WO2005102296A2 - Associations pour traiter des troubles cutanes immunoproliferatifs - Google Patents

Associations pour traiter des troubles cutanes immunoproliferatifs Download PDF

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WO2005102296A2
WO2005102296A2 PCT/GB2005/001532 GB2005001532W WO2005102296A2 WO 2005102296 A2 WO2005102296 A2 WO 2005102296A2 GB 2005001532 W GB2005001532 W GB 2005001532W WO 2005102296 A2 WO2005102296 A2 WO 2005102296A2
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Prior art keywords
combination
vitamin
compounds
cells
cannabinoid
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PCT/GB2005/001532
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English (en)
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WO2005102296A3 (fr
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Richard Mark Edwards
John Martin Clements
Eric Roy Pettipher
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Heptagen Limited
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Priority claimed from GB0409129A external-priority patent/GB0409129D0/en
Priority claimed from GB0413380A external-priority patent/GB0413380D0/en
Priority claimed from GB0502870A external-priority patent/GB0502870D0/en
Application filed by Heptagen Limited filed Critical Heptagen Limited
Publication of WO2005102296A2 publication Critical patent/WO2005102296A2/fr
Publication of WO2005102296A3 publication Critical patent/WO2005102296A3/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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics

Definitions

  • the present invention relates to combinations of compounds which are useful in the treatment of psoriasis and to a method for screening compounds for activity against selected diseases and conditions such as psoriasis.
  • the present inventors have designed a new strategy for the development of combinations of known compounds, which are useful in the treatment of particular conditions.
  • Drug therapy is an attempt to modify aberrant or undesirable cellular behaviour in a targeted way and we have developed a strategy for investigating drug combinations which can be used to target a chosen disease state.
  • Our strategy is to expose cells which are representative of a chosen disease state to combinations of agents that act through different receptors or targets on different pathways within the cell.
  • agents that act through different receptors or targets on different pathways within the cell.
  • the present inventors have used this strategy to identify particular combinations of drugs and natural mediators which are useful for the treatment of immuno- proliferative skin disorders such as psoriasis.
  • topically administered agent which is effective in the treatment of immuno-proliferative skin disorders such as psoriasis and therefore such conditions were selected by the present inventors as candidate conditions for the development of a combination therapy.
  • Particularly desirable was a combination that would reduce the dose of topical retinoid or vitamin D derivative required and reduce or eliminate the need for concomitant treatment with corticosteroids.
  • Immuno-proliferative skin disorders such as psoriasis involve the hyper-proliferation and activation of skin cells (keratinocytes), invasion and activation of T-cells and/or other immune cells, and the activation and invasion of endothelial cells in the form of capillary sprouts (angiogenesis).
  • keratinocytes skin cells
  • T-cells and/or other immune cells invasion and activation of T-cells and/or other immune cells
  • angiogenesis endothelial cells in the form of capillary sprouts
  • a treatment for psoriasis would target more than a single cell-type, ideally all three.
  • the present inventors have identified combinations of agents which are particularly effective in the treatment of psoriasis.
  • agents from the following classes can be combined to give effective treatment of psoriasis:
  • WO-A-03/057162 relates to drug combinations which are useful in the treatment of immunoinflammatory skin disorders and proliferative diseases and, in particular, to combinations of prostaglandins and retinoids. Therefore, these combinations are excluded from the present invention.
  • the document does not suggest that either component could be used in a lower doses than would conventionally be expected.
  • the document does not disclose any other class of agent which may be useful in the treatment of immuno-proliferative skin disorders and it does not teach any method of finding other classes of agent or combinations which would be suitable.
  • the inventors have developed a combination therapy in which each of the individual components of the combination is administered at a dose which, if the component were administered alone, would be sub-optimal or sub-therapeutic. This means that only cells susceptible to all of the different mechanisms of action of the components will be affected by the combination therapy. Therefore, the combination of agents will be more selective than one of the components used alone and the risk of side effects will be greatly reduced.
  • a combination comprising: vitamin D or an analogue, proform or derivative thereof; a cannabinoid or cannabinoid receptor agonist; and a ⁇ -adrenergic receptor agonist.
  • the components of the combination may be present in an amount which, if the component were administered alone, would be sub-optimal or sub-therapeutic. This reduces the side effects of the combination in the patient.
  • combination refers to two or more agents from different classes which have been shown to act together so as to produce an effect on the target cell which is additive or synergistic.
  • a combination of agents may be a mixture of all of the agents or, alternatively, one or more of the agents may be administered separately from the other components of the combination.
  • additive refers to a combination in which the therapeutic effect is greater than the largest of the effects of the individual components.
  • an additive combination formulation containing 0.1 wt% of a first component and 0.1 wt% of a second component has an activity which is at least as great as the activity of a formulation containing, as sole active ingredient, either 0.2 wt% of the first component or 0.2 wt% of the second component.
  • a combination comprising agents selected from two or more of the following classes: Sphingosine and sphinogsine derivatives Prostaglandins Beta-adrenergic receptor agonists HMG-CoA reductase inhibitors Phospholipids or ether lipids Long chain unsaturated alcohols Long chain polyunsaturated fatty acids Cannabinoids or cannabinoid receptor agonists vitamin D analogues, derivatives and proforms Retinoids Purines Hydroxycholesterol; provided that the combination does not contain both a prostaglandin and a retinoid as the sole active agents.
  • the combination does not contain both a prostaglandin and a retinoid even when other active agents are present.
  • the combination may contain compounds from any or all of the classes above but it is preferred that it contains no more than one compound from each of the classes. Examples of suitable compounds from each of the classes are listed below.
  • vitamin D vitamin D
  • vitamin D3 ergocalciferol
  • cholecalciferol vitamin D3
  • the active form 1,25 dihydroxy vitamin D3 calcitriol
  • a synthetic analogue such as calcipitriol (calcipotriene) or
  • 1,24 dihydroxy vitamin D3 tacalcitol
  • a particularly preferred vitamin D compound is cholecalciferol.
  • Cannabinoid receptor agonists and other cannabinoids are also inhibitors of keratinocyte proliferation.
  • cannabinoid receptor agonists include the endogenous ligand arachidonylethanolamide, the cannabinoids delta 8 tetrahydrocannabinoid (THC8) and delta 9 tetrahydrocannabinoid (THC9), hemp oil and, in particular, the synthetic analogue nabilone.
  • cannabinoids such as cannabidiol
  • cannabidiol that do not bind to the cannabinoid receptor
  • They have the advantage that they are not psychoactive, and have a lower propensity for psychological and neurological side effects.
  • the cannabinoid or cannabinoid receptor agonist is cannabidiol or THC9.
