• 专利附录
  • 专利说明
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    • 专利摘要:
    Immunomodulators selected from are useful for the treatment of inflammation, particularly immunologically mediated inflammation such as inflammation as occurs in autoimmune diseases: (a) saturated or cis-unsaturated C 10 -C 20 fatty alcohols or these And esters of C 1 -C 6 alkanoic acid; (b) monoesters of C 2 -C 8 alkanediols or glycerol with saturated or cis-unsaturated C 10 -C 20 fatty acids; And (c) diesters of glycerol and saturated or cis-unsaturated C 10 -C 20 fatty acids.
    公开号:KR20030096312A
    申请号:KR10-2003-7013310
    申请日:2002-04-11
    公开日:2003-12-24
    发明作者:코헨이런알；시니츠키메이어；마가리트라아난
    申请人:예다 리서치 앤드 디벨럽먼트 캄파니 리미티드；
    IPC主号:
    专利说明:

    Fatty alcohols and fatty acid esters useful for treating inflammation {FATTY ALCOHOLS AND FATTY ACID ESTERS USEFUL FOR TREATMENT OF INFLAMMATION}
    [3] Inflammation is usually divided into three phases: acute inflammation, immune response and chronic inflammation. Acute inflammation is an early response to tissue damage and is mediated by the release of histamine, serotonin, bradykinin, prostaglandins and leukotrienes. Usually the immune response following an acute inflammatory phase occurs when the immunological competent cells are activated in response to an antigenic substance or foreign entity released during an acute or chronic inflammatory response. The result of an immune response to the host can be beneficial, as in the case where the invading individual is processed or neutralized by phagocytosis. However, the above results can be detrimental when induced into chronic inflammation without resolving the inherent injury process, as occurs in rheumatoid arthritis.
    [4] Treatment of patients with inflammation includes alleviation or cessation of tissue damage processes, as well as alleviation of pain, which is a major persistent complaint of the patient and present symptoms.
    [5] Anti-inflammatory agents are usually classified as steroidal or glucocorticoids, and nonsteroidal anti-inflammatory agents (NSAIDs). Glucocorticoids are potent anti-inflammatory agents, but with the exception of certain acute inflammatory conditions, their use is limited to the high toxicity associated with chronic corticosteroid treatment. Thus, it is presumed that nonsteroidal anti-inflammatory drugs play a major role in the treatment of chronic conditions such as rheumatoid arthritis.
    [6] Non-steroidal anti-inflammatory agents include different chemicals, including aminoarylcarboxylic acids, arylacetic acids, arylbutyric acids, arylcarboxylic acids, arylpropionic acids, pyrazoles, pyrazolone, derivatives of salicylic acid, and certain anti-joint / antirheumatic agents. Some other derivatives having a structure are included.
    [7] Some fatty alcohols and esters of fatty acids are described as solvents or emulsifiers for use in pharmaceutical compositions. For example, cetyl alcohol can be used in pharmaceutical compositions as emulsifiers and curing agents (The Merck Index, pp. 347-8, # 2037), oleyl alcohol can be used as a pharmaceutical carrier (The Merck Index, p. 1222, # 6900), alkyl esters of oleic acid can be used as medicinal solvents (The MerckIndex, p. 6899, # 6898).
    [8] Mixtures of higher aliphatic primary alcohols isolated predominantly from beeswax have been described as having moderate anti-inflammatory activity. No composition of this mixture is disclosed (Rodriguez et al., 1998).
    [9] Breeding laboratory animals with fish oil rich in long chain n-3 polyunsaturated fatty acids (PUFA), i.e.sapentaenoic acid (20: 5n-3) and docosahexaenoic acid (22: 6n-3), is acute and chronic inflammation It has been described to reduce response, improve survival in endogenous toxins and in models of autoimmunity, and prolong survival of transplant organs, so fish oil supplementation may be clinically useful in acute and chronic inflammatory conditions and after transplantation. Yes, it was suggested (Calder, 1998). Pharmaceutical formulations containing icosapentaenoic acid and / or stearic acid for the treatment of schizophrenia are described in WO 98/16216 and US Pat. No. 6,331,568.
    [10] Modified polyunsaturated fatty acids and their derivatives have been proposed for pharmaceutical use. WO 99/27924 and US 6,280,755 describe anti-inflammatory fatty acids that are not blocked with methylene groups for use in topical pharmaceutical and cosmetic compositions. WO 97/38688 and US Pat. No. 6,262,119 describe polyunsaturated fatty acids having 1 or 2 substitutions selected from oxa and thia at beta or gamma positions for acyl groups for treating or alleviating the symptoms of T-cell mediated disease. . WO 99/58122 and US Pat. No. 6,365,628 describe saturated fatty acids in which one or more methylene groups are substituted with O, S, SO, SO 2 , or Se, and alkyl esters thereof, for the treatment or prevention of diabetes. US 5,019,383 describes synthetic vaccines comprising peptide residues coupled to one or more alkyl or alkenyl groups having at least 12 carbon atoms, or other lipophilic substances, wherein the alkyl or alkenyl groups are N-terminal amino groups of the peptide residues. And / or fatty acid residues coupled to one or more functional groups of the multifunctional group bonded to the C-terminal carboxyl group.
    [11] The literature does not state that isolated fatty alcohols or esters of these and alkanoic acids themselves can be used as medicaments, and specifically that they may be involved in the immunomodulation of inflammation.
    [1] The present invention relates to anti-inflammatory agents useful in the treatment of immunologically mediated inflammation, more particularly fatty alcohols, esters of these with C 1 -C 6 alkanoic acids, or esters of fatty acids with alkanediols or glycerol.
    [2] Abbreviation: AA: Secondary Arthritis: CFA: Complete Freund's adjuvant; EAE: experimental autoimmune encephalomyelitis; GPSCH: guinea pig spine homogenate; IFA: incomplete Freund's adjuvant; OA: oleyl alcohol; PBS: phosphate-buffered saline; SC: Avoid.
    [12] Summary of the invention
    [13] Now surprisingly according to the present invention, certain long-chain fatty alcohols, esters of these with C 1 -C 6 alkanoic acids, or specific esters of long-chain fatty acids with alkanediols or glycerol are used in rats for experimental adjuvant arthritis (AA) and experimental autoimmune encephalomyelitis. In the (EAE) model it has been found that inflammation can be inhibited and transplant rejection can be prevented in mice.
