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WO2008090331A1 - Inhibiteurs de la recaptation de la sérotonine destinés au traitement de l'arthrite - Google Patents

Inhibiteurs de la recaptation de la sérotonine destinés au traitement de l'arthrite Download PDF

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Publication number
WO2008090331A1
WO2008090331A1 PCT/GB2008/000217 GB2008000217W WO2008090331A1 WO 2008090331 A1 WO2008090331 A1 WO 2008090331A1 GB 2008000217 W GB2008000217 W GB 2008000217W WO 2008090331 A1 WO2008090331 A1 WO 2008090331A1
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Prior art keywords
reuptake inhibitor
serotonin reuptake
serotonin
agent
inflammatory
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Brian M. Foxwell
Sandra Sacre
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Ip2ipo Innovations Ltd
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Imperial Innovations Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • 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
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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 serotonin reuptake inhibitors (SRIs) including selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) for treating inflammatory arthritis and related conditions.
  • SRIs serotonin reuptake inhibitors
  • SSRIs selective serotonin reuptake inhibitors
  • SNRIs serotonin norepinephrine reuptake inhibitors
  • the present invention also relates to a kit comprising a pharmaceutical composition comprising a serotonin reuptake inhibitor and instructions indicating that the composition is for use in treating inflammatory arthritis and related conditions.
  • the present invention relates to a method of treating inflammatory arthritis and related conditions comprising administration of a serotonin reuptake inhibitor. The method is preferably carried out on a subject in need of treatment.
  • the inflammatory arthritis is preferably rheumatoid arthritis.
  • Rheumatoid arthritis is a chronic inflammatory disease occurring in 0.5%-l% of the population. This disease affects the joints and is characterized by thickening of the synovial membrane. This disease leads to progressive debilitation in joint function which results in pain, disability, loss of man power and shorter life expectancy. In addition there are a number of similar related conditions; psoriatic arthritis, juvenile arthritis ankylosing spondelytis, Crohn's disease and psoriasis.
  • steroids such as dexamethasone and methyl-prednisolone
  • steroids are widely used in the treatment of rheumatoid arthritis. While treatment with steroids can be effective, there are a number of serious side effects. These side effects include hypertension, growth deficiencies in younger patients, osteoporosis, cataracts, psychosis, elevated blood sugar, glaucoma, etc.
  • some patients are resistant to long-term use of steroids or become so with time.
  • New and alternative treatments currently used for rheumatoid arthritis are based on biologicals such as antibodies and soluble receptors.
  • the most widely used of these is based on blocking TNF function with neutralizing antibodies or soluble receptors and has defined TNF as a key pathway in the inflammatory processes in RA.
  • This type of anti-TNF therapy has been successful in the treatment of a number of diseases, with a substantial proportion of patients (approximately 60%) showing significant clinical benefit Besides treating the inflammation, anti-TNF therapy also prevents joint destruction and thus is considered to have disease modifying anti-arth ⁇ tic drug (DMARD) activity
  • DMARD disease modifying anti-arth ⁇ tic drug
  • DARDS disease modifying anti-rheumatic drugs
  • methotrexate an anti-metabolite drug, which is widely used for the treatment of rheumatoid arthritis, pso ⁇ atic arthritis and pso ⁇ asis.
  • Methotrexate has been successful in the treatment of these diseases, but can cause substantial side effects, such as severe skin reaction, infections such as pneumonia, severe damage to liver, kidneys, lungs and gastrointestinal tract. Again a significant number of patients do not respond or become refractory with time.
  • a number of DMARD pharmaceutical agents containing gold are also used in the treatment of rheumatoid arthritis
  • examples of such agents include gold sodium thiomalate and auranofin
  • Potential side effects from being treated with antiinflammatory gold agents are oral ulcers, altered taste, se ⁇ ous skin rashes, renal problems, inflammation of the intestines (enterocolitis), liver injury and lung disease. Furthermore, resistance to gold has been known to develop in patients
  • a further class of drugs are the non-steroidal anti-inflammatory drugs (NSAED' s). These are used to alleviate symptoms but not modify disease progression and includes the Cox 2 inhibitors "VIOXX” ® , (a registered trademark of Merck & Co., Inc) and "CELEBREX” ® , (a registered trademark of G.D. Searle & Co). However there is major concern about the safety of these drugs with evidence of increased cardiovascular risk.