  • ⁇ -adrenergic receptor agonists act via a different mechanism. It has been found that primary human keratinocytes carry the ⁇ -adrenergic receptor and that activation of the ⁇ -adrenergic receptor on primary human keratinocytes inhibits the release of the inflammatory cytokine interleukin-8 (IL-8). The inhibition of IL-8 inhibits angiogenesis and the immune response which are features of immuno-proliferative skin disorders such as psoriasis.
  • IL-8 cytokine interleukin-8
  • ⁇ -adrenergic receptor agonists include salmeterol, salbutamol, clenbuterol, formoterol, terbutaline, fenoterol, pirbuterol, isoproterenol, epinephrine, metaproterenol, hexoprenaline, isoetharine, isoprenaline, picumeterol, procaterol, reproterol, rimiterol and tulobuterol.
  • Salmeterol is particularly suitable for use in the pharmaceutical compositions of the present invention.
  • An especially preferred combination of the first aspect of the invention therefore comprises cholecalciferol, either cannabidiol or THC9 and salmeterol.
  • Sphingosine and its analogues are inhibitors of keratinocyte proliferation.
  • Sphingosine itself may be used in the compositions of the second aspect of the invention or, alternatively, an analogue of sphinosine such as sphinosine-1- phosphate, phytosphingosine or a sphingolipid such as sphingomyelin.
  • Prostaglandins are also inhibitors of keratinocyte proliferation.
  • Examples of prostaglandins which are effective in inhibiting keratinocyte proliferation include PGD2, PGAl, PGA2, PGBl, PGB2, PGE1, PGE2, PGJ2 and also prostaglandin analogues such as misoprostol, with PGE1 and misoprostol being preferred.
  • HMGCoA reductase inhibitors are, again, inhibitors of keratinocyte proliferation.
  • the HMGCoA reductase inhibitor may be lovastatin, mevinolin, simvastatin, pravastatin, fmvastatin, or atorvastatin. It is preferred, however, that the HMGCoA reductase inhibitor is lovastatin or, especially, mevinolin.
  • Suitable phospholipids include lysophosphatidyl choline, lysophosphatidic acid, platelet activating factor (PAF) or lyso PAF.
  • PAF platelet activating factor
  • phospholipid is lysophosphatidyl choline.
  • Farnesol is a particularly suitable example of a long chain unsaturated alcohol.
  • long chain unsaturated alcohols are inhibitors of keratinocyte proliferation.
  • the long-chain unsaturated fatty acid is eicosatriynoic acid (ETI), arachidonic acid, linoleic acid or linolenic acid.
  • ETI eicosatriynoic acid
  • Retinoids are inhibitors of keratinocyte proliferation.
  • retinoids suitable for use in the present invention are vitamin A, trans-retinoic acid (tretinoin), cis- retinoic acid (isotretinoin) and tazarotene.
  • purines such as adenosine receptor agonists
  • adenosine receptor agonists adenosine receptor agonists
  • Purines suitable for use in the combinations of the present invention include adenosine, adenosine diphosphate (ADP), adenosine triphosphate (ATP) and inosine.
  • ADP adenosine diphosphate
  • ATP adenosine triphosphate
  • inosine inosine.
  • composition of the invention comprises adenosine or a derivative thereof, it preferably also contains an adenosine deaminase inhibitor. This is particularly necessary when the purine is adenosine, which is unstable in vivo.
  • An adenosine deaminase inhibitor is a compound which is capable of inhibiting the human adenosine deaminase protein, which is commercially available.
  • Assay techniques suitable for determining whether or to what extent a given compound inhibits adenosine deaminase are known in the art. An appropriate assay is set out, for example, in Saboury et al, J of Biochem. and Mol. Biol, 1992, vol 35, p 302-305.
  • an adenosine deaminase inhibitor is a compound which has a maximal in vitro activity against human adenosine deaminase protein which is at least 25%, preferably at least 50%, more preferably at least 75%, of the maximal activity achieved with pentostatin under identical assay conditions.
  • the adenosine deaminase inhibitor is pentostatin, inosine or erythro -9-(2- Hydroxy-3-nonyl) adenine hydrochloride, all of which are commercially available or can be prepared by known methods familiar to those of skill in the art.
  • the adenosine deaminase inhibitors can be used as free acids or bases or as pharmaceutically acceptable salts.
  • the adenosine deaminase inhibitor is pentostatin.
  • suitable hydroxycholesterol derivatives include 22-R hydroxycholesterol and 24-S,25-epoxycholesterol. These compounds also inhibit keratinocyte proliferation.
  • Particularly preferred combinations of compounds include those containing a retinoid, in particular one of the retinoids listed above, i.e. vitamin A, trans-retinoic acid (tretinoin), cis-retinoic acid (isotretinoin) or tazarotene.
  • a retinoid in particular one of the retinoids listed above, i.e. vitamin A, trans-retinoic acid (tretinoin), cis-retinoic acid (isotretinoin) or tazarotene.
  • vitamin D2 vitamin D2
  • vitamin D3 cholecalciferol
  • calcitriol 1 ,25-dihydroxy vitamin D3
  • calcipitriol calcipitriol or tacalcitol
  • Still further preferred combinations of compounds are those containing a ⁇ - adrenergic receptor agonist, in particular salmeterol, salbutamol, clenbuterol, formoterol, terbutaline, fenoterol, pirbuterol, isoproterenol, epinephrine, metaproterenol, hexoprenaline, isoetharine, isoprenaline, picumeterol, procaterol, reproterol, rimiterol and tulobuterol; and an adenosine receptor agonist such as include adenosine, adenosine diphosphate (ADP), adenosine triphosphate (ATP) and inosine.
  • ADP adenosine diphosphate
  • ATP adenosine triphosphate
  • combinations which are particularly useful in the treatment of immunoproliferative skin disorders such as psoriasis include combinations comprising: a vitamin D analogue and a retinoid; a vitamin D analogue and a cannabinoid; a vitamin D analogue and a hydroxycholesterol; a retinoid and a cannabinoid; a retinoid and a hydroxycholesterol; a cannabinoid and a hydroxycholesterol; a vitamin D analogue, a retinoid and a cannabinoid; a vitamin D analogue, a retinoid and a hydroxycholesterol; a vitamin D analogue, a retinoid and a hydroxycholesterol; a vitamin D analogue, a cannabinoid and a hydroxycholesterol; a vitamin D analogue, a cannabinoid and a hydroxycholesterol; and a retinoid, a cannabinoi
  • references to cannabinoids includes cannabinoid receptor agonists or cannabidiol and references to hydroxycholesterol include the hydroxycholesterol derivatives described above. Examples of preferred compounds from each of the classes are given above.
  • favourable combinations include any of the above, with the further addition of a ⁇ -agonist, for example a vitamin D analogue, a cannabinoid and a ⁇ -agonist as set out above in the first aspect of the invention.
  • a ⁇ -agonist for example a vitamin D analogue, a cannabinoid and a ⁇ -agonist as set out above in the first aspect of the invention.
