CN1342458A - Application of leflunomide in preparing medicines to treat lupoid nephritis and nephrotic syndrome - Google Patents
Application of leflunomide in preparing medicines to treat lupoid nephritis and nephrotic syndrome Download PDFInfo
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- CN1342458A CN1342458A CN 01126610 CN01126610A CN1342458A CN 1342458 A CN1342458 A CN 1342458A CN 01126610 CN01126610 CN 01126610 CN 01126610 A CN01126610 A CN 01126610A CN 1342458 A CN1342458 A CN 1342458A
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Abstract
An application of leflunomide in preparing medicines to treat lupoid nephritis and nephrotic syndrome is disclosed. The leflunomide can prevent the deposition of circulating immunocomplex in glomeruli and the generation of in-situ immunocomplex to relax inflammations reaction, in addition suppress neutral gramulocyte chemotaxis so as to relax glomerulonephritis, and at the same time, can inhibit the TNF alpha and IL-1 deta expression and the IL-2 information transmission and thus relax inflammation reaction of tissue structure. Its advantages are high curative effect and low by-effect.
Description
Affiliated field
The present invention relates to the application of leflunomide, relate in particular to the application of leflunomide in the medicine of the preparation treatment lupus nephritis and the nephrotic syndrome.
Technical background
Systemic lupus erythematosus (sle) is the autoimmune disease of involving a plurality of systems of whole body, and multiple autoantibody appears in serum, and tangible immunologic derangement is arranged.This disease sees that with the young woman women of child-bearing age account for patient's 90%-95% more.Men and women's ratio is 1: 7-10.The ill population of China is about 70,/10 ten thousand population, accounts for 0.7/1000th of population.Be diagnosed as systemic lupus erythematosus (sle) person, about 70% has tangible renal damage, if Patients with SLE is done the kidney biopsy, almost has lupus nephritis to take place entirely.Feature according to Histological change is divided into four types with lupus nephritis at present.1, mesentery lupus nephritis; 2, focal lupus vegetans nephritis; 3, membranous lupus nephritis; 4, diffusivity lupus vegetans nephritis.All lupus nephritis are all with albuminuria, hypoproteinemia, and the nephrotic syndromes such as anasarca are clinical manifestation, as untimely treatment, will be converted into uremia, and this is the common cause that causes death.So to the lupus nephritis patient, make a definite diagnosis in early days, the early treatment, the control disease development is very important.
The cause of disease of systemic lupus erythematosus (sle) is not bright, with heredity, infection, gonadal hormone, medicine, physics, chemistry and psychological factor certain relation is arranged all.The definite pathogenesis of lupus nephritis is not illustrated at present as yet fully.Under the effect of intrinsic and external inexplicit factor still, body has been lost normal immunologic tolerance, so that the identification autologous tissue that lymphocyte can not be correct, and the autoimmune response that occurs.In this disease, the disorder of T cell function, the TH cell function is strong excessively, except that self B cell is provided specificity auxiliary, also can the reaction of enhancing property to the exotic antigen of its submission.The TH cell function is strong excessively, causes the B cell hyperproliferation, produces a large amount of autoantibodys and falls ill.Around the active stage Patients with SLE, can measure antinuclear antibody, ANCA etc. in the blood.These antibody are combined into immune complex with corresponding antigens in circulation, be deposited on glomerule, are the main pathogenesis of lupus nephritis.DNA is in the glomerular basement membrane combination, and with circulation in the anti-DNA antibody original position form the generation that immune complex also may participate in lupus nephritis.Immune complex deposit is in glomerule, fixing and complement activation, and the chemotactic factor that is discharged attracts neutrophilic granulocyte, discharges inflammatory mediator and cause glomerulonephritis when the latter takes off granule.In addition, TNF α, β can cause the synthetic increase of mesangial cell DNA, promote the mesangial cell inflammation.IL-1 can stimulate the propagation and the differentiation of B cell, and mediation B cell produces antibody, promotes the release of inflammatory protein and inflammatory mediator.IL-2 is also played a role to pathological development.
Aspect the treatment of lupus nephritis, at first consider to use hormone.Hormone has powerful immunosuppressive action, can obviously improve the prognosis of disease.When giving hormone, can add some immunosuppressant, comprise cyclophosphamide, azathioprine, MMF etc.Share synergism with hormone, can reduce the consumption of hormone.But well-known, the side effect of hormone is very big, can cause hyperglycemia, hypertension and digestive tract hemorrhage, obesity etc.Immunosuppressant such as cyclophosphamide also have big side effect, as bone marrow depression, secondary infection, liver injury etc.Old friends are devoted to seek a kind of new better medicine always.