  • NSAED' s non-steroidal anti-inflammatory drugs
  • SRIs are well known for use in the treatment of depression and other related conditions such as OCD. SRIs (including SSRIs and SNRIs) would be expected to promote inflammation as serotonin is associated with inflammation. In addition, other studies have indicated that sertraline, a SSRI, exacerbates inflammation in the carrageenan-induced model of paw inflammation (Abdel-Salam et al., Pharmacol Res 48, 157-165, 2003).
  • the first aspect of the present invention provides a serotonin reuptake inhibitor (SRI) for treating inflammatory arthritis and related conditions.
  • SRI serotonin reuptake inhibitor
  • the inflammatory arthritis is anti-TNF responsive arthritis, as are the related conditions psoriatic arthritis, juvenile arthritis, ankylosing spondelytis, Crohn's disease and psoriasis.
  • These drugs are envisaged to be useful in diseases where treatment with anti-TNF has shown to be beneficial e.g. Crohn's disease and psoriasis, but not useful in diseases where anti-TNF has been shown to be ineffective or to exacerbate disease, e.g. systemic lupus erythematosus, multiple sclerosis and ulcerative colitis.
  • LPS lipopolysaccharide
  • the inflammatory arthritis is rheumatoid arthritis and the related conditions are psoriatic arthritis, juvenile arthritis, ankylosing spondelytis, Crohn's disease and psoriasis.
  • a serotonin reuptake inhibitor of the invention is any compound that inhibits reuptake of serotonin. This includes selective serotonin reuptake inhibitor (SSRI) compounds and serotonin norepinephrine reuptake inhibitor (SNRI) compounds.
  • SSRI selective serotonin reuptake inhibitor
  • SNRI serotonin norepinephrine reuptake inhibitor
  • a SRI is a drug that increases the amount of serotonin (5- hydroxytryptamine or 5-HT) by inhibiting its reuptake into cells.
  • the drug is an inhibitor of the serotonin transporter (5-HTT), a monoamine transporter protein.
  • a SRI of the invention inhibits TNF production.
  • the serotonin reuptake inhibitor of the invention can be amoxapine, amitriptyline ("ELAVIL”, “ENDEP”, “TRYPTANOL”, “TREPILINE”), clomipramine
  • ANAFRANIL desipramine
  • NPRAMIN desipramine
  • PROTfflADEN dothiepin hydrochloride
  • ADAPIN doxepin
  • SINEQUAN imipramine
  • TOFRANIL lofepramine
  • GAMANIL lofepramine
  • PROTAPEL lofepramine
  • PAMELOR nortriptyline
  • VIVACTIL trimipramine
  • trimipramine SURMONTIL
  • the selective serotonin reuptake inhibitor of the invention can be citalopram ("CELEXA”, “CEPRAMIL”, “EMOCAL”, “SEPRAM”, “SEROPRAM”), escitalopram oxalate ("LEXAPRO”, “CIPRALEX”, “ESERTIA”), fluoxetine ("PROZAC”, “FONTEX”, “SEROMEX”, “SERONIL”, “SARAFEM”, “FLUCTIN” (EUR)), fluvoxamine maleate ("LUVOX”, “FAVERIN”), paroxetine ("PAXIL”, “SEROXAT”, “AROPAX”, “DEROXAT”, “PAROXAT”), sertraline (“ZOLOFT”, "LUSTRAL”, “SERLAIN”), dapoxetine or St Johns Wort
  • the serotonin-norepinephnne reuptake inhibitor of the invention can be venlafaxine ("EFFEXOR XR” and “EFEXOR”), nefazodone ("SERZONE”), milnacipran (“DALCIPRAN” and “IXEL”), desipramine (“N0RPRAMINE” and “PERTOFRANEIS”) or duloxetine ("CYMBALTA”).
