CN117442703A - Application of Elamipretide in preparation of drugs for preventing and/or treating tendon injury - Google Patents
Application of Elamipretide in preparation of drugs for preventing and/or treating tendon injury Download PDFInfo
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- CN117442703A CN117442703A CN202311622045.8A CN202311622045A CN117442703A CN 117442703 A CN117442703 A CN 117442703A CN 202311622045 A CN202311622045 A CN 202311622045A CN 117442703 A CN117442703 A CN 117442703A
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- injury
- tendon
- elamipretide
- preventing
- ectopic ossification
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/07—Tetrapeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biomedical Technology (AREA)
- Physical Education & Sports Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, discloses application of Elamipretide in preparing a medicine for preventing and/or treating tendon injury, and particularly discloses application of Elamipretide or a derivative thereof in preparing a medicine for preventing and/or treating sports injury. The invention discloses an application of Elamipretide or a derivative thereof in preventing and/or treating sports injury for the first time, and experiments show that the Elamipretide can obviously reduce ectopic ossification of injured tissues without adverse effect on biomechanical strength of the tissues, and can achieve the purpose of treating sports injury by reducing ectopic ossification of injured tissues, can be used for preparing medicines for preventing and/or treating sports injury, and is convenient for clinical and daily tendon injury health care.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of Elamipretide in preparation of medicines for preventing and/or treating tendon injury.
Background
Tendon injuries are very common in the areas of daily life and sports, especially in the sports medicine area. Ectopic ossification of tendons is a common and serious complication after tendon injury, often complicated by surgical repair of tendon injury, or as a manifestation of chronic functional structural disorders caused after tendon injury. The incidence rate of ectopic ossification after achilles tendon fracture surgery is up to 14% -62%, and symptoms such as pain, tendon mechanical strength reduction, local edema, limited activities of different degrees and the like can be caused. At present, the pathogenesis and treatment method of the tendon ectopic ossification are not completely defined, and no clear medicine is clinically used for preventing and treating the tendon ectopic ossification.
Once the ectopic ossification of the tendon is formed, the ectopic ossification cannot be eliminated by a conservative treatment mode such as medicines, and symptoms can be relieved only by some conservative treatment modes, and the ossification can be removed only by operation under severe symptoms, but the ectopic ossification is easy to relapse due to additional wounds inevitably caused. It is therefore more important to prevent the occurrence of tendon-ectopic ossification than to treat the tendon-ectopic ossification after it has occurred. Nonsteroidal anti-inflammatory drugs (NSAIDs) are clinically commonly used drugs for treating ectopic ossification, and in addition, radiotherapy, physical therapy and intervention of molecular biological mechanisms have certain therapeutic effects on tendon ectopic ossification, but the effects of the means are different, and certain side effects exist. For example, the efficacy of shock wave therapy on tendon ectopic ossification is not yet established, and although some studies confirm its effectiveness, there are studies showing that there is no obvious beneficial effect, and the mechanism of shock wave therapy is not yet clear, and in the present situation, it is a non-optimal choice for alleviating symptoms as a physical therapy, and new, safer and more effective therapeutic methods are expected to appear clinically. Radiation therapy may be applied to prevent post-operative or recurrent ectopic ossification. Since radiotherapy directly interferes with the biological behavior of ectopic calcitic progenitor cells and resident cells, there is a great benefit to high-risk ectopic cases. However, damage to tissues by radiation therapy is unavoidable and may lead to serious systemic complications, side effects including bone nonunion or radiation-induced sarcomas, etc. Non-steroidal anti-inflammatory drugs and glucocorticoids as a conservative treatment may adversely affect tendon self-healing and homeostasis. It has been shown that glucocorticoids induce tendinocyte metaplasia into fibrocartilage-like tissue and induce bone differentiation from spinal ligament-derived cells. The above studies indicate that care should be taken in selecting glucocorticoids for conservative treatment. Non-steroidal anti-inflammatory drugs are clinically commonly used drugs for the treatment of ectopic ossification, which inhibit differentiation of progenitor cells into osteoblasts in ectopic ossification by inhibiting cyclooxygenase to reduce synthesis of inflammatory mediator prostaglandins, and can relieve pain and prevent progression of ectopic ossification. However, it is still controversial whether non-steroidal anti-inflammatory drugs have an adverse effect on tendon self-healing and self-stabilization. Studies have shown that in vitro experiments, non-steroidal anti-inflammatory drugs inhibit proliferation and migration of tenocytes, and in animal experiments, non-steroidal anti-inflammatory drugs damage tendon biomechanics. Furthermore, non-steroidal anti-inflammatory drugs have certain side effects, such as causing gastrointestinal damage and symptoms of the nervous system, urinary system, cardiovascular system. Therefore, developing a drug for preventing tendon ectopic ossification and improving tendon biomechanical strength after tendon injury is a scientific problem to be solved currently.
