CN101926996B - Application of methotrexate and ABC inhibitor to preparation of medicament for treating psoriasis - Google Patents
Application of methotrexate and ABC inhibitor to preparation of medicament for treating psoriasis Download PDFInfo
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- CN101926996B CN101926996B CN 201010253221 CN201010253221A CN101926996B CN 101926996 B CN101926996 B CN 101926996B CN 201010253221 CN201010253221 CN 201010253221 CN 201010253221 A CN201010253221 A CN 201010253221A CN 101926996 B CN101926996 B CN 101926996B
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- methotrexate
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Abstract
The invention relates to application of an inhibitor combining methotrexate and ABC (ATP-binding cassette) to treatment of psoriasis. More specifically, the inhibitor combining the methotrexate and the ABC is applied in a local external use mode when used for treating the psoriasis.
Description
Technical field
The present invention relates to treat the medicinal approach of psoriasis: concrete, the present invention relates to the use in conjunction methotrexate, the ABC inhibitor is used for the treatment of psoriatic external purposes.
Background technology
Psoriasis is the dysimmunity disease under a kind of polygenic inheritance background, because of its have sickness rate higher and mainly involve the characteristics such as between twenty and fifty at department of dermatologry clinical and scientific research field extremely pay attention to.Keratinocyte (KC) hyperplasia, inflammatory cell infiltration, new vessels form its histopathology three elements, although have very complicated interaction and cause effect relation between the three, but it is generally acknowledged, intradermal is assembled and the T lymphocyte of activation is the initiating agent that psoriatic lesion occurs, the T cell of activation can produce the cell/chemotactic factors such as TNF-α and IL-2, thus cause epidermal keratinocytes propagation and differentiation state unusually and induce neutrophilic granulocyte chemotactic and gathering in the epidermis.In addition, the papillary layer of corium Marjoram Extract at psoriatic lesion place is tortuous, permeability, and blood vessel quantity increases.The distribution of blood vessel and the change of formation are considered in the psoriasis pathological change that occurs at first, VEGF (VEGF) and vascular cell adhesion molecule-1 (VCAM-1) etc. increase endotheli ocytosis, vascular permeability by the receptor on the stimulating endothelial cell or other modes.In the psoriasis carcinogenesis of human, Angiogenesis Stimulators in Human and inflammatory mediator, KC, the interactions such as inflammatory cell have finally caused the main pathological change of psoriasis.Present psoriatic class of medications is more, medicine comprises tretinoin medicines, anthraline, glucocorticoid and neotype immunosuppressant etc., but because the above class of medications relative unicity that saves of different side effect and effect scoring ring separately, its therapeutic effect and utilization prospect still can not be entirely satisfactory.
Methotrexate (methotrexate, MTX) is a kind of antimetabolite, is usually used in the treatment of tumor, can significantly suppress cell proliferation.The drugs approved by FDA methotrexate can be used for psoriasis in 1971, to be used for the treatment of the earliest psoriatic cell toxicity medicament (Steigleder GK.Ambulant treatment of psoriasis with methotrexate.Hautarzt.1971,22 (9): 419).Methotrexate is all effective for each psoriasis pustulosa, it is treated psoriatic mechanism and it be unclear that, think that in the past methotrexate reaches the synthetic of block cell DNA by the inhibition to dihydrofolate reductase, the epidermis cell of psoriasis hyper-proliferative is suppressed (Weinstein GD, Goldfaden G, Frost P Methotrexate.Mechanism of actionon DNA synthesis in psoriasis.Arch Dermatol.1971,104 (3): 236-43).But research was found in recent years, and the lymphocyte of abnormality proliferation activation is that methotrexate is treated psoriatic main target cell in psoriatic's body.Treat in the psoriatic in vitro tests at low dosage methotrexate weekly and to find, methotrexate obviously suppresses the lymphoid cell of breeding, the T lymphocyte that particularly activates.The methotrexate drug level is 1 * 10
-7～5 * 10
-7After contacting 24 hours with lymphoid cell during mmol/L, lymphoid cell is killed and wounded to be reached more than 95%.Even but methotrexate concentration is 10
-5Therefore during mmol/L, normal person KC is killed and wounded is lower than 10%, and its toleration to the methotrexate toxic action is higher 1000 times than lymphoid cell, thinks that in vivo the lymphoid cell that is activated of propagation is that methotrexate is treated psoriatic main target cell (EW 3
