Treatment of bone marrow disorders using polysulfated polysaccharides

Abstract

The present invention relates to the medical use of polysulfated polysaccharides and compositions thereof for the treatment of diseases or disorders associated with bone marrow pathology in the mammalian musculoskeletal system. Specifically, the present invention relates to the use of polysulfated polysaccharides, such as pentosan polysulfate, in the treatment of bone marrow edema lesions or Modic endplate changes of the spine, as assessed by magnetic resonance imaging (MRI).

Description

Technical Field

[0001] The present invention relates to the medical use of polysulfated polysaccharides and compositions thereof for the treatment of diseases or disorders associated with myelopathologies in the mammalian musculoskeletal system. Specifically, the present invention relates to the use of polysulfated polysaccharides in the treatment of bone marrow edema lesions or Modic Endplate Changes of the spine, evaluated by magnetic resonance imaging (MRI).

Background Art

[0002] Bone marrow edema lesion Bone marrow edema lesion (BMEL) is a change that occurs in the subchondral bone and is detected by MRI, which depicts the severity of symptoms including pain ([1] - [3]) and cartilage degeneration ([4] - [7]) in patients with osteoarthritis. BMEL is generally evaluated using fat-suppressed proton density-weighted or T2-weighted sequences. In fat-suppressed T2-weighted and fat-suppressed proton density-weighted sequences, BMEL appears as a very intense signal [8].

[0003] The MRI signal associated with BMEL is thought to be due to an increased concentration of blood and interstitial fluid (including infiltrating macrophages) in areas of trabecular microfractures and trabecular crush in the bone marrow [8]. 3D fast spin echo sequences have been suggested to be useful, especially for cartilage imaging, due to improved spatial resolution and multiplanar reconstruction [9].

[0004] Data suggesting that BMEL plays an important role in the etiology of arthritic conditions such as osteoarthritic conditions including knee osteoarthritis are increasing.

[0005] Knee osteoarthritis Osteoarthritis of the knee (OA) is a disorder characterized by bone changes around the knee joint, progressive loss of articular cartilage, narrowing of the joint space, and ultimately complete joint failure. Knee OA results in knee pain, significant physical disability, and a reduced quality of life. Epidemiological studies suggest that in the United States, there are approximately 12 million people aged 50 and older with symptomatic knee OA, of which an estimated 7 million have BML (Body Mass Limitation).

[0006] Patients with osteoarthritis of the knee may present with a BMEL, which appears as an area of ​​increased signal intensity on MRI of the knee. In the disease, the BMEL is associated with knee pain[2], disease severity and progression, including radiological progression of osteoarthritis of the knee

[10] , and MRI-based cartilage loss([5],

[11] ). Furthermore, in progressive osteoarthritis, the BMEL is more likely to persist with increasing associated cartilage loss and increase in size[5]. In addition, the severity of the BMEL has been shown to correlate with the risk of knee arthroplasty

[12] .

[0007] The strong association with BMEL, accompanied by pain and cartilage loss, has increased pharmaceutical interest in targeting this structural lesion to monitor the progression and treatment effectiveness of osteoarthritis of the knee (

[13] -

[15] ).

[0008] chronic lower back pain Chronic low back pain (CLBP) is defined as persistent or fluctuating low back pain that lasts for at least three months. CLBP, or back pain in general, is a costly condition that involves physical disability and increased medical use. Some patients with CLBP show modic changes (MC), which are obvious bone marrow changes in the vertebrae, on MRI of the spine.

[0009] Of the three types of modal cell carcinoma (MC), I, II, and III, Type I changes are low intensity on T1-weighted imaging (T1WI) and hyperintense on T2-weighted imaging (T2WI), representing bone marrow edema and inflammation. Type II changes are hyperintense on T1WI and isointense or slightly hyperintense on T2WI, associated with the transformation of normal red hematopoietic bone marrow into yellow fatty marrow as a result of medulla ischemia. Type III modal changes are depicted as low intensity on both T1WI and T2WI and are thought to represent subchondral osteosclerosis. Mixed I / II and II / III modal changes have also been reported, suggesting that these changes may be convertible from one type to another [15A].

[0010] Of the three types of chronic muscle disorders (MCs) – Type I, Type II, and Type III – Type I is particularly associated with lower back pain, persistent symptoms, and poor outcomes. Epidemiological studies suggest that in the United States, there are approximately 9 million adults with chronic pulmonary palsy (CLBP), and an estimated 1.6 million of them have Type I MCs.

[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 functional loss, resulting loss of work productivity, medical expenses, and disability benefits.

[0012] Patients with CLBP may exhibit micturition (MC). MC is evident on spinal MRI and, based on published studies, is a bone marrow alteration of the vertebrae associated with low back pain. Findings from various studies have demonstrated that the presence of MC, particularly type I MC, correlates with low back pain, predicts persistent symptoms and illness, and is associated with poor outcomes. These findings suggest that MC is a potential target for pharmacological intervention.

[0013] Polysulfated polysaccharides Heparin and structurally related polysulfated polysaccharides such as pentosan polysulfate, chitosan polysulfate, and fukan have been used for many years as anticoagulants [16-21]. Pentosan polysulfate (PPS), although a weaker anticoagulant than heparin [16, 18, 20], has been used as a thrombolytic agent postoperatively and prophylactically

[21] . When administered orally and via the subarachnoid route, PPS has been used to treat interstitial cystitis (inflammation of the bladder) [22-24]. In fact, PPS is the active ingredient in ELMIRON®, the drug currently prescribed for interstitial cystitis. The potential use of PPS in treating inflammatory conditions such as asthma, allergic rhinitis, and / or chronic obstructive pulmonary disease (COPD) has also been described

[25] , as has been described for the use of PPS in osteoporosis

[26] and in bone marrow edema

[27] .

[0014] Current treatment options for BMEL are diverse, with limited reports of improved clinical outcomes. Standard treatment for BMEL in patients with osteoarthritis consists of analgesics or anti-inflammatory drugs combined with weight-bearing reduction and physiotherapy until symptoms disappear

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

[29] -

[32] . The risk of both traumatic and idiopathic fractures is increased in patients receiving continuous corticosteroid therapy

[31] . There is a need for drugs that do not cause these adverse effects in expanding the repertoire of available medicines to provide novel and improved medicines for myelopathy. [Overview of the Initiative] [Problems that the invention aims to solve]

[0015] This invention is based on the remarkable finding that treatment with PPS reduced BMEL volume, and in some cases, showed complete reduction of BMEL in patients who did not report post-treatment adverse events in follow-up. Therefore, PPS may be an improved alternative drug option to NSAIDs and corticosteroids and may possess potential disease-modifying activity. This finding suggests the potential efficacy of PPS as a treatment option for patients with BMEL and joint exudate, as well as for patients with MC. This finding also suggests the potential efficacy of PPS as a treatment for patients with BMEL and joint exudate who also suffer from arthritis conditions such as osteoarthritis. Furthermore, this finding suggests the potential efficacy of PPS as a treatment for patients with MC who also suffer from back pain such as CLBP. [Means for solving the problem]

[0016] According to one embodiment, a method is provided for the treatment of bone marrow edema lesions in mammals, as evaluated by magnetic resonance imaging (MRI), comprising the step of administering a polysulfated polysaccharide or an acceptable salt thereof to a mammal in need of such treatment.

