CN101785770A - Application of methazolamide in preparing medicament for treating ankylosing spondylitis - Google Patents
Application of methazolamide in preparing medicament for treating ankylosing spondylitis Download PDFInfo
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Abstract
The invention discloses a new application of methazolamide, in particular to application in preparing a medicament for treating ankylosing spondylitis. In a concrete application method, a patient orally administrates two methazolamide tablets of 25mg every day after a meal respectively in the morning and at night; and the methazolamide takes effect commonly for one month and can obviously improve and reduce BASDAI and BASFI of the ankylosing spondylitis, lighten neck ache, back ache and hip ache, reduce morning stiffness time and ache joint number and obviously lower the blood sedimentation and immune globulin level of the patient.
Description
Technical field
The present invention relates to a kind of new medical usage of methazolamide, i.e. application in the medicine of preparation treatment ankylosing spondylitis.
Background technology
(ankylosing spondylitis AS) is a kind of connective tissue disease to ankylosing spondylitis, based on axis joint chronic inflammatory disease, mainly involves vertebra and sacroiliac joint, and fibrosis and bony ankylosis appear in the joint, cause deformity at last.This disease also can be involved internal organs and hetero-organization thereof and be caused chronic progressivity rheumatism.Ankylosing spondylitis is more common in 16～30 years old male person between twenty and fifty, and different regions, not agnate sickness rate have very big-difference.The sickness rate of China's ankylosing spondylitis is 0.3%.
Clinically, patients with ankylosing spondylitis presents the multi-joint pathological changes, and the overwhelming majority at first invades sacroiliac joint, the later up cervical vertebra that is developed to.A few patients is invaded simultaneously by cervical vertebra or several spinal column segment earlier, also can invade joint on every side.There is inflammatory pain in joint, early lesion place, with muscle spasm around the joint, stiff sense is arranged.Along with PD, each spinal column segment and joint motion are limited and lopsided, late period whole spinal column and lower limb become strong arc, to front curve.
The ankylosing spondylitis medicine is generally regulated from autoimmune in treatment and is started with, and in conjunction with anti-inflammatory analgetic, absorbs sequestrum, reaches early stage disease controlling, reduces the disability rate purpose.At present, ankylosing spondylitis Drug therapy clinical commonly used drug is as follows:
(1) nonsteroidal antiinflammatory drug (NSAIDs): such medicine has the digestion pain relieving, alleviates stiff and the muscle spasm effect.But this type of medicine has side effect such as edema, hematuria, gastrointestinal reaction and kidney damage.
(2) (sulfasalzine, SSZ): such medicine is the azo complex of 5-aminosalicylic acid and sulfapyridine to sulfasalazine, and is main effective to patient's periphery joint, but to spinal column and Enthesopathy poor effect.This type of medicine side effect is mainly symptom of digestive tract, erythra etc.
(3) (methotrexate, MTX): the curative effect of methotrexate is similar to sulfasalazine, the periphery arthritic symptom is had clear improvement, but the spinal column symptom does not change for methotrexate.This medicine side effect has gastrointestinal reaction, bone marrow depression, stomatitis, alopecia etc.
(4) adrenocortical hormone: when patients with ankylosing spondylitis suffers from acute iritis or periphery arthritis and nonsteroidal antiinflammatory drug simultaneously and fails to respond to any medical treatment, available adrenocortical hormone local injection or oral medication.
(5) Tripterygium glycosides: the anti-inflammatory analgetic effect is arranged.Such medicine side effect has gastrointestinal reaction, leukopenia etc.
Treatment ankylosing spondylitis medicine also has other Chinese patent medicine, comprises capsule for curing rheumatism, sinomenine (trade name ZHENGQINGFENGTONGNING), Radix Paeoniae Alba total glucosides capsule, Colquhounia coccinea Wall. var. mollis (Schlecht.) Prain heel piece etc.In recent years, the biological preparation " benefit match spectrum (Etanercept) " based on the D2E7 fusion rotein also begins in clinical use, and evident in efficacy.Said preparation also is widely used in the treatment rheumatoid arthritis.But this type of medicine is import, costs an arm and a leg.
