CN1784225A - Angiotensin II receptor blockers for preventing the development or progression of microvascular disease due to diabetes - Google Patents

Angiotensin II receptor blockers for preventing the development or progression of microvascular disease due to diabetes Download PDF

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CN1784225A
CN1784225A CNA200480011878XA CN200480011878A CN1784225A CN 1784225 A CN1784225 A CN 1784225A CN A200480011878X A CNA200480011878X A CN A200480011878XA CN 200480011878 A CN200480011878 A CN 200480011878A CN 1784225 A CN1784225 A CN 1784225A
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angiotensin
receptor blockers
diabetes
active oxygen
cell
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山岸松一
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Boehringer Ingelheim International GmbH
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    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
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    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
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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
    • 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
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)

Abstract

The invention relates to the field of inhibitors of angiotensin II receptor blockers and particularly addresses their use in diabetes to prevent the development or progression of microvascular disease (i.e. disease involving small blood vessels) affecting eyes (diabetic retinopathy) and kidneys (diabetic nephropathy).

Description

Be used to prevent the development of the microvascular disease that causes by diabetes or the angiotensin-ii receptor blockers of deterioration
The present invention relates to angiotensin-ii receptor blockers (inhibitors of angiotensin II receptorblockers) field, and be specifically related to described blocker and be used for preventing influencing the development of microvascular disease (promptly relating to microvascular disease) of eyes (diabetic retinopathy) and kidney (diabetic nephropathy) or the purposes of deterioration (progression) in diabetes.
Diabetes be can not be in body the disease of homergy carbohydrate (for example, food starch, sugar, cellulose).This disease is characterised in that, excessive sugar is present in blood (hyperglycemia) and the urine, and insulin generates and/or be under-utilized, and thirsty, hungry and lose weight.Diabetes affects about 2% population.This 10-15% wherein is insulin-dependent (1 type) diabetes, and remaining is non-insulin-dependent (2 type) diabetes.
Retinopathy be by blood capillary change cause to amphiblestroid damage.Diabetic retinopathy is 1 type and the specific microvascular complication of type 2 diabetes mellitus.The sickness rate of retinopathy and the persistent period of the diabetes connection that is closely related.Suffer from diabetes after 20 years, nearly all type 1 diabetes patient and surpass 60% type 2 diabetes mellitus patient and have in various degree retinopathy.The probability that diabetics loses one's sight is higher 25 times than the general population./ 5th retinopathys that have in various degree in newly diagnosing out diabetics.In addition, retinopathy develops is morning, and more serious in having the diabetics of elevated systolic blood pressure levels.Usually, suffer from diabetes after 7 years careful ophthalmologic examination can find slight retinal abnormalities, but after threatening the damage of vision to usually occur in a lot of years.In the crowd at work age of many countries, diabetic retinopathy is the blind reason of the most common initiation.
Early stage at retinopathy causes the expansion (microaneurysm) in blood vessel and the seepage (hemorrhage) of body fluid (transudate) and blood at the medium and small blood vessel of retina weak.The late stage of disease is the hypertrophy retinopathy, and it relates on retina He in the vitreous body and grows crisp new vessels, and occurs colloid substance in eyeball.These blood vessels may break and discharge blood in vitreous body, and this can cause blurred vision or temporary blind.May tie tight retina and therefore cause detachment of retina of the scar tissue that can occur subsequently, it can cause permanent vision loss.The macular edema that expands and cause owing to accumulative body fluid around the macula lutea also may take place, and macula retinae is vital for good vision.If do not treat the hypertrophy retinopathy, only about half of will in 5 years, the losing one's sight among the patient, and in the patient who is treated, only have 5%.
If earlier detection arrives, this disease can be used laser photocoagulation and treat.In addition, at any time reducing the hyperglycemia that is caused by diabetes will significantly reduce the long-term incidence and the deterioration (progression) of retinopathy and develop into visual loss.In EUCLID research, Angiotensin-Converting (ACE) inhibitor lisinopril (lisinopril) can reduce the risk that about 50% retinopathy worsens, and can significantly reduce the risk that the hypertrophy retinopathy worsens.But retinopathy is not a main target in EUCLID research, so this research can not be enough to draw the conclusion with the eyes relevant disease.The expense relevant with DE compared, prevent this advancing of disease or worsen can be under the condition of low relatively expense effective vision protection.Therefore, the object of the invention is to provide the development that prevents diabetic retinopathy or other method of deterioration of being beneficial to.
