CN105362265A - Application of cimetidine in preparing medicine for treating autoimmune conjunctivitis - Google Patents
Application of cimetidine in preparing medicine for treating autoimmune conjunctivitis Download PDFInfo
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- CN105362265A CN105362265A CN201510868349.1A CN201510868349A CN105362265A CN 105362265 A CN105362265 A CN 105362265A CN 201510868349 A CN201510868349 A CN 201510868349A CN 105362265 A CN105362265 A CN 105362265A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
Abstract
The invention provides application of cimetidine in preparing medicine for treating autoimmune conjunctivitis. The invention creatively finds that cimetidine can regulate an immune system so as to be used for treating related pathological damage. To be specific, cimetidine can lower a ratio of Th1 cell subset to Th17 cell subset, maintain integrity of a blood-eye conjunctiva barrier, inhibit macrophage infiltration and inhibit intraocular inflammation reaction. On the basis of above new properties of cimetidine, new application of utilizing cimetidine to treat conjunctivitis is determined, clinical application finds that cimetidine has quick action and exact effect on treating autoimmune conjunctivitis, has no side effect found and has an outstanding popularization prospect.
Description
Technical field
The present invention relates to medical art, relate to the new medical usage of material further, be specifically related to the application of cimetidine in preparation autoimmune membranous conjunctivitis medicine.
Background technology
Cimetidine has another name called cimetidine, safe stomach is beautiful; as alternative bisfentidine; be mainly used in the treatment of peptic ulcer in the prior art; its pharmacological action mainly comprise gastric acid secretion inhibiting, suppress basis and night gastric acid secretion; also can suppress to stimulate by histamine, point peptide gastrin, insulin and food etc. the gastric acid secretion caused; and its acidity is reduced; there are prevention and protective effect to the corrosive gastritis caused because of chemical stimulation, also have obvious curative effects to stress gastric ulcer and upper gastrointestinal hemorrhage.Cimetidine is white or off-white color crystalline powder; Almost odorless, bitter in the mouth; Easily molten in methanol, dissolve in ethanol, slightly molten in isopropyl alcohol, slightly soluble in water, easily molten in dilute hydrochloric acid.
Conjunctivitis is one of common diseases causing blindness of ophthalmology.Infective conjunctivitis and non-infectious conjunctivitis can be divided into according to the cause of disease.Wherein, non-infectious conjunctivitis is considered to a class Autoimmune ophthalmopathy.Be mainly mydriasis, antiinflammatory and immunization therapy to the Therapeutic Method of conjunctivitis in prior art, wherein mydriasis and antiinflammatory are mainly for the treatment means that symptom is taked, and immunization therapy more lays particular emphasis on the removal cause of disease.Immunotherapy medicaments for conjunctivitis in prior art is mainly immunosuppressant, such as azathioprine is by emulative suppression adenine and guanine, thus suppress DNA synthesis and rna transcription, reduce peripheral T lymphocyte, bone-marrow-derived lymphocyte quantity, Immunosuppression lymph reacts, and cyclophosphamide all has cytotoxic effect for the lymphocyte of resting stage and division stage, thus Immunosuppression reaction.
Summary of the invention
The present invention is intended to the technological deficiency for prior art, provides the novelty teabag of cimetidine in preparation autoimmune membranous conjunctivitis medicine, thus provides a kind of new medicament selection for the treatment of autoimmune membranous conjunctivitis.
Another technical problem that the present invention will solve extends the indication scope of cimetidine as medicine;
The technical problem again that the present invention will solve is the therapeutic effect promoting autoimmune membranous conjunctivitis.
For solving above technical problem, the present invention by the following technical solutions:
Formula (1) compound for the preparation of the application of autoimmune membranous conjunctivitis medicine,
Preferably, described medicine reduces the medicine that Th1 lymphocyte content is pharmacological action.
Preferably, described medicine reduces the medicine that Th17 lymphocyte content is pharmacological action.
Preferably, described medicine suppresses the medicine that Th1 lymphocytic emiocytosis IFN-γ is pharmacological action.
Preferably, described medicine suppresses the medicine that Th17 lymphocytic emiocytosis IL-17A is pharmacological action.
Preferably, described medicine suppresses a medicine that conjunctiva macrophages infiltration is pharmacological action.
