ISTITUTO DI RICERCHE FARMACOLOGICHE MARIO NEGRI Dott. Oscar Corli Centro per la Ricerca e lo Studio sul Dolore (CERP) Via Giuseppe La Masa, 19 - 20156 Milano MI - Italy - www.marionegri.it tel +39 02 39014.1 - fax +39 02 354.6277 - firstname.lastname@example.org REPORT INTERMEDIO ATTIVITÀ 2012 TITOLO DELLA RICERCA: Breakthrough cancer pain (BTcP): studio prospettico l
Chemotherapy 2004;50:6–10DOI: 10.1159/000077277 The Return of Ehrlich’s ‘Therapia magna
sterilisans’ and Other Ehrlich Concepts?
Series of Papers Honoring Paul Ehrlich on the Occasion of His 150th Birthday
Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany Key Words
the ‘World Conference on Dosing of Antiinfectives: Dos- Paul Ehrlich W Dyes W Syphilis W Therapia magna ing the Magic Bullets’, which is going to be held in Nürn- berg, Germany, from September 9 to 11, 2004 (seewww.ehrlich2004.org). Apart from the conference topic,this conference will also commemorate a real science Abstract
giant of the last century and yet a modest human being On March 14th of this year, the birthday of Paul Ehrlich, whom, as Robert Koch put it, ‘one had to like’. This article the great German researcher and ‘founder of chemother- recalls Ehrlich’s ingenious concepts, including modern apy’, returned for the 150th time. Interestingly, his later syphilis treatment, one-dose treatment (‘therapia magna colleague Emil von Behring was born one day later in sterilisans’) of Helicobacter pylori infections and intro- 1854. Both were coworkers in Robert Koch’s laboratory duction of an arsenic compound, arsenic trioxide, as well and became Nobel Prize laureates (for their work in as experiments and new exciting data on Congo red, a immunology), making great contributions to antiinfec- tious treatments. Emil von Behring’s approach was through the use of immunological agents, while Ehrlichfavored an approach of antiinfectious treatment bychemical agents. Through an ingenious concept that was Introduction
a clear continuation of his early days in research withdyes, he found the first chemotherapeutic agents. From With this article, Chemotherapy begins a series of pub- his dye work, he had concluded the following: if there are lications on the occasion of Paul Ehrlich’s 150th birthday, dyes that one can use to stain cells, why not develop which occurred on March 14 2004. Emil von Behring, pharmacological agents that, like stains, also attach to a another famous German specialist on infectious diseases, structure in the living pathogen and kill them. He gave was born one day later in 1854. Later in their life, Ehrlich these agents the emotionally charged name ‘magic bul- and von Behring became partners in the laboratory of lets’. This introductory review will initiate a series of Robert Koch, but they also became competitors, and so papers on the occasion of Ehrlich’s 150th birthday and their ‘friendship’ had ups and downs. For a long period, IBMP – Institute for Biomedical and Pharmaceutical Research DE–90562 Nürnberg-Heroldsberg (Germany) Tel. +49 911 518 290, Fax +49 911 518 2920, E-Mail email@example.com Emil von Behring opposed Ehrlich’s approach to curinginfections with ‘chemicals’ rather than vaccines. WhenEhrlich died in 1915, though, it was von Behring who heldan impressive and emotional speech at the funeral ser-vice. This speech showed that von Behring had admiredEhrlich’s ingenious path to chemotherapy, saying thatEhrlich was truly a ‘Magister Mundi’, i.e. master of theworld’s science. In addition, von Behring was aware that Fig. 1. Chemical structure of arsphenamine (‘606’, Salvarsan®).
without Ehrlich, his success with the first diphtheria vac-cine would not have been possible. Emil von Behringreceived the first Nobel Prize ever awarded in medicinealone in 1901, but Ehrlich had to wait until 1908 and then objective of this article is to rethink the concept and to had to share it with Mechnikov. Both had had numerous acknowledge Ehrlich’s great achievements in the year of nominations since the introduction of the Nobel Prize in 1901. It has been speculated and seems to be well docu-mented in the Nobel archives  that had Ehrlich notdied so early, he would have been given the Nobel Prize ‘Therapia magna sterilisans’ of Syphilis
for chemistry together with his Japanese coworker Dr.
