Treatment of bone marrow pathologies with polysulfated polysaccharides

Abstract

To provide methods for the treatment of disease or disorders associated with bone marrow pathologies in the musculoskeletal system of a mammal.SOLUTION: The present invention provides a method for the treatment of bone marrow edema lesions as assessed by magnetic resonance imaging (MRI) in a mammal, the method comprising the step of administering a polysulfated polysaccharide or an acceptable salt thereof, to a mammal in need of such treatment.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for the treatment of a disease or disorder associated with a bone marrow pathology in the mammalian musculoskeletal system. The present invention relates to the medical use of polysulfated polysaccharides and compositions thereof for the treatment of cancer. , bone marrow edema lesions or spinal modic lesions, as assessed by magnetic resonance imaging (MRI) The use of polysulfated polysaccharides in the treatment of modic endplate changes. [Background technology]

[0002] Bone marrow edema lesions Bone marrow edema lesions (BMEL) are changes occurring in the subchondral bone and are a common cause of osteoarthritis in patients with osteoarthritis. The purpose of this study was to characterize the severity of symptoms, including pain ([1]-[3]) and cartilage degeneration ([4]-[7]). BMEL is typically detected by fat-suppressed, proton density weighted or Fat-suppressed T2-weighted and fat-suppressed protocols are used to assess the In contrast, BMEL appears as an extremely strong signal in density-weighted sequences [8].

[0003] BMEL-related MRI signals were localized in areas of intramedullary trabecular microfractures and trabecular collapse. This is thought to be due to an increase in the concentration of blood and interstitial fluid (including infiltrating macrophages) that 8]. Improved spatial resolution and multiplanar reconstruction have enabled three-dimensional imaging, particularly for cartilage imaging. It has been suggested that D fast spin echo sequences may be useful [9].

[0004] In the pathogenesis of arthritic conditions such as osteoarthritic conditions, including knee osteoarthritis, BMEL There is a growing body of data suggesting that plays an important role.

[0005] Knee osteoarthritis Knee osteoarthritis (OA) is a condition characterized by bone changes around the knee joint, progressive loss of articular cartilage, and joint space narrowing. Knee OA is a disorder characterized by knee pain, significant joint pain, and ultimately complete joint failure. Epidemiological studies have shown that in the United States: There are approximately 12 million people aged 50 years or older with symptomatic knee OA, of which an estimated 7 million However, it is suggested that the patient has BML.

[0006] Patients with knee osteoarthritis have areas of increased signal intensity on MRI of the knee. In affected patients, BMEL may be present as a symptom of knee pain [2]. , disease severity and disease progression, including radiological progression of knee osteoarthritis

[10] , and It is associated with MRI-based cartilage loss ([5],

[11] ) and progressive osteoarthritis. In this case, the BMEL may continue and increase in size with associated increased cartilage loss. [5] In addition, the severity of BMEL has been shown to correlate with the risk of knee arthroplasty.

[12]

[0007] The strong association of BMEL with pain and cartilage loss may be a predictor of progression and healing of knee osteoarthritis. There has been growing pharmaceutical interest in targeting this structural lesion to monitor therapeutic efficacy (

[0013] –

[15] ).

[0008] chronic lower back pain Chronic low back pain (CLBP) is defined as persistent or fluctuating low back pain lasting at least 3 months. Defined: CLBP, or back pain in general, is a disabling condition that leads to increased health care utilization. Patients with CLBP have a history of spinal MRI that is evident Some individuals show Modic changes (MC), which are bone marrow changes in the vertebrae.

[0009] MCs were classified into three types: type I, type II, and type III. Type I changes were Hypointense on imaging (T1WI) and hyperintense on T2-weighted imaging (T2WI) Type II changes are hyperintense and represent bone marrow edema and inflammation. Hyperintense on T2WI and isointense or slightly hyperintense on T2WI , marrow ischemia was associated with the transformation of normal red hematopoietic marrow into yellow fatty marrow. Type III Modic changes appear as hypointensity on both T1WI and T2WI. These findings were thought to represent subchondral sclerosis. Changes have also been reported, and these changes indicate that one type may transform into another. [15A]

[0010] MC was classified into three types: type I, type II, and type III. Type I was characterized by low back pain, persistent Epidemiological studies have shown that CLBP is associated with a high incidence of cardiovascular disease in the United States. The number of people with type I MC is approximately 9 million, of which an estimated 1.6 million are thought to have type I MC. will be done.

[0011] The economic costs of CLBP in the United States are estimated to range from $12.2 billion to $90.6 billion annually. Factors contributing to this economic impact include long-term loss of function and consequential reduced work production. These include loss of sexual function, medical costs, and disability benefits.

[0012] Patients with CLBP may exhibit MCs, which are evident on MRI of the spine. Based on published studies, bone marrow changes in the vertebrae are associated with lower back pain. The findings showed that the presence of MCs, especially type I MCs, correlates with low back pain and persistent symptoms and sick leave. These findings suggest that MC is a predictor of adverse outcomes. This suggests that it may be a potential target for intervention.

[0013] Polysulfated polysaccharides Structurally-based peptides such as heparin, pentosan polysulfate, chitosan polysulfate, and fucan Related polysulfated polysaccharides have been used as anticoagulants for many years [16-21]. Pentosan sulfate (PPS) is a weaker anticoagulant than heparin [ 16 , 18 , 20 ], which has been used postoperatively and prophylactically as a thrombolytic agent.

[21] Oral and intrathecal When administered via the intraluminal route, PPS is used for the treatment of interstitial cystitis (inflammation of the bladder). [22-24] In fact, PPS is currently prescribed for interstitial cystitis. The active ingredient in ELMIRON®, a drug that is used to treat PPS in osteoporosis As described in

[26] and the use of PPS in bone marrow edema

[27] , Inflammatory conditions such as asthma, allergic rhinitis, and / or chronic obstructive pulmonary disease (COPD) The potential use of PPS for the treatment of glaucoma has also been described

[25] .

[0014] Current treatment options for BMEL have been associated with limited reports of improved clinical outcomes. The standard treatment for BMEL in patients with osteoarthritis is to It consists of painkillers or anti-inflammatory drugs combined with weight-bearing reduction and physical therapy.

[28] However, nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids have been shown to inhibit bone healing. and adverse effects on cartilage metabolism (

[29] -

[32] ). The risk of both traumatic and idiopathic fractures increases with continued corticosteroid therapy.

[31] . This provides new and improved medicines for bone marrow pathologies. The aim of this study is to expand the repertoire of drugs available for the treatment of chronic conditions without these adverse effects. There is a need for medicines. Summary of the Invention [Problem to be solved by the invention]

[0015] The present invention shows that treatment with PPS reduces BMEL volume and, in some cases, A follow-up study showed a complete reduction in BMEL in patients who did not report any post-treatment adverse events. Therefore, PPS is based on the surprising discovery that NSAIDs and corticosteroids Improved alternative drug options to anticoagulants that may have potential disease-modifying activity This finding may provide a basis for the study of BMEL and joint effusions in patients and MC. This finding suggests the potential efficacy of PPS as a treatment option for B Treatment of patients with MEL and joint effusion who suffer from arthritic conditions such as osteoarthritis This finding also suggests the potential efficacy of PPS as a treatment for MC. However, the potential effectiveness of PPS as a treatment for patients suffering from back pain such as CLBP has not been established. It is suggested. [Means for solving the problem]

[0016] According to one embodiment, bone in a mammal as assessed by magnetic resonance imaging (MRI) A method for the treatment of spinal cord edema lesions, comprising administering a polysulfated polysaccharide or an acceptable salt thereof to to a mammal in need of such treatment.

[0017] According to another aspect, a method for treating a mammalian spine, as assessed by magnetic resonance imaging (MRI), comprising: The present invention relates to a method for the treatment of type I Modic endplate change in a patient with rheumatoid arthritis, comprising administering to said patient a polysulfated polysaccharide or an acceptable salt thereof. and administering the salt thereof to a mammal in need of such treatment. Provided.