Because the ankylosing spondylitis cause of disease is fuzzy, so up to the present, do not have the effective therapy that stops the ankylosing spondylitis progress, no matter in, doctor trained in Western medicine, all also do not have special effective method and specific aim medicine.Widely used anti-ankylosing spondylitis medicine is mainly used in mitigate the disease, but not the treatment of essence.
The histopathological study of ankylosing spondylitis shows that the pathological changes joint part is osseous tissue generation major injury not only, and tangible hyperplasia and inflammation also appear in its synovial tissue.But up to the present, the research of relevant ankylosing spondylitis mostly concentrates on the osseous tissue of pathological changes, and the effect in pathological changes rarely has report to synovial membrane.Even have the research report also to be only limited to research patients'blood and knuckle synovia, but not directly study pathological tissues-synovial membrane.
The methazolamide commodity are called Buddhist nun's order gram department, chemical name is 5-acetamido-4-methyl isophthalic acid-sulfur-3,4-two pyrolle sulfonamide, Acetamide, N-[5-(aminosulfonyl)-3-methyl-1,3,4-thiadiazol-2 (3H)-ylidene]-, molecular weight is 236.274, and molecular formula is C5H8N403S2, and structure is:
Say on the methazolamide drug effect to belong to diuretic, be used for the treatment of primary open angle glaucoma, angle closure glaucoma and some secondary glaucoma.Such medicine can suppress aqueous humor and generate, and most of patient's medication back room water generates can subtract 40%.Methazolamide is the state approval medicine, and its pharmacokinetics, pharmacology and toxicological experiment data are complete.
Proteomic techniques: protein group refers to organize, the interior whole albumen of cell.Along with the decoding of human genome, the research of diseases related has entered the so-called genome times afterwards comprehensively.The pathological research demand for development in the present age is done comprehensively and the analysis of system gene expression product, but not the research of the formula of taking a part for the whole like that in the past.The research theory of proteomics and technology were risen in late nineteen nineties in last century, be technological means broad scale research protein group feature mainly with two dimensional electrophoresis and mass spectrum, comprise the protein expression level, modification after the translation, albumen and protein-interacting etc., can take place disease on molecular level thus, processes such as cellular metabolism are analyzed all sidedly.At present.Proteomic techniques has drawn for the disease of major diseases such as tumor, cardiovascular disease, infectious disease on gene level has deeply obtained very quantum jump mouth aspect the research, for the further investigation of these diseases provides important clue.
Summary of the invention
Utilize proteomic techniques and other Protocols in Molecular Biology, the invention provides a kind of new purposes of methazolamide, be i.e. application in the medicine of preparation treatment ankylosing spondylitis.
Concrete application process is: the patient is oral, and every day, oral 25 milligram quantities methazolamide sheets were two, sooner or later services once after meal; General one month takes effect, and can obviously improve and reduce ankylosing spondylitis BASDAI and BASFI index, alleviates cervicodynia, backache and hip pain, reduces the stiff time in morning and reduce pain to close joint number, can obviously reduce patient's erythrocyte sedimentation rate and immunoglobulin level.
Description of drawings
Fig. 1 is the 2D electrophoresis result of ankylosing spondylitis synovial tissue.
Fig. 2 analyzes the expression of carbonic anhydrase I (CA1) in ankylosing spondylitis synovial tissue for Western blotting, wherein, Fig. 2 (A): compare with rheumatoid arthritis (RA) and osteoarthritis (OA), CA1 is high expressed in ankylosing spondylitis (AS) synovial tissue.Fig. 2 (B): with GADPH is object of reference, analyzes the level relatively that CA1 expresses, and proves CA1 high expressed in ankylosing spondylitis synovial tissue.
Fig. 3 analyzes the expression of carbonic anhydrase I (CA1) in ankylosing spondylitis synovial tissue for immunohistochemical method.
Fig. 4 is the expression of ELISA methods analyst carbonic anhydrase I (CA1) in the ankylosing spondylitis synovial fluid.
