Albrecht Fleckenstein

Albrecht Fleckenstein , actually Albrecht Vinzens Siegfried Fleckenstein (born May 3, 1917 in Aschaffenburg , † April 4, 1992 in St. Ulrich near Freiburg im Breisgau ) was a German pharmacologist and physiologist . Especially he was known as the discoverer of the new drug group of calcium antagonists .

Albrecht Fleckenstein

Life

His parents' house was mainly about his mother, Margareta geb. House associated with the German Center Party . Soon after Albrecht's birth, the family moved to Pirmasens , where the father, Anton Fleckenstein, was state banker at the Bayerische Staatsbank until he was relieved of his post in 1937 for political reasons. The family then moved - Albrecht had just passed the Abitur examination - to Würzburg . From 1937 to 1942 he studied medicine in Würzburg - with an intervening clinical semester in Vienna . While still a student, he published a scientific article written in the Medical Clinic of the University of Würzburg in the physiological journal Pflüger's archive . He was concerned with the mechanism of muscle contraction, a problem that stayed with him throughout his life. The clinic director Erich Grafe then offered him a dissertation topic, and in 1942 he became involved with a thesis on the situation of diabetics in the war. to the Dr. med. PhD .

From 1943 to 1945 he was assigned to the Würzburg Pharmacological Institute, headed by Ferdinand Flury , as a senior physician as part of his military service . This is where his second scientific work came about, published in the pharmacological journal Naunyn-Schmiedebergs Archive for Experimental Pathology and Pharmacology . Its question, the mechanism of inflammation, also had an impact in his later research.

In April 1945, Fleckenstein became an American prisoner of war. Dismissed in early 1947, he took up a senior assistant position at the Pharmacological Institute of the Ruprecht-Karls-Universität Heidelberg with Fritz Eichholtz (1889–1967). As early as 1947 he completed his habilitation there in pharmacology and toxicology with a paper on the mechanism of peripheral pain triggering , which also included his experiments from Würzburg pharmacology. From 1951 to 1952 he was one of the first Germans after the war to spend a year as a British Council Exchange Lecturer at the Pharmacological Institute of Oxford University with Joshua Harold Burn and at the Biochemical Institute of Sheffield University with Hans Adolf Krebs , the 1953 recipient of the Nobel Prize in Physiology or Medicine .

In 1956 he received - in a rare case since he had completed his habilitation in pharmacology and toxicology - a call to the chair of physiology at the Albert-Ludwigs-Universität Freiburg as successor to Paul Hoffmann . The Freiburg institute building on Hebelstrasse was completely destroyed in the war. Fleckenstein first had to work in the premises of the Pharmacological Institute and supervise the new building of a joint Physiological and Biochemical Institute in Hermann-Herder-Straße. In 1958 the new building was ready for occupancy, and in 1960 the new common lecture hall for physiology and biochemistry was inaugurated. It was here that calcium antagonists were discovered, and it is here that Fleckenstein held his lectures, which are well-known beyond the circle of medical students. In 1957 a balneological institute was attached to the Physiological Institute , first headed by Herbert Göpfert (1909–1991) and converted in 1978 into a separate - now repealed - Institute for Applied Physiology and Balneology . In 1975 a second chair was established in the Physiological Institute, initially occupied by Hermann Antoni (* 1929), who headed the Physiological Institute at the University of Frankfurt am Main from 1968 to 1975 . From 1959 to 1962 Fleckenstein was President of the German Physiological Society and in the year of office 1961–1962 Dean of the Freiburg Medical Faculty. He refused calls to Basel and Graz. In addition to Hermann Antoni, three other students were appointed to chairs for physiology or related disciplines, namely Eckehard Gerlach (Aachen, later Munich), Raimund Kaufmann (Düsseldorf) and Helmut Tritthart (Graz).

In 1985 Fleckenstein retired, but still belonged to a project group calcium antagonism of his institute. His grave is in the Ortisei cemetery next to the town's baroque church.

Albrecht Fleckenstein's first marriage was to Ilse Fleckenstein, b. Brabandt. The virologist Bernhard Fleckenstein , the oxygen medicine researcher Wolfgang Fleckenstein and the general practitioner and psychotherapist Margareta Kampmann-Schwantes, b. Fleckenstein are their children.

In his second marriage, Albrecht Fleckenstein was married to Professor Gisa Fleckenstein-Grün . The architect and manager Susanne Fleckenstein, the lawyer Barbara Fleckenstein-Weiland and the ophthalmologist Monika Fleckenstein are their daughters.

plant

Fleckenstein always wanted to penetrate the marginal to the central, create essentials, bring together scattered observations. This is also impressive where later research showed that he was wrong.

