WO2001041783A1 - Procedes et compositions pour le traitement des maladies inflammatoires - Google Patents

Procedes et compositions pour le traitement des maladies inflammatoires Download PDF

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Publication number
WO2001041783A1
WO2001041783A1 PCT/US2000/033239 US0033239W WO0141783A1 WO 2001041783 A1 WO2001041783 A1 WO 2001041783A1 US 0033239 W US0033239 W US 0033239W WO 0141783 A1 WO0141783 A1 WO 0141783A1
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Prior art keywords
compound
treating
cmo
inflammatory disease
composition
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PCT/US2000/033239
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English (en)
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Bruce Levin
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Bruce Levin
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Priority to AU19537/01A priority Critical patent/AU1953701A/en
Publication of WO2001041783A1 publication Critical patent/WO2001041783A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • 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
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/4873—Cysteine endopeptidases (3.4.22), e.g. stem bromelain, papain, ficin, cathepsin H
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/22—Cysteine endopeptidases (3.4.22)
    • C12Y304/22002—Papain (3.4.22.2)

Definitions

  • the present invention provides compositions and methods for prevention and treatment of arthritis and other inflammatory and autoimmune diseases.
  • the present invention relates to a method for treating inflammatory disease to prevent or delay the progression of the disease process or to alleviate the symptoms thereof.
  • Diseases and disorders which have significant inflammatory components are ubiquitous. Skin disorders, bowel disorders, certain degenerative neurological disorders, arthritis, autoimmune diseases and other illnesses afflict many patients.
  • infectious agents may be directly or indirectly responsible for the entire disease process.
  • an infectious or other agent may in some way facilitate an autoimmune or inflammatory response.
  • dietary or environmental factors may trigger an autoimmune or inflammatory response.
  • genetic factors can play a key role. In the majority of cases, the causative elements have not been defined and many of the key pathophysiological components have not been elucidated. Accordingly, treatment options for the majority of these diseases is suboptimal.
  • steroids nonsteroidal anti-inflammatory agents
  • aspirin compounds and cancer chemotherapeutic immunosuppressive agents
  • cancer chemotherapeutic immunosuppressive agents are often used. These agents often do not provide adequate symptomatic relief and are not believed to alter the natural progression of the disease. Indeed, some of these agents may make the disease worse. Furthermore, powerful side effects are found with most all of these therapies. Hence, there is a great need for safe and effective therapy for these disorders.
  • Cetyl my stolenate has been used for treatment of rheumatoid arthritis (Diehl, U.S. Patent No. 4,113,881 ) and osteoarthritis (Diehl, U.S. Patent No.
  • Tetracycline compounds have been found to weakly decrease collagenase and other enzyme activity and decrease certain kinds of cartilage damage found in canine models.
  • human trials have been disappointing thus far.
  • Side effects include dizziness gastrointestinal upset, nausea, and diarrhea.
  • the invention disclosed herein relates to the use of cetyl myristoleate (CMO) and CMO compounds in combination with other compounds useful for treating inflammatory disease.
  • CMO cetyl myristoleate
  • the invention is useful for protection against the development of arthritis and other inflammatory diseases and to provide relief of symptoms in individuals where such disease has been diagnosed.
  • Cetyl myristoleate compounds have herein been found to be particularly useful when used in combination with components of accepted therapies. When used in this manner, cetyl myristoleate compounds can provide significant symptomatic relief.
  • Certain pharmaceutically active compounds or combinations thereof can be coadministered with CMO compounds, but can have significant adverse side effects. Coadministration with CMO compounds allows the use of reduced amounts of such treatment components and reduction or elimination of their undesired or detrimental side effects.
  • CMO compounds can be used to supplement those therapies to slow disease progression or to improve patient outcome.
  • the present invention further contemplates a composition comprising
  • the invention also relates to the use of tetracycline compounds in combination with other compounds useful for treating inflammatory diseases.
  • the invention discloses compositions and methods for topical treatment of inflammation resulting from envenomation or contact with other irritants.