  • the combinations of the present invention are useful in a method for the treatment of immunoproliferative skin disorders, the method comprising administering to a patient in need of such treatment an appropriate amount of a combination according to the present invention.
  • the combination of the present invention may form part of a conventional pharmaceutical formulation or, alternatively, it may be provided as a product in which the components are administered separately, simultaneously or sequentially.
  • composition comprising a combination according to the invention together with a suitable pharmaceutical excipient or adjuvant;
  • the administration when the components are administered separately, the administration can be up to 24 hours apart. However, more usually they will be administered within 24 hours, and preferably within 8 hours, of one another.
  • the product may comprise a two or more single components of the combination or, alternatively a single component and one or more mixtures, or a plurality of mixtures, wherein each mixture contains two or more components of the combination.
  • the pharmaceutical composition or the product of the invention may additionally comprise one or more other compounds known to be of use in the treatment of immuno-proliferative skin disorders such as psoriasis.
  • examples of such compounds include corticosteroids such as hydrocortisone, anthralin and salicylic acid.
  • the amount of each component depends upon the particular compound chosen but is typically from 0.003 wt% to 10 wt%, preferably from 0.0025 wt% to 1 wt%, more preferably from .025 wt% to .1 wt%, for example about 0.05 wt%, based on the total weight of the formulation.
  • composition comprises a retinoid
  • this may be present in an amount of from 0.0002wt% to 0.16 wt%, more usually from 0.0006 wt% to 0.04 wt% and preferably from about 0.0025 wt% to 0.01 wt% and typically about 0.005 wt% based on the total weight of the formulation.
  • composition or product comprises vitamin D or an analogue thereof
  • this may be present in an amount of 0.0002 wt% to .16 wt%, preferably from 0.0006 wt% to 0.04 wt%, more preferably from 0.0025 wt% to .01 wt%, for example about 0.005 wt%, based on the total weight of the composition.
  • the total amount of combination in the composition or product of the invention is from 0.0018 to 11.6 wt%, preferably from 0.0088 to 1.4 wt%, more preferably from 0.05 to 0.2 wt%, for example about .1 wt%, based on the total weight of the formulation.
  • composition or product of the present invention is formulated for topical administration and it may be administered to a patient in an amount such that from 0.00001 to 10 g, preferably from 0.0001 to 1 g active ingredient is delivered per m 2 of the area being treated.
  • the topical formulation may, for example, take the form of a gel, ointment, cream or lotion.
  • said formulation When said formulation is a gel it typically comprises a hydrophilic polymer such as cross-linked polyethylene glycol, cross-linked starch or polyvinyl pyrrolidone.
  • a hydrophilic polymer such as cross-linked polyethylene glycol, cross-linked starch or polyvinyl pyrrolidone.
  • An ointment, cream or lotion typically contains an aqueous phase and an oleaginous phase in admixture.
  • the formulation may additionally contain one or more emollients, emulsifiers, thickeners and/or preservatives, particularly when it is a cream or ointment.
  • Emollients suitable for inclusion in creams or ointments of the present invention are typically long chain alcohols, for example a C8-C22 alcohol such as cetyl alcohol, stearyl alcohol and cetearyl alcohol, hydrocarbons such as petrolatum and light mineral oil, or acetylated lanolin.
  • the total amount of emollient in the formulation is preferably about 5 wt% to about 30 wt%, and more preferably about 5 wt% to about 10 wt% based on the total weight of the formulation.
  • the emulsifier is typically a nonionic surface active agent, e.g., polysorbate 60 (available from ICI Americas), sorbitan monostearate, polyglyceryl-4 oleate and polyoxyethylene(4)lauryl ether.
  • polysorbate 60 available from ICI Americas
  • sorbitan monostearate e.g., polyglyceryl-4 oleate
  • polyoxyethylene(4)lauryl ether e.g., polyoxyethylene(4)lauryl ether.
  • the total amount of emulsifier is about 2 wt% to about 14 wt%, and more preferably about 2 wt% to about 6 wt% by weight based on the total weight of the formulation.
  • thickeners such as Veegum.TM.K (available from R. T. Vanderbilt Company, Inc.), and long chain alcohols (i.e. C8-C22 alcohols such as cetyl alcohol, stearyl alcohol and cetearyl alcohol) can be used.
  • the total amount of thickener present is preferably about 3 wt% to about 12 wt% based on the total weight of the formulation.
  • Preservatives such as methylparaben, propylparaben and benzyl alcohol can be present in the formulation.
  • the appropriate amount of such preservative(s) is known to those skilled in the art.
  • an additional solubilizing agent such as benzyl alcohol, lactic acid, acetic acid, stearic acid or hydrochloric acid can be included in the formulation. If an additional solubilizing agent is used, the amount present is preferably about 1 wt% to about 12 wt% based on the total weight of the formulation.
  • the formulation can contain a humectant such as glycerin and a skin penetration enhancer such as butyl stearate, urea and DMSO.
  • a humectant such as glycerin
  • a skin penetration enhancer such as butyl stearate, urea and DMSO.
  • cetyl alcohol can serve both as an emollient and as a thickener.
  • said formulation or medicament is a cream.
  • the cream typically consists of an oil phase and a water phase mixed together to form an emulsion.
  • the cream comprises an oil-in-water emulsion.
  • the amount of water present in a cream of the invention is about 45 wt% to about 85 wt% based on the total weight of the cream.
  • the formulation or medicament typically comprises a pharmaceutically acceptable ointment base such as petrolatum, or polyethylene glycol 400 (available from Union Carbide) in combination with polyethylene glycol 3350 (available from Union Carbide).
  • a pharmaceutically acceptable ointment base such as petrolatum, or polyethylene glycol 400 (available from Union Carbide) in combination with polyethylene glycol 3350 (available from Union Carbide).
  • the amount of ointment base present in an ointment of the invention is preferably about 60 wt% to about 95 wt% based on the total weight of the ointment.
  • the formulation is a cream which comprises an oil-in- water cream base comprising isostearic acid, cetyl alcohol, stearyl alcohol, white petrolatum, polysorbate 60, sorbiton monostearate, glycerin, xanthum gum, purified water, benzyl alcohol, methylparaban and propyl-paraban.
  • a cream may be in the form of Aldara imiquimod cream which contains 5% imiquimod.
  • Combinations and pharmaceutical compositions of the present invention may be prepared simply by admixing the ingredients in a suitable manner.