The mechanism of skeletal muscle contraction

This is indeed a central problem in biology. Fleckenstein's first work on this, and his first work at all (see above), does not contain a single experiment. Fleckenstein discusses the literature. He doubts that it is a chemical process like the breakdown of adenosine triphosphate that leads directly to contraction . It is reminiscent of the release of potassium from the muscle and the absorption of sodium into the muscle during contraction and the electrical action potentials based on this . He calculates - his main point - that the sodium and potassium shifts following the concentration gradient provide sufficient energy for the mechanical contraction. He concludes that these ion currents initiate the contraction directly, without an intermediate chemical reaction, presumably because the electrical processes "on the membrane ... force the protein molecules of the fiber to make structural changes in the electrical field"; chemical reactions come later and serve to restore the ion gradients.

Much later work was devoted to experimental review, up to a monograph in 1955. In it Fleckenstein draws a link from Giovanni Alfonso Borellis (1608–1679) De motu animalium to his present. “According to a much used parable, the action current is supposed to have the meaning of an igniting spark for the powder keg from which the contraction energy originates. The current of action would accordingly be an activation process without a direct relationship to the contraction. ”However, this, including the assumption of an ATP split between electrical processes and contraction, is wrong. “… In fact, there is no evidence in the living muscle that the electrophysiological phenomenon of depolarization and the mechanical act of contraction are obligatory in the conversion of ATP. In contrast to this, the close connection between the electrical processes (or the underlying ion displacements) and the mechanical changes in state has been proven by a large number of studies. "

The current theory of skeletal muscle contraction, however, assumes that the action potential first leads to an intracellular release of calcium ions in the muscle cells, that calcium then enables ATP to be split at the contractile proteins and this ATP split can shorten the proteins.

Pain release and elimination

Continuing his second scientific work (see above), Fleckenstein showed in his habilitation thesis that many substances that cause pain on mucous membranes or when injected into the skin, for example allyl mustard oil , blocked the citric acid cycle . Other substances, for example high potassium concentrations or the veratrine from the White Germer , caused pain without disrupting the citric acid cycle. Fleckenstein made it probable that what all these "pain substances" have in common was a depolarization of the peripheral pain fibers. Applying a cathode to the skin also caused pain through depolarization. Fleckenstein therefore called the pain substances "Katelectrotonica". Local anesthetics counteracted the painful, depolarizing influences. “The nerve block by local anesthetics is thus similar to the anode block in electrophysiology. Local anesthetics can therefore be called 'anelectrotonics'. ”A little later, in his 1955 monograph (see above), Fleckenstein went further: the basic mechanism of nerve or muscle excitation is an“ increase in permeability for Na ⁺ ”; the basic mechanism of an excitation inhibition is a "seal of the membrane against penetrating Na ⁺ ".

The terms "Katelektrotonica" and "Anelektrotonica" are obsolete today. With his basic mechanisms of arousal and arousal inhibition, however, Fleckenstein argued on the knowledge front of the time. As recently as 1966, a review article hardly gave any more detailed information: “It is, of course, extremely difficult to obtain unequivocal evidence in support of one or another theory for the mechanism of local anesthesia. ... Nevertheless, ... a variety of evidence ... strongly suggests that local anesthetics act in their cationic, rather than their uncharged, form at or in the nerve membrane, through modifying the physicochemical state of its lipid constituents. The result is an alteration of ion permeability followed by conduction block. "

Today we know that local anesthetics block voltage-dependent sodium channels by binding to proteins in the channel opening inside the cell.

The pharmacology of sympathomimetics

Joshua Harold Burn at the Oxford Pharmacological Institute was interested in the change in sensitivity of tissues to sympathomimetics that occurred when the sympathetic nerves of the tissues were cut: the effects of noradrenaline and adrenaline were increased, while the effects of tyramine and amphetamine were weakened or canceled. Fleckenstein's publication from Oxford also deals with this.

Back in Heidelberg, Fleckenstein expanded the subject. It was known that cocaine also changed the sensitivity of tissues to sympathomimetics, in the same way as denervation : cocaine increased the effects of noradrenaline and adrenaline, while weakening the effects of tyramine and amphetamine. Fleckenstein investigated other substances and came to the conclusion that there are three groups of sympathomimetics. The substances in the first group, the catechol derivatives such as noradrenaline and adrenaline, act directly on the cells of the successor organ, such as the smooth muscles ; the substances of the second group, the neuro-sympathomimetics such as tyramine and amphetamine, only have an indirect effect on the cells of the successful organ, namely primarily on the sympathetic nerve endings, perhaps by increasing the release of the neurotransmitter noradrenaline; in between are intermediate substances such as ephedrine . Fleckenstein explained the similar influence of denervation and cocaine with the assumption that cocaine as a local anesthetic "produces a kind of 'pharmacological denervation'".