    [14] Accordingly, the present invention relates to pharmaceutical compositions for the treatment of inflammation, in particular immunologically mediated inflammation, which contain an immunomodulator selected from: (a) saturated or cis-unsaturated C 10 -C 20 Fatty alcohols or esters of these with C 1 -C 6 alkanoic acid; (b) monoesters of C 2 -C 8 alkanediols or glycerol with saturated or cis-unsaturated C 10 -C 20 fatty acids; And (c) diesters of glycerol and saturated or cis-unsaturated C 10 -C 20 fatty acids.
    [15] In another embodiment, the invention relates to the use of an immunomodulator selected from the following for the preparation of a pharmaceutical composition for treating inflammation, in particular immunologically mediated inflammation: (a) saturated or cis-unsaturated C 10 -C 20 fatty alcohols or esters of these with C 1 -C 6 alkanoic acid; (b) monoesters of C 2 -C 8 alkanediols or glycerol with saturated or cis-unsaturated C 10 -C 20 fatty acids; And (c) diesters of glycerol and saturated or cis-unsaturated C 10 -C 20 fatty acids.
    [16] In another embodiment, the invention provides a method of treating an inflammatory disorder, in particular immunologically mediated inflammation, comprising administering to an individual in need thereof an effective amount of an agent selected from an immunomodulator selected from (A) saturated or cis-unsaturated C 10 -C 20 fatty alcohols or esters of these with C 1 -C 6 alkanoic acid; (b) monoesters of C 2 -C 8 alkanediols or glycerol with saturated or cis-unsaturated C 10 -C 20 fatty acids; And (c) diesters of glycerol and saturated or cis-unsaturated C 10 -C 20 fatty acids.
    [17] Brief description of the drawings
    [18] 1 shows the dose response effect of oleyl alcohol (OA) on adjuvant arthritis (AA). Rats were administered subcutaneously with different doses of OA once 14 days prior to AA induction.
    [19] 2 is a graph showing the disease profile of Lewis rats treated with oleyl alcohol with experimental autoimmune encephalomyelitis (EAE). Oleyl alcohol was administered to rats 14 days prior to EAE induction. The control group was treated with incomplete Freund's adjuvant (IFA).
    [20] 3 is a graph showing the disease profile of Lewis rats treated with IFA with EAE. Rats were administered IFA 14 days prior to EAE induction. The control group was not treated.
    [21] Detailed description of the invention
    [22] The present invention provides immunomodulators selected from: (a) saturated or cis-unsaturated C 10 -C 20 fatty alcohols or esters thereof with C 1 -C 6 alkanoic acid; (b) monoesters of C 2 -C 8 alkanediols or glycerol with saturated or cis-unsaturated C 10 -C 20 fatty acids; And (c) diesters of glycerol and saturated or cis-unsaturated C 10 -C 20 fatty acids.
    [23] According to one preferred embodiment of the invention, the pharmaceutical composition contains long chain saturated or unsaturated C 10 -C 20 , preferably C 16 -C 20 , most preferably C 18 fatty alcohols.
    [24] Examples of C 10 -C 20 saturated fatty alcohols which may be used according to the invention include, but are not limited to: decyl alcohol, lauryl alcohol, myristyl alcohol, stearyl alcohol and preferably cetyl alcohol ( Also known as palmityl alcohol).
    [25] Unsaturated fatty alcohols according to the present invention preferably have one or more double bonds in the cis form and 16-18 carbon atoms, including but not limited to: oleyl alcohol (cis-9-octadecenol), Linoleyl alcohol (cis-9,12-octadecadienol), γ-linolenyl alcohol (cis-6,9,12-octadecatrienol) and linolelenyl alcohol (cis-9,12,15-octa Decatrienol). In a preferred embodiment, the fatty alcohols used in the compositions of the present invention are cetyl, linolenyl, or most preferably oleyl alcohol.
    [26] In another embodiment, the pharmaceutical compositions of the present invention contain fatty alcohols as defined above and esters of C 1 -C 6 alkanoic acids such as acetic acid, propionic acid, butyric acid, valeric acid and caproic acid.
    [27] In another embodiment, the pharmaceutical compositions of the present invention contain esters of saturated or cis-unsaturated C 10 -C 20 fatty acids with alcohols selected from C 2 -C 8 alkanediols or glycerol, said esters Monoesters with 2 -C 8 alkanediols or glycerol or diesters with glycerol.
    [28] C 10 -C 20 fatty acids are preferably C 16 -C 20 , most preferably C 18 fatty acids. In one embodiment, the C 10 -C 20 fatty acids are saturated acids, including but not limited to: capric acid, lauric acid, myristic acid, palmitic acid, stearic acid and arachids mountain. In another embodiment, the C 10 -C 20 fatty acid is a cis-unsaturated fatty acid, including, but not limited to: palmitoleic acid (cis-9-hexadecenoic acid), oleic acid (cis-9- Octadecenoic acid), cis-bacsenic acid (cis-11-octadecenoic acid), linoleic acid (cis-9,12-octadecadenoic acid), γ-linolenic acid (cis-6,9,12-octadecatenoic acid) ), Linolenic acid (cis-9,12,15-octadecatenic acid) and arachidonic acid (cis-5,8,11,14-icosatetraenoic acid).
    [29] According to the invention, the alkanediols have 2 to 8 carbon atoms, preferably 2 to 4 carbon atoms, more preferably 2 carbon atoms, and are selected from, but not limited to: 1,3-propanediol, 1,4 Butanediol, preferably 1,2-ethylene glycol. Examples of such esters are 1,2-ethylene glycol monooleate.
    [30] According to another embodiment of the invention, the active ingredient of the pharmaceutical composition is a mono- or di-ester of glycerol and long chain fatty acids. In one preferred embodiment, the monoglyceride is glycerol monooleate. The diglycerides comprise one free hydroxyl group and the other two hydroxyl groups are both esterified with two molecules of long chain fatty acids, such as glyceryl dioleate, or one hydroxyl group with one molecule of long chain fatty acids. And a second hydroxyl group is esterified with C 1 -C 6 alkanoic acid such as acetic acid, propionic acid, butyric acid, valeric acid and caproic acid.