[0017] In another embodiment, a method is provided for treating type I modic endplate changes in the spine of a mammal, as assessed by magnetic resonance imaging (MRI), comprising the step of administering a polysulfated polysaccharide or an acceptable salt thereof to a mammal in need of such treatment.

[0018] In another embodiment, a method is provided for treating back pain in a mammal having type I modic endplate changes in the spine, as assessed by magnetic resonance imaging (MRI), the method comprising the step of administering a polysulfated polysaccharide or an acceptable salt thereof to the mammal in need of such treatment.

[0019] In another embodiment, a composition is provided for the treatment of bone marrow edema lesions in mammals, as evaluated by magnetic resonance imaging (MRI), comprising a polysulfated polysaccharide or an acceptable salt thereof and an acceptable excipient.

[0020] In another embodiment, a composition is provided for use in the treatment of bone marrow edema lesions in mammals, as evaluated by magnetic resonance imaging (MRI), comprising a polysulfated polysaccharide or an acceptable salt thereof and an acceptable excipient.

[0021] In another embodiment, a composition is provided for the treatment of type I modic endplate changes in the mammalian spine, as assessed by magnetic resonance imaging (MRI), comprising a polysulfated polysaccharide or an acceptable salt thereof and an acceptable excipient.

[0022] In another embodiment, a composition is provided for use in the treatment of type I modic endplate changes in the mammalian spine, as assessed by magnetic resonance imaging (MRI), comprising a polysulfated polysaccharide or an acceptable salt thereof and an acceptable excipient.

[0023] In another embodiment, a composition is provided for the treatment of back pain in mammals having type I modic endplate changes in the mammalian spine, as assessed by magnetic resonance imaging (MRI), comprising a polysulfated polysaccharide or an acceptable salt thereof and an acceptable excipient.

[0024] In another embodiment, a composition is provided for use in the treatment of back pain in mammals having type I modic endplate changes in the mammalian spine, as assessed by magnetic resonance imaging (MRI), comprising a polysulfated polysaccharide or an acceptable salt thereof and an acceptable excipient.

[0025] In another aspect, the use of polysulfated polysaccharides or acceptable salts thereof in the treatment of bone marrow edema lesions in mammals, as assessed by magnetic resonance imaging (MRI), is provided.

[0026] According to another aspect, there is provided the use of a polysulfated polysaccharide or an acceptable salt thereof in the manufacture of a medicament for the treatment of bone marrow edema lesions in mammals, as evaluated by magnetic resonance imaging (MRI).

[0027] According to another aspect, there is provided the use of a polysulfated polysaccharide or an acceptable salt thereof in the treatment of type I Modic endplate changes in the spine of mammals, as evaluated by magnetic resonance imaging (MRI).

[0028] According to another aspect, there is provided the use of a polysulfated polysaccharide or an acceptable salt thereof in the manufacture of a medicament for the treatment of type I Modic endplate changes in the spine of mammals, as evaluated by magnetic resonance imaging (MRI).

[0029] According to another aspect, there is provided the use of a polysulfated polysaccharide or an acceptable salt thereof in the treatment of back pain in mammals having type I Modic endplate changes in the spine, as evaluated by magnetic resonance imaging (MRI).

[0030] According to another aspect, there is provided the use of a polysulfated polysaccharide or an acceptable salt thereof in the manufacture of a medicament for the treatment of back pain in mammals having type I Modic endplate changes in the spine, as evaluated by magnetic resonance imaging (MRI).

[0031] Unless otherwise defined herein, scientific and technical terms used in connection with this application shall have the meanings commonly understood by those skilled in the art. Further, unless the context requires otherwise, singular terms shall include their plurals and plural terms shall include their singulars. Thus, as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. For example, the term "cell" includes a population of multiple cells.

[0032] With respect to the definitions provided herein, unless otherwise stated or implicitly stated in the context, defined terms and phrases include the meanings provided. Unless otherwise stated or evident in the context, the following terms and phrases do not exclude the meanings of terms or phrases acquired by those skilled in the art. Since the scope of the invention is limited only by its claims, the definitions provided are for the purpose of assisting in the description of specific embodiments and are not intended to limit the invention described in the claims.

[0033] Throughout this specification, various aspects and components of the present invention may be expressed in range form. Range form is included for convenience and should not be interpreted as an inflexible limitation within the scope of the invention. Therefore, unless otherwise indicated, range descriptions should be considered to specifically disclose individual numerical values ​​within that range, in addition to all possible subranges. For example, a range description such as 1–5 should be considered to specifically disclose individual and partial numbers within the enumerated range, e.g., 1, 2, 3, 4, and 5, in addition to subranges such as 1–2, 1–3, 1–4, 2–3, 2–4, 2–5, 3–4, etc. Where specific values ​​applicable regardless of the width of the disclosed range are required, these will be indicated herein.

[0034] The term “acceptable excipients” includes excipients or agents such as solvents, diluents, dispersions, coatings, antimicrobial agents, antifungal agents, isotonic agents, and absorption retarders, which are physiologically compatible and not harmful to the compounds described herein or their use. The use of such carriers and agents for preparing compositions of pharmaceutically active substances is well known in the art (see, for example, Remington: The Science and Practice of Pharmacy, 21st Edition; Lippincott Williams & Wilkins: Philadelphia, PA, 2005).

[0035] The term “acceptable salts” includes, but is not limited to, inorganic salts such as hydrochlorides, hydrobroms, sulfates, and phosphates; organic salts such as formates, acetates, trifluoroacetates, maleates, and tartrates; sulfonates such as methanesulfonates, benzenesulfonates, and p-toluenesulfonates; amino acid salts such as arginates, aspartates, and glutamates; metal salts such as sodium salts, potassium salts, and cesium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and organic amine salts such as triethylamine salts, pyridine salts, picolines, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, and N,N'-dibenzylethylenediamine salts.

[0036] Salts of bases include, but are not limited to, those formed from sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammoniums such as those formed from triethylamine, alkoxyammoniums such as those formed from ethanolamine, and those formed from pharmaceutically acceptable cations such as ethylenediamine, choline, or amino acids such as arginine, lysine, or histidine. General information regarding the types of acceptable salts and their formation is known to those skilled in the art and is found in common textbooks such as "Handbook of Pharmaceutical Salts" PHStahl, CGWermuth, 1st edition, 2002, Wiley-VCH.

[0037] The terms “administration of” and / or “administering” the compound should be understood to mean providing the compound of the present invention to an individual in need of treatment.

[0038] As used herein, the term “composition” is intended to encompass all products obtained directly or indirectly from a given combination of a given amount of a given component, in addition to products containing a given component in a given amount.

[0039] Throughout this specification, the word “comprise,” or variations thereof such as “comprises” or “comprising,” will be understood to mean the inclusion of the element, integer, or step, or group of elements, integers, or steps, as stated, but not the exclusion of any other element, integer, or step, or group of elements, integers, or steps.