[0018] According to another embodiment, the present invention relates to a method for treating type I modality in the spine, as assessed by magnetic resonance imaging (MRI). 20. A method for treating back pain in a mammal having back endplate alterations comprising the steps of: administering the polysaccharide or an acceptable salt thereof to a mammal in need of such treatment. A method is provided that includes:

[0019] According to another embodiment, a method for the treatment of a mammalian encephalopathy, comprising administering to the mammal a therapeutically effective amount of a cerebrospinal fluid (EC 60.1.1.2) comprising administering to the mammalian encephalopathy, A composition for the treatment of bone marrow edema lesions, comprising a polysulfated polysaccharide or an acceptable salt thereof and and an acceptable excipient.

[0020] According to another embodiment, a method for the treatment of a mammalian encephalopathy, comprising administering to the mammal a therapeutically effective amount of a cerebrospinal fluid (EC 60.1.1.2) comprising administering to the mammalian encephalopathy, A composition for use in the treatment of bone marrow edema lesions, comprising a polysulfated polysaccharide or an acceptable salt thereof. Compositions comprising the salts thereof and acceptable excipients are provided.

[0021] According to another aspect, a method for treating a mammalian spine, as assessed by magnetic resonance imaging (MRI), comprising: The present invention relates to a composition for treating type I Modic endplate change in a patient with rheumatoid arthritis, the composition comprising a polysulfated polysaccharide or a soluble sucrose. Compositions comprising an acceptable salt thereof and an acceptable excipient are provided.

[0022] According to another aspect, a method for treating a mammalian spine, as assessed by magnetic resonance imaging (MRI), comprising: 23. A composition for use in the treatment of type I Modic endplate change in patients with glaucoma, comprising: A composition is provided that includes a polysaccharide or an acceptable salt thereof and an acceptable excipient.

[0023] According to another aspect, a method for treating a mammalian spine, as assessed by magnetic resonance imaging (MRI), comprising: A composition for treating back pain in a mammal with Modic endplate type I changes. In accordance with the present invention, a composition is provided that comprises a polysulfated polysaccharide or an acceptable salt thereof and an acceptable excipient. can be.

[0024] According to another aspect, a method for treating a mammalian spine, as assessed by magnetic resonance imaging (MRI), comprising: Composition for use in treating back pain in mammals with type I Modic endplate changes - Patents.com A composition comprising a polysulfated polysaccharide or an acceptable salt thereof and an acceptable excipient. A composition is provided.

[0025] According to another embodiment, a method for the treatment of a mammalian encephalopathy, comprising administering to the mammal a therapeutically effective amount of a cerebrospinal fluid (EC 60.1.1.2) comprising administering to the mammalian encephalopathy, The use of a polysulfated polysaccharide or an acceptable salt thereof in the treatment of bone marrow edema lesions is provided. do.

[0026] According to another embodiment, a method for the treatment of a mammalian encephalopathy, comprising administering to the mammal a therapeutically effective amount of a cerebrospinal fluid (EC 60.1.1.2) comprising administering to the mammalian encephalopathy, A method for the manufacture of a medicament for the treatment of bone marrow edema lesions, comprising administering to said patient a polysulfated polysaccharide or an acceptable carrier thereof. The use of salt is provided.

[0027] According to another aspect, a method for treating a mammalian spine, as assessed by magnetic resonance imaging (MRI), comprising: Polysulfated polysaccharides or acceptable salts thereof for the treatment of type I Modic endplate change in patients with glaucoma - Patents.com The use of

[0028] According to another aspect, a method for treating a mammalian spine, as assessed by magnetic resonance imaging (MRI), comprising: Polysulfated polysaccharides or are provided for use as acceptable salts thereof.

[0029] According to another embodiment, the present invention relates to a method for treating type I modality in the spine, as assessed by magnetic resonance imaging (MRI). Polysulfated polysaccharides or soluble glycerol in the treatment of back pain in mammals with back endplate alterations Acceptable uses of salts thereof are provided.

[0030] According to another embodiment, the present invention relates to a method for treating type I modality in the spine, as assessed by magnetic resonance imaging (MRI). In the manufacture of a medicament for the treatment of back pain in a mammal having back endplate alterations, The use of a sulfated polysaccharide or an acceptable salt thereof is provided.

[0031] Unless otherwise defined herein, scientific and technical terms used in connection with this application Terms used herein shall have the meanings commonly understood by those of ordinary skill in the art. Unless otherwise required by paragraph, singular terms include their plurals and plural terms include the singular. Accordingly, where used in this specification and the appended claims, In this case, the singular forms "a," "an," and "the" are used unless the context requires otherwise. Unless otherwise clearly indicated above, the word "cell" includes multiple referents. , comprising a population of multiple cells.

[0032] With respect to the definitions provided herein, unless otherwise stated or implied from the context, Unless otherwise specified, defined terms and phrases have the meanings given. Unless otherwise clear from context, the following terms and phrases are understood to be of the same meaning as those used herein by those of ordinary skill in the relevant art. The scope of the invention extends to the claims contained therein. The above definitions are provided to aid in describing particular embodiments, since the invention is limited only by and are not intended to limit the invention as defined by the claims.

[0033] Throughout this specification, various aspects and components of this invention may be presented in a range format. The range format is included for convenience and should not be construed as an inflexible limitation on the scope of the invention. Therefore, ranges should be stated to cover all possible parts unless otherwise indicated. In addition to a range of minutes, each individual numerical value within the range should be deemed to be specifically disclosed. For example, a range such as 1-5 can be expressed as 1-2, 1-3, 1-4, 2-3, 2-4, In addition to subranges such as 2 to 5, 3 to 4, etc., individual numbers and subranges within the recited ranges are should be considered to specifically disclose appropriate numbers, e.g., 1, 2, 3, 4, and 5. This is where specific values ​​are needed that apply regardless of the breadth of the ranges disclosed. These will be indicated herein.

[0034] The term "acceptable excipient" refers to any excipient that is physiologically compatible and is capable of reacting with any of the compounds described herein. Solvent, diluent, dispersion medium, coating agent, antibacterial agent, which is not harmful to the compound or its use The pharmaceutical composition may include excipients or agents such as anti-inflammatory agents, antifungal agents, isotonic agents, and absorption delaying agents. The use of such carriers and agents to prepare compositions of active substances is well known in the art. (e.g., Remington: The Science and Practice of Pharmacy, 21s (See t Edition; Lippincott Williams & Wilkins: Philadelphia, PA, 2005).

[0035] The term "acceptable salt" includes, but is not limited to, hydrochloride, hydrobromide, sulfate, etc. salts, inorganic acid salts such as phosphates, formates, acetates, trifluoroacetates, maleates Salts, organic acid salts such as tartrates, methanesulfonates, benzenesulfonates, p- Sulfonates such as toluenesulfonates, arginates, aspartates, Amino acid salts such as glutamate, sodium salts, potassium salts, cesium salts, etc. alkaline earth metal salts such as calcium salts, magnesium salts, and the like; Triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine amine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc. This includes organic amine salts such as:

[0036] Base salts include, but are not limited to, sodium, potassium, lithium, calcium Al, such as salts formed from magnesium, zinc, ammonium, and triethylamine Alkoxyammonium, such as those formed with alkoxyammonium and ethanolamine and ethylenediamine, choline, or arginine, lysine, or histidine and salts formed from pharma- ceutically acceptable cations, such as salts formed from amino acids such as General information regarding the types of acceptable salts and their formation is available to those skilled in the art. Known in "Handbook of Pharmaceutical salts" by P.H. Stahl, C.G. Wermuth, 1st ed. This is as described in general textbooks such as ed., 2002, Wiley-VCH.

[0037] The terms "administration of" and / or "administering" a compound refer to administering a compound of the invention to a subject It should be understood to mean providing a therapeutic agent to an individual in need of treatment.

[0038] As used herein, the term "composition" refers to a product containing specified ingredients in specified amounts. In addition, all products derived directly or indirectly from the combination of the specified ingredients in the specified amounts. It is intended to encompass products.

[0039] Throughout this specification, the words "comprises" or "comprises )" or variations thereof such as "comprising" include the elements, integers, or step, or a group of elements, integers, or steps, but Any other element, integer, or step, or group of elements, integers, or steps It will be understood that no exclusion is implied.

