WO2004096211A1 - Inhibiteurs du recepteur de l'angiotensine ii empechant l'apparition ou d'enrayer la progression d'une maladie microvasculaire due au diabete - Google Patents

Inhibiteurs du recepteur de l'angiotensine ii empechant l'apparition ou d'enrayer la progression d'une maladie microvasculaire due au diabete

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Publication number
WO2004096211A1
WO2004096211A1 PCT/EP2004/004616 EP2004004616W WO2004096211A1 WO 2004096211 A1 WO2004096211 A1 WO 2004096211A1 EP 2004004616 W EP2004004616 W EP 2004004616W WO 2004096211 A1 WO2004096211 A1 WO 2004096211A1
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WO
WIPO (PCT)
Prior art keywords
angiotensin
diabetes
progression
receptor blocker
development
Prior art date
Application number
PCT/EP2004/004616
Other languages
English (en)
Inventor
Sho-Ichi Yamagishi
Original Assignee
Boehringer Ingelheim International Gmbh
Boehringer Ingelheim Pharma Gmbh & Co. Kg
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim International Gmbh, Boehringer Ingelheim Pharma Gmbh & Co. Kg filed Critical Boehringer Ingelheim International Gmbh
Priority to MXPA05011760A priority Critical patent/MXPA05011760A/es
Priority to CA002524248A priority patent/CA2524248A1/fr
Priority to EP04730529A priority patent/EP1622607A1/fr
Priority to AU2004233597A priority patent/AU2004233597A1/en
Priority to JP2006505345A priority patent/JP2006525269A/ja
Priority to BRPI0409853-6A priority patent/BRPI0409853A/pt
Publication of WO2004096211A1 publication Critical patent/WO2004096211A1/fr

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    • G—PHYSICS
    • 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
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • 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
    • 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
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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)