  • the use may be of combinations of two or more SRIs, which may be for simultaneous, separate or sequential use.
  • the SRI may be used in combination with a further anti-inflammatory agent.
  • Administration of the SRI and other anti-inflammatory agent can be simultaneous, separate and/or sequential
  • the SRI, in combination with another pharmaceutical agent, can act additively or synergistically.
  • the other anti -inflammatory agent may be termed a non-steroidal anti-inflammatory agent (NSAID), a disease modifying anti-rheumatic drug (DMARD), a statin (including HMG-CoA reductase inhibitors such as simvastatin), a biological agent (biologicals), a steroid, an immunosuppressive agent, a salicylate and/or a microbicidal agent.
  • NSAID non-steroidal anti-inflammatory agent
  • DMARD disease modifying anti-rheumatic drug
  • statin including HMG-CoA reductase inhibitors such as simvastatin
  • a biological agent biologicals
  • a steroid an immunosuppressive agent
  • an immunosuppressive agent a salicylate and/or a microbicidal agent.
  • Non-steroidal anti-inflammatory agents include anti-metabolite agents (including methotrexate) and anti-inflammatory gold agents (including gold sodium thiomalate, aurothiomalate or gold
  • Biologicals include anti-TNF agents (including adalimumab, etanercept, infliximab, anti-EL-1 leagents, anti-IL-6 reagents, anti-B cell reagents (retoximab), anti-T cell reagents (anti-CD4 antibodies), anti-IL-15 reagents, anti-CLTA4 reagents, anti-RAGE reagents), antibodies, soluble receptors, receptor binding proteins, cytokine binding proteins, mutant proteins with altered or attenuated functions, RNAi, polynucleotide aptmers, antisense oligonucleotides or omega 3 fatty acids
  • Steroids include cortisone, prednisolone or dexamethasone.
  • Immunosuppressive agents include cylcospo ⁇ n, FK506, rapamycin, mycophenolic acid Salicylates include aspirin, sodium salicylate, choline salicylate and magnesium salicylate. Microbicidal agents include quinine and chloroquine.
  • the SRI may be administered in combination with one or more of an NSAID, DMARD, or immunosuppressant.
  • the further anti-inflammatory agent is administered by any appropriate route, for example oral (including buccal or sublingual), suppositories, topical (including buccal, sublingual or transdermal), or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • oral including buccal or sublingual
  • suppositories including buccal, sublingual or transdermal
  • parenteral including subcutaneous, intramuscular, intravenous or intradermal
  • the SRIs of the present invention are those SRIs which are non-toxic to living cells.
  • the present invention also provides the use of a serotonin reuptake inhibitor (SRI) in the manufacture of a medicament for treating inflammatory arthritis and related conditions.
  • SRI serotonin reuptake inhibitor
  • the second aspect of the invention is a kit comprising a pharmaceutical composition comprising an SRI and instructions indicating that the composition is for use in treating inflammatory arthritis and related conditions.
  • compositions in accordance with the invention may be supplied as part of a sterile, pharmaceutical composition which will normally include a pharmaceutically acceptable earner.
  • This pharmaceutical composition may be in any suitable form. It may be provided in unit dosage form and will generally be provided in a sealed container.
  • the kit of the invention may comprise a plurality of said unit dosage forms.
  • compositions may be presented as discrete units such as capsules or tablets; as powders or granules; as solutions, syrups or suspensions (in aqueous or non-aqueous liquids; or as edible foams or whips; or as emulsions).
