Application of pirfenidone in preparation of medicine for treating neurogenic bladder

Abstract

The invention discloses application of pirfenidone in preparation of a medicine for treating neurogenic bladder, and belongs to the technical field of biological medicine. The invention discloses an application of pirfenidone in preparation of a medicine for treating neurogenic bladder, and experiments prove that PFD treatment can effectively reduce the bladder weight and volume of the neurogenic bladder caused by sacromyeloid injury, improve urokinetics, reduce collagen and reduce inflammation-related factors.

Description

Technical Field

[0001] The present invention relates to the field of biological medicine technology, and particularly to the application of pirfenidone in the preparation of a drug for treating neurogenic bladder. Background Art

[0002] Neurogenic bladder (NB), also known as neurogenic lower urinary tract dysfunction, is a disorder of urination and / or urine storage caused by lesions in the central or peripheral nervous system that innervate the bladder and urethra. Spinal cord injury (SCI) is a common cause of NB clinically, and clinical treatment is difficult, which is a worldwide medical problem. The incidence of SCI in China is 6 / 100,000, and SCI is generally caused by trauma. The incidence of NB in SCI patients is 70% - 84%. Different parts and types of SCI cause different clinical symptoms, and the clinical symptoms vary depending on the spinal cord segment affected by the spinal cord injury (SCI). Severe sacral spinal cord injury (SSCI), such as spina bifida, tethered cord syndrome, presacral meninges, and sacral canal cysts, will disrupt the micturition reflex arc, resulting in the loss of detrusor reflex, decreased detrusor contractility, and symptoms such as urinary retention and dysuria. Prolonged bladder distension will compress blood vessels, reduce blood flow, and cause hypoxia. These clinical manifestations are bladder micturition dysfunction, urinary retention, and recurrent urinary tract infections, which seriously affect the quality of life, and end-stage patients mostly die of complications caused by renal failure. Unfortunately, there is still no radical cure for neurogenic bladder at present, and clean intermittent self-catheterization is still the gold standard for reducing upper urinary tract residue and incomplete micturition. However, intermittent catheterization 4 - 6 times a day will seriously affect the quality of life of patients and may cause serious complications, such as complicated urinary tract infections. Moreover, the current drug treatment has limited effects. The treatment principle of NB is to improve the micturition function of patients, prevent upper urinary tract injury, and improve the quality of life of patients. However, the bladder fibrosis lesion caused by long-term NB is an important factor affecting the efficacy of various treatment methods. Therefore, it is necessary to study how to prevent and delay the bladder fibrosis caused by NB.

[0003] NB is a worldwide problem, and there is still no radical cure. Some studies have shown that nerve anastomosis technology can reconstruct the NB nerve reflex, improve the micturition function of NB rats, and reduce bladder fibrosis in rats. However, the clinical application of this technology is still controversial. Stem cell transplantation technology, gene therapy, etc. have also been used in the experiments of NB animals. However, bladder fibrosis caused by spinal cord injury is still an important factor affecting the efficacy of various treatment methods. Therefore, finding drugs to control the bladder fibrosis caused by neurogenic bladder caused by spinal cord injury will improve the quality of life of the vast number of patients and provide good social benefits.

[0004] Pirfenidone (PFD) has the effects of anti-tissue fibrosis, anti-inflammation and anti-oxidative stress. It was launched in 2008 and is clinically used in patients with mild to moderate idiopathic pulmonary fibrosis. It can delay the deterioration of the disease, moderately increase the survival time of patients, and reduce the mortality of this disease. In addition, it also has the effect of inhibiting fibrosis of the heart, liver, lung, kidney and skin. The current main administration method of pirfenidone is oral administration. The drug is rapidly absorbed by the gastrointestinal tract after oral administration and excreted from the urine 6 hours after ingestion. It is a relatively safe clinical drug. At present, there is no report on the use of pirfenidone for the treatment of neurogenic bladder. Summary of the Invention

[0005] The object of the present invention is to provide the application of pirfenidone in the preparation of a drug for treating neurogenic bladder to solve the problems existing in the above-mentioned prior art. Pirfenidone can play a role in neurogenic bladder caused by spinal cord injury, can restore bladder function and can prevent and treat bladder fibrosis caused by NB, which will be of great significance for the treatment of this disease.

