount of a flavonoid having antioxidant properties; and, optionally, an acceptable carrier.
2. The method of claim 1 , wherein treating peripheral neural and vascular ailments comprises treating a systemic effect of the peripheral neural and vascular ailment.
3. The method of claim 1 , wherein treating peripheral neural and vascular ailments comprises treating a local effect of the peripheral neural and vascular ailment.
4. The method of claim 1 , wherein treating a peripheral neural and vascular ailment is selected from the group consisting of decreasing pain, decreasing tingling, normalizing sensitivity to heat or cold, decreasing cramping, decreasing muscle weakness, decreasing numbness, decreasing hair loss, promoting angiogenesis, regenerating damaged nerves, generating new nerves and improving peripheral circulation.
5. The method of claim 1 , wherein the flavonoid having antioxidant properties is selected from the group consisting of (-)-epigallocatechin; (-)- epigallocatechin-gallate; 1,2,3,6-tetra-o-gallyol-β-d-glucose; 2'o- acetylacetoside; 3,3',4-tri-o-methyl-ellagic acid; 6,3',4'-trihydroxy-5,7,8- trimethoxyflavone; 6-hydroxy-luteolin; 6-hydroxykaempferol-3 ,6-dimethyl ether; 7-o-acetyl-8-epi-loganic acid; acacetin; acetoside; acetyl trisulfate quercetin; amentoflavone; apigenin; apiin; astragalin; avicularin; axillarin; baicalein; brazilin; brevifolin carboxylic acid; caryophyllene; catechin; chrysin; chrysin-5,7-dihydroxyflavone; chrysoeriol; chrysosplenol; chrysosplenoside-a; chrysosplenoside-d; cosmosiin; δ-cadinene; curcumin; dihydroquercetin; dimethylmussaenoside; diacerylcirsimaritin; diosmetin; dosmetin; ellagic acid; ebinin; epicatechin; ethyl brevifolin carboxylate; flavocannibiside; flavosativaside; genistein; ginkgo flavone glycosides; ginkgo heterosides; gossypetin; gossypetin-8-glucoside; haematoxylin; hesperidine; hispiduloside; hyperin; indole; iridine; isoliquiritigenin; isoliquiritin; isoquercitrin; jionoside; juglanin; kaempferol; kaempferol-3-rhamnoside; kaempferol-3-neohesperidoside; kolaviron; licuraside; linariin; linarin; lonicerin; luteolin; luteolin-7-glucoside; luteolin-7-glucoronide; macrocaφal- a; macrocaφal-b; macrocaφal-d; macrocaφal-g; maniflavone; morin; methyl scutellarein; myricetin; naringenin; naringin; nelumboside; nepetin; nepetrin; nerolidol; oligomeric proanthocyanidins; oxyayanin-a; pectolinarigenin; pectolinarin; quercetagetin; quercetin; quercimertrin; quercitrin; quercitryl-2" acetate; reynoutrin; rhamnetin; rhoifolin; rutin; scutellarein; sideritoflavone; silibin; silydianin; silychristine; silymarin; sophoricoside; sorbarin; spiraeoside; trifolin; vitexin; wogonin; and a component of green tea; and pharmaceutically acceptable salts thereof.
6. The method of claim 1, wherein the flavonoid having antioxidant properties is selected from the group consisting of (-)-epigallocatechin-3-gallate, catechin, rutin, quercetin, quercitrin, myricetin, kaempferol, myrecetrin luteolin, morin, fisetin, silymarin, apigenin, hesperitin, citrin, gossypetin, chrysin, oligomeric proanthocyanidins, polyphenols, biacalein, curcumin, epicatechin, dihydroquercetin, ginkgo flavone glycosides, ginkgo heterosides, silibin, silydianin, silychristine, a component of green tea, and pharmaceutically acceptable salts thereof.
7. The method of claim 1 , wherein the flavonoid having antioxidant properties is selected from the group consisting of quercetin, quercitrin, myricetin, rutin, kaempferol, myrecetrin, galangin, monoHER, diHER, triHER, tetraHER, naringenin, naringin, taxifolin, diosmin, phloretin, phloridzin, cyanidin, pelargonidin, a component of green tea, and pharmaceutically acceptable salts thereof.
8. The method of claim 1, wherein the flavonoid having antioxidant properties is selected from the group consisting of quercetin, quercitrin, myricetin, rutin, kaempferol, myrecetrin, a component of green tea, and pharmaceutically acceptable salts thereof.
