WO2001028543A1 - Traitement des pathologies associees au polynucleaire eosinophile par modulation de l'activite de pkc-$g(d) - Google Patents

Traitement des pathologies associees au polynucleaire eosinophile par modulation de l'activite de pkc-$g(d) Download PDF

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Publication number
WO2001028543A1
WO2001028543A1 PCT/US2000/027277 US0027277W WO0128543A1 WO 2001028543 A1 WO2001028543 A1 WO 2001028543A1 US 0027277 W US0027277 W US 0027277W WO 0128543 A1 WO0128543 A1 WO 0128543A1
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WO
WIPO (PCT)
Prior art keywords
pkcδ
agent
activity
rottlerin
modulated
Prior art date
Application number
PCT/US2000/027277
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English (en)
Inventor
Gerald J. Gleich
Jennifer L. Bankers-Fulbright
Scott O'grady
Original Assignee
Mayo Foundation For Medical Education And Research
Regents Of The University Of Minnesota
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Application filed by Mayo Foundation For Medical Education And Research, Regents Of The University Of Minnesota filed Critical Mayo Foundation For Medical Education And Research
Priority to AU78513/00A priority Critical patent/AU7851300A/en
Priority to EP00968629A priority patent/EP1233765A1/fr
Priority to CA002387786A priority patent/CA2387786A1/fr
Priority to JP2001531373A priority patent/JP2003512321A/ja
Publication of WO2001028543A1 publication Critical patent/WO2001028543A1/fr

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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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

