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WO1998006417A1 - Procedes de traitement des lesions ischemiques cerebrales et d'autres maladies neuronales - Google Patents

Procedes de traitement des lesions ischemiques cerebrales et d'autres maladies neuronales Download PDF

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Publication number
WO1998006417A1
WO1998006417A1 PCT/US1997/014201 US9714201W WO9806417A1 WO 1998006417 A1 WO1998006417 A1 WO 1998006417A1 US 9714201 W US9714201 W US 9714201W WO 9806417 A1 WO9806417 A1 WO 9806417A1
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WIPO (PCT)
Prior art keywords
adjuvant
antagonist
pharm
ther
drapeau
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PCT/US1997/014201
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English (en)
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WO1998006417A9 (fr
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Eric T. Whalley
Jane K. Relton
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Cortech, Inc.
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Priority to JP50997298A priority Critical patent/JP2002515878A/ja
Priority to AU40637/97A priority patent/AU4063797A/en
Publication of WO1998006417A1 publication Critical patent/WO1998006417A1/fr
Publication of WO1998006417A9 publication Critical patent/WO1998006417A9/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/043—Kallidins; Bradykinins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/49—Urokinase; Tissue plasminogen activator
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • 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

Definitions

  • the present invention relates generally to the use of antagonists which selectively affect
  • bradykinin 2 receptor Bj
  • agonists which selectively affect the bradykinin 1 receptor (B,) to treat cerebral ischemic injury, whether due to strpke or other causes, and in particular to striatal ischemic injuiy and cortical ischemic injury.
  • the present invention also relates to using B 2 antagonists and/or B, agonists to treat Parkinson's disease and Huntington's disease or other
  • the B 2 antagonist and/or B, agonists chosen can be used alone or together as the therapeutic agent or alone and together in combination with other therapeutic agents. Description of the Bac trrnnnrl
  • Cerebral ischemic injury due to stroke has been attributed to the depolarization of neurons upon energy deprivation which causes impaired glutamate receptor function and can result in mitochondrial injury, enzyme activation/inactivation, cellular swelling, and excitotoxicity. Therefore, pharmacological strategies for stroke include: blockade of glutamate receptor function using channel blockers, NMD A or AMPA receptor antagonists; free radical
  • Bradykinin causes neuronal damage and injury (Francel, 9 J. Neurotrauma S27
  • bradykinin the precursor for bradykinin, is consumed during ischemia and reperfusion of the brain in rats and in humans undergoing neurosurgical treatment for stenotic and occlusive carotid damage.
  • bradykinin antagonists have been shown to attenuate the vascular response to hyperventilation following brain injury in rabbits (Ellis, 4 New Trends Lipid Mediators Res. 129).
  • bradykinin B 2 and Bj receptor antagonists worsen the condition whereas the B 2 agonist bradykinin and the Bj agonist, des-Arg -BK, are protective.
  • a B, antagonist has also been shown to reverse the protective effect of a B 2 antagonist on survival in porcine endo toxic shock. Siebeck et al, Immunopharmacology. However, no clear understanding of B, role in normal physiology has been reached.
  • B 2 antagonist and/or a B, agonist, alone or in combination with another treatment.
  • Figure 1 The effect of the bradykinin B 2 receptor antagonist CP-0597 on total infarct volume in the rat 24 hours following permanent occlusion of the middle cerebral artery. This figure shows a dose-dependent, protective effect of CP-0597 compared to control untreated rats. Note that the 30 ng/kg/min dose of CP-0597 used a separate group of control rats (b).
  • Figure 2 The effect of the bradykinin B 2 receptor antagonist, CP-0597 on striatal infarct volume
  • Figure 3 The effect of the combined B ⁇ , receptor antagonist B9430 on total infarct volume in the rat 24 hours following permanent occlusion of the middle cerebral artery. This shows that blocking both B 2 and B, receptors provided no protection and may have worsened the damage compared to saline-treated control rats.
  • Figure 4 The effect of a B, antagonist (B-9858) alone and in combination with the B 2 antagonist, CP-0597, on total infarct volume 24 hours following permanent occlusion of the middle cerebral artery in the rat. This shows that a B, antagonist alone had no effect on infarct volume and when given in combination with CP-0597, reversed the protective effect of CP-0597 alone (see Figure 1) and may have worsened the damage compared to saline-treated controls.
  • Figure 5 The effect of the B 2 antagonists HOE140 and NPC17731 on total infarct volume in the rat 24 hours following permanent occlusion in the rat. Both these B 2 receptor antagonists provided protection against damage compared to controls.
  • Figure 6 The effect of the bradykinin B 2 receptor antagonists HOE140 and NPC17731 on striatal infarct volume 24 hours following permanent occlusion of the middle cerebral artery in the rat. Both these B 2 receptor antagonists provided significant protection against striatal damage compared to controls.
  • Figure 7 The effect of the NMDA antagonist MK801 on total infarct volume in the rat 24 hours following permanent occlusion of the middle cerebral artery in the rat. MK801 provided significant protection from damage compared to control rats.