Nephropathy is the decline of kidney.Diabetic nephropathy is the specific microvascular complication of 1 type and type 2 diabetes mellitus.The easier end-stage renal disease (ESRD) that causes being called end-stage renal disease of type 1 diabetes.Diabetic nephropathy has five stages, and five-stage is ESRD.From a stage development is that the next stage can be through many years, and the average length of time that develops into five-stage is 23 years.Diabetes are the modal reasons that cause ESRD, are higher than 40% case in the U.S. and can cause ESRD.
Make great efforts control and slow down advancing of disease for the treatment of diabetic nephropathy.Protecting in the renal function to being controlled at of aggressivity blood pressure is important factors.Angiotensin converting enzyme inhibitor is considered to and can provides best protection for kidney.According to RENAAL research (Brenner etc.; The NewEngland Journal of Medicine 345:861-869; 2001) angiotensin-ii receptor blockers losartan (losartan) may provide similar protection, but measures still very care for patient crowd and result now.Because flaw and incomplete data on these methods under study for action, still there is not answer (Fisman etc., CardiovascularDiabetology 1:2,2002) for the query of effectiveness in treatment of diabetic nephropathy and safety.Data (Lewis etc. from similar IDNT research; The NewEngland Journal of Medicine 345:851-860; 2001); obtained protecting the nephropathy that causes by type 2 diabetes mellitus in order to avoid the development nervous plain II receptor blocking agent irbesartan of medium vessels (irbesartan) is effective as drawing a conclusion.Yet ward off disease development or deterioration have the ability of protection renal function.Therefore, another aspect of the present invention provides other method to help preventing the development or the deterioration of diabetic nephropathy.
Angiotensin II plays an important role in pathophysiology, particularly can be used as the most effective blood pressure growth promoter of the mankind.Angiotensin H receptor blocking agent is specially the blocker of 1 receptor, is used for the treatment of hypertension and congestive heart failure in mammal.The example of angiotensin-ii receptor blockers (being also referred to as the Angiotensin II antagonist) is described in EP-A-253310, EP-A-323841, EP-A-324377, EP-A-420237, EP-A-43983, EP-A-459136, EP-A-475206, EP-A-502314, EP-A-504888, EP-A-514198, WO 91/14679, WO 93/20816, US 4,355,040 and US 4, in 880,804.Concrete angiotensin-ii receptor blockers is for example Candesartan (candesartan), Eprosartan (eprosartan), irbesartan (irbesartan), losartan (losartan), Olmesartan (olmesartan), Tasosartan (tasosartan), telmisartan (telmisartan) or a valsartan (valsartan) of husky smooth class.
Set up ongoing diabetic retinopathy Candesartan test (DIRECT) project, to detect the sickness rate and the deterioration that whether can prevent diabetic retinopathy by the AT1-receptor of Candesartan blocking-up.This project relates to normotensive individuality or the hypertensive individuality through treating, and will assess the effectiveness of AT1-receptor blocking agent in the eye pathological change that protection is caused by diabetes.(sjlieand?Chaturvedi，Joumal?of?Human?Hypertension(August?2002)16?Suppl，pages?42-46)。
In the context of the present invention, angiotensin-ii receptor blockers is to detect in the cell culture system of having avoided extensive clinical trial to the development of retinopathy or the effect in the deterioration.No matter selected or possible Angiotensin II inhibitor whether in the development that prevents retinopathy or in worsening effectively, this system all can detect.
Only by two kinds of cells, epithelial cell and perithelial cells constitute the blood vessel of microvasculature.The epithelial growth of perithelial cells regulation and control co-cultivation, and in keeping the microvascular homeostasis, play important effect.For example their protect the function of the epithelial cell of co-cultivation with the generation prostacyclin, and protect it not to be subjected to lipid-peroxide-inductive damage.Pericyte loss and dysfunction are the early stage observed distinctive histopathology signs at diabetic retinopathy.
The method according to this invention can be specially preventing that development of diabetic retinopathy or nephropathy or the angiotensin-ii receptor blockers that worsens from screening angiotensin-ii receptor blockers.This method comprises
(a) exist or do not exist under the situation of effective angiotensin-ii receptor blockers chemical compound, using or do not use Angiotensin II to handle the perithelial cells tissue culture cells
(b) measure the amount of the active oxygen in cell, produce, and
(c) identify described chemical compound, it suppresses, and inductive cell interior produces active oxygen owing to there is Angiotensin II in culture medium.