[0040] The present invention relates to the treatment of mammalian subjects. A "mammalian" subject may be considered to be treating a "mammalian individual" with a particular condition or need for treatment. have clinical signs of a condition suggestive of a medical condition, are receiving treatment for a condition, or are being treated for a condition He has been diagnosed with a condition called

[0041] Thus, unless otherwise specifically indicated, the present invention is applicable to humans and other non-human mammals. It should be understood that the human can be male or female. Other non-human Mammals include primates, livestock, and farm animals (e.g., sheep, horses, cattle, pigs, household pets such as cats and dogs, performance animals (e.g., race horses, camels, greyhounds), clinical laboratory animals (e.g., mice, rabbits) , rats, and guinea pigs), which are usually found in the wild, but can also be found in zoos, wildlife parks, etc. The animal may be one that is likely to be amenable to treatment because it is an animal found in

[0042] As used herein, the terms "treating," "treat," or "treatment" and its modifications are intended to alter the natural course of a subject during the course of a clinical condition. The desired effect of treatment includes slowing the progression of the disease, improving or slowing the progression of the condition. For example, one or more of the above treatment outcomes may be achieved. When a plurality of these is achieved, the subject is successfully "treated." The terms "treat," "treat" or "treatment" and variations thereof refer to the treatment of a clinical illness. "Prevention" may be understood to refer to clinical interventions intended to prevent the onset of disease processes. "preventing" or "prevention."

[0043] An "effective amount" is the amount needed to produce a measurable improvement in a particular disease (e.g., bone marrow edema). This specification includes a "therapeutically effective" amount, which refers to at least the minimum concentration or amount that is achieved. The effective amount described herein will depend on the disease state, age, sex, and weight of the patient, and on the individual's ability to produce the desired response. The effective amount may vary depending on factors such as the ability of the PPS to induce a therapeutic effect. It is also the amount in which the beneficial effects outweigh any toxic or adverse effects of PPS. " refers to the amount of drug or the rate of drug administration required to obtain the desired prophylactic result. Also encompassed by the term "prophylactically effective" amount is an amount that is DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0044] Description of the embodiments The present disclosure relates to bone marrow edema in mammals as assessed by magnetic resonance imaging (MRI). A method for the treatment of a lesion, comprising administering a polysulfated polysaccharide or an acceptable salt thereof to such The present invention relates to a method comprising administering to a mammal in need of such treatment.

[0045] Preferably, the mammal is suffering from an arthritic condition. Preferably, the arthritic condition is a joint rheumatoid or osteoarthritis. Preferably, the arthritic condition is rheumatoid arthritis. Preferably, the arthritic condition is osteoarthritis. Preferably, osteoarthritis is , ankle, hip, knee, shoulder, spine, and wrist. Preferably, the osteoarthritis is in the knee joint. The disease is in the spine (spondylosis).

[0046] The present disclosure relates to the detection of I in the mammalian spine as assessed by magnetic resonance imaging (MRI). A method for the treatment of Modic endplate change comprising administering to a subject a polysulfated polysaccharide or an acceptable salt thereof. to a mammal in need of such treatment.

[0047] The present disclosure relates to a method for treating a patient with Modic I endplate syndrome in the spine as assessed by magnetic resonance imaging (MRI). A method for the treatment of back pain in a mammal having a back disorder comprising administering to said mammal a polysulfated polysaccharide or or administering an acceptable salt thereof to a mammal in need of such treatment. It concerns the method.

[0048] Preferably, the back pain is selected from the group consisting of general back pain, acute back pain, and chronic back pain. Preferably, the back pain is selected from the group consisting of general lower back pain, acute lower back pain, and chronic lower back pain. Preferably, the back pain is chronic lower back pain. Type II Modic endplate changes in the spine are associated with Type II Modic endplate changes in the spine. In addition, type I Modic endplate changes in the spine are similar to type III Modic endplate changes in the spine. It is related to change.

[0049] The present disclosure relates to bone marrow edema in mammals as assessed by magnetic resonance imaging (MRI). A composition for treating a lesion, comprising a polysulfated polysaccharide or an acceptable salt thereof and an acceptable salt thereof. The present invention relates to a composition comprising an excipient that is

[0050] The present disclosure relates to bone marrow edema in mammals as assessed by magnetic resonance imaging (MRI). A composition for use in the treatment of a lesion, comprising a polysulfated polysaccharide or an acceptable salt thereof. The present invention relates to a composition comprising the salt and an acceptable excipient.

[0051] Preferably, the mammal is suffering from an arthritic condition. Preferably, the arthritic condition is a joint rheumatoid or osteoarthritis. Preferably, the arthritic condition is rheumatoid arthritis. Preferably, the arthritic condition is osteoarthritis. Preferably, osteoarthritis is , ankle, hip, knee, shoulder, spine, and wrist. Preferably, the osteoarthritis is in the knee joint. The disease is in the spine (spondylosis).

[0052] The present disclosure relates to the detection of I in the mammalian spine as assessed by magnetic resonance imaging (MRI). A composition for the treatment of Modic endplate changes, comprising a polysulfated polysaccharide or an acceptable salt thereof. It also relates to a composition comprising the salt and an acceptable excipient.

[0053] The present disclosure relates to the detection of I in the mammalian spine as assessed by magnetic resonance imaging (MRI). 20. A composition for use in the treatment of Modic endplate change comprising a polysulfated polysaccharide or relates to compositions comprising acceptable salts thereof and acceptable excipients.

[0054] The present disclosure provides a method for the detection of a type I model in a mammalian spine, as assessed by magnetic resonance imaging (MRI). A composition for the treatment of back pain in a mammal having rheumatoid endplate changes comprising a polysulfide. The present invention relates to a composition comprising an oxidized polysaccharide or an acceptable salt thereof and an acceptable excipient.

[0055] The present disclosure provides a method for the detection of a type I model in a mammalian spine, as assessed by magnetic resonance imaging (MRI). The present invention relates to a composition for use in treating back pain in mammals having vascular endplate alterations. The present invention relates to a composition comprising a polysulfated polysaccharide or an acceptable salt thereof and an acceptable excipient. do.

[0056] Preferably, the back pain is selected from the group consisting of general back pain, acute back pain, and chronic back pain. Preferably, the back pain is selected from the group consisting of general lower back pain, acute lower back pain, and chronic lower back pain. Preferably, the back pain is chronic lower back pain. Type II Modic endplate changes in the spine are associated with Type II Modic endplate changes in the spine. In addition, type I Modic endplate changes in the spine are similar to type III Modic endplate changes in the spine. It is related to change.

[0057] The present disclosure relates to bone marrow edema in mammals as assessed by magnetic resonance imaging (MRI). The present invention relates to the use of polysulfated polysaccharides or acceptable salts thereof in the treatment of lesions.

[0058] The present disclosure relates to bone marrow edema in mammals as assessed by magnetic resonance imaging (MRI). Use of a polysulfated polysaccharide or an acceptable salt thereof in the manufacture of a medicament for the treatment of a pathology Regarding.

[0059] Preferably, the mammal is suffering from an arthritic condition. Preferably, the arthritic condition is a joint rheumatoid or osteoarthritis. Preferably, the arthritic condition is rheumatoid arthritis. Preferably, the arthritic condition is osteoarthritis. Preferably, osteoarthritis is , ankle, hip, knee, shoulder, spine, and wrist. Preferably, the osteoarthritis is in the knee joint. The disease is in the spine (spondylosis).

[0060] The present disclosure relates to the detection of I in the mammalian spine as assessed by magnetic resonance imaging (MRI). US20130233633A1 - Use of polysulfated polysaccharides or acceptable salts thereof in the treatment of Modic endplate changes - Google Patents Regarding.

[0061] The present disclosure provides a method for the detection of type I inflammatory bowel disease in mammals, as assessed by magnetic resonance imaging (MRI). The use of polysulfated polysaccharides or acceptable salts thereof in the manufacture of a medicament for the treatment of vascular endplate changes Regarding the use of salt.

[0062] The present disclosure relates to a method for treating a patient with Modic I endplate syndrome in the spine as assessed by magnetic resonance imaging (MRI). Polysulfated polysaccharides or acceptable salts in the treatment of back pain in mammals with Concerning the use of said salts.

[0063] The present disclosure relates to a method for treating a patient with Modic I endplate syndrome in the spine as assessed by magnetic resonance imaging (MRI). In the manufacture of a medicament for the treatment of back pain in a mammal having a The present invention relates to the use of sugar or an acceptable salt thereof.