Definitions

  • the present 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).
  • microvascular disease i.e. disease involving small blood vessels
  • kidneys diabetic nephropathy
  • Diabetes is a disorder in which the body is unable to metabolize carbohydrates (e.g., food starches, sugars, cellulose) properly.
  • carbohydrates e.g., food starches, sugars, cellulose
  • the disease is characterized by- excessive amounts of sugar in the blood (hyperglycemia) and urine, inadequate production and/or utilization of insulin, and by thirst, hunger, and loss of weight. Diabetes is affecting about 2% of the population. Of these 10-15% are insulin dependant (type 1) diabetics and the remainder non insulin dependant (type 2) diabetics.
  • Retinopathy is damage to the retina caused by microvascular changes. Diabetic retinopathy is a specific microvascular complication of both typel and type 2 diabetes. The prevalence of retinopathy is strongly linked to the duration of diabetes. After 20 years of diabetes nearly all patients with type 1 diabetes and over 60% of patients with type 2 diabetes have some degree of retinopathy. A diabetic is 25 times more likely to go blind than a person in the general population. Upton a fifth of newly diagnosed diabetics have been found to have some retinopathy. Additionally, retinopathy develops earlier and is more severe in diabetics with elevated systolic blood pressure levels.
  • Diabetic retinopathy is the most common cause of blindness in the working age population in many countries.
  • Proliferative retinopathy In the early phases of retinopathy, weakening of the small blood vessels in the retina produces bulges in the vessels (microaneurysms) and leakage of fluid (exudates) and blood (hemorrhages). Proliferative retinopathy, a later stage of the disease, involves the growth of fragile new blood vessels on the retina and into the vitreous, a jelly-like substance inside the eyeball. These vessels can rupture and release blood into the vitreous, which causes blurred vision or temporary blindness. The scar tissue that may subsequently develop can pull on the retina and cause retinal detachment, which may lead to permanent vision loss. Macular edema-swelling due to fluid accumulating around the macular, the part of the retina most crucial for fine vision, may also occur. If proliferative retinopathy is left untreated, about half of those who have it will become blind within five years, compared to just 5% of those who receive treatment.
  • the condition can be treated with laser photocoagulation, if it is detected early. Additionally, reduction in hyperglycemia at any time in the course of diabetes will result in a significant decrease in the long-term incidence and progression of retinopathy and in the development of visual loss.
  • the angiotensin converting enzyme (ACE) inhibitor lisinopril reduced the risk of . i ., progression of retinopathy by approximately 50%, and also significantly reduced the, risk of progression to proliferative retinopathy.
  • ACE angiotensin converting enzyme
  • Preventing the development or progression of the condition has the potential to save vision at a relatively low cost compared to the costs associated with a loss of vision.
  • Nephropathy is the deterioration of the kidneys. Diabetic nephropathy is a specific microvascular complication of both typel and type 2 diabetes. Type 1 diabetes is more likely to lead to the final stage of nephropathy called end-stage renal disease (ESRD). There are five stages of diabetic nephropathy, the fifth stage is ESRD. Progress from one stage to the next can take many years, with 23 years being the average length of time to reach stage five. Diabetes is the most common cause of ESRD accounting for more than 40 percent of cases in the US.
  • ESRD end-stage renal disease
  • angiotensin-ll-receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type II diabetes. Yet, preventing the development or progression of the condition has the potential/to save kidney function.
  • Angiotensin II plays a major role in pathophysiology, especially as the most potent blood pressure increasing agent in humans.
  • Angiotensin II receptor blockers particularly blockers of the type 1 receptor, are used for treating elevated blood pressure and congestive heart failure in a mammal.
  • angiotensin II receptor blockers also called angiotensin II antagonists
  • 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 4,880,804.
  • angiotensin II receptor blockers are sartans such as candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan or valsartan.
  • the ongoing Diabetic Retinopathy Candesartan Trials (DIRECT) program has been established to determine whether AT1 -receptor blockade with candesartan can prevent the incidence and progression of diabetic retinopathy.
  • This program involves normotensive or treated hypertensive individuals and will assess the potential of an AT1 -receptor blocker to protect against the pathological changes in the eye following diabetes. (Sj ⁇ lie and Chaturvedi, Journal of Human Hypertension (March 2002) 16 Suppl, pages 42-46).
  • angiotensin II receptor blockers the effect of angiotensin II receptor blockers on the development or progression of retinopathy is determined in a cell culture system avoiding extensive clinical trials.
  • the system allows to determine, whether or not a selected or potential angiotensin II inhibitor is effective in the prevention of the development or progression of retinopathy.
  • Pericytes regulate the growth of co-cultured endothelial cells and serve a pivotal role in the maintenance of microvascular: homeostasis. For instance they preserve the ability of co-cultured endothelial; cells .to produce prostacyclin y and to protect them against.lipid-peroxide-induced:.inj ⁇ ry..Pericyte loss and dysfunction. are characteristic histopathological hallmarks. observed. in the early phase ofdiabetic retinopathy.
  • the method according to the present invention allows to screen for angiotensin II receptor blockers, and in particular for angiotensin II receptor blockers which prevent the development or progression of diabetic retinopathy or nephropathy. It comprises
  • the cell culture system used is based on pericytes isolated from mammalian retina such as bovine retina.
