Formulation for treating spinal cord disease in dog and method for treating spinal cord disease in dog

Abstract

The present invention relates to a method for treating a spinal cord disease in a dog, the method involving administering a formulation containing, as an active ingredient, a compound represented by formula (I) (in the formula, R represents hydrogen or a pharmacologically acceptable cation) to a dog with a spinal cord disease. The present invention also relates to a formulation for treating a spinal cord disease in a dog, to be administered to a dog with a spinal cord disease, the formulation comprising, as an active ingredient, a compound represented by formula (I) (in the formula, R represents hydrogen or a pharmacologically acceptable cation).

Description

Formulation for treating spinal cord diseases in dogs and method for treating spinal cord diseases in dogs

[0001] The present invention relates to a formulation for treating spinal cord diseases in dogs and a method for treating spinal cord diseases in dogs.

[0002] Spinal cord disorders (SCD) in dogs are a major veterinary health problem, with an incidence of 27.8 cases per 10,000 dogs across all breeds, and 141.5 to 237.1 cases per 10,000 dogs in the predisposed breed, the dachshund, even when limited to intervertebral disc disease (Non-Patent Document 1). Spinal cord disorders in dogs are diseases characterized by various lesions in the spinal cord of the central nervous system, presenting specific movement disorders and clinical symptoms depending on the location and degree of the disorder. Movement disorders include complete or incomplete paralysis of the limbs, standing or walking disorders accompanied by pain in the back or limbs, and behavioral disorders that interfere with daily life such as eating. Clinical symptoms include reduced appetite, reduced activity, and weight loss (Non-Patent Documents 2 and 3).

[0003] Caring for and managing patient animals with such disorders and symptoms is a major burden in daily life for many owners. In fact, in a survey on breeding management conducted on 40 owners of dog patients with chronic spinal cord injury accompanied by hindlimb paralysis, it was reported that the owners spent 1 to 30 hours (median 10 hours) per week on exercise management (Non-Patent Document 4). In particular, in clinical practice, euthanasia is frequently performed on dog patients with spinal cord diseases whose movement disorders and clinical symptoms do not recover (Non-Patent Document 5), which is also a major problem from the perspective of animal welfare. Therefore, in the case of spinal cord diseases in dogs, existing treatments do not fully meet medical needs, and an epoch-making treatment method for improving movement disorders and clinical symptoms is urgently needed.

[0004] The pathogenesis, pathophysiology, clinical symptoms, and treatment methods of spinal cord diseases in dogs differ significantly from those in humans due to anatomical and kinematic differences between animal species. In fact, unlike humans, dogs have a vestigial clavicle (the clavicle is absent), their scapula (shoulder blade) does not articulate with the torso skeleton, and the weight of the upper body is supported solely by the muscles of the forelimbs. Furthermore, the vertebrae are arranged horizontally from the ground, and it is known that impact loads during quadrupedal locomotion and jumping cause adjacent vertebrae to shift vertically, thus displacing the load (Non-Patent Literature 6). The absence of a clavicle is also an anatomical feature that distinguishes dogs from cats, a related species belonging to the same order, Carnivora (Non-Patent Literature 6). On the other hand, humans, who walk upright on two legs, have vertebrae arranged vertically from the ground, and their spine is curved in an S-shape, resulting in a skeletal structure where the weight of the upper body is concentrated in the lumbar region. This skeletal structure is thought to be the trigger for the development of lumbar spinal stenosis and other lumbar pain diseases unique to humans (Non-Patent Literature 7). Therefore, when treating spinal cord diseases in dogs, it is crucial to apply treatment methods that have been thoroughly studied for their effectiveness and safety in canine patients, rather than simply extrapolating treatment methods used in other animal species.

[0005] In clinical practice, canine spinal cord diseases are differentiated based on various tests and clinical symptoms, following the joint statement issued by the International Veterinary Medical Association (Non-Patent Literature 8) and guidelines established by national and regional veterinary neurology societies and veterinary neurologists (Non-Patent Literature 9 and 10), to include intervertebral disc disease (IVDD), Wobbler syndrome, degenerative myelopathy (DM), progressive myelomalacia, atlantoaxial instability, syringomyelia, spinal cord injury due to spinal cord / vertebral tumors, spinal cord injury, spinal cord injury due to idiopathic sterile suppurative granuloma of the epidural space, myelitis, and spinal cord infarction.

[0006] For spinal cord diseases in dogs, conservative therapies such as rest, acupuncture, physical therapy, and rehabilitation are used, and / or the administration of therapeutic drugs or supplements such as steroidal anti-inflammatory drugs, nonsteroidal anti-inflammatory drugs, neuropathic pain medications, opioid analgesics, prostaglandin E1 derivatives, neutrophil elastase inhibitors, fatty acids, vitamins, and curcumin. Among these, steroidal anti-inflammatory drugs, nonsteroidal anti-inflammatory drugs, and neuropathic pain medications, which are frequently used, are known to have various side effects.

[0007] Treatment for intervertebral disc disease is broadly divided into surgical therapy, other conservative therapies, and pharmaceutical therapies. The application of each is recommended to be determined based on the grading of the neurological severity of the spinal cord injury and the clinical course. In cases of relatively mild intervertebral disc disease, conservative therapy (cage rest) based on 4 to 6 weeks of complete rest is applied. During this time, owners should carefully observe whether neurological dysfunction is progressing, and if any progression is observed, surgical therapy should be considered as early as possible. If the animal is unable to walk or if neurological dysfunction rapidly worsens, emergency surgical therapy should be applied (Non-Patent Literature 10).

[0008] When surgical treatment is performed for spinal cord diseases, there are many cases that are not suitable for surgery or do not result in sufficient recovery, and recurrence after surgery is common. As a result, satisfaction with the treatment of spinal cord diseases in dogs is low, and there has been a strong desire for more reliable and effective treatment methods.

[0009] Furthermore, there are treatment-resistant animal patients whose motor impairments and clinical symptoms do not improve with the above treatments alone (Non-Patent Documents 3, 8, and 11). In fact, it has been reported that 19% to 79% of canine intervertebral disc disease patients are resistant to conservative or pharmaceutical treatments, depending on the grade classification of the neurological severity of the spinal cord injury (Non-Patent Document 8). In particular, many patients with intervertebral disc herniation suffer from sequelae that make them unable to walk, which severely limits their subsequent activities of daily living (ADL) and quality of life (QOL), placing a significant psychological and economic burden on their owners (Non-Patent Document 12). Thus, there is a strong need in clinical practice for new treatment methods that can help overcome treatment-resistant spinal cord diseases.

[0010] Beraprost sodium (hereinafter sometimes abbreviated as BPS) is a prostacyclin (PGI) ２ It is a derivative (also known as BPS). Preparations containing BPS as an active ingredient are widely used in clinical practice as approved drugs for the treatment of chronic kidney disease in cats, chronic arterial occlusion in humans, and pulmonary hypertension (Non-Patent Documents 13, 14, and 15). Furthermore, Non-Patent Document 16 shows that, similar to humans, administering BPS at a dose of 13.2 to 22.0 μg / kg per day for one week improves circulatory function in dogs with pulmonary hypertension.

[0011] The contents described in Patent Document 1, Non-Patent Document 17, and Non-Patent Document 18 are the work of the same principal investigator. In these documents, a canine model of chronic compression of the cauda equina was created by anesthetizing experimental dogs, performing a partial laminectomy in the prone position, inserting an inflatable balloon into the seventh lumbar vertebra, and filling the balloon with liquid konjac to induce compressive damage to the cauda equina nerves of the peripheral nervous system. In this model, BPS was administered at a dose of 25 μg / kg or 50 μg / kg twice a day for 6 days to investigate the effect of BPS on compressive nerve damage. As a result, a decrease in nerve conduction velocity was observed due to the compressive damage, and it was shown that BPS suppressed this decrease. Patent Document 1 suggests, based on the results of the above model, that BPS may be effective not only in peripheral nerves such as the cauda equina, but also in compressive nerve damage in general, including the central nervous system.

[0012] However, as described in Non-Patent Document 9, the conus medullaris at the caudal end of the canine spinal cord remains within the spinal canal between the 5th and 6th lumbar vertebrae. In the embodiment of Patent Document 1, and in Non-Patent Documents 17 and 18, the nerve that caused compressive damage within the 7th lumbar vertebra is not the spinal cord of the central nervous system, but the cauda equina nerve of the peripheral nervous system.

[0013] Furthermore, the spinal cord of the central nervous system differs morphologically from the peripheral nervous system, and also has poorer regenerative capacity compared to the peripheral nervous system (Non-Patent Literature 19), making the development of effective treatments for spinal cord diseases extremely difficult. Moreover, the spinal cord contains a mechanism that controls the permeability of drugs from blood vessels (blood-cerebrospinal fluid barrier), so the required properties of drugs that act on peripheral nerves, which lack such a mechanism, differ greatly from those that act on the spinal cord.

[0014] Based on the above points, it cannot be said that the results from the cauda equina model animals described in Patent Document 1 and Non-Patent Documents 17 and 18 make it easy to conceive and implement the idea that BPS administration is effective for canine spinal cord diseases, which are central nervous system disorders.

[0015] Patent Document 2 reports the results of in vitro studies in rat fetal nerve cells and human glioma cells to investigate the protective effect of BPS on nervous system constituent cells. The results showed that rat fetal nerve cells necrotized and were lost in serum-free medium, but BPS prevented this loss and increased the number of viable cells. Human glioma cells showed a decrease in cell viability after peroxide treatment, but BPS suppressed this decrease.

[0016] Patent Document 3 reports the results of an in vitro study in rat fetal microglia cells in which BPS was added to investigate the hepatocyte growth factor-inducing effect of BPS. The results showed that BPS induced hepatocyte growth factor production in rat fetal microglia cells.