  • a target cell type or types implicated in the selected disease process i. selecting a target cell type or types implicated in the selected disease process; ii. screening a set of compounds for their ability to induce a therapeutic effect in the target cell of interest; iii. identifying a subset of compounds which induce a therapeutic effect in the target cell of interest; iv. where possible, grouping the subset of compounds into classes defined by their mechanism of action; v. selecting individual compounds from two or more classes and screening them in combination for their ability to induce a therapeutic effect in the target cell of interest;
  • the method of the invention has the advantage that it enables combinations of agents to be identified in which each member of the combination acts on the cell via a different mechanism. There is therefore potential for developing a combination therapy in which each of the individual components of the combination is administered at a dose which, if the component were administered alone, would be sub-optimal or sub-therapeutic. This means that only cells which are susceptible to all of the different mechanisms of action would be likely to be affected by the combination therapy. Thus, the combination of agents is likely to be far more selective than one of the components used alone and the risk of side effects is likely to be greatly reduced.
  • the agents have been found to act synergistically, although this is not a requirement of the present invention - an additive effect is sufficient for the combination of agents to be useful.
  • nism refers to the means by which the agent being screened acts on the target cell.
  • the term “mechanism” therefore includes cell-surface receptors, nuclear receptors, signalling pathways, ion channels, enzymes etc.
  • the steps of screening the compounds (step ii) and identifying compounds of interest (step iii) may be divided into a primary screening step to identify a group having some activity at the target cell, followed by one or more re-screening steps to identify the subset of compounds which induce a therapeutic effect.
  • the method further comprises an initial step of expression profiling to confirm the presence of the relevant receptor or other drug target.
  • an initial step of expression profiling to confirm the presence of the relevant receptor or other drug target.
  • expression profiling it is possible to avoid excessive screening by limiting the screen to those drugs or natural mediators which are likely to interact with the target cell of interest.
  • the number of compounds in the initial screen can be limited to as little as two hundred, and sometimes less than this.
  • the method of the invention may be used to identify combinations of agents which are active against a large number of diseases and conditions.
  • One class of disease for which the inventors have developed useful therapeutic combinations is immuno-proliferative skin disorders, for example psoriasis and particularly useful combinations are described above.
  • the method is effective for identifying agents which have therapeutic effects in a disease involving inflammatory, hyperproliferative, and angiogenic responses, it will also be applicable to other disease states that involve one or all of these processes.
  • diseases include for example dermatitis and arthritis and other autoimmune or inflammatory diseases involving leucocytes, which can therefore be used as the target cells in the method of the invention.
  • the approach is also readily applicable to cancer therapy, by targeting the growth, differentiation and chemotaxis of endothelial cells, thus depriving solid tumours of a blood supply.
  • the approach will also be useful in directly targeting cancer cells, by stimulating multiple independent pathways to trigger apoptosis. This approach is useful in the treatment of leukemias as well as solid and disseminated tumours.
  • suitable target cells include the following.
  • Endothelial cells for solid tumours. These cells line blood vessels and form capillaries and a therapeutic effect is indicated by the ability of an agent to inhibit the growth, differentiation or chemotaxis of endothelial cells, which would deprive solid tumours of a blood supply.
  • tumour cells Isolated representative tumour cells.
  • expression profiling is carried out on RNA extracted from the tumour cell in order to identify receptors or drug targets present on the tumour cell. Apoptosis of the tumour cell is a desirable therapeutic effect.
  • Immuno-proliferative skin disorders are skin disorders characterised by keratinocyte proliferation, which are mediated by an abnormal immune response. Examples include dermatitis, acne and psoriasis. Such disorders are widespread and, for example, the prevalence of psoriasis is around 1-2%, and is about 2% in the UK.
  • Immuno-proliferative skin disorders can vary in severity from rather common and mildly irritating diseases through to severe and life-threatening illnesses. They necessarily involve the hyper-proliferation of skin cells (keratinocytes) and invasion of T-cells and/or other immune cells.
  • suitable target cells include the following.
  • keratinocytes which, in conditions such as psoriasis, show excessive growth. Therefore inhibition of keratinocyte proliferation is an indication of a therapeutic effect in immuno-proliferative skin disorders such as psoriasis.
  • T-cells are implicated in immunoproliferative skin disorders and therefore a therapeutic effect is indicated by the ability of a compound to inhibit T-cell activation.
  • Endothelial cells line blood vessels and form capillaries and are a suitable target because of the excessive blood vessel formation associated with psoriatic lesions. Therefore, inhibition of endothelial cell proliferation is also a desirable therapeutic effect.
  • Endothelial cell growth is also a feature of blood vessel formation in solid tumours and therefore can be used as a suitable target cell when the method of the invention is used to develop therapeutic combinations for the treatment of solid tumours.
  • FIGURE 1 is a keratinocyte assay growth curve
  • FIGURE 2 shows an example of results obtained from a primary screen
  • FIGURE 3 shows the results titrations with 7-, 8- and 9-component combinations
  • FIGURE 4 shows results obtained in a screen of three-way combinations
  • FIGURE 5 shows results obtained in a screen of three-way combinations
  • FIGURE 6 relates to Example 21 and shows the inhibition of keratinocyte proliferation by retinoids
  • FIGURE 7 relates to Example 11 and shows the inhibition of keratinocyte proliferation by sphingosine and sphingosine derivatives
  • FIGURE 8 relates to Example 12 and shows the inhibition of keratinocyte proliferation by adenosine
  • FIGURE 9a relates to Example 13 and shows the inhibition of keratinocyte proliferation by prostaglandins
  • FIGURE 9b also relates to Example 13 and shows the inhibition of keratinocyte proliferation by prostaglandins
  • FIGURE 10 relates to Example 14 and shows the inhibition of keratinocyte proliferation by the beta-adrenergic receptor agonist salmeterol;
  • FIGURE 11 relates to Example 15 and shows the inhibition of keratinocyte proliferation by the HMG CoA reductase inhibitor mevinolin;
  • FIGURE 12 relates to Example 16 and shows the inhibition of keratinocyte proliferation by phospholipids and ether lipids
  • FIGURE 13 relates to Example 17 and shows the inhibition of keratinocyte proliferation by the polyunsaturated alcohol farnesol
  • FIGURE 14 relates to Example 18 and shows the inhibition of keratinocyte proliferation by polyunsaturated fatty acids
  • FIGURE 15 relates to Example 19 and shows the inhibition of keratinocyte proliferation by cannabinoid receptor agonists
  • FIGURE 16 relates to Example 20 and shows the inhibition of keratinocyte proliferation by 22-R-hydroxy cholesterol;
  • FIGURE 17 relates to Example 10 and shows the inhibition of keratinocyte proliferation by vitamin D analogues
  • FIGURE 18 relates to Example 22 and shows the inhibition of keratinocyte proliferation by combinations of 1,25 dihydroxycalciferol with compounds from other classes;
  • FIGURE 19 relates to Example 23 and shows the inhibition of keratinocyte proliferation by combinations of cholecalciferol with compounds from other classes;
  • FIGURE 20 relates to Example 24 and shows the inhibition of keratinocyte proliferation by combinations of retinoic acid with compounds from other classes ;
  • FIGURE 21 relates to Example 25 and shows the inhibition of keratinocyte proliferation by combinations of retinoic acid with compounds from other classes.