9. The method of claim 1 , wherein the flavonoid having antioxidant properties comprises a component of green tea.
10. The method of claim 1 , wherein the composition is further formulated from a non-flavonoid antioxidant compound.
11. The method of claim 10, wherein the non-flavonoid antioxidant compound is selected from the group consisting of ascorbyl palmitate, ascorbic acid, vitamin A, vitamin E and its pharmaceutically acceptable esters, α-lipoic acid, coenzyme Q10, glutathione, a polyphenol, a component of green tea, and pharmaceutically acceptable salts thereof.
12. The method of claim 10, wherein the non-flavonoid antioxidant compound comprises glutathione.
13. The method of claim 10, wherein the non-flavonoid antioxidant compound comprises a component of green tea.
14. The method as claimed in any of claims 1 through 13, wherein the composition is further formulated from vitamin D3, 1,25-dihydroxyvitamin D3, 1 (S), 3(R)-dihydroxy-20(R)-( 1 -ethoxy-5-ethyl-5-hydroxy-2-heptyn- 1 -yl)-9, 10-seco-pregna-5(Z), 7(E), 10 (19)-triene, or a pharmaceutically acceptable salt thereof.
15. The method as claimed in any of claims 1 through 13, wherein the acceptable carrier comprises a sufficient amount of a panthenol selected from D- panthenol and DL-panthenol to promote penetration of one or more compounds of the composition into the skin.
16. The method of claim 1, wherein administering comprises oral administration.
17. The method of claim 16, wherein treating peripheral neural and vascular ailments comprises at least one of maintaining and/or supporting neural health, maintaining and/or supporting vascular health, maintaining and/or supporting circulation, maintaining and/or supporting muscular health, maintaining sensory integrity and supporting the health of the skin.
18. The method as claimed in any of claims 1 through 13, wherein the acceptable carrier comprises a sufficient amount of at least one non-U.S.P. hydrophilic ointment base to form a substantially topical composition.
19. The method of claim 13, wherein treating a peripheral neural and vascular ailment is selected from the group consisting of reducing or preventing redness of skin, reducing or preventing discoloration of skin, beautifying skin, improving appearance of skin, promoting attractiveness of skin, cleansing skin, removing dead or damaged skin or skin cells from skin and moisturizing skin.
20. The method of claim 13, wherein the step of applying comprises rubbing, pouring, spraying or sprinkling.
21. The method of claim 18, wherein the composition comprises a moisturizer, DL-panthenol, quercetin, and a further antioxidant.
22. The method of claim 18, wherein the composition comprises a hydrophilic ointment base, 2 to lOOg of sodium L-pyrrolidone carboxylic acid per pound of the composition, 1 to lOcc of DL-panthenol per pound of the composition, lOg to 50g of quercetin per pound of the composition, and 18 to 50g of a compound selected from the group consisting of glutathione and rutin, per pound of the composition.
23. A method of treating diabetic neuropathy comprising the step of administering to a patient having diabetic neuropathy a composition consisting of a therapeutically effective amount of a flavonoid having antioxidant properties and a acceptable carrier.
24. A method of treating diabetic neuropathy comprising the step of administering to a patient having diabetic neuropathy a composition comprising a therapeutically effective amount of a flavonoid having antioxidant properties; and, optionally, a acceptable carrier; with the proviso that said composition does not include vitamin D or a vitamin D3 analog.
25. The method of claim 23, wherein the flavonoid having antioxidant properties is selected from the group consisting of quercetin, quercitrin, myricetin, rutin, kaempferol, myrecetrin, galangin, monoHER, diHER, triHER, tetraHER, naringenin, naringin, taxifolin, diosmin, phloretin, phloridzin, cyanidin, pelargonidin and pharmaceutically acceptable salts thereof.