Fig. 5 is the therapeutic effect of carbonic anhydrase inhibitors methazolamide to ankylosing spondylitis, and wherein, Fig. 5 (A) is AS activity index contrast sketch map; Fig. 5 (B) is AS function index contrast sketch map; Fig. 5 (C is) ESR contrasts sketch map; Fig. 5 (D) is IgG contrast sketch map; Fig. 5 (E) is IgA contrast sketch map; Fig. 5 (F) is IgM contrast sketch map.ESR normal reference value＜20mm/h, CRP normal reference value＜6g/L, IgG normal reference value 7-16g/L, IgA normal reference value 0.7-4g/L, IgM normal reference value 0.4-2.3g/L.
The specific embodiment
The present invention is further illustrated below in conjunction with embodiment:
Embodiment 1: in order to explore the ankylosing spondylitis pathogenic factor, the present inventor utilizes proteomic techniques that patients with ankylosing spondylitis synovial tissue is studied.
For the pathogenic protein factor of finding that ankylosing spondylitis is special, do contrast with osteoarthritis and rheumatoid arthritis synovial tissue.Osteoarthritis is old retrograde bone injury, and rheumatoid arthritis is self-immune disease.Though the two all shows as arthritis, does contrast with the two, can remove effectively those only with bone injury and immune proteins associated, and find the albumen of ankylosing spondylitis specifically expressing.It is still rare in proteomics research to compare three kinds of diseases simultaneously.
Method: extract the total protein of pathological changes synovial tissue (every kind disease each 10 specimen) at first according to a conventional method, the total protein of measuring behind its protein concentration each synovial membrane specimen of disease of the same race mixes by equal proportion concentration, forms the sample pool of diseased tissue separately.This is a sample processing method common in the proteomics research process.Each sample pool is carried out two-dimentional protein electrophorese, the total protein of chorista, the protein expression collection of illustrative plates of three kinds of disease samples relatively then.With scan method the expression of each protein site is carried out quantitative analysis, the protein site on the same position is if there is the expression difference more than three times then to be considered to obvious differential expression.
Result: by comparing with osteoarthritis and rheumatoid arthritis synovial tissue protein expression profiles, find that carbonic anhydrase I (Carbonic Anhydrase I) presents specificity overexpression in ankylosing spondylitis synovial tissue, as shown in Figure 1, contrast through electrophoresis result with rheumatoid arthritis and osteoarthritis, find carbonic anhydrase I (CA1, #5 protein site) high expressed in ankylosing spondylitis synovial tissue.
With western blotting method the synovial membrane sample of above every kind of disease is analyzed one by one, confirmed that carbonic anhydrase I presents specificity overexpression in ankylosing spondylitis synovial tissue, as shown in Figure 2, as seen from the figure, compare with rheumatoid arthritis (RA) and osteoarthritis (OA), CA1 is high expressed in ankylosing spondylitis (AS) synovial tissue.With GADPH is object of reference, analyzes the level relatively that CA1 expresses, and proves CA1 high expressed in ankylosing spondylitis synovial tissue.
The inventor also studies the expression and distribution of carbonic anhydrase I in ankylosing spondylitis synovial tissue with immunohistochemical method, found that this enzyme presents highdensity immune signal in the pathological changes synovial membrane, illustrated that carbonic anhydrase I expresses in ankylosing spondylitis synovial tissue.In addition, with detecting in the knuckle synovia of ELISA method to patients with ankylosing spondylitis, as shown in Figure 3, compare with rheumatoid arthritis (RA) and osteoarthritis (OA), CA1 is high expressed in ankylosing spondylitis (AS) synovial tissue.Find that carbonic anhydrase I also presents high level expression in this sick synovial fluid sample, as shown in Figure 4, compare that CA1 is high level expression in ankylosing spondylitis (AS) synovial fluid with rheumatoid arthritis (RA) and osteoarthritis (OA) synovial fluid.