Elamipretide (also known as SS-31, MTP-131 and Bendavia) is a mitochondrial targeting polypeptide consisting of four amino acids with the sequence D-Arg-dimethylTyr-Lys-Phe-NH2. The drug readily penetrates the cell membrane and targets the inner mitochondrial membrane, and by binding to the labeled phospholipid of the inner mitochondrial membrane, cardiolipin, plays a role in many biological processes within mitochondria, including respiration and energy conversion. This peptide-cardiolipin binding has been shown to repair mitochondrial inner membrane deletions, normalize mitochondrial membrane structure, and thereby improve mitochondrial function. The compound shows good effects in a series of indications such as primary mitochondrial myopathy, heart failure, dry age-related macular degeneration, papanicolaou syndrome, huntington's chorea, acute kidney injury, heterochromatic iridocyclitis, leber hereditary optic neuropathy and the like, and a plurality of indications have been approved by the United states Food and Drug Administration (FDA) to enter clinical trials. On month 5 and 12 of 2022, biotechnology company Stealth Biotherapeutics announced that the FDA has been assigned the name of Elamipretide orphan for the treatment of Dunaliella Muscular Dystrophy (DMD). The chemical structural formula of the Elamipretide used in the invention is shown as follows:
the main indications reported for elamipentide today are: 1) Primary mitochondrial myopathy; 2) Heart failure; 3) Dry age-related macular degeneration; 4) Barbituric syndrome; 5) Huntington's chorea; 6) Acute kidney injury; 7) Heterochromatic iridocyclitis; 8) Leber hereditary optic neuropathy; 9) Duchenne muscular dystrophy. To date, there is no report on the prevention of tendon ectopic ossification and improvement of tendon biomechanical strength after tendon injury by elamipentide, and it cannot be inferred whether it has the effect of preventing tendon ectopic ossification and improving tendon biomechanical strength after tendon injury by the known properties of elamipentide.
Disclosure of Invention
The object of the first aspect of the present invention is to provide the use of elamipentide or a derivative thereof in the manufacture of a medicament for the prevention and/or treatment of sports injuries.
The object of the second aspect of the present invention is to provide the use of elamipentide or a derivative thereof in the manufacture of a medicament for inhibiting ectopic ossification following tissue damage.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
in a first aspect of the invention there is provided the use of elamipentide or a derivative thereof in the manufacture of a medicament for the prevention and/or treatment of sports injury.
The Elamipretide used has been FDA granted orphan drug designation, and research shows that there are no obvious toxic side effects.
In some embodiments of the invention, the athletic injury comprises at least one of acute injury, chronic injury.
In some embodiments of the invention, the athletic injury comprises at least one of tendon injury, ligament injury.
In some embodiments of the invention, the ligament injury comprises at least one of an elbow periarticular ligament injury, a knee periarticular ligament injury, and a cruciate ligament injury.
In some preferred embodiments of the invention, the motor injury is a tendon injury.
In some more preferred embodiments of the present invention, the tendon injury comprises at least one of rotator cuff injury, biceps long-head tendon injury, triceps brachii tendon injury, adductor femoral tendon injury, iliotibial band injury, quadriceps femoris tendon injury, patellar tendon rupture, patellar tendon end disease, achilles tendon injury; further achilles tendon injury.
In some embodiments of the invention, the derivatives include pharmaceutically acceptable salts, hydrates, solvates, polymorphs, tautomers and prodrugs.
In some embodiments of the invention, the pharmaceutically acceptable salt comprises at least one of hydrochloride, hydrobromide, acetate, citrate, benzoate, succinate, suberate, fumarate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, tartrate, maleate, or trifluoroacetate.
In some embodiments of the invention, the medicament achieves the goal of treating and/or preventing sports injury by reducing ectopic ossification of the damaged tissue.
In some embodiments of the invention, the medicament further comprises one or more pharmaceutically acceptable excipients.
In some embodiments of the invention, the pharmaceutically acceptable excipients comprise at least one of a slow release agent, an excipient, a filler, a binder, a wetting agent, a disintegrant, an absorption enhancer, a surfactant, and a lubricant.
In some embodiments of the invention, the dosage form of the medicament comprises at least one of a solid formulation, a liquid formulation, and a semi-solid formulation.
In some embodiments of the invention, the medicament comprises at least one of a tablet, capsule, granule, pill, drop pill, liquid formulation, decoction, suspension, dispersion, syrup, suppository, gel, aerosol, patch.
In some embodiments of the invention, the Elamipretide is administered at a dose of 2 to 6mg/kg of subject.
In a second aspect, the invention provides the use of elamipentide or a derivative thereof in the manufacture of a medicament for inhibiting ectopic ossification formation following tissue damage.