  • Figure 8 The effect of the NMDA antagonist MK801 on striatal infarct volume 24 hours following permanent occlusion in the rat. MK801 provided no protection against striatal damage
  • Figure 9 The effect of the bradykinin B 2 receptor antagonist CP-0597 on a) total, b) cortical and c) striatal infarct volume 24 hours following permanent occlusion of the middle cerebral artery.
  • the compound was given 30 to 40 minutes after occlusion of the artery and represents post-treatment.
  • CP-0597 provided significant protection of striatal damage but not cortical damage.
  • Figure 10 Structures of CP-0597, HOE140 and NPC17731.
  • Figure 11 Effect of the B 2 antagonist CP-0597 on behavioral score before and after reversible MCAO in the rat. Treatment with CP-0597 significantly improved mean behavioral score compared to vehicle treated controls measured 24 hours after reversible MCAO. (P ⁇ 0.01).
  • Figure 12 Effect of CP-0597 on change in body weight 24 hours after reversible MCAO in the rat. Mean drop in body weight over the experimental period was significantly less (p ⁇ 0.01) in
  • Figure 13 Dorsal view of rat brain indicating sections used in the rMCAO model of stroke. Illustrates a dorsal view of the rat brain indicating the points at which sections were taken for histological analysis of brain damage.
  • Figure 14 Coronal sections of rat brain 24 hours post rMCAO. Distribution of brain damage on H&E stained brain sections (A-E) from rats treated with either vehicle or CP-0597.
  • Figure 15 Effect of CP-0597 on edema: percent increase in hemisphere size. The percentage increase in hemisphere size observed after reversible MCAO was significantly reduced in all brain sections (A-E) from rats treated with CP-0597 compared to vehicle treated controls
  • Figure 16 Effect of CP-0597 on absolute infarct area 24 hours after rMCAO. The area of absolute brain infarction was reduced in all brain sections (A-E) in rats treated with CP-0597 compared to vehicle treated controls.
  • Figure 17 Effect of CP-0597 on absolute infarct volume 24 hours after rMCAO. Total absolute infarct volume was calculated as the area under the curve of infarct areas on sequential brain
  • Figure 18 Effect of CP-0597 on infarct area 24 hours after rMCAO.
  • the area of pallor on each brain section was sketched onto stereotaxic maps and extent of infarction quantified from the maps to adjust for hemispheric swelling.
  • the area of infarction calculated in this manner was reduced in all brain sections (A-E) in rats treated with CP-0597 compared to vehicle treated
  • Figure 19 Effect of CP-0597 on infarct volume 24 hours after rMCAO. Total adjusted infarct volume was calculated as above. Infarct volume was significantly reduced by 57% (p ⁇ 0.001) in CP-0597 treated rats compared to vehicle treated controls. Cortical and subcortical regions were protected by 60% and 49% respectively.
  • Figure 20 Areas of rat brain sampled for neuronal damage. Illustrates the specific regions of the brain sample for neuronal counts. The number of necrotic neurons were counted at identical sites on section C of H&E stained brain sections from vehicle and CP-0597 treated animals.
  • Figure 21 Neuronal counts, Section C, Area ⁇ . Shows photomicrographs (20X magnification) of H&E stained C sections (area ⁇ , parietal cortex) from a) a sham operated control, b) a vehicle treated rat 24 hours after rMCAO and c) a CP-0597 treated rat 24 hours after rMCAO.
  • Figure 22 Effect of CP-0597 on number of dead neurons per 80X field. The number of necrotic neurons in areas I-IV was significantly reduced in CP-0597 treated rats compared to vehicle treated controls.
  • FIG. 23 Identification of bradykinin B, receptors in rat brain following a) one hour of ischemia and b) 24 hours of reperfusion. Note B, receptors (black stain) in b) associated with specific neurons.
  • bradykinin overproduction of the naturally-occurring peptide bradykinin.
  • B 2 or B, receptors' role in pathological states associated with bradykinin was unclear. The confusion was primarily because no experimentation had been done, and no conclusions had been made, but also because conflicting evidence of bradykinin's role in
  • B 2 antagonists and/or B agonists as therapeutic agents. Newly discovered and clinically significant is the ability of B 2 antagonists and/or B,
  • B 2 antagonists are generally separated into two categories: peptide-based and non- peptide-based. Those in the art are aware of the available B 2 antagonists, and are also aware of
  • B 2 B, Kj ratio is greater than 100. However, ratios in the range of 500 to 1000 are preferred. Most preferred is a compound with a Bj B, ratio greater than 1000.
  • Peptide-based B 2 antagonist compounds are listed, for example, in the following publications: Cheronis et. al, 35 J. Med. Chem. 1563 (1992); Kyle & Burch, 2 Curr. Opin. Invest. Drugs 5 (1993); Hock et al, 102 Br. J. Pharmacol. 769 (1991); Hock et al, 102 Br. J. Pharmacol 11 (1991); Burke et. al, 5(4) Exp. Opin. Ther. Patents 331 (1995), and others. All
  • Non-peptide and peptoid B 2 antagonist compounds include those mentioned by: Sawutz et. al, 91 Proc NaflAcad. Sci. 4693 (1994); Lam et. al, 52 Tetrahedron 481 (1996); Inamura
  • bradykinin B 2 antagonists reduce total infarct volume with the major effect being protection of striatal rather than cortical damage. Bradykinin antagonists also reduce brain edema in man. Thus, the combination of a bradykinin B 2 antagonist with an adjuvant is synergistic and provides protection against both cortical and striatal damage.