[0040] This invention relates to the treatment of mammalian subjects. The treatment of a “mammalian” subject may be considered as the treatment of a “patient” or “individual.” The “mammalian” subject is exhibiting clinical signs of a particular symptom or a symptom that suggests the need for treatment, is receiving treatment for a condition, or has been diagnosed with a condition that will be treated.

[0041] Therefore, unless otherwise specified, the present invention should be understood to be applicable to humans and other non-human mammals. Humans may be male or female. Other non-human mammals may include primates, livestock, and farm animals (e.g., sheep, horses, cattle, pigs), domestic pets such as cats and dogs, performance animals (e.g., racehorses, camels, greyhounds), and laboratory animals (e.g., mice, rabbits, rats, guinea pigs), as well as animals that are usually found in the wild but are considered easy to treat, such as those found in zoos or wildlife parks.

[0042] As used herein, the terms “to treat,” “to cure,” and “treatment,” and their variations, refer to a clinical intervention intended to alter the natural course of a subject during the course of a clinical condition. Desired effects of treatment include a slowing of disease progression, improvement or mitigation of symptoms, and remission or improvement of prognosis. For example, if one or more of the above treatment outcomes are achieved, the subject is successfully “treated.” As used herein, the terms “to treat,” “to cure,” and their variations, and their variations, will be understood to encompass “to prevent,” “to prevent,” and “prevention,” which refer to a clinical intervention intended to avoid the occurrence of a clinical condition.

[0043] "Effective dose" encompasses a "therapeutably effective" dose, which refers to the minimum concentration or amount required to obtain a measurable improvement in a particular disease (e.g., bone marrow edema). Effective doses as used herein may vary depending on factors such as the patient's condition, age, sex, weight, and the PPS's ability to elicit a desired response in the individual. An effective dose is also the amount at which the therapeutically beneficial effect outweighs any toxic or adverse effects of the PPS. "Effective dose" also encompasses a "prophylactically effective" dose, which refers to the amount or rate of drug administration required to obtain a desired prophylactic outcome. [Modes for carrying out the invention]

[0044] Description of the Embodiment This disclosure relates to a method for treating bone marrow edema lesions in mammals, as assessed by magnetic resonance imaging (MRI), comprising the step of administering a polysulfated polysaccharide or an acceptable salt thereof to a mammal in need of such treatment.

[0045] Preferably, the mammal suffers from an arthritis condition. Preferably, the arthritis condition is selected from rheumatoid arthritis or osteoarthritis. Preferably, the arthritis condition is rheumatoid arthritis. Preferably, the arthritis condition is osteoarthritis. Preferably, the osteoarthritis is located in a joint selected from the group consisting of the ankle, hip, knee, shoulder, spine, and wrist. Preferably, the osteoarthritis is located in the knee joint. Preferably, the osteoarthritis is located in the spine (spondylosis).

[0046] This disclosure relates to a method for treating type I modic endplate changes in the spine of a mammal, as assessed by magnetic resonance imaging (MRI), comprising the step of administering a polysulfated polysaccharide or an acceptable salt thereof to a mammal in need of such treatment.

[0047] This disclosure relates to a method for treating back pain in mammals having type I modic endplate changes in the spine, as assessed by magnetic resonance imaging (MRI), the method comprising the step of administering a polysulfated polysaccharide or an acceptable salt thereof to the mammal in need of such treatment.

[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 low back pain, acute low back pain, and chronic low back pain. Preferably, the back pain is chronic low back pain. Preferably, type I modic endplate changes in the spine are associated with type II modic endplate changes in the spine. Preferably, type I modic endplate changes in the spine are associated with type III modic endplate changes in the spine.

[0049] This disclosure relates to a composition for the treatment of bone marrow edema lesions in mammals, as assessed by magnetic resonance imaging (MRI), comprising a polysulfated polysaccharide or an acceptable salt thereof and an acceptable excipient.

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

[0051] Preferably, the mammal suffers from an arthritis condition. Preferably, the arthritis condition is selected from rheumatoid arthritis or osteoarthritis. Preferably, the arthritis condition is rheumatoid arthritis. Preferably, the arthritis condition is osteoarthritis. Preferably, the osteoarthritis is located in a joint selected from the group consisting of the ankle, hip, knee, shoulder, spine, and wrist. Preferably, the osteoarthritis is located in the knee joint. Preferably, the osteoarthritis is located in the spine (spondylosis).

[0052] This disclosure relates to a composition for the treatment of type I modic endplate changes in the mammalian spine, as assessed by magnetic resonance imaging (MRI), comprising a polysulfated polysaccharide or an acceptable salt thereof and an acceptable excipient.

[0053] This disclosure relates to a composition for use in the treatment of type I modic endplate changes in the mammalian spine, as assessed by magnetic resonance imaging (MRI), comprising a polysulfated polysaccharide or an acceptable salt thereof and an acceptable excipient.

[0054] This disclosure relates to a composition for the treatment of back pain in mammals having type I modic endplate changes in the mammalian spine, as assessed by magnetic resonance imaging (MRI), comprising a polysulfated polysaccharide or an acceptable salt thereof and an acceptable excipient.

[0055] This disclosure relates to a composition for use in the treatment of back pain in mammals having type I modic endplate changes in the mammalian spine, as assessed by magnetic resonance imaging (MRI), comprising a polysulfated polysaccharide or an acceptable salt thereof and an acceptable excipient.

[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 low back pain, acute low back pain, and chronic low back pain. Preferably, the back pain is chronic low back pain. Preferably, type I modic endplate changes in the spine are associated with type II modic endplate changes in the spine. Preferably, type I modic endplate changes in the spine are associated with type III modic endplate changes in the spine.

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

[0058] This disclosure relates to the use of polysulfated polysaccharides or acceptable salts thereof in the manufacture of agents for the treatment of bone marrow edema lesions in mammals, as assessed by magnetic resonance imaging (MRI).

[0059] Preferably, the mammal suffers from an arthritis condition. Preferably, the arthritis condition is selected from rheumatoid arthritis or osteoarthritis. Preferably, the arthritis condition is rheumatoid arthritis. Preferably, the arthritis condition is osteoarthritis. Preferably, the osteoarthritis is located in a joint selected from the group consisting of the ankle, hip, knee, shoulder, spine, and wrist. Preferably, the osteoarthritis is located in the knee joint. Preferably, the osteoarthritis is located in the spine (spondylosis).

[0060] This disclosure relates to the use of polysulfated polysaccharides or acceptable salts thereof in the treatment of type I modic endplate changes in the mammalian spine, as assessed by magnetic resonance imaging (MRI).

[0061] This disclosure relates to the use of polysulfated polysaccharides or acceptable salts thereof in the manufacture of agents for the treatment of type I modic endplate changes in mammals, as assessed by magnetic resonance imaging (MRI).

[0062] This disclosure relates to the use of polysulfated polysaccharides or acceptable salts thereof in the treatment of back pain in mammals having type I modic endplate changes in the spine, as assessed by magnetic resonance imaging (MRI).