[0064] Preferably, the back pain is selected from the group consisting of general back pain, acute back pain, and chronic back pain. Preferably, the back pain is selected from the group consisting of general lower back pain, acute lower back pain, and chronic lower back pain. Preferably, the back pain is chronic lower back pain. Type II Modic endplate changes in the spine are associated with Type II Modic endplate changes in the spine. In addition, type I Modic endplate changes in the spine are similar to type III Modic endplate changes in the spine. It is related to change.

[0065] The present disclosure relates to a method for the preparation of a polysulfated polysaccharide, the method comprising the steps of: Paran sulfate, pentosan polysulfate, chondroitin polysulfate, chitosan polysulfate, del Matane polysulfate sulodexide, dextran sulfate, polysulfated inulin, sulfated lactobic acid Aldonamide, sulfated bis-aldonic acid amide, sucrose octasulfate, fucoidan-1, fucoidan Coidan-2, sulfated β-cyclodextrin, sulfated γ-cyclodextrin, and Selected from the group consisting of small sulfated compounds including, but not limited to, inositol hexasulfate. Also contemplated are the above-mentioned methods, compositions and uses, which are selected from the group consisting of

[0066] Preferably, the polysulfated polysaccharide is a high molecular weight heparin, a low molecular weight heparin, a polysulfate pentasaccharide, or a combination thereof. Polysulfate chitosan (PPS), polychondroitin sulfate, and polychitosan sulfate. It is selected.

[0067] Preferably, the polysulfate pentosan (PPS) is a sodium salt of polysulfate pentosan ( NaPPS), magnesium salt of pentosan polysulfate (MgPPS), pentosan polysulfate The calcium salt of pentosan polysulfate (CaPPS) and the zinc salt of pentosan polysulfate (ZnPPS) were The compound is selected from the group consisting of:

[0068] Preferably, the polysulfate pentosan (PPS) is sodium polysulfate pentosan (Na PPS).

[0069] In a preferred embodiment, NaPPS is available from Bene-PharmaChem Gm bH&Co KG, Geretsried, Germany, in compliance with the US FDA and Manufactured according to specifications submitted to the European Community EMEA.

[0070] PPS and PPS compositions suitable for administration by various routes are described in Remington: The Science and Practice of Pharmacy, 21st Edition; Lippincott Williams & Wilkins: Philadel Formulate the formulation by referring to standard textbooks in this field, such as Philip, PA, (2005). It will be appreciated by those skilled in the art that these compositions can be administered by injection, oral (gastrointestinal) or other suitable route. Drug absorption extenders and enhancers This includes tablets and capsules containing the active ingredient, intravenous, etc.

[0071] Preferably, the treatment is administered by injection via the intramuscular (IM) or subcutaneous (SC) routes, i.v. intraarticular (IV), intra-articular (IA), peri-articular, topical, via suppository, or by oral administration.

[0072] Preferably, the treatment comprises administering a polysulfated polysaccharide or an acceptable salt thereof at a dose of about 1 to 20 mg / kg. By administration to the mammal at an effective amount of 2 mg / kg of mammal.

[0073] Preferably, the treatment comprises administering about 2 ml of polysulfated polysaccharide or an acceptable salt thereof per dose. By administration to the mammal in an effective amount of 100 mg / kg of mammal. In particular embodiments, the effective amount is about 1.0 to 2.0 mg / kg of subject per dose. In this case, the effective amount is about 1.0 to 1.5 mg / kg, 1.5 to 2.0 mg / kg, 0.5 mg g / kg, 1.0 mg / kg, 1.5 mg / kg, or 2.0 mg / kg. In one embodiment, the effective amount is a fixed dose between about 25 mg and 4000 mg. In one embodiment, the effective amount is a fixed dose of between about 25 mg and 300 mg. In embodiments, the effective amount is about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, g, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, and is a fixed dose of 300 mg. In certain embodiments, the effective amount is about 350 mg, 00mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg , 750mg, 800mg, 850mg, 900mg, 950mg, 1000mg, 20 The drugs are available in fixed doses of 00mg, 3000mg, or 4000mg.

[0074] Preferably, the treatment is by injection. Preferably, the treatment is by subcutaneous (SC) administration. Preferably, the treatment is by intramuscular (IM) injection. be.

[0075] Preferably, administration to a human is by a once-daily, twice-weekly, or three-times-weekly treatment regimen. Preferably, administration to a human is by administration in a twice weekly treatment regimen. Preferably, administration to humans is performed with an interval of at least 3 days and at most 4 days between doses. Preferably, the administration to humans is by a twice weekly treatment regimen of 10 days. is by administration in a twice weekly treatment regimen for six weeks. The total dose of polysulfated polysaccharide administered in the regimen is approximately 200-4000 mg.

[0076] Thus, dosing would be adjusted accordingly for heavier or lighter weight individuals. Treatment regimens may be adapted according to the severity of the pain experienced by the subject. In some cases where patients are experiencing severe pain, the PPS should be replaced as soon as possible to provide a therapeutic alternative. This may involve, for example, administering the drug once a day until the pain resolves. Doses of about 1.0 mg / kg or more of PPS may be required.

[0077] When administered by injection, this is typically performed by a nurse / physician in a clinical setting. The key to successful treatment will be achieving an optimal therapeutic dose near the tissue lesion. Those skilled in the art will understand that the key to effective treatment is to administer sufficient PPS to a subject. PPS is known to accumulate in connective tissues and over time, e.g. A loading dose of 100 g PPS / kg per day for 4-5 days may be achieved. In cases, the subject will receive more than one treatment course per year, perhaps two or three times per year. It is expected that many of the existing

[0078] From a safety perspective, a lower dose range ( A fixed dose of 1-2 mg PPS / kg or about 25-50 mg is preferred. If PS is a known anticoagulant, then at higher doses (>3 mg PPS / kg or approximately 150– 200 mg fixed dose) may increase basal APT, thereby This is because it may promote bleeding from open wounds.

[0079] Although administration by injection is preferred, oral or topical formulations of PPS may be used as initial IM or It can be used as a follow-up treatment (maintenance dose) for PPS treatment of SC. For administration by IV infusion, a lower dose of 0.5 mg once daily may be used. 5-1 mg PPS / kg is preferred.

[0080] The present disclosure also contemplates the administration of polysulfated polysaccharides in combination with other therapeutic agents. When employed in combination with the compounds of the present invention, they may be used in combination with, for example, Physicia The amount set forth in the Proposed Desk Reference (PDR) or otherwise Amounts determined by the manufacturer may be used.

[0081] The specific dose levels and dosing times for any particular patient may vary. The activity of the specific compound employed, the metabolic safety and length of activity of that compound, age, , body weight, general health condition, sex, diet, mode and time of administration, excretion rate, drug combinations The effectiveness of the treatment will vary depending on a variety of factors, including the severity of the particular condition, as well as the recipient receiving the therapy. It will be appreciated that larger animals, for example, may require larger doses. By way of example, a large animal such as a horse may require approximately 4000 mg of solids. Fixed doses may be required.

[0082] Determining suitability for the treatment of the present disclosure, or in other words, bone marrow edema lesions (BMEL) The diagnosis of pulmonary circulation may be made through the use of MRI. For example, in T1-weighted images of MRI As a decrease in signal intensity and an increase in signal intensity on T2-weighted images. Clinical outcomes were assessed by BME L by MRI assessment or by using patient-reported outcome measures. Patient reported pain and / or functional outcomes may be used. These included the Numerical Rating Scale (NRS) for pain

[0033] , the Lysholm Knee Score for function

[34] , and the Pain, Symptoms, Function, and Life Assessment Scale

[35] . Knee injury and Osteoarthritis Outcome Score for quality of care The Koso Outcome Score (KOOS)

[35] and the Oswestry Disability Outcome Score for low back function Oswestry Disability Index (Oswestry Low Back Pain Disability Questionnaire) The questionnaire includes the National Institutes of Health (NIH)-reported Back Pain Disability Questionnaire (NHI), also known as the National Institutes of Health (NIH)-reported Back Pain Disability Questionnaire (NHI).

[36]

[0083] Preferably, the mammal's pain is alleviated following treatment. The mammal's pain is reduced as determined by the neuromuscular response rating (NRS).

[0084] Preferably, the function of the mammal is improved following treatment. The functionality of the mammal is improved as determined by the joint score.