  • the cells are maintained in commercially available cell culture media such as Dulbecco ' s Eagle ' s medium usually supplemented with fetal bovine serum.
  • reactive oxygen species comprises molecules like hydrogen peroxide, ions like the hypochlorite ion, radicals like the hydroxyl radical which is the most reactive of them all, and the superoxide anion which is both ion and radical.
  • An important aspect of the method is the finding that the intracellular generation of reactive oxygen species in pericytes increases in a dose-dependent manner after treating the cultured cells with angiotensin II.
  • VEGF vascular permeability factor
  • PDGF-B platelet - derived growth factor-B
  • Angiotensin II is a trigger of high blood pressure known as a major risk factor for diabetic retinopathy and nephropathy. Reactive oxygen species damage other molecules and, thus, the cell structures of which they are part. Generally cells use a variety of defenses against the harmful effects of reactive oxygen species including small molecules with antioxidative properties such as : alpha-tocopherol (vitamin E), uric acid, and.vitamin C or the two enzymes superoxide dismutase and catalase. Adding additional amounts of antioxidants like N-acetylcystein (NAC) during the treatment of pericytes with angiotensin II reverses the increase in the generation of reactive oxygen species induced by the presence of angiotensin II.
  • NAC N-acetylcystein
  • compounds which are devoid of antioxidative properties will prevent the development or progression of diabetic retinopathy or nephropathy, if they are capable of inhibiting in pericyte cell cultures the intracellular generation of reactive oxygen species induced by the presence of angiotensin II in the cell culture medium.
  • compounds can be screened by treating pericytes 1-48 hours, preferably 24 hours with or without angiotensin II in the presence or absence of such a compound. Following treatment the generation of reactive oxygen species is measured.
  • angiotensin II receptor blockers such as telmisartan were found to inhibit in pericyte cell cultures the increase in the generation of reactive oxygen species induced by angiotensin II, whereas treatment with the receptor blocker alone did not affect the generation of reactive oxygen species.
  • activation of angiotensin II receptor signaling in pericytes contributes to the pathogenesis of diabetic microvascular disease and antagonizing angiotensin II with compounds such as telmisartan prevent the development or progression of diseases such as diabetic retinopathy by attenuating pericyte loss and dysfunction.
  • the present invention teaches a method of 5 preventing the development or progression of microvascular disease due to diabetes such diabetic retinopathy or nephropathy comprising administering to an individual in need thereof a pharmaceutically effective amount of an angiotensin II receptor blocker.
  • the angiotensin II receptor blockers can be used for the production of a pharmaceutical composition to prevent the development or progression of 10 microvascular disease due to diabetes in an individual in need thereof.
  • angiotensin II receptor blockers are candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan or valsartan, but any receptor blocker can be used which is capable of inhibiting in pericyte cell cultures the: increase in the
  • the amount of receptor blocker used is dependent on the actual active ingredient and usually corresponds to the amount used to treat hypertension.
  • the active compounds can be administered orally, bucally, parenteraliy, by inhalation spray, rectally or topically, the oral administration being preferred. Parenteral administration
  • 25 may include subcutaneous, intravenous, intramuscular and intrasternal injections and infusion techniques.
  • the pharmaceutical composition for preventing the development or progression of diabetic retinopathy comprising a pharmaceutically effective amount of an 30 angiotensin II receptor blocker is primarily dependent on the way of administration. Dosage ranges include 0.5 to 500 mg/kg p.o., preferably 2 to 80 mg/kg p.o., and 3 mg/kg i.v.
  • the active compounds can be orally administered in a wide variety of different dosage forms, i.e. they may be formulated with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspensions, elixirs, syrups, and the like.
  • Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
  • oral pharmaceutical formulations can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for such purposes.
  • the compounds of this invention are present in such oral dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition, in amounts which are sufficient to provide the desired unit dosages.
  • Other suitable dosage forms for the compounds of this - -invention include controlled release formulations and devices well known to hose •who practice in the art.
  • tablets containing various excipients su ⁇ h as sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch and preferably potato or tapioca starch, alginic acid and certain complex silicate, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • disintegrants such as starch and preferably potato or tapioca starch, alginic acid and certain complex silicate, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc or compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules; included lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying agents and/or water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • solutions of the compounds in sesame or peanut oil or in aqueous propylene glycol may be employed, as well as sterile aqueous solutions of the corresponding pharmaceutically acceptable salts.
  • aqueous solutions should be suitably buffered if necessary, and the liquid diluent rendered isotonic with sufficient saline or glucose.
  • sterile aqueous media employed are readily obtained by standard techniques well known to those skilled in the art.
  • distilled water is ordinarily used as the liquid diluent and the final preparation is passed through a suitable bacterial filter such as a sintered glass filter or a diatomaceousearth or unglazed porcelain filter.