  • Such compositions comprise local anaesthetics, either alone, or in combination with one or more of proteases, steroids, tetracycline compounds, and CMO compounds.
  • Such compositions may further comprise ingredients which enhance absorption.
  • compositions of the invention comprise CMO and/or CMO compounds in combination with another substance known or thought to be useful for treatment of inflammatory disease.
  • CMO compounds refers to cetyl myristoleate and related compounds. These related compounds are esters of an unsaturated fatty acid and an aicohol.
  • Unsaturated fatty acids include, for example, palmitoleic acid, oleic acid, linoleic acid, arachidonic acid, nervonic acid and the like.
  • Preferred unsaturated fatty acids have cis double bonds.
  • preferred unsaturated fatty acids have 12 or more carbon atoms.
  • the preferred alcohol is long chain.
  • Modified cetyl myristoleate compounds refers to the CMO compounds of the invention other than cetyl myristoleate itself, as described above.
  • compositions of the invention are pharmaceutical compositions which include one or more CMO compounds and at least one additional compound having potential utility for treatment of arthritis and other related inflammatory, autoimmune diseases or inflammatory diseases.
  • Examples include, for example, tetracycline compounds, doxycycline, NSAIDs, and Cox-2 inhibitors, steroids (e.g. cortisone), cancer chemotherapeutic agents, chelating agents such as EDTA, inhibitors of tumor necrosis factor (TNF)(e.g. Embrel ® ), metalloprotease inhibitors, glucosamine, chondroitin sulfate, methyl sulfonal methane (MSM), S-adenosylmethionine (SAME) or other sulfur or methyl group donors, and synovial fluid supplements (e.g. Synvisc ® and Hyalagan ® ).
  • TNF tumor necrosis factor
  • MSM methyl sulfonal methane
  • SAME S-adenosylmethionine
  • synovial fluid supplements e.g. Synvisc ® and Hyalagan ®
  • one composition of the present invention includes a CMO compound and at least one compound selected from the group consisting of a tetracycline compound, a Cox-2 inhibitor, a non-steroidal anti-inflammatory drug (NSAID), a corticosteroid, a chelating agent, a matrix metalloprotease inhibitor, an inhibitor of inflammatory cytokines (e.g., interleukin inhibitor, inhibitor of interleukin synthetases), a local anaesthetic, glucosamine, chondroitin sulfate and collagen hydrolysate.
  • tetracycline compounds include, but are not limited to, tetracycline, doxycycline, minocycline, tetracycline homologs and modified tetracycline compounds.
  • a second composition of the invention includes a tetracycline compound and at least one compound selected from the group consisting of a Cox-2 inhibitor, a corticosteroid, a chelating agent, a matrix metalloprotease inhibitor, an inhibitor of inflammatory cytokines (e.g., interleukin inhibitor, inhibitor of interleukin synthetases), a local anaesthetic, glucosamine, chondroitin sulfate and collagen hydrolysates.
  • a tetracycline compound and at least one compound selected from the group consisting of a Cox-2 inhibitor, a corticosteroid, a chelating agent, a matrix metalloprotease inhibitor, an inhibitor of inflammatory cytokines (e.g., interleukin inhibitor, inhibitor of interleukin synthetases), a local anaesthetic, glucosamine, chondroitin sulfate and collagen hydrolysates.
  • inflammatory cytokines e.g.
  • compositions for the treatment of inflammatory diseases which includes a modified cetyl or sphingo myristoleate compound, with or without an additional compound.
  • compositions of the invention can be used for treatment of arthritis.
  • the present invention is also applicable to other autoinflammatory diseases as well as degenerative bone and joint diseases including osteoarthritis, crystal arthritis and capsulitis and other arthropathies.
  • the methods and compositions can be used for treating tendonitis, ligamentitis and traumatic joint injury.
  • the invention further contemplates treatment of other inflammatory immune disorders, including but not limited to rheumatic diseases, allergic disorders, asthma, allergic rhinitis, skin disorders, gastrointestinal disorders such as Crohn's disease and ulcerative colitis, transplant rejection, poststreptococcal and autiommune renal failure, septic shock, systemic inflammatory response syndrome (SIRS), adult respiratory distress syndrome (ARDS) and envenomation.