[0006] To achieve the above object, the present invention provides the following solutions:

[0007] One of the technical solutions of the present invention is the application of pirfenidone in the preparation of a drug for treating neurogenic bladder.

[0008] Another technical solution of the present invention is a drug for treating neurogenic bladder, which comprises pirfenidone.

[0009] Based on the above technical solutions, the present invention has the following technical effects:

[0010] The present invention discloses the application of pirfenidone in the preparation of a drug for treating neurogenic bladder, and through experiments, it is confirmed that PFD treatment can effectively reduce the bladder weight and volume of neurogenic bladder caused by sacral spinal cord injury, improve urodynamics, reduce collagen, and reduce inflammation-related factors. Brief Description of the Drawings

[0011] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required to be used in the embodiments. Obviously, the following drawings are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0012] Figure 1 It is a schematic diagram of PFD treatment.

[0013] Figure 2Comparison of bladder appearance and weight after 4 weeks of PFD treatment. Among them, A is the comparison of bladder appearance; B is the statistical chart of bladder width; C is the statistical chart of bladder length; D is the comparison chart of bladder weight / body weight.

[0014] Figure 3 Urodynamic comparison after 4 weeks of PFD treatment. Among them, A is the urodynamic images of each group, B is the change and quantification of the maximum cystometric capacity in each group, C is the change and quantification of the leak point pressure in each group, and D is the change and quantification of bladder compliance in each group.

[0015] Figure 4 Comparison of collagen and inflammation indexes in rat bladder after 4 weeks of PFD treatment. Among them, A is the HE and Masson staining diagrams of the bladder, B is the statistical chart of bladder collagen, C is the statistical chart of inflammation and collagen by qPCR, D is the protein expression level of WB, and E is the protein statistical chart of WB. Detailed implementation manners

[0016] The various exemplary implementation manners of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, characteristics, and implementation manners of the present invention.

[0017] It should be understood that the terms described in the present invention are only for describing specific implementation manners and are not used to limit the present invention. Additionally, for the numerical ranges in the present invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Each intermediate value within any stated value or stated range, as well as each smaller range between any other stated value or intermediate value within the stated range, is also included in the present invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0018] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention pertains. Although the present invention only describes preferred methods and materials, any methods and materials similar or equivalent to those described herein can also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials related to the documents. In case of conflict with any incorporated document, the content of this specification shall prevail.

[0019] Without departing from the scope or spirit of the present invention, various improvements and changes can be made to the specific implementation manners of the present invention specification, which are obvious to those skilled in the art. Other implementation manners obtained from the specification of the present invention are obvious to those skilled in the art. The specification and examples of this application are only exemplary.

[0020] As used herein, terms such as "comprising", "including", "having", "containing", etc. are all open-ended terms, meaning including but not limited to.

[0021] The technical solutions described in the present invention are all conventional solutions in the art unless otherwise specified. The reagents or raw materials used are all purchased from commercial channels or are publicly available unless otherwise specified.

[0022] The embodiments of the present invention provide the use of pirfenidone in the preparation of a drug for treating neurogenic bladder.

[0023] In some specific embodiments, the neurogenic bladder includes the neurogenic bladder caused by sacral spinal cord injury.

[0024] The embodiments of the present invention also provide a drug for treating neurogenic bladder, comprising pirfenidone.

[0025] In some specific embodiments, it further comprises a pharmaceutically acceptable excipient.

[0026] In some specific embodiments, the dosage form of the drug is a solid dosage form, a liquid dosage form, a paste dosage form or an emulsion dosage form.

[0027] Example 1

[0028] 16 - 8-week-old female SD rats were divided into three groups for experiments, namely the NC group, the neurogenic bladder group with sacral spinal cord injury (NB) group, and the PFD treatment group (PFD) after modeling, with 16 rats in each group.