  • suitable bacterial filter such as a sintered glass filter or a diatomaceousearth or unglazed porcelain filter.
  • Preferred filters of this type include the Berkefeld, the Chamberland and the Asbestos Disk-Metal Seitz filter, wherein the fluid is sucked into a sterile container with the aid of a suction pump. The necessary steps should be taken throughout the preparation of these injectable solutions to insure that the final products are obtained in a sterile condition.
  • the dosage form of the particular compound or compounds may include, by way of example, solutions, lotions, ointments, creams,, gels, suppositories, rate-limiting sustained release formulations and devices therefor.
  • dosage forms comprise the particular compound or compounds and may include ethanol, water, penetration enhancer and inert carriers such as gel-producing materials, mineral oil, emulsifying agents, benzyl alcohol and the like.
  • Angiotensin II receptor blockers may be administered in a daily dosage of 10 mg (or 0.143 mg/kg, based on a person of 70 kg) to 500 mg (7.143 mg/kg) orally and of about 20 mg (0.286 mg/kg) parenterally, preferably of 20 mg (0.286 mg/kg) to 100 mg (1.429 mg/kg) orally.
  • Particularly preferred is an oral daily dosage of 40 mg (0.571 mg/kg) to 80 mg (1.143 mg/kg) or specifically of about 80 mg (1.143 mg/kg).
  • angiotensin II receptor blockers are already on the market and can be used for administration, e.g. Approvel®, Atacand®, Blopress®, Cozaar®, Diovan®, Karvea®, Lortaan®, Lorzaar®, Losaprex®, Micardis®, Neo-Lotan® or Oscaar®, and Teveten®. Examples
  • Pericytes were isolated from bovine retina and maintained in Dulbecco ' s Eagle ' s medium supplemented with 20% of fetal bovine serum (FBS) as described in Yamagishi et al, Circulation 87:1969, 1993.
  • FBS fetal bovine serum
  • Angiotensin II treatment was carried out in medium containing 2% FBS. Pericytes were treated with or without 10 "7 or 10 "6 M angiotensin II in the presence or absence of 10 "7 M telmisartan for 24 hours. Then the intracellular formation of reactive oxygen species was detected as described in Yamagishi et al, A J Biol Chem 276:25096, 2001 by using the fluorescent probe CM-H 2 DCFDA (Molecular Probes Inc, Eugene, OR).
  • Angiotensin II increased intracellular generation of reactive oxygen species in a dose-dependent manner. 10 "6 M angiotensin II resulted in an increase of about 1.3 fold. Telmisartan was found to completely inhibit the angiotensin ll-induced increase in the generation of reactive oxygen species in pericytes, while telmisartan alone did not affect the generation.
  • Example 2 Measurement of [ 3 H]thymidine incorporation in pericytes
  • Pericytes were treated with or without 10 "7 M angiotensin in the presence or absence of 1mM N-acetylcystein (NAC) for 24 hours, and then [ 3 H]thymidine incorporation in cells was determined as described in Yamagishi et al, FEBS Lett 384:103, 1996.
  • Angiotensin II significantly inhibited DNA synthesis in pericytes.
  • NAC significantly prevented the angiotensin ll-induced decrease in DNA synthesis in pericytes.
  • Example 3 Quantitative reverse transcription PCR of VEGF m-RNA
  • RNAs were isolated from cells treated with or without 10 "7 M angiotensin II in the presence or absence of 10 "7 M telmisartan or 1 mM NAC for 4 hours, and analyzed by quantitative reverse transcription PCR (RT-PCR) as described in Yamagishi et al, Diabetologia 41 :1435, 1998.
  • RT-PCR quantitative reverse transcription PCR
  • VEGF mRNA level was about 1.5 fold higher than the basal level when exposed to 10 "7 M angiotensin II. Telmisartan and NAC were found to completely inhibit the angiotensin ll-induced up-regulation of VEGF mRNA levels in pericytes.
  • Partial cDNAs for bovine PDGF-B were cloned using primer sequences designed from the conserved amino acid sequences GELESL and NNRNVQ in human and sheep PDGF-B.
  • the upstream and downstream primers were 5'-GGCGAGCTGGAGAGCTT-3 ' and 5 ' -CTGCACGTTGCGGTTGT-3 ⁇ , respectively.
  • a 213-base pair RT-PCR product was amplified from 30 ng of bovine retinal pericyte poly(A) + RNA and cloned using the pGEM-T Easy Vector System according to the manufacturer's instructions (Promega, Madison, Wl, USA).
  • PCR products were sequenced by the chain termination method according to the manufacturer ' s instructions (DNA Sequencing Kit, Applied Biosystems, Foster, CA, USA).
  • the cloned bovine cDNA fragments showed strong sequence similarity with human and sheep PDGF-B. Nucleotide identities were 91% and 94%, amino acid identities 91% and 96% with human and sheep PDGF-B, respectively.
  • poly(A) + RNAs were isolated from cells treated with or without 10 "7 M angiotensin II in the presence or absence of 10 "7 M telmisartan or 1mM NAC for 4 hours, and analyzed by RT-PCR as. described in Yamagishi et al, Kidney Int 63:464, 2003.
  • the amounts of poly(A) + RNA templates (about 30ng) and cell cycle numbers for amplification (28 cycles for PDGF-B gene and 22 cycles for ⁇ -actin gene) were chosen in quantitative ranges were reactions proceeded linearly, which had been determined by plotting signal intensities as functions of the template amounts and cell cycle numbers as described in Yamagishi et al, J Biol Chem 277:20309, 2002. Sequences of primers for detecting bovine ⁇ -actin mRNAs were the same as described in Okamoto et al, FASEB J 16:1928, 2002.
  • PDGF-B has been implicated in vascular proliferative retinopathies, and hemizygous rhodopsin promoter/PDGF-B transgenic mice were shown to exhibit proliferation of vascular cells, glial cells and retinal pigment epithelial cells resulting in retinal detachment.
  • angiotensin II was found to significantly up- regulate PDGF-B mRNA levels in pericytes.
  • the PDGF-B mRNA level was about 5-fold higher than the basal level.
  • Telmisartan or NAC were found to significantly inhibit the angiotensin II induced up-regulation of PDGF mRNA levels.
  • angiotensin ll-type 1 receptor interaction is involved in the pathogenesis of retinal detachment in proliferative diabetic retinopathy through overexpression of PDGF-B, and that antagonizing angiotensin II action by angiotensin II receptor blockers delays or even prevents the progression of diabetic retinopathy by attenuating PDGF-B expression in vivo.