Fleckensteins Classification of sympathomimetic - in modern terminology in direct-acting sympathomimetic (precise adrenoceptor - agonist ) and indirectly acting sympathomimetic - has become textbook knowledge. Its interpretation had to be modified - in particular the interpretation of the effect of cocaine as "pharmacological denervation" was abandoned when Julius Axelrod and his group discovered about ten years later that sympathetic nerve endings have a transporter for norepinephrine which is blocked by cocaine. The Würzburg pharmacologist Ullrich Trendelenburg developed today's ideas about changes in sensitivity to sympathomimetics .

Calcium antagonists

During his investigations into skeletal muscle contraction, Fleckenstein measured the content of adenosine triphosphate and other energy-rich phosphates, first in Sheffield with Hans Adolf Krebs, then in Heidelberg. Since the late 1950s, he concentrated more and more on the metabolism of the high-energy phosphates in the heart. He saw how, on the one hand, a lack of energy-rich phosphates, for example in ischemia , and on the other hand, an inability of the heart to use the energy-rich phosphates available, for example in the case of calcium deficiency, led to heart failure. In 1963 he summarized his findings in a textbook article.

L-type calcium channel with (red) the three groups of calcium antagonists

In November of the same year, two pharmaceutical companies asked him to test two new cardiac drugs with an apparently similar mechanism of action to beta blockers : Prenylamine ( Segontin® ) from Farbwerke Hoechst AG in Frankfurt-Höchst and Verapamil ( Isoptin® ) from Knoll AG in Ludwigshafen on Rhine , now part of Abbott Laboratories . Fleckenstein compared them with the well-known beta blockers pronethalol and propranolol . Initially, the beta blocker similarity was confirmed. Among other things, prenylamine and verapamil such as pronethalol led in high doses to anesthetized guinea pigs to heart failure, namely - like calcium deficiency - by disrupting the use of energy-rich phosphates. In 1965, however, the Freiburg physiologists observed something that contradicted their previous views. The heart failure caused by pronethalol and propranolol could not be reversed by agonists at beta-adrenoceptors such as adrenaline - or only with very high agonist doses; that was plausible because of the blockage of the beta-adrenoceptors. The heart failure caused by verapamil and prenylamine improved even after small doses of beta-adrenoceptor agonists. Apparently, after administration of verapamil and prenylamine, the cardiac beta-adrenoceptors were hardly or not at all blocked. Experiments with other methodology followed. The results were published in 1967 in two essays rich in material, the reading of which shows the authors' struggle for interpretation. The term “ calcium antagonist ” appears for the first time in the summary . The four substances, it is said, reduce the cleavage of adenosine triphosphate on the contractile proteins in two ways: on the one hand, by blocking the beta adrenoceptors - this is the main mechanism in pronethalol and propranolol; on the other hand through "hindrance of the Ca ⁺⁺ influx during excitation or through Ca ⁺⁺ displacement in the contractile system" - this is the main mechanism of the "Ca ⁺⁺ antagonists" prenylamine and verapamil.

The question of whether the entry of calcium into the cells or the binding of calcium to its intracellular sites of action was inhibited remained open in 1967. However, it was soon decided in favor of inhibiting calcium entry: Calcium antagonists blocked calcium channels . The further development consisted among other things in the synthesis of new calcium antagonists. The 1,4-dihydropyridine derivative nifedipine became particularly important . His research showed that there are different types of calcium channels and that calcium antagonists selectively block the L-type calcium channels , which are therefore also called "dihydropyridine receptors". Further development included the knowledge that the calcium channels are not only blocked in the heart muscle , but also in other organs, especially the smooth muscles . Finally, further development included research into medicinal application, which today mainly extends to arterial hypertension , coronary heart disease and cardiac arrhythmias .

In 2009, almost 2 billion daily doses ( “defined daily doses” ) of calcium antagonists were prescribed in Germany at the expense of statutory health insurance , which corresponds to an intake of around 25 daily doses per inhabitant and year. The calcium antagonists are thus the fourth most powerful group of drugs for cardiovascular diseases after the inhibitors of the renin-angiotensin system , beta blockers and diuretics . Verapamil has been prescribed a lot of the two prototypes to this day: In 2009 it was 146 million daily doses for statutory health insurance - “the most important achievement from research at Knoll AG”.