  • Bradykinin B agonists can be made, identified and assayed as described in the references. Bradykinin B, agonists can also be purchased from a variety of commercial sources including Phoenix Pharmaceuticals, Inc. (Mountain View, California),
  • the rat model of permanent middle cerebral artery occlusion mimics the human condition of stroke and is a standard model used for the evaluation of compounds believed to be of potential therapeutic benefit for the treatment of this disorder. Tamura et. al, 1(1) J. Cereb.
  • Any chemist skilled in the art of peptide synthesis can synthesize the peptides useful in this invention by standard solution methods or by manual or automated solid phase methods.
  • the method of treatment according to this invention involves administering internally or topically to subject an effective amount of active compound. Doses of active compounds in the
  • inventive method are an efficacious, nontoxic quantity selected from the range of 0.01 to 500 mg kg of active compound, preferably 0.1 to 50 mg kg.
  • the desired dose is administered to a subject from 1 to 6 or more times daily, intravenously, orally, rectally, parenterally, topically, or by inhalation.
  • the desired dose may also be given by continuous, intravenous infusion; this is the preferred mode of administration.
  • the compounds may be formulated in aqueous injection solutions which may contain antioxidants, buffers, bacteriostats, etc.
  • aqueous injection solutions may be prepared from sterile pills, granules, or tablets which may contain diluents, dispersing and surface active agents, binders and lubricants which materials are all well known to the ordinary skilled artisan.
  • fine powders or granules of the compound may be formulated with diluents and dispersing and surface active agents, and may be prepared in water or in a syrup, in capsules or cachets in the dry state or in a non-aqueous suspension, where a suspending agent may be included.
  • the compounds may also be administered in tablet form along with optional binders and lubricants, or in a suspension in water or syrup or an oil or in a water/oil emulsion and may include flavoring, preserving, suspending, thickening, and emulsifying agents.
  • the granules or tablets for oral administration may be coated or other pharmaceutically acceptable agents and formulations may be utilized which are all known to those skilled in the pharmaceutical art.
  • Solid or liquid carriers can also be used.
  • Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • Liquid carriers include syrup, peanut oil, olive oil, saline, and water.
  • Ointments and creams are prepared using various well known hydrophilic and hydrophobic bases.
  • Topical reservoirs are suitably prepared using known polymeric materials such as various acrylic-based
  • Suppositories are prepared from standard bases such as polyethylene glycol and cocoa butter.
  • MCA left middle cerebral artery
  • Groups of animals were pretreated with bradykinin antagonist or vehicle in a blinded fashion.
  • Drug, or saline was delivered subcutaneously via pre-activated mini-osmotic pumps implanted just before MCA surgery. Doses of 10, 30, 100 and 300 ng/kg/min of CP-0597 were compared with vehicle control given for the 24 hour period.
  • CP-0597 produced a dose-dependent significant reduction in infarct size in this model of stroke.
  • the NMDA antagonist MK801 given at a dose of 4 mg kg sec, was also tested in this model.
  • CP-0597 produced an equivalent degree of reduction in infarct size at a total dose of only
  • CP-0597 produced a dose-dependent reduction in total infarct size in this model of stroke
  • halothane and MCAO produced by the insertion of a 4-0 nylon monofilament into the right external carotid artery, through the internal carotid artery to the origin of the MCA. After 1 hour the filament was retracted to allow reperfusion of the ischemic region.
  • Primed mini-osmotic pumps containing vehicle or CP-0597 were implanted into the subcutaneous space immediately after
  • MCAO MCAO.
  • Infarct size was calculated as both absolute volume as well as volume adjusted for cerebral edema.
  • the area of pallor on each brain section stained with H&E was quantified directly from fixed sections (absolute area) and from sketches made onto stereotaxic maps (adjusted area) for sections A-E. Both absolute and adjusted infarct areas were reduced on all sections analyzed in CP-0597 treated animals compared to vehicle treated controls ( Figures 16 and 18).
  • CP-0597 significantly reduced the number of necrotic neurons in the parietal and preoptic cortices and the striatum compared to vehicle treated control animals ( Figure 21 and 22).
  • CP-0597 Treatment with the bradykinin B 2 receptor antagonist CP-0597, after induction of ischemia and before the time of tissue reperfusion significantly protected the brain against ischemic injury in a model of reversible focal cerebral ischemia in the rat.
  • the pathology of this model is clinically representative of the human condition of stroke and the present data suggest that CP-0597 may be of significant benefit in the treatment of this and other ischemia-related disorders.
  • the combined B1/B2 antagonist B9430 at 300 ng/kg/min s.c. had no effect on infarct volume.
  • Lys0-des-Arg9-Leu8-BK (CP-0298) when given together with CP-0597 also reversed the protective effect of CP-0597.
  • B, receptors are not normally present in normal brain. Twenty Four hours after reperfusion following 1 hour of ischemia (reversible middle cerebral artery occlusion) B t receptors can be identified in the stroked side of the brain in the cortex and striatum. No Bj receptors can be identified in the non-stroked contralateral hemisphere. This would suggest that