  • SIRS systemic inflammatory response syndrome
  • ARDS adult respiratory distress syndrome
  • the invention further contemplates utilizing CMO compounds alone or in combination with another compound for the treatment of inflammatory bowel disease.
  • Poor gastrointestinal absorption following ingestion of a CMO compound leads to increased distal intraluminal delivery of these compounds to the distal gastrointestinal tract.
  • Such action places the compound in direct topical proximity to diseased intestinal, colonic or rectal mucosa or other tissues.
  • the amount of a CMO compound to be administered per day is from about 25 mg to about 1000 mg.
  • the amount of the CMO compound is from about 75 mg to about 750 mg.
  • Tetracycline compounds affect protein synthesis and appear to have anti- inflammatory properties in addition to their anti-microbial properties which are useful for treatment of arthritis. For example, there are other antibiotics that may be useful, and perhaps even more effective at killing acne bacteria but tetracycline compounds are more effective in treating acne. It is believed by the inventor that this is a result of tetracycline's anti-inflammatory activity. The anti- inflammatory activity of tetracycline compounds make them useful for treating other inflammatory disorders, even in the absence of an infectious agent.
  • Tetracycline compounds can inhibit enzymes associated with inflammatory diseases such as matrix metalloproteases (MMPs), collagenase, gelatinase and elastase. While it is widely thought that tetracycline compounds decrease enzyme activity by chelation, they may also decrease inflammation by decreasing production of proinflammatory or other compounds. Tetracycline compounds may be effective when used with other compounds in the treatment of inflammatory conditions.
  • MMPs matrix metalloproteases
  • collagenase collagenase
  • gelatinase gelatinase
  • elastase elastase.
  • Tetracycline compounds may be effective when used with other compounds in the treatment of inflammatory conditions.
  • tetracycline compounds include tetracycline and modified tetracyclines which may or may not have altered biological activity. For example, modification at specific positions can lead to the loss of antimicrobial bioactivity. See, e.g. Mitscher, The Chemistry of Tetracyclines, p.211 (1978).
  • modified tetracycline compounds are those which lack the dimethylamino group at position 4 and tetracycline compounds modified at the 2-carbon position to produce a nitrile.
  • tetracycline compounds can be employed, including those having reduced antimicrobial activities provided they retain anti-inflammatory activity. Examples of preferred tetracycline compounds include, but are not limited to doxycycline, minocycline,
  • a composition of the invention comprises at least one CMO compound and at least one tetracycline compound.
  • the amount of tetracycline compound used according to the invention is an amount effect for treating an inflammatory disease and need not be a dose used for antimicrobial treatments.
  • the tetracycline compound is doxycycline
  • the dose for a human can be from about 5-10 mg to about 800 mg daily.
  • other tetracycline compounds can be used in normally prescribed amounts or in lesser doses which maintain effectiveness but reduce unwanted side effects.
  • the amount of tetracycline compounds used can be from about 10 mg to about 1200 mg.
  • the particular dosage combination to be used for any individual is easily determinable. For example, when determining effective dosage for the relief of pain of arthritis, the practitioner will start with a recommended dose of the tetracycline compound and then adjust the amounts of the components to determine the smallest dosage which provides effective pain relief.
  • doxycycline can first be administered in a daily dose of up to about 800 mg, followed by a reduction to a minimal effective amount.
  • the minimal effective dose can be about 5-10 mg or lower.
  • a preferred dose is about 100 mg.
  • the minimal effective amount to be administered can be determined by monitoring symptoms of the disease and determining the smallest dose which results in symptom suppression.
  • Symptoms of the disease can be monitored by any invasive or noninvasive means which is convenient for measuring relevant aspects of the disease. For example, where the disease is osteoarthritis or another inflammatory joint disease, progression can be measured by determining amounts of collagenase in synovial fluid, by X-rays, or by other well known evaluation procedures which are applicable to the disease. Higher doses may be needed to inhibit the actual progression of the disease process pathophysiology.