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Abstract

L'invention concerne des inhibiteurs du récepteur de l'angiotensine II, singulièrement leur utilisation dans le domaine du diabète comme moyens d'enrayer l'apparition ou la progression de maladies microvasculaires (c'est-à-dire de maladies touchant les petits vaisseaux sanguins) affectant les yeux (rétinopathie diabétique) et les reins (néphropathie diabétique).
PCT/EP2004/004616 2003-05-02 2004-04-30 Inhibiteurs du recepteur de l'angiotensine ii empechant l'apparition ou d'enrayer la progression d'une maladie microvasculaire due au diabete WO2004096211A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
MXPA05011760A MXPA05011760A (es) 2003-05-02 2004-04-30 Bloqueadores del receptor de angiotensina ii para prevenir el desarrollo o pregresion de enfermedad microvascular ocasionada por diabetes.
CA002524248A CA2524248A1 (fr) 2003-05-02 2004-04-30 Inhibiteurs du recepteur de l'angiotensine ii empechant l'apparition ou d'enrayer la progression d'une maladie microvasculaire due au diabete
EP04730529A EP1622607A1 (fr) 2003-05-02 2004-04-30 Inhibiteurs du recepteur de l'angiotensine ii empechant l'apparition ou d'enrayer la progression d'une maladie microvasculaire due au diabete
AU2004233597A AU2004233597A1 (en) 2003-05-02 2004-04-30 Angiotensin II receptor blockers for preventing the development or progression of microvascular disease due to diabetes
JP2006505345A JP2006525269A (ja) 2003-05-02 2004-04-30 糖尿病による微小血管疾患の発症または進行を防止するためのアンジオテンシンｉｉ受容体ブロッカー
BRPI0409853-6A BRPI0409853A (pt) 2003-05-02 2004-04-30 bloqueadores receptores de angiotensina ii para evitar o desenvolvimento ou a progressão de doença microvascular em conseqüência de diabetes

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10319592.0 2003-05-02
DE10319592A DE10319592A1 (de) 2003-05-02 2003-05-02 Behandlung von diabetischer Retinopathie mit Angiotensin II-Rezeptorblockern

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WO2009087900A1 (fr) * 2008-01-11 2009-07-16 Daiichi Sankyo Company, Limited Agent pharmaceutique pour la prévention ou le traitement de maladies accompagnées par une hyperperméabilité vasculaire intraoculaire
JP5860210B2 (ja) * 2010-12-07 2016-02-16 株式会社オフテクス アンジオテンシンｉｉ受容体拮抗薬であるテルミサルタン及びロサルタンの少なくとも１種を有効成分とする涙液分泌促進用組成物、及びそれを含有する涙液分泌促進用経口投与用製剤
KR102233673B1 (ko) * 2016-01-27 2021-03-30 보령제약 주식회사 당뇨병성 신장질환의 예방 또는 치료용 약학적 조성물

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RU2005137361A (ru) 2006-07-27
MXPA05011760A (es) 2006-01-26
CA2524248A1 (fr) 2004-11-11
DE10319592A1 (de) 2004-11-18
JP2006525269A (ja) 2006-11-09
AU2004233597A1 (en) 2004-11-11
CN1784225A (zh) 2006-06-07

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