The cell culture system that adopts is based on from the mammal retina isolating perithelial cells of bovine retina for example.This cell is at the cell culture medium that usually replenishes hyclone that commerce can get for example in Dulbecco ' sEagle ' s culture medium.The term active oxygen comprises molecule such as hydrogen peroxide, ion such as hypochlorite ion, and group such as hydroxyl, this hydroxyl are to have reactivity most in all they, and are the superoxide anion of ion and group simultaneously.An important aspect of this method is to have found that after handling cultured cells with Angiotensin II producing in the cell of active oxygen increases in the dose dependent mode in perithelial cells.Simultaneously in perithelial cells by mix [ 3H] the synthetic reduction of DNA measured of thymidine, and the mRNA of vascular permeability factor (VEGF) and platelet derived growth factor-B (PDGF-B) increases, wherein vascular permeability factor is the epithelial specificity mitogen that relates in the pathogeny of proliferative diabetic retinopathy, and platelet derived growth factor-B is the effective mitogen and the chemoattractant of blood capillary epithelial cell and glial cell in the retina.
Angiotensin II is hypertensive initiator, and known hypertension is the main hazard factor of diabetic retinopathy and nephropathy.Other molecule of reactive oxygen species damage, and therefore destroy cellularity.Usually cell is used the illeffects that various defensive measures prevent active oxygen, comprises micromolecule for example alpha tocopherol (vitamin E), uric acid and vitamin C or two kinds of enzyme superoxide dismutase and catalase with anti-oxidation characteristics.When handling perithelial cells, add additional amount antioxidant such as N-acetylcystein (NAC) and will reverse by the increase that exists the inductive active oxygen of Angiotensin II to produce with Angiotensin II.
Based on these discoveries, can suppress in perithelial cells is cultivated owing to producing in the cell that is present in the inductive active oxygen of Angiotensin II in the cell culture medium if lack the chemical compound of anti-oxidation characteristics, they will prevent the development or the deterioration of diabetic retinopathy or nephropathy.Therefore, can under chemical compound existence or non-existent condition, handle perithelial cells 1-48 hour, preferred 24 hours, screen this chemical compound by using or do not use Angiotensin II.After the treatment, the generation of detection of active oxygen class.Angiotensin-ii receptor blockers such as telmisartan (telmisartan) have been found with this screening technique, being suppressed at the increase that perithelial cells is produced by the inductive active oxygen of Angiotensin II in cultivating, yet only can not influence the generation of active oxygen with the processing of receptor blocking agent.Therefore, help the pathogenesis of diabetic microangiopathy in the activation of the nervous plain II receptor signal conduction of perithelial cells medium vessels, use chemical compound for example the nervous plain II of telmisartan antagonizing vessel prevented the disease for example development or the deterioration of diabetic retinopathy by reducing pericyte loss and malfunction.
Result as these discoveries, the present invention has instructed a kind of preventing to comprise the angiotensin-ii receptor blockers to the individual administration pharmacy effective dose of needs by the caused microvascular disease of diabetes for example diabetic retinopathy or the development of nephropathy or the method for deterioration.Angiotensin-ii receptor blockers can be used for pharmaceutical compositions to prevent development or the deterioration by the caused microvascular disease of diabetes in the individuality of needs.
The preferred example of angiotensin-ii receptor blockers is Candesartan, Eprosartan, irbesartan, losartan, Olmesartan, telmisartan or valsartan, as long as but can in cultivating, suppress perithelial cells the increase that produces by the inductive active oxygen of Angiotensin II, and any receptor blocking agent all can use.Thinking needs the individuality of this treatment to be influenced by one or more diabetic retinopathy risk factor.The example of this risk factor is diabetes, hyperglycemia level, albuminuria, high blood urea nitrogen, high blood creatinine, microalbuminuria or systemic hypertension.
The amount of the receptor blocking agent that adopts depends on actual active ingredient, and is equivalent to be used for the treatment of hypertensive amount usually.Can be according to per os, buccal, parenteral, suction spraying, rectum or topical reactive compound, preferred oral administration.That the parenteral administration can comprise is subcutaneous, vein, intramuscular and breastbone inner injection and infusion techniques.
Be used to prevent that diabetic retinopathy from developing or the angiotensin-ii receptor blockers of the pharmacy effective dose that the pharmaceutical composition of deterioration comprises, it depends on the mode of administration substantially.Dosage range comprises 0.5-500mg/kg p.o., preferred 2-80mg/kg p.o., and 3mg/kg i.v.
