Application of type 5 phosphodiesterase inhibitor in preparation of medicine for treating chronic spinal cord injury

Abstract

The invention discloses application of a type 5 phosphodiesterase inhibitor in preparation of a medicine for treating chronic spinal cord injury, the type 5 phosphodiesterase inhibitor shows an excellent treatment effect in treatment of the chronic spinal cord injury, the improvement rate of the spinal cord motor function score of a patient reaches 81.25%, and the improvement rate of the spinal cord sensory function score reaches 62.5%.

Description

Technical Field

[0001] The invention discloses a new medical application of a type 5 phosphodiesterase inhibitor and belongs to the technical field of pharmaceutical preparations. Background Art

[0002] Spinal cord injury (SCI) is one of the main disabilities treated in the clinical rehabilitation setting. It is multifactorial because patients suffer from motor and sensory impairments and many other complications throughout their lives. In recent years, many clinical trials have been conducted around the recovery of the damaged spinal cord. However, only a few drug treatments are used in clinical practice, and their effects on nerve regeneration and recovery of spinal cord function are still very limited. Many drugs have been intensively investigated in large multicenter prospective randomized controlled trials, including methylprednisolone sodium succinate (MPSS) and subsequent trials. Although MPSS and immunoglobulin G (IgG), chondroitinase ABC (CHABC) and others have good preclinical animal data, the main results of these clinical trials are mostly negative. There is still a lack of drugs with excellent therapeutic effects in the clinical treatment of spinal cord injury in this field.

[0003] Sildenafil is a selective phosphodiesterase-5 (PDE-5) inhibitor. In March and September of 1998, FDA and EMEA respectively approved the marketing of sildenafil citrate under the trade name of Viagra for the treatment of erectile dysfunction (ED). Currently, the selective phosphodiesterase-5 inhibitors on the market also include tadalafil, avanafil, and vardenafil. The purpose of the present invention is to provide a new use of a selective phosphodiesterase-5 inhibitor in the preparation of drugs for the treatment of chronic spinal cord injury. Summary of the invention

[0004] Based on the above objectives, the present invention first provides the use of a type 5 phosphodiesterase inhibitor, an active fragment thereof or a derivative thereof in the preparation of a drug for treating chronic spinal cord injury.

[0005] The phosphodiesterase type 5 inhibitor of the present invention refers to a class of drugs that can inhibit the activity of phosphodiesterase. The active fragment of the phosphodiesterase type 5 inhibitor refers to a chemical structure that can still maintain or substantially maintain the activity of the phosphodiesterase type 5 inhibitor after losing some chemical groups, and the derivative of the phosphodiesterase type 5 inhibitor refers to a compound that can still maintain the activity of the phosphodiesterase type 5 inhibitor after addition, substitution, or modification, such as a compound in the form of a drug salt or drug ester of the phosphodiesterase type 5 inhibitor.

[0006] In a preferred embodiment, the type 5 phosphodiesterase inhibitor includes sildenafil, tadalafil, avanafil, and vardenafil. The chemical name of sildenafil is: 1-{4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1 hydrogen-pyrazolo[4,3d]pyrimidin-5-yl)benzenesulfonyl}-4-methylpiperazine citrate, molecular formula: C 22 H 30 N6O4S·C6H8O7, structural formula see formula I: (I).

[0007] The chemical name of tadalafil is 6-(1, 3-benzodioxolan-5-yl)-2, 3, 6, 7, 12, 12a-hexahydro-2-methyl, (6R, 12aR)-pyrazino[1'2':1, 6]pyrido[3, 4-b]indole-1, 4-dione, molecular formula: C 22 H 19 N3O4, structural formula see formula II: (II).

[0008] The chemical name of Avanafil is 4-([3-chloro-4-methoxybenzyl)amino]-2-([2S)-2(-hydroxymethyl)pyrrolidin-1-yl]-N(-pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, and its molecular formula is C 23 H 26 CIN7O3, structural formula see formula III: (III).

[0009] The chemical name of Vardenafil is 2-[2-ethoxy-5-(4-ethyl-piperazine-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazole [5,1-f]-[1,2,4] triazine-4-one monohydrochloride trihydrate, with a molecular formula of C 23 H 32 N6O4S·HCl·3H2O, the structural formula is shown in Formula IV: (IV).

[0010] The above drugs are all PDE5 inhibitors, which are mainly used in clinical practice to treat male erectile dysfunction.

[0011] In another preferred embodiment, the drug for treating chronic spinal cord injury refers to a drug that improves the symptoms of pain, spasticity, numbness, urinary dysfunction, bowel dysfunction, and / or motor dysfunction caused by chronic spinal cord injury.