Summary of the invention
The object of the present invention is to provide a kind of really effectively and the little treatment lupus nephritis of toxic and side effects and the medicine of the nephrotic syndrome.
The present invention uses the medicine of leflunomide as the preparation treatment lupus nephritis and the nephrotic syndrome.
Leflunomide is an isoxazole compounds, chemical name α, and α, α ,-three fluoro-5-methyl-isoxazole-N-acyl group-para-totuidine, molecular formula is C
12H
9F
3N
2O
2, molecular weight is 270.2, its structural formula is as follows:
The structural formula of the active metabolite A771726 of leflunomide is as follows:
Leflunomide is national I kind new medicine, and its commodity are called Ai Ruohua, is a kind of immunomodulator of novel low toxicity, can suppress humoral immunization, cellular immunization and nonspecific immunity.In liver and intestinal wall, be converted into active metabolite A771726 after the leflunomide oral absorption rapidly, bring into play all pharmacological actions in vivo by A771726.Its mechanism of action is as follows:
1, A771726 is by suppressing dihydroorate dehydrogenase, and the blocking-up dihydrooratic acid is converted into orotic acid, thus the de novo synthesis of blocking-up pyrimidine, prevent the excessive generation of pyrimidine, influence the synthetic of DNA and RNA, the blocking-up cell enters the S phase from the G1 phase, makes activatory cell be in resting state.Relying on the cell of de novo synthesis, is the main target cell of leflunomide effect as activated lymphocytes.
2, leflunomide can suppress kinase whose activity of butyric acid and cell adhesion.
3, suppress bone-marrow-derived lymphocyte and be converted into plasma cell, reduce production of antibodies and secretion.
In lupus nephritis, the TH cell function is strong excessively, and leflunomide passes through to suppress the de novo synthesis of pyrimidine, thereby makes activated lymphocyte be in resting state, thereby the strong excessively TH cell of function is remained static, and has stoped its influence to the B cell.
In lupus nephritis, the B cell hyperproliferation produces a large amount of autoantibodys and falls ill.Leflunomide passes through to suppress the de novo synthesis of pyrimidine, thereby has stoped the propagation of B cell, and has stoped the B cell to transform to plasma cell, thereby has suppressed production of antibodies.In addition, leflunomide also can directly suppress the secretion of antibody, the inhibition that the B cell is produced IgG and IgM is respectively 61% and 96%, thereby reduced the generation of circulating immune complex, alleviate circulating immune complex in the deposition of glomerule and the formation of original position immune complex, alleviated inflammatory reaction.
In addition, immune complex deposit is fixed and complement activation in glomerule, and the chemotactic factor that is discharged attracts neutrophilic granulocyte, causes glomerulonephritis.Leflunomide can suppress the neutrophilic granulocyte chemotactic, thereby has alleviated glomerulonephritis.
In lupus nephritis, TNF α, β can cause the synthetic increase of the DNA of mesangial cell, promote the mesangial cell inflammation.IL-1 can mediate the B cell and produce antibody.IL-2 expresses increase, and disease progression is also played a role.Leflunomide can suppress the expression of TNF α, IL-1 β, and the information conduction of IL-2 is had inhibitory action, so can slow down the inflammatory reaction of organizational structure.Can infer that from above-mentioned several respects leflunomide has better therapeutical effect to the lupus nephritis and the nephrotic syndrome.The metabolism of leflunomide
In intestinal wall and liver, be converted into active metabolite-A771726 after the leflunomide oral absorption rapidly, it brings into play all main pharmacological actions in vivo, the concentration of leflunomide in blood plasma is very low, in initial leflunomide pharmacokinetic, the plasma concentration of main detection of active metabolite A771726.The peak time of A771726 is at 0.558 ± 0.506 day, 8.79 ± 0.77 days half-life.