  • the composition comprises at least one CMO compound and a NSAID or Cox-2 inhibitor.
  • the amount of CMO compound to be administered per day is from about 25 mg to about 2000 mg. More preferably, the amount of CMO compound is from about 75 mg to about 750 mg.
  • the amount of the NSAID or Cox-2 inhibitor to be administered for treatment of an inflammatory disease is an amount effective in combination with CMO compound to provide relief from pain or other symptoms of the disease, or to provide a significant reduction in one or more indications of disease progression.
  • the NSAID may be selected from the various classes of such compounds, and include for example, salicylates such as acetylsalicyclic acid, and diflunisal, acetic acids such as indomethacin, sulindac, tolmetin, diclofenac, and etodolac, propionic acids such as flurbiprofen, naproxen, ketoralac, and ketoprofen, fenamates such as meclofenamate, oxicams such as piroxicam, and oxindoles such as tenidap.
  • salicylates such as acetylsalicyclic acid, and diflunisal
  • acetic acids such as indomethacin
  • sulindac sulindac
  • tolmetin tolmetin
  • diclofenac diclofenac
  • etodolac etodolac
  • propionic acids such as flurbiprofen, naproxen
  • the composition comprises at least one CMO compound, a tetracycline compound and a Cox-2 inhibitor.
  • the amount of CMO compound to be administered per day is from about 25 mg to about 1000 mg. More preferably, the amount of CMO compound is from about 75 mg to about 750 mg. Where doxycycline is used as the tetracycline compound, the amount to be administered can be from about 5-10 mg to about
  • the Cox-2 inhibitor is in an amount which, when combined with CMO compound and tetracycline compound, results in a relief of symptoms or a significant reduction in one or more indications of disease progression.
  • CMO compounds can be used in combination with corticosteroids for treatment of inflammatory diseases.
  • Corticosteroids are commonly used for treatment of certain inflammatory diseases and conditions.
  • periarticular injection of methylprednisolone (Depo-Medrol) can be effective for treatment of clinical sacroiliitis in patients with seronegative spondylarthropathy.
  • Glucocorticoids are potent anti-inflammatory agents that play an important role in the therapy of many patients with connective tissue diseases, including systemic lupus erythematosus, polymyalgia rheumatica, various types of vasculitis, and complications of rheumatoid arthritis.
  • Glucocorticoids reduce the function of lymphocytes, monocytes, and eosinophils in peripheral blood and inhibit release of lysosomal enzymes. Glucocorticoids have proved to be effective in the treatment of inflammatory manifestations of disease, but long term dosing of increasing amounts are often required with their attendant side effects becoming common and severe. Among significant adverse effects of glucocorticoid therapy which can be minimized by the use addition of CMO compounds or tetracycline compounds and the reduction in the amount of glucocorticoids are osteoporosis, aseptic necrosis of bone, steroid myopathy, diabetes and defective collagen synthesis.
  • CMO compounds or tetracycline compounds include chelating agents such as EDTA, metalloprotease inhibitors and various inhibitors of synthesis or activity of immunostimulatory factors such as tumor necrosis factor (TNF) and IL-1.
  • TNF tumor necrosis factor
  • Activated oxygen species and other mediating substances from triggered phagocytes appear to exacerbate and perpetuate the rheumatoid condition.
  • Iron excesses are capable of aggravating arthritic inflammation, probably through their pro-oxidant potentials.
  • Iron chelating drugs and anti-oxidants have potential for clinical use to reduce free radical-induced tissue damage in rheumatoid arthritis.
  • Matrix metalloproteases are a family of enzymes that can degrade all the components of the extracellular matrix. To prevent unlimited connective tissue destruction a number of inhibitors exist to limit their activity. Artificial inhibitors which are useful for preventing cartilage erosion include cartilage protective agent (CPA) Ro 32-3555 (Roche) and CGS 27023A (Ciba).
  • TNF-alpha Treatment with a chimeric mAb to TNF-alpha has been shown to suppress inflammation and improve patient well-being in rheumatoid arthritis (RA).