[0085] Preferably, bone marrow edema lesions or modic lesions are not present, as assessed by magnetic resonance imaging. The presence of endplate changes is reduced. Preferably, bone is Any medullary edema lesions or Modic endplate changes present are resolved. [Brief description of the drawings]

[0086] [Figure 1] MRI images of patients in the study of Example 1. Pre-treatment coronal (A) and sagittal (B) 3T proton density fat saturation images demonstrating medial compartment bone edema that is more evident on the fibular side. Axial (C) proton density fat saturation images at the level of the suprapatellar capsule demonstrating knee joint effusion. Corresponding post-treatment coronal (D) and sagittal (E) 3T proton density fat saturation images demonstrating resolution of medial compartment bone edema. Axial (F) proton density fat saturation images at the level of the suprapatellar capsule demonstrating reduction in size of knee joint effusion. [Diagram 2] Figures 2A-2C show selected MRI images from the medical history of Example 2. A: MRI showing BME lesion (arrow) effusion within joint cavity (arrow) before PPS; high NRS pain score = 8; Lysholm score: 37 (poor knee function). B: MRI showing complete resolution of BME lesion and effusion after PPS treatment; pain NRS = 0 (resolved pain); Lysholm score: 65 (satisfactory knee function).

[0087] Example embodiment 1. Healing of bone marrow edema lesions in mammals as assessed by magnetic resonance imaging (MRI) The present invention relates to a method for the treatment of a cancer of the present invention, the method comprising administering a polysulfated polysaccharide or an acceptable salt thereof to a patient receiving said treatment. administering to a mammal in need thereof.

[0088] 2. The method of embodiment 1, wherein the mammal is suffering from osteoarthritis.

[0089] 3. Osteoarthritis is present in the following groups: ankle, hip, knee, shoulder, spine, and wrist. 3. The method of embodiment 2, wherein the selected articulating joint is located at the articulating joint.

[0090] 4. The method of embodiment 3, wherein the osteoarthritis is in the knee joint.

[0091] 5. The method of embodiment 3, wherein the osteoarthritis is in the spine (spondylosis).

[0092] 6. Type I Modification in the Mammalian Spine as Assessed by Magnetic Resonance Imaging (MRI) A method for the treatment of endplate alterations comprising administering a polysulfated polysaccharide or an acceptable salt thereof to administering to a mammal in need of such treatment.

[0093] 7. Patients with type I Modic endplate changes in the spine as assessed by magnetic resonance imaging (MRI) 20. A method for the treatment of back pain in a mammal comprising administering to said mammal a polysulfated polysaccharide or an acceptable salt thereof. Administering a salt thereof to a mammal in need of such treatment.

[0094] 8. The back pain is selected from the group consisting of general back pain, acute back pain, and chronic back pain. The method described in embodiment 7.

[0095] 9. The back pain is selected from the group consisting of general back pain, acute back pain, and chronic back pain. The method described in Example 8.

[0096] 10. The method of embodiment 9, wherein the back pain is chronic lower back pain.

[0097] 11. Type I Modic Endplate Changes in the Spine Type II Modic Endplate Changes in the Spine The method according to any one of embodiments 6 to 10, wherein

[0098] 12. Type I Modic endplate changes in the spine are related to type III Modic endplate changes in the spine. The method according to any one of embodiments 6 to 10, wherein the method is associated with

[0099] 13. The diagnosis of bone marrow edema lesions in mammals as assessed by magnetic resonance imaging (MRI) A therapeutic composition comprising a polysulfated polysaccharide or an acceptable salt thereof and an acceptable A composition comprising an excipient.

[0100] 14. The diagnosis of bone marrow edema lesions in mammals as assessed by magnetic resonance imaging (MRI) A composition for use in therapy comprising a polysulfated polysaccharide or an acceptable salt thereof and and an acceptable excipient.

[0101] 15. The method of claim 13 or 14, wherein the mammal is suffering from osteoarthritis. Composition.

[0102] 16. Osteoarthritis is classified into the following groups: ankle, hip, knee, shoulder, spine, and wrist. The composition of embodiment 15, wherein the composition is in an articular joint selected from the group consisting of:

[0103] 17. The composition of embodiment 16, wherein the osteoarthritis is in the knee joint.

[0104] 18. The composition of embodiment 16, wherein the osteoarthritis is in the spine (spondylosis).

[0105] 19. Type I model in mammalian spine assessed by magnetic resonance imaging (MRI) A composition for treating vascular endplate changes, comprising a polysulfated polysaccharide or an acceptable salt thereof. and an acceptable excipient.

[0106] 20. Type I model in mammalian spine assessed by magnetic resonance imaging (MRI) A composition for use in the treatment of vascular endplate changes comprising a polysulfated polysaccharide or A composition comprising the compound according to the present invention and an acceptable excipient.

[0107] 21. Type I Modic Inflammation in Mammalian Spines Assessed by Magnetic Resonance Imaging (MRI) A composition for the treatment of back pain in a mammal having endplate alterations, comprising a polysulfated polysaccharide. A composition comprising a sugar or an acceptable salt thereof and an acceptable excipient.

[0108] 22. Type I Modic Inflammation in Mammalian Spines Assessed by Magnetic Resonance Imaging (MRI) 1. A composition for use in treating back pain in a mammal having endplate alterations, comprising: A composition comprising a polysulfated polysaccharide or an acceptable salt thereof and an acceptable excipient.

[0109] 23.Which of the following categories of back pain in mammals is classified: general back pain, acute back pain, and chronic back pain? 23. The composition of embodiment 21 or 22, wherein the composition is selected from the group consisting of

[0110] 24. The back pain is selected from the group consisting of general back pain, acute back pain, and chronic back pain. The composition of Example 23.

[0111] 25. The composition of embodiment 24, wherein the back pain is chronic lower back pain.

[0112] 26. Type I Modic Endplate Changes in the Spine Type II Modic Endplate Changes in the Spine The composition of any one of embodiments 19 to 25, wherein

[0113] 27. Type I Modic endplate changes in the spine are related to type III Modic endplate changes in the spine. The composition of any one of embodiments 19 to 25, wherein the composition is associated with

[0114] 28. The diagnosis of bone marrow edema lesions in mammals as assessed by magnetic resonance imaging (MRI) 20. Use of a polysulfated polysaccharide, or an acceptable salt thereof, in therapy.

[0115] 29. The diagnosis of bone marrow edema lesions in mammals as assessed by magnetic resonance imaging (MRI) 20. Use of a polysulfated polysaccharide, or an acceptable salt thereof, in the manufacture of a medicament for treatment.

[0116] 30. The method of claim 28 or 29, wherein the mammal suffers from osteoarthritis. For.

[0117] 31. Osteoarthritis is classified into the following groups: ankle, hip, knee, shoulder, spine, and wrist. The use of embodiment 30 in an articulating joint selected from the group consisting of:

[0118] 32. The use according to embodiment 31, wherein the osteoarthritis is in the knee joint.

[0119] 33. The use according to embodiment 31, wherein the osteoarthritis is in the spine (spondylosis).

[0120] 34. Type I model in mammalian spine assessed by magnetic resonance imaging (MRI) 5. Use of a polysulfated polysaccharide or an acceptable salt thereof in the treatment of vascular endplate changes.

[0121] 35. Type I model in mammalian spine assessed by magnetic resonance imaging (MRI) The use of polysulfated polysaccharides or acceptable salts thereof in the manufacture of a medicament for the treatment of vascular endplate changes Use of salt.

[0122] 36. You have type I Modic endplate changes in your spine as assessed by magnetic resonance imaging (MRI). Polysulfated polysaccharides or acceptable salts thereof in the treatment of back pain in a mammal having Use of.

[0123] 37. You have type I Modic endplate changes in your spine as assessed by magnetic resonance imaging (MRI). The use of a polysulfated polysaccharide or is acceptable use of its salts.

[0124] 38. The back pain is selected from the group consisting of general back pain, acute back pain, and chronic back pain. The use according to embodiment 36 or 37.

[0125] 39. A method for treating back pain, comprising administering to a patient a therapeutically effective amount of medication to a patient, the method ... Use according to embodiment 38.

[0126] 40. The use of embodiment 39, wherein the back pain is chronic lower back pain.