Definitions

  • PKC protein kinase C
  • the , ⁇ legal ⁇ 2 and ⁇ isoforms are Ca 2+ , phospholipid- and diacylglycerol-dependent and represent the classical isoforms of PKC, whereas the other isoforms are activated by phospholipid and diacylglycerol but are not dependent on Ca 2+ (House et al. Science, 23_&, 1726 (1987)).
  • U.S. Patent Application Serial Number 08/985,613 discloses the use of a sulfonylurea receptor (SUR) binding agent to treat IL-5 mediated pathologies.
  • SUR sulfonylurea receptor
  • This application also discloses a method for inhibiting cytokine- induced eosinophil survival or activation with a sulfonylurea receptor binding agent, optionally in combination with one or more topical anesthetics and/or glucocorticoids.
  • the application also discloses a method for treating a disease mediated by ' IL-5 with an agent that is able to modify (e.g., block) ATP- dependent potassium channels, or a protein with which an ATP-dependent potassium channel interacts (such as a SUR). dependent potassium channels, or a protein with which an ATP-dependent potassium channel interacts (such as a SUR).
  • the present invention provides a method to treat an eosinophil-associated pathology in a mammal, comprising modulating the activity of PKC ⁇ in said mammal.
  • PKC ⁇ modulation is not achieved by administering lidocaine or other topical anaesthetics as described in U.S. Patent Nos. 5,510,339, 5,631,267 and 5,837,713, supra.
  • Figure 1 illustrates the specific binding of varying concentrations of lidocaine to both high and low density PKC ⁇ surfaces.
  • Figure 2 illustrates the inhibition of eosinophil superoxide production by the PKC ⁇ -selective blocker rottlerin.
  • Figure 3 illustrates the inhibition of eosinophil degranulation by rottlerin.
  • hypersensitivity diseases and conditions associated with elevated levels of eosinophil activation and accumulation are amenable to treatment by the present therapy.
  • These conditions include, but are not limited to, nasal inflammation, conjunctivitis, chronic eosinophilic pneumonia, allergic rhinitis, allergic sinusitis, allergic gastroenteropathy, eosinophilic gastroenteritis, atopic dermatitis, bullous pemphigoid, episodic angioedema associated with eosinophilia, ulcerative colitis, inflammatory bowel disease, vernal conjunctivitis, giant papillary conjunctivitis, and allergic conjunctivitis.
  • PCK ⁇ activity can be modulated in a mammal (i.e., increased or decreased with respect to the level that would have existed in said mammal in the absence of intervention) using any suitable manner known in the art.
  • PCK ⁇ activity can be modulated by administering an effective amount of a chemical agent that acts upon PKC ⁇ (e.g., an inhibitor), such as the specific inhibitor of the PKC ⁇ isozyme, rottlerin (CAS Registry No. 82-08-6), also known as mallotoxin.
  • Rottlerin is available from commercial sources, including R.B.I. (Natick, MA., U.S.A.) and Calbiochem (California, U.S.A.).
  • DEX dexniguldipine hydrochloride
  • EPO erythropoietin
  • PKC ⁇ protein kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinas
  • human recombinant PKC ⁇ protein is also commercially available (BioMol Cat. No. SE-147).
  • DNA encoding PKC ⁇ can be used to alter the amount of PKC ⁇ in a cell.
  • DNA encoding any protein which interacts with PKC ⁇ , so as to modulate its activity (e.g., inhibit or increase its activity), is also envisioned.
  • DNA encoding PKC ⁇ , or a PKC ⁇ modulating protein can be readily introduced into host cells (e.g., mammalian, bacterial, yeast or insect cells) by transfection with an expression vector comprising DNA encoding PKC ⁇ , a PKC ⁇ modulating protein, or comprising DNA complementary to DNA encoding PKC ⁇ or a PKC ⁇ modulating protein.
  • host cells e.g., mammalian, bacterial, yeast or insect cells
  • an expression vector comprising DNA encoding PKC ⁇ , a PKC ⁇ modulating protein, or comprising DNA complementary to DNA encoding PKC ⁇ or a PKC ⁇ modulating protein.
  • This can be done by any procedure useful for the introduction into a particular cell (e.g., physical or biological methods), to yield a transformed cell having the recombinant DNA stably integrated into its genome, so that the DNA molecules, sequences, or segments, of the present invention are expressed by the host cell, as described by Sambrook et al., Molecular Cloning: A Laboratory
  • Physical methods to introduce a preselected DNA into a host cell include calcium phosphate precipitation, lipofection, particle bombardment, microinjection, electroporation, and the like.
  • Biological methods to introduce the DNA of interest into a host cell include the use of DNA and RNA viral vectors.
  • the main advantage of physical methods is that they are not associated with pathological or oncogenic processes of viruses. However, they are less precise, often resulting in multiple copy insertions, random integration, disruption of foreign and endogenous gene sequences, and unpredictable expression. For mammalian gene therapy, it is desirable to use an efficient means of precisely inserting a single copy gene into the host genome.