    [31] The immune system in both the innate and acquired branches is involved in the regulation of all types of inflammation, and inflammation is not only in the acquired immune response seen in autoimmunity, allergy, transplant rejection and infection, but also in wound healing, connective tissue remodeling, neovascularization, It is a major factor in organ regeneration and neuroprotection processes (see Cohen, 2000; Schwartz and Cohen, 2000). Thus, anti-inflammatory agents that modulate the inflammatory response as described herein will be useful in a variety of conditions.
    [32] Inflammatory disorders that can be treated with the immunomodulators of the present invention include, but are not limited to: immunologically mediated chronic or acute inflammatory disorders selected from autoimmune diseases, severe allergies, asthma, transplant rejection, or Treatment and neuroprotection, organ regeneration, chronic ulceration of skin and schizophrenia in the treatment of chronic degenerative diseases such as Alzheimer's disease.
    [33] Examples of autoimmune diseases that can be treated according to the invention include multiple sclerosis or human arthritis conditions such as rheumatoid arthritis, reactive arthritis indicating Reiter's syndrome, ankylosing spondylitis and other inflammation of the joint mediated by the immune system. There is this. Other autoimmune diseases are included and listed in the list below, depending on the organ or tissue involved. That is, according to the present invention, immunologically mediated inflammatory disorders include myasthenia gravis, Guillain-Barre syndrome and other inflammatory diseases of the nervous system; Psoriasis, vulgaris and other diseases of the skin; Systemic lupus erythematosus, glomerulonephritis and other diseases affecting the kidneys; Atherosclerosis and other inflammation of blood vessels; Autoimmune hepatitis, inflammatory bowel disease such as Crohn's disease, pancreatitis, and other conditions of the gastrointestinal tract; Type 1 diabetes (insulin dependent diabetes mellitus or IDDM), autoimmune thyroiditis (Hashimoto thyroiditis), and other diseases of the endocrine system.
    [34] One model used to evaluate the anti-inflammatory activity of an agent according to the present invention is an experimental disease of the joint that is inducible by immunizing Mycobacterium tuberculosis bacteria in complete Freund's adjuvant (CFA) to some strains of rats. Secondary arthritis (AA). In such animals, arthritis similar in character to human rheumatoid arthritis occurs, resulting in human arthritis conditions such as rheumatoid arthritis, reactive arthritis in Reiter's syndrome, ankylosing spondylitis and other inflammations of the joints that appear to be mediated by the immune system. Act as an animal model (Pearson, 1964). Adjuvant arthritis also generally serves as a model of immune-mediated inflammation, including cell-mediated autoimmune responses, transplant rejection and allergic responses. For example, treatments that can inhibit rheumatoid arthritis include immunosuppressive agents, such as the corticosteroid cyclosporin A (Jaffee et al., 1989; Pollock et al., 1989), azathioprine and others widely used in the treatment of autoimmune diseases. Immunosuppressants are included. Thus, inhibition of adjuvant arthritis by a therapeutic agent suggests that the agent is potentially useful as a wide range of anti-inflammatory agents.
    [35] The pharmaceutical compositions provided by the present invention may be in solid, semisolid or liquid form and may further contain pharmaceutically acceptable fillers, carriers or diluents, and other inert ingredients and excipients. The composition may be administered by any suitable route, including but not limited to: oral, topical or parenteral, such as subcutaneous, intravenous, intramuscular injection, or any other suitable route. Since many compounds are oily, they are preferably administered parenterally, more preferably subcutaneously. When given continuously, the compounds of the present invention are each typically administered by 1-4 injections per day, or by continuous subcutaneous infusion, eg using a minipump. Dosage will depend on the condition of the patient and the severity of the disease and will be determined as deemed appropriate by the physician.
    [36] For parenteral administration, the compounds are in pharmaceutically acceptable carriers, ie injectable forms (solutions, Suspensions or emulsions), which can be formulated by mixing in the desired purity, respectively. In general, formulations are prepared by contacting a compound of the present invention uniformly and intimately with a liquid carrier or a finely divided solid carrier or both. If necessary, the product is then shaped into the desired formulation. Preferably the carrier is a parenteral carrier, more preferably a solution that is isotonic with the blood of the recipient. Examples of such carrier carriers include water, saline, Ringer's solution and dextrose solution. In addition to liposomes, nonaqueous carriers such as fixed oils may also be useful. Such formulations may be prepared by conventional methods known in the art, for example as described in "Remington's Pharmaceutical Science", A. R. Gennaro, 17th Edition, 1985, Mack Publishing Company, Easton, PA, USA.
    [37] The invention will now be illustrated by the following non-limiting examples.
    [38] Example 1 Protection Against Adjuvant Arthritis (AA) —Anti-inflammatory Effects of Oleyl Alcohol and Other Agents
    [39] AA is inbred 8-10 weeks old Lewis rats (Harlan-Olac) Limited, Blackthorn, Oxon, UK) was induced by immunizing 1 mg / 0.1 mL of killed Mycobacterium tuberculosis (Sigma) in IFA (Sigma) as described in (Pearson, 1956). And occurred on day 0 and scored on the 0-4 scale on a scale of 0-16 scale of severity of inflammation of each of the four legs on the 0-4 scale. Peaks of arthritis were usually observed around 26 days after immunization.
    [40] Control rats were untreated or treated with saline injection. Positive controls of immunosuppression were obtained including rat groups treated with dexamethasone (200 μg), a corticosteroid preparation administered intraperitoneally every 12 days, starting 12 days after induction.
    [41] The immunomodulators (100 μl oleyl alcohol, glycerol monooleate, linolelenyl alcohol or cetyl alcohol) of the present invention were administered subcutaneously (SC) once 14 days before AA induction or 12 days after AA induction. The percent inhibition of inflammation measured on the day of maximal inflammation was calculated as follows:
    [42] (Average maximum score of test group / average maximum score of control group) × 100%
    [43] All four compounds showed> 60% inhibition of inflammation and appeared effective, while oleic acid was ineffective. The results are summarized in Table 1.
    [44] Two additional experiments showed that 500 μl of oleyl alcohol (100 μl corresponds to about 90 mg of oleyl alcohol) inhibited inflammation 96% and 91%.
