Prostaglandin E1 : New Aspects on Pharmacology, Metabolism and Clinical Efficacy

125 Pages·1991·2.986 MB·English

by  K. Schrör (auth.), Prof. Dr. med. Curt Diehm, Prof. Dr. med. Helmut Sinzinger, Dr. med. Waltraud Rogatti (eds.)

c.
Diehm H. Sinzinger W Rogatti (Eds.)
Prostaglandin E1
New Aspects on Pharmacology,
Metabolism and Clinical Efficacy
Springer -Verlag
Berlin Heidelberg New York
London Paris Tokyo
Hong Kong Barcelona
Budapest
Prof. Dr. med. Curt Diehm
Med. Klinik im Rehabilitationskrankenhaus Karlsbad
D-7516 Karlsbad
Prof. Dr. med. Helmut Sinzinger
Wilhelm-Auerswald-Atheroskleroseforschungsgruppe Wien
Nadlergasse 1
A-1090 Wi en
Dr. med. Waltraud Rogatti
NerthusstraBe 3a
D-5000 Kaln 91
ISBN-13:97S-3-540-54524-S e-ISBN-13:97S-3-642-76910-S
DOl: lO.1007/97S-3-642-7691O-S
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Preface
Although prostaglandin El (PGE1) has been clinically available for a long
time, only in recent years has its effectiveness in peripheral arterial occlusive
disease been confirmed in controlled studies. Not surprisingly, the favour
able results achieved both in patients with critical limb ischaemia and in
those with intermittent claudication has stimulated research activities into
the clinical pharmacology of this prostaglandin.
As a consequence of these efforts, exciting new findings have revealed
that PGE has anti thrombotic , endothelium-stabilizing and leucocyte-stabi
1
lizing properties as well as effects on lipid metabolism, all of which, quite
apart from its well-known anti-aggregating and vasodilator effects, may add
to the clinical efficacy of the substance.
New data have also been gathered on the metabolism of PGE most
b
notably the detection of 13,14-dihydro-PGE a metabolite which was
b
recently isolated in humans following the administration of PGE1. Being
biologically active, the pharmacodynamic spectrum of 13,14-dihydro-PGE
1
very closely resembles that of PGE1. This finding may help to explain the
efficacy of PGE despite its rapid metabolization when given intravenously.
1
This volume summarizes the papers presented at a symposium on PGE
1
which was organized by Schwarz Pharma AG, Monheim, during the fifth
International Symposium on Prostaglandins in the Cardiovascular System,
held in Vienna in September 1991. Taken together, the articles compiled
here reflect the current state of knowledge with respect to the pharmaco
logy, metabolism and clinical effect of PGE in peripheral arterial occlusive
1
disease. Future research will have to resolve as yet unanswered questions
concerning further mechanisms of action, metabolites and potential new
indications.
Curt Diehm
Helmut Sinzinger
Waltraud Rogatti
Contents
Cellular Sites of Action of Prostaglandins in the Cardiovascular
System
K. Schror 1
On the Metabolism and Pharmacokinetics of Prostaglandin El
Administered by Intra-arterial or Intravenous Infusions
B. A. Peskar, W. H. Hesse, W. Rogatti, and C. Rudofsky . . . 6
Actions of PGE1, PGEo and 15-keto-PGE1 on Vessel Tone In Vitro
M. Braun, L. Bruch, P. Ney, C. Torsello, and K. Schror . . . 12
13,14-dihydro-PGE1 (PGEo) but not 15-keto-PGE1 is a Potent
Inhibitor of Human Platelet and Neutrophil Activation
P. Ney, M. Braun, C. Szymanski, and K. Schror . . . . . . . . 21
Comparable Inhibitory Action of PGE and 13-14-dihydro-PGE
1 1
on Smooth Muscle Cell Activity and Extracellular Matrix Production
I. Neumann, P. Fitscha, J. O. 'Crady, B. A. Peskar,
and H. Sinzinger . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
PGE and 13,14-dihydro-PGE Increase Low-Density Lipoprotein
1 1
Receptors and Improve Arterial Wall Lipid Metabolism
H. Sinzinger, I. Virgolini, C. Lupattelli, and M. Banyai . . . . . . 39
Effect of Intra-arterial and Intravenous Application of Prostaglandin El