[0012] In a more preferred embodiment, the chronic spinal cord injury treatment drug refers to a drug for improving the spinal cord motor function score of patients with chronic spinal cord injury. The spinal cord motor function score refers to the evaluation of gait, urination and defecation functions.

[0013] In a specific embodiment of the present invention, the spinal motor function score is an mALS score, in which the gait score includes 0. Normal gait and normal lower limb strength 1. Weak lower limb strength, but walking is not limited, 2. Limited exercise tolerance, 3. Need a cane or a support when walking, 4. Need two crutches when walking, 5. Cannot stand, bedridden or need a wheelchair. The urination function score includes: 0. Normal, 1. Urgent, frequent, delayed urination, 2. Occasional incontinence or retention, 3. Persistent incontinence or retention. The bowel function score includes: 0. Normal, 1. Mild constipation, good response to laxatives, 2. Occasional incontinence or persistent severe constipation, 3. Persistent incontinence.

[0014] In another preferred embodiment, the chronic spinal cord injury treatment drug refers to a drug that improves the spinal cord sensory function score of patients with chronic spinal cord injury. The spinal cord sensory function score refers to the evaluation of numbness and pain.

[0015] In a specific embodiment of the present invention, the spinal cord sensory function score is an mDS score. In the mDS score, the numbness score includes 1. No numbness, 2. Occasional mild numbness, 3. Moderate numbness, no obvious impact on work and life, 4. Severe numbness, continuous occurrence, serious impact on life. The pain score includes: 1. No pain, 2. Occasional mild pain, no need for drug treatment, 3. Moderate pain, occasional drug treatment, no impact on life, 4. Moderate to severe pain, frequent drug treatment, impact on life, 5. Unbearable continuous or severe pain, drug treatment is required.

[0016] In a preferred embodiment, the chronic spinal cord injury includes: spinal vascular malformation, dural arteriovenous fistula, spinal cavernous malformation, anterior spinal artery syndrome, spinal cord infarction, spinal venous hypertensive injury, spinal cord hemorrhage, spinal cord ischemia, anterior cord syndrome, posterior cord syndrome, central canal perivascular syndrome, hemisection syndrome, complete spinal cord injury, conus medullaris injury, cauda equina injury, intervertebral disc injury, central gray and white matter injury of the spinal cord, traumatic spinal cord injury, postoperative spinal cord space-occupying lesions, and cervical spondylotic myelopathy.

[0017] In a preferred embodiment, the phosphodiesterase type 5 inhibitor is prepared as an injection, a lyophilized agent, an aerosol, an oral agent, a suppository or an external preparation.

[0018] In a more preferred embodiment, the phosphodiesterase type 5 inhibitor is oral sildenafil.

[0019] The present invention provides the use of a type 5 phosphodiesterase inhibitor in the preparation of a drug for treating chronic spinal cord injury. The type 5 phosphodiesterase inhibitor shows excellent therapeutic effect in the treatment of chronic spinal cord injury, with the improvement rate of the patient's spinal cord motor function score reaching 81.25%, and the improvement rate of the spinal cord sensory function score reaching 62.5%. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 .Comparison of mALS improvement effects between the treatment group and the control group during treatment; Figure 2 . Comparison of mDS improvement effects between the treatment group and the control group during treatment. DETAILED DESCRIPTION

[0021] The present invention will be further described below in conjunction with specific embodiments, and the advantages and features of the present invention will become clearer as the description proceeds. However, these embodiments are merely exemplary and do not constitute any limitation on the scope of protection defined by the claims of the present invention.

[0022] Example 1. Clinical evaluation of sildenafil for chronic spinal cord injury 1. Clinical scoring criteria for chronic spinal cord injury (1) The modified Aminoff & Logue score (mALS) is the most widely used spinal cord function score in clinical practice. It mainly evaluates gait, urination, and defecation.

[0023] .

[0024] (2) Modified Denis score (mDS): includes numbness and pain.

[0025] .

[0026] 2. Clinical grouping and treatment plan 16 patients with spinal cord injury caused by different reasons were recruited. Their current diseases have been cured by surgery (1 patient with traumatic spinal cord injury was treated conservatively and did not need surgery), and their spinal cord function has recovered to a stable level (spinal cord function score has not changed in the past 3 months). Patients with contraindications in the drug instructions were excluded. Sildenafil 50 mg / day was taken orally for more than 2 weeks (Pfizer Pharmaceuticals Co., Ltd., 50 mg / tablet). The control group was a patient cohort with the same baseline (sex, age) matched by the Department of Neurosurgery of Xuanwu Hospital, Capital Medical University according to the experimental group. Sildenafil was not treated, and the spinal cord function was evaluated again after 3 months.