    [45] Effect of various preparations on inflammation of secondary arthritis Evaluation compound% Inhibition (100 μl) Glycerol Mono-oleate98% Oleyl alcohol78% Linoleyl alcohol75% Cetyl alcohol66%
    [46] Example 2. Protection Against AA with Different Doses of Oleyl Alcohol
    [47] To study the dose response effect of oleyl alcohol in AA, oleyl alcohol was administered subcutaneously in 10, 50, 100 or 500 mg doses to Lewis rats once 14 days before the induction of AA as described in Example 1 above. .
    [48] 1 shows the dose response effect of oleyl alcohol. It can be seen that as the dose of oleyl alcohol increases, arthritis is suppressed. On day 26 of the peak disease, inflammation was inhibited by 14% (10 μl), 61% (50 μl), 78% (100 μl) and 90% (500 μl).
    [49] Example 3 Anti-inflammatory Effects and Protection of Oleyl Alcohol and Other Immunomodulators Against EAE in DA Rats
    [50] Experimental autoimmune encephalomyelitis (EAE) is in some strains of myelin basic protein (MBP) or proteolipid protein (PLP) in complete Freund's adjuvant (CFA), or CFA or incomplete Freund's adjuvant (IFA). It is an experimental autoimmune disease inducible by immunization of spinal emulsions of rats. EAE in DA rats is considered a model of chronic EAE. Within two to three weeks, cellular infiltration of central nervous system myelin develops that causes demyelination and paralysis in animals. Most animals die, but others show milder symptoms, and some animals have chronic type diseases similar to chronic relapse and multiple sclerosis (MS) in humans. Thus, the animal with EAE acts as a model of human MS autoimmune disease. EAE occurs in animals about 12 days after immunization and is characterized by varying degrees of paralysis due to inflammation of the central nervous system. In some strains, such as Lewis rats, paralysis can last 6-7 days, and rats usually recover if they do not die during the peak of their acute paralysis. In other lineage rats, such as DA rats, paralysis can be chronic and dual.
    [51] For the induction and clinical evaluation of EAE, vertebrae obtained from DA rats were frozen, thawed and sliced into spatula prior to immunization. In the dorsal base of the rat tail, either 1: 1 IFA (Difco, Detroit, MI, USA) and antigen (volume / weight, i.e. 100 μl IFA / 100 mg whole vertebrae) or 1: 1 CFA (4 mg / ml in IFA) 200 μl of an emulsion prepared from tuberculosis strain 37RA enriched) and antigen (volume / weight, ie 100 μl CFA / 100 mg total spine) was immunized with a single subcutaneous injection (just below the skin). Emulsions were prepared by titration with a closed glass syringe and a 1.2 mm diameter needle. Rat weights were measured regularly to examine clinical signs of EAE. Grade 4 scale was used to assess clinical severity: 0, no paralysis; 1, the tail is weakened (hanging); 2, posterior paralysis; 3, posterior and forefoot paralysis; 4, severe general paralysis (Lorentzen et al., 1995).
    [52] The posterior bases of 5 or 7 DA lineage female rat groups, 8-9 weeks old, were immunized with 0.1 mL per foot (total 200 mg per rat) with IFAs comprising 100 mg of the entire DA vertebrae homogenized. On the day of immunization, rats were treated with SC injection with oleyl alcohol or other preparations according to the invention (100 μl) or paraffin oil (control). Rats were scored for EAE on a severity scale of 0-4 as described above.
    [53] Example 4 Anti-inflammatory Effect and Protection Against EAE of Oleyl Alcohol in Lewis Rats
    [54] EAE induced in Lewis rats is considered a model of acute inflammation in the brain (as opposed to chronic disease in DA rats).
    [55] For EAE induction, three lyophilized guinea pig spine homogenate (GPSCH) emulsions were prepared as follows: (i) 25 mg of lyophilized GPSCH (GP2) was suspended in 2.5 ml of sterile PBS (Sigma). And incubated at 37 ° C. for 1 hour; (ii) 54.1 mg of Mycobacterium tuberculosis H37Ra (MT, Difco) was suspended in 13.5 ml of CFA (Sigma) containing 1 mg / ml MT to give 5 mg / ml MT; (iii) 2.5 ml CFA (5 mg / ml MT) was added into a vial containing 2.5 ml PBS containing 25 mg GPSCH to give 5 mg / ml GPSCH and 2.5 mg / ml MT. The mixture was transferred through a Luer lock bridge into a glass syringe connected to a second glass syringe. The material was transferred from one syringe to another syringe for about 10 minutes and mixed well until the material was well emulsified. An emulsion of 0.5 mg / rat dose MT and 1 mg / rat dose GPSCH in CFA induced EAE in rats (based on previous titrations).
    [56] For treatment, two groups of eight 9-10 week old Lewis rats (Harlan, Israel) were treated with test specimens (oleyl alcohol or IFA) 14 days prior to EAE induction. The IFA treated group was used as a control. Test samples were injected once subcutaneously at a 0.5 ml / kg dose. Eight rats of the third group were not treated and served as untreated controls.
    [57] EAE was induced in all three groups of rats after 14 days of injection of test specimens by injecting each posterior base with GPSCH emulsion (0.2 ml per rat) in 0.1 ml of CFA.
    [58] EAE clinical signs were observed and scored from 9 days after EAE induction to the end of the experiment according to the following 5 scale scale for assessing clinical severity: 0, normal behavior; 1, weight loss; 2, tail weakening; 3, posterior tension and weakness; 4, posterior paralysis; 4, severe general paralysis; 5, breathing disorders and / or cramps and / or complete paralysis or death. All rats scored at least 1 were considered sick.