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Abstract

Cette invention concerne d'une manière générale l'utilisation d'antagonistes qui affectent sélectivement le récepteur de bradykinine 2 (B2) et/ou d'agonistes qui affectent sélectivement le récepteur B1 pour traiter les lésions ischémiques cérébrales qu'elles soient dues à une attaque ou à d'autres causes et en particulier les lésions ischémiques striatales et les lésions ischémiques corticales. Cette invention concerne également l'utilisation d'antagonistes de B2 et/ou d'agonistes de B1 pour traiter la maladie de Parkinson et la maladie de Huntington. L'antagoniste de B2 et/ou l'agoniste de B1 sélectionné peut être utilisé seul ou conjointement en tant qu'agent thérapeutique ou en combinaison avec d'autres agents thérapeutiques.
PCT/US1997/014201 1996-08-16 1997-08-15 Procedes de traitement des lesions ischemiques cerebrales et d'autres maladies neuronales WO1998006417A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP50997298A JP2002515878A (ja) 1996-08-16 1997-08-15 脳虚血性損傷およびその他の神経の病気を治療する方法
AU40637/97A AU4063797A (en) 1996-08-16 1997-08-15 Methods to treat cerebral ischemic injury and other neuronal diseases

Applications Claiming Priority (8)

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US2403896P 1996-08-16 1996-08-16
US60/024,038 1996-08-16
US3111096P 1996-11-14 1996-11-14
US60/031,110 1996-11-14
US3798197P 1997-02-13 1997-02-13
US60/037,981 1997-02-13
US91045397A 1997-08-05 1997-08-05
US08/910,453 1997-08-05

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WO1998006417A1 true WO1998006417A1 (fr) 1998-02-19
WO1998006417A9 WO1998006417A9 (fr) 1998-07-02