26. The method of claim 23, wherein the flavonoid having antioxidant properties is selected from the group consisting of quercetin, quercitrin, myricetin, rutin, kaempferol, myrecetrin, and pharmaceutically acceptable salts thereof.
27. The method of claim 23, wherein the composition further comprises a non- flavonoid antioxidant.
28. The method of claim 23 wherein the non-flavonoid antioxidant is selected from the group consisting of ascorbyl palmitate, ascorbic acid, vitamin A, vitamin E and its pharmaceutically acceptable esters, α-lipoic acid, coenzyme Q10, glutathione, and pharmaceutically acceptable salts thereof.
29. The method of claim 23 wherein the acceptable carrier further comprises a moisturizer and DL-panthenol.
30. A composition for the treatment of small fiber neuropathy or peripheral vascular disease comprising a mixture formulated from a flavonoid having antioxidant properties in a therapeutically effective amount for the treatment of small fiber neuropathy or peripheral vascular disease; and a non-flavonoid antioxidant in a therapeutically effective amount for the treatment of small fiber neuropathy or peripheral vascular disease; wherein said composition is an oral formulation or a topical formulation further comprising a penetrant.
31. The composition of claim 29, wherein the flavonoid having antioxidant properties is selected from the group consisting of (-)-epigallocatechin; (-)- epigallocatechin-gallate; 1,2,3,6-tetra-o-gallyol-β-d-glucose; 2'o- acetylacetoside; 3,3',4-tri-o-methyl-ellagic acid; 6,3',4'-trihydroxy-5,7,8- trimethoxyflavone; 6-hydroxy-luteolin; 6-hydroxykaempferol-3 ,6-dimethyl ether; 7-o-acetyl-8-epi-loganic acid; acacetin; acetoside; acetyl trisulfate quercetin; amentoflavone; apigenin; apiin; astragalin; avicularin; axillarin; baicalein; brazilin; brevifolin carboxylic acid; caryophyllene; catechin; chrysin; chrysin-5,7-dihydroxyflavone; chrysoeriol; chrysosplenol; chrysosplenoside-a; chrysosplenoside-d; cosmosiin; δ-cadinene; curcumin; dihydroquercetin; dimethylmussaenoside; diacerylcirsimaritin; diosmetin; dosmetin; ellagic acid; ebinin; epicatechin; ethyl brevifolin carboxylate; flavocannibiside; flavosativaside; genistein; ginkgo flavone glycosides; ginkgo heterosides; gossypetin; gossypetin-8-glucoside; haematoxylin; hesperidine; hispiduloside; hyperin; indole; iridine; isoliquiritigenin; isoliquiritin; isoquercitrin; jionoside; juglanin; kaempferol; kaempferol-3-rhamnoside; kaempferol-3-neohesperidoside; kolaviron; licuraside; linariin; linarin; lonicerin; luteolin; luteolin-7-glucoside; luteolin-7-glucoronide; macrocaφal- a; macrocaφal-b; macrocaφal-d; macrocaφal-g; maniflavone; morin; methyl scutellarein; myricetin; naringenin; naringin; nelumboside; nepetin; nepetrin; nerolidol; oligomeric proanthocyanidins; oxyayanin-a; pectolinarigenin; pectolinarin; polyphenols, including green tea polyphenols; quercetagetin; quercetin; quercimertrin; quercitrin;- quercitryl-2" acetate; reynoutrin; rhamnetin; rhoifolin; rutin; scutellarein; sideritoflavone; silibin; silydianin; silychristine; silymarin; sophoricoside; sorbarin; spiraeoside; trifolin; vitexin; wogonin; a component of green tea; and pharmaceutically acceptable salts thereof.
32. The composition of claim 29, wherein the flavonoid having antioxidant properties is selected from the group consisting of (-)-epigallocatechin-3- gallate, catechin, rutin, quercetin, quercitrin, myricetin, kaempferol, myrecetrin luteolin, morin, fisetin, silymarin, apigenin, hesperitin, citrin, gossypetin, chrysin, oligomeric proanthocyanidins, polyphenols, biacalein, curcumin, epicatechin, dihydroquercetin, ginkgo flavone glycosides, ginkgo heterosides, silibin, silydianin, silychristine, a component of green tea, and pharmaceutically acceptable salts thereof.