  • Viral vectors and especially retroviral vectors, have become the most widely used method for inserting genes into mammalian cells, such as human cells.
  • Other viral vectors can be derived from poxviruses, herpes simplex virus I, adenoviruses and adeno-associated viruses, and the like.
  • Antisense technology can also be used to alter the expression of PKC ⁇ in a mammal, for example, by administering to the mammal an effective amount of "antisense” mRNA transcripts or antisense oligonucleotides that encode PKC ⁇ which, when expressed from an expression cassette in a host cell, can alter PKC ⁇ expression.
  • antisense means a sequence of nucleic acid which is the reverse complement of at least a portion of a RNA or DNA molecule that codes for PKC ⁇ .
  • the introduced nucleic acid may be useful to modulate the expression of PKC ⁇ in mammals with an eosinophil-associated indication.
  • the administration of an expression vector encoding PKC ⁇ peptide may increase the PKC ⁇ activity and thus be efficacious for diseases which are characterized by decreased levels of PKC ⁇ .
  • the administration of an expression vector comprising antisense PKC ⁇ sequences may be useful to prevent or treat a disorder associated with increased PKC ⁇ expression.
  • a dominant-negative mutant of PKC ⁇ may also specifically inhibit PKC ⁇ expression.
  • Modulation of PKC ⁇ activity by the administration of antibodies which specifically react with PKC ⁇ is also contemplated.
  • An anti-PKC ⁇ antibody is commercially available from BioMol (Cat. No. S A- 148). The invention will now be illustrated by the following non- limiting examples.
  • Sensor chip CM5 (available from BIACORE AB, Uppsala, Sweden) was the surface of choice for this assay since it provides a versatile, flexible, robust surface which has high binding capacity and allows immobilization through primary amine coupling. Use of this surface in conjunction with a BIACORE® 2000 (BIACORE AB, Uppsala, Sweden) allows multi-channel analysis of four independent sensor surfaces termed flow cells.
  • HBS-N (0.01 M HEPES pH 7.4, 0.15 M NaCl) buffer was degassed and filtered prior to use and employed as running buffer throughout these experiments. This buffer was employed in order to avoid any possible detergent effects on binding interactions.
  • PKC ⁇ was diluted to 20 ⁇ g/ml in 10 mM Sodium Acetate, pH 4.5, using standard amine coupling procedures. The surface was derivatized through injection of a 1 : 1 EDC NHS mixture for 7 minutes, followed by injection of PKC ⁇ , followed by blocking of remaining activated carboxyl groups by 1 M ethanolamine, pH 8.5. The flow rate throughout was 10 ⁇ l/min. Low-density and high-density surfaces were prepared by controlled PKC ⁇ injections (6176.0 R.U.s and 15968.0 R.U.s respectively). A control surface was also prepared by exposing a separate flow cell to the activation and blocking steps.
  • Lidocaine hydrochloride was dissolved in running buffer (HBS-N) and this stock solution diluted to concentrations of 5 ⁇ g/ml, 10 ⁇ g/ml, 25 ⁇ g/ml and 40 ⁇ g/ml. These solutions were then injected over prepared surfaces at a flow rate of 20 ⁇ l/min for two minutes ( Figure 1).
  • PKC ⁇ coupled to the sensor chip surface, remained active to the binding of lidocaine following the immobilization procedure.
  • Two different surface densities of PKC ⁇ were employed to show that binding of lidocaine to PKC ⁇ was specific. Comparison to the control surface also discriminates between bulk refractive index changes and specific binding interactions. This data demonstrates that lidocaine binds PKC ⁇ .
  • Rottlerin a selective blocker of PKC ⁇ , was found to act like lidocaine by blocking superoxide production and inhibiting the activation of eosinophils.
  • Inhibitors were added immediately before stimulation unless otherwise noted.
  • a stock solution of rottlerin (Calbiochem) was diluted in HBSS so that the final concentration of DMSO or EtOH was less than 0.5%.
  • the rate of eosinophil superoxide production was calculated using the linear part of the superoxide production curve (usually 20 to 50 minutes following IL-5 stimulation) and is presented as nanomoles of superoxide produced per minute (Figure 2).
  • Supernatants from the superoxide assays were stored at -20°C and the degree of degranulation (EDN release) was assayed by RIA as described (Abu-Ghazaleh et al., J. Immunol.. 142. 2393-2400 (1989)) ( Figure 3).
  • PKC ⁇ -selective blocker inhibited the rate of superoxide production and magnitude of degranulation in a concentration- dependent manner, with IC 50 values (0.7 ⁇ M and 0.6 ⁇ M respectively) for rottlerin consistent with inhibition of PKC ⁇ catalytic activity (3-6 ⁇ M).
  • IC 50 values 0.7 ⁇ M and 0.6 ⁇ M respectively
  • PKC ⁇ likely plays a central role in the regulation of NADPH oxidase activity and degranulation in eosinophils.
  • agents that modulate the activity of PKC ⁇ are useful to treat diseases wherein activation of eosinophils is implicated (e.g., hypersensitivity diseases such as asthma).