  • Suitable excipients for tablets or hard gelatine capsules include lactose, maize starch or derivatives thereof, stea ⁇ c acid or salts thereof
  • Suitable excipients for use with soft gelatine capsules include for example vegetable oils, waxes, fats, semi-solid, or liquid polyols etc
  • excipients which may be used include for example water, polyols and sugars
  • suspensions oils e g vegetable oils
  • compositions may contain preserving agents, solubilising agents, stabilising agents, wetting agents, emulsifiers, sweeteners, colourants, odourants, salts, buffers, coating agents or antioxidants They may also contain further therapeutically active agents
  • Route of administration may include, parenterally (including subcutaneous, intramuscular, intravenous, by means of, for example a d ⁇ p patch), some further suitable routes of administration include (but are not limited to) oral (including buccal and sublingual), rectal, nasal, topical, infusion, vaginal, intradermal, intrape ⁇ toneally, intracranially, intrathecal and epidural administration or administration via oral or nasal inhalation, by means of, for example a nebuliser or inhaler, or by an implant
  • the may be delivered using a mechanical form including, but not restricted to, an inhaler or nebuliser device
  • administration is by a SPAG (small particulate aerosol generator) may be used
  • Dosages of the substances of the present invention can vary between wide limits, depending upon the condition to be treated, the health of the individual to be treated, etc and a physician may determine approp ⁇ ate dosages to be used The dosage may be repeated as often as approp ⁇ ate
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy
  • the amount of active ingredient which can be combined with a earner matenal to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration
  • the amount of active ingredient which can be combined with a earner material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect
  • compositions and uses described in this application are envisaged to have human, animal and veterinary applications They are preferably applicable to mammals, in particular humans but are also applicable for use in production animals, in particular sheep, cows, pigs, chickens and goats, as well as companion animals, in particular cats and dogs and sporting animals, such as horses
  • the third aspect of the invention is a method of treating inflammatory arthritis and related conditions comprising administration of a serotonin reuptake inhibitor
  • the method is preferably earned out on a subject in need of treatment
  • the term "treatment” includes prophylactic treatment (i e prevention)
  • prophylactic treatment i e prevention
  • prevention of inflammatory arthntis or a related condition is unlikely to be earned out Usually, it is only when the presence of inflammatory arthntis or a related condition is diagnosed in a subject that prevention means are applied
  • prophylactic treatment may be appropnate if there is i) a known family history of significant inflammatory arthntis or a related condition or if tests (e g genetic tests) identify that an individual has a predisposition to inflammatory arthntis or a related condition
  • Figure 1 illustrates inhibition of spontaneous cytokine release from RA synovial membrane cultures by citalopram and fluoxetine hydrochlonde (“PROZAC")
  • Graph (A) illustrates a dose dependent inhibition of TNF levels and IL- l ⁇ levels by fluoxetine hydrochlo ⁇ de (“PROZAC”) as measured by ELISA
  • Graph (B) illustrates a dose dependent inhibition of TNF in cells incubated with citalopram
  • Figure 3 illustrates inhibition of disease progression in the CIA model of rheumatoid arthritis by fluoxetine hydrochlo ⁇ de (“PROZAC").
  • A illustrates clinical score
  • Figure 4 Graph (A) illustrates inhibition by fluoxetine hydrochlonde of TNF production from human macrophages activated by LPS (10ng/ml), Flagelhn (lOng/ml), R848 (l ⁇ g/ml) and malp-2 (lOng/ml)
  • Graph (B) illustrates TNF production in murine RAW264.7 macrophages stimulated with 20 ⁇ g/ml poly IC in the presence of media alone or fluoxetine hydrochlo ⁇ de
  • Graph (C) illustrates inhibition by fluoxetine hydrochlo ⁇ de of TNF production in CpG stimulated mu ⁇ ne RAW264 7 macrophages.
  • FIG. 5 illustrates that inhibition of TNF production by R-848 is common to the serotonin reuptake inhibitors.