    [59] Calculation of the EAE results was performed as follows:
    [60] (i) calculating the incidence of disease
    [61] The number of sick animals in each group was added up. Incidence and activity of the disease were calculated as follows:
    [62] Incidence of disease = (number of sick rats per group / number of rats per group) × 100%
    [63] Activity% * = [1-(Incidence of disease in control group / Disease incidence in control group)] × 100%
    [64] * = (Depending on incidence)
    [65] (ii) Calculation of mean maximum score (MMS)
    [66] The maximum score of each rat per group was summed. The mean maximum score (MMS) and% activity of the groups were calculated as follows:
    [67] Average Maximum Score = ΣMaximum Score for Each Rat / Number of Rats per Group
    [68] % Active * = [1-(MMS of treatment group / MMS of control)] × 100
    [69] * = (% Activity according to MMS)
    [70] (iii) Calculation of group mean score (GMS)
    [71] The mean score of each rat was summed over the observation period (score 5 was calculated as progression). Group mean scores and their activity percentages were calculated as follows:
    [72] Mean score = Σgroup score of each rat / number of rats per group
    [73] % Active * = [1-(GMS of treatment group / GMS of control)] × 100
    [74] * = (% Activity according to GMS)
    [75] (iv) calculating the average onset of disease
    [76] The days of disease onset for each rat in the group were summed. The average onset of disease for the group was calculated. The onset of disease for rats without EAE was considered 25 days (study period).
    [77] (v) Calculation of average duration of disease
    [78] The disease duration (days) of each rat in each group was summed. The mean disease duration of the groups was calculated. Disease persistence in rats without EAE was considered zero.
    [79] Evaluation of clinical manifestations of EAE, ie% incidence of disease, MMS, GMS, mean duration and onset of EAE disease, are summarized in Table 2. Graphs of disease profiles for each group are shown in FIGS. 2 and 3 for the treatment of oleyl alcohol and IFA respectively.
    [80] As shown in the results, no intrinsic difference in incidence (62.5% to 75% incidence) or mean maximum score (1.75 to 2.38 MMS) of disease was observed between the IFA-injected and untreated controls. Oleyl alcohol showed a beneficial effect on all clinical parameters tested. The water showed 77.1% activity according to the group mean score (GMS) and 63% activity according to the mean maximum score (MMS) compared to the untreated control. The average onset of disease was 15.5 days in the untreated control group, compared with 18.6 days in the oleyl alcohol treated group. The duration of disease was 5.13 days in the untreated control group, compared to 2.0 days in the oleyl alcohol treated group. The duration of EAE clinical signs in the test group was 1 to 7 days, except for one rat in the IFA treated group. IFA, if present, showed less effect on rat EAE. Except for one rat in the untreated control group, no death was observed in the treated group.
    [81] Evaluation of EAE Clinical Outcomes Military numberTest specimenIncidence%Incidence Rate ActiveMMSMMS activity%GMSGMS activity%Average onset of the disease (days)Disease duration (days) OneOA50.0%33.3%0.8863.0%0.2277.1%18.62.0 2IFA62.5%16.7%1.7526.5%0.5245.8%17.03.75 3NTC75.0%NA2.38NA0.96NA15.55.13 OA-oleyl alcohol; NTC-untreated control; NA-data not available.
    [82] Example 5 Effect of Oleyl Alcohol on Skin Allograft Survival
    [83] The immune system represents a strong barrier to the successful transplantation of organs or tissues between donors and recipients that are not genetically identical. Both CD4 + and CD8 + T cells are involved in transplant rejection.
    [84] Dermal graft implantation was performed essentially as described above (Birk et al., 1999). That is, the mice were shaved and 1 cm 2 sections of the dorsal skin of the sacrificed donors were cut and washed in PBS. Two patches of dorsal skin, each 1 cm 2, were cut from anesthetized recipients in an allograft formulation (Nembutal 6 mg / ml, 0.25 ml / mouse). Two donor allografts per recipient were implanted on the dorsal injured patch. Histoacryl (B. Braun Melsungen AG, Melsungen, Germany) was applied around the implant. Nobecutan (ASTR, Astra Tech, Glos G15, UK) was sprayed onto the implant.
    [85] In the experiment, a group of 6 BALB / c magnetic mice, 8 weeks old, were implanted with 1 cm 2, full thickness skin implants from 8 week old C57BL / 6 magnetic mice. On the day of transplantation, groups of recipient mice were treated with paraffin oil or 100 μl of oleyl alcohol or another immunomodulator according to the invention. Rejection days were scored. Transplanted skin in mice treated with immunomodulators survived longer compared to untreated control mice.
    [86] Example 6 Prevention and Treatment of SLE
    [87] Systemic lupus erythematosus is an autoimmune disease involving both autoantibodies and immune complexes. To test the immunomodulators of the invention, one can use either FZ mice (NZBxNZW) or those with experimental SLE that naturally develop autoimmune diseases very similar to SLE.
    [88] To induce experimental SLE, the posterior base of BALB / c mice was immunized with human or murine anti-DNA monoclonal antibody 16 / 6Id (20 μg / mouse) in CFA, and after 3 weeks the same amount of immunized antibody in PBS Booster. The mice were then tested for clinical expression characteristic for autoantibody production and experimental SLE. To prevent the induction of experimental SLE or to treat diseased mice, mice were treated subcutaneously (100 μl per mouse) with oleyl alcohol or another immunomodulator according to the invention prior to or simultaneously with and several weeks after immunization. The number of injections was based on the effect of the test compound on disease induction and progression. Animal body weights are measured regularly and examined for clinical signs of SLE as described, for example, in WO 96/30057.
    [89] Example 7 Treatment and Prevention of Autoimmune Thyroiditis
    [90] Experimental autoimmune thyroiditis (EAT) can be induced in several animals by immunization of thyroglobulin in CFA. Both T DTH cells and humoral antibodies to tyroglobulin are produced resulting in thyroid inflammation. EAT appears to best mimic Hashimoto's thyroiditis.
    [91] EAT was induced as described previously by subcutaneous injection of tyroglobulin extract obtained from one thyroid to each mouse (Rose et al., 1971). The extract was emulsified in IFA (Difco Laboratories, Detroit, Mich.), And 7 mg / ml of Mycobacterium tuberculosis H37Ra strain (Difco Laboratories) was added thereto. The injection was repeated after 1 week. Donors of tyroglobulin extracts were mice of the C3H / eB strain. After 4-5 weeks, EAT was analyzed by removing the thyroid of the recipient mouse and fixing it in a 10% formalin solution followed by 70% alcohol to examine the microscopic sections stained with hematoxylin and eosin. Microscopic slides were coded and examined without their identity. EAT was diagnosed by observation of one or more apparent infiltrating lesions by monocytes. Treatment with SC injection of oleyl alcohol or another immunomodulator (100 μl per animal) prior to, concurrently or after induction of EAT (control animals injected with paraffin oil), and animal weights are measured periodically to determine Clinical signs of EAT by conventional methods were examined.