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Immunology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Otolaryngology (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des procédés de traitement des affections associées à l activation du polynucléaire eosinophile, telles que les maladies ou conditions d'hypersensibilité (par exemple, l'asthme), par l'administration d'un agent modulant l'activité de PKCδ.
PCT/US2000/027277 1999-10-15 2000-10-03 Traitement des pathologies associees au polynucleaire eosinophile par modulation de l'activite de pkc-$g(d) WO2001028543A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU78513/00A AU7851300A (en) 1999-10-15 2000-10-03 Treatment of eosinophil associated pathologies by modulating pkc-delta activity
EP00968629A EP1233765A1 (fr) 1999-10-15 2000-10-03 Traitement des pathologies associees au polynucleaire eosinophile par modulation de l'activite de pkc-$g(d)
CA002387786A CA2387786A1 (fr) 1999-10-15 2000-10-03 Traitement des pathologies associees au polynucleaire eosinophile par modulation de l'activite de pkc-$g(d)
JP2001531373A JP2003512321A (ja) 1999-10-15 2000-10-03 ＰＫＣ−δ活性のモジュレーションによる好酸球関連疾病の治療

Applications Claiming Priority (2)

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US15987299P 1999-10-15 1999-10-15
US60/159,872 1999-10-15

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WO2001028543A1 true WO2001028543A1 (fr) 2001-04-26

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EP (1) EP1233765A1 (fr)
JP (1) JP2003512321A (fr)
AU (1) AU7851300A (fr)
CA (1) CA2387786A1 (fr)
WO (1) WO2001028543A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004084889A1 (fr) * 2003-03-28 2004-10-07 Pfizer Inc. Utilisation de l'inhibiteur de la proteinekinase c pour supprimer l'excitation postsynaptique lente soutenue (sspe) de neurones enteriques
WO2005107789A1 (fr) * 2004-04-30 2005-11-17 The Board Of Trustees Of The Leland Stanford Junior University Utilisation de peptides delta pkc pour la modulation d'especes d'oxygene reactif
US7563772B2 (en) 2005-01-04 2009-07-21 The Board Of Trustees Of The Leland Stanford Junior University Methods of increasing cerebral blood flow

Citations (8)

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Publication number Priority date Publication date Assignee Title
WO1990004918A2 (fr) * 1988-10-25 1990-05-17 Wake Forest University Derives lipidiques d'ether ou d'ester contenant une amine quaternaire, et compositions therapeutiques
US5470860A (en) * 1991-12-13 1995-11-28 Byk Gulden Lomberg Chemische Fabrik Gmbh 1,4-dihydropyridines for use in the treatment of dermatoses
US5510339A (en) * 1993-02-02 1996-04-23 Mayo Foundation For Medical Education And Research Method for the treatment of bronchial asthma by administration of topical anesthetics
WO1997038693A1 (fr) * 1996-04-18 1997-10-23 Alcon Laboratories, Inc. Antagonistes du calcium utilises comme inhibiteurs de la degranulation du mastocyte conjonctival chez l'homme pour le traitement d'allergies oculaires
US5922571A (en) * 1997-03-06 1999-07-13 Incyte Pharmaceuticals, Inc. Polynucleotides encoding a protein kinase C homolog
WO1999046264A1 (fr) * 1998-03-13 1999-09-16 Astrazeneca Ab Nouveaux composes
WO1999062537A1 (fr) * 1998-06-04 1999-12-09 The Rockefeller University Procedes et agents permettant la modulation de la reponse immunitaire et de l'inflammation par modulation des proteines membranaires des monocytes et des cellules dendritiques
WO2000070091A1 (fr) * 1999-05-18 2000-11-23 Isis Pharmaceuticals, Inc. MODULATION OLIGONUCLEOTIDIQUE ANTISENS DE L'EXPRESSION DE LA PROTEINE KINASE C-δ HUMAINE

Patent Citations (8)