[0017] However, spinal cord diseases in dogs are multifactorial diseases that involve extensive damage not only to the spinal cord of the central nervous system, but also to surrounding structures such as the pia mater, arachnoid mater, dura mater, epidural space including blood vessels and adipose tissue, inner dura mater, outer dura mater, subarachnoid space, and dentate ligaments supporting the lateral part of the spinal cord (Non-Patent Literature 9), in addition to genetic predispositions and environmental factors such as temperature (Non-Patent Literature 20), as described later. Given these characteristics of spinal cord diseases, it is impossible to predict, based solely on results showing in vitro protective effects on some cells that may be involved in the disease, the improvement effect on motor impairment and clinical symptoms when actually administering a drug to dogs with spinal cord diseases, or whether that effect will occur at a dose that does not pose a safety risk.

[0018] Japanese Patent Application Publication No. 11-130678 International Publication No. 98 / 41209 Japanese Patent Application Publication No. 11-322612

[0019] Bergknut N, Egenvall A, Hagman R, et al. Incidence of intervertebral disk degeneration-related diseases and associated mortality rates in dogs. J Am Vet Med Assoc 2012; 240: 1300-1309. 2012 / 05 / 23. DOI: 10.2460 / javma.240.11.1300.LeCouteur RA. Spinal cord disorders. Journal of Feline Medicine and Surgery 2003; 5: 121-131.Sulla I, Hornak S, Ledecky V, et al. A review of novel trends in management of canine spinal cord injury. Acta Veterinaria Brno 2019; 88: 207-217.Freeman PM, Holmes MA, Jeffery ND, et al. Time requirement and effect on owners of home-based management of dogs with severe chronic spinal cord Injury. Journal of Veterinary Behavior 2013; 8: 439-443. Pegram C, Gray C, Packer RMA, et al. Proportion and risk factors for death by euthanasia in dogs in the UK. Sci Rep 2021; 11: 9145. 2021 / 05 / 06. DOI: 10.1038 / s41598-021-88342-0. Peppy. Dog Body Seminar: Legs and Hips - A Thorough Study of the Strengths and Weaknesses of Dog Legs and Hips. Retrieved June 26, 2024. https: / / www.peppynet.com / library / archive / old / html / 12aw_170. Yoshiharu Takemitsu. Essay: The Light and Shadow of Bipedalism in Human Evolution - From the Perspective of Orthopedic Medicine.Asahikawa Medical University Research Forum 2011; 12: 23-26. Olby NJ, Moore SA, Brisson B, et al. ACVIM consensus statement on diagnosis and management of acute canine thoracolumbar intervertebral disc extrusion. J Vet Intern Med 2022; 36: 1570-1596. 2022 / 07 / 27. DOI: 10.1111 / jvim.16480. Hasegawa D, Edamura K, Saito M. Canine and Feline Neurology: General Principles and Techniques. Midori Shobo, Tokyo 2016: Chapters 1-11, 28-321. Hasegawa D, Edamura K, Saito M. Canine and Feline Neurology: Specific Topics. Midori Shobo, Tokyo 2015: Chapters 23-41, 314-330. Henea ME, Sindilar EV, Burtan LC, et al. Recovery of Spinal Walking in Paraplegic Dogs Using Physiotherapy and Supportive Devices to Maintain the Standing Position. Animals (Basel) 2023; 13 2023 / 04 / 28. DOI: 10.3390 / ani13081398. Asari K, Kobayashi T. Disability profile and physiotherapy intervention in a dachshund with severe paraplegia. Physical Therapy Science 2010; 25: 517-522. Toray Industries, Inc. Lapros Package Insert, created January 2017. Retrieved June 27, 2024, https: / / www.vm.nval.go.jp / public / detail / 16941 / 1 Toray Industries, Inc. Dorner Tablets 20μg Package Insert. 2024 Revised July (2nd Edition). Retrieved August 26, 2024. https: / / med.toaeiyo.co.jp / products / dorner / pdf / tenpu-dor.pdf Toray Industries, Inc. Careload LA Tablets 60μg Package Insert, Revised July 2024 (2nd Edition). Retrieved August 26, 2024. https: / / med.toaeiyo.co.jp / jp / products / careload / pdf / tenpu-cld.pdfSuzuki R, Yuchi Y, Saito T, et al. Beraprost Sodium for Pulmonary Hypertension in Dogs: Effect on Hemodynamics and Cardiac Function. Animals (Basel) 2022; 12 2022 / 08 / 27. DOI: 10.3390 / ani12162078.Konno S, Arai I, Otani K, et al. Effects of beraprost sodium on canine cauda equina function and blood flow using a chronic spinal cord compression model. J Spinal Disord 2001; 14: 336-338. 2001 / 08 / 02. DOI: 10.1097 / 00002517-200108000-00009. Konno Shinichi. Preservative therapy for lumbar intervertebral stenosis. Journal of Japanese Society for Lumbar Pain 2004; 10: 10-13. Tsintou M, Dalamagkas K and Makris N. Taking central nervous system regenerative therapies to the clinic: curing rodents versus nonhuman primates versus humans. Neural Regen Res 2020; 15: 425-437. 2019 / 10 / 02. DOI: 10.4103 / 1673-5374.266048. Barandun MA, Bult S, Demierre S, et al. Colder Ambient Temperatures Influence Acute Onset Canine Intervertebral Disc Extrusion. Front Vet Sci 2020; 7: 175. 2020 / 04 / 23. DOI: 10.3389 / fvets.2020.00175.

[0020] The present invention aims to provide a method and drug for treating spinal cord diseases in dogs that improve motor impairments and clinical symptoms associated with spinal cord diseases in dogs, and that can be effective in treating dogs that are resistant to existing treatments.

[0021] As a result of diligent research to solve the above problems, the inventors have found that a specific compound represented by formula (I) has a remarkable effect in improving motor disorders and clinical symptoms associated with spinal cord diseases in dogs.

[0022] The present invention is as follows: [1] Formula (I) below:

[0023]

[0024] [In the formula, R represents hydrogen or a pharmacologically acceptable cation.] A preparation containing a compound represented by as an active ingredient, for administration to dogs with spinal cord disease, for use in the treatment of canine spinal cord disease. [2] The preparation for the treatment of canine spinal cord disease according to [1], wherein the spinal cord disease is at least one selected from the group consisting of intervertebral disc disease, Wobbler syndrome, degenerative myelopathy, degenerative spondylosis, progressive myelomalacia, atlantoaxial instability, syringomyelia, spinal cord tumor, spinal cord injury associated with spinal tumor, myelitis, spinal cord injury due to idiopathic sterile pyogenic granuloma of the epidural space, malformation disease of the spine and spinal cord, spinal cord injury, and spinal cord infarction. [3] The preparation for the treatment of canine spinal cord disease according to [1] or [2], wherein the spinal cord disease is intervertebral disc disease, and the intervertebral disc disease corresponds to grades 1 to 5 of the neurological severity classification of spinal cord injury. [4] A therapeutic preparation for canine spinal cord disease according to any one of [1] to [3], wherein the spinal cord disease is an intervertebral disc disease, and the intervertebral disc disease corresponds to Hansen type I, Hansen type II, or Hansen type III of the intervertebral disc disease classification. [5] A therapeutic preparation for canine spinal cord disease according to any one of [1] to [4], wherein the spinal cord disease is an intervertebral disc disease, and the dog is a chondrodystrophic breed or a non-chondrodystrophic breed. [6] The chondrodystrophic dog breed is at least one selected from the group consisting of Dachshund, Miniature Dachshund, French Bulldog, Pug, Boston Terrier, Pekingese, Shih Tzu, Welsh Corgi, Beagle, Basset Hound, Cocker Spaniel, Papillon, Poodle, Chihuahua, Bichon Frise, Lhasa Apso, and Cavalier King Charles Spaniel, as well as their respective subspecies and mixed breeds, and the non-chondrodystrophic dog breed is at least one selected from the group consisting of Yorkshire Terrier, Pomeranian, Miniature Pinscher, Schnauzer, Maltese, Whippet, Shetland Sheepdog, Siberian Husky, and Labrador Retriever, as well as their respective subspecies and mixed breeds, as described in [5].[7] A therapeutic preparation for canine spinal cord disease according to any one of [1] to [6], wherein the spinal cord disease satisfies at least one of the following (A) to (F) before administration of the preparation: (A) an intervertebral disc disease corresponding to grade 1 to 5 of the neurological severity classification of spinal cord injury, (B) a spinal cord disease in which the dog's Olby score is 0 to 13, (C) a spinal cord disease in which the sum of the proprioceptive scores of the dog's four limbs is 0 to 7, (D) a spinal cord disease in which the sum of the jump reaction scores of the dog's four limbs is 0 to 7, (E) a spinal cord disease causing abnormal activity in the dog, and (F) a spinal cord disease causing abnormal appetite in the dog. [8] A therapeutic preparation for canine spinal cord disease according to any one of [1] to [7], wherein the dog has shown resistance to conservative therapy, including at least one of rest therapy, acupuncture therapy, physical therapy, and rehabilitation, or has shown resistance to the administration of a therapeutic agent or supplement, including at least one of steroidal anti-inflammatory drugs, nonsteroidal anti-inflammatory drugs, neuropathic pain treatment agents, opioid analgesics, prostaglandin E1 derivatives, neutrophil elastase inhibitors, fatty acids, antinol (PCSO-524), antinol plus (EAB-277), vitamins, and curcumin, prior to administration of the preparation. [9] A therapeutic preparation for canine spinal cord disease according to any one of [1] to [8], which improves at least one of the motor impairment and clinical symptoms of the dog compared to before administration of the preparation. [9a] A therapeutic preparation for canine spinal cord disease according to any one of [1] to [9], wherein the spinal cord disease is a grade of neurological severity of spinal cord injury to which the spinal cord disease corresponds, and at least one of the dog's Olby score, proprioceptive score, jump response score, activity level, and appetite are improved compared to before administration of the preparation. [9b] ​​A therapeutic preparation for canine spinal cord disease according to any one of [1] to [9] and [9a], wherein the spinal cord disease is a degenerative myelopathy and the progression of the pathology of the degenerative myelopathy is suppressed.

[10] A therapeutic preparation for canine spinal cord disease according to any one of [1] to [9], [9a], [9b], and [9c], wherein the compound represented by formula (I) is beraprost sodium or a pharmacoacceptable salt thereof.

