Rudolf Gottlieb

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Rudolf Gottlieb (born September 1, 1864 in Vienna , † October 31, 1924 in Heidelberg ) was a German doctor and pharmacologist . The main source of knowledge about his life and work is the obituary of his teacher Hans Horst Meyer , who, although eleven years older, outlived him by fifteen years.

Pharmacologists at the Strasbourg Institute in 1908. Oswald Schmiedeberg in the center. Rudolf Gottlieb third from the right. Hans Horst Meyer in front of the bottom step, third from the left.

Life

Gottlieb's parents were the merchant Julius Gottlieb and his wife Josefine geb. Landau. Rudolf studied medicine in Vienna and was awarded a Dr. med. PhD ; this did not require a dissertation in Austria . As a clinical assistant he recognized his preference for theory and attended the Vienna "Laboratory for Applied Medicinal Chemistry" of the chemist Ernst Ludwig (1842–1915) for further training. It was there that his "Contributions to the Knowledge of Iron Excretion through the Urine" were made. After staying with Paul Ehrlich in Berlin and Carl Weigert in Frankfurt am Main, in 1889 he went to the Pharmacological Institute of Oswald Schmiedeberg in Strasbourg, which had opened two years earlier and which, as he wrote in an obituary for Schmiedeberg, “had a powerful attraction for Germany Youth exercised ”. Here he found a circle of a little older, talented colleagues such as Heinrich Dreser , later laboratory manager at Bayer AG and co-inventor of aspirin , Carl Jacobj , later professor in Göttingen and Tübingen, Hans Horst Meyer, later professor in Dorpat, now Tartu , Marburg and Vienna , Poul Edvard Poulsson (1858–1935), later professor at the University of Oslo , and Waldemar von Schroeder (1850–1898), later professor at Heidelberg. In 1890 he moved to Hans Horst Meyer in Marburg, and in 1891 to Waldemar von Schroeder in Heidelberg, who had just moved into his new institute in the Friedrichsbau . There he completed his habilitation in 1892 with the thesis "Studies on the Effect of Picrotoxin ". In the same year he converted from the Jewish faith to the Protestant denomination, and a year later he married the daughter of the Heidelberg physiologist Wilhelm Kühne Susette Elisabeth Helene, with whom he had two children. He declined calls to chairs in Innsbruck and Prague. When von Schroeder died unexpectedly in 1898, he became his successor. For two terms he was dean of the medical faculty, for one term in 1913/14 he was prorector of the university - the grand duke of Baden was the rector . For his family, friends and students, death came "too early, but not unexpectedly, after the last year of his life was overshadowed by severe suffering."

research

In his obituary, Meyer lists 58 publications with Gottlieb as author or co-author, as well as 169 publications by his assistants and students without his name, "mostly inspired or input by him, but all of which came about with his intellectual, in particular critical, participation."

iron

In his dissertation, Gottlieb found that oral iron intake did not increase the amount of iron excreted in the urine. Consequently, his second work begins on the topic: “The question of the resorbability of iron salts is still undecided today, despite their high therapeutic importance.” He demonstrated that 60 to 90% of iron injected intravenously or subcutaneously was excreted in the stool in animal experiments. The "basic work" was later used as a warning to be careful with absorption and balance experiments, because "iron that has already been absorbed is again excreted in the intestine".

Convulsive toxins

Picrotoxin triggers convulsions similar to a tonic-clonic epileptic seizure . According to Gottlieb's habilitation thesis, it works both via points of attack in the spinal cord and points of attack in the medulla oblongata . Camphor caused cramps through points of attack in the entire central nervous system. In 1923 Gottlieb compiled his knowledge of the pharmacology of camphor in a manual. Camphor was an important medicinal substance at the time. Gottlieb and Hans Horst Meyer wrote in their textbook (see below; here after the 7th edition, the last one co-authored by Gottlieb): “The cramps caused by high doses of camphor in warm-blooded animals ... start in the cerebral cortex. ... The therapeutic importance of the central effects of camphor is based on the fact that even less than the antispasmodic doses stimulate vital functions of the cerebrum and the medulla oblongata. ... The indication for the use of these substances that stimulate the central nervous system is given in all acute paralysis that is characterized by a loss of vital functions, the respiratory and vascular nerve centers. ”In addition, camphor should also act directly on a damaged heart:“ With the therapeutic application to stimulate the circulation in the agone, when the stimulus generation in the heart threatens to go out, we have to consider camphor primarily as a heart medicine. ”With Werner Schulemann , the head of the pharmacological laboratory of Bayer AG, at that time paint factories . Friedrich Bayer & Co. , Gottlieb developed a more water-soluble camphor derivative that was marketed as Hexeton ® . Clinicians recommended it “warm”. Under Gottlieb's continued influence, his student Fritz Hildebrandt (1887–1961) introduced the similarly acting pentetrazole ( Cardiazol ® ) in 1926 in collaboration with the Knoll AG company in Ludwigshafen am Rhein . Today these substances, also known as “ analeptics ”, are important for epilepsy research, but are obsolete as drugs. As early as the mid-1930s, the pharmacologist Otto Krayer made ironic comments about “the time when no patient was allowed to die before being given an analeptic. In France it was huile camphrée, in England strychnine and in Germany Cardiazol. "