Sahachiro Hata, with whom he developed ‘compound Soon after its introduction into clinical medicine, peni- 606’ (arsphenamine and as trade name Salvarsan®) in cillin became the standard for syphilis treatment, and 1910. That success marks the beginning of chemotherapy.
Ehrlich’s Salvarsan became of marginal importance. Ben- Thus, there is no doubt that Paul Ehrlich is not only the zathine penicillin is still successfully used today to treat founder of chemotherapy, but he actually invented that syphilis . That form of penicillin provides long-lasting penicillin G levels in the blood and tissues, and hence a In spite of the undoubted breakthrough in the treat- single dose may be successful in many cases.
ment of syphilis, the use of Salvarsan was a matter of dis- Of course we do not know much about the pharmaco- cussion in Germany and around the world. In spite of kinetics of Salvarsan, and it is not clear whether it was due Ehrlich’s great caution to have it used appropriately, it to a pharmacokinetic reason that ‘therapia magna sterili- was misused and adverse events were inevitable. Together sans’ of syphilis failed with this agent. However, it is my with the use of Salvarsan, Ehrlich also introduced the con- hypothesis that Ehrlich’s Salvarsan had – among other cept of the ‘therapia magna sterilisans’, as he called it.
reasons – too short a half-life to be dosed once only.
‘Therapia magna sterilisans’ means successful treatment We also should not forget the fact, though, that single- of an infectious disease by a single dose of that agent. Ehr- dose therapy has been an aspect in the management of lich liked to use Latin language to define his major most common sexually transmitted diseases, such as hypotheses or theories, like the very famous one leading to syphilis, gonorrhea, trichomoniasis and chancroid. Of the the receptor concept: ‘copora non agunt nisi fixata’. The agents used in addition to benzathine penicillin in syphilis hope of realizing single-dose treatment was in fact sup- treatment, azithromycin has such a long half-life in plas- ported by Ehrlich’s experiments with dyes and finally Sal- ma and tissues that it has become the modern choice for varsan in animals and humans. Very soon after the begin- syphilis treatment. A very recent study with this agent ning of Salvarsan treatment in patients, Ehrlich had to showed that – as in Ehrlich’s day – one has to assess the admit, though, that this concept of one large dose may not adverse events very carefully. In fact, in their study, Rekart et al.  used another important concept of phar- Since then, the concept of ‘therapia magna sterilisans’ macology, which is dosing according to weight, forming at has been forgotten, although used in many instances with- least two dosing groups. That led to a reduction in gas- out knowing. It was taken as a relic of the early times of trointestinal adverse events. This concept was also origi- chemotherapy, not worth thinking about it. I now report nally introduced and used by Ehrlich. Very early on in the several examples from modern times and even most use of Salvarsan therapy, Ehrlich suggested dosing accord- recent times of documented cases where ‘a single dose’ of ing to weight and gender. An excellent review of this ‘dou- an antiinfective has been used successfully in clinical ble-edged sword’ of single-dose therapy has been pub- studies with today’s standards of clinical research. The Paul Ehrlich’s 150th Birthday – Still Alive? the prevention of resistance. As Polk  points out, thesestrategies, however, would only be expected to workagainst organisms that become resistant by selection ofresistant mutations, and would not be expected to beeffective against organisms that require the acquisition ofnew resistant genes. However, whether the same thinghappens in humans is less clear, and there are a number ofreasons why dose optimization is not likely to be a veryeffective strategy. Foremost is that most of the species ofbacteria that are increasingly resistant to chemotherapyarise not from the pathogen pool (analogous to theinfected mouse thigh), but from the pool of innocent bys-tanders (the gastrointestinal flora of the infected mouse).