In some embodiments of the invention, the tissue comprises at least one of a tendon, a ligament; further tendons.
In some embodiments of the invention, the tendon comprises at least one of Achilles tendon, rotator cuff, supraspinatus; further the achilles tendon.
In some embodiments of the invention, the ligament comprises at least one of an perielbow ligament, an periknee ligament, and a cruciate ligament.
In some embodiments of the invention, the derivatives include pharmaceutically acceptable salts, hydrates, polymorphs of solvates, tautomers and prodrugs.
In some embodiments of the invention, the pharmaceutically acceptable salt comprises at least one of hydrochloride, hydrobromide, acetate, citrate, benzoate, succinate, suberate, fumarate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, tartrate, maleate, or trifluoroacetate.
In some embodiments of the invention, the medicament further comprises one or more pharmaceutically acceptable excipients.
In some embodiments of the invention, the pharmaceutically acceptable excipients comprise at least one of a slow release agent, an excipient, a filler, a binder, a wetting agent, a disintegrant, an absorption enhancer, a surfactant, and a lubricant.
In some embodiments of the invention, the dosage form of the medicament comprises at least one of a solid formulation, a liquid formulation, a semi-solid formulation.
In some embodiments of the invention, the medicament comprises at least one of a tablet, capsule, granule, pill, drop pill, liquid formulation, decoction, suspension, dispersion, syrup, suppository, gel, aerosol, patch.
In some embodiments of the invention, the Elamipretide is administered at a dose of 2 to 6mg/kg of subject.
The beneficial effects of the invention are as follows:
the invention discloses an application of Elamipretide or a derivative thereof in preventing and/or treating sports injury for the first time, and experiments show that the Elamipretide can obviously reduce ectopic ossification of injured tissues without adverse effect on biomechanical strength of the tissues, and can achieve the purpose of treating sports injury by reducing ectopic ossification of injured tissues, can be used for preparing medicines for preventing and/or treating sports injury, and is convenient for clinical and daily tendon injury health care.
Drawings
FIG. 1 shows the effect of Elamipretide on biomechanical parameters after fracture injury to the achilles tendon of mice; wherein A is an influence graph of Elamipretide on the elastic modulus of the mice after the achilles tendon is broken and damaged, B is an influence graph of Elamipretide on the cross-sectional area of the mice after the achilles tendon is broken and damaged, and C is an influence graph of Elamipretide on the maximum tensile force of the mice after the achilles tendon is broken and damaged; d is a graph of the effect of elamipentide on the maximum stress after fracture injury of the achilles tendon in mice, where ns represents no statistical difference.
FIG. 2 is a graph showing the effect of Elamipretide on ectopic ossified volume following a broken injury to the achilles tendon in mice; wherein A is a CT scanning 3D reconstruction graph of the effect of Elamipretide on the ectopic ossification of the tendon after the fracture and injury of the achilles tendon of the mouse, and B is a graph of the statistical result of the effect of Elamipretide on the ectopic ossification of the tendon after the fracture and injury of the achilles tendon of the mouse, wherein P is less than 0.05.
Detailed Description
The present invention will be described in further detail with reference to specific examples.
It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention.
The materials, reagents and the like used in this example are commercially available materials and reagents unless otherwise specified.
Example 1 Effect of Elamipretide on biomechanical Properties after repair of broken injury to the Achilles tendon in mice
20 female C57BL/6 mice (provided by experimental animal centers of southern medical university, fed into SPF-class animal houses of southern hospital of southern medical university, squirrel cages and used utensils are strictly sterilized, fed and drunk with purified water, and whether other clinical symptoms exist or not is observed before experiments) are randomly divided into two groups, tendon rupture injury is simulated by adopting an achilles tendon rupture model, and the construction method of the achilles tendon rupture model is specifically as follows: after the mice are successfully anesthetized by preoperative injection of tribromoethanol, the mice are supine on an operating table, and the skin at the heel of the right is dehaired and conventionally disinfected; a longitudinal incision of about 1 cm was made aseptically in the skin at the right heel, exposing the myomembrane and achilles tendon; the skin was sutured with the plantar tendon and the achilles tendon transected at the midsection of the achilles tendon.
The administration was started the next day after molding (control: 50. Mu.L of PBS per mouse; experimental: 50. Mu.L of Elamipretide (available from GLPBIO Co., cat. Number: GC 30014) per mouse), and Elamipretide was diluted with a sterile PBS solution before injection and administered at a dose of 2.5mg/kg depending on the body weight of the mouse), and intraperitoneal injection was carried out for a total of 4 weeks every week for 5 consecutive days. The achilles tendon of the mouse is taken 4 weeks after molding for biomechanical tensile test, and the specific method is as follows: mice were euthanized, right lower limbs of the mice were removed, rinsed with PBS, and then washed with a 3D laser scanner (HandySCAN 3D TM ) The Cross-sectional area (Cross area) of the achilles tendon was measured and the achilles tendon was subjected to a tensile test using a universal material tester (INSTRON) to calculate the Modulus of elasticity (module), the maximum Stress (Max Stress), and the maximum tension (Max Force).