  • TNF antagonists shown to be effective for short term treatment include infliximab and etanercept.
  • antagonism of the cytokine IL-1 may be useful for prevention of joint destruction.
  • CMO compounds or tetracycline compounds can be used in combination with one or more nutraceutical agents. Many nutraceuticals are believed to possess biological activities which are useful for disease treatment. Several studies claim glucosamine, chondroitin sulfate and collagen hydrolysate to be somewhat useful for symptomatic treatment of osteoarthritis. In an embodiment of the invention, treatment with CMO compounds and tetracycline compounds will slow cartilage and tissue deterioration and increase the effectiveness of these and other nutraceutical agents or factors which stimulate new cartilage formation, presumably by decreasing cartilage destruction.
  • the amount of glucosamine or chondroitin sulfate administered per day ranges from about 500 mg to about 2500 mg.
  • CMO compounds can be administered in combination with the aforementioned agents to obtain increased benefit, for example, where stronger remedial effects are desired.
  • the amount of CMO compound to be administered per day is from about 25 mg to about
  • the amount of CMO compound is from about 75 mg to about 750 mg. Tetracycline compounds can be added for increased effectiveness.
  • Viscosupplementation of synovial fluid has been used for treatment of arthritis patients.
  • treatment of synovial fluid of RA patients with intra-articularly injected hyaluronate has been found to result in clinical improvement.
  • synthetic crosslinked hyaluronans having improved viscosity characteristics such as hylan G-F 20 (Synvisc)
  • Viscosupplementation has also been tested in combination with treatment with NSAIDs.
  • CMO compounds or tetracycline compounds are used in combination with such treatments in a dose from about 25 mg to about 1000 mg. More preferably, the amount of CMO compounds is from about 75 mg to about 750 mg.
  • joint disease is suspected from, for example, clinical or radiographic findings.
  • Clinical signs of joint disease include lameness, pain, joint capsule distension, periarticular soft tissue swelling, crepitus, laxity, and thickening or enlargement of a joint by fibrosis or osteophytosis.
  • Radiographic indications for arthroscopy include increased joint fluid, joint capsule thickening, periarticular soft tissue swelling, osteophyte formation, sclerosis, joint space narrowing, cartilaginous or osseous deformities or defects, bone chips or fragments, and joint laxity or subluxation.
  • Conditions which can diagnosed arthroscopically include osteochondritis dissecans (OCD) of the shoulder, and elbow, meniscal injuries, partial and complete cruciate ligament ruptures, fragmentation of the medial coronoid process, degenerative joint disease, intra-articular fractures, synovitis, bicipital tendonitis, bicipital tendon rupture, and neoplasia.
  • OCD osteochondritis dissecans
  • Cartilage lesions can be detected before the onset of degenerative joint disease.
  • Obtaining biopsy specimens of synovial membrane from more than one joint with a minimally invasive technique is particularly helpful in the diagnosis of immune-mediated arthropathies.
  • certain local anaesthetics can be used to reduce symptoms of envenomation, particularly inflammation, when topically applied.
  • localized inflammation and dermal irritation can be similarly treated.
  • causes of such inflammation or irritation include, but are not limited to, contact with toxins, immunogens or other irritants.
  • Local anaesthetics include for example lidocaine, ropivicaine, prilocaine, americaine, benzocaine, bupivicaine, long acting topical anaesthetic (LTA; AstraZeneca), EMLA ® (eutectic mixture of local anaesthetics; AstraZeneca) anaesthetics (from Astra Pharmaceuticals), and other eutectic mixtures of local anaesthetics.
  • EMLA ® is a mixture of lidocaine and prilocaine in a ratio of about
  • the local anaesthetic is used in combination with CMO compounds, tetracycline compounds, papain or other proteases or peptidases, steroids or topical antibiotics to reduce inflammation, pain or infection risk.
  • the CMO compounds, tetracycline compounds, papain or other proteases or peptidases, steroids, or topical antibiotics can be topically applied or administered by another route.
  • the local anaesthetic will usually be topically applied.
  • Local anaesthetics typically are applied in amounts as are known in the pharmaceutical art and commonly used to deaden sensation.