[0063] This disclosure relates to the use of polysulfated polysaccharides or acceptable salts thereof in the manufacture of agents for the treatment of back pain in mammals having type I modic endplate changes in the spine, as assessed by magnetic resonance imaging (MRI).

[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 low back pain, acute low back pain, and chronic low back pain. Preferably, the back pain is chronic low back pain. Preferably, type I modic endplate changes in the spine are associated with type II modic endplate changes in the spine. Preferably, type I modic endplate changes in the spine are associated with type III modic endplate changes in the spine.

[0065] This disclosure also explores the above-mentioned methods, compositions, and uses, wherein the polysulfated polysaccharide is preferably selected from the group consisting of small sulfated compounds including high molecular weight heparin, low molecular weight heparin, heparan sulfate, polysulfate pentosan, polysulfate chondroitin, polysulfate chitosan, dermatan polysulfate thulodoxide, sulfate dextran, polysulfated inulin, sulfated lactobionic acid amide, sulfated bis-aldonic acid amide, octasulfate sucrose, fucoidan-1, fucoidan-2, sulfated β-cyclodextrin, sulfated γ-cyclodextrin, and, but not limited to, inositol hexasulfate.

[0066] Preferably, the polysulfated polysaccharide is selected from the group consisting of high molecular weight heparin, low molecular weight heparin, polysulfate pentosan (PPS), polysulfate chondroitin, and polysulfate chitosan.

[0067] Preferably, the pentosan polysulfate (PPS) is selected from the group consisting of sodium pentosan polysulfate (NaPPS), magnesium pentosan polysulfate (MgPPS), calcium pentosan polysulfate (CaPPS), and zinc pentosan polysulfate (ZnPPS).

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

[0069] In a preferred embodiment, NaPPS is manufactured by Bene-PharmaChem GmbH&Co KG, Geretried, Germany, in accordance with specifications filed with the U.S. FDA and the European Community (EMEA).

[0070] Those skilled in the art will recognize that PPS and PPS compositions suitable for administration via various routes can be formulated by referring to standard textbooks in this field, such as Remington: The Science and Practice of Pharmacy, 21st Edition; Lippincott Williams & Wilkins: Philadelphia, PA, (2005). These compositions include those administered by injection, orally (including tablets and capsules containing gastrointestinal drug absorption extenders and drug absorption enhancers), intravenously, and other means.

[0071] Preferably, treatment is administered by injection via intramuscular (IM) or subcutaneous (SC) route, intravenous (IV), intra-articular (IA), peri-articular, local, suppository, or oral administration.

[0072] Preferably, treatment involves administering polysulfated polysaccharides or acceptable salts thereof to mammals at an effective dose of approximately 1-2 mg / kg of mammal per dose.

[0073] Preferably, treatment involves administering a polysulfated polysaccharide or an acceptable salt thereof to a mammal at an effective dose of about 2 mg / kg of mammal per dose. Preferably, the effective dose is about 1.0–2.0 mg / kg of subject per dose. In certain embodiments, the effective dose is about 1.0–1.5 mg / kg, 1.5–2.0 mg / kg, 0.5 mg / kg, 1.0 mg / kg, 1.5 mg / kg, or 2.0 mg / kg. In certain embodiments, the effective dose is a fixed dose between about 25 mg and 4000 mg. In certain embodiments, the effective dose is a fixed dose between about 25 mg and 300 mg. In certain embodiments, the effective dose is a fixed dose of about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, or 300 mg. In a particular embodiment, the effective dose is a fixed dose of approximately 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 2000 mg, 3000 mg, or 4000 mg.

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

[0075] Preferably, administration to humans is in the form of a treatment regimen of once daily, twice a week, or three times a week. Preferably, administration to humans is in the form of a treatment regimen of twice a week. Preferably, administration to humans is in the form of a treatment regimen of twice a week with a minimum interval of 3 days and a maximum interval of 4 days between doses. Preferably, administration to humans is in the form of a treatment regimen of twice a week for 6 weeks. Preferably, the total dose of polysulfated polysaccharides administered in the treatment regimen is approximately 200 to 4000 mg.

[0076] Therefore, medication will be adjusted according to the weight of the individual, whether heavier or lighter. The treatment regimen may be adapted according to the severity of the pain the subject is experiencing. In some cases where the patient is experiencing a high level of pain, it is desirable to reach a therapeutically effective dose of PPS as quickly as possible. This may require, for example, administration of PPS at a dose of approximately 1.0 mg / kg or more once daily until the pain subsides.

[0077] When administered by injection, this would typically be performed by a nurse / physician in a clinical setting. Those skilled in the art will understand that the key to successful treatment is administering sufficient PPS to the target to achieve the optimal therapeutic dose near the tissue lesion. Since PPS is known to accumulate in connective tissue, the load can be achieved over time, for example, with a daily dose of 1 mg PPS / kg over 4-5 days. In severe chronic cases, it is expected that the target will require more than one course of treatment per year, possibly two or three courses per year.

[0078] From a safety standpoint, a lower dose range (1-2 mg PPS / kg or a fixed dose of approximately 25-50 mg) with fewer administrations over a longer period is preferred. This is because PPS is a known anticoagulant, and higher doses (>3 mg PPS / kg or a fixed dose of approximately 150-200 mg) may increase basal APT, thereby potentially promoting bleeding from any open wound.

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

[0080] This disclosure also considers the combined administration of polysulfated polysaccharides with other therapeutic agents. When other therapeutic agents are used in combination with the compounds of the present invention, they may be used, for example, in amounts specified in the Physician's Desk Reference (PDR) or otherwise determined by those skilled in the art.

[0081] It should be understood that specific dose levels and administration frequencies for any particular patient may vary and will depend on various factors, including the activity of the specific compound used, its metabolic safety and duration of activity, age, weight, general health, sex, diet, mode and timing of administration, excretion rate, drug combinations, severity of the particular condition, and the recipient of the therapy. For example, it should be understood that larger animals may require higher doses. As an example, large animals such as horses may require a fixed dose of approximately 4000 mg.

[0082] Determining suitability for treatment according to this disclosure, or in other words, diagnosing bone marrow edema lesions (BMELs), may be done via the use of MRI, for example, as decreased signal intensity on T1-weighted images and increased signal intensity on T2-weighted images of MRI. Clinical outcomes may be measured by MRI evaluation of BMELs or by using patient-reported outcome measuring devices. Patient-reported pain and / or functional outcomes may be used. These include the Numerical Rating Scale (NRS) for pain

[33] , the Lysholm knee joint score for function

[34] , the Knee Injury and Osteoarthritis Outcome Score (KOOS)

[35] for pain, symptoms, function, and quality of life, and the Oswestry Disability Index (also known as the Oswestry Low Back Pain Disability Questionnaire)

[36] for lumbar function.

[0083] Preferably, the mammalian pain is reduced after treatment. Preferably, the mammalian pain is reduced as determined by a numerical rating scale (NRS).

[0084] Preferably, mammalian function improves after treatment. Preferably, mammalian function improves as determined by the Lysholm knee joint score.