The biomechanical property is the most important index for evaluating tendon injury repair effect, in this example, the mouse Achilles tendon is detected by injecting elamipride into the abdominal cavity of the mouse with fracture injury of Achilles tendon, and the results show in fig. 1 that the elastic modulus, cross-sectional area, maximum stress, maximum tensile force of the Achilles tendon of the mice in the experimental group have no statistical difference with the cross-sectional area, maximum stress and maximum tensile force of the Achilles tendon of the mice in the control group, which indicates that elamipride does not adversely affect the biomechanical property of the Achilles tendon after fracture injury repair of the mice.
Example 2 Effect of Elamipretide on ectopic ossification of tendons in mice following Achilles tendon rupture injury
16 female C57BL/6 with 7 weeks of age are randomly divided into two groups, 8 mice in each group, tendon rupture injury is simulated by adopting an achilles tendon rupture model, and the construction method of the achilles tendon rupture model is specifically as follows: after the mice are successfully anesthetized by preoperative injection of tribromoethanol, the mice are supine on an operating table, and the skin at the heel of the right is dehaired and conventionally disinfected; a longitudinal incision of about 1 cm was made aseptically in the skin at the right heel, exposing the myomembrane and achilles tendon; the skin was sutured with the plantar tendon and the achilles tendon transected at the midsection of the achilles tendon.
The administration was started the next day after molding (control: 50. Mu.L of PBS per mouse; experimental: 50. Mu.L of Elamipretide per mouse, diluted with sterile PBS solution before injection, administered at a dose of 2.5mg/kg according to the body weight of the mouse) and was given by intraperitoneal injection for a total of 6 weeks every week for 5 days. The achilles tendon of the mouse was taken 10 weeks after molding for micro-CT detection and analysis. The specific detection steps of the micro-CT detection of the achilles tendon of the mouse are as follows: mice were euthanized, right lower limbs of the mice were rinsed with PBS and fixed with 4% paraformaldehyde for 24 hours before storage in PBS tubes. The right lower limb is placed and fixed in parallel in a detection cabin of a living X-ray Micro-CT (Skyscan 1276) of a small animal, and after the scanning is finished, the size of the ectopic ossification is analyzed by using CTan software.
In this example, micro-CT test was performed on the achilles tendon of the mice, and the result is shown in fig. 2, and compared with the control group, the ectopic ossification volume formed after tendon injury of the mice in the experimental group is significantly reduced (P < 0.05), that is, elamipentide can significantly reduce the ectopic ossification volume after tendon injury, which indicates that elamipentide can inhibit the formation of ectopic ossification of tendon after tendon rupture injury.
The embodiments of the present invention have been described in detail with reference to the accompanying drawings, but the present invention is not limited to the above embodiments, and various changes can be made within the knowledge of one of ordinary skill in the art without departing from the spirit of the present invention. Furthermore, embodiments of the invention and features of the embodiments may be combined with each other without conflict.
Claims (10)
- Use of elamipentide or derivatives thereof for the preparation of a medicament for the prevention and/or treatment of sports injuries.
- 2. The use of claim 1, wherein the athletic injury comprises at least one of acute injury, chronic injury.
- 3. The use of claim 2, wherein the sports injury comprises at least one of tendon injury, ligament injury.
- 4. The use according to claim 3, wherein the tendon injury is at least one of rotator cuff injury, biceps longus tendon injury, triceps brachii tendon injury, adductor femoral tendon injury, iliotibial band injury, quadriceps femoral tendon injury, patellar tendon rupture, patellar tendon end disease, achilles tendon injury.
- 5. The use according to any one of claims 1 to 4, wherein the derivatives comprise pharmaceutically acceptable salts, hydrates, solvates, polymorphs, tautomers and prodrugs.
- Use of elamipentide or a derivative thereof in the manufacture of a medicament for inhibiting ectopic ossification following tissue damage.
- 7. The use of claim 6, wherein the tissue comprises at least one of a tendon, a ligament.
- 8. The use of claim 7, wherein the tendon comprises at least one of an achilles tendon, a rotator cuff, and an supraspinatus muscle.
- 9. The use according to any one of claims 6 to 8, wherein the derivatives comprise pharmaceutically acceptable salts, hydrates, solvate polymorphs, tautomers and prodrugs.
- 10. The use according to claim 9, wherein the pharmaceutically acceptable salt comprises at least one of hydrochloride, hydrobromide, acetate, citrate, benzoate, succinate, suberate, fumarate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, tartrate, maleate or trifluoroacetate.
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