    [92] references
    [93] Birk et al., 1999. The 60kDa heat shock protein modulates allograft rejection. Proc. Nat. Acad. Science USA. 96: 5159-63.
    [94] Calder, PC. Immunoregulatory and anti-inflammatory effects of n-3 polyunsaturated fatty acids. Braz. J. Med. Biol. Res. 31: 467-90.
    [95] Cohen, IR. 2000, Tending Adam's Garden: Evolving the Cognitive Immune Self. Academic Press, London, UK.
    [96] Cohen, IR. 2000. "Discrimination and Dialogue in the Immune System". Seminars in Immunology. 12: 215-219; 269-271; 321-323.
    [97] Holoshitz, Y. et al., 1983. "Lines of T lymphocytes mediate or vaccinate against autoimmune arthritis", Science 219: 56.
    [98] Jaffee, B.D. Et al., 1989, "The effect of immunomodulating drugs on adjuvant-induced arthritis in Lewis rats", Agents Actions. 27 (3-4): 344-6.
    [99] Lorentzen J.C. Et al., 1995, "Protracted, relapsing and demyelinating experimental autoimmune encephalomyelitis in DA rats immunized with syngeneic spinal cord and incomplete Freund's adjuvant", J. Neuroimmunology. 63: 193-205.
    [100] Pearson, CM. 1964, "Experimental models in rheumatoid disease", Arthritis Rheum. 7: 80.
    [101] Pearson, CM. 1956, "Development of arthritis, periarthritis and periostitis in rats given adjuvant", Proc. Soc. Exp. Biol. Med. 91: 91.
    [102] Pollock et al., 1989, "Pharmacokinetic analysis of cyclosporine in adjuvant arthritic rats", Drug Metab. Dispos. 17 (6): 595-9.
    [103] Rodriguez, M.D., Gamez, R., Sanchez, M and H. Garcia. 1998, J. Appl. Toxicol. 18: 313-6.
    [104] Rose, N.R., F.J. Twarog and A.J. Crowe. 1971.Murine thryoiditis: importance of adjuvant and mouse strain for the induction of thyroid lesions. J. Immunol. 106: 698)
    [105] Schwartz, M. and Cohen. IR. 2000, "Autoimmunity can benefit self-maintenance". Immunol Today. 21: 265-8.
    [106] The Merck Index, 13th Edition, 2001, Merck & Co. Inc., Rahway, N.J., U.S.A.
    权利要求:
    Claims (60)
    [1" claim-type="Currently amended] Pharmaceutical compositions for the treatment of inflammation, in particular immunologically mediated inflammation, comprising immunomodulators selected from the following: (a) saturated or cis-unsaturated C 10 -C 20 fatty alcohols or these and C 1- Esters of C 6 alkanoic acid; (b) monoesters of C 2 -C 8 alkanediols or glycerol with saturated or cis-unsaturated C 10 -C 20 fatty acids; And (c) diesters of glycerol and saturated or cis-unsaturated C 10 -C 20 fatty acids.
    [2" claim-type="Currently amended] The pharmaceutical composition of claim 1, wherein the active ingredient is saturated C 10 -C 20 fatty alcohol.
    [3" claim-type="Currently amended] The pharmaceutical composition of claim 2, wherein the saturated C 10 -C 20 fatty alcohol is selected from decyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol and stearyl alcohol.
    [4" claim-type="Currently amended] The pharmaceutical composition of claim 1, wherein the active ingredient is a cis-unsaturated C 16 -C 18 fatty alcohol.
    [5" claim-type="Currently amended] The pharmaceutical composition according to claim 4, wherein the cis-unsaturated C 16 -C 18 fatty alcohol is selected from oleyl alcohol, linoleyl alcohol, γ-linolenyl alcohol, and linolenyl alcohol.
    [6" claim-type="Currently amended] The pharmaceutical composition of claim 1, wherein the active ingredient is an ester of saturated or cis-unsaturated C 10 -C 20 fatty alcohol with C 1 -C 6 alkanoic acid.
    [7" claim-type="Currently amended] The pharmaceutical composition of claim 1, wherein the active ingredient is a monoester of saturated or cis-unsaturated C 10 -C 20 fatty acids and C 2 -C 8 alkanediol.
    [8" claim-type="Currently amended] 8. The pharmaceutical composition of claim 7, wherein said alkanediol is selected from 1,2-ethylene glycol, 1,3-propanediol and 1,4-butanediol.
    [9" claim-type="Currently amended] The pharmaceutical composition of claim 1, wherein the active ingredient is a monoester of saturated or cis-unsaturated C 10 -C 20 fatty acids and glycerol.
    [10" claim-type="Currently amended] The pharmaceutical composition of claim 1, wherein the active ingredient is a diester of saturated or cis-unsaturated C 10 -C 20 fatty acids with glycerol.
    [11" claim-type="Currently amended] The pharmaceutical composition of claim 1, wherein the fatty acid is a saturated C 10 -C 20 fatty acid.
    [12" claim-type="Currently amended] The pharmaceutical composition of claim 11, wherein the saturated fatty acid is selected from capric acid, lauric acid, myristic acid, palmitic acid, stearic acid and arachidic acid.
    [13" claim-type="Currently amended] The pharmaceutical composition according to any one of claims 1 and 7 to 10, wherein said fatty acid is a cis-unsaturated C 10 -C 20 fatty acid.
    [14" claim-type="Currently amended] The pharmaceutical composition of claim 13, wherein the cis-unsaturated C 10 -C 20 fatty acid is selected from palmitoleic acid, oleic acid, cis-bacsenic acid, linoleic acid, γ-linolenic acid, linolenic acid, and arachidonic acid.
    [15" claim-type="Currently amended] The pharmaceutical composition according to claim 14, wherein said active ingredient is glycerol monooleate.
    [16" claim-type="Currently amended] The pharmaceutical composition of claim 14, wherein said active ingredient is glycerol dioleate.