[0085] Preferably, the presence of bone marrow edema lesions or modic endplate changes is reduced, as assessed by magnetic resonance imaging. Preferably, the presence of bone marrow edema lesions or modic endplate changes is eliminated, as assessed by magnetic resonance imaging. [Brief explanation of the drawing]

[0086] [Figure 1] This figure shows MRI images of the patient in the experiment of Example 1. Pre-treatment coronal (A) and sagittal (B) 3T proton-density fat-saturated images clearly showing more pronounced bone edema in the medial compartment on the fibular side. Axial (C) proton-density fat-saturated image at the level of the suprapatellar bursa clearly showing knee joint exudate. Corresponding post-treatment coronal (D) and sagittal (E) 3T proton-density fat-saturated images clearly showing the resolution of bone edema in the medial compartment. Axial (F) proton-density fat-saturated image at the level of the suprapatellar bursa clearly showing the reduction in the size of knee joint exudate. [Figure 2] This figure shows specific MRI images from the medical history of Example 2. A: MRI before PPS showing exudate from the BME lesion (arrow) in the joint cavity (arrow); high NRS pain score = 8; Lysholm score: 37 (poor knee joint function). B: MRI after PPS treatment showing complete resolution of the BME lesion and exudate; pain NRS = 0 (pain resolution); Lysholm score: 65 (sufficient knee joint function).

[0087] Example of an embodiment 1. A method for treating bone marrow edema lesions in mammals, as assessed by magnetic resonance imaging (MRI), comprising the step of administering a polysulfated polysaccharide or an acceptable salt thereof to a mammal in need of such treatment.

[0088] 2. The method according to Embodiment 1, wherein the mammal is suffering from osteoarthritis.

[0089] 3. The method according to Embodiment 2, wherein the osteoarthritis is located in a joint selected from the group consisting of the ankle, hip, knee, shoulder, spine, and wrist.

[0090] 4. The method according to Embodiment 3, wherein osteoarthritis is present in the knee joint.

[0091] 5. The method according to Embodiment 3, wherein the osteoarthritis is located in the spine (spondylosis).

[0092] 6. A method for treating type I modic endplate changes in the spine of a mammal, as assessed by magnetic resonance imaging (MRI), comprising the step of administering a polysulfated polysaccharide or an acceptable salt thereof to a mammal in need of such treatment.

[0093] 7. A method for treating back pain in a mammal having type I modic endplate changes in the spine, as assessed by magnetic resonance imaging (MRI), comprising the step of administering a polysulfated polysaccharide or an acceptable salt thereof to the mammal in need of such treatment.

[0094] 8. The method according to Embodiment 7, wherein the back pain is selected from the group consisting of general back pain, acute back pain, and chronic back pain.

[0095] 9. The method according to Embodiment 8, wherein the back pain is selected from the group consisting of general lower back pain, acute lower back pain, and chronic lower back pain.

[0096] 10. The method according to Embodiment 9, wherein the back pain is chronic lower back pain.

[0097] 11. The method according to any one of Embodiments 6 to 10, wherein type I modic endplate changes in the spine are associated with type II modic endplate changes in the spine.

[0098] 12. The method according to any one of Embodiments 6 to 10, wherein type I modic endplate changes in the spine are associated with type III modic endplate changes in the spine.

[0099] 13. A composition for the treatment of bone marrow edema lesions in mammals, as evaluated by magnetic resonance imaging (MRI), comprising a polysulfated polysaccharide or an acceptable salt thereof and an acceptable excipient.

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

[0101] 15. The composition according to Embodiment 13 or 14, wherein the mammal is suffering from osteoarthritis.

[0102] 16. The composition according to Embodiment 15, wherein the osteoarthritis is located in a joint selected from the group consisting of the ankle, hip, knee, shoulder, spine, and wrist.

[0103] 17. The composition according to Embodiment 16, wherein osteoarthritis is present in the knee joint.

[0104] 18. The composition according to Embodiment 16, wherein the osteoarthritis is located in the spine (spondylosis).

[0105] 19. A composition for the treatment of type I modic endplate changes in the mammalian spine, as assessed by magnetic resonance imaging (MRI), comprising a polysulfated polysaccharide or an acceptable salt thereof and an acceptable excipient.

[0106] 20. A composition for use in the treatment of type I modic endplate changes in the mammalian spine, as assessed by magnetic resonance imaging (MRI), comprising a polysulfated polysaccharide or an acceptable salt thereof and an acceptable excipient.

[0107] 21. A composition for the treatment of back pain in mammals having type I modic endplate changes in the mammalian spine, as assessed by magnetic resonance imaging (MRI), comprising a polysulfated polysaccharide or an acceptable salt thereof and an acceptable excipient.

[0108] 22. A composition for use in the treatment of back pain in mammals having type I modic endplate changes in the mammalian spine, as assessed by magnetic resonance imaging (MRI), comprising a polysulfated polysaccharide or an acceptable salt thereof and an acceptable excipient.

[0109] 23. The composition according to Embodiment 21 or 22, wherein the mammalian back pain is selected from the group consisting of general back pain, acute back pain, and chronic back pain.

[0110] 24. The composition according to Embodiment 23, wherein the back pain is selected from the group consisting of general lower back pain, acute lower back pain, and chronic lower back pain.

[0111] 25. The composition according to Embodiment 24, wherein the back pain is chronic lower back pain.

[0112] 26. The composition according to any one of Embodiments 19 to 25, wherein a type I modic endplate change in the spine is associated with a type II modic endplate change in the spine.

[0113] 27. The composition according to any one of Embodiments 19 to 25, wherein a type I modic endplate change in the spine is associated with a type III modic endplate change in the spine.

[0114] 28. Use of polysulfated polysaccharides or acceptable salts thereof in the treatment of bone marrow edema lesions in mammals, as assessed by magnetic resonance imaging (MRI).

[0115] 29. Use of polysulfated polysaccharides or acceptable salts thereof in the manufacture of drugs for the treatment of bone marrow edema lesions in mammals, as assessed by magnetic resonance imaging (MRI).

[0116] 30. Use according to Embodiment Example 28 or 29, in which a mammal is suffering from osteoarthritis.

[0117] 31. The use according to Embodiment 30, wherein the osteoarthritis is located in a joint selected from the group consisting of the ankle, hip, knee, shoulder, spine, and wrist.

[0118] 32. Use according to Embodiment 31, in which osteoarthritis is present in the knee joint.

[0119] 33. Use as described in Embodiment 31 for osteoarthritis located in the spine (spondylosis).

[0120] 34. Use of polysulfated polysaccharides or acceptable salts thereof in the treatment of type I modic endplate changes in mammalian vertebrae, as assessed by magnetic resonance imaging (MRI).

[0121] 35. Use of polysulfated polysaccharides or acceptable salts thereof in the manufacture of agents for the treatment of type I modic endplate changes in mammalian vertebrae, as assessed by magnetic resonance imaging (MRI).

[0122] 36. Use of polysulfated polysaccharides or acceptable salts thereof in the treatment of back pain in mammals with type I modic endplate changes in the spine, as assessed by magnetic resonance imaging (MRI).