RdMcCullough JL, Pittelkow MR, McCormick A, Almanzor J, Liu G, Dang M, Voss K, Voss J, Schlotzhauer A, et al.Methotrexate therapy of psoriasis:differential sensitivity of proliferating lymphoid and epithelialcells to the cytotoxic and growth-inhibitory effects of methotrexate.Jeffes.J Invest Dermatol.1995,104 (2): 183-8).Research finds that methotrexate can suppressor T cell TNF secretion-α and the various kinds of cell/chemotactic factor such as IL-2 and reach therapeutical effect.In recent years, expression angiogenesis inhibiting (Johnston A but Yamasaki E etc. find low dose of methotrexate establishment vascular cell adhesion molecule-1 (VCAM-1), Gudjonsson JE, Sigmundsdottir H.Ludviksson BR.Valdimarsson H.The anti-inflammatory action ofmethotrexate is not mediated by lymphocyte apoptosis, but by the suppression of activation andadhesion molecules.Clin Immunol.2005,114 (2): 154-63), start MTX at the research boom of the effect of vascular endothelial cell and mechanism, think that it is another important mechanisms of this drug effect that methotrexate suppresses the interior angiogenesis of psoriatic lesion.The curative effect of methotrexate in psoriasis certainly, system uses at short notice mitigate the disease, but the side effect of methotrexate is larger, it is generally acknowledged and enter in the body rear relevant in enrichment and the long-term accumulation of hepatic and renal tissue with this medicine, therefore, the system applies of methotrexate in curing psoriasis generally not as first-selection.Seeking increases it at target cell such as keratinocyte, and the combination formulations of the concentration in T cell and the vascular endothelial cell becomes the new targeting of curing psoriasis.Britain and Canadian Patents (GB19830016763 and CA19870538541) disclose methotrexate ointment and the application of external preparation in the treatment psoriasis.Japan Patent (JP19920214465) discloses the effect of methotrexate derivatives in the treatment psoriasis.
Methotrexate can be pumped the extracellular by ABC (ATP-binding cassette) transport protein superfamily member after entering histiocyte, this is very common in the chemotherapy process of tumor cell, the cell of methotrexate effluxes mechanism and has directly caused tumor cell to its insensitive (Banerjee D, Mayer Kuckuk P, Capiaux G, Budak-Alpdogan T, GorlickR, Bertino J R.Novel aspects of resistance to drugs targeted to dihydrofolate reductase andthymidilate synthase.Biochim Biophys Acta.2002,1587 (2-3): 164-173).The abc transport superfamily protein is one group of transmembrane protein, present known 49 members that have, be divided into 7 subfamily ABCA-ABCG, this family forms passage in the cross-film district, transport the different medicine of many structures and pass cell membrane by passage, 2 ATP bonding pads are positioned at the cytoplasm inner face, and hydrolysising ATP is finished the substrate transhipment.There is low the expression in this family member in the most tissues of human body, but overexpression in skin histology and endotheliocyte and some tumor cell.Its Major Members ABCB, ABCC (have another name called multidrug-associated protein: multidrug resistance protein, MRP), ABCG (has another name called breast drug-resistance protein: breast cancerresistance protein, BCRP) subfamily is relevant with tumor multi-medicine drug-resistant, the chemotherapeutics that participates in the mediation wide spectrum comprises alkaloids, antitumor antibiotic, alkylating agent, glucuronide conjugate and some novel gene target drugs efflux.Masuda and his colleague find that in 1997 methotrexate is obstructed at the bile excretion of ABCC2 clpp gene deratization, extracellular transport process (the Masuda H that ABCC2 participates in the mediation methotrexate is proposed, I ' izuka M, Yamazaki Y, Nishigaki M, Kato R, Ni ' inuma Y, Suzuki K, Sugiyama Y.Methotrexate is excreted into the bile by canalicular multispecific organic anion transporter in rats.Cancer Res.1997,57:3506-351).The methotrexate that follow-up test confirmation ABCC1-5 has consisted of Energy Dependence together produces system, (Zeng H plays an important role in the drug resistance of cell to methotrexate, Chen ZS, Belinsky MG, Rea PA, Kruh GD.Transport of methotrexate (MTX) andfolates by multi-drug resistance protein (MRP) 3 and MRP1:effect of poly-glutamylation onMTX transport.Cancer Res.2001,61:7225-7232).Volk equal to find first in 2000 breast carcinoma Nai Mituo uh quinone cell strain MCF/MX have the high expressed of ABCG2, there is the crossing drug resistant to methotrexate simultaneously in this drug-resistant cell strain, think that ABCG2 also participates in mediating (the Volk EL that effluxes of methotrexate, Rohde K, Rhee M, McGuire JJ, DoyleLA.Ross DD.Schneider E.Methotrexate cross-resistance in a mitoxantrone-selectedmultidrug-resistant MCF7 breast cancer cell line is attributable to enhanced energy-dependentdrug efflux.Cancer Res.2000,60:3514-3521).The methotrexate that has successively the inhibitor that studies confirm that utilization ABCG2 can effectively block HEK293/ABCG2 transfectional cell film bubble is carried.Thereby make people flow out cellular pathways to methotrexate new cognition has been arranged.How to utilize abc transport pump inhibitor blocking-up methotrexate by the therapeutic effect that effluxes in the cell the Effective Raise methotrexate, good potential applicability in clinical practice is arranged.About methotrexate and other drug coupling treatment psoriasis, United States Patent (USP) (US2000602949) discloses interleukin 10 (Interleukin 10) and methotrexate coupling suppressor T cell propagation treatment psoriasis.