In above technical scheme, described medicine is the innerlich anwenden with administered in oral forms.The discovery cimetidine immunity-regulating systemic effect of novelty of the present invention, thus be used for the treatment of related pathologies damage.Specifically, Th1 cell subsets, Th17 cell subsets ratio can be lowered, maintain blood eye conjunctiva barrier integrity, suppress macrophages infiltration, suppress ocular inflammatory response.Can suppress conjunctiva STAT1, STAT3 and phosphorylated protein expression thereof simultaneously, suppress the expression of NF-κ Bp65, its anti-inflammatory effect realizes by suppressing STAT1, STAT3 approach and NF-κ B signal transduction pathway.
Based on the above new property of cimetidine, the present invention determines the novelty teabag utilizing its treatment conjunctivitis, and clinical practice finds, the treatment of cimetidine to autoimmune membranous conjunctivitis is rapid-action, determined curative effect, and does not find side effect, has outstanding promotion prospect.
Accompanying drawing explanation
Fig. 1 is control group mice and cimetidine treatment group laboratory animal eye fundus image in the embodiment of the present invention; Wherein part A is matched group laboratory animal fundus Oculi Manifestations, and part B is cimetidine treatment group laboratory animal fundus Oculi Manifestations.
Fig. 2 is control group mice and cimetidine treatment group laboratory animal clinical score result in the embodiment of the present invention.
Fig. 3 is control group mice and cimetidine treatment group tissues of experimental animals appraisal result in the embodiment of the present invention.
Fig. 4 is control group mice and cimetidine treatment group laboratory animal eye conjunctiva vascular perfusion radiography eye conjunctiva paving sheet in the embodiment of the present invention; Wherein part A is control group mice result, and part B is cimetidine treatment group mouse results.
Fig. 5 is control group mice and cimetidine treatment group laboratory animal helper T lymphocyte subgroup distribution situation figure in the embodiment of the present invention.
Detailed description of the invention
Below will be described in detail the specific embodiment of the present invention.In order to avoid too much unnecessary details, in the examples below to belonging to known structure or function will not be described in detail.
The approximating language used in following examples can be used for quantitative expression, shows to allow quantity to have certain variation when not changing basic function.Therefore, this exact value itself is not limited to the numerical value that the language such as " approximately ", " left and right " is revised.In certain embodiments, " approximately " represents and allows its numerical value revised to change in the positive and negative scope of 10 (10%), such as, and any numerical value that what " about 100 " represented can be between 90 to 110.In addition, in the statement of " about first numerical value is to second value ", revise the first and second numerical value two numerical value approximately simultaneously.In some cases, approximating language may be relevant with the precision of gauge.
Apart from outside definition, technology used in following examples and scientific terminology have the identical meanings generally understood with those skilled in the art of the invention.
The foundation of 1 ill model
Get 6-8 mice in age in week, body weight 15-20g, raises in standardization specific pathogen free animal (SPF) level Animal House, laboratory animal standard particle forage feed, freely drinks water and ingests, and room temperature is (22 ± 2) DEG C,, the IRBP of subcutaneous injection emulsifying after adaptability raising 2-7d
1-20vola pad, bilateral root of the tail and rear buttocks behind model group mice side, injections of antigens 300 μ g altogether, the pertussis bacilli * 1 of intraperitoneal injection simultaneously μ g destroys the general immunity tolerance of mice, and to strengthen immune effect, immunity was denoted as the 0th day (day0) same day.
2 administering modes
Start to carry out gastric infusion to cimetidine group mice continuously every day with the dosage of 25mg/kgday, until after immune modeling the 21st day (day21) from first 3 days of immune modeling (day-3).Because cimetidine is organic compound, be dissolved in organic solvent DMSO and be insoluble to PBS, therefore cimetidine dissolves with 10 μ lDMSO+140 μ lPBS, matched group is adopted in the same way with the process of blank solvent 10 μ lDMSO+140 μ lPBS gavage.
3 therapeutic effect are observed
In the 12nd day (day12) after immunity every day Continuous Observation matched group and cimetidine group mice damage of fundus situation, method is: after the abundant mydriasis of compound tropicamide eye drops, uses binocular indirect ophthalmoscope, auxiliary+90D preset lens darkroom examination.