33. The composition of claim 29, wherein the flavonoid having antioxidant properties is selected from the group consisting of quercetin, quercitrin, myricetin, rutin, kaempferol, myrecetrin, galangin, monoHER, diHER, triHER, tetraHER, naringenin, naringin, taxifolin, diosmin, phloretin, phloridzin, cyanidin, pelargonidin, a component of green tea, and pharmaceutically acceptable salts thereof.
34. The composition of claim 29, wherein the flavonoid having antioxidant properties is selected from the group consisting of quercetin, quercitrin, myricetin, rutin, kaempferol, myrecetrin, a component of green tea, and pharmaceutically acceptable salts thereof.
35. The composition of claim 29, wherein the non-flavonoid antioxidant compound is selected from the group consisting of ascorbyl palmitate, ascorbic acid, vitamin A, vitamin E and its pharmaceutically acceptable esters, α-lipoic acid, coenzyme Q10, glutathione, a component of green tea, and pharmaceutically acceptable salts thereof.
36. The composition of claim 29, wherein the non-flavonoid antioxidant compound comprises glutathione.
37. The composition of claim 29, wherein the non-flavonoid antioxidant compound comprises a component of green tea.
38. The composition as claimed in any of claims 29 through 36, wherein the composition is further formulated from vitamin D3, 1, 25-dihydroxyvitamin D3, 1(S), 3(R)-dihydroxy-20(R)-(l-ethoxy-5-ethyl-5-hydroxy-2-heptyn-l-yl)- 9, 10-seco-pregna-5(Z), 7(E), 10 (19)-triene, or a pharmaceutically acceptable salt thereof.
39. The composition as claimed in any of claims 29 through 36, wherein the acceptable carrier further comprises a sufficient amount of a panthenol selected from D-panthenol and DL-panthenol to promote penetration of one or more compounds of the composition into the skin.
40. The composition of claim 38, wherein the composition comprises a moisturizer, DL-panthenol, quercetin, and a further antioxidant.
41. The composition of claim 38, wherein the composition comprises a hydrophilic ointment base, 2 to lOOg of sodium L-pyrrolidone carboxylic acid per pound of the composition, 1 to lOcc of DL-panthenol per pound of the composition, lOg to 50g of quercetin per pound of the composition, and 18 to 50g of a compound selected from the group consisting of glutathione and rutin, per pound of the composition.
42. A method for improving the appearance of skin comprising applying to the skin of a mammal afflicted with a peripheral neural and vascular ailment a topical composition which comprises at least one flavonoid compound formulated in a carrier acceptable for a topical composition in an amount effective to improve appearance of the skin.
43. The method of claim 42, wherein improving the appearance of skin is selected from the group consisting of reducing or preventing redness of skin, reducing or preventing discoloration of skin, beautifying skin, improving appearance of skin, promoting attractiveness of skin, cleansing skin, removing dead or damaged skin or skin cells from skin and moisturizing skin.
44. The method of claim 42, wherein applying comprises rubbing, pouring, spraying or sprinkling.
PCT/US2002/035654 2001-12-19 2002-11-06 Methods for the treatment of peripheral neural and vascular ailments WO2003053336A2 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
EP02789474A EP1455778A4 (en) 2001-12-19 2002-11-06 Methods for the treatment of peripheral neural and vascular ailments
MXPA04006039A MXPA04006039A (en) 2001-12-19 2002-11-06 Methods for the treatment of peripheral neural and vascular ailments.
IL16250502A IL162505A0 (en) 2001-12-19 2002-11-06 Method for treatment of peripheral neural and vascular ailments
AU2002352501A AU2002352501B2 (en) 2001-12-19 2002-11-06 Methods for the treatment of peripheral neural and vascular ailments
JP2003554096A JP2005518381A (en) 2001-12-19 2002-11-06 Treatment of peripheral nerve and vascular disease
CA002470603A CA2470603A1 (en) 2001-12-19 2002-11-06 Methods for the treatment of peripheral neural and vascular ailments
NZ533439A NZ533439A (en) 2001-12-19 2002-11-06 Methods for the treatment of peripheral neural and vascular ailments using flavonoid compositions