    [17" claim-type="Currently amended] 17. The method according to any one of claims 1 to 16, for the treatment of immunologically mediated chronic or acute inflammatory disorders, or Alzheimer's disease, selected from autoimmune diseases, severe allergies, asthma, transplant rejection, and Pharmaceutical compositions for the treatment of such chronic degenerative diseases and for neuroprotection, organ regeneration, chronic ulceration of the skin and schizophrenia.
    [18" claim-type="Currently amended] 18. The pharmaceutical composition of claim 17, wherein the autoimmune disease is multiple sclerosis or human arthritic condition.
    [19" claim-type="Currently amended] 19. The pharmaceutical composition of claim 18, wherein the human arthritic condition is selected from rheumatoid arthritis, reactive arthritis indicative of Reiter's syndrome, ankylosing spondylitis and inflammation of other joints mediated by the immune system.
    [20" claim-type="Currently amended] 18. The method of claim 17, wherein said immunologically mediated inflammatory disorders include myasthenia gravis, Guillain-Barre syndrome and other inflammatory diseases of the nervous system; Psoriasis, vulgaris and other diseases of the skin; Systemic lupus erythematosus, glomerulonephritis and other diseases affecting the kidneys; Atherosclerosis and other inflammation of blood vessels; Autoimmune hepatitis, inflammatory bowel disease, pancreatitis, and other conditions of the gastrointestinal tract; A pharmaceutical composition which is type 1 diabetes mellitus, autoimmune thyroiditis, and other diseases of the endocrine system.
    [21" claim-type="Currently amended] Use for the preparation of pharmaceutical compositions for the treatment of inflammation, in particular immunologically mediated inflammation, of immunomodulators selected from: (a) saturated or cis-unsaturated C 10 -C 20 fatty alcohols or these with C 1 -C 6 Esters of alkanic acid; (b) monoesters of C 2 -C 8 alkanediols or glycerol with saturated or cis-unsaturated C 10 -C 20 fatty acids; And (c) diesters of glycerol and saturated or cis-unsaturated C 10 -C 20 fatty acids.
    [22" claim-type="Currently amended] Use according to claim 21, wherein said immunomodulator is saturated C 10 -C 20 fatty alcohol.
    [23" claim-type="Currently amended] 23. The use according to claim 22, wherein said saturated C 10 -C 20 fatty alcohol is selected from decyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol and stearyl alcohol.
    [24" claim-type="Currently amended] Use according to claim 21, wherein said immunomodulator is cis-unsaturated C 16 -C 18 fatty alcohol.
    [25" claim-type="Currently amended] 25. The use of claim 24, wherein the cis-unsaturated C 16 -C 18 fatty alcohol is selected from oleyl alcohol, linoleyl alcohol, γ-linolenyl alcohol and linolenyl alcohol.
    [26" claim-type="Currently amended] 22. The use according to claim 21, wherein the immunomodulator is an ester of saturated or cis-unsaturated C 10 -C 20 fatty alcohol with C 1 -C 6 alkanoic acid.
    [27" claim-type="Currently amended] 22. The use of claim 21, wherein said immunomodulator is a monoester of saturated or cis-unsaturated C 10 -C 20 fatty acids and C 2 -C 8 alkanediols.
    [28" claim-type="Currently amended] 28. The use of claim 27, wherein said alkanediol is selected from 1,2-ethylene glycol, 1,3-propanediol and 1,4-butanediol.
    [29" claim-type="Currently amended] Use according to claim 21, wherein said immunomodulator is a monoester of glycerol and saturated or cis-unsaturated C 10 -C 20 fatty acids.
    [30" claim-type="Currently amended] 22. The use according to claim 21, wherein said immunomodulator is a diester of glycerol and saturated or cis-unsaturated C 10 -C 20 fatty acids.
    [31" claim-type="Currently amended] 31. The use according to any of claims 21 and 27-30, wherein said fatty acid is a saturated C 10 -C 20 fatty acid.
    [32" claim-type="Currently amended] 32. The use of claim 31, wherein the saturated C 10 -C 20 fatty acid is selected from capric acid, lauric acid, myristic acid, palmitic acid, stearic acid and arachidic acid.
    [33" claim-type="Currently amended] 31. Use according to any of claims 21 and 27-30, wherein said fatty acid is a cis-unsaturated C 10 -C 20 fatty acid.
    [34" claim-type="Currently amended] 34. The use of claim 33, wherein the cis-unsaturated C 10 -C 20 fatty acid is selected from palmitoleic acid, oleic acid, cis-bacsenic acid, linoleic acid, γ-linolenic acid, linolenic acid and arachidonic acid.
    [35" claim-type="Currently amended] 35. The use of claim 34, wherein said immunomodulatory agent is glyceryl monooleate.
    [36" claim-type="Currently amended] 35. The use of claim 34, wherein said immunomodulator is glyceryl dioleate.
    [37" claim-type="Currently amended] 37. The method according to any one of claims 21 to 36, wherein the pharmaceutical composition is an immunologically mediated chronic or acute inflammatory disorder selected from autoimmune diseases, severe allergies, asthma, transplant rejection or chronic such as Alzheimer's disease. Use for the treatment of degenerative diseases and for neuroprotective, organ regeneration, chronic ulceration of skin and schizophrenia.
    [38" claim-type="Currently amended] 38. The use of claim 37, wherein the autoimmune disease is multiple sclerosis or human arthritis state.
    [39" claim-type="Currently amended] 39. The use according to claim 38, wherein said human arthritic condition is selected from rheumatoid arthritis, reactive arthritis indicative of Reiter syndrome, ankylosing spondylitis and other inflammations of the joint mediated by the immune system.
    [40" claim-type="Currently amended] 38. The method of claim 37, wherein said immunologically mediated inflammatory disorders include myasthenia gravis, Mullein-Barre syndrome and other inflammatory diseases of the nervous system; Psoriasis, vulgaris and other diseases of the skin; Systemic lupus erythematosus, glomerulonephritis and other diseases affecting the kidneys; Atherosclerosis and other inflammation of blood vessels; Autoimmune hepatitis, inflammatory bowel disease, pancreatitis, and other conditions of the gastrointestinal tract; Use for type 1 diabetes, thyroiditis, and other diseases of the endocrine system.