[0029] In the NB group, a rat model of neurogenic bladder caused by sacral spinal cord injury was prepared. The modeling method was: using the method of cutting and destroying to cause damage to make the spinal cord lose its anatomical continuity; if there was rapid local congestion and edema after the injury, and the hind limbs twitched and the tail swung, the modeling was successful. According to the standard, from the second day after the operation to the spinal shock period, the rats should completely lose the motor function of the hind limbs, showing a dragging state of the hind limbs when walking with the forelimbs. Specifically, the same experimenter used the Basso Beattie Bresnahan (BBB) scoring system for evaluation: the rats were placed in an observation cage, and the cage wall was gently tapped to prompt them to move, and the movement coordination of their trunk and hip, knee, ankle, and foot joints was systematically observed. The scoring range was 0 - 21 points, with 0 points representing no movement of the hind limbs, and the higher the score, the closer the motor function was to normal. In this example, the BBB score of the rats after the operation must be 0 points, otherwise they will be excluded. After the operation, the establishment of the neurogenic bladder model was confirmed by urodynamics, immunohistochemical staining, gait analysis, magnetic resonance, etc.

[0030] The PFD group received oral gavage treatment with PFD after the model was prepared, and the dose was pirfenidone 250 mg * kg -1 *d -1 .

[0031] The NC group only opened the skin and did not perform spinal cord injury treatment.

[0032] Four weeks after the operation, 15 rats were sacrificed from each group to evaluate bladder function and fibrosis. The functional changes of the rats after the operation were evaluated by urodynamic examination. For the bladder tissue, the expression changes of related genes such as COL1A1 / COL1A3 / TNF-a / IL-1β were detected by pathological staining, immunohistochemistry, q-RT-PCR, WB, etc. to judge the fibrosis and inflammation of the model.

[0033] 2 Experimental results

[0034] 2.1 Changes in bladder shape of the three groups of rats after treatment

[0035] Four weeks after treatment, it was found that in terms of bladder appearance, the bladder of the rats treated with pirfenidone for four weeks was smaller than that of the NB group, and the weight was also smaller ( Figure 2 ).

[0036] 2.2 Comparison of urodynamics of the three groups of rats after treatment

[0037] In the urodynamic examination, the rats in the NB group had the lowest leak point pressure, the largest bladder capacity, and the greatest compliance among the three groups. The rats treated with PFD had a higher leak point pressure, a smaller bladder capacity, a lower compliance, and the urodynamic curve shape was closer to that of the NC group than that of the rats in the NB group ( Figure 3 ).

[0038] 2.3 Comparison of collagen and inflammation of the three groups of rats after treatment

[0039] The results of tissue staining showed that the bladder walls of the NB group and the PFD group were thicker than those of the sham operation group; the results of Masson staining showed that the collagen volume fractions of the NB group and the PFD group were significantly higher than those of the sham operation group, but the PFD group had less collagen than the NB group. qPCR and WB detections found that the collagen in the rats treated with PFD was reduced and the inflammation-related factors were lower ( Figure 4 ).

[0040] Obviously, the above embodiments of the present invention are merely examples for clearly explaining the present invention, rather than limiting the implementation manners of the present invention. For those of ordinary skill in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to enumerate all the implementation manners here. Any modifications, equivalent replacements, and improvements made within the spirit and principle of the present invention shall be included in the protection scope of the claims of the present invention.

Claims

1. Use of pirfenidone in the preparation of a drug for treating neurogenic bladder.

2. The application according to claim 1, wherein The neurogenic bladder includes a neurogenic bladder caused by sacral spinal cord injury.

3. A drug for treating neurogenic bladder, characterized in that, It includes pirfenidone.

4. The medicament according to claim 3, characterized in that, It also includes pharmaceutically acceptable excipients.

5. The medicament according to claim 3, characterized in that, The dosage form of the drug is a solid dosage form, a liquid dosage form, an ointment dosage form or an emulsion dosage form.

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