[0127] 41. Type I Modic Endplate Changes in the Spine Type II Modic Endplate Changes in the Spine The use according to any one of embodiments 34 to 40, in conjunction with

[0128] 42. Type I Modic endplate changes in the spine are related to type III Modic endplate changes in the spine. The use of any one of embodiments 34 to 40, wherein the use is associated with

[0129] 43. Polysulfated polysaccharides include high molecular weight heparin, low molecular weight heparin, heparan sulfate, poly Pentosan sulfate, chondroitin polysulfate, chitosan polysulfate, dermatan polysulfate Dexide, dextran sulfate, polysulfated inulin, sulfated lactobionic acid amide, sulfate Hydroxylated bis-aldonic acid amide, sucrose octasulfate, fucoidan-1, fucoidan-2, sulfate Examples of suitable cyclodextrins include, but are not limited to, sulfated β-cyclodextrin, sulfated γ-cyclodextrin, and the like. is selected from the group consisting of small sulfated compounds including inositol hexasulfate. The method according to any one of Examples 1 to 12, the method according to any one of Examples 13 to 27 The composition or use according to any one of embodiments 28 to 42.

[0130] 44. Polysulfated polysaccharides are high molecular weight heparin, low molecular weight heparin, polysulfate pentosan ( PPS), chondroitin polysulfate, and chitosan polysulfate 44. The method, composition or use according to embodiment 43.

[0131] 45. Polysulfate pentosan (PPS) is a sodium salt of polysulfate pentosan (NaPP S), magnesium salt of polysulfate pentosan (MgPPS), calcium salt of polysulfate pentosan The group consisting of calcium salts of pentosan polysulfate (CaPPS), and zinc salts of pentosan polysulfate (ZnPPS) 45. The method, composition or use of embodiment 44, selected from:

[0132] 46. ​​Pentosan polysulfate (PPS) is sodium pentosan polysulfate (NaPPS) The method, composition, or use of embodiment 45,

[0133] 47. Treatment is by injection via intramuscular (IM) or subcutaneous (SC) routes, intravenous (IV) ), intra-articular (IA), peri-articular, topical, via suppository, or orally. The method or composition according to any one of embodiments 1 to 46, wherein the administration is by oral administration. Or use.

[0134] 48. Treatment involves administering polysulfated polysaccharide or an acceptable salt thereof at a dose of approximately 1-2 mg / kg / day. The effective or fixed dose per kg of mammal is about 25 mg, 50 mg, 75 mg, 10 mg, 0mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, by administration to a mammal in an effective amount of 275 mg or 300 mg. 47. The method, composition or use according to any one of embodiments 1 to 47.

[0135] 49. Treatment involves administering polysulfated polysaccharides or acceptable salts thereof at a dose of approximately 2 mg / milk per feeding. 1. The method of claim 1, wherein the effective amount of the compound is administered to a mammal per kg of the animal. 8. The method, composition, or use according to any one of claims 1 to 8.

[0136] 50. The method according to any one of embodiments 47 to 49, wherein the treatment is by injection. The methods, compositions, or uses described herein.

[0137] 51. The method of embodiment 50, wherein the treatment is by subcutaneous (SC) injection administration. Composition, or use.

[0138] 52. Administration to humans is by once-daily, twice-weekly, or three-times-weekly treatment regimens. The method, composition or use according to any one of embodiments 47 to 51, .

[0139] 53. Example 5, in which administration to a human is by administration in a twice weekly treatment regimen. 2. The method, composition, or use according to claim 2.

[0140] 54. The drug is administered to humans in a twice-weekly regimen with a minimum of 3 days and a maximum of 4 days between doses. The method, composition, or use of embodiment 53, wherein the administration is in a therapeutic regimen. For.

[0141] 55. Administration to humans is by twice-weekly treatment regimen for 6 weeks. 54. The method, composition or use according to claim 53.

[0142] 56. The total dose of polysulfated polysaccharide administered in the treatment regimen is approximately 200-4000 mg. The method, composition, or use according to Example 55,

[0143] 57. Any one of embodiments 1 to 56, wherein the mammal's pain is relieved after treatment. The described method, composition, or use.

[0144] 58. The pain of a mammal is reduced as determined by the Numeric Rating Scale (NRS). The method, composition, or use according to Example 57.

[0145] 59. Any one of embodiments 1 to 58, wherein the mammal's function is improved after treatment. The described method, composition, or use.

[0146] 60. As determined by the Lysholm knee score described herein, 60. The method, composition or use of embodiment 59, wherein the functionality of the mammal is improved.

[0147] 61. Bone marrow edema lesions or Modic endplate changes as assessed by magnetic resonance imaging The method, composition, or method according to any one of embodiments 1 to 60, wherein the presence of is used.

[0148] 62. Bone marrow edema lesions or Modic endplate changes as assessed by magnetic resonance imaging The method, composition, or embodiment of any one of embodiments 1 to 60, wherein the presence of is used. EXAMPLES

[0149] [Example 1] Clinical evaluation of pain and function in knee OA patients (n=35) with bone marrow edema lesions on MRI. Effect of pentosan on bed outcomes Example 1 is available under the TGA Special Access Scheme (B): A patient with osteoarthritis and bone marrow edema of the knee joint was treated with PPS. The safety, tolerability, and outcomes of a study conducted in Australia in which an injectable form of PPS was As PPS was not a registered product in the US, approval of its use as a treatment for patients was not available. Under the Special Access Scheme (SAS), the Australian Government , obtained from the Department of Drugs and Pharmaceuticals, Ministry of Health.)

[0150] Patients in this study had the following characteristics: - High pain score - Poor joint function score - MRI evidence of bone marrow edema lesions and joint effusions - Kellgren-La, who is currently on the waiting list for knee replacement surgery wrence(3~4)OA target - Failure of standard treatments, including intra-articular corticosteroid injections

[0151] The protocol featured the following: - Treatment: 2mg / kg intramuscular injection twice weekly for 3 weeks (total of 6 injections) - All patients refrained from NSAIDs during PPS treatment - Pain and function treatment outcomes were assessed before PPS treatment and 2-4 weeks after the last PPS injection was later scored - All patients had baseline subchondral BML

[0152] Clinical outcomes, including BMEL assessment, pain scores, and functional outcome scores, are shown in Table 1.

[0153] [Table 1]

[0154] Legend for Table 1 The Numeric Rating Scale (NRS)

[33] is an 11-point scale (0–10). A 0 is the worst pain imaginable and a 10 is the worst pain imaginable.

[0155] The Lysholm knee score

[34] is an eight-point scale based on the Lysholm knee score scale. is a total score ranging from 0 to 100 calculated based on the results obtained from the functional components of : Lameness (5 points), Support (5 points), Rocking symptoms (15 points), Instability (25 points), pain (25 points), swelling (10 points), stair climbing (10 points) This total score is then calculated based on the following assessment categories: 95-100 indicates excellent functioning, 84-94 A score of 65–83 indicates good function, and a score of 65–83 indicates equivocal function. A score below 65 indicates poor functioning.

[0156] In conclusion, under the TGA SAS(B), patients with bone marrow edema and osteoarthritis No adverse events were reported with the use of PPS in patients with A standard 4-week course resulted in a clearly visible reduction in BMEL, with no significant improvement in pain or mobility. Mobility scores improved.

[0157] Further studies will involve PP administered by slow SC injection twice weekly for 6 weeks. The administration and treatment regimen of a fixed dose of S2mg / kg or 150mg resulted in magnetic resonance imaging. Consistent reduction in BMEL volume, as assessed by ultrasound imaging, and in some cases, A complete reduction of the BMEL was surprisingly obtained.

[0158] [Example 2] Case report of osteoarthritis of the knee overview Example 2 is a patient with knee osteoarthritis who was scored 8 on the Numeric Rating Scale (NRS). Features indicating high levels of knee pain and a poor Lysholm knee score of 37 We describe the case of a 70-year-old woman with limited mobility. MRI scan of the knee joint revealed Subchondral bone marrow edema (BML) lesions were found in the medial femoral condyle and medial fibular plateau. Patients were treated with a single dose of pentosan polysulfate sodium (PPS) twice weekly for three weeks. A course of 100 mg / kg / day was administered intramuscularly. MRI scans 2 weeks after treatment showed that the medial femoral condyle and fibula The patient showed complete resolution of bone marrow edema in the medial plateau and recovery of pain (NRS pain score 0.01). ) and a 43% improvement in Lysholm knee joint score. Subsequent MRI scans also showed a significant reduction in joint effusion. The interpretation of these MRIs was: Support improvements in clinical outcome measures following therapeutic intervention using PPS.

