WO2001056590A2 - Verwendung von proteinkinase-inhibitor-alpha - Google Patents
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- WO2001056590A2 WO2001056590A2 PCT/EP2001/001002 EP0101002W WO0156590A2 WO 2001056590 A2 WO2001056590 A2 WO 2001056590A2 EP 0101002 W EP0101002 W EP 0101002W WO 0156590 A2 WO0156590 A2 WO 0156590A2
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- A—HUMAN NECESSITIES
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- A61P9/12—Antihypertensives
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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
- G01N33/94—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors
- G01N33/9453—Cardioregulators, e.g. antihypotensives, antiarrhythmics
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- 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
Definitions
- the present invention relates to the use of protein kinase inhibitor-alpha (PKI-alpha), the use of inhibitors of protein kinase inhibitor-alpha and methods for screening for beta-agonists and beta-antagonists.
- PKI-alpha protein kinase inhibitor-alpha
- myocardial stunning was first described in 1975. This refers to the property of the myocardium to show long-lasting, reversible myocardial dysfunction after short-term ischemia as a result of coronary occlusions, ie the heart muscle does not show the expected contractility. This reversible state lasts for several hours and contradicts the prevailing view among experts that an ischemic state of more than 45 minutes is irrevocably associated with myocyte death.
- the protein kinase A present in the heart (henceforth also referred to as PKA), which regulates myocardial contractility by means of phospholamban and phosphorylation of troponin I, is controlled by receptors which are coupled to the adenylate cyclase, which in turn is regulated by catecholamines.
- the enzyme activity is both by protein kinase inhibitors (hereinafter referred to as PKI) and regulated by cAMP.
- PKI protein kinase inhibitors
- the ⁇ -form is six times more effective than the ⁇ -form.
- a protein kinase inhibitor known in the art is the protein kinase inhibitor alpha (also referred to herein as PKI-alpha).
- PKI-alpha has a length of 76 amino acids, whereby the part of the primary sequence that is essential for the inhibitory effect seems to be limited to the range of amino acids 14 to 22. This sequence is 100% identical in humans, pigs, chickens, rats and mice. At the level of the mRNA, the 5 'end of the total porcine mRNA shows a sequence homology of about 90% compared to that of the human, mouse, rat and chicken genome.
- a recombinant PKI-alpha comprising only amino acids 14 to 22 of the complete PKI-alpha amino acid sequence is cell permeable and available from Calbiochem (product number # 476485).
- the porcine PKI-alpha coding cDNA has at its 5 'end a second open reading frame which codes for a 9 amino acid polypeptide and several different poly (A) signal sequences at its 3' end (GenBank # bankit256111 AF132737)
- the present invention has for its object to provide new uses for PKI-alpha and for an inhibitor of PKI-alpha.
- the object is achieved by using PKI-alpha and / or its derivatives for lowering blood pressure.
- the object is achieved according to the invention by using PKI-alpha and / or its derivatives as a beta-antagonist.
- the object is achieved by the use of PKI-alpha and / or its derivatives for the production of a medicament for the prevention and / or treatment of diseases in which a beta-antagonist can be used.
- the PKI-alpha is one of SEQ ID No. 2 amino acid sequence shown comprises.
- the PKI-alpha is encoded by a nucleic acid which corresponds to the coding sequence of the sequence shown in SEQ ID No. 1 or a sequence resulting therefrom as a result of the degeneracy of the genetic code or a nucleic acid hybridizing thereon.
- the PKI-alpha is used in a shortened form.
- the PKI-alpha contains the amino acids 14 to 22 of the PKI-alpha sequence, in particular the sequence of PKI-alpha according to SEQ ID No.1 or SEQ ID No. 2 includes.
- the PKI-alpha or its derivative is used for the treatment and / or prevention of diseases which are selected from the group consisting of cardiac arrhythmias, hyperkinetic cardiac syndrome, angina pectoris, myocardial infarction, acute myocardial infarction , Heart failure, arterial hypertension, essential and renal hypertension, portal hypertension, bleeding from esophageal varices, pheochromocytoma, overdosage of beta-sympathomimetics and choline receptor blockers, glaucoma simplex, hyperthyroidism, thyroid toxicity regimen, migraines, and migraines, migraines, migraines, erectile dysentery, migraines, migraines, and migraines, migraines, migraines, migraines, migraines, migraines, and migraines.