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/US2001/049297 WO2002049575A2 (en) 2000-12-21 2001-12-19 Method and composition for the treatment of diabetic neuropathy
USPCT/US01/49297 2001-12-19

Publications (2)

Publication Number Publication Date
WO2003053336A2 true WO2003053336A2 (en) 2003-07-03
WO2003053336A3 WO2003053336A3 (en) 2003-11-27

Family

ID=21743140

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2002/035654 WO2003053336A2 (en) 2001-12-19 2002-11-06 Methods for the treatment of peripheral neural and vascular ailments

Country Status (8)

Country Link
EP (1) EP1455778A4 (en)
JP (1) JP2005518381A (en)
CA (1) CA2470603A1 (en)
IL (1) IL162505A0 (en)
MX (1) MXPA04006039A (en)
NZ (1) NZ533439A (en)
WO (1) WO2003053336A2 (en)
ZA (1) ZA200404614B (en)

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006083105A (en) * 2004-09-16 2006-03-30 Ito En Ltd Ameliorant for blood fluidity and food and beverage
EP1681297A1 (en) * 2003-10-30 2006-07-19 Meiji Seika Kaisha Ltd. Tyrosinase activity inhibitor and ameliorant for facial blood flow
EP1683805A1 (en) * 2003-10-24 2006-07-26 Meiji Seika Kaisha Ltd. Novel inhibitor for advanced glycation endproduct formation and aldose reductase inhibitor
EP1684774A2 (en) * 2003-11-05 2006-08-02 Osteoscreen, Inc. STIMULATION OF HAIR GROWTH BY i GINKGO BILOBA /i FLAVANOIDS
DE102005048778A1 (en) * 2005-10-10 2007-04-12 Beiersdorf Ag Cosmetic formulations to improve the appearance of the skin
DE102005048777A1 (en) * 2005-10-10 2007-04-12 Beiersdorf Ag Cosmetic formulations to improve the microcirculation of the skin
FR2904557A1 (en) * 2006-08-01 2008-02-08 Pierre Fabre Medicament Sa NOVEL EUCALYPTUS EXTRACT, PREPARATION METHOD THEREOF AND THERAPEUTIC USES THEREOF
WO2008032105A2 (en) * 2006-09-15 2008-03-20 The Babraham Institute Flavonoid derivatives and their uses
WO2009032888A2 (en) * 2007-09-04 2009-03-12 The Procter & Gamble Company Oral compositions, products, and methods of use
EP2317994A2 (en) * 2008-07-23 2011-05-11 Massachusetts Institute of Technology Activation of histone deacetylase 1 (hdac1) protects against dna damage and increases neuronal survival
CN102151281A (en) * 2011-01-24 2011-08-17 中国药科大学 Flavonoid compound for preventing and treating diabetes and medicament application thereof
CN102526248A (en) * 2012-03-22 2012-07-04 赵海潞 Traditional Chinese medicine prescription capable of curing diabetes wound fester and continuously reducing blood sugar
WO2013062424A1 (en) * 2011-10-26 2013-05-02 Anzamed International Limited Method and composition for the treatment of pain and/or inflammation
EP2596787A1 (en) * 2010-07-20 2013-05-29 Natural Medicine Institute Of Zhejiang Yangshengtang Co., Ltd. New use of hesperetin
ITRM20120335A1 (en) * 2012-07-13 2014-01-14 Aboca Spa Societa Agricola NEW COMPOSITIONS FOR NEUROPATHIC PAIN TREATMENT.
WO2014095289A3 (en) * 2012-12-20 2014-12-31 Unilever Plc Method of treating hair ageing
US9115053B2 (en) 2011-07-22 2015-08-25 Massachusetts Institute Of Technology Activators of class I histone deacetlyases (HDACS) and uses thereof
CN107126437A (en) * 2016-02-29 2017-09-05 上海中医药大学 A kind of medicinal usage of Sophoricoside
US9844531B2 (en) 2013-03-15 2017-12-19 Abbott Laboratories Methods of maintaining and improving muscle function
WO2018078412A1 (en) * 2016-10-31 2018-05-03 Posi Visionary Solutions Llp Topical microemulsion of diosmetin and uses thereof
CN108164489A (en) * 2018-03-20 2018-06-15 武汉轻工大学 A kind of preparation method of Galangin
WO2019178658A3 (en) * 2018-03-21 2019-11-21 BARBOZA DA ROCHA, Pedro Healing, moisturizing, humectant and emolient composition for topical administration in intertrigo skin lesions, skin lesions due to urinary and faecal incontinence and other related injuries.
WO2020051644A1 (en) * 2018-09-13 2020-03-19 Norbio No. 2 Pty Ltd Treatment of peripheral nervous tissue inflammation
CN112014480A (en) * 2019-05-28 2020-12-01 黄河科技学院 Method for detecting content of effective components in Jiangzhining granules by UPLC-MS/MS (ultra performance liquid chromatography-Mass Spectrometry/Mass Spectrometry)
EP3884937A1 (en) * 2012-03-23 2021-09-29 Cardero Therapeutics, Inc. Compounds and compositions for the treatment of muscular disorders
US11273144B2 (en) 2012-03-23 2022-03-15 Epirium Bio Inc. Compounds and compositions for the treatment of muscular disorders and bone disorders
CN114392256A (en) * 2022-02-22 2022-04-26 中山大学附属第八医院（深圳福田） Application of cyanidin in preventing and treating vascular calcification
WO2022157381A1 (en) * 2021-01-25 2022-07-28 Universiteit Hasselt Phloretin for use in the treatment of neurodegenerative and demyelinating diseases
CN115317497A (en) * 2022-01-13 2022-11-11 宁夏医科大学 Application of liquiritin in preparing thoracic aorta vasodilation medicine