(20mg, qd) continuous 30 days, its A771726 blood drug level was near stable state for multiple dose administration.In clinical practice, use three days (50mg/ days) loading doses can reach Css fast.The bioavailability 80% that leflunomide is oral, high fat diet can not produce big influence to the A771726 blood concentration.A771726 distributed density in liver, kidney and skin histology is higher, and content is low in the cerebral tissue.Free A771726 concentration is lower, and extensive and plasma protein combination (99.3%), and conjugated protein amount is linear when treatment concentration.Leflunomide is metabolised to primary product A771726 and many micro-metabolite after absorbing, and has only 5-trifluoromethylaniline (TFMA) energy detected in these micro-metabolite, seldom measures parent compound in blood plasma.Find that with in vitro tests liver and gastrointestinal wall have metabolism in the body.The microsome of cytoplasm of liver and cell is by the position of drug metabolism.A771726 is further metabolism in vivo, from renal excretion and directly from bile excretion.43% drains from urine, and 48% drains from feces, and sample analysis shows that initial metabolite in urine is the phenyloxamic acid derivant of glucosiduronate and A771726, and the major metabolite of feces is A771726.In two metabolic pathways, initial 96 hours mainly is from renal excretion, and later defecate is occupied an leading position.Reported in literature, in intravenously administrable (A771726) research, the about 31ml/h of clearance rate.Active carbon or cholestyramine can promote drug metabolism, and the half-life that makes A771726 in the body, enterohepatic circulation was to cause long principal element of A771726 half-life from be reduced to about 1 day greater than 1 week.Hemodialysis and peritoneal dialysis studies show that A771726 can not dialyse.The toxicological effect of leflunomide
Leflunomide mice single is irritated stomach or intraperitoneal injection, observes to record LD50 in 14 days and be respectively 258.9mg/kg and 166.9mg/kg.6 months oral leflunomides of SD rat (1.8,3.5,6.6mg/kg) long term toxicity test shows that high dose group has anorexia, the phenomenon that loses weight, and female rats ALP and AST have the phenomenon of increasing, and 7 (23%) die from infection in the administration phase in the high dose group.Low, middle dosage group does not have animal dead.Use transplantation model, oral high dose leflunomide 20mg/kg and 30mg/kg treatment rat 112 days show that its target organ is the active organ of regeneration: bone marrow, spleen, mucous membrane of small intestine, and immune organ coincide with foreign data as thymus and spleen.Liver function injury and bone marrow depression appear in the Lewis rat.6 months oral leflunomides of Bagle Canis familiaris L. (2,10,16,20mg/kg) long term toxicity test shows, only high dose group slightly descends the erythroid cells sum and hematocrit reduces.Coming fluorine is special microorganism reverse mutation test, mammal cultured cell chromosomal aberration test, and rodent micronucleus test result does not all have mutagenic action.Leflunomide has teratogenesis in middle and high dosage 10,20mg/kg.
In sum, leflunomide has better therapeutical effect to the lupus nephritis and the nephrotic syndrome, and toxic and side effects is little, and the use of clinical case has confirmed that further this medical instrument has significant curative effect.Therefore, leflunomide is used for lupus nephritis and the nephrotic syndrome has application promise in clinical practice.Clinical report
15 routine SLE patients through leflunomide (Ai Ruohua) treatment all meet the nineteen eighty-two Americanism damp disease SLE of association diagnostic criteria.Age is 15-51 year (average 37 ± 13).Wherein the woman is 13,2 of men.The course of disease is 2 months to 7 years.All confirm that through the nephridial tissue pathological biopsy lupus nephritis is arranged, II type 3 examples wherein, IV type 8 examples, V-type 3 examples, VI type 1 example.Patient's overview such as table 1.
Therapeutic scheme: the difference according to state of an illness weight and body weight gives leflunomide 60mg/ day 3-7 day, then decrement to 7 days 40mg/ days or directly decrement to maintenance dose 20mg/ day.For making a definite diagnosis the patient who once used immunosuppressant for many years, the hormone amount is constant, add with the leflunomide moon surplus after hormone decrement gradually, do not use other immunosuppressant.For the patient who has just made a definite diagnosis, to use hormone therapy in routine and take leflunomide simultaneously, month surplus hormone decrement is not used other immunosuppressant.
Evaluation index: monitoring routine blood test, routine urinalysis, 24h urine protein quantitation, immune indexes, the biochemical series of blood (liver function, kidney merit, blood glucose, blood fat, plasma protein, ion, creatase).Survey blood, routine urinalysis and 24h urine protein quantitation after taking medicine weekly one time, surveyed once biochemical series and immune indexes in every month.