- the PKI-alpha or its derivative is used for post-infarct medication, prophylaxis of the rein
- the object is also achieved by using an inhibitor of PKI-alpha or a derivative thereof for increasing blood pressure.
- the object is achieved by using an inhibitor of PKI-alpha or a derivative thereof as a beta agonist.
- the object is achieved by using an inhibitor of the PKI-alpha or a derivative thereof for the manufacture of a medicament for the treatment and / or prevention of diseases in which a beta-agonist can be used.
- the inhibitor influences the transcription of the PKI-alpha.
- the PKI-alpha is a PKI-alpha as described herein.
- the inhibitor of the PKI-alpha comprises an amino acid sequence which is selected from the group consisting of the sequences with the SEQ ID No. 3 and SEQ ID No. 4 includes.
- the PKI-alpha inhibitor is intended to be used to treat and / or prevent diseases selected from the group consisting of heart failure, heart attack, chronic and acute heart failure and hypotension.
- the object is achieved by a method according to the invention for screening for agents for lowering blood pressure, beta-antagonists and / or agents for the treatment and / or prevention of
- a mixture of a beta receptor, a beta agonist of the beta receptor and a candidate beta antagonist is provided, and
- the change in the binding behavior of the beta-agonist to the beta-receptor observed under the influence of the candidate beta-antagonist is compared with that under the influence of the beta-antagonist as described herein , observed change in the binding behavior of the beta agonist to the beta receptor.
- the beta receptor is selected from the group comprising betal and beta2 receptors.
- the beta agonist is a sympathomimetic, in particular one which is selected from the group comprising noradrenaline, adrenaline, dopamine and dobutamine.
- the beta-agonist is a beta-agonist as described herein.
- the object is achieved by a method of screening for agents for lowering blood pressure, beta-agonists and / or agents for the treatment and / or prevention of diseases in which a beta-agonist can be used, wherein
- a candidate beta agonist is added to the transcription system and
- the change in the transcription of the beta-antagonist observed under the influence of the candidate beta-agonist is compared with the change in the observed under the influence of the beta-agonist as described herein Transcription of the beta antagonist.
- the beta-antagonist is one as described herein.
- the beta-antagonist can be obtained by one of the methods according to the invention.
- the present invention is based on the surprising finding that PKI-alpha has a negative inotropic, that is to say an effect which worsens the myocardial function.
- This effect comes about through an inhibition of protein kinase A, which is responsible for the phosphorylation of Phospholamban and troponin is responsible (so-called beta-adrenergic signal transduction).
- beta-adrenergic signal transduction As a result of the negative inotropic effect of PKI-alpha, inhibition of PKI-alpha in turn improves myocardial function, particularly in the case of heart failure.
- PKI-alpha has a concentration-dependent, negative inotropic effect and is involved in beta-adrenergic signal transduction.
- PKI-alpha can be used as a beta antagonist. The latter is due to the fact that the effect of the beta-receptors binding the catecholamines on the contractility-regulating protein kinase A can be counteracted by the protein kinase inhibitors, which thus show a beta-antagonistic effect.
- beta-antagonistic effect of the PKI-alpha it is also suitable for the manufacture of medicaments for the treatment of diseases in which a beta-antagonist is generally used.
- this or derivatives thereof can be used in medication in place of or in addition to the beta-antagonist (s) previously used.
- PKI-alpha or a medicament containing it now provides a replacement for any medicament containing a beta-antagonist as pharmaceutical active ingredient.
- PKI-alpha Since the PKI-alpha is not only expressed in muscle tissue, but also in nerve tissue, in particular in the brain, neurophysiological fields of indication for PKI-alpha and inhibitors thereof are also within the scope of the present invention.
- the group of pharmaceutically active compounds is expanded considerably, particularly to the extent that a completely new class of compounds is introduced into this therapeutically very important indication area.
- the use of PKI-alpha and inhibitors thereof is also advantageous in that they start very early in the cascade of beta-adrenergic signal transduction and are therefore not subject to the undesired down-regulation of the beta-receptors which is associated with various disadvantages.