[0159] Medical history A 70-year-old woman with a history of arthroscopic partial medial meniscectomy presented with left knee pain. The patient presented with rheumatoid arthritis and was on the waiting list for total knee arthroplasty. did not respond to intravenous cortisol administration. 3 Tesla proton density turbo spin echo fat MRI scans of the knee joint were acquired with TR 3000 ms and TE 30 ms using saturation. Focal full-thickness cartilage defects on the medial aspect of the weight-bearing medial femoral condyle and medial fibular plateau The BML measurements for the medial femoral condyle were 11 × 7 × 12 mm. (CC × transverse diameter × AP), and the BML measurement of the medial fibular plateau was 8 × 8 × 8 mm (CC In addition, the axial proton density at the level of the suprapatellar capsule was Sum imaging revealed knee joint effusion and re-tear of the medial meniscus (body and posterior horn) After patient consent, pain assessment scores were calculated using a numerical rating scale (NRS)

[33] . Functional capacity was assessed using the Lysholm knee score

[34] . Before treatment, the NRS pain score was severe, with a score of 8 out of 10 (range 0-10). The Lysholm knee score was 37 out of 100, which is consistent with the stair climbing and limp This reflects poor knee function suggesting a problem with the gait.

[0160] Because PPS is a weak anticoagulant with activity 1 / 15 that of heparin, Therefore, a complete blood count should be performed before and periodically during treatment with pentosan polysulfate sodium. Calculations, APTT, prothrombin time, liver function tests, renal function tests, and serum calcium Patients were monitored throughout the course of treatment and follow-up by assessing The clinical status of the patients was reviewed regularly.

[0161] After evaluation, the patient was treated with pentosan polysulfate sodium (PPS) under SAS. Patients were deemed suitable for treatment. The interval between doses was set to a minimum of 3 days and a maximum of 4 days. PPS was administered at 2 mg / kg twice weekly for 6 days over a 3-week period. The treatment was administered into the gluteus maximus muscle over a 1-week period (2 injections per week). Three follow-up visits were scheduled: on days 0, 24, and 38. Five weeks after the first PPS injection, Spatial acquisition was performed with a TR of 1200 ms and a TE of 28 ms using 3 Tesla proton density fat saturation. MRI scans were performed, revealing bone marrow in the medial femoral condyle and medial fibular plateau. Complete resolution of the edematous lesion was demonstrated. Furthermore, axial imaging at the level of the suprapatellar capsule showed The patient demonstrated a reduction in the size of the knee joint effusion. The lm knee joint score was 65, showing a significant improvement of 43% in function, and the NRS score was 65. The pain score was annotated as 0, indicating a robust recovery from pain. During the study and follow-up period, patients did not experience any drug-related or non-drug-related adverse reactions. There wasn't.

[0162] Discussion and Conclusion Spatial acquisition with TR 1200ms and TE 28ms using 3 Tesla proton density fat saturation The findings of the MRI performed after one course of intramuscular PPS were The results clearly demonstrated that complete resolution of the BML in the medial plateau of the femur and the femoral neck was achieved (Figure 1 and In addition, axial imaging at the level of the suprapatellar capsule was performed to assess the size of the knee joint effusion. Furthermore, patients reported no adverse effects from PPS administration. There wasn't.

[0163] In conclusion, treatment with PPS reduces the reporting of post-treatment adverse events in patient follow-up. The results from this case report showed a complete reduction in BMEL without any associated morbidity. and the potential efficacy of PPS as a treatment option for joint effusion was suggested, on BMEL and joint effusion in patients suffering from arthritic conditions such as osteoarthritis These findings also suggest the potential effectiveness of PPS as a treatment option for glaucoma.

[0164] [Example 3] Case report of chronic low back pain Type I Modic pattern on MRI scans of the L3 / L4 and L4 / L5 spinal regions GW, a 52-year-old male patient with chronic lower back pain and Modix IV, is currently using NSAIDs for Modix IV. Clinically, patients presented with persistent pain that did not resolve despite treatment with standard therapies for rheumatoid arthritis. did.

[0165] The baseline NRS pain score before treatment with PPS was high at 7. Patients were administered a fixed dose of 150 mg of PPS by subcutaneous injection twice weekly for 4 weeks. The patient reported improvement in pain immediately after the fourth injection. After the eighth injection (completion of treatment), the patient experienced a significant reduction in pain, with a reduction of 2-3%. During the course of treatment, patients were asked to refrain from any other therapeutic interventions. No adverse events were experienced during or after the course of PPS treatment. It was.

[0166] Further studies will involve PP administered by slow SC injection twice weekly for 6 weeks. The administration and treatment regimen of a fixed dose of S2mg / kg or 150mg resulted in magnetic resonance imaging. Surprisingly, consistent resolution of Modic changes, as assessed by acoustic imaging, was obtained. Ta.

[0167] Numerous variations and / or modifications may be made to the above without departing from the broad and general scope of the present disclosure. Those skilled in the art will appreciate that the above embodiments may be modified in various ways. The embodiments are to be considered in all respects as illustrative and not restrictive. .