[0027] 3. Clinical treatment results A total of 16 patients took sildenafil 50 mg qd for more than 2 weeks, and 13 patients (81.25%) had improved spinal cord motor function scores (mALS, including gait, bowel and bladder function evaluation), with a statistically significant difference compared with the control group. Ten patients had improved spinal cord sensory function scores (mDS, including numbness and pain) (see Figure 1 and Figure 2 Compared with patients who did not take the drug, patients who took sildenafil orally had more improvements in motor and sensory function), and the difference was statistically significant compared with the control group. All 4 patients (100%) with spasticity improved compared with before.

[0028] Table 1. Statistics of symptom improvement in 16 patients who took sildenafil 50 mg qd for more than 2 weeks

[0029] Note: G: gait, U: urination, F: defecation.

[0030] Among the 16 patients, 13 (81.2%) patients showed improvement in mALS (spinal cord motor function), including 6 patients with improved gait, 9 patients with improved urination function, and 5 patients with improved defecation function; 10 patients (62.5%) patients showed improvement in mDS (spinal cord sensory function), including 7 patients with relief of numbness and 4 patients with relief of pain.

[0031] Table 2. Continuation of Table 1: Statistics of mALS and mDS scores of 16 patients who took sildenafil 50 mg qd for more than 2 weeks .

[0032] Table 3. Baseline conditions of the control group and follow-up spinal cord function evaluation after 3 months

[0033] In the control group, only 3 patients showed spontaneous improvement in motor function, while 0 patients showed improvement in sensory function, and 2 patients showed worsening of numbness, which was significantly different from the improvement in the treatment group.

[0034] Table.4 Statistical table of spinal cord function mALS and mDS scores of 16 patients in the control group followed up 3 months later in Table 3

[0035] 2. Adverse reactions * Patient 3 showed improvement in urination in the second week of oral administration. He stopped taking the drug in the fifth week due to lower limb edema. He stopped taking the drug for 4 consecutive weeks, and his urination function was still maintained. There was no regression to the state before medication after stopping the drug. Except for the above-mentioned irreversible adverse reactions in patient 3 (6.25%), the other adverse reactions were transient (completely relieved by oral medication within 4 hours), including 4 cases of headache or dizziness, 2 cases of facial flushing, and 1 case of perineum burning sensation. A total of 5 patients had the above complications, and the incidence of mild adverse reactions was 31.3%.

Claims

1. Use of type 5 phosphodiesterase inhibitors, their active fragments or derivatives in the preparation of drugs for the treatment of chronic spinal cord injury.

2. The use according to claim 1, characterized in that: The phosphodiesterase type 5 inhibitors include sildenafil, tadalafil, avanafil, and vardenafil.

3. The use according to claim 1, characterized in that: The chronic spinal cord injury therapeutic drug refers to a drug that improves the symptoms of pain, spasm, numbness, urinary dysfunction, bowel dysfunction, and / or motor dysfunction caused by chronic spinal cord injury.

4. The use according to claim 3, characterized in that: The chronic spinal cord injury treatment drug refers to a drug that improves the spinal cord motor function score of patients with chronic spinal cord injury.

5. The use according to claim 4, characterized in that: The spinal cord motor function score is the mALS score.

6. The use according to claim 3, characterized in that: The chronic spinal cord injury therapeutic drug refers to a drug that improves the spinal cord sensory function score of patients with chronic spinal cord injury.

7. The use according to claim 6, characterized in that: The spinal cord sensory function score is the mDS score.

8. The use according to claim 1, characterized in that: The chronic spinal cord injury includes: spinal vascular malformation, dural arteriovenous fistula, spinal cavernous malformation, anterior spinal artery syndrome, spinal cord infarction, spinal venous hypertensive injury, spinal cord hemorrhage, spinal cord ischemia, anterior cord syndrome, posterior cord syndrome, central canal perisyndrome, hemisection syndrome, complete spinal cord injury, conus medullaris injury, cauda equina injury, intervertebral disc injury, central gray and white matter injury of the spinal cord, traumatic spinal cord injury, postoperative spinal cord space-occupying lesions, and cervical spondylotic myelopathy.

9. The use according to claim 1, characterized in that: The type 5 phosphodiesterase inhibitor is prepared as an injection, a lyophilized agent, an atomizer, an oral agent, a suppository or an external preparation.

10. The use according to claim 9, characterized in that The phosphodiesterase type 5 inhibitor is an oral sildenafil.

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