on Neutrophil Function in Peripheral Arterial Occlusive Disease
F.-J. Neumann, T. Weiss, J. Mollenhauer, M. Schneider, I. Ott,
H.-M. Haupt, and C. Diehm ............... 49
A Comparison of Different Dosages of Intra-arterial and
Intravenous Administered Prostaglandin El in Healthy Volunteers
C. Rudofsky and B. A. Peskar . . . . . . . . . . . . . . . . . . . 58
VIII Contents
Transcutaneous Oxygen Pressure at Different Dosages
of Intravenous Prostaglandin El in Patients with Severe Arterial
Occlusive Disease: A Double-Blind, Placebo-Controlled Study
A. Creutzig, L. Caspary, and K. Alexander . . . . . . . . . . . . 72
Transcutaneous P0 During Intra-arterial and Intravenous PGE
2 1
Infusion in Patients with Critical Limb Ischaemia
T. Weiss, J. Griefthaber, W. Rogatti, O. Kistner, E. Hsu, T. Jansen,
and C. Diehm . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
Effects of Intravenous PGE on Blood Flow and Microcirculation:
1
A Double-Blind, Placebo-Controlled Study in Patients with Critical
Limb Ischaemia
P. Scheffler, D. de la Hamette, G. Leipnitz, and J. Groft. . . . . . 91
Therapeutic Efficacy of Intravenous Prostaglandin El
Versus Pentoxifylline in Patients with Intermittent Claudication
W. Hepp, S. von Bary, D. Corovic, C. Diehm, E. Milhe,
G. Rudofsky, P. Scheffler, G. Trilbestein, and M. Vogelpohl. 101
Adjuvant Intravenous PGE Treatment After Profundaplasty
1
for Limb Salvage
J. D. Gruft . . 109
Subject Index 115
List of Contributors
Prof. Dr. K. Alexander
Medizinische Hochschule Hannover, Abt. Angiologie,
Konstanty-Gutschow-Str. 8, 3000 Hannover 1
Dr. M. Banyai
Wilhelm Auerswald-Atherosclerosis Research Group (ASF), Nadlergasse 1,
A-1090 Wien
Prof. Dr. S. von Bary
Kreiskrankenhaus Marienhohe, Abt. Chirurgie, Mauerfeldchen 25,
5102 Wlirselen
Dr. M. Braun,
Institut flir Pharmakologie, Heinrich-Heine-Universitat DUsseldorf, Moorenstr. 5,
4000 DUsseldorf 1
Dr. L. Bruch
Univesitatsklinik Innere Medizin (Charite) Berlin, 1040 Berlin
Dr. L. Caspary
Medizinische Hochschule Hannover, Abt. Angiologie,
Konstanty-Gutschow-Str. 8, 3000 Hannover 1
PD Dr. D. Corovic
Abt. f. Thorax-, Herz- und GefiiBchirurgie, Klinik Schildautal, Lautenthaler StraBe,
3370 Seesen
Prof. Dr. A. Creutzig
Medizinische Hochschule Hannover, Abt. Angiologie,
Konstanty-Gutschow-Str. 8, 3000 Hannover 1
Prof. Dr. C. Diehm
Med. Klinik im Rehabilitationskrankenhaus Karlsbad
7516 Karlsbad
Doz. Dr. P. Fitscha
II. Medizinische Abt., Allgemeine Poliklinik, Mariannengasse 10, A-1090 Wien
Prof. Dr. J. O'Grady
Daiichi Pharmaceutical Company Limited, International Press Centre, 76 Shoe Lane,
London EC4A 3JB, UK
X List of Contributors
J. GrieBhaber
Medizinische Universitatsklinik, Abt. flir Kardiologie/Angiologie, Bergheimer Str. 58,
6900 Heidelberg
Prof. Dr. J. D. GruB
Kurhessisches Diakonissen-Krankenhaus, GefaBchirurg. Abt., Goethestr. 85,
3500 Kassel
Dr. D. de la Hamette
Universitat des Saarlandes, Abt. flir Hamostaseologie und Transfusionsmedizin,
Oscar-Orth-Str., 6650 Homburg/Saar
H.-M. Haupt
Medizinische Universitatsklinik, Abt. flir Kardiologie/Angiologie, Bergheimer Str. 58,
6900 Heidelberg
Prof. Dr. W. Hepp
Universitatsklinikum Rudolf Virchow, Chirurg. Klinik u. Poliklinik, Spandauer
Damm 130, 1000 Berlin 19
W. H. Hesse
Ruhruniversitat, Abt. flir Pharmakologie und Toxikologie, Universitatsstr. 150,
4630 Bochum
Dr. E. Hsu
Medizinische Universitatsklinik, Abt. flir Kardiologie/Angiologie, Bergheimer Str. 58,
6900 Heidelberg
Dr. Th. Jansen
Medizinische Universitatsklinik, Abt. flir Kardiologie/Angiologie, Bergheimer Str. 58,
6900 Heidelberg
Dr. O. Kistner
Medizinische Universitatsklinik, Abt. flir Kardiologie/Angiologie, Bergheimer Str. 58,
6900 Heidelberg
Dr. G. Leipnitz
Universitat des Saarlandes, Abt. flir Hamostaseologie und Transfusionsmedizin,
Oscar-Orth-Str., 6650 Homburg/Saar
Dr. G. Lupattelli