  • Graph (A) illustrates TNF production from macrophages stimulated with l ⁇ g/ml R848 or 10ng/ml LPS in the media alone or in the presence of 30 ⁇ g/ml citalopram, lO ⁇ g/ml fluoxetine hydrochlo ⁇ de (“PROZAC") or 5 ⁇ g/ml sertraline (“ZOLOFT”)
  • FIG.B illustrates TNF levels from macrophages stimulated with 10ng/ml Pam3, 10ng/ml LPS, 10ng/ml Flagelhn, l ⁇ g/ml R848 and 10ng/ml malp-2 in media alone or in the presence of 5 ⁇ g/ml sertraline (“ZOLOFT”)
  • Figure 6 illustrates that TLR3, 7, 8 and 9 are expressed in the rheumatoid synovial membrane cultures but only TLR3 and 8 induce TNF production Graph
  • Graph (C) illustrates TNF production in rheumatoid membrane synovial cells after stimulation with 20 ⁇ g/ml Poly IC (TLR3), l ⁇ g/ml imiquimod (TLR7), l ⁇ g/ml R-848 (TLR7/8) and 2 ⁇ M CpG (TLR9).
  • Figure 7 illustrates the effect of serotonin on TNF and EL-I levels in RA membrane cell cultures Graph
  • Cell culture reagents used were Penicillin-Streptomycin, RPMI 1640 and DMEM obtained from Cambrex (Belgium), Indomethacin from Sigma (USA) and FBS from PAA (Aust ⁇ a).
  • the TLR hgands used were chloroform extracted Escherichia coli (E.coh) LPS, resiquimod (R-848), mu ⁇ ne CpG (ODN1826), human CpG (ODN 2006) and imiquimod from Invivogen (USA), Macrophage-activating hpopeptide (Malp-2), Flagellin (pu ⁇ fied) and serotonin (5-HT) hydrochlo ⁇ de were from Alexis (UK) Fluoxetine hydrochlo ⁇ de (“PROZAC”) and chloroquine diphosphate salt, Sertraline (“ZOLOFT”) and citalopram were purchased from Sigma (USA) Pam 3 cys- ser(lys) 4 3HCl (Pam3) was from Alex
  • TTGAAGGCTTGGGACCAAGGCA-S 1 were used with an annealing temperature of
  • the primers 5'- TCTACCTGGGCCAAAACTGTT-3' and 5'- GGCAC ATGCTGAAGAG AGTTA-3' were used with an annealing temperature of 6O 0 C.
  • AATGCTTCATTTGGGATGTGCT-3' were used with an annealing temperature of
  • ELISA enzyme-linked immunosorbent assay
  • Macrophages or RA synovial membrane cell cultures were stimulated with lOng/ml chloroform-extracted LPS, 20 ⁇ g/ml poly IC, 2 ⁇ M CpG (murine or human), 10ng/ml Pam3, 10ng/ml Flagellin, 10ng/ml Malp-2 or l ⁇ g/ml R-848 in complete media for 6h.
  • Supernatants from RA cultures were harvested after 24 hours.
  • AU reagents other than LPS were free from LPS contamination as assessed using the limulus amebocyte lysate (LAL) assay from Cambrex (USA).
  • Sandwich ELISAs were employed to measure TNF, (Pharmingen, UK), IP-10 (R&D, USA) and IL- l ⁇ (Bioscource, USA). Absorbance was read on a spectrophotometric ELISA plate reader (Labsystems Multiscan Biochromic) and analyzed using Ascent software V2.6 (Thermo Labsystems, Cambridge, United Kingdom). All results are expressed as the mean cytokine concentration ⁇ SD obtained from triplicate cultures per condition. Cell viability was not significantly affected over this time period when examined by the 3-[4,5 dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) assay (Sigma).
  • MTT 3-[4,5 dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide
  • RA synovial membrane cells were isolated from patients undergoing joint replacement surgery as previously desc ⁇ bed (Foxwell et al., Proc. Natl. Acad. Sci. USA 95,8211-8215, 1998). All patients gave w ⁇ tten informed consent and the study was approved by the local ethics committee. Immediately after isolation, cells were used for mRNA analysis, stained by FACS or cultured at IxIO 5 cells/well in 96-well tissue culture plates (Falcon, UK) in RPMI 1640 containing 10% (v/v) FBS and 100 U/ml penicillin/streptomycin. Pe ⁇ pheral blood monocytes were isolated and cultured as previously desc ⁇ bed (Foxwell et al., Proc. Natl.