Reactive compound that can the various different dosage forms of oral administration, promptly it can use various pharmaceutical acceptable inert carriers to be mixed with the form of tablet, capsule, lozenge, buccal tablet, hard sugar agent, powder, spray, aqueous suspension, elixir, syrup etc.Described carrier comprises solid diluent or filler, sterile aqueous media and various nonpoisonous organic solvents etc.And these oral pharmaceutical formulations can be carried out suitable increase sweet taste and/or seasoning by using the various additives that are used for the common type of this type of purpose.Usually, the concentration level of chemical compound of the present invention in these peroral dosage forms counted about 0.5%-90% with the weight of whole compositionss, and this dosage is enough to provide the unit dose of expectation.The suitable dosage form of other of The compounds of this invention comprises sustained release preparation and equipment well known to those of ordinary skill in the art.
In order to be used for oral administration, comprise various excipient for example the tablet of sodium citrate, calcium carbonate and calcium phosphate can comprise various disintegrating agents such as the preferred Rhizoma Solani tuber osi of starch or tapioca, alginic acid and some composition silicate, and binding agent such as polyvidon, sucrose, gelatin and arabic gum.In addition, the compositions of lubricant such as magnesium stearate, sodium lauryl sulfate and Talcum or similar type also can be used as filler and is employed in the soft hard filling gelatine capsule; This filler comprises lactose (lactose) or lactose (milk sugar) and high molecular weight polyethylene glycol.When hope is used for oral administration with aqueous suspension and/or elixir, wherein necessary active component can with various sweeting agents or flavoring agent, coloring agent or dyestuff, if desired, emulsifying agent and/or water, ethanol, propylene glycol, glycerol and its various combinations are combined.
In order to be used for the parenteral administration, can adopt chemical compound at Oleum sesami or Oleum Arachidis hypogaeae semen or the solution in aqueous propylene glycol, and at corresponding officinal salt aseptic aqueous solution.If desired, described aqueous solution can suitably be cushioned, and this liquid diluent waits with the saline of capacity or glucose and oozes.These concrete aqueous solutions can be specially adapted to intravenous, intramuscular and subcutaneous injection purpose.At this on the one hand, the sterile aqueous media of employing can easily be obtained by standard technique well known to those of ordinary skill in the art.For example, use distilled water usually, and final preparation is by suitable biofilter such as sintered glass filter or kieselguhr or unglazed porcelain filter as liquid diluent.The preferred filter of this type comprises Berkefeld, Chamberland and Asbestos Disk-Metal Seitz filter, and wherein said liquid is inhaled into sterile chamber under the help of suction pump.In the preparation of these Injectable solutions, need take necessary step is aseptic condition with the final products of guaranteeing to obtain.In order to be used for transdermal administration, the dosage form of particular compound can comprise for example extended release preparation and the equipment thereof of solution, washing liquid, ointment, cream, gel, suppository, speed limit.These dosage forms comprise particular compound, also can comprise material that ethanol, water, penetration enhancer and inert carrier for example produce gel, liquid Paraffin, emulsifying agent, benzyl alcohol etc.
Angiotensin-ii receptor blockers can be 10mg (or 0.143mg/kg according to dosage every day, in the body weight for humans is 70kg) to 500mg (7.143mg/kg) oral administration, with with the administration of about 20mg (0.286mg/kg) parenteral, preferably with 20mg (0.286mg/kg) to 100mg (1.429mg/kg) oral administration.Particularly preferably be according to every day dosage be that 40mg (0.571mg/kg) is to 80mg (1.143mg/kg) or be in particular about 80mg (1.143mg/kg) oral administration.
Some angiotensin-ii receptor blockers have appeared on the market and can be used for administration, for example Approvel , Atacand , Blopress , Cozaar , Diovan , Karvea , Lortaan , Lorzaar , Losaprex , Micardis , Neo-Lotan  or Oscaar  and Teveten .
Embodiment
All value representations are meansigma methods ± standard error (SE).Use Shi Didunteshi t test for the paired evaluation of relatively carrying out significance,statistical, it is significant that P＜0.05 is considered to.
The detection of embodiment 1 active oxygen in perithelial cells
As at Yamagishi etc., Circulation 87:1969, described in 1993 like that, from bovine retina, separate perithelial cells, and in being supplemented with Dulbecco ' sEagle ' s culture medium of 20% hyclone (FBS), cultivate.