    [41" claim-type="Currently amended] A method of treating inflammation, in particular immunologically mediated inflammation, comprising administering to a patient in need thereof an effective amount of an immunomodulator selected from: (a) saturated or cis-unsaturated C 10 -C 20 fatty alcohols Or esters of these with C 1 -C 6 alkanoic acid; (b) monoesters of C 2 -C 8 alkanediols or glycerol with saturated or cis-unsaturated C 10 -C 20 fatty acids; And (c) diesters of glycerol and saturated or cis-unsaturated C 10 -C 20 fatty acids.
    [42" claim-type="Currently amended] 42. The method of claim 41, wherein said immunomodulator is saturated C 10 -C 12 fatty alcohol.
    [43" claim-type="Currently amended] 43. The method of claim 42, wherein the saturated C 10 -C 20 fatty alcohol is selected from decyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol and stearyl alcohol.
    [44" claim-type="Currently amended] 42. The method of claim 41, wherein said immunomodulator is cis-unsaturated C 16 -C 18 fatty alcohol.
    [45" claim-type="Currently amended] 45. The method of claim 44, wherein the cis-unsaturated C 16 -C 18 fatty alcohol is selected from oleyl alcohol, linoleyl alcohol, γ-linolenyl alcohol, and linolenyl alcohol.
    [46" claim-type="Currently amended] 42. The method of claim 41, wherein the immunomodulator is an ester of saturated or cis-unsaturated C 10 -C 20 fatty alcohol with C 1 -C 6 alkanoic acid.
    [47" claim-type="Currently amended] 42. The method of claim 41, wherein said immunomodulator is a monoester of saturated or cis-unsaturated C 10 -C 20 fatty acids and C 2 -C 8 alkanediols.
    [48" claim-type="Currently amended] 48. The method of claim 47, wherein said alkanediol is selected from 1,2-ethylene glycol, 1,3-propanediol and 1,4-butanediol.
    [49" claim-type="Currently amended] 42. The method of claim 41, wherein said immunomodulator is a monoester of glycerol and saturated or cis-unsaturated C 10 -C 20 fatty acids.
    [50" claim-type="Currently amended] 42. The method of claim 41, wherein said immunomodulator is a diester of glycerol and saturated or cis-unsaturated C 10 -C 20 fatty acids.
    [51" claim-type="Currently amended] 51. The method of any one of claims 41 and 47-50, wherein said fatty acid is a saturated C 10 -C 20 fatty acid.
    [52" claim-type="Currently amended] 53. The method of claim 51, wherein said saturated C 10 -C 20 fatty acid is selected from capric acid, lauric acid, myristic acid, palmitic acid, stearic acid and arachidic acid.
    [53" claim-type="Currently amended] 51. The method of any one of claims 41 and 47-50, wherein said fatty acid is a cis-unsaturated C 10 -C 20 fatty acid.
    [54" claim-type="Currently amended] 54. The method of claim 53, wherein said cis-unsaturated C 10 -C 20 fatty acid is selected from palmitoleic acid, oleic acid, cis-bacsenic acid, linoleic acid, γ-linolenic acid, linolenic acid and arachidonic acid.
    [55" claim-type="Currently amended] 55. The method of claim 54, wherein said immunomodulatory agent is glyceryl monooleate.
    [56" claim-type="Currently amended] 55. The method of claim 54, wherein said immunomodulator is glyceryl dioleate.
    [57" claim-type="Currently amended] The treatment according to any one of claims 41 to 56 for the treatment of immunologically mediated inflammatory disorders selected from autoimmune diseases, severe allergies, asthma, transplant rejection or treatment of chronic degenerative diseases such as Alzheimer's disease, and neurons. Method for protection, organ regeneration, chronic ulceration of skin and treatment of schizophrenia.
    [58" claim-type="Currently amended] 59. The method of claim 57, wherein said autoimmune disease is multiple sclerosis or human arthritic condition.
    [59" claim-type="Currently amended] 59. The method of claim 58, wherein said human arthritic condition is selected from rheumatoid arthritis, reactive arthritis indicative of Reiter syndrome, ankylosing spondylitis, and other inflammation of the joint mediated by the immune system.
    [60" claim-type="Currently amended] 59. The method of claim 57, wherein said immunologically mediated inflammatory disorders are severe myasthenia gravis, Mullein-Barré syndrome and other inflammatory diseases of the nervous system; Psoriasis, vulgaris and other diseases of the skin; Systemic lupus erythematosus, glomerulonephritis and other diseases affecting the kidneys; Atherosclerosis and other inflammation of blood vessels; Autoimmune hepatitis, inflammatory bowel disease, pancreatitis, and other conditions of the gastrointestinal tract; Type 1 diabetes, thyroiditis, and other diseases of the endocrine system.
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    同族专利:
    公开号 | 公开日
    CN100352433C|2007-12-05|
    EP1385500A1|2004-02-04|
    JP2004525180A|2004-08-19|
    DE60237148D1|2010-09-09|
    HU0303881A2|2004-03-01|
    CA2442953A1|2002-10-24|
    PL366586A1|2005-02-07|
    AU2002255241B2|2007-08-02|
    MXPA03009341A|2004-02-12|
    US20060183797A1|2006-08-17|
    CN1514723A|2004-07-21|
    EP1385500A4|2004-12-29|
    NO20034558D0|2003-10-10|
    AT475416T|2010-08-15|
    IL142535D0|2002-03-10|
    EP1385500B1|2010-07-28|
    NZ528784A|2007-06-29|
    ZA200307783B|2004-10-06|
    NO20034558L|2003-12-10|
    HU0303881A3|2009-10-28|
    WO2002083122A1|2002-10-24|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2001-04-11|Priority to IL14253501A
    2001-04-11|Priority to IL142535
    2002-04-11|Application filed by 예다 리서치 앤드 디벨럽먼트 캄파니 리미티드
    2002-04-11|Priority to PCT/IL2002/000294
    2003-12-24|Publication of KR20030096312A
    优先权:
    申请号 | 申请日 | 专利标题
    IL14253501A|IL142535D0|2001-04-11|2001-04-11|Pharmaceutical compositions for the treatment of inflammation|
    IL142535|2001-04-11|
    PCT/IL2002/000294|WO2002083122A1|2001-04-11|2002-04-11|Fatty alcohols and fatty acid esters useful for treatment of inflammation|
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