The personality

Albrecht Fleckenstein impressed both physically and mentally. He used all his strength to help what he recognized to be correct to success. "He was admirable not only in terms of 'inventing' the calcium antagonists, but above all in terms of the commitment, enthusiasm and tenacity with which he made this principle known and implemented worldwide."

Some colleagues complained that the term “calcium antagonist” was not very happy, then local anesthetics would also have to be called “sodium antagonists”. "Calcium channel blocker" would be a better name. Fleckenstein argues against this in his History of calcium antagonists . In the oral discussion, however, he liked to say disarmingly: "The term 'calcium antagonist' is better because I coined it."

As a professor, he fascinated his students, but was also able to confront them. In 1968 a new rector was to be elected, but about 40 students blocked the door to the voting room with a sit-in . When Fleckenstein asked for passage, a student warned: “There is Flecki.” Fleckenstein wanted to push through. Result: “About 15 people attacked me.” Two students who grabbed his tie were knocked down by the professor: “I really hit them in the face. After all, I was trained in hand-to-hand combat with the airborne troops during the war. ”Bleeding from scratches on his neck, he entered the voting room, but could not vote: his colleagues had shied away from fighting the students.

Hermann Antoni writes about the togetherness in the institute: “Like very few university professors at that time, Albrecht Fleckenstein made no secret of his view, but instead stuck to the principle of performance as the basis for scientific assessments. ... So (he) was often not a comfortable boss, but a superior, with whom all members of the institute felt safe, knowing that if necessary he would stand up for them with the full weight of his personality. "

Honors

Fleckenstein was an honorary doctor of the medical faculties of the Ludwig Maximilians University in Munich (1984), the Ruprecht Karls University of Heidelberg (1986), the Rijksuniversiteit Limburg (Netherlands; 1986), the Universidad Nacional de La Plata (Argentina; 1987) and the University of Basel (1990).

In 1984 he received the Paul Morawitz Prize of the German Society for Cardiovascular Research and the Franz Gross Prize of the German Hypertension League . In 1986 he received the Ernst Jung Prize , in 1987 the Schmiedeberg Plaque from the German Pharmacological Society , the University Medal from the Albert Ludwig University of Freiburg and the ASPET Award from the American Society for Pharmacology and Experimental Therapeutics . In 1989 he received the Karl Heinz Beckurts Prize from the foundation of the same name and the Carl Ludwig commemorative coin from the German Society for Cardiovascular Research.

He was an honorary member of the German Physiological Society (1986) and the Egyptian Cardiological Society (1988).

On the occasion of his retirement he received the Grand Cross of Merit of the Federal Republic of Germany .

Web links

• Literature by and about Albrecht Fleckenstein in the catalog of the German National Library