Result: be used for methotrexate therapy 15 routine lupus nephritis patients over nearly 8 months.Wherein 1 example is treated because of self reason and was withdrawed from treatment on the 3rd day automatically.Other 1 example can not tolerate medicine and withdraws from treatment because of occurring nausea,vomiting,diarrhea after two weeks of taking medicine.(dosage is at totally 7 days 60mg/ day---at totally 7 days 40mg/ day).This patient (woman, lupus nephritis V-type) has made a definite diagnosis SLE3, and edema, arthralgia, peripheral blood leucocyte are lower than 4.0 * 10 during morbidity
9/ 1, face erythema, cardiopalmus, dyspnea, urine protein (2+)-(3+) give the strong and CTX of first and treat, and CTX uses about 2 years, shared 12g, and urine protein was once turned out cloudy, but nearly 1 year half patient's urine protein (1+)-(2+) all the time.Patient's pathological biopsy is membranous nephropathy (a lupus nephritis V-type).Patient's oral prednisone 30mg/ day before with leflunomide, twenty-four-hour urine protein determination total protein 3.8g/l (2750ml), taking one week of leflunomide back urine total protein is 1g/l (2300ml), the 2nd week the urine total protein be 0.6g/l.Existing patient's general state is good, no edema and heating, weak.Take prednisone 20mg/ day.13 routine patients' the treatment situation of surplusing is as follows:
Before treatment back, the treatment back index treatment of treatment back, treatment back
2 all 4 all 6 all 2 months 24h urine protein quantitation 4.05 ± 3.65 3 ± 1.98 3.02 ± 1.66 1.54 ± 0.63
*1.24 ± 0.63
ANA 1: 93.32 (11/15) 1: 22.97 (1/4) 1: 20 anti-dsDNA antibody (29 ± 16) % (13.6 ± 2.2) % (12 ± 2) %
C3 0.56±0.17(9/15) 0.59±0.05(1/4) 0.83±0.43
C4 0.207±0.029 0.24±0.09 0.26±0.07
T-Ch 6.34±2.32 10.18±3.74?9.08±1.79 6.97±1.06 5.76±0.73
TG 3.475±2.32 4±2.57 3.65±3.06 4.28±4.28 1.44±0.56
ALB 32.15±9.19 29.14±9.92?34.14±6.28 38.30±3.48 36.40±4.73
BUN 9.07±3.48 8.53±3.78 6.12±1.80 6.06±1.68 5.33±1.81
Cr 108.6 ± 78.75 85.3 ± 30.2 81.3 ± 4.69 53.93 ± 13.48 64.03 ± 14.8
*P＜0.05 is that the 24h urine protein is determined at and 6 weeks compared statistical significance during with 2 months with before the medication.▲ all the other indexs are compared no obvious significant difference before 2 months with before the medication, but thoughtful 6
BUN, Cr, ALB recover normal substantially in the time of 2 months.
Therefore obviously reduce at 6 urine protein quantitation of 24h thoughtful 2 months the time, plasma protein recovers normally gradually, and anasarca disappears, and the kidney merit takes a turn for the better until recovering normal, and the hyperlipidemia level reduces gradually.Immune indexes ANA and anti-ds-DNA antibody titer reduce, C
3, C
4It is normal that level is recovered.
Have 4 examples side effect to occur in 15 examples, be mainly gastrointestinal symptom, feel sick, vomiting, anorexia, mostly be original " gastritis ", medication metenteron symptom obviously increases the weight of.Only 1 example is because of the nausea,vomiting,diarrhea leflunomide treatment of stopping using, 3 examples of surplusing take motilium suit the medicine to the illness dispose after symptom all alleviate, do not influence treatment.
Claims (1)
1, the application of leflunomide in the medicine of the preparation treatment lupus nephritis and the nephrotic syndrome.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100404030C (en) * | 2003-09-29 | 2008-07-23 | 欣凯医药化工中间体（上海）有限公司 | Application of leflunomide in the preparation process of anti SARS virus medicine |
| CN103961349A (en) * | 2013-02-06 | 2014-08-06 | 西南大学 | Application of antirheumatic drug--leflunomide in inhibition of growth of neuroblastoma |
| CN107375278A (en) * | 2017-09-04 | 2017-11-24 | 扬州大学 | The application of leflunomide or its active metabolite A771726 in the medicine for preparing treatment diabetes B |
| CN110772634A (en) * | 2019-12-09 | 2020-02-11 | 上海交通大学医学院附属仁济医院 | Application of renalamine related active polypeptide RP220 in preparation of medicine for treating kidney diseases |
-
2001
- 2001-08-31 CN CN 01126610 patent/CN1342458A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100404030C (en) * | 2003-09-29 | 2008-07-23 | 欣凯医药化工中间体（上海）有限公司 | Application of leflunomide in the preparation process of anti SARS virus medicine |
| CN103961349A (en) * | 2013-02-06 | 2014-08-06 | 西南大学 | Application of antirheumatic drug--leflunomide in inhibition of growth of neuroblastoma |
| CN107375278A (en) * | 2017-09-04 | 2017-11-24 | 扬州大学 | The application of leflunomide or its active metabolite A771726 in the medicine for preparing treatment diabetes B |
| CN110772634A (en) * | 2019-12-09 | 2020-02-11 | 上海交通大学医学院附属仁济医院 | Application of renalamine related active polypeptide RP220 in preparation of medicine for treating kidney diseases |
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