  • FIGURE 22 relates to Example 26 and shows the inhibition of keratinocyte proliferation by delta-8 tetrahydrocannabinol, delta-9 tetrahydrocannabinol and cannabidiol.
  • FIGURE 23 relates to Example 26 and is a plot of amount of drug against keratinocyte growth -which demonstrates an additive interaction between cholecalciferol and cannabidiol.
  • FIGURE 24 which relates to Example 27, shows the results of three separate experiments in which the ability of the beta agonist salbutamol to inhibit keratinocyte activation as measured by inhibition of IL8 release was measured.
  • FICURE 25 again relates to Example 27 and shows that the beta agonists salbutamol and salmeterol at 2nM concentration can completely block trypsin-induced keratinocyte activation.
  • Cpd Compound which inhibits keratinocyte proliferation
  • Cpd/CAL combination of 1,25 dihydroxycalciferol and another compound which inhibits keratinocyte proliferation
  • Cpd/CCF combination of cholecalciferol and another compound which inhibits keratinocyte proliferation
  • Cpd/TRA combination of trans-retinoic acid and another compound which inhibits keratinocyte proliferation
  • THC delta-9 tetrahydrocannabinol
  • AAA arachidonic acid
  • HCH 22-(R) hydroxycholesterol
  • LPA lysophosphatidic acid
  • Immuno-proliferative skin disorders are skin disorders characterised by keratinocyte proliferation, which are mediated by an abnormal immune response. Examples include dermatitis, acne and psoriasis. Such disorders are widespread. Thus, for example, the prevalence of psoriasis is around 1-2%, with a trend to higher occurrence rates in northern latitudes. In the UK, prevalence is 2%
  • Psoriasis can vary in severity from rather common and mildly irritating diseases through to severe and life-threatening illnesses. They necessarily involve the hyper- proliferation and activation of skin cells (keratinocytes), invasion and activation of T-cells and/or other immune cells, and the activation and invasion of endothelial cells in the form of capillary sprouts (angiogenesis). Each of these cell types would therefore represent a good target for intervention in psoriasis.
  • a treatment for psoriasis would target more than a single cell-type, ideally all three.
  • HTK human epidermal keratinocytes isolated from skin were obtained from TCS Cellworks, Botolph Claydon, Buckingham, MK18 2LR, UK. Cells were maintained in EpiLife, a defined basal medium designed for human keratinocytes supplemented with selected hormones and growth factors (TCS Cellworks). Cells were maintained for a maximum of 15 population doublings to ensure the cultures do not terminally differentiate.
  • Proliferating cultures were trypsinised, harvested, treated with a trypsin inhibitor and resuspended in growth medium. The viable cells were counted then replated into 24 or 96 well cell culture plates at a density of approximately 2,500 cells/cm 2 . Cells were incubated overnight at 37°C at 5% CO 2 to allow recovery, the spent medium aspirated from the wells and replaced with fresh growth medium. The cells were then returned to the incubator for a further 3-5 days. AlamarBlue 2%v/v was added to the wells and reduction measured fluorometrically using a Molecular Dynamics BioLumin 9600 microtitre plate reader using excitation wavelength at 530nM and absorbance wavelength at 590nM.
  • Example 4 Primary screen for compounds that inhibit keratinocyte proliferation
  • HNK human epidermal keratinocytes
  • Proliferating cultures were trypsinised, harvested, treated with a trypsin inhibitor and resuspended in growth medium. The viable cells were counted then re-plated into a 96 well cell culture plate at a density of approximately 2,500 cells/cm 2 as described above. Cells were incubated overnight at 37°C at 5% CO2 to allow recovery, the spent medium aspirated from the wells and replaced with fresh growth medium.
  • HTK human epidermal keratinocytes isolated from skin were obtained from TCS Cellworks and maintained as in Example 2. Proliferating cultures were trypsinised, harvested, treated with a trypsin inhibitor and resuspended in growth medium. The viable cells were counted then re-plated into a 96 well cell culture plate at a density of approximately 2,500 cells/cm 2 as described above. Cells were incubated overnight at 37°C at 5% CO 2 to allow recovery, the spent medium aspirated from the wells and replaced with fresh growth medium. Compounds were made up as a lOmM stock solution in DMSO, methanol or water as appropriate.
  • Mevinolin gave a complex dose response curve, with partial inhibitory effects at low concentrations ( ⁇ 1 microM), and essentially complete inhibition at concentrations greater than 50 microM.
  • Salmeterol gave a reproducible increase in proliferation at low doses, with an inhibitory effect at higher doses (EC50 ⁇ 20 microM).
  • Example 5 we explored the scope for exploiting the additive inhibitory effects of seven compounds chosen from the list identified in Example 5. These were chosen on the basis of their potency and/or their suitability for formulation and product development. The compounds are listed in Table 3, along with their estimated EC50.
  • All compounds were held as lOmM stock solutions.
  • a ligand mix was made by diluting 20 microlitre of each compound into the same 10 ml of growth medium and mixed thoroughly. One ml of this was added to one well of a 24-well plate to give a top concentration of 20 microM for each compound, or 140 microM ligand mix.
  • HNK human epidermal keratinocytes
  • Proliferating cultures were trypsinised, harvested, treated with a trypsin inhibitor and resuspended in growth medium. The viable cells were counted then re-plated into 24 well cell culture plate at a density of approximately 2,500 cells/cm 2 as described above. Cells were incubated overnight at 37°C at 5% CO 2 to allow recovery, the spent medium aspirated from the wells and replaced with fresh growth medium.
  • the compounds were made up to a stock concentration as given in the accompanying table, such that addition of 20 microlitres to 2 ml of medium in the wells would give the required final concentration. All 168 permutations of the nine additions (eight compounds plus water) were explored in duplicate, along with 24 controls with no additions made, in eight 24-well microtitre plates. A computer programme was used to randomise additions to the wells and generate templates for ease of manual addition using a repeating pipettor. After making the additions, the cells were returned to the incubator for 3 days. The proliferation assay was carried out using Alamar Blue as described in Example 2. The data are presented as percentage of growth seen in the control wells without added compounds.
  • HNK human epidermal keratinocytes
  • Proliferating cultures were trypsinised, harvested, treated with a trypsin inhibitor and resuspended in growth medium. The viable cells were counted then replated into a 96 well cell culture plate at a density of approximately 1,000 cells/well as described in Example 2. Cells were incubated overnight at 37°C at 5% CO 2 to allow recovery, the spent medium aspirated from the wells and replaced with fresh growth medium. 1,25 dihydroxy- Vitamin D 3 was made up as a lOmM stock solution in DMSO. Ergocalciferol and cholecalciferol were made up as a lOmM stock solutions in methanol. All three compounds were obtained from Sigma- Aldrich. Serial dilutions of the above compounds were made in the growth medium and added to the cells to give final concentrations ranging from 0.1 to 100 microM, and the cells returned to the incubator for 2 days. The proliferation assay was carried out as described in Example 2.