Analyze: carbonic anhydrase I is one of erythrocytic main protein composition, and molecular weight is about 30000 dalton, contains protein chain and zinc ion calmodulin binding domain CaM of a crimped.The carbonic anhydrase most important function is catalysis carbon dioxide (CO
2) hydration formation carbonic anhydride HCO
3-.This reaction is reversible reaction, carries out fast under physiological pH condition (pH ≌ 7).Above-mentioned reaction pair Repiration is very important, can be with refuse CO in the body
2Take out of external by blood circulation.The major physiological function of carbonic anhydrase is included in blood and the hetero-organization thereof keeps acid-base balance, helps in-vivo tissue to get rid of CO
2, guarantee with CO
2And HCO
3-be the concentration of substrate of the enzyme maintenance appropriateness of catalytic substrate.In fact, extensively there is carbonic anhydrase in occurring in nature, and this enzyme source has efficient quick catalysis CO in plant, animal, microbial body and residual body thereof
2And HCO
3-between the function of mutual conversion, the Carbon cycle and the calcium circulation of terrestrial ecosystem played an important role.
The inventor studies the meaning of carbonic anhydrase I high level expression in the ankylosing spondylitis synovium of joint: set up an external reaction system, add carbonic anhydrase I and the calcium chloride that extracts in the ORBC in Tris-HCl buffer (pH=7).Feed CO
2After, CO
2In this reaction system, be catalyzed into HCO by carbonic anhydrase I
3 -Unsettled HCO
3 -Very fast the combination with the calcium ion of calcium chloride forms precipitation of calcium carbonate (CaCO
3).In fact, Ramana and Parissa also finished similar experiment respectively, obtained similar results.Calcium salt is the important composition composition of bone.It is extremely important step in the new bone formation process that calcium deposit forms crystals of calcium salts.According to the zymetology feature and the experiment in vitro result of carbonic anhydrase, the inventor thinks: the carbonic anhydrase I of great expression can break original C O in the ankylosing spondylitis synovium of joint
2And HCO
3 -Acid-base balance and the appropriateness concentration of substrate, impel CO
2Hydrate produces a large amount of HCO
3 -, form calcium precipitation at pathological changes joint synovial bursa and tendon attachment point place, thereby promote bone calcification and mineralization process to cause new bone formation.And new bone formation is the deterministic process of ankylosing spondylitis joint fibrosis and bony ankylosis just.Have experiment to show in addition, deformity appears in the tooth of feeding carbonic anhydrase inhibitors mouse, illustrate that the certain and bone formation of carbonic anhydrase I has substantial connection.This is to utilize proteomics method to find the unusual associated gene that takes place of the new bone in ankylosing spondylitis joint first.More than find prompting, the activity that suppresses carbonic anhydrase I in the ankylosing spondylitis synovium of joint is a key point of this disease of treatment.
In high vertebrates (comprising the mankind) body, found 15 kinds of carbonic anhydrase isozymes at present, mainly participated in physiological process such as the intravital Repiration of machine, body fluid circulation, biosynthesis reaction (generating), tumor generation, bone resorption as glyconeogenesis, fat and carbamide.Because carbonic anhydrase has important physical and pathological effect, have in a large number and report, and this enzyme inhibitor is extensive use of already as medicine about the research of this enzyme inhibitor.The carbonic anhydrase inhibitors of Shi Yonging mainly contains inorganic metal complex and sulphone amide derivative 2 classes clinically, and wherein the sulfonamides inhibitor is an of paramount importance class.The sulfonamides carbonic anhydrase inhibitors of Shi Yonging is mainly used in treatment glaucoma, conjunctivitis, iritis, uveitis or uveitis clinically, so far have the history in 50 years, its mechanism of action is to reduce the aqueous humor generation by suppressing the carbonic anhydrase isozyme, reduces intraocular pressure.If present this class drug main acetazolamide (acetazolamide) and methazolamide (methazolamide).Acetazolamide and methazolamide are the medicine of state approval, and high amount of drug kinetics, pharmacology, toxicological experiment data are arranged.Because the drug effect of methazolamide makes about 50 times of acetazolamide, therefore, the drug effect of methazolamide has substituted acetazolamide and has been extensive use of.