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20080081807A (en) * 2005-06-28 2008-09-10 케이지케이 시너자이즈 인코포레이티드 Compositions to improve the bioavailability of polymethoxyflavones and tocotrienols for the treatment of cardiovascular disease
JP5132889B2 (en) * 2006-02-27 2013-01-30 株式会社ポッカコーポレーション Nerve growth factor potentiator
CN101460499A (en) * 2006-04-05 2009-06-17 沃泰克斯药物股份有限公司 Deazapurines useful as inhibitors of JANUS kinases
JP5415216B2 (en) * 2009-10-02 2014-02-12 日本メナード化粧品株式会社 Topical skin preparation
KR101021835B1 (en) 2010-09-06 2011-03-17 충남대학교산학협력단 A composition comprising chrysosplenol c for treating and preventing heart disease
CN104547872A (en) * 2015-01-30 2015-04-29 山东省立医院 Traditional Chinese medicine composition for treating epilepsy
KR101828379B1 (en) 2016-03-30 2018-02-12 우석대학교 산학협력단 Compositions for the improvement of memory and cognition ability, or prevention, delay, improvement or treatment of Alzheimer's disease comprising Rosa rugosa THUNB flower extracts or fractions
KR101715294B1 (en) * 2016-06-09 2017-03-10 연세대학교 산학협력단 Composition having effects of skin moisturizing, exfoliating, improving skin elasticity, inhibiting erythema, anti-wrinkle or improving skin photoaging comprising diosmin or salt thereof

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03232851A (en) * 1989-12-26 1991-10-16 Nippon Flour Mills Co Ltd Aldose reductase inhibitor
JPH09235284A (en) * 1995-02-23 1997-09-09 Nissan Chem Ind Ltd Indole-type thiazolidine compound
IT1291113B1 (en) * 1997-03-20 1998-12-29 Sigma Tau Ind Farmaceuti NUTRITIONAL THERAPEUTIC COMPOSITION FOR SUBJECTS WITH DIABETES MELLITUS
IT1302307B1 (en) * 1998-09-01 2000-09-05 Sigma Tau Healthscience Spa COMPOSITION WITH ANTIOXIDANT ACTIVITY AND FOR IMPROVING THE METABOLIC USE OF GLUCOSE, INCLUDING ACETYL
JP4497566B2 (en) * 1998-09-02 2010-07-07 株式会社 日本薬用食品研究所 Aldose reductase inhibitors and novel saponins and novel sapogenols
TWI233353B (en) * 2000-04-11 2005-06-01 Takara Bio Inc Therapeutic or preventive agents containing polyphenols
AU2002231095B2 (en) * 2000-12-21 2005-11-24 The Quigley Corporation Method and composition for the treatment of diabetic neuropathy

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 1990, MACK PUBLISHING CO.