  • Example 11 Inhibition of keratinocyte proliferation by sphingosine and sphingosine-related compounds
  • HNK human epidermal keratinocytes
  • Proliferating cultures were trypsinised, harvested, treated with a trypsin inhibitor and resuspended in growth medium. The viable cells were counted then replated into a 96 well cell culture plate at a density of approximately 1,000 cells/well as described above. Cells were incubated overnight at 37°C at 5% CO 2 to allow recovery, the spent medium aspirated from the wells and replaced with fresh growth medium. Sphingosine and spingosine-1 -phosphate were made up as a lOmM stock solution in DMSO. Both compounds were obtained from Sigma- Aldrich.
  • sphingosine was reproducibly more potent as an inhibitor than sphingosine- 1 -phosphate.
  • HNK human epidermal keratinocytes
  • Proliferating cultures were trypsinised, harvested, treated with a trypsin inhibitor and resuspended in growth medium. The viable cells were counted then replated into a 96 well cell culture plate at a density of approximately 1,000 cells/well as described above. Cells were incubated overnight at 37°C at 5% CO 2 to allow recovery, the spent medium aspirated from the wells and replaced with fresh growth medium. Adenosine was obtained from Sigma-Aldrich and made up as a lOmM stock solution in DMSO.
  • the pattern of inhibition seen with adenosine is consistent with its role as a reversible inhibitor of adenosine proliferation.
  • Example 13 Inhibition of keratinocyte proliferation by prostaglandins and prostaglandin analogues
  • Cryopreserved human epidermal keratinocytes (HEK) isolated from skin were obtained from TCS Cellworks and maintained as in Example 2.
  • Proliferating cultures were trypsinised, harvested, treated with a trypsin inhibitor and resuspended in growth medium. The viable cells were counted then replated into a 96 well cell culture plate at a density of approximately 1,000 cells/well as described above. Cells were incubated overnight at 37oC at 5% CO 2 to allow recovery, the spent medium aspirated from the wells and replaced with fresh growth medium.
  • Prostaglandins and the synthetic prostaglandin El analogue misoprostol were made up as a lOmM stock solutions in methanol. All compounds were obtained from Sigma-Aldrich.
  • Example 14 Inhibition of keratinocyte proliferation by beta adrenergic receptor agonists
  • HNK human epidermal keratinocytes
  • Proliferating cultures were trypsinised, harvested, treated with a trypsin inhibitor and resuspended in growth medium. The viable cells were counted then replated into a 96 well cell culture plate at a density of approximately 1,000 cells/well as described above. Cells were incubated overnight at 37°C at 5% CO 2 to allow recovery, the spent medium aspirated from the wells and replaced with fresh growth medium.
  • Salmeterol was obtained from Tocris Cookson and made up as a lOmM stock solution in DMSO.
  • HNK human epidermal keratinocytes
  • Proliferating cultures were trypsinised, harvested, treated with a trypsin inhibitor and resuspended in growth medium. The viable cells were counted then replated into a 96 well cell culture plate at a density of approximately 1,000 cells/well as described above. Cells were incubated overnight at 37°C at 5% CO 2 to allow recovery, the spent medium aspirated from the wells and replaced with fresh growth medium.
  • Mevinolin (lovastatin) obtained from Sigma-Aldrich was made up as a lOmM stock solution in DMSO.
  • Example 16 Inhibition of keratinocyte proliferation by phospholipids and ether lipids
  • HNK human epidermal keratinocytes
  • Proliferating cultures were trypsinised, harvested, treated with a trypsin inhibitor and resuspended in growth medium. The viable cells were counted then replated into a 96 well cell culture plate at a density of approximately 1,000 cells/well as described above. Cells were incubated overnight at 37°C at 5% CO 2 to allow recovery, the spent medium aspirated from the wells and replaced with fresh growth medium.
  • HNK human epidermal keratinocytes
  • Proliferating cultures were trypsinised, harvested, treated with a trypsin inhibitor and resuspended in growth medium. The viable cells were counted then replated into a 96 well cell culture plate at a density of approximately 1,000 cells/well as described above for adenosine. Cells were incubated overnight at 37°C at 5% CO 2 to allow recovery, the spent medium aspirated from the wells and replaced with fresh growth medium.
  • Farnesol was obtained from Sigma-Aldrich and made up as a lOmM stock solution in methanol.
  • Example 18 Inhibition of keratinocyte proliferation by long-chain unsaturated fatty acids
  • HNK human epidermal keratinocytes
  • Proliferating cultures were trypsinised, harvested, treated with a trypsin inhibitor and resuspended in growth medium. The viable cells were counted then replated into a 96 well cell culture plate at a density of approximately 1,000 cells/well as described above. Cells were incubated overnight at 37°C at 5% CO 2 to allow recovery, the spent medium aspirated from the wells and replaced with fresh growth medium. Eicosatriynoic acid arachidonic acid and linoleic acid were made up as lOmM stock solutions in methanol. Both compounds were obtained from Sigma-Aldrich.
  • HNK human epidermal keratinocytes
  • Proliferating cultures were trypsinised, harvested, treated with a trypsin inhibitor and resuspended in growth medium. The viable cells were counted then replated into a 96 well cell culture plate at a density of approximately 1,000 cells/well as described above. Cells were incubated overnight at 37°C at 5% CO 2 to allow recovery, the spent medium aspirated from the wells and replaced with fresh growth medium.
  • Delta-8 and delta-9 tetrahydrocannabinol, and arachidonylethanolamide (anandamide) were made up as lOmM stock solutions in methanol. All three compounds were obtained from Sigma-Aldrich.
  • HNK human epidermal keratinocytes
  • Proliferating cultures were trypsinised, harvested, treated with a trypsin inliibitor and resuspended in growth medium. The viable cells were counted then replated into a 96 well cell culture plate at a density of approximately 1,000 cells/well as described above for adenosine. Cells were incubated overnight at 37°C at 5% CO 2 to allow recovery, the spent medium aspirated from the wells and replaced with fresh growth medium.
  • the cholesterol derivative 22(R)-hydroxycholesterol was obtained from Sigma- Aldrich and made up as a lOmM stock solution in methanol.
  • HNK human epidermal keratinocytes
  • Proliferating cultures were trypsinised, harvested, treated with a trypsin inhibitor and resuspended in growth medium. The viable cells were counted then replated into a 96 well cell culture plate at a density of approximately 1,000 cells/well as described above. Cells were incubated overnight at 37°C at 5% CO 2 to allow recovery, the spent medium aspirated from the wells and replaced with fresh growth medium.