Caffeine and theobromine

In the mid-1890s, the structure of the methylxanthines caffeine , theobromine and theophylline was definitely determined. Probably stimulated by this, and by Waldemar von Schroeder's interest in the diuretic effect of caffeine, Gottlieb turned to the fate of caffeine and theobromine in the body. The experiments "led to a completely unexpected result", namely that a large part of the two substances was demethylated. The demethylation product was the monomethylxanthine "Heteroxanthine", 7-methylxanthine. A researcher at the Pharmacological Institute in Strasbourg came to the same conclusion simultaneously and independently. In this way one of the practically most important foreign matter biotransformations was discovered.

adrenaline

The 1894 discovery by George Oliver and Edward Albert Schäfer in London that extracts from the adrenal medulla increased blood pressure enormously sparked a spate of research, especially when it was discovered that the extracts acted in a manner similar to stimulating sympathetic nerves . Gottlieb contributed to these early results in three ways - even before the adrenal medulla hormone adrenaline was shown in pure form, its structure was clarified, chemically synthesized and called "adrenaline" or "epinephrine" between 1901 and 1904. As early as 1896, he confirmed the view of Oliver and Schäfer that the extracts acted directly on the blood vessels and the heart and not, as had been claimed, primarily on nerve cells in the brain that control circulation. Second, he demonstrated, including on isolated hearts, that the effect on the heart was independent of the vascular effect. He was wrong when he suspected that "contrary to the muscular theory of Oliver and Schäfer, the increase in blood pressure ... is due to a specific effect of the poison on the excitability of intracardial motor ganglia and those peripheral vascular ganglia which control the vascular width". With "ganglia" were meant nerve cells; de facto, adrenaline attacks the cardiac and vascular muscle cells directly. Third, Gottlieb encouraged his employees to develop sensitive and specific biological analysis methods, “ bioassays ”, with the aim of quantifying adrenaline in the blood. Chemical analysis methods were too insensitive. As a hormone in the sense of the time - substance released into the blood by an endocrine gland to control other organs - adrenaline was supposed to be present in the blood.

Adrenaline dilates the pupil. Using this reaction as a “bioassay”, in Gottlieb's laboratory it was indeed possible to detect “adrenaline” - more precisely a substance that acts like adrenaline - in the blood of the adrenal veins of rabbits, but not in mixed venous blood from the whole body of the animals. "So it has been proven that adrenaline pours into the circulation as a physiological secretion of the adrenal glands." With the contraction of muscle strips of the uterus of rabbits and the contraction of blood vessels of frogs as a "bioassay", however, "adrenaline" also became in the venous system Mixed blood found. So the findings contradicted each other.

In 1912, Gottlieb and his colleague James Malachy O'Connor (1886–1974) compared the analysis methods. O'Connor, later a physiologist at University College Dublin , then undertook "at the instigation of Professor Gottlieb ... to explain the causes of the various failures of the reactions". He confirmed the earlier measurements in Heidelberg and Freiburg. However, the substance found in mixed venous blood was not adrenaline. The earlier experiments were carried out with blood serum , the fluid that remains after the blood clots . Blood plasma , the liquid that remains without coagulation after the blood cells have been separated , did not work in the bioassays, for example on frog blood vessels . “ The substances that simulate adrenaline thus get into the serum during coagulation. We can only give an imperfect answer to the question of which elements they come from. It is probable that they arise from the disintegration of the platelets , which are known to perish when they clot. In fact, it has been shown that extracts of rabbit platelets ... have a strong effect on the frog vessels. The relevant attempts have not yet been completed. ... The proof that a vasoconstricting substance is released from the disintegrating cells during coagulation also seems to me to be of teleological importance for the understanding of hemostasis; it is advisable that the substances produced during coagulation are able to locally narrow the vessels from which the bleeding occurs. ”O'Connor's work is one of the most elegant from Gottlieb's sphere of activity. It laid the groundwork for more realistic measurements of adrenaline in the blood and was a prophecy of the blood platelet component serotonin . Vittorio Erspamer , whose work led to the identification of serotonin from 1937, wrote (from the English): “As early as 1912, from careful experiments, O'Connor concluded that the vasoconstricting substance of the serum is not present in the circulating plasma, but rather in the coagulation of blood cells , probably the platelets, is released. ... Already O'Connor put forward the hypothesis that the substance could contribute to hemostasis if it, released from a thrombus , causes the surrounding vascular muscles to contract. "