- Heart failure is one of the most important diseases in western industrialized countries due to its high prevalence (1-1.5%) and morbidity of the adult population as well as its correspondingly high costs (Sharpe N. et al .; Lancet 352 (suppi I), 3 - 7 (1998)).
- a number of medications are used to treat them, but only a few of them are really effective, ie they will continue to be effective for many years to come.
- the calcium antagonists e.g.
- substance classes are increasingly sought which have their place of action further above the ß-
- the PKI-alpha in particular amino acids 14-22 thereof, appears to belong in the desired substance class.
- an inhibitor of PKI-alpha appears to be particularly interesting, in particular the inhibitor of PKI-alpha (PKI-alpha-1) encoded by the second open reading frame of PKI-alpha.
- PKI-alpha-1 encoded by the second open reading frame of PKI-alpha.
- both the beta-antagonistic and the beta-agonistic effects can be brought to bear by using PKI-alpha or an inhibitor thereof.
- PKI-alpha The amino acid sequence of PKI-alpha is shown in SEQ ID No.1 together with the nucleic acid sequence encoding it and as an amino acid sequence as such in SEQ ID No. 2. It turns out for the person skilled in the art that the PKI-alpha is not restricted to the PKI-alpha which contains the sequences SEQ ID No. 1 and SEQ ID No. 2 sequences shown. Rather, a PKI-alpha is understood here to mean any protein kinase inhibitor which influences the activity of protein kinase A. To this extent, the term protein kinase inhibitor is based on a functional definition.
- nucleic acid sequence shown in SEQ ID No.1 is also only an example of a sequence coding for a protein kinase inhibitor. Other sequences result from the degeneracy of the genetic code.
- the protein kinase inhibitor-alpha has a length of 76 amino acids in its native form. In fact, that extends to the inhibitory Effect-relevant region of the primary sequence of amino acids 14 to 22, so that shortened (“truncated") forms of protein kinase inhibitors, in particular PKI-alpha, can also be used according to the invention.
- PKI-alpha whose Sequence is limited to amino acids 14 to 22 of the complete amino acid sequence
- This shortened PKI-alpha is membrane-permeable or membrane-permeable, ie it can enter the intracellular space via a cytoplasmic membrane and there the intracellular compartments, in particular the sarcoplasmic reticulum and the protein kinase A, PKI-alpha and in particular a shortened form and especially amino acids 14 to 22 of the complete primary sequence of the PKI-alpha, as shown in SEQ ID No. 1 or SEQ ID No.2, can thus achieve an intracoronary, intraperitoneal form or given intravenously.
- PKI-alpha and its inhibitor can be present in modified form. Such a modification can take place, for example, in connection with the requirements of galenics. Other modifications can affect the pharmacological and toxicological properties.
- Formulations comprising PKI-alpha or an inhibitor thereof may include the usual pharmaceutical excipients and ingredients such as pharmaceutically acceptable carriers and buffers.
- Beta blockers i.e. Beta-antagonists, and thus PKI-alpha and their derivatives according to the invention, are used, for example, as or for
- Antiarrhythmic drugs (irregular heartbeat)
- Anti-anginal drugs angina pectoris
- Improvement of the prognosis in patients with myocardial infarction post-infarct medication
- acute myocardial infarction and prophylaxis of the pure infarct
- Glaucoma on the eye (Glaucoma simplex)
- an inhibitor of PKI-alpha (hereinafter also referred to as PKI-alpha-1) is based in turn on the surprising finding that PKI-alpha has a concentration-dependent, inotropic effect and is involved in beta-adrenergic signal transduction.
- an inhibitor of PKI-alpha can modify and reverse the effects of PKI-alpha.
- an inhibitor of PKI-alpha can be used to increase blood pressure or a suitable medication.
- the inhibitor of PKI-alpha After the inhibitor of PKI-alpha has been inhibited by an inhibitor of the beta adrenergic signal transmission, it acts as a beta agonist and can be used accordingly.
- This use generally includes the use in the manufacture of a medicament for the treatment and prevention of diseases in which beta-agonists can be used: thus an inhibitor of PKI-alpha can be used in medication in addition to the beta-agonist (s) previously used become. Basically, there are no restrictions, so that the PKI-alpha inhibitor now provides a replacement for any medicament containing a beta-agonist as active pharmaceutical ingredient.
- inhibitor of PKI-alpha is based on a functional definition.