  • retinoic acid obtained from Sigma-Aldrich were made up as a lOmM stock solutions in methanol.
  • Example 22 Inhibition of keratinocyte proliferation by combinations of 1,25 dihydroxy vitamin D and compounds from other classes.
  • HNK human epidermal keratinocytes
  • Proliferating cultures were trypsinised, harvested, treated with a trypsin inhibitor and resuspended in growth medium. The viable cells were counted then replated into 24 well cell culture plates at a density of approximately 1,000 cells/well as described above. Cells were incubated overnight at 37°C at 5% CO 2 to allow recovery, the spent medium aspirated from the wells and replaced with fresh growth medium.
  • the appropriate dilutions of the compounds were made in the growth medium and added to the cells to give the final concentrations depicted in the above table.
  • the cells were returned to the incubator for a further 3 days.
  • the proliferation assay was carried out as described in Example 2.
  • Example 23 Inhibition of keratinocyte proliferation by combinations of cholecalciferol and compounds from other classes
  • HNK human epidermal keratinocytes
  • Proliferating cultures were trypsinised, harvested, treated with a trypsin inhibitor and resuspended in growth medium. The viable cells were counted then replated into 24 well cell culture plates at a density of approximately 1,000 cells/well as described above. Cells were incubated overnight at 37°C at 5% CO 2 to allow recovery, the spent medium aspirated from the wells and replaced with fresh growth medium.
  • the appropriate dilutions of the compounds were made in the growth medium and added to the cells to give the final concentrations depicted in the above table.
  • the cells were returned to the incubator for a further 3 days.
  • the proliferation assay was carried out as described in Example 2.
  • Example 24 Inhibition of keratinocyte proliferation by combinations of retinoic acid and compounds from Other Classes Cryopreserved human epidermal keratinocytes (HEK) isolated from skin were obtained from TCS Cellworks and maintained as in Example 2.
  • HEK human epidermal keratinocytes
  • Proliferating cultures were trypsinised, harvested, treated with a trypsin inhibitor and resuspended in growth medium. The viable cells were counted then replated into 24 well cell culture plates at a density of approximately 1,000 cells/well as described above. Cells were incubated overnight at 37°C at 5% CO 2 to allow recovery, the spent medium aspirated from the wells and replaced with fresh growth medium.
  • the appropriate dilutions of the compounds were made in the growth medium and added to the cells to give the final concentrations depicted in Table 21.
  • the cells were returned to the incubator for a further 3 days.
  • the proliferation assay was carried out as described in Example 2.
  • Example 25 Inhibition of keratinocyte proliferation by combinations of retinoic acid and compounds from Other Classes
  • HNK human epidermal keratinocytes
  • Proliferating cultures were trypsinised, harvested, treated with a trypsin inhibitor and resuspended in growth medium. The viable cells were counted then replated into 24 well cell culture plates at a density of approximately 1,000 cells/well as described above. Cells were incubated overnight at 37°C at 5% CO 2 to allow recovery, the spent medium aspirated from the wells and replaced with fresh growth medium.
  • the appropriate dilutions of the compounds were made in the growth medium and added to the cells to give the final concentrations depicted in Table 22.
  • the cells were returned to the incubator for a further 3 days.
  • the proliferation assay was carried out as described in Example 2.
  • Example 26 Inhibition of keratinocyte proliferation by cannabidiol Cryopreserved human epidermal keratinocytes (HEK) isolated from skin were obtained from TCS Cellworks and maintained as in Example 2.
  • HEK human epidermal keratinocytes
  • Proliferating cultures were trypsinised, harvested, treated with a trypsin inhibitor and resuspended in growth medium. The viable cells were counted then replated into a 96 well cell culture plate at a density of approximately 1,000 cells/well as described above. Cells were incubated overnight at 37°C at 5% CO 2 to allow recovery, the spent medium aspirated from the wells and replaced with fresh growth medium. Delta-8 and delta-9 tetrahydrocannabinol, and cannabidiol were made up as lOmM stock solutions in methanol. All three compounds were obtained from Sigma- Aldrich.
  • cannabidiol although reported as an antagonist at the cannabinoid receptors, is almost as effective at inhibiting keratinocyte proliferation as THC8 and THC9. This suggests that the cytostatic and cytotoxic effects of the cannabinoids are not mediated by the classic cannabinoid receptors. It also offers practical benefits in the development of therapies for psoriasis, as cannabidiol is devoid of the psychoactive effects of THC8 and THC9.
  • a keratinocyte activation assay was developed in which primary human keratinocytes were stimulated by mild treatment with trypsin, which activates the receptor PAR2. The cells responded by releasing a number of cytokines, including IL-8, a potent chemokine that attracts and activates neutrophils, and in addition promotes angiogenesis.
  • cytokines including IL-8, a potent chemokine that attracts and activates neutrophils, and in addition promotes angiogenesis.
  • Figure 24 gives the results of three experiments that show this response. It also demonstrates that the release of IL-8 was potently inhibited by the beta-adrenergic receptor agonist salbutamol with an EC50 of about 300 pM. The beta-adrenergic receptor agonist appears to be acting via a cAMP independent process, as it was not enhanced by the phosphodiesterase inhibitor rolipram.
  • HNK human epidermal keratinocytes isolated from skin were obtained from TCS Cellworks and maintained as in Example 2. Proliferating cultures were trypsinised, harvested, treated with a trypsin inhibitor and resuspended in growth medium. The viable cells were counted then added to a 96 well cell culture plate at a density of approximately 10,000 cells/well as described above to provide a confluent monolayer. Cells were incubated overnight at 37°C at 5% CO 2 to allow recovery, the spent medium aspirated from the wells and replaced with fresh growth medium. The cells were incubated at 37°C at 5% CO 2 for a further 24 hours.

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Abstract

L'invention concerne des associations de composés qui sont efficaces pour traiter des troubles cutanés immunoprolifératifs. La quantité de chacun des composés de l'association est inférieure à la quantité utilisée dans les compositions pharmaceutiques traditionnelles ne comportant qu'un seul agent actif, de manière à réduire la possibilité d'effets secondaires.