After immunity, the 21st day (day21) carries out the clinical score of mice damage of fundus to two groups of mices, and standards of grading are in table 1.Jointly randomized, double-blind marking is carried out to all mice bilateral damage of fundus situations by two ophthalmologistss.
Table 1 disease mice clinical score standard
4 mice eye fundus images gather
After immunity, the 21st day (day21) carries out eye fundus image collection to two groups of mices.With the abundant mydriasis of compound tropicamide eye drops, Oxybuprocaine hydrochloride eye drops topical anesthesia, anterior corneal surface is coated with Medical sodium hyaluronate gel, and the impact of corneal curvature eliminated by upper covering slide.Peep into optical fundus with 0 degree of otoscope, computer generated image system acquisition eye fundus image.
The HE stained of getting matched group and cimetidine group eyeball of mouse respectively observes the organizational structure of a conjunctiva and vitreous chamber, inflammatory cell infiltration situation under an optical microscope, and carries out histopathological scores, and standards of grading are in table 2.Jointly two groups of eyeball of mouse are cut into slices by two ocular pathology doctors and carry out randomized, double-blind marking respectively.
Table 2 disease mice histopathological scores standard
5 azovan blue (EB) vascular perfusion radiography eye conjunctiva paving sheet
After immunity, matched group and cimetidine group are got 4 mices by the 21st day (day21) respectively, carry out EB vascular perfusion radiography eye conjunctiva paving sheet.
(1) anaesthetize: after weighing, 10% chloral hydrate is with 300mg/kg intraperitoneal injection of anesthesia;
(2) EB injection: 29G syringe needle punctures into tail intravenous injection 2%EB100 μ l, circulates 2 hours;
(3) fixing: put to death mice, win eyeball, being placed in concentration is that 4% paraformaldehyde solution fixes 3 hours;
(4) eye conjunctiva is peeled off: under operating microscope, cut about 0.5mm place after eyeball corneoscleral junction with corneosclera cut off, removing cornea, iris, give birth to crystalline lens and vitreous body.Cut off 4 cuttves by radial centered by optic disc for eye conjunctiva, be placed on microscope slide, carefully sclera is overturn with micro-toothed forceps, completely isolate a conjunctiva, be laid on microscope slide;
(5) mounting: with coverslip mounting after a little mountant;
(6) take a picture: be placed in laser scanning co-focusing fluorescence microscopy Microscopic observation, photograph immediately.
6 mouse boosting cell flow cytometries
After immunity, the 21st day (day21) detects treatment group mice and PBS matched group splenic T h17 cell, Th1 cell account for mononuclearcell ratio, and Treg cell, Th0 cell account for the lymphocytic ratio of CD4+T respectively, often organize and get 5 mices.
The preparation of 6.1 mouse spleen single cell suspensions
(1) mice is with after 10% chloral hydrate intraperitoneal injection of anesthesia, immerse 75% ethanol in 10 minutes, mice gets right arm reclining, successively cut abdominal cavity open, abundant exposure spleen, take out spleen under aseptic condition and put into sterile petri dish containing 1%BSA, carefully remove fascia and fatty tissue, and with shears, spleen is divided into fine grained chippings (1-2mm);
(2) aseptic 50ml centrifuge tube is placed 40 μm of aseptic sterile nylon nets, the spleen tissue split is inserted on it, aseptic dropper instillation 1%BSA;
(3) grind spleen gently with bolt in the syringe of 5ml, add appropriate 1%BSA simultaneously and rinse, abundant to grinding, about 10ml spleen single cell suspension altogether;
(4) centrifuge tube is placed in centrifuge, adjustment centrifugal condition: 25 DEG C, 1200rpm, centrifugal 5min, gently supernatant discarded;
(5) adding 5-6ml erythrocyte cracked liquid and slowly shaking makes cell resuspended;
(6) indoor standing 4-5min, treats that erythrocyte splitting completes, and adds the aseptic PBS of 10ml and stops lysis;
(7) centrifugal after adding 10ml1%BSA, 25 DEG C, 1200rpm, centrifugal 10min, abandons supernatant, adds 10ml1%BSA, gently shakes centrifuge tube, re-suspended cell;
(8) after leaving standstill 2-3min, 25 DEG C, 1200rpm, centrifugal 10min, abandons supernatant, adds 700 μ l1%BSA, re-suspended cell;
(9) 10 μ l single cell suspensions are got, row cell counting;
(10) adjusting cell density according to cell counts is 5 × 10
6/ ml.