- An inhibitor of PKI-alpha is thus any compound which inhibits the action of PKI-alpha, irrelevant to what extent the inhibition of PKI-alpha takes place, to which chemical compound class the inhibitor of PKI-alpha can be assigned and on based on what mechanism the PKI-alpha inhibitor works.
- a mechanism that can be the basis of the action of an inhibitor of PKI-alpha is the inhibition of the transcription of PKI-alpha.
- the gene product of the second open reading frame of the PKI-alpha gene acts as an inhibitor in this sense. It appears from Wang X. et al .; that the gene product can be the active agent. Mol Pharm 54, 514-524 (1998).
- the amino acid sequence of this human gene product was
- the corresponding pork sequence is Met Trp lle Phe Val Ser Asn Asp
- the difference between the two types of humans and pigs in the form of an amino acid exchange at position 5 of the amino acid sequence is based on an exchange at the nucleic acid level, with position 2 of the fifth codon being changed.
- glycine is found as the fifth amino acid, whereas in the case of the pig sequence it is valine.
- the corresponding base exchange is a change from G (human) to T (pig).
- Beta agonists and thus inhibitors of PKI-alpha, as disclosed herein, can be used for
- the methods according to the invention are methods by means of which compounds are determined or provided which are known as PKI-alpha, i.e. can be used as inhibitors of protein kinase A or as inhibitors thereof, in particular in connection with one or more of the diseases or indication fields disclosed herein.
- the methods can also be directed to the fact that one or more of a number of compounds should be determined with a corresponding property (“screening”).
- Screening A compound which may have a corresponding property is also referred to herein as "Candidate" connection referred to.
- the receptor provided can be present as an isolated molecule, for example in solution or immobilized.
- a biological system can be an in vitro system or an in vivo system.
- a typical in vitro system is a translation or transcription system.
- a typical in vivo system is a cellular system, for example a cell, in particular a myocardial or nerve cell, which contains the genetic information for PKI-alpha.
- a cellular system can also be a cell into which, preferably by means of genetic engineering methods, a nucleic acid coding for PKI-alpha or a part thereof or its or its expression controlling nucleic acid is introduced.
- a nucleic acid coding for PKI-alpha or a part thereof or its or its expression controlling nucleic acid is introduced.
- the stress inducibility of PKI-alpha which is also disclosed here.
- the effectiveness of a candidate antagonist is assessed on the basis of a comparison of the activity of PKI-alpha and its derivatives, as described herein.
- the method according to the invention can also provide that a beta agonist as described herein is used.
- the beta-agonist provided can be present as an isolated molecule, for example in solution or immobilized.
- the candidate agonist is present in a biological system.
- a biological system can be an in vitro system or an in vivo system.
- a typical in vitro system is typically a cell-free translation or transcription system.
- a typical in vivo system is a cellular system, for example a cell, in particular a myocardial or nerve cell, which contains the genetic information for the candidate beta-agonist.
- a cellular system can also be a cell into which, preferably by means of genetic engineering methods, the nucleic acid coding for the candidate beta-agonist or a part thereof or its or its expression controlling nucleic acid is introduced.
- the transcription system for a beta-antagonist used in the process according to the invention can be an in vivo system or an in vitro system.
- a typical in vitro system is a translation or transcription system.
- a typical in vivo system is a cellular system, for example a cell, in particular a myocardial or nerve cell, which contains the genetic information for PKI-alpha.
- the cellular system can also be a cell into which, preferably by means of genetic engineering methods, the nucleic acid coding for PKI-alpha or a part thereof or its or its expression-controlling nucleic acid is introduced.
- use can be made of the stress inducibility of PKI-alpha, which is also disclosed here.
- the transcription system for a beta-antagonist also includes the candidate beta-agonist or the nucleic acid coding for it or controlling its expression.
- beta-antagonists and beta-agonists as disclosed and described herein or that can be determined or determined as such by one of the methods disclosed herein are used therein.
- the effectiveness of a candidate beta agonist is assessed on the basis of a comparison of the change in the transcription of the beta antagonist observed under the influence of the candidate beta agonist with that under the influence of a beta -Agonists, as described herein, observed changes in beta antagonist transcription.
- the effectiveness of the tested compounds can be quantified at a very early stage in the screening or development process of novel beta-agonists.