[0123] 37. Use of polysulfated polysaccharides or acceptable salts thereof in the manufacture of drugs for the treatment of back pain in mammals having type I modic endplate changes in the spine, as assessed by magnetic resonance imaging (MRI).

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

[0125] 39. The use according to Embodiment 38, wherein the back pain is selected from the group consisting of general low back pain, acute low back pain, and chronic low back pain.

[0126] 40. The use described in Embodiment Example 39, where the back pain is chronic lower back pain.

[0127] 41. Use according to any one of Embodiment Examples 34 to 40, wherein type I modic endplate changes in the spine are associated with type II modic endplate changes in the spine.

[0128] 42. Use according to any one of Embodiment Examples 34 to 40, wherein type I modic endplate changes in the spine are associated with type III modic endplate changes in the spine.

[0129] 43. The method according to any one of Embodiments 1 to 12, the composition according to any one of Embodiments 13 to 27, or the use according to any one of Embodiments 28 to 42, wherein the polysulfated polysaccharide is selected from the group consisting of high molecular weight heparin, low molecular weight heparin, heparan sulfate, polysulfate pentosan, polysulfate chondroitin, polysulfate chitosan, dermatan polysulfate thulodoxide, sulfate dextran, polysulfated inulin, sulfated lactobionic acid amide, sulfated bis-aldonic acid amide, octasulfate sucrose, fucoidan-1, fucoidan-2, sulfated β-cyclodextrin, sulfated γ-cyclodextrin, and small sulfated compounds including inositol hexasulfate, but not limited to these.

[0130] 44. The method, composition, or use according to Embodiment 43, wherein the polysulfated polysaccharide is selected from the group consisting of high molecular weight heparin, low molecular weight heparin, polysulfate pentosan (PPS), polysulfate chondroitin, and polysulfate chitosan.

[0131] 45. The method, composition, or use according to Embodiment 44, wherein the pentosan polysulfate (PPS) is selected from the group consisting of sodium sodium polysulfate (NaPPS), magnesium sodium polysulfate (MgPPS), calcium sodium polysulfate (CaPPS), and zinc sodium polysulfate (ZnPPS).

[0132] 46. ​​The method, composition, or use according to Embodiment Example 45, wherein pentosan polysulfate (PPS) is sodium pentosan polysulfate (NaPPS).

[0133] 47. The method, composition, or use according to any one of Embodiments 1 to 46, wherein the treatment is administered by injection via an intramuscular (IM) or subcutaneous (SC) route, intravenous (IV), intra-articular (IA), peri-articular, local, suppository, or oral route.

[0134] 48. The method, composition, or use described in any one of Embodiments 1 to 47, wherein treatment is by administering a polysulfated polysaccharide or an acceptable salt thereof to a mammal in an effective dose of approximately 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, or 300 mg, as an effective dose or fixed dose of approximately 1 to 2 mg per kilogram of mammal per dose.

[0135] 49. The method, composition, or use according to any one of Embodiments 1 to 48, wherein the treatment involves administering a polysulfated polysaccharide or an acceptable salt thereof to a mammal in an effective dose of approximately 2 mg / kg of mammal per dose.

[0136] 50. The method, composition, or use of any one of the embodiments 47 to 49, wherein the treatment is administered by injection.

[0137] 51. The method, composition, or use according to Embodiment 50, wherein the treatment is administered by subcutaneous (SC) injection.

[0138] 52. The method, composition, or use according to any one of Embodiments 47 to 51, wherein administration to humans is by a therapeutic regimen of once daily, twice weekly, or three times weekly.

[0139] 53. The method, composition, or use according to Embodiment 52, wherein administration to humans is by administration in a twice-weekly treatment regimen.

[0140] 54. The method, composition, or use according to Embodiment 53, wherein administration to humans is by a treatment regimen administered twice a week with an interval of at least 3 days and at most 4 days between doses.

[0141] 55. The method, composition, or use according to Embodiment 54, wherein administration to humans is by a treatment regimen of twice-weekly administration over a period of six weeks.

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

[0143] 57. A method, composition, or use according to any one of Embodiments 1 to 56, wherein pain in a mammal is reduced after treatment.

[0144] 58. The method, composition, or use according to Embodiment 57, which reduces pain in a mammal as determined by a numerical rating scale (NRS).

[0145] 59. The method, composition, or use described in any one of Embodiments 1 to 58, wherein the function of a mammal is improved after treatment.

[0146] 60. The method, composition, or use described in Embodiment 59, which improves mammalian function as determined by the Lysholm knee joint score described herein.

[0147] 61. The method, composition, or use described in any one of Embodiments 1 to 60, which reduces the presence of bone marrow edema lesions or modic endplate changes as assessed by magnetic resonance imaging.

[0148] 62. The method, composition, or use described in any one of Embodiments 1 to 60, wherein the presence of bone marrow edema lesions or modic endplate changes is dissipated as assessed by magnetic resonance imaging. [Examples]

[0149] [Example 1] The effect of pentosan on clinical outcomes of pain and function in knee osteoarthritis patients (n=35) with bone marrow edema lesions on MRI. Example 1 describes the safety, tolerability, and results of a study conducted under the TGA Special Access Scheme (B) in which patients with bone marrow edema lesions of the knee joint and osteoarthritis were treated with PPS. (Since the injectable form of PPS was not a registered product in Australia, approval for the use of PPS as a treatment for patients was obtained from the Australian government and the Department of Health's Drug Administration under the Special Access Scheme (SAS).)

[0150] The patients in this study had the following characteristics: - High pain score - Poor joint function score - MRI evidence of bone marrow edema lesions and joint effusion - Currently on the waiting list for total knee arthroplasty (Kellgren-Lawrence (3-4) OA patients) - Failure of standard treatment, including intra-articular injections of corticosteroids.

[0151] The protocol featured the following: - Treatment: Intramuscular injection of 2 mg / kg twice a week for 3 weeks (total of 6 injections) - During PPS treatment, all patients refrained from using NSAIDs. - Treatment outcomes for pain and function were scored before PPS treatment and 2–4 weeks after the last PPS injection. - All patients had baseline subchondral BML.

[0152] Table 1 shows the clinical outcomes, including BMEL assessment, pain score, and functional outcome score.

[0153] [Table 1]

[0154] Explanation of Table 1 The Numerical Rating Scale (NRS)

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

[0155] The Lysholm knee joint score

[34] is a total score from 0 to 100 calculated based on results from eight functional components of the Lysholm knee joint score scale: limping (5 points), support (5 points), locking symptoms (15 points), instability (25 points), pain (25 points), swelling (10 points), climbing stairs (10 points), and squatting (5 points). This total score is categorized into the following evaluation categories: 95–100 suggests very good function, 84–94 suggests good function, 65–83 suggests neither good nor bad function, and less than 65 suggests poor function.

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

[0157] Further studies have shown that a treatment regimen of fixed-dose PPS 2 mg / kg or 150 mg administered twice weekly via slow SC injection for 6 weeks remarkably resulted in consistent reduction of BMEL volume, as assessed by magnetic resonance imaging, and in some cases, complete reduction of the BMEL.