  • Macrophages were de ⁇ ved from monocytes after differentiation for 4 days with 100 ng/ml M-CSF (PeproTech, UK).
  • the mouse macrophage cell line RAW 264.7 was maintained in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum.
  • Example 1 Rheumatoid arthritis synovial membrane cells were cultured for 24 hours in the presence of media alone or media containing 5 ⁇ g/ml orlO ⁇ g/ml fluoxetine hydrochlo ⁇ de ("PROZAC"). Supernatants were harvested and levels of cytokines (A) TNF or IL- 1 were measured by ELISA Addition of fluoxetine hydrochlo ⁇ de (“PROZAC") at the time of culture led to a dose dependent decrease in the levels of TNF and IL-I ( Figure 1, Graph A).
  • Rheumatoid arthritis synovial membrane cells were also cultured in the presence of media alone or media containing lO ⁇ g/ml, 20 ⁇ g/ml and 30 ⁇ g/ml citalopram and levels of TNF were measured. TNF production was dose dependently inhibited in cells treated with citalopram (see Figure IB).
  • the murine CIA model has been shown to be clinically similar to human rheumatoid arthritis with a comparable synovitis, bone erosion and panus formation.
  • CFA Co Laboratories, West Molesey, U.K.
  • mice were given an interperitoneal injection of vehicle (PBS) or 25mg/kg of citalopram or fluoxetine hydrochlo ⁇ de once a day for 7 days Mice were assessed for ( Figures 2A and 3A) clinical score on a daily basis.
  • PBS vehicle
  • citalopram or fluoxetine hydrochlo ⁇ de
  • mice treated with citalopram at the day of onset of arthritis exhibited an attenuated disease progression over a 7 day pe ⁇ od.
  • Disease pathogenesis was assessed by measuring clinical score
  • the mice treated with citalopram showed a significant improvement to the control group from day 2-3 onwards ( Figure 2, Graph A) Histology samples taken from the hind paws of mice treated with citalopram showed a decreased histology score over the control group ( Figure 2B).
  • mice treated with fluoxetine hydrochlo ⁇ de at the day of onset of arthritis exhibited an attenuated disease progression over a 7 day pe ⁇ od. Disease pathogenesis was assessed by measu ⁇ ng clinical score.
  • the mice treated with fluoxetine hydrochlo ⁇ de showed a significant improvement to the control group ( Figure 3, Graph A, B).
  • This effect of fluoxetine hydrochlo ⁇ de was dose dependent as 10mg/kg showed a significant improvement throughout the study from the vehicle control, whilst the lOmg/kg group showed a small but not significant improvement (Figure 3, Graph A). This was also reflected in the measurement of hind paw swelling that also showed a significant improvement throughout the study for both the 10mg/kg and 20mg/kg treated groups ( Figure 3, Graph B).
  • P ⁇ mary human macrophages and munne RAW 264 7 cells were incubated with fluoxetine hydrochlonde for 30 minutes and then stimulated for 6 hours with TLR ligands (R-848, LPS, flagellin, malp-2, poly IC or CpG).
  • TLR ligands R-848, LPS, flagellin, malp-2, poly IC or CpG.
  • Human macrophages showed a decreased production of TNF in response to R-848 but not LPS, flagellin or Malp-2 in the presence of fluoxetine hydrochloride ( Figure 4, Graph A).
  • Murine RAW 264.7 cells were used to examine poly IC and CpG induced TNF, as unlike human macrophages they respond to poly IC a TLR3 ligand and CpG, a TLR9 ligand to produce TNF. Fluoxetine hydrochloride was able to inhibit TNF production in these cells on stimulation with poly IC ( Figure 4, Graph B) and CPG ( Figure 4, Graph C).