- Fig. 1 shows the function of protein kinase A and PKI-alpha in beta-adrenergic signal transduction: More precise
- ßl and ß2 AR Signal transduction cascade of the ßl and ß2 receptors (ßl and ß2 AR) shown that activate the protein kinase A via a, ß and y-G protein subunits as well as the adenylate cyclase (AC) and cAMP increases.
- the protein kinase A can be inhibited by the PKI-alpha, whereby the effects of the protein kinase A can be antagonized.
- Protein kinase A phosphorylates in particular phospholamban, which explains the positive inotropic effect.
- Fig. 2 shows the decrease in the function of the left cardiac ventricle
- the hearts of a total of six Sprague Dawley rats weighing approximately 300 g were isolated and, as in Schulze et al. (Schulze et al .; Circulation 1990: 959-69). Hemodynamic parameters including contractility, external cardiac work (EHW), coronary artery and aortic flow were recorded approximately 15 minutes after antegrade perfusion. Cell permeable, recombinant PKI-alpha (amino acids 14 to 22, Calbiochem # 476485) was then administered. The compound was infused directly into the atrium cannula using a motor pump.
- the infusion rate was continually adjusted to the ejection volume (the sum of aortic and coronary flow) and increased at five-minute intervals in order to reach the final PKI-alpha concentrations in the perfusate of 0.5, 1.0 and 2.0 ⁇ mol / l.
- the results relating to the external heart volume and the course of dp / dt max under these test conditions are shown in FIG. 2.
- the infusion of the shortened -PKI-alpha caused a pronounced, reversible, concentration-dependent (up to 2 ⁇ mol) depression of the myocardial function, which was comparable to the dysfunction observed after short coronary occlusion.
- the protein kinase inhibitor-alpha truncated to amino acids 14 to 22, was added to cell cultures of myocytes (e.g. C9H2 cells, available from the American Type Culture Collection) and the activity of protein kinase A was determined. A dose-dependent decrease in activity was found.
- the 9 amino acid long PKI-alpha inhibitor (the gene product of the second open reading frame of the PKI gene in humans and in pigs) was added to cell cultures of myocytes and the expression of the PKI-alpha and the activity of the protein kinase A were determined. An increase in the activity of the PKA depending on the dose of the PKI-alpha inhibitor was found.
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Abstract
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Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
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AU2001233723A AU2001233723A1 (en) | 2000-02-03 | 2001-01-31 | Utilization of protein kinase inhibitor alpha |
JP2001556489A JP2003531114A (ja) | 2000-02-03 | 2001-01-31 | プロテインキナーゼα阻害剤の使用 |
EP01905712A EP1253931A2 (de) | 2000-02-03 | 2001-01-31 | Verwendung von proteinkinase-inhibitor-alpha |
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DE10004858A DE10004858A1 (de) | 2000-02-03 | 2000-02-03 | Verwendung von Proteinkinase-Inhibitor-alpha |
DE10004858.7 | 2000-02-03 |
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WO2001056590A2 true WO2001056590A2 (de) | 2001-08-09 |
WO2001056590A3 WO2001056590A3 (de) | 2002-06-20 |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2006527177A (ja) * | 2003-06-06 | 2006-11-30 | ウニベルジテートスクリニクム フライブルク | 門脈圧亢進症の予防及び/又は治療のため薬剤又は医薬組成物 |
US9974759B2 (en) | 2013-05-31 | 2018-05-22 | Indiana University Research And Technology Corporation | Beta 2 adrenoceptor antagonists for treating orthostatic hypotension |