  • steroids are used in concentrations typically available in commercially available creams and salves and in an amount sufficient to cover the area to be treated.
  • Tetracycline compounds are applied in amounts from about 10 ⁇ g to about 1000 ⁇ g.
  • CMO compounds are useful when applied in amounts from about 25 ⁇ g to 500 ⁇ g.
  • Proteases are typically formulated in ointments, pastes or other vehicles which can be topically applied in an amount from 0.1 % to 50% by weight. When the protease is papain, the preferred concentration is from about 0.5% to about 5%.
  • topical preparations may further comprise substances which enhance absorption.
  • absorption enhancers are well known to those of ordinary skill in the art. Examples include, but are not limited to dimethyl sulfoxide (DMSO), fatty acids, micelles, and microsome and liposome preparations.
  • DMSO or related compounds can have analgesic or anti-inflammatory properties.
  • compositions of the invention can be administered by a variety methods which are well known in the art.
  • Routes of administration include, but are not limited to oral, topical, sublingual, rectal, intranasal, intraocular, intravenous, intramuscular, transdermal, and by inhalation.
  • compositions for delivery to specific sites of inflammation, other means can be used for administering the composition such as, for example, by intraarticular, periarticular or intraosseous injection.
  • Delivery methods can employ microsomes or liposomes.
  • active components can be formulated into timed-release products.
  • Target specific delivery may be helpful as in colonic delivery of tetracycline compounds, CMO compounds, local anaesthetics or other agents to patients with colitis, or using transport peptides to bring effective compounds deeper into joint collagen or other tissues.
  • active components can be delivered locally to specific sites of action, for example by intraarticular, periarticular and intraosseous injection.
  • a proteolytic enzyme e.g., papain or stromolysin, collagenase
  • local anaesthetics is effective in relieving pain and decreasing inflammation.
  • CMO compounds or tetracycline compounds to the therapy, applied topically or otherwise administered can further increase efficacy.
  • active components used in treatment can be administered by the same route or at the same time.
  • a tetracycline compound is administered orally according to a first schedule and CMO compound is administered orally according to a second schedule.
  • a tetracycline compound and a Cox-2 inhibitor are injected and a CMO compound is administered orally.
  • viscosupplementation by intraarticular injection is combined with intraarticular administration of a CMO compound.
  • “pharmaceutically acceptable vehicle” means any of the standard pharmaceutical vehicles. Vehicles include any and all solvents, dispersion media, coatings, bandages, patches, antibacterial and antifungal agents, isotonic and absorption delaying or enhancing agents, transport polypeptides and lipids, sweeteners and the like.
  • the pharmaceutically acceptable vehicles may be prepared from a wide range of materials including, but not limited to, diluents, binders and adhesives, lubricants, disintegrants, coloring agents, bulking agents, flavoring agents, sweetening agents and miscellaneous materials such as buffers and absorbents that may be needed in order to prepare a particular therapeutic composition.
  • the use of such media and agents with pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • suitable vehicles include, but are not limited to, any of the standard vehicles such as phosphate buffered saline, phosphate buffered saline containing Polysorb, water, emulsions such as oil/water emulsion, and various types of wetting agents.
  • pharmaceutical compositions of the invention are for administration to a human.
  • a pharmaceutical composition can be administered to any animal.
  • treatment of joint diseases according to the invention can include reduction of gravitational or other forces acting on the affected joint or at vulnerable locations of the affected joint.
  • External tractions or mechanical support devices e.g., specially shaped foam or other viscoelastic compositions which decrease forces acting on the affected joint will be helpful. Splinting of the hand to maintain a joint in a neutral position can help treatment of joints of the hand. Similarly, other joints can be appropriately supported.
  • Doxycycline therapy was used for treatment of a middle aged male suffering from bilateral hip arthritis and experiencing severe pain despite increasing doses of NSAIDs. Rapid relief of pain to a more acceptable level was obtained with the addition of doxycycline but gastrointestinal upset was problematic.