Cited By (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1683805A1 (en) * 2003-10-24 2006-07-26 Meiji Seika Kaisha Ltd. Novel inhibitor for advanced glycation endproduct formation and aldose reductase inhibitor
EP1683805A4 (en) * 2003-10-24 2009-06-17 Meiji Seika Kaisha Novel inhibitor for advanced glycation endproduct formation and aldose reductase inhibitor
US7863248B2 (en) 2003-10-30 2011-01-04 Meiji Seika Kaisha, Ltd. Tyrosinase activity inhibitor and ameliorant for facial blood flow
EP1681297A1 (en) * 2003-10-30 2006-07-19 Meiji Seika Kaisha Ltd. Tyrosinase activity inhibitor and ameliorant for facial blood flow
EP1681297A4 (en) * 2003-10-30 2009-06-17 Meiji Seika Kaisha Tyrosinase activity inhibitor and ameliorant for facial blood flow
EP1684774A2 (en) * 2003-11-05 2006-08-02 Osteoscreen, Inc. STIMULATION OF HAIR GROWTH BY i GINKGO BILOBA /i FLAVANOIDS
US7678395B2 (en) 2003-11-05 2010-03-16 Osteoscreen, Inc. Stimulation of hair growth by isoginkgetin
EP1684774A4 (en) * 2003-11-05 2009-07-01 Osteoscreen Inc STIMULATION OF HAIR GROWTH BY i GINKGO BILOBA /i FLAVANOIDS
JP2006083105A (en) * 2004-09-16 2006-03-30 Ito En Ltd Ameliorant for blood fluidity and food and beverage
DE102005048778A1 (en) * 2005-10-10 2007-04-12 Beiersdorf Ag Cosmetic formulations to improve the appearance of the skin
DE102005048777A1 (en) * 2005-10-10 2007-04-12 Beiersdorf Ag Cosmetic formulations to improve the microcirculation of the skin
FR2904557A1 (en) * 2006-08-01 2008-02-08 Pierre Fabre Medicament Sa NOVEL EUCALYPTUS EXTRACT, PREPARATION METHOD THEREOF AND THERAPEUTIC USES THEREOF
RU2445112C2 (en) * 2006-08-01 2012-03-20 Пьер Фабр Медикаман New eucalyptus extract, method for producing and using it for therapeutic purposes
WO2008017752A3 (en) * 2006-08-01 2008-04-10 Pf Medicament Eucalyptus extract, method of preparation and therapeutic uses thereof
WO2008017752A2 (en) * 2006-08-01 2008-02-14 Pierre Fabre Medicament Eucalyptus extract, method of preparation and therapeutic uses thereof
WO2008032105A3 (en) * 2006-09-15 2008-10-09 Babraham Inst Flavonoid derivatives and their uses
WO2008032105A2 (en) * 2006-09-15 2008-03-20 The Babraham Institute Flavonoid derivatives and their uses
WO2009032888A3 (en) * 2007-09-04 2009-12-03 The Procter & Gamble Company Method for providing energy, relieving stress and mood enhancing benefits comprising administering a composition comprising cholecalciferol and a tea extract
WO2009032888A2 (en) * 2007-09-04 2009-03-12 The Procter & Gamble Company Oral compositions, products, and methods of use
AU2008296311B2 (en) * 2007-09-04 2014-07-03 The Procter & Gamble Company Method for providing energy, relieving stress and mood enhancing benefits comprising administering a composition comprising cholecalciferol and a tea extract
EP2317994A4 (en) * 2008-07-23 2012-09-12 Massachusetts Inst Technology Activation of histone deacetylase 1 (hdac1) protects against dna damage and increases neuronal survival
EP2317994A2 (en) * 2008-07-23 2011-05-11 Massachusetts Institute of Technology Activation of histone deacetylase 1 (hdac1) protects against dna damage and increases neuronal survival
EP2596787A1 (en) * 2010-07-20 2013-05-29 Natural Medicine Institute Of Zhejiang Yangshengtang Co., Ltd. New use of hesperetin
EP2596787A4 (en) * 2010-07-20 2013-12-25 Natural Medicine Inst Zhejiang Yangshengtang Co Ltd New use of hesperetin
CN102151281A (en) * 2011-01-24 2011-08-17 中国药科大学 Flavonoid compound for preventing and treating diabetes and medicament application thereof
US10167277B2 (en) 2011-07-22 2019-01-01 Massachusetts Institute Of Technology Activators of class I histone deacetlyases (HDACs) and uses thereof
US9115053B2 (en) 2011-07-22 2015-08-25 Massachusetts Institute Of Technology Activators of class I histone deacetlyases (HDACS) and uses thereof
US11084803B2 (en) 2011-07-22 2021-08-10 Massachusetts Institute Of Technology Activators of class I histone deacetylases (HDACs) and uses thereof
WO2013062424A1 (en) * 2011-10-26 2013-05-02 Anzamed International Limited Method and composition for the treatment of pain and/or inflammation
CN102526248A (en) * 2012-03-22 2012-07-04 赵海潞 Traditional Chinese medicine prescription capable of curing diabetes wound fester and continuously reducing blood sugar
US11273144B2 (en) 2012-03-23 2022-03-15 Epirium Bio Inc. Compounds and compositions for the treatment of muscular disorders and bone disorders
EP3884937A1 (en) * 2012-03-23 2021-09-29 Cardero Therapeutics, Inc. Compounds and compositions for the treatment of muscular disorders
WO2014009936A1 (en) * 2012-07-13 2014-01-16 Aboca S.P.A. Societa' Agricola Compositions for the treatment of neuropathic pain
ITRM20120335A1 (en) * 2012-07-13 2014-01-14 Aboca Spa Societa Agricola NEW COMPOSITIONS FOR NEUROPATHIC PAIN TREATMENT.
WO2014095289A3 (en) * 2012-12-20 2014-12-31 Unilever Plc Method of treating hair ageing
US9844531B2 (en) 2013-03-15 2017-12-19 Abbott Laboratories Methods of maintaining and improving muscle function
CN107126437A (en) * 2016-02-29 2017-09-05 上海中医药大学 A kind of medicinal usage of Sophoricoside
WO2018078412A1 (en) * 2016-10-31 2018-05-03 Posi Visionary Solutions Llp Topical microemulsion of diosmetin and uses thereof
CN108164489A (en) * 2018-03-20 2018-06-15 武汉轻工大学 A kind of preparation method of Galangin
WO2019178658A3 (en) * 2018-03-21 2019-11-21 BARBOZA DA ROCHA, Pedro Healing, moisturizing, humectant and emolient composition for topical administration in intertrigo skin lesions, skin lesions due to urinary and faecal incontinence and other related injuries.
WO2020051644A1 (en) * 2018-09-13 2020-03-19 Norbio No. 2 Pty Ltd Treatment of peripheral nervous tissue inflammation
CN112014480A (en) * 2019-05-28 2020-12-01 黄河科技学院 Method for detecting content of effective components in Jiangzhining granules by UPLC-MS/MS (ultra performance liquid chromatography-Mass Spectrometry/Mass Spectrometry)
CN112014480B (en) * 2019-05-28 2023-03-28 黄河科技学院 Method for detecting content of effective components in Jiangzhining granules by UPLC-MS/MS
WO2022157381A1 (en) * 2021-01-25 2022-07-28 Universiteit Hasselt Phloretin for use in the treatment of neurodegenerative and demyelinating diseases
CN115317497A (en) * 2022-01-13 2022-11-11 宁夏医科大学 Application of liquiritin in preparing thoracic aorta vasodilation medicine
CN114392256A (en) * 2022-02-22 2022-04-26 中山大学附属第八医院（深圳福田） Application of cyanidin in preventing and treating vascular calcification