other topics

Immediately after Hans Horst Meyer and Charles Ernest Overton established the lipoid theory of anesthesia from 1899 to 1901, Gottlieb wrote one - the first - thorough review. “The speaker sees the essential advance that the new theory of alcohol anesthesia means, above all, in the fact that the investigations by Hans Meyer and Overton have for the first time uncovered regular relationships, which in a series of similarly acting connections between poisonous effects and a demonstrable physical one -chemical bond to certain cell components exist. ”The will to physico-chemical explanation is also evident in work on differences in the effects of enantiomers . At least quantitatively, Gottlieb's most productive colleague was Rudolf Magnus , who later founded the Netherlands' first pharmacological institute in Utrecht . Together or separately they wrote “About Diuresis” (5 so-titled messages), about “Experiments on the surviving small intestine of mammals” (6 so-titled messages), about “The constipating effect of morphine” (2 so-called messages) and about cardiac glycosides . Cardiac glycosides were also an issue for others at the institute, for example for Albert Fraenkel (physician, 1864) , who practiced as a doctor in Badenweiler in the summer and experimented in the Heidelberg institute in winter. He did a fundamental work on the accumulation ("accumulation") of some cardiac glycosides in the body when taken for a long time.

"The Meyer-Gottlieb"

  • Title of the 9th edition of "Meyer-Gottlieb" 1936

  • (1) From the suburb for the 1st edition 1910

  • (2) Original title page

  • (3) Purified title page

In 1910, "The experimental pharmacology as the basis for drug treatment" was published by Hans Horst Meyer, Vienna, and Rudolf Gottlieb, Heidelberg. In the foreword, the authors understand pharmacology on the one hand as "part of biology" and on the other hand as the "theoretical basis of drug treatment", as Oswald Schmiedeberg understood the subject to which they and the internist Bernhard Naunyn dedicated the book. It had nine editions, in the course of which it grew from 483 to 813 pages. Gottlieb remained a co-author until the 7th edition in 1925, which appeared one year after his death. Meyer wrote the 8th edition, 1933, with Ernst Peter Pick, who worked at his institute in Vienna . In the 9th edition, 1936, the main text remained unchanged, but was supplemented and updated by a 62-page addendum.

Sigurd Janssen , who worked for Gottlieb from 1921 to 1923, wrote: “The textbook ... became understandable and attractive for doctors and students whose thinking had been trained in anatomy and physiology. Up until 1933 there was no textbook in pharmacology that had more influence on the medical world than 'the Meyer-Gottlieb'. The work of both authors has thus become fundamental and of the greatest importance for our science and for medicine as a whole. "

After 1933, however, the book was harassed by National Socialism . Rudolf Gottlieb and Hans Peter Pick were Jews; with Hans Horst Meyer one was apparently not sure. The change in front cover during the printing of the 9th edition shows an Orwellian censorship practice . The titles exist in two versions, an original and a “de-Jewised”. The extract from the foreword of the 1st edition (1) remained unchanged. The original title page (2) corresponded completely to earlier editions with the names of Meyer, Gottlieb and Pick. In the purified version (3) Gottlieb and Pick and the reference to the addendum have been deleted.

student

The following scientists completed their habilitation in Heidelberg during Gottlieb's time or achieved leading academic positions after their work there (with the year they entered the institute):

  • Rudolf Magnus (1898) s. o., habilitation in 1900
  • Martin Jacoby (1900) obtained his habilitation in 1901
  • Erwin Rohde (1904) qualified as a professor in 1910
  • JM O'Connor (1911) s. O.
  • Philipp Ellinger (1913) qualified as a professor in 1921; later professor in Düsseldorf; * 1887 in Frankfurt am Main, † 1952 in London
  • Hermann Freund (1919) qualified as a professor in 1921; later professor in Münster; * 1882 in Breslau, † 1944 in Auschwitz concentration camp
  • Fritz Hildebrandt (1919) s. o., habilitated in 1921; later professor in Düsseldorf and Giessen; * 1887 in Mannheim, † 1961 in Freudenstadt
  • Sigurd Janssen (1921) later professor in Freiburg im Breisgau; * 1891 in Düsseldorf, † 1968 in Freiburg im Breisgau
  • 1923 Karl Zipf (1923) later professor in Königsberg and Munich; * 1895 in Oberkirch (Baden) , † 1990 in Leutershausen an der Bergstrasse .