[11] A therapeutic preparation for canine spinal cord disease according to any one of [1] to

[10] , [9a], [9b], and [9c], used in such a dose of the compound represented by formula (I) as 0.05 to 600 μg / kg per day.

[12] A therapeutic preparation for canine spinal cord disease according to any one of [1] to

[11] , [9a], [9b], and [9c], used to be administered in two divided doses per day.

[13] A therapeutic preparation for canine spinal cord disease according to any one of [1] to

[12] , [9a], [9b], and [9c], used to be administered orally.

[14] A therapeutic preparation for canine spinal cord disease according to any one of [1] to

[13] , [9a], [9b], and [9c], which is used to be administered during or after meals.

[15] A method for treating canine spinal cord disease, comprising administering a therapeutic preparation for canine spinal cord disease according to any one of [1] to

[14] , [9a], [9b], and [9c] to a dog with spinal cord disease.

[0025]

[16] The following formula (I):

[0026]

[0027] A method for treating a spinal cord disease in a dog, comprising administering a preparation containing a compound represented by [wherein R represents hydrogen or a pharmacologically acceptable cation] as an active ingredient to a dog with a spinal cord disease.

[17] The method for treating a spinal cord disease in a dog according to

[16] , wherein the spinal cord disease is at least one selected from the group consisting of intervertebral disc disease, Wobbler syndrome, degenerative myelopathy, degenerative spondylosis, progressive myelomalacia, atlantoaxial instability, syringomyelia, spinal cord tumor, spinal cord injury associated with spinal tumor, myelitis, spinal cord injury due to idiopathic sterile pyogenic granuloma of the epidural space, malformation disease of the spine and spinal cord, spinal cord injury, and spinal cord infarction.

[18] The method for treating a spinal cord disease in a dog according to

[17] , wherein the spinal cord disease is intervertebral disc disease, and the intervertebral disc disease corresponds to grades 1 to 5 of the neurological severity classification of spinal cord injury.

[19] The method for treating a spinal cord disease in a dog according to

[17] or

[18] , wherein the spinal cord disease is an intervertebral disc disease, and the intervertebral disc disease corresponds to Hansen type I, Hansen type II, or Hansen type III of the intervertebral disc disease classification.

[20] The method for treating a spinal cord disease in a dog according to any one of

[17] to

[19] , wherein the spinal cord disease is an intervertebral disc disease, and the dog is a chondrodystrophic breed or a non-chondrodystrophic breed.

[21] The method for treating spinal cord disease in dogs according to

[20] , wherein the chondrodystrophic dog breed is at least one selected from the group consisting of dachshunds, miniature dachshunds, French bulldogs, pugs, Boston terriers, Pekingese, Shih Tzus, Welsh corgis, beagles, Basset hounds, cocker spaniels, papillons, poodles, chihuahuas, Bichon frises, Lhasa Apsos, and Cavalier King Charles Spaniels, as well as their respective subspecies and crossbreeds, and the non-chondrodystrophic dog breed is at least one selected from the group consisting of Yorkshire terriers, Pomeranians, miniature pinschers, schnauzers, Maltese, Whippets, Shetland sheepdogs, Siberian huskies, and Labrador retrievers, as well as their respective subspecies and crossbreeds.

[22] A method for treating a spinal cord disease in a dog according to any one of

[16] to

[21] , wherein the spinal cord disease satisfies at least one of the following (A) to (F) before administration of the preparation: (A) an intervertebral disc disease that corresponds to grade 1 to 5 of the neurological severity classification of spinal cord injury; (B) a spinal cord disease in which the dog's Olby score is 0 to 13; (C) a spinal cord disease in which the sum of the proprioceptive scores of the dog's four limbs is 0 to 7; (D) a spinal cord disease in which the sum of the jump reaction scores of the dog's four limbs is 0 to 7; (E) a spinal cord disease in which the dog's activity level is abnormal; and (F) a spinal cord disease in which the dog's appetite is abnormal.

[23] A method for treating a spinal cord disease in a dog according to any one of

[16] to

[22] , wherein the dog has shown resistance to conservative therapy, including at least one of rest therapy, acupuncture therapy, physical therapy, and rehabilitation, or has shown resistance to the administration of a therapeutic agent or supplement, including at least one of steroidal anti-inflammatory drugs, nonsteroidal anti-inflammatory drugs, neuropathic pain treatment agents, opioid analgesics, prostaglandin E1 derivatives, neutrophil elastase inhibitors, fatty acids, antinol (PCSO-524), antinol plus (EAB-277), vitamins, and curcumin, prior to administration of the preparation.

[24] A method for treating a spinal cord disease in a dog according to any one of

[16] to

[23] , wherein at least one of the motor impairment and clinical symptoms of the dog is improved compared to before administration of the preparation.

[25] A method for treating a spinal cord disease in a dog according to any one of

[16] to

[24] , wherein the grade of the neurological severity classification of spinal cord injury to which the spinal cord disease corresponds, and at least one of the dog's Olby score, proprioceptive score, jump response score, activity level, and appetite are improved compared to before administration of the preparation.

[26] A method for treating a spinal cord disease in a dog according to any one of

[16] to

[25] , wherein the grade of the neurological severity classification of spinal cord injury to which the spinal cord disease corresponds is improved to a level less than 1.

[27] A method for treating a spinal cord disease in a dog according to any one of

[16] to

[26] , wherein the spinal cord disease is degenerative myelopathy, and the progression of the pathology of degenerative myelopathy is suppressed.

[28] A method for treating a spinal cord disease in dogs according to any one of

[16] to

[27] , wherein the compound represented by formula (I) is beraprost sodium or a pharmacoacceptable salt thereof.

[29] A method for treating a spinal cord disease in dogs according to any one of

[16] to

[28] , wherein the dose of the compound represented by formula (I) is 0.05 to 600 μg / kg per day.

[30] A method for treating a spinal cord disease in dogs according to any one of

[16] to

[29] , wherein the preparation is administered in two divided doses per day.

[31] A method for treating a spinal cord disease in dogs according to any one of

[16] to

[30] , wherein the preparation is administered orally.

[32] A method for treating a spinal cord disease in dogs according to any one of

[16] to

[31] , wherein the preparation is administered during or after meals.

[33] A preparation for the method for treating a spinal cord disease in dogs according to any one of

[16] to

[32] .

[34] The following formula (I):

[0028]

[0029] A therapeutic agent for canine spinal cord disease, comprising a compound represented by [wherein R represents hydrogen or a pharmacologically acceptable cation] as an active ingredient.

[35] For manufacturing a therapeutic agent for canine spinal cord disease, the following formula (I):

[0030]

[0031] Use of compounds represented by [wherein R represents hydrogen or a pharmacologically acceptable cation].

[36] For use as a therapeutic agent for canine spinal cord disease, the following formula (I):

[0032]

[0033] Compounds represented by [wherein R represents hydrogen or a pharmacologically acceptable cation].

[0034] The therapeutic formulation for canine spinal cord disease of the present invention contains a compound represented by formula (I) as an active ingredient, thereby improving motor impairments and clinical symptoms associated with canine spinal cord disease, and exhibiting therapeutic effects particularly in dogs that are resistant to existing treatments. Furthermore, the method for treating canine spinal cord disease of the present invention can achieve the above effects by administering the above therapeutic formulation to a dog with spinal cord disease.

[0035] As will be described later, preferred embodiments of the present invention concerning the treatment of canine spinal cord disease, as described below, can also be applied to the therapeutic formulation for canine spinal cord disease of the present invention.

[0036] <Treatment Method> The present invention provides a method for treating spinal cord disease in dogs, comprising administering a formulation containing a compound represented by formula (I), described later, as an active ingredient to a dog with spinal cord disease.

[0037] Administering the above-mentioned preparation to dogs with spinal cord disease, particularly dogs with intervertebral disc disease such as intervertebral disc herniation, can improve the motor impairment and clinical symptoms of the dogs. Specifically, it is preferable that at least one of the motor impairment and clinical symptoms of the dogs being treated improves compared to before administration of the preparation. More specifically, it is even more preferable that the grade of the neurological severity classification of the spinal cord disorder to which the spinal cord disease belongs, as well as at least one of the motor function evaluation, neurological test values, and general condition of the dogs being treated, improves compared to before administration of the preparation. Examples of indicators for the motor function evaluation include the Olby score, examples of neurological test values ​​include the proprioception score and the jump response score, and examples of indicators for the general condition include activity level and appetite. Specifically, it is even more preferable that the grade of the neurological severity classification of the spinal cord disorder to which the spinal cord disease belongs, as well as at least one of the Olby score, proprioception score, jump response score, activity level, and appetite of the dogs being treated, improves compared to before administration of the preparation. Furthermore, it is even more preferable to improve the neurological severity classification grade of the spinal cord disorder to which the spinal cord disease falls, to a grade less than 1, i.e., to a state in which the spinal cord disorder has completely disappeared.

[0038] Furthermore, administering the above-mentioned preparation to dogs with degenerative myelopathy can suppress the progression of the disease. Specifically, the period from the onset of symptoms to the inability to stand on both hind limbs, the decrease in weight-bearing capacity of both forelimbs, and death can be extended compared to cases where the above-mentioned preparation is not administered. More preferably, the above period can be extended by, for example, 3 to 6 months or more.

[0039] The treatment method of the present invention is preferably applied to canine spinal cord diseases exhibiting at least one of the following characteristics (1) to (5). The treatment method of the present invention can treat these spinal cord diseases more effectively. (1) Intervertebral disc disease, which corresponds to grades 1 to 5 of the neurological severity classification of spinal cord injury. (2) Intervertebral disc disease, which corresponds to Hansen type I, Hansen type II, or Hansen type III of the intervertebral disc disease classification. (3) Spinal cord disease in dogs of chondrodystrophic or non-chondrodystrophic breeds. (4) Spinal disc disease that corresponds to grades 1 to 5 of the neurological severity classification of spinal cord injury; spinal cord disease in which the dog to be treated has an Olby score of 0 to 13; spinal cord disease in which the sum of the proprioception scores of the four limbs of the dog to be treated is 0 to 7; spinal cord disease in which the sum of the jump response scores of the four limbs of the dog to be treated is 0 to 7; spinal cord disease in which the dog to be treated has abnormal activity levels; or spinal cord disease in which the dog to be treated has abnormal appetite levels. (5) A spinal cord disease in which the dog to be treated has shown resistance to conservative therapy, including at least one of rest therapy, acupuncture therapy, physical therapy, and rehabilitation, prior to administration of the above-mentioned preparation, or has shown resistance to the administration of therapeutic drugs or supplements, including at least one of steroidal anti-inflammatory drugs, nonsteroidal anti-inflammatory drugs, neuropathic pain medications, opioid analgesics, prostaglandin E1 derivatives, neutrophil elastase inhibitors, fatty acids, Antinol (PCSO-524), Antinol Plus (EAB-277), vitamins, and curcumin.