[0168] References 1. Davies-Tuck ML, Wluka AE, Wang Y, English DR, Giles GG, Cicuttini F. The natu ral history of bone marrow lesions in community-based adults with no clinical kn ee osteoarthritis. Annals of the Rheumatic Diseases. 2009;68(6):904-8. 2. Felson DT, Chaisson CE, Hill CL, Totterman SM, Gale ME, Skinner KM, et al. Th e association of bone marrow lesions with pain in knee osteoarthritis. Annals of internal medicine. 2001;134(7):541-9. 3. Zhai G, Blizzard L, Srikanth V, Ding C, Cooley H, Cicuttini F, et al. Correla tes of knee pain in older adults: Tasmanian Older Adult Cohort Study. Arthritis and rheumatism. 2006;55(2):264-71. 4. Roemer FW, Guermazi A, Javaid MK, Lynch JA, Niu J, Zhang Y, et al. Change in MRI-detected subchondral bone marrow lesions is associated with cartilage loss: the MOST Study. A longitudinal multicentre study of knee osteoarthritis. Ann Rhe um Dis. 2009; 68(9): 1461-5. 5. Hunter DJ, Zhang Y, Niu J, Goggins J, Amin S, LaValley MP, et al. Increase in bone marrow lesions associated with cartilage loss: a longitudinal magnetic res onance imaging study of knee osteoarthritis. Arthritis and rheumatism. 2006;54(5 ):1529-35. 6. Wluka AE, Wang Y, Davies-Tuck M, English DR, Giles GG, Cicuttini FM. Bone mar row lesions predict progression of cartilage defects and loss of cartilage volum e in healthy middle-aged adults without knee pain over 2 yrs. Rheumatology (Oxfo rd, England). 2008;47(9):1392-6. 7. Wluka AE, Hanna F, Davies-Tuck M, Wang Y, Bell RJ, Davis SR, et al. Bone marr ow lesions predict increase in knee cartilage defects and loss of cartilage volu me in middle-aged women without knee pain over 2 years. Ann Rheum Dis. 2009;68(6 ):850-5. 8. Starr AM, Wessely MA, Albastaki U, Pierre-Jerome C, Kettner NW. Bone marrow e dema: pathophysiology, differential diagnosis, and imaging. Acta radiologica (St ockholm, Sweden : 1987). 2008;49(7):771-86. 9. Altahawi FF, Blount KJ, Morley NP, Raithel E, Omar IM. Comparing an accelerat ed 3D fast spin-echo sequence (CS-SPACE) for knee 3-T magnetic resonance imaging with traditional 3D fast spin-echo (SPACE) and routine 2D sequences. Skeletal r adiology. 2017;46(1):7-15. 10. Felson DT, McLaughlin S, Goggins J, LaValley MP, Gale ME, Totterman S, et al . Bone marrow edema and its relation to progression of knee osteoarthritis. Anna ls of internal medicine. 2003;139(5 Pt 1):330-6. 11. Raynauld JP, Martel-Pelletier J, Berthiaume MJ, Abram F, Choquette D, Haraou i B, et al. Correlation between bone lesion changes and cartilage volume loss in patients with osteoarthritis of the knee as assessed by quantitative magnetic r esonance imaging over a 24-month period. Ann Rheum Dis. 2008;67(5):683-8. 12. Tanamas SK, Wluka AE, Pelletier JP, Pelletier JM, Abram F, Berry PA, et al. Bone marrow lesions in people with knee osteoarthritis predict progression of di sease and joint replacement: a longitudinal study. Rheumatology (Oxford, England ). 2010;49(12):2413-9. 13. Lowitz T, Museyko O, Bousson V, Laouisset L, Kalender WA, Laredo JD, et al. Bone marrow lesions identified by MRI in knee osteoarthritis are associated with locally increased bone mineral density measured by QCT. Osteoarthritis and cart ilage. 2013;21(7):957-64. 14. Laslett LL, Dore DA, Quinn SJ, Boon P, Ryan E, Winzenberg TM, et al. Zoledro nic acid reduces knee pain and bone marrow lesions over 1 year: a randomised con trolled trial. Ann Rheum Dis. 2012;71(8):1322-8. 15. Varenna M, Zucchi F, Failoni S, Becciolini A, Berruto M. Intravenous neridro nate in the treatment of acute painful knee osteoarthritis: a randomized control led study. Rheumatology (Oxford, England). 2015;54(10):1826-32. 15A. Rahme R, Moussa R. The modic vertebral endplate and marrow changes: patholo gic significance and relation to low back pain and segmental instability of the lumbar spine. AJNR Am J Neuroradiol. 2008 May;29(5):838-42. 16. Scully MF, Weerasinghe KM, Ellis V, Djazaeri B, Kakkar VV. Anticoagulant an d antiheparin activities of a pentosan polysulphate. Thrombosis Research 1983; 31(1):87-97. 17. Krupinski K, Breddin HK, Casu B. Anticoagulant and antithrombotic effects o f chemically modified heparins and pentosan polysulfate. Haemostasis 1990; 20(2 ):81-92. 18. Shanmugam M, Mody KH. Heparinoid-active sulphated polysaccharides from mari ne algae as potential blood anticoagulant agents. Current Science 2000; 79(12): 1672-1683. 19. Vongchan P, Sajomsang W, Kasinrerk W, Subyen D, Kongrawelert P. Anticoagula nt activities of the chitosan polysulfate synthesized from marine crab shell by semi-heterogeneous conditions. Science Asia 2003; 29:115-120. 20. Vinazzer H. Prevention of recurrence of cerebrovascular thromboses. A rand omized comparative study acetylsalicylic acid and sodium pentosan polysulfate. Fortschr Med 1987; 105(5):79-85. 21. Losonczy H, David M, Nagy I. Effect of pentosan polysulfate on activated pa rtial thromboplastin time, thrombin time, euglobulin clot lysis and tissue-type plasminogen activator and plasminogen activator inhibitor activities in patients with thromboembolic disease. Semin Thromb Hemost 1991; 17(4):394-8. 22. Anderson VR, Perry CM. Pentosan polysulfate: a review of its use in the re lief of bladder pain or discomfort in interstitial cystitis. Drugs 2006; 66(6): 821-35. 23. Dimitrakov J, Kroenke K, Steers WD, Berde C, Zurakowski D, Freeman MR, Jacks on JL. Pharmacologic management of painful bladder syndrome / interstitial cystit is: a systematic review. Arch Intern Med 2007; 167(18):1922-9. 24. Davis EL, El Khoudary SR, Talbott EO, Davis J, Regan LR. Safety and efficac y of the use of intravesical and oral pentosan polysulfate sodium for interstiti al cystitis: a randomized double-blind clinical trial. J Urol 2008; 179(1):177 -85. 25. WO 2008 / 144836. Sulphated xylans for treatment or prophylaxis of respirator y diseases. 26. WO 2002 / 41901. Treatment of osteoporosis. 27. WO 2012 / 103588. Treatment of bone marrow (oedema) with polysulfated polysac charides. 28. Mayerhoefer ME, Krmaer J, Breitenseher MJ, Norden C, Vakil-Adli A, Hofmann S et al. Short-term outcome of painful bone marrow oedema of the knee following o ral treatment with iloprost or tramadol: results of an exploratory phase II stud y of 41 patients. Rheumatology. 2007;46(9):1460-5. 29. Batemen D, Kennedy J. Non-steroidal anti-inflammatory drugs and elderly pati ents. British Medical Journal. 1995;310:817-8. 30. Brandt KD. Should nonsteroidal anti-inflammatory drugs be used to treat oste oarthritis? Rheumatic diseases clinics of North America. 1993;19(1):29-44. 31. O'Mahony D. Prevention of corticosteroid-induced osteoporosis and fractures. Journal of Clinical Pharmacy and Therapeutics. 1999;24(2):83-5. 32. Miyata N, Kumagai K, Osaki M, Murata M, Tomita M, Hozumi A, et al. Pentosan reduces osteonecrosis of femoral head in SHRSP. Clinical and experimental hypert ension (New York, NY : 1993). 2010;32(8):511-6. 33. Hjermstad MJ, Fayers PM, Haugen DF, Caraceni A, Hanks GW, Loge JH, et al. St udies comparing Numerical Rating Scales, Verbal Rating Scales, and Visual Analog ue Scales for assessment of pain intensity in adults: a systematic literature re view. Journal of pain and symptom management. 2011;41(6):1073-93. 34. Briggs KK, Kocher MS, Rodkey WG, Steadman JR. Reliability, validity, and res ponsiveness of the Lysholm knee score and Tegner activity scale for patients wit h meniscal injury of the knee. The Journal of bone and joint surgery American vo lume. 2006;88(4):698-705. 35. Roos EM, Lohmander LS. Knee injury and Osteoarthritis Outcome Score (KOOS): from joint injury to osteoarthritis. Health Qual Life Outcomes 2003;1:64. 36. Fairbank JCT and Pynsent PB (2000) The Owestery Disability Index. Spine, 25( 22):2940-2953.

Claims

1. A pharmaceutical composition for the treatment of chronic low back pain resulting from the presence of type I and / or type II modic endplate changes in the mammalian spine, as assessed by magnetic resonance imaging (MRI), The composition comprises pentosan polysulfate or an acceptable salt thereof. The aforementioned treatment involves administering the composition intramuscularly at a dose of approximately 1 to 2 mg per kg of human body, twice a week, three times a week, or daily, for a period of six weeks. The aforementioned pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the type I modic endplate change in the spine is related to the type II modic endplate change in the spine.

3. The pharmaceutical composition according to claim 1, wherein only type I modic endplate changes are present in the spine.

4. The pharmaceutical composition according to claim 1, wherein only type II modic endplate changes are present in the spine.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pentosan polysulfate (PPS) is selected from the group consisting of sodium salt of pentosan polysulfate (NaPPS), magnesium salt of pentosan polysulfate (MgPPS), calcium salt of pentosan polysulfate (CaPPS), and zinc salt of pentosan polysulfate (ZnPPS).

6. The pharmaceutical composition according to claim 5, wherein the pentosan polysulfate (PPS) is sodium pentosan polysulfate (NaPPS).

7. The pharmaceutical composition according to claim 1, wherein the treatment is administered by injection via an intramuscular (IM) or subcutaneous (SC) route, intravenous (IV) administration, intra-articular (IA) administration, peri-articular administration, local administration, administration via suppository, or oral administration.

8. The pharmaceutical composition according to claim 1, wherein the treatment is administered to a mammal in an effective dose of about 1 to 2 mg / kg of mammal per dose.

9. The pharmaceutical composition according to claim 1, wherein the treatment is administered to a mammal in an effective dose of about 2 mg / kg of mammal per dose of pentosan polysulfate or an acceptable salt thereof.

10. The pharmaceutical composition according to any one of claims 7 to 9, wherein the treatment is administered by injection.

11. The pharmaceutical composition according to claim 10, wherein the treatment is administered by subcutaneous (SC) injection.

12. The pharmaceutical composition according to claim 11, wherein administration to humans is by administration in a treatment regimen twice a week.

13. The pharmaceutical composition according to claim 12, wherein administration to humans is by a treatment regimen administered twice a week, with an interval of at least three days and at most four days between doses.

14. The pharmaceutical composition according to claim 13, wherein administration to humans is by administering in a treatment regimen twice a week for six weeks.

15. The pharmaceutical composition according to claim 14, wherein the total dose of pentosan polysulfate administered in the treatment regimen is approximately 200 to 4000 mg.

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