  • Cox-2 inhibitors were substituted for the NSAID agents with better results. However, over time, it was necessary to increase the doses of both agents to two to three times the initial dose in order to maintain adequate symptomatic relief. Side effects noted at that time included dizziness, nausea and abdominal pain. A CMO compound was added and the dosage of the other agents decreased to initial levels. The side effects disappeared and improved symptomatic relief was noted. The Cox-2 agent was discontinued with no increase in severity of symptoms. Attempts to discontinue doxycycline were unsuccessful, with symptoms increasing during doxycycline free periods. Similarly, attempts to discontinue CMO treatment were met with worsening symptomatology.
  • a bee sting on one arm was treated with papain with mild relief from pain and swelling.
  • a second bee sting on the other arm was treated with papain, a eutectic mixture of local anaesthetics (EMLA ® ) and a topical steroid (Kenalog).
  • EMLA ® eutectic mixture of local anaesthetics
  • Kenalog topical steroid

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Abstract

On décrit des compositions utiles pour traiter les maladies inflammatoires y compris l'arthrite qui renferment des composés de myristoléate de cétyle ou des composés similaires et au moins un composé utile pour traiter les maladies inflammatoires, tel que les composés de tétracycline, les inhibiteurs Cox-2, les médicaments antiinflammatoires non stéroïdiens (AINS), les corticostéroïdes, les anesthésiques locaux, les agents chélateurs, les inhibiteurs de la métalloprotéase matricielle, les inhibiteurs de cytokines inflammatoires, la glucosamine, le sulfate de chondroïtine et l'hydrolysat de collagène. On décrit également des compositions pharmaceutiques et des procédés de traitement des maladies inflammatoires, de l'inflammation locale et de l'irritation cutanée ainsi que des compositions renfermant de la tétracycline et au moins un composé utile pour traiter les maladies inflammatoires.
PCT/US2000/033239 1999-12-09 2000-12-08 Procedes et compositions pour le traitement des maladies inflammatoires WO2001041783A1 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002002111A1 (fr) * 2000-07-01 2002-01-10 Lts Lohmann Therapie-System Ag Systeme therapeutique dermique contenant des antiphlogistiques non steroidiens a inhibition selective de la cox-2
WO2003015797A1 (fr) * 2001-08-14 2003-02-27 Pharmacia Corporation Compositions assurant le traitement et la prevention de douleurs et d'inflammations a l'aide d'un inhibiteur selectif de cyclooxygenase-2 et de glucosamine
WO2003015799A1 (fr) * 2001-08-14 2003-02-27 Pharmacia Corporation Compositions destinees au traitement et a la prevention de douleurs et d'inflammations a l'aide d'un inhibiteur selectif de cyclooxygenase-2 et d'un sulfate de chondroitine
WO2004069240A2 (fr) * 2003-02-07 2004-08-19 Research & Innovation Soc. Coop. A. R. L. Nouveaux composes de type endocannabinoide et leur utilisation
WO2009010707A1 (fr) * 2007-07-13 2009-01-22 Prototype Bioforum Limited Compositions pharmaceutiques injectables contenant du panthénol
WO2010079514A1 (fr) 2009-01-12 2010-07-15 Council Of Scientific & Industrial Research Procédé pour la préparation de cis-9-tétradécénoate d'hexadécyle et de cis-10-tétradécénoate d'hexadécyle
EP2283836A1 (fr) * 2009-08-13 2011-02-16 Jeffrey M. Golini Compositions anti-inflammatoires à base de créatine et d'acides gras cetylés
US8034796B2 (en) 2004-04-07 2011-10-11 The University Of Georgia Research Foundation, Inc. Glucosamine and glucosamine/anti-inflammatory mutual prodrugs, compositions, and methods