The processing of Angiotensin II is carried out in comprising the culture medium of 2%FBS.Exist or do not have 10 -7Under the condition of M telmisartan, use or do not use 10 -7Or 10 -6The M Angiotensin II was handled perithelial cells 24 hours.Use fluorescent probe CM-H then 2(Molecular Probes Inc, Eugene OR) according to by Yamagishi etc., produce in the A J Biol Chem 276:25096, the cell of 2001 described method detection of active oxygen classes DCFDA.
Angiotensin II has increased active oxygen in intracellular generation in the dose dependent mode.10 -6The M Angiotensin II has caused about 1.3 times increase.Have been found that telmisartan can be suppressed at the increase that is produced by the inductive active oxygen of Angiotensin II in the perithelial cells fully, and only telmisartan can not influence this generation.
[3H] thymidine that embodiment 2 detects in perithelial cells mixes
Exist or do not exist under the condition of 1mM N-acetylcystein (NAC), use or do not use the 10-7M angiotensin to handle perithelial cells 24 hours, then according at Yamagishi etc., FEBSLett 384:103, the method described in 1996 detects that [3H] thymidine mixes in the cell.
The DNA that Angiotensin II has suppressed significantly in perithelial cells is synthetic.NAC has prevented in perithelial cells by Angiotensin II inductive in the disease of DNA aspect synthetic significantly.
The quantitative reverse transcription PCR of embodiment 3 VEGF m-RNA
The sequence and the primer that are used to detect VEGF and beta-actin mRNAs are described in Yamagishi etc., and J Biol Chem 272:8723 is in 1997.
Poly (A) +RNAs is by cell separation, this cell exists or does not exist under the condition of 10-7M telmisartan or 1mM NAC, use or do not use the 10-7M Angiotensin II to handle 4 hours, and this Poly (A)+RNAs is according to Yamagishi etc., Diabetologia 41:1435,1998 described quantitative reverse transcription PCRs (RFPCR) are analyzed.Poly (A) +Amount of RNA template (about 30ng) and expanded cells division cycle number (28 cycles of VEGF gene, 22 cycles of beta-actin gene) be selected at quantitative scope, be to carry out linear reaction, it is according at Yamagishi etc., J BiolChem 277:20309, that describes in 2002 passes through signal intensity is detected as the function construction of template amount and cell cycle numbers.
Reported and from single VEGF gene, had five kinds of optional montage products (splicedproduct).They are called as VEGF121, VEGF145, VEGF165, VEGF189 and VEGF206.Because the analysis of the RNA marking can not clearly distinguish this five kinds of mRNA products, we adopt at Okamoto etc., FASEB J 16:1928, the responsive more sxemiquantitative RT-PCR technology of describing in 2002.In these experiments, the cDNA product of 486 and 618 base pair length is increased by the mRNA of VEGF121 and VEGF165 respectively.Angiotensin II can just regulated these secreted forms of VEGF mRNA level significantly in perithelial cells.When being exposed to the 10-7M Angiotensin II, VEGF mRNA level is higher approximately 1.5 times than basic horizontal.Have been found that telmisartan and NAC are suppressed in the perithelial cells the just adjusting by Angiotensin II-inductive VEGF mRNA level fully.
The molecular cloning of 4 Ns of PDGF-B Partial cDNA of embodiment
Cattle PDGF-B Partial cDNA uses primer sequence to clone, and this primer sequence is designed by conserved amino acid sequence GELESL and NNRNVQ in people and sheep PDGF-B.The upstream and downstream primer is respectively 5 '-GGCGAGCTGGAGAGCTT-3 ' and 5 '-CTGCACGTTGCGGTTGT-3 '.According to the manufacturer (Promega, Madison, WI, pGEM-T Easy Vector System is used in USA) explanation, is obtained the RT-PCR product of 213-base pair by 30ng bovine retina perithelial cells Poly (A)+RNA amplification and clone.Clone's PCR product according to manufacturer explanation (the determined dna sequence test kit, Applied Biosystems, Foster, CA USA) uses the chain termination method to check order.Clone's cattle cDNA fragment demonstrates and people and the surprising sequence similarity of sheep PDGF-B.Compare with people and sheep PDGF-B, nucleotide identifies and is respectively 91% and 94% that aminoacid is identified and is respectively 91% and 96%.