Summary of the invention
The purpose of this invention is to provide a class and treat psoriatic external used medicine.
Further, the purpose of this invention is to provide a kind of new psoriatic pharmaceutical composition, external used medicine of associating methotrexate and ABC inhibitor of being used for the treatment of.
Methotrexate and ABC inhibitor share be used for the treatment of psoriasis, experimental result shows that use in conjunction ABC inhibitor compares with alone methotrexate with methotrexate, can suppress methotrexate and discharge in born of the same parents, increases its intracellular concentration, thereby increases its curative effect.Wherein with the Zaprinast of MRP5 and Lapatinib and the methotrexate combination optimum of ABCG2.
When associating methotrexate and ABC inhibitor local skin were tried out, the preparation that adopts can be the external preparation of this area routine, comprises ointment, gel, patch etc.The forms such as medicine can flexible nano-liposomes, solid lipid nanoparticle, microemulsion are present in ointment, gel, the patch substrate.
With the compound recipe methotrexate, when ABC inhibitor ointment part is on probation, the concentration of MTX should be at 0.1%-10% (wt/wt), the concentration of ABC inhibitor is 0.05%-10%, and the each amount of application of MTX is equivalent to 5-15mg, and the amount of application of ABC inhibitor is 1-20mg.
Be used for the treatment of psoriasis although patent (US200060249, CA19870538541, JP199202214465) discloses the various external preparation of methotrexate and derivant and other drug (such as interleukin 10) coupling, have no methotrexate and the coupling of ABC inhibitor is used for the treatment of psoriatic relevant report.The present application people is devoted to study psoriatic effects anb Mechanism research for many years, has abundant psoriasis pathology specimen and ripe psoriasis to transplant mouse model, and tumor drug resistance and reverse mechanism thereof are also had certain research.Use in conjunction methotrexate and ABC inhibitor are used for the treatment of psoriasis, suppress effluxing of methotrexate, can bring into play to greatest extent the therapeutical effect of methotrexate, the serious adverse reaction of avoiding it to cause.
Description of drawings
Fig. 1 is that each MRP-5 inhibitor absorbs inhibiting comparison to the MTX that MRP-5 mediates.
Embodiment
Further specify the present invention below by specific embodiments.Described embodiment only is used for explanation or explains embodiment of the present invention, and can not limit protection scope of the present invention.
Embodiment 1MRP-5 inhibitor effluxes inhibiting research to MTX
The film bubble conveying of the MTX of research MRP-5 inhibitor blocking-up MRP-5 mediation is share MRP-5 inhibitor and MTX in this experiment.The MRP-5 inhibitor that this experiment is used has probenecid, MK571, trequinsin, sldenafil, zaprinast (Zaprinast), indomethacin, Sulfinpyrazone, dipyridamole, pemetrexed, 5-FdUMP.
Abc transport pump dependency ATP picked-up MTX can carry experiment to estimate by the film bubble, and the film bubble that this experiment needs can obtain from the HEK293 cell of MRP-5 transfection.