In addition, the pharmacokinetics/pharmacodynamicsparameters in the commensal pool, such as those in thegastrointestinal tract or the skin, are very different frompharmacokinetics/pharmacodynamics parameters basedon serum concentrations, and it is unknown what the con-centration-effect relationships are in these noninfectedareas. These theses of Polk  certainly deserve discus-sion.
One-Day Quadruple Therapy for Helicobacter
Not too far back, the eradication of H. pylori involved Fig. 2. One of the rare pictures where these two great German
a 3-week treatment with a not insignificant number of researchers, Ehrlich and von Behring, are shown together, in the adverse events in these therapies with up to four drugs.
newspaper the ‘Illustrirte Zeitung’ of Berlin (today it reads ‘Illus- Many attempts were made to shorten that treatment, and trierte’). (Reprinted courtesy of Aventis Behring, Germany.) short-period treatment has been introduced. Most recent-ly, most spectacular results were published by Lara et al.
. In a randomized, prospective, open-labeled equiva- ‘Therapia magna sterilisans’ and Emergence of
lence trial with a parallel-group design to compare eradi- Resistance
cation rates of H. pylori in 160 patients, the 1-day groupusing four agents (524 mg of bismuth subsalicylate, Recently, Coates et al. , in an excellent review of 500 mg of metronidazole and 2,000 mg of amoxicillin modern antimicrobial treatment and its failures, short- four times a day, and 30 mg of lansoprazole twice a day) comings and misconceptions, suggested shorter treatment had a slightly higher eradication rate (95%) than the 7-day that may consequently include ‘one-day’ treatment. Dis- group (90%). Interestingly, the adverse events with, for cussion on shorter versus longer treatment to prevent example, 8 g of amoxicillin per day were not different resistance has very recently become a controversial topic between the groups, although this finding may have been again. With their articles, these authors may pave the way hampered by the means of assessing adverse events, to a complete rethinking of antimicrobial chemotherapy.
which was undertaken several weeks after treatment. This Along those lines, arguments have been put forth that finding needs to be confirmed in additional trials, but for ‘dose optimization’ of an antimicrobial can prevent the the moment it remains a most interesting finding. Other emergence of resistant microorganisms. This idea has than in the case of benzathine penicillin and azithromy- great appeal, and there are good in vitro and animal data cin, this drug combination has no component with a long that support it [6, 7]. The animal work clearly shows that half-life, suggesting that other mechanisms must underlie there is a relationship between the dose administered and Arsenic Trioxide
Although Ehrlich’s arsenic compound 606 (Salvarsan) was an organic arsenic with arsenic captured chemically,it was his achievement to make arsenic compounds and torender their toxicity preventable and countable. On thisbasis, the recent introduction of arsenic trioxide recallsEhrlich, who made these agents usable in human medi-cine. Arsenic trioxide has demonstrated efficacy and safe-ty in patients with first and subsequent relapsed or refrac-tory acute promyelocytic leukemia, regardless of the dis-ease-free interval. Treatment of relapsed and refractorypatients with this novel therapy produces complete remis-sion in 87 of patients and molecular remission in 83%.
Studies have documented the efficacy of autologous andallogeneic transplantation as salvage therapy in relapsedand refractory acute promyelocytic leukemia .
Fig. 3. Paul Ehrlich (1854–1915). The founder of chemotherapy and
winner of the Nobel Prize in Medicine in 1908. (Photo reprinted
Ehrlich’s Dyes and Old ‘Non-Ehrlich Dyes’ in
Modern Molecular Pharmacology and Drug
It was one of Ehrlich’s great achievements to carry the concept of the use of dyes through from histology to che-motherapy. His first dye to be used was methylene bluefor treatment of malaria in human patients. Althoughactive, methylene blue did not become a ‘magic bullet’.