[0158] [Example 2] Case report of knee osteoarthritis overview Case 2 details the case of a 70-year-old woman with osteoarthritis of the knee, presenting with high levels of knee pain (rated 8 on the Numerical Rating Scale - 8) and functional limitation (showing a poor Lysholm knee joint score of 37). MRI scans of the knee joint revealed subchondral bone marrow edema lesions (BML) at the medial femoral condyle and medial fibular plateau. The patient received a single course of intramuscular pentosan sodium polysulfate (PPS) twice weekly for three weeks. MRI scans two weeks after treatment showed complete resolution of bone marrow edema at the medial femoral condyle and medial fibular plateau, along with simultaneous pain recovery (NRS pain score 0) and a 43% improvement in the Lysholm knee joint score. Furthermore, MRI scans after PPS therapy also showed a significant reduction in joint effusion. These MRI interpretations support the improvement in clinical outcome measures following therapeutic intervention with PPS.

[0159] Medical history A 70-year-old woman with a history of arthroscopic partial medial meniscectomy presented with left knee pain and was on the waiting list for total knee arthroplasty. This patient did not respond to intra-articular cortisol administration during arthroscopy. MRI scans of the knee joint, acquired using 3 Tesla proton-density turbospin echo with fat saturation at TR 3000 ms and TE 30 ms, revealed localized full-thickness cartilage defects and associated subchondral BML on the medial surfaces of the weight-bearing medial femoral condyle and medial fibular plateau. BML measurements of the medial femoral condyle were 11 × 7 × 12 mm (CC × transverse diameter × AP), and BML measurements of the medial fibular plateau were 8 × 8 × 8 mm (CC × transverse diameter × AP). Furthermore, axial proton-density fat saturation imaging at the suprapatellar bursa level revealed knee joint exudate and re-rupture of the medial meniscus (main body and posterior horn). After obtaining patient consent, pain assessment scores were determined using a numerical rating scale (NRS)

[33] , and functional capacity assessment included the Lysholm knee joint score

[34] . Prior to treatment, the NRS pain score was severe, at 8 out of 10 (ranging from 0 to 10), and the Lysholm knee joint score was 37 out of 100, reflecting poor knee joint function suggesting problems with stair climbing and limping.

[0160] Because PPS is a weak anticoagulant with 1 / 15 the activity of heparin, for safety reasons, patients were monitored before initiating treatment with pentosan sodium polysulfate and regularly during treatment by evaluating complete blood count, APTT, prothrombin time, liver function tests, kidney function tests, and serum calcium. The clinical status of patients was regularly checked throughout the course of treatment and the follow-up period.

[0161] Following evaluation, the patient was deemed suitable for treatment with pentosan sodium polysulfate (PPS) under the condition of SAS. The patient received 2 mg / kg of PPS twice weekly, with intervals of a minimum of 3 days and a maximum of 4 days. Six intramuscular injections were administered into the gluteus maximus over a period of 3 weeks (2 injections per week). Three follow-up appointments were scheduled on days 10, 24, and 38 after completion of the injection regimen. Five weeks after the initial PPS injection, a spatial acquisition MRI scan was performed using a 3 Tesla proton-density fat-saturated MRI with TR 1200 ms and TE 28 ms, showing complete resolution of bone marrow edema lesions in the medial femoral condyle and medial fibular plateau. Furthermore, axial imaging at the suprapatellar bursa level clearly demonstrated a reduction in the size of knee joint exudate. The patient showed remarkable functional improvement of 43% and a score of 65 on the Lysholm knee joint score four weeks after the last injection, and demonstrated a strong recovery from pain, as noted by an NRS pain score of 0. During PPS treatment and the follow-up period, the patient experienced no drug-related or non-drug-related adverse reactions.

[0162] Discussion and Conclusion MRI findings performed using a 3 Tesla proton density fat-saturated MRI with spatial acquisition at TR 1200 ms and TE 28 ms clearly demonstrated that a single course of intramuscular PPS resulted in complete dissipation of BML in the medial femoral condyle and medial fibular plateau (see Figures 1 and 2). Furthermore, axial imaging at the suprapatellar bursa level clearly demonstrated a reduction in the size of knee joint exudate. In addition, patients reported no adverse effects from PPS administration.

[0163] In conclusion, treatment with PPS resulted in a complete reduction of BMEL with no reported post-treatment adverse events in the patient's follow-up. The results from this case report suggest the potential efficacy of PPS as a treatment option for BMEL and joint effusion, and also suggest the potential efficacy of PPS as a treatment option for BMEL and joint effusion in patients with arthritis conditions such as osteoarthritis.

[0164] [Example 3] Case reports of chronic low back pain GW, a 52-year-old male patient with chronic low back pain exhibiting a type I modic pattern on MRI scans of the L3 / L4 and L4 / L5 regions of the spine, presented with persistent, unresolved pain clinically despite treatment with current standard therapy for modic lesions using NSAIDs.

[0165] The baseline NRS pain score before treatment with PPS was high, at 7. The patient received a fixed dose of 150 mg of PPS subcutaneously twice weekly for 4 weeks (i.e., a total of 8 injections). The patient experienced pain improvement immediately after the 4th injection and significant pain reduction after the 8th injection (completion of treatment), with a low NRS pain score of 2–3 recorded. The patient refrained from all other therapeutic interventions during this course of treatment. No adverse events were experienced during or after the course of PPS treatment.

[0166] Further studies have shown that a fixed dose of PPS 2 mg / kg or 150 mg administered twice weekly via slow SC injection for 6 weeks remarkably resulted in consistent dissipation of modic changes, as assessed by magnetic resonance imaging.

[0167] Those skilled in the art will appreciate that many variations and / or modifications can be made to the embodiments described above without departing from the broad general scope of this disclosure. Therefore, these embodiments should be considered illustrative and not restrictive in all respects.