recognition

In 1911 Gottlieb became a member of the German Academy of Sciences Leopoldina , and in 1913 a member of the Heidelberg Academy of Sciences .

literature

Individual evidence

  1. ^ A b R. Gottlieb: Contributions to the knowledge of iron excretion through the urine . In: Archives of Experimental Pathology and Pharmacology . 26, 1889, pp. 139-146. doi : 10.1007 / BF01829463 .
  2. ↑ Kipnis.
  3. ↑ a b R. Gottlieb: Studies on the effect of the picrotoxin . In: Archives of Experimental Pathology and Pharmacology . 30, 1892, pp. 21-40. doi : 10.1007 / BF01960494 .
  4. ↑ Janssen 1964.
  5. ↑ Meyer 1925, p. III.
  6. ↑ R. Gottlieb: About the precipitation ratios of iron In: Zeitschrift für Physiologische Chemie 15, pp. 371–386, 1891.
  7. ↑ E. Starkenstein: Iron. In: A. Heffter and W. Heubner (Hrsg.): Handbuch der experimental Pharmakologie. Third volume, part 2, pp. 682-1286, here pp. 843-845. Published by Julius Springer, Berlin 1934.
  8. ↑ R. Gottlieb: The camphor group. In: A. Heffter (Hrsg.): Handbuch der experimental Pharmakologie. First volume, pp. 1147-1198. Published by Julius Springer, Berlin 1923.
  9. ↑ Hans H. Meyer and R. Gotlieb: The experimental pharmacology as the basis of drug treatment. Seventh edition. Urban & Schwarzenberg, Berlin and Vienna 1925, pp. 30, 31 and 318.
  10. ↑ R. Gottlieb and W. Schulemann: About "Hexeton", an isomeric camphor which can be injected in aqueous solution . In: German Medical Weekly . 49, 1923, pp. 1533-1535.
  11. ↑ Dr. Krehl and Dr. Franz: About the effect of the hexetone on sick people . In: German Medical Weekly . 49, 1923, pp. 1535-1536.
  12. ↑ F. Hildebrandt: Pentamethylene tetrazole (cardiazole). I. Communication . In: Naunyn-Schmiedeberg's archive for experimental pathology and pharmacology . 116, 1926, pp. 100-109. doi : 10.1007 / BF01863959 .
  13. ↑ TJ Feuerstein: Anticonvulsants, convulsives - pharmacotherapy of epilepsies. In: K. Aktories, U. Förstermann, F. Hofmann and K. Starke: General and special pharmacology and toxicology. 10th edition, Munich, Elsevier GmbH 2009, pp. 283-293. ISBN 978-3-437-42522-6
  14. ^ Klaus Starke: A history of Naunyn-Schmiedeberg's Archives of Pharmacology . In: Naunyn-Schmiedeberg's Archives of Pharmacology . 358, 1998, pp. 1–109, here p. 49. doi : 10.1007 / PL00005229 .
  15. ↑ St. Bondzyński and R. Gottlieb: About methylxanthine, a metabolic product of theobromine and coffeïn . In: Archives of Experimental Pathology and Pharmacology . 36, 1895, pp. 45-55. doi : 10.1007 / BF01825013 .
  16. ↑ St. Bondzyński and R. Gottlieb: About the constitution of methylxanthine, which occurs in the urine according to Coffeïn and Theobromine . In: Archives of Experimental Pathology and Pharmacology . 37, 1895, pp. 385-388. doi : 10.1007 / BF01824927 .
  17. ↑ Manfredi Albanese: About the behavior of the Coffein and theobromine in the organism . In: Archives of Experimental Pathology and Pharmacology . 35, 1895, pp. 449-466. doi : 10.1007 / BF01826090 .
  18. ^ MJ Arnaud: Products of metabolism of caffeine. In: P. B: Dews (Ed.): Caffeine. Perspectives from Recent Research. Springer-Verlag, Berlin 1984. ISBN 3-540-13532-4 , pp. 3-38.
  19. ↑ K. Starke: Methylxanthine. In: K. Aktories, U. Förstermann, F. Hofmann and K. Starke: General and special pharmacology and toxicology. 10th edition, Munich, Elsevier GmbH 2009, pp. 174-178. ISBN 978-3-437-42522-6
  20. ↑ G. Oliver and EA Schäfer: On the physiological action of extract of the suprarenal capsules. In: The Journal of Physiology 16, SI-IV, 1894. PMC 1514529 (free full text).
  21. ↑ George Oliver and EA Schäfer: The physiological effects of extracts of the surparenal capsuls. In: The Journal of Physiology 18, pp. 230-276, 1895.