[0040] 1. Spinal cord diseases in dogs covered by the present invention. Spinal cord diseases in the present invention include all diseases resulting from damage to the spinal cord, regardless of their cause or whether they are congenital or acquired. Causes of damage include, for example, vertebral stenosis or deformity, intervertebral disc degeneration or deformity, primary or metastatic tumors of the spinal cord, and trauma. The affected area is the part of the spine where the spinal cord is located, and includes damage to the cervical, thoracic, and lumbar vertebrae from L1 to L6.

[0041] Although canine spinal cord diseases are treated as spinal column and spinal cord diseases (supervised by Daisuke Hasegawa et al., Monograph on Neurology of Dogs and Cats, Midori Shobo, Tokyo 2015: pages 314 - 330), the present invention targets diseases in which the spinal cord is damaged among them. Specific examples of the spinal cord diseases in the present invention include intervertebral disc diseases such as cervical intervertebral disc herniation and thoracolumbar intervertebral disc herniation, wobbler syndrome, degenerative myelopathy, progressive myelomalacia, atlantoaxial instability, syringomyelia, spinal cord tumor, spinal cord damage associated with spinal tumor, myelitis, spinal cord damage caused by idiopathic aseptic pyogenic granuloma in the epidural space, congenital diseases of the spinal column and spinal cord, spinal cord injury, and spinal cord infarction, and also include diseases with the same content as these. Further, both the case where these diseases occur alone and the case where they occur plurally are included. As the spinal cord diseases in the present invention, intervertebral disc diseases such as intervertebral disc herniation, degenerative myelopathy, atlantoaxial instability, syringomyelia, and congenital diseases of the spinal column and spinal cord are more preferable, and intervertebral disc diseases are even more preferable. When the spinal cord disease is one of these diseases, the effect of the treatment method of the present invention is more suitably exhibited.

[0042] Hereinafter, each disease targeted by the present invention will be outlined.

[0043] ・Intervertebral disc disease It is known that the symptoms of intervertebral disc disease in dogs differ depending on the site of occurrence, and it is roughly classified into cervical intervertebral disc herniation and thoracolumbar intervertebral disc herniation, and the present invention is suitably used in any case. Intervertebral disc herniation is classified into Hansen type I, Hansen type II, and Hansen type III (also called acute non-compressive or high-speed low-volume intervertebral disc extrusion) according to the difference in the pathogenesis of intervertebral disc degeneration (Daisuke Hasegawa, Kazuya Edamura, Miyoko Saito. Monograph on Neurology of Dogs and Cats. Midori Shobo, Tokyo 2015: pages 314 - 330, and Fenn J et al. Front Vet Sci 2020; 7: 579025. 2020 / 11 / 03).

[0044] Hansen type I intervertebral disc disease is caused by chondromalacia and dystrophic calcification in the nucleus pulposus of the intervertebral disc. The degenerated nucleus pulposus ruptures the annulus fibrosus and protrudes into the spinal canal, damaging the spinal cord. Cartilage-dystrophic dog breeds have a genetic background that makes them prone to chondromalacia from an early age and are likely to develop Hansen type I intervertebral disc disease. In fact, in this dog breed, clinical signs of intervertebral disc disease often appear between the ages of 3 and 7, and the lesions are reported to be more common in the cervical or thoracolumbar regions (Hansen HJ. Acta Orthop Scand Suppl 1952; 11: 1-117). In the present invention, representative cartilage-dystrophic dog breeds to be treated include dachshund, miniature dachshund, French bulldog, pug, Boston terrier, Pekingese, Shih Tzu, Welsh corgi, beagle, basset hound, cocker spaniel, papillon, poodle, Chihuahua, Bichon Frise, Lhasa apso, and Cavalier King Charles spaniel, as well as their respective subspecies and mixed breeds.

[0045] Hansen type II intervertebral disc disease is caused by age-related fibrous degeneration in the annulus fibrosus. The nucleus pulposus of the intervertebral disc moves into the ruptured annulus fibrosus due to degeneration and damages the spinal cord. The dog breeds prone to Hansen type II intervertebral disc disease are called non-cartilage-dystrophic dog breeds. Representative dog breeds include Yorkshire terrier, Pomeranian, miniature pinscher, schnauzer, Maltese, whippet, Shetland sheepdog, Siberian husky, and Labrador retriever, as well as their respective subspecies and mixed breeds.

[0046] Conventionally, the classification of canine intervertebral disc disease was the two types of Hansen type I and Hansen type II mentioned above. However, in recent years, a further type, Hansen type III, has been reported, which is characterized by the escape of intervertebral disc material from an undegenerated intervertebral disc and causing a non-compressive disorder to the spinal cord (Henke D et al., J Am Vet Med Assoc 2013; 242: 217-222).

[0047] When the spinal cord disease covered by the present invention is an intervertebral disc disease, it is preferable that the intervertebral disc disease falls under Hansen type I, Hansen type II, or Hansen type III of the intervertebral disc disease classification. While any of these classifications is acceptable, Hansen type I or Hansen type II is more preferable because these types account for a particularly large number of cases.

[0048] Wobbler syndrome is a general term for spinal cord injury diseases caused by spinal cord malformations that occur during postnatal growth, and are more common in large breeds such as Dobermans, Great Danes, Saint Bernards, and Mastiffs. It is particularly prevalent in Dobermans and Great Danes. It is a disease in which spinal cord compression occurs in the 1st-2nd-3rd-4th cervical vertebrae and the 5th-6th-7th cervical vertebrae due to malformations of the cervical spine in dogs, or where thickening of non-bony tissues occurs due to chronic cervical instability, damaging the cervical spinal cord. Canine wobbler syndrome can affect any cervical vertebra and is sometimes called posterior cervical spinal stenosis, cervical spondylolisthesis, cervical spinal instability, cervical spondylosis, or cervical spinal malformation.

[0049] Degenerative Myelopathy: Degenerative myelopathy is a painless, slowly progressing spinal cord disease that is common in German Shepherds but also occurs in Boxers and Bernese Mountain Dogs. It is particularly prevalent in Welsh Corgis, which are numerous in Japan. It begins with paralysis of the hind legs around the age of 10, then slowly progresses to the front legs. Within a few years, the paralysis spreads throughout the entire spinal cord, eventually leading to respiratory failure and death. Currently, there is no effective treatment for this disease, including surgical therapy, and owners can only watch as the paralysis of the limbs slowly progresses and ultimately leads to death from respiratory failure.

[0050] • Degenerative spondylosis: Degenerative spondylosis is a disease in which the intervertebral discs deform, causing bone protrusions (osteophytes) to form on the edges of the vertebral bodies, or bone components that connect bones in a bridge-like manner to form, which narrows the range of motion of the spine and causes pain. It is more common in boxers and German Shepherds.

[0051] Progressive myelomalacia refers to the widespread, progressive necrosis of the spinal cord parenchyma that occurs as a result of severe acute spinal cord injury caused by Hansen type I intervertebral disc herniation.

[0052] Atlantoaxial instability is a disorder that causes spinal cord damage related to instability, subluxation, and dislocation of the atlas and axis vertebrae, and is often associated with congenital malformations of the atlantoaxial joint. It is particularly common in breeds such as Chihuahuas, Pomeranians, Yorkshire Terriers, Shih Tzus, Maltese, Miniature Dachshunds, and Toy Poodles.

[0053] Syringomyelia Syringomyelia is caused by an excessive accumulation of clear cerebrospinal fluid in the spinal cord. The name comes from the fact that the excess cerebrospinal fluid accumulates in a tunnel-like shape in the center of the spinal cord, making it appear as if a cavity has formed in the spinal cord. It is commonly seen in small dogs, including Cavalier King Charles Spaniels, Yorkshire Terriers, Pomeranians, Chihuahuas, and Miniature Dachshunds.

[0054] • Spinal cord tumors: There are many types of tumors that occur in the spinal cord, and they are classified into epidural tumors, intradural / extramedullary tumors, and intramedullary tumors. When secondary spinal cord damage occurs due to compression by a tumor, clinical symptoms similar to those of other spinal cord diseases, such as pain and dizziness, appear.

[0055] Spinal cord disorders associated with spinal tumors: Spinal tumors are broadly classified into primary tumors and metastatic tumors. There is no preferred site for spinal tumors; they can occur in any part of the spine. In the case of primary tumors, nonspecific symptoms such as loss of appetite and lethargy occur in the early stages, but when the spinal cord is damaged by the tumor, symptoms such as pain and unsteadiness appear, which are very similar to those of other spinal cord diseases such as herniated discs and arthritis. In the case of metastatic tumors, similar symptoms are observed when the spinal cord is damaged.

[0056] Spinal cord injury is an injury caused by external energy, resulting from spinal cord damage due to fracture or dislocation, and associated secondary complications such as bleeding and edema. In dogs, spinal cord injury due to vertebral fracture is the most common, and causes include, for example, traffic accidents, falls from heights, and fights with other animals.

[0057] Other spinal cord diseases: Other spinal cord diseases not listed above include spinal cord injury due to spontaneous sterile pyogenic granuloma of the epidural space, myelitis, spinal cord infarction, and damage caused by compression of the spinal cord due to malformations of the spine and spinal cord.