Also Published As

Publication number Publication date
MXPA04006039A (en) 2004-09-27
JP2005518381A (en) 2005-06-23
EP1455778A4 (en) 2007-09-12
AU2002352501A1 (en) 2003-07-09
IL162505A0 (en) 2005-11-20
WO2003053336A3 (en) 2003-11-27
ZA200404614B (en) 2005-08-29
CA2470603A1 (en) 2003-07-03
EP1455778A2 (en) 2004-09-15
NZ533439A (en) 2006-06-30

Similar Documents

Publication Publication Date Title
US7410659B2 (en) Methods for the treatment of peripheral neural and vascular ailments
WO2003053336A2 (en) Methods for the treatment of peripheral neural and vascular ailments
US6555573B2 (en) Method and composition for the topical treatment of diabetic neuropathy
US20030105031A1 (en) Methods for the treatment of skin disorders
AU2002309615B2 (en) Nutritional supplements and methods for prevention, reduction and treatment of radiation injury
US6753325B2 (en) Composition and method for prevention, reduction and treatment of radiation dermatitis
US7399783B2 (en) Methods for the treatment of scar tissue
US20030118536A1 (en) Topical compositions and methods for treatment of adverse effects of ionizing radiation
US7435725B2 (en) Oral compositions and methods for prevention, reduction and treatment of radiation injury
AU2002309615A1 (en) Nutritional supplements and methods for prevention, reduction and treatment of radiation injury
CA2431079C (en) Method and composition for the treatment of diabetic neuropathy
AU2002352501B2 (en) Methods for the treatment of peripheral neural and vascular ailments
TW200526236A (en) Methods for the treatment of peripheral neural and vascular ailments
JP2007063224A (en) Tyrosinase activity inhibitor

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2002352501

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2002789474

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2004/04614

Country of ref document: ZA

Ref document number: 533439

Country of ref document: NZ

Ref document number: 200404614

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: 162505

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 1683/DELNP/2004

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 2470603

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: PA/a/2004/006039

Country of ref document: MX

Ref document number: 2003554096

Country of ref document: JP

WWP Wipo information: published in national office

Ref document number: 2002789474

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 2002352501

Country of ref document: AU