Individual evidence

1. ^ ^{A b} H. Antoni: In memory of Professor Albrecht Fleckenstein. In: Special issue Calcium Antagonismus aktuell. 1992, pp. 24-26.
2. ^ Hermann Antoni, Rainer Greger: The Physiological Institute of the Albert Ludwig University of Freiburg i. Br. In: Physiology. A journal of the German Physiological Society. 4, 1995, pp. 10-17.
3. ↑ ^{a b} A. Fleckenstein: Contribution to the mechanism of muscle contraction and to the development of the currents of action. In: Pflüger's archive. 246, 1942, pp. 411-427.
4. ↑ A. Fleckenstein: Contribution to the mechanism of experimental serous inflammation by allyl formate. In: Naunyn-Schmiedeberg's archive for experimental pathology and pharmacology. 203, 1944, pp. 151-170.
5. ↑ Who is who? 21st Edition (1981). P. 297.
6. ↑ Kronenberg HG: In memorium Albrecht Fleckenstein, Cardiovasc Drug Rev . tape 10 1 , 1992.
7. ↑ Who's who in the world 2003 . 2003, p. 747 .
8. ↑ ^{a b} Albrecht Fleckenstein: The potassium-sodium exchange as an energy principle in muscles and nerves. Springer-Verlag, Berlin 1955.
9. ↑ A. Fleckenstein: About the mechanism of action of peripherally painful and local anesthetic substances. In: Acta neurovegetativa. 7, 1953, pp. 94-105.
10. ^ JM Ritchie, Paul Greengard: On the mode of action of local anesthetics. In: Annual Review of Pharmacology . 6, 1966, pp. 405-430.
11. ^ A. Fleckenstein, JH Burn: The effect of denervation on the action of sympathomimetic amines on the nictitating membrane. In: British Journal of Pharmacology and Chemotherapy . 8, 1955, pp. 69-78.
12. ↑ A. Fleckenstein, H. Bass: On the mechanism of strengthening and weakening the effect of sympathomimetic amines by cocaine and other pharmaceuticals. I. Communication. The sensitization of the cat's nictitating membrane to sympathomimetics of the catechol series. In: Naunyn-Schmiedeberg's archive for experimental pathology and pharmacology. 220, 1953, pp. 143-156.
13. ↑ A. Fleckenstein, D. Stöckle: On the mechanism of strengthening and weakening the effect of sympathomimetic amines by cocaine and other pharmaceuticals. II. Communication. The inhibition of the neuro-sympathomimetics by cocaine. In: Naunyn-Schmiedeberg's archive for experimental pathology and pharmacology. 224, 1955, pp. 401-415.
14. ↑ A. Fleckenstein, J. Janke, RE Davies, HA Krebs: Contraction of muscle without fission of adenosine triphosphate or creatine phosphate. In: Nature. 174, 1954, pp. 1081-1083.
15. ↑ A. Fleckenstein: Physiology and pathophysiology of the myocardial metabolism in interaction with the bioelectrical and mechanical fundamental processes. In: W. Bargmann, W. Doerr (Ed.): Das Herz des Menschen. Volume I, Georg Thieme Verlag, Stuttgart 1963, pp. 355-411.
16. ↑ U. Förstermann: Pharmacology of the cardiovascular system. In. K. Aktories, U. Förstermann, F. Hofmann, K. Starke: General and special pharmacology and toxicology. 10th edition. Elsevier, Munich 2009, ISBN 978-3-437-42522-6 , pp. 449-485.
17. ↑ A. Fleckenstein: The importance of the energy-rich phosphates for contractility and tone of the myocardium. In: Negotiations of the German Society for Internal Medicine. 70, 1964, pp. 81-99.
18. ↑ A. Fleckenstein, H. Kammermeier, HJ Döring, HJ Freund, G. Grün, A. Kienle: On the mechanism of action of novel coronary dilators with simultaneous oxygen-saving myocardial effects, prenylamine and iproveratril. In: Journal for Circulatory Research . 56, 1967, pp. 716-744 and pp. 839-858.
19. ↑ M. Kohlhardt, B. Bauer, H. Krause, A. Fleckenstein: Differentiation of the transmembrane Na and Ca channels by the use of specific inhibitors. In: Pflüger's archive. 335, 1972, pp. 309-322.
20. ↑ A. Fleckenstein, G. Grün, H. Tritthart, K. Byon, P. Harding: Uterus relaxation through highly active Ca ⁺⁺ antagonistic inhibitors of the electro-mechanical coupling such as iosoptin (verapamil, iproveratril), substance D 600 and segontin (Prenylamine). In: Clinical weekly. 49, 1971, pp. 32-41.
21. ↑ G. Grün, A. Fleckenstein: The electromechanical decoupling of the smooth vascular muscles as a basic principle of coronary dilatation by 4- (2'-nitrophenyl) -2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (BAY a 1040, nifedipine). In: drug research . 22, 1972, pp. 334-344.
22. ↑ ^{a b} A. Fleckenstein: History of calcium antagonists. In: Circulation Research . 52, Supplement, 1983, pp. I-3 to I-16.
23. ↑ Hermann Antoni: The discovery of calcium antagonism as a therapeutic principle. In: Christoph Rüchardt (Ed.): 550 years of the Albert Ludwig University of Freiburg. Volume 4, Karl Alber Verlag, Freiburg / Munich 2007, ISBN 978-3-495-48254-4 , pp. 136-140.
24. ↑ Ulrich Schwabe, Dieter Pfaffrath (Ed.): Drug Ordinance Report 2010. Springer-Verlag, Berlin 2010, ISBN 978-3-642-13379-4 .
25. ↑ Rolf Kretzschmar, Hans Dieter Lehmann: Pharmacological laboratories of the drug companies Knoll AG, Ludwigshafen, and Nordmark-Werke GmbH, Uetersen, and BASF AG, Ludwigshafen. In: Athineos Philippu: History and work of the pharmacological, clinical-pharmacological and toxicological institutes in German-speaking countries. Berenkamp-Verlag, Innsbruck 2004, ISBN 3-85093-180-3 , pp. 905-922.
26. ↑ H. Scholz: A. Fleckenstein has made a name for himself. In: Special issue Calcium Antagonismus aktuell. 1992, pp. 30-31.
27. ↑ Personal details . In: Der Spiegel. 23rd December 1968.