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6489308B1 (en) 1999-03-05 2002-12-03 Trustees Of University Of Technology Corporation Inhibitors of serine protease activity, methods and compositions for treatment of nitric-oxide-induced clinical conditions
US6849605B1 (en) 1999-03-05 2005-02-01 The Trustees Of University Technology Corporation Inhibitors of serine protease activity, methods and compositions for treatment of viral infections
AU2001275411B2 (en) * 2000-06-09 2005-04-28 Bristol-Myers Squibb Company Methods for regulating a cell-mediated immune response by blocking lymphocytic signals and by blocking lfa-1 mediated adhesion
WO2008000803A1 (fr) * 2006-06-29 2008-01-03 Exonhit Therapeutics Sa identification et utilisation de variantes de GPRC pour le traitement et le diagnostic de la maladie de parkinson
US7704958B1 (en) 1999-03-05 2010-04-27 Bio Holding, Inc. Methods and compositions for inhibiting apoptosis using serine protease inhibitors
WO2011141188A1 (fr) 2010-05-14 2011-11-17 Max-Delbrück-Centrum für Molekulare Medizin Utilisation thérapeutique d'agonistes ou d'antagonistes du récepteur 1 ou 2 de la bradykinine, pour la modulation de la croissance de vaisseaux sanguins collatéraux
EP2420245A1 (fr) * 2010-08-18 2012-02-22 Max-Delbrück-Centrum Für Molekulare Medizin Utilisation thérapeutique d'agonistes ou d'antagonistes des récepteurs 1 ou 2 de la bradykinine, pour moduler la croissance des vaisseaux collatéraux
US10119979B2 (en) 2006-05-25 2018-11-06 Biogen Ma Inc. Methods of treating stroke and traumatic brain injury using humanized AQC2 anti-VLA-1 antibodies

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5610142A (en) * 1992-10-08 1997-03-11 Scios Inc. Bradykinin antagonist pseudopeptide derivatives of substituted 4-keto-1,3,8-triazaspiro[4.5]decan-3-alkanoic acids

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5610142A (en) * 1992-10-08 1997-03-11 Scios Inc. Bradykinin antagonist pseudopeptide derivatives of substituted 4-keto-1,3,8-triazaspiro[4.5]decan-3-alkanoic acids

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6489308B1 (en) 1999-03-05 2002-12-03 Trustees Of University Of Technology Corporation Inhibitors of serine protease activity, methods and compositions for treatment of nitric-oxide-induced clinical conditions
US6849605B1 (en) 1999-03-05 2005-02-01 The Trustees Of University Technology Corporation Inhibitors of serine protease activity, methods and compositions for treatment of viral infections
US7704958B1 (en) 1999-03-05 2010-04-27 Bio Holding, Inc. Methods and compositions for inhibiting apoptosis using serine protease inhibitors
US8071551B2 (en) 1999-03-05 2011-12-06 BioHolding, Inc. Methods and compositions for treating diabetes
AU2001275411B2 (en) * 2000-06-09 2005-04-28 Bristol-Myers Squibb Company Methods for regulating a cell-mediated immune response by blocking lymphocytic signals and by blocking lfa-1 mediated adhesion
US10119979B2 (en) 2006-05-25 2018-11-06 Biogen Ma Inc. Methods of treating stroke and traumatic brain injury using humanized AQC2 anti-VLA-1 antibodies
WO2008000803A1 (fr) * 2006-06-29 2008-01-03 Exonhit Therapeutics Sa identification et utilisation de variantes de GPRC pour le traitement et le diagnostic de la maladie de parkinson
WO2011141188A1 (fr) 2010-05-14 2011-11-17 Max-Delbrück-Centrum für Molekulare Medizin Utilisation thérapeutique d'agonistes ou d'antagonistes du récepteur 1 ou 2 de la bradykinine, pour la modulation de la croissance de vaisseaux sanguins collatéraux
EP2568995B1 (fr) * 2010-05-14 2016-07-20 Max-Delbrück-Centrum für Molekulare Medizin Utilisation thérapeutique d'agonistes du récepteur 1 de la bradykinine, pour moduler la croissance des vaisseaux collatéraux
US9492495B2 (en) 2010-05-14 2016-11-15 Max-Delbrueck-Centrum Fuer Molekulare Medizin Therapeutic use of agonists or antagonists of bradykinin receptor 1 or 2, for modulation collateral blood vessel growth
EP2420245A1 (fr) * 2010-08-18 2012-02-22 Max-Delbrück-Centrum Für Molekulare Medizin Utilisation thérapeutique d'agonistes ou d'antagonistes des récepteurs 1 ou 2 de la bradykinine, pour moduler la croissance des vaisseaux collatéraux

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CA2261130A1 (fr) 1998-02-19

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