The film bubble is to utilize the physics smudge cells to obtain under cryogenic conditions, and 20 μ g films bubble is hatched 1h with each inhibitor on ice, containing 20mM MgCl
2, 4mM ATP or 4mM AMP-PNP are in phosphagen and the creatine kinase ATP Laemmli buffer system Laemmli.Add 100 μ M[
3H]-MTX hatches 10min at 37 ℃.Add 3ml stop buffer (0.25M sucrose, 100mMNaCl and 10mM Tri(Hydroxymethyl) Amino Methane Hydrochloride, PH7.5) stopped reaction.Washing, in the film bubble [
3H]-MTX with liquid scintillation counting (Packard Instrument Company, Inc.) measure.It is as follows to record the result.
This experiment can draw to draw a conclusion, and the MRP-5 inhibitor is compared with giving separately the MTX matched group with MTX use in conjunction group, the picked-up of film bubble [
3H]-MTX obviously reduces, and namely the MRP-5 inhibitor is carried the film bubble of the MTX of MRP-5 mediation inhibitory action.The inhibitory action of PDE5 inhibitor (PDE5inhibitor) zaprinast (Zaprinast) is the strongest in the MRP-5 inhibitor.
Embodiment 2ABCG2 inhibitor effluxes inhibiting research to MTX
The film bubble conveying of the MTX of research ABCG2 inhibitor blocking-up ABCG2 mediation is share ABCG2 inhibitor and MTX in experiment.
The inhibitory action of tyrosine kinase inhibitor in the ABCG2 inhibitor (TKIs) is particularly outstanding, Nilotinib, Lapatinib, Erlotinib, Sunitinib in this experiment high spot reviews tyrosine kinase inhibitor (TKIs) are with the positive contrast of FTC.
In this experiment [
3H]-film of MTX bubble carries experiment to measure with embodiment 1 method.The film bubble is hatched 1h with the inhibitor of each concentration on ice.Add 100 μ M[
3H]-MTX hatches 10min at 37 ℃.Add 3ml stop buffer (0.25M sucrose, 100mMNaCl and 10mM Tri(Hydroxymethyl) Amino Methane Hydrochloride, PH7.5) stopped reaction.Washing, in the film bubble [
3H]-MTX with liquid scintillation counting (Packard Instrument Company, Inc.) measure.It is as follows to record the result.
The film bubble of the MTX of tyrosine kinase inhibitor (TKIs) blocking-up ABCG2 mediation is carried
This experiment can draw to draw a conclusion, ABCG2 inhibitor and MTX use in conjunction group with give separately the MTX matched group and compare, the picked-up of film bubble obviously reduces, namely the ABCG2 inhibitor has inhibitory action to the film bubble of the MTX of ABCG2 mediation is carried.Wherein Lapatinib (Lapatinib) inhibitory action is the strongest.
Embodiment 3 methotrexate gels
Prescription forms
The composition consumption
Methotrexate 500mg
Card pool nurse 1.0g
Triethanolamine 1.5g
DMSO 2ml
Distilled water adds to 100g
Preparation method
Card taking pool nurse is soaked in water, and makes its abundant swelling, adds glycerol, drips triethanolamine and becomes clear gel.MTX adds in the gel after with an amount of DMSO mixing, adds water to capacity, grinds well.
Embodiment 4 compound recipe methotrexates, Lapatinib gel
Prescription forms
The composition consumption
Methotrexate 500mg
Lapatinib 1.0mg
Card pool nurse 1.0g
Triethanolamine 1.5g
DMSO 2ml
Distilled water adds to 100g
Preparation method
Card taking pool nurse is soaked in water, and makes its abundant swelling, adds glycerol, drips triethanolamine and becomes clear gel.MTX and Lapatinib add in the gel after with an amount of DMSO mixing, add water to capacity, grind well.
Get 36 of the ICR mices of body weight 20～30g, male and female half and half are divided at random blank group, MTX group and compound recipe ABC inhibitor and MTX and organize 3 groups, 12 every group.Each is organized and smears mouse tail every day 2 times (0.2g
-1D
-1).Put to death mice behind the continuous use 14d, get apart from the back epidermis at the about 1.8cm of root of the tail place, carry out the conventional organization section, HE dyeing.Observe under the light microscopic, the scale epidermis between all two follicular orifices has the granular cell layer person who embarks on journey continuously, is called the scale that has granular layer to form.Count the scale number that granular layer is arranged in per 100 scales, respectively organize data.