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The inventions described in the original claims of this application are listed below. [Invention 1] A method for treating bone marrow edema lesions in mammals, as assessed by magnetic resonance imaging (MRI), comprising the step of administering a polysulfated polysaccharide or an acceptable salt thereof to a mammal in need of such treatment. [Invention 2] The use of polysulfated polysaccharides or their acceptable salts in the treatment of bone marrow edema lesions in mammals, as assessed by magnetic resonance imaging (MRI). [Invention 3] The use of polysulfated polysaccharides or acceptable salts thereof in the manufacture of drugs for the treatment of bone marrow edema lesions in mammals, as assessed by magnetic resonance imaging (MRI). [Invention 4] The method according to any one of inventions 1 to 3, wherein the mammal is suffering from osteoarthritis. [Invention 5] The method according to Invention 4, wherein the osteoarthritis is located in a connected joint selected from the group consisting of the ankle, hip, knee, shoulder, spine (spondylosis), and wrist. [Invention 6] A method for treating type I modic endplate changes in the spine of a mammal, as assessed by magnetic resonance imaging (MRI), comprising the step of administering a polysulfated polysaccharide or an acceptable salt thereof to a mammal in need of such treatment. [Invention 7] The use of polysulfated polysaccharides or their acceptable salts in the treatment of type I modic endplate changes in mammalian vertebrae, as assessed by magnetic resonance imaging (MRI). [Invention 8] The use of polysulfated polysaccharides or acceptable salts thereof in the manufacture of drugs for the treatment of type I modic endplate changes in the mammalian spine, as assessed by magnetic resonance imaging (MRI). [Invention 9] A method for treating back pain in a mammal having type I modic endplate changes in the spine, as assessed by magnetic resonance imaging (MRI), comprising the step of administering a polysulfated polysaccharide or an acceptable salt thereof to the mammal in need of such treatment. [Invention 10] Use of polysulfated polysaccharides or acceptable salts thereof in the treatment of back pain in mammals with type I modic endplate changes in the spine, as assessed by magnetic resonance imaging (MRI). [Invention 11] Use of polysulfated polysaccharides or acceptable salts thereof in the manufacture of drugs for the treatment of back pain in mammals with type I modic endplate changes in the spine, as assessed by magnetic resonance imaging (MRI). [Invention 12] The method according to Invention 9 or the use according to Invention 10 or 11, wherein the back pain is selected from the group consisting of general back pain, acute back pain, chronic back pain, general lower back pain, acute lower back pain, and chronic lower back pain. [Invention 13] The method according to invention 6 or 9, or the use according to any one of inventions 7, 8, 10, or 11, wherein the type I modic endplate change in the spine is related to a type II modic endplate change in the spine. [Invention 14] The method according to invention 6 or 9, or the use according to any one of inventions 7, 8, 10, or 11, wherein the type I modic endplate change in the spine is related to a type III modic endplate change in the spine. [Invention 15] The method or use of any one of Inventions 1 to 14, wherein the polysulfated polysaccharide is selected from the group consisting of high molecular weight heparin, low molecular weight heparin, heparan sulfate, polysulfate pentosan, polysulfate chondroitin, polysulfate chitosan, dermatan polysulfate thulodoxide, sulfate dextran, polysulfated inulin, sulfated lactobionic acid amide, sulfated bis-aldonic acid amide, octasulfate sucrose, fucoidan-1, fucoidan-2, sulfated β-cyclodextrin, sulfated γ-cyclodextrin, and small sulfated compounds including inositol hexasulfate, but not limited to the following. [Invention 16] The method or use according to Invention 15, wherein the polysulfated polysaccharide is selected from the group consisting of high molecular weight heparin, low molecular weight heparin, polysulfate pentosan (PPS), polysulfate chondroitin, and polysulfate chitosan. [Invention 17] The method or use of invention 16, wherein the aforementioned 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). [Invention 18] The method or use of Invention 17, wherein the aforementioned pentosan polysulfate (PPS) is sodium pentosan polysulfate (NaPPS). [Invention 19] The method or use of any one of Inventions 1 to 18, wherein the treatment is administered by injection via an intramuscular (IM) or subcutaneous (SC) route, intravenous (IV), intra-articular (IA), peri-articular, local, suppository, or oral route. [Invention 20] The method or use according to any one of Inventions 1 to 19, wherein the treatment involves administering a polysulfated polysaccharide or an acceptable salt thereof to a mammal in an effective dose between approximately 25 mg and 300 mg, as an effective dose or fixed dose of approximately 1 to 2 mg per kilogram of mammal per dose. [Invention 21] The method or use according to any one of Inventions 1 to 20, wherein the treatment involves administering a polysulfated polysaccharide or an acceptable salt thereof to a mammal in an effective dose of about 150 mg, with an effective dose of about 1-2 mg / kg of mammal per dose or a fixed dose. [Invention 22] The method or use of any one of inventions 19 to 21, wherein the treatment is administered by subcutaneous (SC) injection. [Invention 23] The method or use of the invention according to invention 22, wherein the SC injection is a slow SC injection. [Invention 24] The method or use according to any one of Inventions 19 to 23, wherein the administration to humans is by a treatment regimen of once daily, twice weekly, or three times weekly. [Invention 25] The method or use of Invention 24, wherein administration to humans is by administration in a twice-weekly treatment regimen. [Invention 26] The method or use of Invention 25, wherein administration to humans is by administering the drug in a twice-weekly treatment regimen with an interval of at least 3 days and at most 4 days between doses. [Discussion 27] The method or use of Invention 26, wherein administration to humans is by administering the drug twice a week for a period of six weeks. [Invention 28] The method or use according to any one of Inventions 19 to 27, wherein the total dose of polysulfated polysaccharides administered in the aforementioned treatment regimen is approximately 200 to 4000 mg. [Invention 29] The method or use of any one of Inventions 1 to 28, wherein the pain of the mammal is reduced after treatment. [Invention 30] The method or use of invention 29, wherein the pain of the mammal is reduced as determined by a numerical rating scale (NRS). [Invention 31] The method or use of any one of Inventions 1 to 30, wherein the function of the mammal is improved after treatment. [Invention 32] The method or use of Invention 31, wherein the function of the mammal is improved as determined by the Lysholm knee joint score described herein. [Invention 33] The method or use of any one of Inventions 1 to 32, wherein the presence of bone marrow edema lesions or modic endplate changes is reduced as assessed by magnetic resonance imaging. [Invention 34] The method or use of any one of Inventions 1 to 32, wherein the presence of bone marrow edema lesions or modic endplate changes is dissipated as assessed by magnetic resonance imaging.

Claims

1. A pharmaceutical composition for improving knee function in a person having bone marrow edema lesions evaluated by magnetic resonance imaging (MRI) and Kellgreen-Lawrence (3-4) knee osteoarthritis, and requiring treatment thereof, The pharmaceutical composition comprises pentosan polysulfate or an acceptable salt thereof. The aforementioned human was one who had failed to treat the knee with corticosteroids. The aforementioned treatment involves intramuscular administration of the pharmaceutical composition at a dose of approximately 1-2 mg / kg of human body twice, three times, or daily for six weeks, so as to improve knee joint function by approximately 23% to approximately 89% as determined by the Lysholm knee joint score. The aforementioned pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the function of the knee joint is improved by approximately 23% to approximately 43%.

3. The pharmaceutical composition according to claim 2, wherein the function of the knee joint is improved by approximately 23% to approximately 35%.

4. The pharmaceutical composition according to any one of claims 1 to 3, 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).

5. The pharmaceutical composition according to claim 4, wherein the aforementioned pentosan polysulfate (PPS) is sodium pentosan polysulfate (NaPPS).

6. A pharmaceutical composition according to any one of claims 1 to 5, which is administered to humans once a day or twice a week as part of a treatment regimen.

7. The pharmaceutical composition according to claim 6, which is administered to humans in a treatment regimen twice a week.

8. The pharmaceutical composition according to claim 7, which is administered to humans in a treatment regimen of twice a week, with an interval of at least three days and at most four days between doses.

9. The pharmaceutical composition according to claim 8, which is administered to humans in a treatment regimen of twice a week for six weeks.

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