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Publication number Priority date Publication date Assignee Title
WO1990004918A2 (fr) * 1988-10-25 1990-05-17 Wake Forest University Derives lipidiques d'ether ou d'ester contenant une amine quaternaire, et compositions therapeutiques
US5470860A (en) * 1991-12-13 1995-11-28 Byk Gulden Lomberg Chemische Fabrik Gmbh 1,4-dihydropyridines for use in the treatment of dermatoses
US5510339A (en) * 1993-02-02 1996-04-23 Mayo Foundation For Medical Education And Research Method for the treatment of bronchial asthma by administration of topical anesthetics
WO1997038693A1 (fr) * 1996-04-18 1997-10-23 Alcon Laboratories, Inc. Antagonistes du calcium utilises comme inhibiteurs de la degranulation du mastocyte conjonctival chez l'homme pour le traitement d'allergies oculaires
US5922571A (en) * 1997-03-06 1999-07-13 Incyte Pharmaceuticals, Inc. Polynucleotides encoding a protein kinase C homolog
WO1999046264A1 (fr) * 1998-03-13 1999-09-16 Astrazeneca Ab Nouveaux composes
WO1999062537A1 (fr) * 1998-06-04 1999-12-09 The Rockefeller University Procedes et agents permettant la modulation de la reponse immunitaire et de l'inflammation par modulation des proteines membranaires des monocytes et des cellules dendritiques
WO2000070091A1 (fr) * 1999-05-18 2000-11-23 Isis Pharmaceuticals, Inc. MODULATION OLIGONUCLEOTIDIQUE ANTISENS DE L'EXPRESSION DE LA PROTEINE KINASE C-δ HUMAINE

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BHEEKHAESCURA R.,CHANCE S.R. ET AL.: "Pharmacologic regulation of histamine release by the human recombinant histamine-releasing factor.", JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, vol. 103, no. 5 part 1, May 1999 (1999-05-01), pages 937 - 943, XP000991205 *
KIM H.M.,KO S.G. ET AL.: "Interleukin-3 or immunoglobulin E promotes expression of protein kinase C delta gene in murine mast cells.", PHARMACOLOGICAL RESEARCH, vol. 40, no. 2, August 1999 (1999-08-01), pages 147 - 151, XP000991210 *
MODY V.D., MANGALAN S., PANDYA K.K. ET AL.: "Absorption of Herbinol - a polyherbal topical cream", JOURNAL OF PHARMACY TECHNOLOGY, vol. 10, no. 2, 1994, pages 71 - 74, XP000992187 *
MYERS J R ET AL: "Should supplemental estrogens be used as steroid-sparing agents in asthmatic women? [see comments].", CHEST, (1994 JUL) 106 (1) 318-9., XP000991209 *
SHANMUGAM MALATHY ET AL: "Regulation of protein kinase C delta by estrogen in the MCF-7 human breast cancer cell line.", MOLECULAR AND CELLULAR ENDOCRINOLOGY, vol. 148, no. 1-2, 25 February 1999 (1999-02-25), pages 109 - 118, XP000991396, ISSN: 0303-7207 *
TANG Y ET AL: "Dexniguldipine hydrochloride, a protein kinase C-specific inhibitor, suppresses in vitro growth of human pancreatic and colon cancer cells.", PROCEEDINGS OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH ANNUAL, vol. 36, 1995, Eighty-sixth Annual Meeting of the American Association for Cancer Research;Toronto, Ontario, Canada; March 18-22, 1995, 1995, pages 436, XP000990227, ISSN: 0197-016X *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004084889A1 (fr) * 2003-03-28 2004-10-07 Pfizer Inc. Utilisation de l'inhibiteur de la proteinekinase c pour supprimer l'excitation postsynaptique lente soutenue (sspe) de neurones enteriques
WO2005107789A1 (fr) * 2004-04-30 2005-11-17 The Board Of Trustees Of The Leland Stanford Junior University Utilisation de peptides delta pkc pour la modulation d'especes d'oxygene reactif
US7563772B2 (en) 2005-01-04 2009-07-21 The Board Of Trustees Of The Leland Stanford Junior University Methods of increasing cerebral blood flow
US8492348B2 (en) 2005-01-04 2013-07-23 The Board Of Trustees Of The Leland Stanford Junior University Methods of increasing cerebral blood flow

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CA2387786A1 (fr) 2001-04-26
JP2003512321A (ja) 2003-04-02
EP1233765A1 (fr) 2002-08-28
AU7851300A (en) 2001-04-30

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