The impact that compound recipe MTX, Lapatinib gel form mouse tail scale granular layer of epidermis
Annotate: compare with the blank group, #P＜0.05 is compared with MTX gel group in * P＜0.01
The result shows, compare with blank gel-type vehicle matched group, MTX gel group and compound recipe MTX, Lapatinib gel group are formed with obvious facilitation to Mus tail scale granular layer of epidermis, there is the scale digital display work of granular layer to increase, compare (being P＜0.01) with the blank group wherein the most obvious with compound recipe MTX, the effect of Lapatinib gel group, with MTX gel group, significant difference (P＜0.05) is arranged between two groups.
Embodiment 6 compound recipe methotrexates, ABC inhibitor gel for treating psoriasis volunteer's effect
Case is selected: 72 routine ordinary property plaque psoriasis (having done pathology makes a definite diagnosis) volunteers, clinical manifestation typical case.Be divided at random 3 groups.MTX gel group 24 examples, 22～58 years old age, average 35.1 ± 10.2 years old, male 14 examples, women 10 examples, the course of disease 5 months～15 years; Compound recipe MTX, Lapatinib gel group 24 examples, 18～56 years old age, average 37.2 ± 12.2 years old, male 11 examples, women 13 examples, the course of disease 5 months to 15 years; External hormone (Dexamethasone ointment) group 24 examples, 20～54 years old age, average 36.4 ± 10.1 years old, male 12 examples, women 12 examples, the course of disease 5 months to 15 years.Three groups age, sex, the state of an illness, course of disease difference not statistically significant (P＞0.05).Three groups of patients are all without the other system illness.
Therapeutic Method: MTX gel group adopts the MTX gel to be applied to local skin lesion place, and one day twice, compound recipe MTX, Lapatinib gel group and external hormone group were with same medication.6 weeks of successive administration.
Curative effect determinate standard: 1. clinical recovery or be almost recovered: the skin lesion such as erythema, squama disappear more than 90% or disappear fully; 2. produce effects: the skin lesion such as erythema, squama disappear 〉=and 60%; 3. taking a turn for the better: the skin lesion such as erythema, squama disappear 〉=and 30%; 4. invalid: the skin lesion such as erythema, squama disappear＜and 30%.Adopt psoriatic lesion area-severity index (PASI scoring) that the psoriatic before and after the treatment is marked, analyze its variation.
The result:
The situation in the 3rd week of 3 groups of plaque psoriasis patient treatments and the 6th week
Annotate: compound recipe MTX, Lapatinib gel group are compared P＜0.05 with MTX gel group and are compared P＜0.05 with Dexamethasone group
The result shows, compound recipe MTX, the 3rd week of Lapatinib gel group and the 6th all cure rates are all large than Dexamethasone group and MTX gel group with total effective rate, and the 6th all compound recipe MTX, Lapatinib gel group and MTX gel group phase P＜0.05 are compared P＜0.05 with Dexamethasone group.
Claims (6)
1. methotrexate and ABC inhibitor are preparing the purposes for the treatment of in the psoriasis; Described ABC inhibitor is MRP5 inhibitor and micromolecule tyrosinase inhibitor, and wherein the MRP5 inhibitor is selected from tadalafil, sldenafil, zaprinast, trequinsin and Vardenafil; The micromolecule tyrosinase inhibitor is selected from imatinib, nilotinib, gefitinib, Erlotinib, Lapatinib, Dasatinib, Sutent and Bosutinib.
2. according to the purposes of claim 1, wherein said medicine is the medicine of local topical.
3. according to the purposes of claim 1, wherein the MRP5 inhibitor is zaprinast.
4. according to the purposes of claim 1, wherein said micromolecule tyrosinase inhibitor is Lapatinib.
5. according to the purposes of one of claim 1-4, the concentration of methotrexate is 0.1%-10%wt/wt in the wherein said preparation, and the concentration of ABC inhibitor is 0.05%-10%.
6. according to the purposes of one of claim 1-4, the each amount of application of MTX is 5-15mg, and the amount of application of ABC inhibitor is 1-20mg.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101378760A (en) * | 2005-11-18 | 2009-03-04 | 维克特拉集团有限公司 | Pharmaceutical compositions comprising methotrexate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101378760A (en) * | 2005-11-18 | 2009-03-04 | 维克特拉集团有限公司 | Pharmaceutical compositions comprising methotrexate |
Non-Patent Citations (1)
| Title |
|---|
| Warren Richard B.等.genetic variation in efflux transporters influences outcome to mehtotrexate therapy in patients with psoriasis.《JOURNAL OF INVESTIGATIVE DERMATOLOGY》.2008,第128卷(第8期),1925-1929. * |
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