US8361990B2 (en) 2004-04-07 2013-01-29 University Of Georgia Research Foundation, Inc. Glucosamine and glucosamine/anti-inflammatory mutual prodrugs, compositions, and methods
US8906966B2 (en) 2006-07-13 2014-12-09 Paul Sherwood Medicaments containing panthenol

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US4049824A (en) * 1976-05-03 1977-09-20 Harry Weldon Diehl Cetyl myristoleate
US5260066A (en) * 1992-01-16 1993-11-09 Srchem Incorporated Cryogel bandage containing therapeutic agent
US5874479A (en) * 1991-03-01 1999-02-23 Warner-Lambert Company Therapeutic permeation enhanced-wound healing compositions and methods for preparing and using same
WO1999052508A1 (fr) * 1998-04-16 1999-10-21 Dosumu Johnson Thomas Procede de traitement de l'asthme
WO2000064436A1 (fr) * 1999-04-28 2000-11-02 Cg And Associates Procedes d'administration de cetyl myristoleate

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US3860702A (en) * 1972-07-11 1975-01-14 Schuyler Dev Corp Anti-inflammatory compositions
US4049824A (en) * 1976-05-03 1977-09-20 Harry Weldon Diehl Cetyl myristoleate
US5874479A (en) * 1991-03-01 1999-02-23 Warner-Lambert Company Therapeutic permeation enhanced-wound healing compositions and methods for preparing and using same
US5260066A (en) * 1992-01-16 1993-11-09 Srchem Incorporated Cryogel bandage containing therapeutic agent
WO1999052508A1 (fr) * 1998-04-16 1999-10-21 Dosumu Johnson Thomas Procede de traitement de l'asthme
WO2000064436A1 (fr) * 1999-04-28 2000-11-02 Cg And Associates Procedes d'administration de cetyl myristoleate

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002002111A1 (fr) * 2000-07-01 2002-01-10 Lts Lohmann Therapie-System Ag Systeme therapeutique dermique contenant des antiphlogistiques non steroidiens a inhibition selective de la cox-2
WO2003015797A1 (fr) * 2001-08-14 2003-02-27 Pharmacia Corporation Compositions assurant le traitement et la prevention de douleurs et d'inflammations a l'aide d'un inhibiteur selectif de cyclooxygenase-2 et de glucosamine
WO2003015799A1 (fr) * 2001-08-14 2003-02-27 Pharmacia Corporation Compositions destinees au traitement et a la prevention de douleurs et d'inflammations a l'aide d'un inhibiteur selectif de cyclooxygenase-2 et d'un sulfate de chondroitine
WO2004069240A2 (fr) * 2003-02-07 2004-08-19 Research & Innovation Soc. Coop. A. R. L. Nouveaux composes de type endocannabinoide et leur utilisation
WO2004069240A3 (fr) * 2003-02-07 2004-11-11 Res & Innovation Soc Coop A R Nouveaux composes de type endocannabinoide et leur utilisation
US8361990B2 (en) 2004-04-07 2013-01-29 University Of Georgia Research Foundation, Inc. Glucosamine and glucosamine/anti-inflammatory mutual prodrugs, compositions, and methods
US8034796B2 (en) 2004-04-07 2011-10-11 The University Of Georgia Research Foundation, Inc. Glucosamine and glucosamine/anti-inflammatory mutual prodrugs, compositions, and methods
US8906966B2 (en) 2006-07-13 2014-12-09 Paul Sherwood Medicaments containing panthenol
WO2009010707A1 (fr) * 2007-07-13 2009-01-22 Prototype Bioforum Limited Compositions pharmaceutiques injectables contenant du panthénol
WO2010079514A1 (fr) 2009-01-12 2010-07-15 Council Of Scientific & Industrial Research Procédé pour la préparation de cis-9-tétradécénoate d'hexadécyle et de cis-10-tétradécénoate d'hexadécyle
US8816109B2 (en) 2009-01-12 2014-08-26 Council Of Scientific & Industrial Research Process for preparation of hexadecyl cis-9-tetradecenoate and hexadecyl cis-10-tetradecenoate
EP2283836A1 (fr) * 2009-08-13 2011-02-16 Jeffrey M. Golini Compositions anti-inflammatoires à base de créatine et d'acides gras cetylés
US9968581B2 (en) 2009-08-13 2018-05-15 Jeffrey M. Golini Cetylated fatty acid and alkali buffered creatine anti-inflammatory composition

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