[0058] 2. Diagnostic Methods for Spinal Cord Diseases Canine spinal cord diseases are diagnosed based on neurological examinations and clinical symptoms, but imaging studies are also used in some cases, including plain X-ray examinations, myelography, X-ray CT scans, and magnetic resonance imaging (MRI). Electrophysiological examinations, histopathological examinations, molecular biological examinations including DNA testing, and clinicopathological examinations are also performed. However, even with these methods, there are cases where a definitive diagnosis is difficult or where it is impossible to distinguish between different types of spinal cord diseases, and many cases involve the co-occurrence of various diseases. Therefore, in this invention, all cases in which a veterinarian determines that a dog has a spinal cord disease based on neurological examinations, motor function assessments, and clinical symptoms are included, and a definitive diagnosis using imaging studies is not required.

[0059] 3. Target Dog Breeds The target dog breeds for the treatment method of the present invention are not particularly limited, but if the spinal cord disease is an intervertebral disc disease, the dog may be a chondrodystrophic breed or a non-chondrodystrophic breed. Specifically, chondrodystrophic breeds may be at least one selected from the group consisting of Dachshunds, Miniature Dachshunds, French Bulldogs, Pugs, Boston Terriers, Pekingese, Shih Tzus, Welsh Corgis, Beagles, Basset Hounds, Cocker Spaniels, Cavalier King Charles Spaniels, Papillons, Poodles, Chihuahuas, Bichon Frises, and Lhasa Apsos, as well as their respective subspecies and crossbreeds. Non-chondrodystrophic dog breeds may be at least one selected from the group consisting of Yorkshire Terriers, Pomeranians, Miniature Pinschers, Schnauzers, Miniature Schnauzers, Maltese, Whippets, Shetland Sheepdogs, Siberian Huskies, and Labrador Retrievers, as well as their respective subspecies and crossbreeds. However, the dogs to be treated are not necessarily limited to the breeds listed above.

[0060] 4. Assessment of the Severity of Spinal Cord Diseases The severity of spinal cord diseases can be assessed using the neurological severity classification grade for spinal cord injuries, the Olby score, neurological examinations, and general condition. The effects of the present invention can also be evaluated using these assessment indicators. These evaluation methods will be described in detail below. These assessment indicators provide a different perspective on spinal cord diseases, and the present invention applies when an abnormality is found in even one of these indicators. Cases in which multiple of these indicators are abnormal also fall under the scope of the present invention.

[0061] (1) Neurological Severity of Spinal Cord Injuries In intervertebral disc disease among spinal cord diseases in dogs, the grade is evaluated based on neurological examination and general physical examination according to the "neurological severity of spinal cord injury" (also called the modified Frankel score classification), and an appropriate treatment method is selected based on this (Daisuke Hasegawa et al., Neurology of Dogs and Cats: Specific Topics. Midori Shobo, 2015: 314-330., and Olby NJ et al. Front Vet Sci 2020; 7: 596059). In this grading classification of neurological severity of spinal cord injury, intervertebral disc disease in dogs can be diagnosed as follows. Grade 1: There is no spinal cord dysfunction and no neurological abnormalities, but the dog is experiencing spinal pain. This includes symptoms such as hunching over, hesitating to go up and down stairs, and reluctance to exercise. Pain can also be confirmed by pressing on the spine during a physical examination. Grade 2: There is partial paralysis or ataxia of the hind limbs. The dog can walk, but due to weakness in the hind limbs, it walks unsteadily or drags its toes, resulting in worn-down claws. Grade 3: There is severe partial paralysis of the hind limbs. The dog cannot walk on its hind limbs, but can stand with support. When the dog starts walking, it moves only on its forelimbs, dragging its hind limbs. Grade 4: There is complete paralysis of the hind limbs, but deep pain sensation is still present. Grade 5: There is complete paralysis of the hind limbs, and deep pain sensation is absent. Cervical disc herniation is evaluated on grades 1-3, while thoracolumbar disc herniation is evaluated on grades 1-5.

[0062] The method of the present invention may be used in any of the above Grade 1 to 5 cases, but Grade 1 to 3 is preferred, and Grade 2 to 3 is more preferred. In these cases, the treatment method of the present invention shows particularly remarkable improvement in motor function and clinical symptoms.

[0063] (2) Olby Score The Olby score is a method of visually evaluating a dog's gait on a 15-point scale, used in clinical practice to assess motor function (Olby NJ, et al. Am J Vet Res 2001; 62: 1624-1628). Specifically, first, a dog patient with a spinal cord disease is made to walk on a non-slip surface such as concrete at various intervals, with the caregiver ensuring that the dog can voluntarily move its hind limbs without supporting its weight. At least 10 steps of this walking are then videotaped from the left, right, and rear. Next, two independent evaluators observe the recorded video and diagnose the score and stage as shown in the table below.

[0064]

[0065] The method of the present invention may be used in any case with a score of 0 to 13, but a score of 5 to 13 is preferred, and a score of 8 to 13 is more preferred. In such cases, the treatment method of the present invention shows particularly remarkable improvement in motor function and clinical symptoms.

[0066] (3) Neurological examination of spinal cord injury (a) Proprioception score The proprioception score is an examination that evaluates whether the dog has a conscious awareness of where its toes are, what position they are in, and how to move them to properly support its body. The examination is performed by supporting the dog's weight, extending the leg naturally, gently turning the leg over, and then evaluating how quickly the dog returns the leg to its original position when the top of the foot is placed on the ground. The examination is performed for all four limbs. The evaluation is performed for each limb on a three-point scale: 0: no reaction at all, 1: slow reaction, 2: immediate reaction, with 2 being normal.

[0067] (b) Jump-back reaction score The jump-back reaction is assessed by keeping the leg being tested on the ground and shifting the body axis outward to see if the dog jumps back up. The test is performed on all four limbs. In the case of large dogs, it is not necessary to lift them up forcibly; simply moving them to the side is sufficient for some assessment. Each limb is evaluated on a three-point scale, with "0" indicating no jump-back, "1" indicating a delay in the start of the jump-back or abnormalities in the jump-back process, and "2" indicating a normal jump.

[0068] The treatment method of the present invention can be used in cases where at least one limb shows a proprioceptive score or jump reaction score of 0 or 1. Furthermore, it can be effectively used even when a score of 0 or 1 is observed in multiple limbs, and can be used in cases where the sum of the proprioceptive score or jump reaction score when all four limbs are evaluated is between 0 and 7, but preferably between 4 and 7, and more preferably between 6 and 7. In such cases, the treatment method of the present invention shows particularly remarkable improvement in motor function and clinical symptoms. However, in the present invention, if the neurological severity of the spinal cord injury or abnormalities in the Olby score are observed as described above, the present invention can also be used even if abnormalities in the proprioceptive score or jump reaction score are not observed in all four limbs.

[0069] Neurological examinations also include the righting reflex, standing reflex, wheelbarrow reflex, and postural extensor thrust reflex, and since each evaluates different nerve regions, multiple tests are often performed. The present invention can be suitably used when even one of these test values ​​is abnormal.

[0070] (4) General condition Since spinal cord diseases affect the overall condition, it is also important to consider the general condition. Since many patients experience a decline due to the disease, activity and appetite are examined. As an example, evaluation is performed using a 3- to 7-point scoring system. In this invention, abnormal activity and appetite refer to a state where there is no activity and the patient hardly moves throughout the day, or a state where there is no appetite, with 0 being the score. For example, a score of 0 or 1 on a 3-point scale (0 to 2, where 2 is normal), a score of 0 to 2 on a 4-point scale (0 to 3, where 3 is normal), a score of 0 to 3 on a 5-point scale (0 to 4, where 4 is normal), a score of 0 to 4 on a 6-point scale (0 to 5, where 5 is normal), a score of 0 to 5 on a 7-point scale (0 to 6, where 6 is normal), and so on. The treatment method of the present invention may be used in any case where the activity and appetite scores are, for example, 0 to 3 on a 5-point scale (0 to 4, with 4 being normal), but cases with scores of 1 to 3 are more preferred, and cases with scores of 1 to 2 are even more preferred. In such cases, the treatment method of the present invention shows particularly remarkable improvement in motor function and clinical symptoms.

[0071] The state of spinal cord disease in dogs can be evaluated from many angles using these examination methods, but these tests are often not performed depending on the patient's condition. This invention does not require any specific tests.

[0072] 5. Relationship between Conventional Treatments and the Present Invention Among the treatments performed for spinal cord diseases in dogs, conservative therapies include rest therapy, acupuncture, physical therapy, rehabilitation, massage, exercise therapy, and jet bath therapy. In addition, treatments using drugs or supplements include the administration of drugs or supplements such as steroidal anti-inflammatory drugs, nonsteroidal anti-inflammatory drugs, neuropathic pain medications, opioid analgesics, prostaglandin E1 derivatives, neutrophil elastase inhibitors, fatty acids, PCSO-524, EAB-277, vitamins, and curcumin.

[0073] Among the drugs conventionally used to treat spinal cord diseases, steroidal anti-inflammatory drugs include prednisolone, methylprednisolone succinate, dexamethasone, betamethasone valerate, triamcinolone acetonide, methylprednisolone, and betamethasone + chlorpheniramine maleate (trade name: Celestamine), with prednisolone being particularly frequently used. Nonsteroidal anti-inflammatory drugs include the neutrophil elastase inhibitor sivelestat sodium hydrate.

[0074] If pain is present, analgesics are used to alleviate it. Specifically, NSAIDs such as firocoxib, robenacoxib, meloxicam, and mavacoxib are administered. Other analgesics with different mechanisms of action, such as pregabalin and gabapentin, which are indicated for human neuropathic pain, are also used for their analgesic effects. Grapiprant, a selective antagonist of the EP4 receptor, one of the receptors for the pain-causing substance prostaglandin E2, is used as an analgesic with another mechanism of action. Furthermore, tramadol, buprerphine, fentanyl, and morphine are also used.

[0075] Other types of drugs include prostaglandins, such as prostaglandin E1 preparations like limaprost, prostandin, and ripple-pulx.

[0076] In addition to medications, many supplements are also used. Specifically, these include Neuroact, a nerve supplement; Neurovitan, a vitamin combination; Antinol (PCSO-524), which consists of various fatty acids; and Antinol Plus (EAB-277), which is Antinol combined with krill oil to aid absorption into the body.