The quantitative reverse transcription PCR of embodiment 5 PDGF-B m-RNA
In order to study Angiotensin II effect to PDGF-B gene expression in the retina perithelial cells of cultivating, Poly (A)+RNA separated from cell and according at Yamagishi etc., KidneyInt 63:464, RT-PCR described in 2003 analyzes, wherein said cell exists or does not exist under the condition of 10-7M telmisartan or 1mM NAC, uses or do not use the 10-7M Angiotensin II to handle 4 hours.The amount of Poly (A)+RNA template (about 30ng) and be used for expanded cells periodicity (28 cycles of PDGF-B gene, 22 cycles of beta-actin gene) be selected at quantitative scope, be to carry out linear reaction, it is according at Yamagishi etc., J Biol Chem 277:20309, the description in 2002 is by detecting signal intensity as the function construction of template amount and cell cycle numbers.The primer sequence that is used to detect cattle beta-actin mRNA with at Okamoto etc., FASEB J16:1928, identical in 2002.
Relate to PDGF-B in the blood vessel hyperplasia retinopathy, the rhodopsin that narrows starts the factor/PDGF-B transgenic mice and demonstrates vascular cell, glial cell and the retinal pigment epithelium hypertrophy that causes detachment of retina.Find that in this experiment Angiotensin II just regulating PDGF-B mRNA level significantly in perithelial cells.When being exposed to the 10-7M Angiotensin II, PDGF-B mRNA level is higher about 5 times than basic horizontal.Find that telmisartan or NAC suppress significantly by the inductive just adjusting to PDGF mRNA level of Angiotensin II.Draw thus as drawing a conclusion, in the pathogeny of the detachment of retina of the proliferative diabetic retinopathy by overexpression PDGF-B, relate to the interaction of Angiotensin II and 1 receptor, thereby and postpone by the expression that in body, reduces PDGF-B or even prevented the deterioration of diabetic retinopathy by the effect of the nervous plain II of angiotensin-ii receptor blockers antagonizing vessel.

Claims (11)

1. the method that the microvascular disease that prevents to be caused by diabetes develops or worsens comprises the angiotensin-ii receptor blockers to the individual administration pharmacy effective dose of needs.
2. the method for claim 1, wherein angiotensin-ii receptor blockers is for suppressing the receptor blocking agent that active oxygen produces in cell in perithelial cells is cultivated, and this active oxygen is inductive by the Angiotensin II that is present in the culture medium in intracellular generation.
3. the method for claim 2, wherein angiotensin-ii receptor blockers is selected from Candesartan, Eprosartan, irbesartan, losartan, Olmesartan, telmisartan or valsartan.
4. the method for claim 1, it prevents the development or the deterioration of diabetic retinopathy.
5. the process of claim 1 wherein that described individuality is subjected to the influence of one or more risk factors, this risk factor is diabetes, hyperglycemia level, albuminuria, high blood urea nitrogen, high blood creatinine, microalbuminuria or systemic hypertension.
6. a screening technique that is used to prevent to be caused by diabetes the angiotensin-ii receptor blockers of microvascular disease development or deterioration comprises
(a) exist or do not exist under the condition of effective angiotensin-ii receptor blockers chemical compound, using or do not use Angiotensin II to handle the cultured cell of perithelial cells tissue,
(b) measure the amount of the active oxygen in cell, produce, and
(c) identify described chemical compound, this chemical compound suppresses the inductive cell interior generation active oxygen owing to there is Angiotensin II in culture medium.
7. be used to prevent cause that by diabetes for example diabetic retinopathy develops microvascular disease or the pharmaceutical composition of deterioration, comprises the angiotensin-ii receptor blockers of pharmacy effective dose.
8. the purposes of angiotensin-ii receptor blockers in pharmaceutical compositions, said composition prevent for example development or the deterioration of diabetic retinopathy of microvascular disease that caused by diabetes in the individuality of needs.
9. the purposes of claim 8, wherein angiotensin-ii receptor blockers is for suppressing the receptor blocking agent that active oxygen produces in cell in perithelial cells is cultivated, and this active oxygen is inductive by the Angiotensin II that is present in the culture medium in intracellular generation.
10. the purposes of claim 9, wherein angiotensin-ii receptor blockers is selected from Candesartan, Eprosartan, irbesartan, losartan, Olmesartan, telmisartan or valsartan.
11. the purposes of claim 8, wherein said individuality are subjected to one or more risk factor influences, this risk factor is diabetes, hyperglycemia level, albuminuria, high blood urea nitrogen, high blood creatinine, microalbuminuria or systemic hypertension.
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