Embodiment 2: clinical treatment
Patient's data: screen 2 ankylosing spondylitis patients (dividing another name patient S and patient L).Conditions of patients is in the similar morbidity stage.The New York standard of revision in 1984 is adopted in diagnosis.More than 2 patients meet ankylosing spondylitis feature in mid-term by following staging diagnosis standard, i.e. 1. neck, the back of the body, waist, hip, knee joint, shoulder, sternoclavicular joint, intercostal nerves, sacro-iliac joint pain, limitation of activity is accompanied slightly tetanic; 2. X-ray film shows that the sacro-iliac joint face destroys joint edge blurry, gap turn narrow; 3. lab testing shows that erythrocyte sedimentation rate increases (ESR), and c reactive protein increases (CRP).All meet three standards.History, phenomenon or the sequela of patient's aniridia inflammation, rheumatoid factor RF feminine gender.The patient once accepted the conventional therapy of above-mentioned ankylosing spondylitis in the past, and the state of an illness is eased, but did not have obvious curative effects.Doctor's health check-up shows that organs such as two patient's hearts, lung, liver are normal, does not also have the eye disease.Blood testing, urine detection show two patients except that immunoglobulin G, ESR, CRP, and other physical signs is normal.In addition, two patients' rheumatoid factor and anti-CCP negative antibody.
Therapeutic Method: use the methazolamide sheet that the patient is treated.The patient has cut out other medicines more than 3 months before receiving treatment.The methazolamide sheet is produced by Hangzhou Aoyi Baoling Pharmaceutical Co., Ltd, the accurate word H20000035 of traditional Chinese medicines.Everyone every day of patient, oral 25 milligram quantities methazolamide sheets were two, sooner or later serviced once after meal, and the treatment phase is three months.For observing the methazolamide therapeutic effect, during treating, do not take other medicines.Check in every month once before treatment and after the treatment, record patient ankylosing spondylitis AS activity index (BASDAI) and AS function index (BASFI) situation, go forward side by side promoting the circulation of blood routine, routine urinalysis, hepatic and renal function and blood biochemical analysis, emphasis detects the variation of patient ESR, CRP, also writes down the untoward reaction situation.The patient all signs the right to know agreement.
The result:
Patient S, the man, 28 years old, the ankylosing spondylitis medical history in 12 years is arranged, treat after one month, AS function index BASFI reduces to by 51 and reduces to 31 after 37, the second months.AS disease activity index BASDAI treatment is reduced to by 27 after one month and is reduced to 22 after 25, the three months.Relatively, patient B ASDAI and BASFI all descend before and after the treatment, and difference all has statistical significance (all P＜0.05).The patient after treatment, cervicodynia, backache, hip pain, press pain and morning deadlock have progressively and improve, the pain in other joint obviously has improvement, pain is closed joint number and is reduced.Simultaneously, patient's joint motion ability obviously strengthens.Before the CRP treatment is 45mg/L, reduces to 16mg/L after two months, and the ESR treatment was reduced to 9mm/h by 36mm/h after three months.Relatively before and after the treatment, ESR obviously all descends, and difference all has statistical significance (all P＜0.05).The obvious overrun of IgG before the patient treatment, but IgA and IgM are in normal range.After treating three months, patients serum IgG, IgA and IgM obviously descend, and IgG reduces to normal range, illustrate to be in that sb.'s illness took a favorable turn the stage.The patient does not have obvious adverse reaction during the treatment, but after three months, urine examination shows that urine protein slightly rises.In addition, treat first month after, the blood samples of patients calcium ion concentration is reduced to normal range by the 3.05mmol/L that is higher than normal value.More than the results are shown in Figure 5.By clinical observation and conventional sense find, the patient is through the methazolamide treatment after three months, AS activity index (BASDAI), AS function index (BASFI) and ESR obviously descend, the demonstration methazolamide is to the good therapeutic effect of this disease.