[0077] The treatment method of the present invention can be effectively used in cases where sufficient improvement has not been observed with conventional treatments, or in cases where it is difficult to continue conventional treatment due to the occurrence of side effects, etc. In other words, it is preferable that the dogs to be treated have shown resistance to conservative therapy, including at least one of rest therapy, acupuncture, physical therapy, and rehabilitation, or have shown resistance to the administration of therapeutic drugs or supplements, including at least one of steroidal anti-inflammatory drugs, nonsteroidal anti-inflammatory drugs, neuropathic pain treatment drugs, opioid analgesics, prostaglandin E1 derivative drugs, neutrophil elastase inhibitors, fatty acids, Antinol (PCSO-524), Antinol Plus (EAB-277), vitamins, and curcumin, prior to the administration of the formulation in the treatment method of the present invention. In such cases, the therapeutic effect of the present invention is particularly pronounced.

[0078] Furthermore, the treatment method of the present invention makes it possible to reduce the dosage or frequency of administration of steroidal anti-inflammatory drugs, nonsteroidal anti-inflammatory drugs, neuropathic pain treatment drugs, opioid analgesics, and especially steroidal anti-inflammatory drugs and analgesics that are administered to improve symptoms. Since these drugs often cause side effects, this leads to a reduction in the burden on sick dogs.

[0079] Furthermore, the method of the present invention is also preferable to be combined with the conventional conservative treatment described above.

[0080] Furthermore, the method of the present invention can, of course, be combined with surgical therapy. If the above-mentioned preparation is prescribed before surgical therapy, it is possible to delay the time until surgery, such as spinal surgery, or even avoid surgery altogether. If the preparation is administered after surgery, it is possible to reduce or restore residual motor and neurological disorders, as well as deterioration of the general condition, and maintain a good postoperative course.

[0081] The compounds that can be used in the present invention are those represented by the following formula (I).

[0082]

[0083] In formula (I), R represents hydrogen or a pharmacologically acceptable cation.

[0084] Pharmacologically acceptable cations include alkali metals such as sodium, potassium, and calcium, alkaline earth metals, amines represented by mono-, di-, and trimethylamine, methylpiperidine, mono-, di-, and triethanolamine, and lysine, as well as basic amino acids. Among these, sodium and potassium are particularly preferred.

[0085] The compound represented by formula (I) also includes its stereoisomers. In the present invention, the compound represented by formula (I) may include any one of the stereoisomers, or a combination of multiple stereoisomers.

[0086] Furthermore, as the compound represented by formula (I), beraprost or a pharmacologically acceptable salt thereof is preferably used. Among these, in addition to beraprost, the sodium salt of beraprost, BPS, or the potassium salt of beraprost (beraprost potassium) is particularly preferred. BPS is a 1:1:1:1 mixture of four stereoisomers, but it is more preferable to include BPS-314d (Sodium(+)-(1R,2R,3aS,8bS)-2,3,3a,8b-tetrahydro-2-hydroxy-1-[(E)-(3S,4S)-3-hydroxy-4-methyl-1-octen-6-ynyl]-1H-cyclopenta[b]benzofuran-5-butyrate), which has the strongest pharmacological effect among its stereoisomers, and it may also contain only BPS-314d. However, the above are merely examples, and the compound represented by formula (I) is not limited to these.

[0087] The compound represented by formula (I) used in the present invention is known and can be produced by known methods described in, for example, Japanese Patent Publication No. 1-53672, Japanese Patent Publication No. 7-5582, Japanese Patent Application Publication No. 3-7275, Japanese Patent Publication No. 6-62599, etc.

[0088] Furthermore, the compound represented by formula (I) can be used alone or in combination of two or more compounds.

[0089] (Dosage and Administration) In the therapeutic method of the present invention, the dosage of the compound represented by formula (I) or BPS is preferably expressed as a dosage per unit of body weight of the dog with spinal cord disease that is the target of treatment. This is because the body weight of dogs varies from individual to individual. In this case, the dosage is preferably 0.05 to 600 μg / kg per day, more preferably 1 to 300 μg / kg, and even more preferably 10 to 200 μg / kg. The above dosage may be, for example, 0.05 to 200 μg / kg per day. When the compound represented by formula (I) is beraprost potassium, the dosage is preferably 0.052 to 624 μg / kg per day, more preferably 1.1 to 312 μg / kg, and even more preferably 11 to 208 μg / kg.

[0090] The number of times the formulation in the therapeutic method of the present invention is administered to dogs per day is not particularly limited, but it is usually administered 1 to 4 times per day, more preferably in two divided doses per day. However, if there are no particular problems with side effects, administration once a day is also acceptable. Furthermore, the number of doses may be set to coincide with meals. It is preferable, but not limited to, that the above formulation be administered continuously for 7 days or more, more preferably for 14 days or more, and even more preferably for 30 days or more.

[0091] There are no particular restrictions on when the above preparation is administered during the day, but it is preferable to administer it during or after meals in the morning and evening. Furthermore, under the guidance of a physician or veterinarian, the above preparation can be added to the dog's prescription food beforehand and administered; in this case, it is also possible to divide the administration into the same number of meals as the dog in a day.

[0092] As mentioned above, BPS consists of four stereoisomers, and among them, BPS-314d has the strongest pharmacological effect. For this reason, formulations containing only BPS-314d are also preferably used. When BPS is administered, the plasma concentration of BPS-314d is approximately 1 / 4 of both the AUC (area under the blood concentration time curve; the area enclosed by the curve representing the time course of blood concentration (drug blood concentration-time curve) and the horizontal axis (time axis)) and Cmax (peak blood concentration) in humans (Shimamura et al. J Clin Pharmacol. (2017) 57, 524-535) and rats (Matsumoto et al., Pharmacokinetics (1989), 4(6), 713-725), and this trend is thought to be similar in dogs. Therefore, when administering a preparation containing the active form of BPS (e.g., BPS-314d) alone, the effective daily dose of BPS-314d is 1 / 4 of the dose of BPS alone. Furthermore, administration of the active form of beraprost potassium (Potassium(+)-(1R,2R,3aS,8bS)-2,3,3a,8b-tetrahydro-2-hydroxy-1-[(E)-(3S,4S)-3-hydroxy-4-methyl-1-octen-6-ynyl]-1H-cyclopenta[b]benzofuran-5-butyrate) alone is also particularly preferred, but in this case, the preferred daily dose is 1 / 4 of the dose when beraprost potassium is administered.

[0093] (Dosage Form) Various dosage forms can be used for the formulation in the therapeutic method of the present invention. Specifically, for oral administration, it can be a tablet, chewable tablet, powder, fine granules, granules, liquid, syrup, capsule, pill, or spray. Furthermore, the molded product can be film-coated, sugar-coated, or capsule-filled. More preferably, it can be a tablet, powder, fine granules, granules, liquid, syrup, or capsule.

[0094] The formulations used in the therapeutic method of the present invention may be administered parenterally in the form of a bactericidal solution or the like. In this case, other solutes, such as sodium chloride or glucose sufficient to make the solution isotonic, may also be used. Examples of dosage forms for parenteral administration include various injectables, nasal drops, ear drops, eye drops, transdermal preparations, ointments, suppositories, etc.

[0095] Oral administration is more preferred as the form of administration for the therapeutic agent of the present invention.

[0096] In the therapeutic method of the present invention, the formulations used in humans are preferably Dorner® and Procyclin®. Furthermore, a formulation of Rapros®, a feline chronic kidney disease treatment drug approved for manufacture and sale in Japan, with a modified drug content, is preferably used, and can be prepared, for example, by the following method.

[0097] As excipients, lactose and starch are placed in a stirring granulator, and granulation is carried out while stirring, with a pre-prepared solution of BPS and binder (hypromellose) added. The granules are crushed, dried, and sized to obtain dry granules, to which a lubricant (magnesium stearate) is added and mixed in a mixer, and then uncoated tablets are obtained using a rotary tablet press. The obtained uncoated tablets are placed in a coating device, and after coating with a pre-prepared coating solution (polyethylene glycol, hypromellose) while spraying, carnauba wax is added to produce film-coated tablets.

[0098] In addition to excipients, lubricants, and binders, additives such as stabilizers and solubilizers may also be added to the formulation in the therapeutic method of the present invention. The additives are not particularly limited as long as they are pharmacologically acceptable, but examples of excipients include lactose, sucrose, D-mannitol, sorbitol, xylitol, crystalline cellulose, corn starch, gelatin, polyvinylpyrrolidone, dextran, polyethylene glycol (hereinafter abbreviated as PEG, also known as macrogol) 1500, PEG4000, PEG6000, PEG20000, and polyoxyethylene polyoxypropylene glycol (PEP101 (trademark), Pluronic (registered trademark)). Examples of lubricants include magnesium stearate, calcium stearate, and talc. Examples of binders include hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), methylcellulose, stearic acid, and propylene glycol. Examples of stabilizers include butylhydroxytoluene, butylhydroxyanisole, ascorbic acid, propyl gallate, dibutylmethylphenol, and sodium thiosulfate. Examples of solubilizers include hydrogenated polyethylene castor oil and polyethylene glycol monostearate. The amount of these additives is appropriately selected depending on their type, purpose, etc.

[0099] Furthermore, acrylic acid polymers, polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), carnauba wax, and various commercially available premix coating agents can also be used as coating agents for the tablets.

[0100] Dogs with spinal cord diseases may experience a decrease in appetite. Adding scents or flavors that dogs like to the medication can make drug administration easier and increase the chances that dogs will eat willingly. Examples of additives used to add flavor to the medication include natural or synthetic flavors such as meat, fish, and yeast.

[0101] Furthermore, in addition to the process described above, other processes such as continuous production can also be used as methods for preparing oral formulations, and the manufacturing process is not particularly restricted.

[0102] The form of the formulation containing the compound represented by formula (I) that can be used in the present invention is not particularly limited, but in the case of oral administration, tablets are preferred. The tablet diameter is important as it greatly affects the administration of medication by dogs, and a suitable oral size for dogs is preferably 4.5 to 33.5 mm in diameter, more preferably 5.0 to 22.5 mm. Also, when filling particles or fine particles with a diameter of 10 to 1000 μm into capsules, the size of the capsule is preferably 4.5 to 9.0 mm × 11.0 to 25.0 mm in inner diameter × total length after filling, so that it can be easily mixed with food and can be administered as is.