  22. ↑ Klaus Starke: The history of the α-adrenoceptor agonists . In: Pharmacy in our time . 6, 2011, pp. 456-461. doi : 10.1002 / pauz.201100439 . On the first page of the publication, right column, second line, instead of "adrenal medulla extract" it incorrectly reads "adrenal cortex extract."
  23. ↑ a b R. Gottlieb: On the effect of adrenal extracts on heart and blood pressure . In: Archives of Experimental Pathology and Pharmacology . 38, 1896, pp. 99-112. doi : 10.1007 / BF01824070 .
  24. ^ R. Gottlieb: About the effect of the adrenal extracts on the heart and blood vessels . In: Archives of Experimental Pathology and Pharmacology . 43, 1899, pp. 286-304. doi : 10.1007 / BF01961157 .
  25. ↑ Rud. Ehrmann: About a physiological determination of the value of adrenaline and its detection in the blood . In: Archives of Experimental Pathology and Pharmacology . 53, 1905, pp. 97-111. doi : 10.1007 / BF01842818 .
  26. ↑ A. Fraenkel: About the adrenaline content of the blood in chronic nephritis and Basedowi's disease . In: Archives of Experimental Pathology and Pharmacology . 60, 1909, pp. 395-407. doi : 10.1007 / BF01840970 .
  27. ↑ Paul Trendelenburg : Determination of the adrenaline content in normal blood as well as when the effect of a single intravenous adrenaline injection subsides using a physiological measurement method . In: Archives of Experimental Pathology and Pharmacology . 63, 1910, pp. 161-176. doi : 10.1007 / BF01840948 .
  28. ↑ DK O'D: Editorial (short biography of James M. O'Connor). In: Irish Journal of Medical Science Sixth Series, No. 491, pp. 463-464, 1966.
  29. ↑ R. Gottlieb and JM O'Connor: About the detection and determination of adrenaline in the blood. In: Emil Abderhalden (Ed.): Handbuch der biochemischen Arbeitsverbindungen 6, pp. 585–603, 1912.
  30. ↑ JM O'Connor: About the adrenaline content of the blood . In: Archives of Experimental Pathology and Pharmacology . 67, 1912, pp. 195-232. doi : 10.1007 / BF01910879 .
  31. ^ Klaus Starke: A history of Naunyn-Schmiedeberg's Archives of Pharmacology . In: Naunyn-Schmiedeberg's Archives of Pharmacology . 358, 1998, pp. 1-109, here pp. 39-40. doi : 10.1007 / PL00005229 .
  32. ↑ V. Erspamer: Pharmacology of indolealkylamines . In: Pharmacological Reviews . 6, 1954, pp. 425-487.
  33. ↑ R. Gottlieb: Theory of anesthesia. In: Results of Physiology . First vintage. II. Department. Biophysics and psychophysics. Pp. 666-679, 1902.
  34. ↑ R. Gotlieb: About the difference in action of optical isomers . In: Journal of Physiological Chemistry . 130, 1923, pp. 374-379. doi : 10.1515 / bchm2.1923.130.1-6.374 .
  35. ↑ Albert Fraenkel: Comparative studies on the cumulative effect of digital bodies . In: Archives of Experimental Pathology and Pharmacology . 51, 1904, pp. 84-102. doi : 10.1007 / BF01840741 .
  36. ^ Klaus Starke: A history of Naunyn-Schmiedeberg's Archives of Pharmacology . In: Naunyn-Schmiedeberg's Archives of Pharmacology . 358, 1998, pp. 1-109, here pp. 34-35. doi : 10.1007 / PL00005229 .
  37. ↑ Hans H. Meyer and R. Gottlieb: The experimental pharmacology as the basis of drug treatment. Urban & Schwarzenberg, Berlin and Vienna 1910.
  38. ↑ Hans H. Meyer and Ernst P. Pick: The experimental pharmacology as the basis of drug treatment. Ninth edition. Urban & Schwarzenberg, Berlin and Vienna 1936.
  39. ↑ Janssen 1964.
  40. ^ Jürgen Lindner and Heinz Lüllmann: Pharmacological institutes and biographies of their directors. Aulendorf, Editio-Cantor-Verlag 1996
personal data
SURNAME Gottlieb, Rudolf
BRIEF DESCRIPTION German doctor and pharmacologist
DATE OF BIRTH September 1, 1864
PLACE OF BIRTH Vienna
DATE OF DEATH October 31, 1924
Place of death Heidelberg