Patient L, the man, 28 years old, nearly 3 years ankylosing spondylitis medical history is arranged, the state of an illness is lighter relatively.Treat after one month, AS disease activity index BASFI reduces to by 12 and reduced to 5 in 8, three months.AS activity index BASDAI treatment is reduced to by 12 after one month and is reduced to 3 after 8, three months.Generally speaking, relatively, patient B ASDAI and BASFI all obviously descend before and after the treatment, and difference all has statistical significance (all P＜0.05).After three months, cervicodynia, backache and hip are obvious bitterly to be improved behind the patient treatment, and other arthritis pain and stiff disappearance in morning illustrate that disease is significantly better than before treating.All in normal range, reduce to by 7 in the ESR treatment first month and reduce to 4 after 6, three months before and after this patient CRP and the ESR treatment.IgG is higher than normal value, IgA a little more than normal value before the patient treatment, and IgM is in normal range.Treat after two months, IgG descends to some extent, reduces to normal value 12.38mg/L.IgA does not have much variations, is higher than normal value a little always.IgM treatment self-consistentency is in normal value.After three months phases of treatment, urine examination shows that urine protein, bilirubin and leukocyte slightly rise.Patient treatment has diarrhoea and skin pruritus symptom after first month, but disappears after three months in treatment.Do not have big the variation before and after the treatment of blood samples of patients calcium ion concentration, be in normal range always.The results are shown in Figure 5.
Discuss: observe by bimestrial treatment to above 2 patients, discovery was taken the methazolamide sheet after one month, can obviously improve and reduce ankylosing spondylitis BASDAI and BASFI index, alleviate cervicodynia, backache and hip pain, reduce the stiff time in morning and reduce pain and close joint number, show that the methazolamide sheet has tangible curative effect to the treatment ankylosing spondylitis.The result shows that also when ESR was higher relatively, the methazolamide treatment can obviously reduce ESR.Influence differs to the patients with ankylosing spondylitis immunoglobulin level in the methazolamide treatment.After treating first month, can obviously reduce patient's immunoglobulin G level, but immunoglobulin A and M are not had big influence.Though methazolamide treatment non-evident effect, the protein level of two patient's urines all slightly rises, and diarrhoea and skin pruritus also appear in a patient, and be consistent with the described drug side effect of medicine description.Imaging examination does not find that patients with ankylosing spondylitis spinal column and sacroiliac joint have the state of an illness to increase the weight of trend.
Conclusion: the methazolamide sheet is the active drug of potential treatment ankylosing spondylitis, is worth using in clinical treatment is done from now on.
Meaning: up to the present, traditional ankylosing spondylitis medicine all is to go to treat this disease by the inflammation-inhibiting path.And ankylosing spondylitis is except inflammation, and more obviously the histopathology characteristics are unusual new osteogenesis and cause rigid spine.So traditional medicine all can only mitigate the disease and can't be reached the purpose of basic healing, because these medicines can't stop the paraplasm of bone.In addition, the special medicine that does not also have the treatment ankylosing spondylitis up to now.Existing medicine has better therapeutic effect to rheumatoid arthritis, and the treatment that ankylosing spondylitis is described needs the medicine at its pathological characteristic.Methazolamide can effectively suppress the carbonic anhydrase activity, suppresses calcium carbonate crystal and forms---this osteogenetic decisive step, thus reach the tetanic purpose of treatment bone.
Claims (1)
1. the application of methazolamide in the medicine of preparation treatment ankylosing spondylitis.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1276210A (en) * | 2000-06-08 | 2000-12-13 | 李学军 | Application of carbonic anhydrase inhibitor in preparing male contraceptives |
| US20050119262A1 (en) * | 2003-08-21 | 2005-06-02 | Pharmacia Corporation | Method for preventing or treating an optic neuropathy with a cox-2 inhibitor and an intraocular pressure reducing agent |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1276210A (en) * | 2000-06-08 | 2000-12-13 | 李学军 | Application of carbonic anhydrase inhibitor in preparing male contraceptives |
| US20050119262A1 (en) * | 2003-08-21 | 2005-06-02 | Pharmacia Corporation | Method for preventing or treating an optic neuropathy with a cox-2 inhibitor and an intraocular pressure reducing agent |
Non-Patent Citations (1)
| Title |
|---|
| 《international journal of immunopathology》 20081231 caccavo D et al antibodies to carbonic anhydrase in patients with connective tissue diseases :relationship with lung involvement 第659-667页 1 第21卷, 第3期 2 * |
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