The flow cytometer detection of 6.2 mouse spleen Th1 and Th17 cell
6.2.1 Th1 and Th17 cytokine secretion is stimulated
(1) aseptic 24 orifice plates are got, every hole adds the above-mentioned spleen single cell suspension of 100 μ l, the culture medium that 900 μ l prepare, 0.5 μ l1mg/mlPMA (final concentration is 500ng/ml), 0.5 μ l1mg/ml ionomycin (final concentration is 500ng/ml), 1 μ lBFA (1 μ g/ml), mixes gently, and 4h cultivated by 37 DEG C of aseptic incubators.
(2) take out 24 orifice plates, mix liquid in hole gently, in sucking-off to corresponding streaming pipe.
(3) the streaming pipe that cell suspension is housed is placed in centrifuge centrifugal: 25 DEG C, 2000rpm, 3min, abandon supernatant.
(4) add 2mlPBS re-suspended cell, 25 DEG C of centrifugal 2000rpm, 3min, abandon supernatant.
6.2.2Th1 with Th17 cell born of the same parents dye outward
(1) streaming pipe label, add mice FITC-CD4 antibody, beat mixing gently, room temperature lucifuge hatches 15min;
(2) add 1mlPBS mixing, 2000rpm, 25 DEG C, centrifugal 5min, abandons supernatant;
(3) again add 1mlPBS resuspended, 2000rpm, 25 DEG C, centrifugal 5min, abandons supernatant.
6.2.3 dyeing in born of the same parents
(1) 500 μ l rupture of membranes agent are added in each streaming pipe, room temperature lucifuge rupture of membranes 20min;
(2) 25 DEG C, 350g, centrifugal 5min, abandons supernatant;
(3) add 1ml rupture of membranes buffer (1 ×), re-suspended cell, 25 DEG C, 350g in each streaming pipe, centrifugal 5min, abandons supernatant;
(4) for adding 1 μ l mice PE-IL-17 antibody in the streaming pipe of Th1 cell dyeing, for adding 1 μ l mice PE-IFN-gamma antibodies in the streaming pipe of Th17 cell dyeing, beat mixing gently, room temperature lucifuge hatches 20min;
(5) add 1mlPBS solution, re-suspended cell, be placed in centrifuge centrifugal, condition: 25 DEG C, 350g, centrifugal 5min, abandons supernatant;
(6) previous step is repeated;
(7) add 500 μ l4% formalin fixed cells, 4 DEG C keep in Dark Place and spend the night;
(8) 25 DEG C, 350g, centrifugal 5min, abandons supernatant;
(9) 500 μ l sheath fluid re-suspended cells are added, strainer filtering, upper machine testing analysis.
7 experimental results
7.1 the mice fundus Oculi Manifestations under cimetidine intervention
The incidence on Continuous Observation matched group and all mice optical fundus of cimetidine group from the 12nd after mouse immune day, and the 21st day after immunity carries out optical fundus picture collection to mice.Image display control group mice has that obvious eye conjunctivitis oozes out, vasculitis and papilloedema (Figure 1A), and cimetidine group mice optical fundus does not find obviously to ooze out, edema or inflammatory lesion (Figure 1B).Comparatively inflammation performance in control group mice optical fundus is light for cimetidine group mice.
Comparatively inflammation performance in control group mice optical fundus is light for cimetidine group mice.Eye fundus image collection was carried out to mice in 21st day after immunity.Figure 1A shows, control group mice fundus Oculi Manifestations, and visible significantly eye conjunctivitis oozes out, eye conjunctiva vasculitis, papilloedema; Figure 1B shows cimetidine group mice fundus Oculi Manifestations, and eye conjunctiva has no and obviously oozes out, and blood vessel is normally out of shape, depending on nipple boundary clear
Clinical score under 7.2 cimetidine interventions
Clinical score was carried out to two groups of mice eye ground in the 21st day after immunity according to disease mice clinical score standard.As shown in Figure 2, cimetidine group is compared with matched group, and clinical score significantly reduces.