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006111424A1 (fr) * 2005-04-22 2006-10-26 Life & Brain Gmbh Procedes permettant d'identifier des modulateurs des recepteurs cannabinoides cb1 et cb2 et leur utilisation dans la cicatrisation des blessures
EP1719507A1 (fr) 2005-04-13 2006-11-08 Astion Development A/S Des agonistes de bêta-2 adrénocepteur pour le traitement de maladies du tissus conjonctifs
WO2007102011A1 (fr) * 2006-03-09 2007-09-13 Sosei R & D Ltd. Utilisation de bêta-aminoalcools dans le traitement de troubles inflammatoires et de la douleur
EP1923060A1 (fr) * 2006-11-08 2008-05-21 Nederlandse Organisatie voor Toegepast-Natuuurwetenschappelijk Onderzoek TNO Combinaisons d'une sphingolipide d'un inhibiteur de la reductase HMG-CoA destinées au traitement de la hypercholesterémie
WO2008140335A3 (fr) * 2007-05-14 2009-12-30 Fonterra Co-Operative Group Limited Procédés de stimulation immunitaire ou hématologique, inhibant une formation ou croissance de tumeur, et traitant ou empêchant un cancer, des symptômes de cancer ou des symptômes de traitements contre le cancer
WO2010019120A1 (fr) * 2008-08-15 2010-02-18 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health Of Human Services, National Institutes Of Health S0x9, prostaglandine d2 et acide rétinoïque utilisés pour traiter les affections pigmentaires et le mélanome
FR2965477A1 (fr) * 2010-10-05 2012-04-06 Oreal Utilisation de cannabidiol contre les desequilibres de la microflore cutanee
US10835501B2 (en) * 2016-10-01 2020-11-17 Indication Bioscience Llc Pharmaceutical compositions comprising a statin and a cannabinoid and uses thereof
WO2024012400A1 (fr) * 2022-07-11 2024-01-18 南京毓浠医药技术有限公司 Composé alcool-amine de trétinoïne, son procédé de préparation et son utilisation

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0579915A1 (fr) * 1992-05-20 1994-01-26 F. Hoffmann-La Roche Ag Composition pharmaceutique contenant de l'acide 9-cis- ou 13-cis retinoique ou de l'acitretine et un dérivé de la vitamine D
WO1995005829A1 (fr) * 1993-08-21 1995-03-02 Lts Lohmann Therapie-Systeme Gmbh & Co. Kg Systeme therapeutique pour le traitement du psoriasis
WO1997009987A1 (fr) * 1995-09-15 1997-03-20 Centre International De Recherches Dermatologiques Galderma (Cird Galderma) Nouvelles compositions a base d'un melange synergetique entre au moins un ligand de vdr et un retinoide
US6251883B1 (en) * 1991-01-08 2001-06-26 Bone Care International, Inc. Methods for preparation and use of 1α,24(S)-dihydroxy vitamin D2
WO2003057162A2 (fr) * 2002-01-04 2003-07-17 Combinatorx, Incorporated Combinaison pour le traitement de troubles immuno-inflammatoires et de maladies de la peau proliferatives

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6251883B1 (en) * 1991-01-08 2001-06-26 Bone Care International, Inc. Methods for preparation and use of 1α,24(S)-dihydroxy vitamin D2
EP0579915A1 (fr) * 1992-05-20 1994-01-26 F. Hoffmann-La Roche Ag Composition pharmaceutique contenant de l'acide 9-cis- ou 13-cis retinoique ou de l'acitretine et un dérivé de la vitamine D
WO1995005829A1 (fr) * 1993-08-21 1995-03-02 Lts Lohmann Therapie-Systeme Gmbh & Co. Kg Systeme therapeutique pour le traitement du psoriasis
WO1997009987A1 (fr) * 1995-09-15 1997-03-20 Centre International De Recherches Dermatologiques Galderma (Cird Galderma) Nouvelles compositions a base d'un melange synergetique entre au moins un ligand de vdr et un retinoide
WO2003057162A2 (fr) * 2002-01-04 2003-07-17 Combinatorx, Incorporated Combinaison pour le traitement de troubles immuno-inflammatoires et de maladies de la peau proliferatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GL[SER R ET AL: "Hyperpigmentation due to topical calcipotriol and photochemotherapy in two psoriatic patients." THE BRITISH JOURNAL OF DERMATOLOGY. JUL 1998, vol. 139, no. 1, July 1998 (1998-07), pages 148-151, XP002340470 ISSN: 0007-0963 *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8426475B2 (en) 2005-04-13 2013-04-23 Astion Development A/S Treatment of connective tissue diseases of the skin
EP1719507A1 (fr) 2005-04-13 2006-11-08 Astion Development A/S Des agonistes de bêta-2 adrénocepteur pour le traitement de maladies du tissus conjonctifs
US9907765B2 (en) 2005-04-13 2018-03-06 Cipher Pharmaceuticals Inc. Treatment of connective tissue diseases of the skin
WO2006111424A1 (fr) * 2005-04-22 2006-10-26 Life & Brain Gmbh Procedes permettant d'identifier des modulateurs des recepteurs cannabinoides cb1 et cb2 et leur utilisation dans la cicatrisation des blessures
WO2007102011A1 (fr) * 2006-03-09 2007-09-13 Sosei R & D Ltd. Utilisation de bêta-aminoalcools dans le traitement de troubles inflammatoires et de la douleur
WO2008069652A1 (fr) * 2006-11-08 2008-06-12 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno Combinaisons d'un sphingolipide et d'un inhibiteur de la hmg-coa réductase pour le traitement de l'hypercholestérolémie
EP1923060A1 (fr) * 2006-11-08 2008-05-21 Nederlandse Organisatie voor Toegepast-Natuuurwetenschappelijk Onderzoek TNO Combinaisons d'une sphingolipide d'un inhibiteur de la reductase HMG-CoA destinées au traitement de la hypercholesterémie
WO2008140335A3 (fr) * 2007-05-14 2009-12-30 Fonterra Co-Operative Group Limited Procédés de stimulation immunitaire ou hématologique, inhibant une formation ou croissance de tumeur, et traitant ou empêchant un cancer, des symptômes de cancer ou des symptômes de traitements contre le cancer
WO2010019120A1 (fr) * 2008-08-15 2010-02-18 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health Of Human Services, National Institutes Of Health S0x9, prostaglandine d2 et acide rétinoïque utilisés pour traiter les affections pigmentaires et le mélanome
US8946291B2 (en) 2008-08-15 2015-02-03 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Compositions and methods for treating pigmentary conditions and melanoma
AU2008360658B2 (en) * 2008-08-15 2015-02-19 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services S0X9, prostaglandin D2 and retinoic acid for treating pigmentary conditions and melanoma
FR2965477A1 (fr) * 2010-10-05 2012-04-06 Oreal Utilisation de cannabidiol contre les desequilibres de la microflore cutanee
US10835501B2 (en) * 2016-10-01 2020-11-17 Indication Bioscience Llc Pharmaceutical compositions comprising a statin and a cannabinoid and uses thereof
US20230055662A1 (en) * 2016-10-01 2023-02-23 Indication Bioscience Llc Compositions and Methods Using a Cannabinoid to Enhance Bioavailability of a Statin
US11786482B2 (en) * 2016-10-01 2023-10-17 Indication Bioscience Llc Compositions and methods using a cannabinoid to enhance bioavailability of a statin
WO2024012400A1 (fr) * 2022-07-11 2024-01-18 南京毓浠医药技术有限公司 Composé alcool-amine de trétinoïne, son procédé de préparation et son utilisation

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