  • TLRs toll-like receptors
  • TLR3, 7, 8 and 9 are expressed in human RA synovial tissue. mRNA from synovial tissue was extracted, DNAase treated and then analysed by RT-PCR. Expression of message for TLR3, 7, 8 and 9 was detected by RT-PCR from the mixed population of cells in human rheumatoid synovial tissue in three unrelated donors 1-3 ( Figure 6, Graph A). TLR3, 8 and 9 were further investigated using FACS. Cells were washed, then blocked with 10% human serum in PBS containing 0.01% azide for 30 minutes at 4°C or for intracellular staining cells were fixed in 2% paraformaldehyde and permeabilised with 0.1% saponin (Sigma, USA) before blocking.
  • TLR3, 8 and 9 protein expression was detected at low levels on the cell surface but was more readily detected upon intracellular staining ( Figure 6, Graph B).
  • the main mechanism of action of the antidepressants (SRIs) used in this study is to increase the amount of serotonin by inhibiting serotonin reuptake receptors.
  • SRIs antidepressants
  • Fluoxetine hydrochlo ⁇ de (“PROZAC"), citalopram and sertraline have been demonstrated as being able to inhibit selective TLRs TLR3, 7, 8 and 9 are classically viewed as having an endosomal localization. Chloroquine has been reported to inhibit the function of TLR3, 7, 8 and 9, by increasing the pH inside vesicles, which is essential for functional signaling from TLR3, 7, 8 and 9.
  • chloroquine inhibits spontaneous TNF and EL-I release but serotonin does not

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des inhibiteurs de la recaptation de la sérotonine (IRS) qui comprennent des inhibiteurs sélectifs de la recaptation de la sérotonine (ISRS) et des inhibiteurs sélectifs de la recaptation de la sérotonine et de la norepinephrine (ISRSN) destinés au traitement de l'arthrite inflammatoire et des états associés. L'invention se rapporte également à une trousse comprenant une composition pharmaceutique renfermant un inhibiteur de la recaptation de la sérotonine et des instructions indiquant que la composition est destinée au traitement de l'arthrite inflammatoire et des états associés. L'invention porte enfin sur un procédé de traitement de l'arthrite inflammatoire et d'états associés qui consiste à administrer un inhibiteur de la recaptation de la sérotonine. Le procédé est mis en oeuvre de préférence chez un sujet qui a besoin d'un traitement. De préférence, l'arthrite inflammatoire est une arthrite rhumatoïde.
PCT/GB2008/000217 2007-01-22 2008-01-22 Inhibiteurs de la recaptation de la sérotonine destinés au traitement de l'arthrite Ceased WO2008090331A1 (fr)

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GB0701171.1 2007-01-22
GBGB0701171.1A GB0701171D0 (en) 2007-01-22 2007-01-22 Compositions and uses thereof

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WO2008090331A1 true WO2008090331A1 (fr) 2008-07-31

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GB (1) GB0701171D0 (fr)
WO (1) WO2008090331A1 (fr)

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WO2009019473A1 (fr) * 2007-08-08 2009-02-12 Imperial Innovations Limited Traitements contre l'arthrite inflammatoire
WO2010029958A1 (fr) 2008-09-11 2010-03-18 アステラス製薬株式会社 Nouvelle composition pharmaceutique pour le traitement de la douleur nociceptive
RU2703723C1 (ru) * 2018-08-06 2019-10-22 Федеральное Государственное бюджетное образовательное учреждение высшего образования Дагестанский государственный медицинский университет Министерства здравоохранения Российской Федерации Даггосмедуниверситет Способ коррекции тревожно-депрессивных расстройств у больных с системными заболеваниями соединительной ткани

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009019473A1 (fr) * 2007-08-08 2009-02-12 Imperial Innovations Limited Traitements contre l'arthrite inflammatoire
WO2010029958A1 (fr) 2008-09-11 2010-03-18 アステラス製薬株式会社 Nouvelle composition pharmaceutique pour le traitement de la douleur nociceptive
RU2703723C1 (ru) * 2018-08-06 2019-10-22 Федеральное Государственное бюджетное образовательное учреждение высшего образования Дагестанский государственный медицинский университет Министерства здравоохранения Российской Федерации Даггосмедуниверситет Способ коррекции тревожно-депрессивных расстройств у больных с системными заболеваниями соединительной ткани

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