Histopathological scores under 7.3 cimetidine interventions
According to ill model clinical score standard, histopathological scores is carried out to little rathole conjunctiva HE stained.As shown in Figure 3, cimetidine group is compared with matched group, and histopathological scores significantly reduces.
7.4EB vascular perfusion radiography eye conjunctiva paving sheet result
A conjunctiva paving sheet is carried out respectively to matched group and cimetidine group mice, to evaluate the effect of cimetidine to eye conjunctiva vascular permeability and BRB integrity.Result shows: the visible EB of matched group is extensive and Mass ground outwards oozes out (Fig. 4 A) from eye conjunctiva blood vessel, and the eye conjunctiva blood vessel of cimetidine group mice is normally out of shape, has no obvious dyestuff and oozes out (Fig. 4 B) from blood vessel.
As shown in Figure 4 A, control group mice is after azovan blue vascular perfusion circulates 2 hours, and a large amount of fluorescent dye outwards oozes out from eye conjunctiva blood vessel.As shown in Figure 4 B, cimetidine group mice has no obvious azovan blue dyestuff and exosmoses.
7.5 Flow cytometry mouse spleen helper T lymphocyte subgroup results
Flow cytometry is a kind of emerging detection means can carrying out quantitative analysis from functional level to cell.Adopt flow cytometry to carry out quantitative analysis to matched group and cimetidine group mouse spleen helper T lymphocyte subgroup, inquire into cimetidine to the impact of disease mice spleen helper T lymphocyte subgroup.Flow cytometry results display cimetidine group mice Th1 cell, Th17 cell account for mononuclearcell group ratio comparatively control group mice reduction (Fig. 5 A, B).
As shown in Figure 5, A. Flow cytometry CD4, IFN-γ labelling mouse spleen Th1 cell mass, cimetidine group comparatively matched group significantly reduces.B. Flow cytometry CD4, IL-17 labelling mouse spleen Th17 cell mass, cimetidine group comparatively matched group significantly reduces.
In sum, can prove that oral cimetidine has therapeutical effect to autoimmune membranous conjunctivitis, its therapeutical effect is the imbalance by regulating helper T lymphocyte subgroup, maintains the integrity of blood eye conjunctiva barrier, suppresses ophthalmic macrophages infiltration to realize.
Claims (6)
1. formula (1) compound is for the preparation of the application of autoimmune membranous conjunctivitis medicine,
2. application according to claim 1, is characterized in that described medicine reduces the medicine that Th1 lymphocyte content is pharmacological action.
3. application according to claim 1, is characterized in that described medicine reduces the medicine that Th17 lymphocyte content is pharmacological action.
4. application according to claim 1, is characterized in that described medicine suppresses the medicine that Th1 lymphocytic emiocytosis IFN-γ is pharmacological action.
5. application according to claim 1, is characterized in that described medicine suppresses the medicine that Th17 lymphocytic emiocytosis IL-17A is pharmacological action.
6. application according to claim 1, is characterized in that described medicine suppresses a medicine that conjunctiva macrophages infiltration is pharmacological action.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101180038A (en) * | 2005-03-23 | 2008-05-14 | 伊兰制药国际有限公司 | Nanoparticulate corticosteroid and antihistamine formulations |
| CN105030753A (en) * | 2015-06-26 | 2015-11-11 | 天津医科大学总医院 | Application of flavonoids compounds in preparation of T lymphocyte subsets regulating drug |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101180038A (en) * | 2005-03-23 | 2008-05-14 | 伊兰制药国际有限公司 | Nanoparticulate corticosteroid and antihistamine formulations |
| CN105030753A (en) * | 2015-06-26 | 2015-11-11 | 天津医科大学总医院 | Application of flavonoids compounds in preparation of T lymphocyte subsets regulating drug |
Non-Patent Citations (3)
| Title |
|---|
| 李殿富等: "《全国乡镇（社区）医护人员培训室试用教材 眼科学分册》", 30 June 2011 * |
| 肖进文: "西咪替丁的几种新用途", 《江西医药》 * |
| 赵越筑: "西咪替丁治疗重症春季角结膜炎的临床疗效", 《中国实用眼科杂志》 * |
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Application publication date: 20160302 |