[0103] In the therapeutic method of the present invention, sustained-release formulations, particularly oral sustained-release formulations, can also be used as the preparation. As described in the Pharmaceutical Society of Japan's glossary of pharmaceutical terms, a sustained-release formulation can be defined as "a formulation that reduces the number of doses and avoids side effects by slowing down the release of the active ingredient from the formulation and maintaining a constant concentration of the active ingredient in the blood for a long period of time."

[0104] Orally administered sustained-release formulations include single-unit and multiple-unit types. Many single-unit formulations gradually release the drug while maintaining its dosage form in the gastrointestinal tract. Examples of single-unit formulations include wax matrix, Gradumet, Repetab, Rontab, and Spantab. In multiple-unit formulations, the administered tablet or capsule rapidly disintegrates, releasing granules that exhibit sustained release. Examples of multiple-unit formulations include Spastab, Spansuru, and granules. Furthermore, formulations can be classified into reservoir and matrix types based on their release control mechanism. Reservoir formulations consist of a tablet or granules containing the drug coated with a polymer film; the drug release rate is determined by the properties and thickness of this film. Repetab, Spastab, Spansuru, and granules belong to the reservoir type. Matrix formulations disperse the drug in a base such as a polymer or wax; the release rate is determined by the diffusion rate of the drug molecules within the matrix. Wax matrix type, Gradumet type, Rontab type, Spantab type, etc. belong to the matrix type. As long as they have the aforementioned release characteristics, the method of sustained release is not limited, and various sustained-release formulations can be used.

[0105] Among the above, the sustained-release formulations that can be used in the present invention are not particularly limited, but for example, International Publication No. 98 / 41210 and International Publication No. 2004 / 103350 describe sustained-release BPS formulations that incorporate a hydrogel base as a BPS release control component, and it is also possible to use the sustained-release BPS formulations produced by this method.

[0106] Furthermore, as another form of sustained-release formulation containing BPS, an oral sustained-release pharmaceutical composition containing multiple granules with a particle size of 1000 μm or less is described in International Publication No. 2004 / 103350, and it is also possible to use this formulation.

[0107] Even in the case of parenteral administration, depending on the characteristics of the formulation, it is possible to individually control the release, such as by applying sustained-release or delayed-release mechanisms. For example, the above formulation can be given a sustained-release function using existing methods, and a wide range of administration methods, such as implantable sustained-release pumps (e.g., Alzamini pumps), can be applied.

[0108] <Therapeutic Drugs and Therapeutic Preparations> The therapeutic drug of the present invention is suitable as a preparation for use in the therapeutic method of the present invention. The therapeutic preparation of the present invention is a preparation containing a compound represented by formula (I) as an active ingredient, and is a therapeutic preparation for canine spinal cord disease, to be administered to dogs with spinal cord disease. The compound represented by formula (I) and additives contained in the therapeutic drug or therapeutic preparation of the present invention, the suitable dosage and method of use of the therapeutic drug or therapeutic preparation, the administration form and dosage form, etc. are the same as those described above for preparations used in the therapeutic method of the present invention.

[0109] The present invention will now be described in detail with reference to examples and comparative examples, but the present invention is not limited thereto.

[0110] (Example 1) Preparation of BPS Tablets In the examples and comparative examples of this application, the drug administered to dogs was beraprost sodium (BPS), represented by formula (I), and film-coated tablets of 20 μg / tablet and 55 μg / tablet were prepared by the following method. Lactose and starch as excipients were placed in a stirring granulator, and granulation was carried out while stirring, with a pre-prepared solution of BPS and a binder (hypromellose) added. The granules were crushed, dried, and sized to obtain dried granules, to which a lubricant (magnesium stearate) was added and mixed in a mixer, and then uncoated tablets were obtained using a rotary tablet press with a 6 mm, 8R mortar and pestle. The obtained uncoated tablets were placed in a coating apparatus, and after coating with a pre-prepared coating solution (polyethylene glycol, hypromellose) while spraying, carnauba wax was added to obtain film-coated tablets.

[0111] (Example 2) The effect of administering a BPS preparation to dogs with spinal cord disease was investigated. At the implementing facility, cases that met the following selection and exclusion criteria were included in the study. 1. Selection criteria: Cases that meet all of the following criteria are included. (1) The dog's weight is less than 15 kg. (2) Myelopathy is diagnosed by general physical examination (visual inspection, auscultation, palpation, weight measurement, temperature measurement), imaging examination (X-ray, X-ray contrast, CT, MRI, or a combination of these), and neurological examination (observation and postural response). (3) Informed consent for participation in the study has been obtained from the dog's owner. 2. Exclusion criteria: Cases that meet any of the following criteria are not included. (1) The dog is in the growth stage (e.g., less than 8-10 months old for small breeds, less than 15-18 months old for large breeds). (2) The dog is pregnant or may be pregnant. (3) A disease other than spinal cord disease that may affect the observation results or evaluation of the effect is diagnosed. For enrollment, patients were randomly assigned to either a high-dose group or a low-dose group according to a pre-prepared randomization schedule. Blinding was not performed.

[0112] The period from initial inclusion in the study to the start of BPS administration was defined as the pre-treatment period. During this period, cage rest was maintained as a general rule. New concomitant medications or therapies were not permitted. Furthermore, while dose reduction and discontinuation were permitted for medications used prior to the study, dose increases were not allowed. At the study site, before the start of BPS administration, the neurological severity of spinal cord injury was graded on a three-point scale (grades 1 to 3) for cervical disc herniation and on a five-point scale (grades 1 to 5) for thoracolumbar disc herniation. Neurological examinations included the Olby score, proprioception score, and jump response score. Activity and appetite scores were also evaluated on a five-point scale to assess general condition: 1 for very poor, 2 for poor, 3 for normal, 4 for good, and 5 for very good. Owners were consulted to determine which category applied to their pet's condition.

[0113] The study drugs used were Dorner tablets (registered trademark) containing 20 μg of BPS per tablet, and Lapros (registered trademark), a feline formulation containing 55 μg of BPS. The tablets were divided to 1 / 4 depending on the dog's body weight, and the BPS dose was administered orally twice daily after meals, with a dose of 10.1–19.8 μg / kg (12.5 ± 2.1 μg / kg (mean ± standard deviation)) for the high-dose group and 1.9–4.3 μg / kg (2.7 ± 0.7 μg / kg (mean ± standard deviation)) for the low-dose group. The combined dose for both groups was 9.1 ± 5.0 μg / kg (mean ± standard deviation). Evaluation points were 7, 14, 28, and 56 days after administration, and the Olby score, proprioception score, jump response score, activity score, and appetite score were assessed. The final observation date was defined as the day immediately preceding the discontinuation of BPS administration. In addition to the neurological examinations and general condition assessments described above, the grade of the neurological severity classification of spinal cord injury was evaluated. The treatment period was defined as the period from the start of BPS administration to the final observation date. For statistical analysis, the difference between the pre-treatment period and the treatment period was used for the grade of the neurological severity classification of spinal cord injury. For the Olby score, proprioception score, jump response score, activity score, and appetite score, the difference between the final evaluation and the start of the treatment period was used. A list of the background characteristics of the dogs included is shown in Tables 2 and 3.

[0114]

[0115]

[0116] The cases included cervical and thoracolumbar intervertebral disc herniation, as well as lumbosacral instability and syringomyelia. The intervertebral disc herniation cases included Hansen classification types I and II. The dogs studied were predominantly chondrodystrophic breeds.

[0117] In both the pre-treatment period (labeled as "existing treatment" in the table) and the treatment period (labeled as "BPS administration" in the table), cases where the neurological severity classification grade of spinal cord injury became 0 were defined as cured ("Cured (Yes)"). Table 4 summarizes the number of cases that were not cured ("Cured (No)"). The McNemar test was used for statistical analysis. No cases of spinal cord disease were observed with existing treatment, but a significantly higher number of cases were observed to be cured with BPS treatment. Thus, it became clear that BPS administration can eliminate motor function and clinical symptoms. No problematic side effects were observed during the BPS administration period.

[0118]

[0119] (Example 3) From the same cases as in Example 2, we selected cases in which, despite receiving existing treatment during the pre-treatment period, no improvement in the neurological severity classification grade of spinal cord injury was observed. Table 5 shows the number of individuals whose grade became 0, i.e., cured, after BPS administration, and Table 6 shows the change in the number of individuals whose grade decreased, i.e., whose symptoms improved. With BPS administration, both the number of cured cases and the number of cases whose symptoms improved were significantly higher compared to the pre-treatment period used for comparison. Thus, it became clear that BPS has a remarkable effect in cases resistant to existing treatments, significantly improving motor function and clinical symptoms, and in some cases leading to complete asymptomatic treatment. Furthermore, even when the site of injury in cases resistant to existing treatments was limited to the neck, a significant (p < 0.05) improvement in clinical symptoms was observed with BPS administration (Table 7). The McNemar test was used for statistical analysis.

[0120]

[0121]

[0122]

[0123] (Example 4) To evaluate the motor function of dogs, the Olby score, proprioception score, and jump response score were compared before BPS administration and on the final observation day. To evaluate the general condition, the activity score and appetite score were also compared. As shown in Table 8, significant improvements in these scores were observed with BPS administration. Similarly, significant improvements in all scores were observed even when limited to the high-dose BPS group. The Wilcoxon signed-rank test was used for statistical analysis. In the table, * indicates a significant difference at p < 0.05, ** indicates a significant difference at p < 0.01, and *** indicates a significant difference at p < 0.001.

[0124]

[0125] Even when limited to the 14 cases in the low-dose BPS group among the cases shown in Tables 2 and 3, a significant improvement in the Olby score (P = 0.0431) was observed. However, the Z-score, an indicator of the magnitude of the effect, was 2.02 in the low-dose group, which was smaller than the 2.77 in the high-dose group, indicating a tendency for the high-dose group to show a greater effect from BPS administration. Furthermore, while there was a trend towards improvement in parameters other than the Olby score, no significant differences were observed, and the Z-scores were smaller than in the high-dose group, indicating a lower effect compared to the high-dose group.