His second attempt was trypan red, which he used to treattrypanosomes, but this was only tested in animals and afew humans. Finally, Ehrlich found ‘606’, which was notpart of a synthesis of dyes but happened to be a yellowdye. These three colors are used in the logo of the confer-ence commemorating his 150th birthday . A veryrecent report from Harvard Medical School  showed Fig. 4. Emil von Behring (1854–1917). Winner of the Nobel Prize in
that the dye Congo red has been successfully tested to rid Medicine in 1901. (Photo reprinted courtesy of Aventis Behring, mice of a neurogenerative condition similar to Hunting- ton’s disease by dissolving clumps of abnormal proteins inthe brain. Interestingly, these investigators used two ofEhrlich’s concepts. The first is the staining of amyloiddeposits in dead brain by Congo red, which led to testing Conclusions
of this dye as a pharmacological agent to rescue live Hun-tington’s disease cells. Before that may successfully hap- This very short review of Ehrlich’s impact on today’s pen in humans, an agent must be found that acts like Con- scientific work shows very clearly that honoring Paul Ehr- go red in the brain cells but which can – unlike Congo red lich with this great ‘World Conference on Dosing of – also pass the blood-brain barrier. In addition, the blood Antiinfectives: Dosing the Magic Bullets’ will review on barrier was first described by one of Ehrlich’s coworkers, an international level the use of modern ‘magic bullets’ – Goldman, revealing the second aspect of this modern the least the modern chemotherapy community and this research related to Ehrlich’s work and interest.
journal can do to remember a great German scientist. Weare continuing Ehrlich’s chemotherapy.
Paul Ehrlich’s 150th Birthday – Still Alive? References
1 The Nomination Database for the Nobel Prize 5 Coates A, Hu Y, Bax R, Page C: The future 10 Douer D, Hu W, Giralt S, Lill M, DiPersio J: in Physiology or Medicine, 1901–1949. The challenges facing the development of new an- Arsenic trioxide (trisenox) therapy for acute timicrobial drugs. Nat Rev Drug Discov 2002; promyelocytic leukemia in the setting of hema- tion. Copyright® 2003 The Nobel Foundation.
topoietic stem cell transplantation. Oncologist http://www.nobel.se/medicine/nomination/da- 6 Drusano GL: Prevention of resistance: A goal for dose selection for antimicrobial agents. Clin 11 Sörgel F: World Conference on Dosing of An- 2 Burstein GR, Workowski KA: Sexually trans- Infect Dis 2003;36(suppl 1):S42–S50.
tiinfectives: ‘Dosing the Magic Bullets’. Cele- mitted diseases treatment guidelines. Curr 7 Andes D, Craig WA: Animal model pharmaco- brating the 150th Birthday of Paul Ehrlich, the kinetics and pharmacodynamics: A critical re- ‘Founder of Chemotherapy’, September 9–11, 3 Rekart ML, Patrick DM, Chakraborty B, Ma- view. Int J Antimicrob Agents 2002;19:261– ginley JJ, Jones HD, Bajdik CD, Pourbohloul B, Brunham RC: Targeted mass treatment for 8 Polk R: Can we use the clinical pharmacology 12 Sanchez I, Mahlke C, Yuan J: Pivotal role of syphilis with oral azithromycin. Lancet 2003; of antibacterial drugs to predict (and prevent) oligomerization in expanded polyglutamine the propensity for development of antimicro- neurodegenerative disorders. Nature 2003; 4 Kingston M, Carlin E: Treatment of sexually bial resistance? Presented at the 103rd General transmitted infections with single-dose thera- Meeting, American Society for Microbiology Annual Meeting, Washington, D.C., May 21, 9Lara LF, Cisneros G, Gurney M, Van Ness M, Jarjoura D, Moauro B, Polen A, Rutecki G,Whittier F: One-day quadruple therapy com-pared with 7-day triple therapy for Helicobac-ter pylori infection. Arch Intern Med 2003;163:2079–2084.
Gender matters V A N I T A N A Y A K M U K H E R J E E ‘The empowerment and autonomy of women and the improvement of their political, social, economic and health status is a highly important end in itself. In addition, it is essential for the achievement of sustainable development. The full participation and partnership of both women and men is required in productive and reproductive life,