Universita degli Studi, 2nd Clinica Medica Generale e Terapie Medica,
Policlinico Monteluce, 1-06100 Perugia
Dr. J. Mollenhauer
Medizinische Universitatsklinik, Abt. flir Kardiologie/Angiologie, Bergheimer Str. 58,
6900 Heidelberg
Prof. Dr. E. Miihe
Kreiskrankenhaus Boblingen, Chirurg. Klinik, Bunsenstr. 120, 7030 Boblingen
Dr. P. Ney
Schwarz Pharma AG, Alfred-Nobel-Str. 10,4019 Monheim
Dr. F.-J. Neumann
Medizinische Universitatsklinik, Abt. flir Kardiologie/Angiologie, Bergheimer Str. 58,
6900 Heidelberg
List of Contributors XI
Dr. I. Neumann
Nuklearmedizinische Universitiitsklinik, Gamisongasse 13, A-1090 Wien
Dr. I. Ott
Medizinische UniversiHitsklinik, Abt. flir Kardiologie/Angiologie, Bergheimer Str. 58,
6900 Heidelberg
Prof. Dr. B. A. Peskar
Ruhruniversitat, Abt. flir Pharmakologie und Toxikologie, Universitatsstr. 150,
4630 Bochum
Dr. W. Rogatti
Nerthusstr. 3a, 5000 Kaln 91
Prof. Dr. G. Rudofsky
Universitatsklinikum Essen, Angiologische Klinik, Hufelandstr. 55, 4300 Essen
PD Dr. P. Scheffler
Universitat des Saarlandes, Abt. flir Hamostaseologie und Transfusionsmedizin,
Oscar-Orth-Str., 6650 Homburg/Saar
M. Schneider
Medizinische Universitatsklinik, Abt. flir Kardiologie/Angiologie, Bergheimer Str. 58,
6900 Heidelberg
Prof. Dr. K. Schror
Institut flir Pharmakologie, Heinrich-Heine-Universitat Dusseldorf, Moorenstr. 5,
4000 Dusseldorf 1
Prof. Dr. H. Sinzinger
Wilhelm-Auerswald-Atherosclerosis Research Group (ASF), Nadlergasse 1,
A-1090 Wi en
Dr. C. Szymanski
Institut flir Pharmakologie, Heinrich-Heine-Universitat Dusseldorf, Moorenstr. 5,
4000 Dusseldorf 1
Dr. G. Torsello
Chirurgische Klinik der Heinrich-Heine-Universitat, Moorenstr. 5, 4000 Dusseldorf 1
Prof. Dr. G. Trtibestein
Spessartklinik Bad Orb, Wurzburger Str. 7/11, 6482 Bad Orb
Dr. I. Virgolini
Wilhelm Auerswald-Atherosclerosis Research Group (ASF), Nadlergasse 1,
A-1090 Wien
Dr. M. Vogelpohl
Universitat Ulm, Innere Medizin 4, Abt. Angiologie, Oberer Eselsberg 40, 7900 Ulm
Dr. Th. Weiss
Medizinische Universitatsklinik, Abt. flir Kardiologie/Angiologie, Bergheimer Str. 58,
6900 Heidelberg
Cellular Sites of Action of Prostaglandins
in the Cardiovascular System
K. SCHROR
Introdnction
Prostaglandins and thromboxanes represent one of the most widespread
lipid-mediator systems for intercellular signaling in the body. Major cellular
targets in the cardiovascular system are vascular smooth muscle and circulat
ing blood cells, including platelets and white cells (Table 1). Intracellular
signal transfer is probably best studied in the platelet and involves receptor
related, G protein-mediated changes in cellular effector molecules, includ
ing cAMP, prostacyclin (PGI2), IP3 and Ca2+ -release thromboxane A2
(TXA2) as well as phospholipase C-dependent steps, finally resulting in
alterations of cytosolic Ca2+ -levels, protein phosphorylation, and modula
tion of cellular activity level.
Similar to other mediator systems, availability of the free precursor, i.e.,
arachidonic acid, determines the amount of products formed. There are
several important control mechanisms that limit excessive local generation
of these compounds: regulation of the number of available stimulating
receptors at the plasma membrane, e.g., PGH /TXA in platelets, and,
2 2
Table 1. Selected arachidonic acid metabolites and their major biological functions
Metabolite Formed by Action on Type of action
PGI Endothelium Platelets Inhibition
2
Vascular smooth muscle Relaxation
Macrophages Inhibition
TXA Platelet Platelet Stimulation
2
Vascular smooth muscle Contraction
12-H(P)ETE Platelet, Leukocytes Stimulation
endothelium,
vasculature,
myocytes Vascular smooth muscle Contraction
LTB4 Granulocyte Granulocytes Stimulation
Vascular permeability Increase
LTC4, LTD4 Leukocytes Vascular permeability Increase
Vascular smooth muscle Contraction