[0126] (Example 5) In the pre-treatment phase of spinal cord disease, cases in which no improvement in the neurological severity classification grade of spinal cord injury was observed were selected, and changes in each score before and after BPS administration were evaluated. As shown in Table 9, significant improvements were observed in the Olby score, proprioception score, jump reaction score, and activity score. An improvement trend was also observed in the appetite score, although not statistically significant. Furthermore, when limited to the high-dose BPS group, the p-values ​​when comparing the Olby score, proprioception score, jump reaction score, activity score, and appetite score before administration and at the final administration were 0.0169, 0.0030, 0.0119, 0.0103, and 0.0339, respectively, indicating significant improvements in all cases. In the low-dose group, the p-value for the Olby score was 0.0431, indicating a significant improvement. Although an improvement trend was observed in other parameters, no statistically significant differences were found. Furthermore, the Z-values, which are an indicator of the magnitude of the effect, were smaller in all groups compared to the high-dose group, indicating a weaker effect. The Wilcoxon signed-rank test was used for statistical analysis. In the table, * indicates a statistically significant difference at p < 0.05, ** indicates p < 0.01, and *** indicates p < 0.001.

[0127]

[0128] (Example 6) The cases from Example 2 were evaluated separately for cases where the hernia was located in the cervical region and cases where it was located in the thoracolumbar region. As shown in Table 10, significant improvements were observed in both the Olby score and the proprioceptive score in both the cervical and thoracolumbar regions. A tendency toward improvement was also observed in other scores. The Wilcoxon signed-rank test was used for statistical analysis. In the table, * indicates a significant difference at p < 0.05, and ** indicates a significant difference at p < 0.01.

[0129]

[0130] (Example 7) In the cases shown in Tables 2 and 3, drugs or supplements expected to have an effect on spinal cord disease were administered during the pretreatment period, and in cases where no improvement in the neurological severity classification grade of spinal cord injury was observed during the pretreatment period, each score was compared before and after BPS administration. As shown in Table 11, significant improvements were observed in the Olby score, proprioception score, and activity score. Although not statistically significant, a tendency towards improvement was also observed in the jump response score and appetite score. The Wilcoxon signed-rank test was used for statistical analysis. In the table, * indicates a statistically significant difference at p < 0.05, and ** indicates a statistically significant difference at p < 0.01.

[0131]

[0132] (Example 8) In the cases shown in Tables 2 and 3, in cases where no drugs or supplements expected to have an effect on spinal cord disease were administered during the prior treatment period, and where no improvement in the neurological severity classification grade of spinal cord injury was observed during the prior treatment period, each score was evaluated before and after BPS administration. As shown in Table 12, significant improvements were observed in the Olby score, proprioception score, and jump reaction score. Although not statistically significant, a tendency toward improvement was also observed in the activity score and appetite score. These results indicate that BPS administration alone, without concomitant use of drugs or supplements for spinal cord disease, can improve motor function and clinical symptoms. The Wilcoxon signed-rank test was used for statistical analysis. In the table, * indicates a statistically significant difference at p < 0.05, and ** indicates a statistically significant difference at p < 0.01.

[0133]

[0134] (Example 9) Of the 33 dogs with spinal cord disease listed in Table 2, in 12 dogs (case numbers 3, 4, 6, 8, 12, 15, 19, 23, 24, 30, 32, and 33), the dosage or frequency of steroid and / or analgesic administration could be reduced, or it was determined that administration was unnecessary. In addition, in 5 dogs (case numbers 20, 21, 30, 32, and 33), it was determined that planned intervertebral disc herniation surgery was unnecessary. Thus, by administering this drug, it was possible to reduce or discontinue the administration of steroids and analgesics and avoid surgery, thereby significantly reducing the burden on dogs with spinal cord disease.

[0135] (Example 10) Effect of BPS on dogs with degenerative myelopathy The treatment progression of dogs with degenerative myelopathy treated with BPS is summarized below. BPS was administered orally twice daily at a dose of 10-20 μg / kg using Lapros tablets (registered trademark), either whole or in divided form. The onset of the disease was defined as May 2020, when the owner noticed something unusual about the dog's behavior. Administration of BPS began in June 2022. Clinical symptoms were observed thereafter, and the timing of each symptom and the number of months since the onset of the disease were recorded, as follows: - Inability to stand on both hind limbs: October 2022 (29 months from onset) - Reduced weight bearing on both forelimbs: April 2023 (35 months from onset) - Death: December 2023 (43 months from onset) It was confirmed that the progression of the disease was suppressed at each point in time compared to the case where BPS was not administered, as shown in the comparative example below. Furthermore, no problematic side effects were observed during the BPS administration period.

[0136] (Comparative Example) In the same facility as Example 10, in 40 cases of degenerative myelopathy in dogs that were not administered BPS, the median number of months from the onset of symptoms to the onset of inability to stand on both hind limbs, decreased weight bearing on both forelimbs, and death, and the 95% confidence interval were 10 months / 0–22 months, 21 months / 10–32 months, and 36 months / 18–52 months, respectively.

[0137] Although the present invention has been described in detail with reference to specific embodiments, it will be apparent to those skilled in the art that various changes and modifications are possible without departing from the spirit and scope of the invention. This application is based on Japanese Patent Application No. 2024-199753, filed on 15 November 2024, which is incorporated herein by reference in its entirety.

Claims

1. The following formula (I): A preparation containing a compound represented by [wherein R represents hydrogen or a pharmacologically acceptable cation] as an active ingredient, for administration to dogs with spinal cord disease, for the treatment of canine spinal cord disease.

2. The therapeutic preparation for canine spinal cord disease according to claim 1, wherein the spinal cord disease is at least one selected from the group consisting of intervertebral disc disease, Wobbler syndrome, degenerative myelopathy, degenerative spondylosis, progressive myelomalacia, atlantoaxial instability, syringomyelia, spinal cord tumor, spinal cord injury associated with spinal tumor, myelitis, spinal cord injury due to idiopathic sterile pyogenic granuloma of the epidural space, malformation disease of the spine and spinal cord, spinal cord injury, and spinal cord infarction.

3. The therapeutic preparation for canine spinal cord disease according to claim 1 or 2, wherein the spinal cord disease is an intervertebral disc disease, and the intervertebral disc disease corresponds to grades 1 to 5 of the neurological severity classification of spinal cord injury.

4. A therapeutic preparation for canine spinal cord disease according to any one of claims 1 to 3, wherein the spinal cord disease is an intervertebral disc disease, and the intervertebral disc disease corresponds to Hansen type I, Hansen type II, or Hansen type III of the intervertebral disc disease classification.

5. A therapeutic preparation for a canine spinal cord disease according to any one of claims 1 to 4, wherein the spinal cord disease is an intervertebral disc disease, and the dog is a chondrodystrophic breed or a non-chondrodystrophic breed.

6. The therapeutic preparation for canine spinal cord disease according to claim 5, wherein the chondrodystrophic dog breed is at least one selected from the group consisting of Dachshund, Miniature Dachshund, French Bulldog, Pug, Boston Terrier, Pekingese, Shih Tzu, Welsh Corgi, Beagle, Basset Hound, Cocker Spaniel, Papillon, Poodle, Chihuahua, Bichon Frise, Lhasa Apso, and Cavalier King Charles Spaniel, as well as their respective subspecies and crossbreeds, and the non-chondrodystrophic dog breed is at least one selected from the group consisting of Yorkshire Terrier, Pomeranian, Miniature Pinscher, Schnauzer, Maltese, Whippet, Shetland Sheepdog, Siberian Husky, and Labrador Retriever, as well as their respective subspecies and crossbreeds.

7. A therapeutic preparation for a canine spinal cord disease according to any one of claims 1 to 6, wherein the spinal cord disease satisfies at least one of the following (A) to (F) before administration of the preparation: (A) an intervertebral disc disease corresponding to grade 1 to 5 of the neurological severity classification of spinal cord injury; (B) a spinal cord disease in which the dog's Olby score is 0 to 13; (C) a spinal cord disease in which the sum of the proprioceptive scores of the dog's four limbs is 0 to 7; (D) a spinal cord disease in which the sum of the jump response scores of the dog's four limbs is 0 to 7; (E) a spinal cord disease causing abnormal activity in the dog; and (F) a spinal cord disease causing abnormal appetite in the dog.

8. A therapeutic preparation for canine spinal cord disease according to any one of claims 1 to 7, wherein the dog has shown resistance to conservative therapy, including at least one of rest therapy, acupuncture therapy, physical therapy, and rehabilitation, prior to administration of the preparation, or has shown resistance to administration of a therapeutic agent or supplement, including at least one of steroidal anti-inflammatory drugs, nonsteroidal anti-inflammatory drugs, neuropathic pain treatment agents, opioid analgesics, prostaglandin E1 derivatives, neutrophil elastase inhibitors, fatty acids, antinol (PCSO-524), antinol plus (EAB-277), vitamins, and curcumin.

9. A therapeutic preparation for canine spinal cord disease according to any one of claims 1 to 8, which improves at least one of the motor impairment and clinical symptoms of the canine compared to before administration of the preparation.

10. The therapeutic preparation for canine spinal cord disease according to any one of claims 1 to 9, wherein the compound represented by formula (I) is beraprost sodium or a pharmaceutically acceptable salt thereof.

11. A therapeutic preparation for canine spinal cord disease according to any one of claims 1 to 10, wherein the dosage of the compound represented by formula (I) is used to be 0.05 to 600 μg / kg per day.

12. A therapeutic preparation for canine spinal cord disease according to any one of claims 1 to 11, which is used to be administered in two divided doses per day.

13. A therapeutic formulation for canine spinal cord disease according to any one of claims 1 to 12, to be used for oral administration.

14. A therapeutic formulation for canine spinal cord disease according to any one of claims 1 to 13, which is used to be administered during or after a meal.

15. A method for treating a canine spinal cord disease, comprising administering a therapeutic preparation for canine spinal cord disease according to any one of claims 1 to 14 to a dog suffering from a spinal cord disease.

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