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PL2056882T3 (pl) * | 2006-08-01 | 2013-03-29 | Univ Texas | Identyfikacja mikro-RNA, który aktywuje ekspresję łańcucha ciężkiego beta-miozyny |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998022122A1 (en) * | 1996-11-21 | 1998-05-28 | Promega Corporation | Alkyl peptide amides and applications |
WO1998044349A1 (en) * | 1997-04-03 | 1998-10-08 | University Technology Corporation | Method for identifying adrenergic receptor antagonists having good tolerability |
US5846720A (en) * | 1989-07-18 | 1998-12-08 | Oncogene Science, Inc. | Methods of determining chemicals that modulate expression of genes associated with cardiovascular disease |
-
2000
- 2000-02-03 DE DE10004858A patent/DE10004858A1/de not_active Withdrawn
-
2001
- 2001-01-31 WO PCT/EP2001/001002 patent/WO2001056590A2/de not_active Application Discontinuation
- 2001-01-31 JP JP2001556489A patent/JP2003531114A/ja active Pending
- 2001-01-31 EP EP01905712A patent/EP1253931A2/de not_active Withdrawn
- 2001-01-31 AU AU2001233723A patent/AU2001233723A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5846720A (en) * | 1989-07-18 | 1998-12-08 | Oncogene Science, Inc. | Methods of determining chemicals that modulate expression of genes associated with cardiovascular disease |
WO1998022122A1 (en) * | 1996-11-21 | 1998-05-28 | Promega Corporation | Alkyl peptide amides and applications |
WO1998044349A1 (en) * | 1997-04-03 | 1998-10-08 | University Technology Corporation | Method for identifying adrenergic receptor antagonists having good tolerability |
Non-Patent Citations (5)
Title |
---|
FRANCIOSA J A: "BETA-ADRENERGIC BLOCKING AGENTS: PAST, PRESENT, AND FUTURE PERSPECTIVES" CORONARY ARTERY DISEASE, CURRENT SCIENCE LTD, XX, Bd. 10, Nr. 6, September 1999 (1999-09), Seiten 369-376, XP001000657 ISSN: 0954-6928 * |
KNOELL, R. (1) ET AL: "The protein kinase inhibitor - alpha gene: Another key to postischaemic myocardial dysfunction." EUROPEAN HEART JOURNAL, (AUG., 1999) VOL. 20, NO. ABSTR. SUPPL., PP. 315. MEETING INFO.: XXIST CONGRESS OF THE EUROPEAN SOCIETY OF CARDIOLOGY BARCELONA, SPAIN AUGUST 28-SEPTEMBER 1, 1999 EUROPEAN SOCIETY OF CARDIOLOGY., XP000999001 * |
MARULLO S ET AL: "EXPRESSION OF HUMAN BETA-1 AND BETA-2 ADRENERGIC RECEPTORS IN ESCHERICHIA-COLI AS A NEW TOOL FOR LIGAND SCREENING" BIO-TECHNOLOGY (NEW YORK), Bd. 7, Nr. 9, 1989, Seiten 923-927, XP001018679 ISSN: 0733-222X * |
MITCHELL R D ET AL: "Heat-stable inhibitor protein derived peptide substrate analogs: phosphorylation by cAMP-dependent and cGMP-dependent protein kinases." BIOCHEMISTRY, (1995 JAN 17) 34 (2) 528-34. , XP001021452 * |
VAN PATTEN S M ET AL: "The alpha- and beta-isoforms of the inhibitor protein of the 3',5'-cyclic adenosine monophosphate-dependent protein kinase: characteristics and tissue- and developmental-specific expression." MOLECULAR ENDOCRINOLOGY, (1992 DEC) 6 (12) 2114-22. , XP001021716 * |
Cited By (5)
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JP2006527177A (ja) * | 2003-06-06 | 2006-11-30 | ウニベルジテートスクリニクム フライブルク | 門脈圧亢進症の予防及び/又は治療のため薬剤又は医薬組成物 |
JP2009280602A (ja) * | 2003-06-06 | 2009-12-03 | Universitaetsklinikum Freiburg | 門脈圧亢進症の予防及び/又は治療 |
JP2010195821A (ja) * | 2003-06-06 | 2010-09-09 | Universitaetsklinikum Freiburg | 門脈圧亢進症の予防及び/又は治療 |
US9278097B2 (en) | 2003-06-06 | 2016-03-08 | Universitatsklinikum Freiburg | Prophylaxis and/or treatment of portal hypertension |
US9974759B2 (en) | 2013-05-31 | 2018-05-22 | Indiana University Research And Technology Corporation | Beta 2 adrenoceptor antagonists for treating orthostatic hypotension |
Also Published As
Publication number | Publication date |
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AU2001233723A1 (en) | 2001-08-14 |
WO2001056590A3 (de) | 2002-06-20 |
JP2003531114A (ja) | 2003-10-21 |
DE10004858A1 (de) | 2001-08-16 |
EP1253931A2 (de) | 2002-11-06 |
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