Conteben

Conteben, which was used as a treatment for tuberculosis, was discovered in 1950.^[1] German scientists named Belmisch, Mietzsch and Gerhard Domagk have been credited with contributing to its discovery. In November 1947, Professor Dr. Ludwig Heilmeyer spoke of the "weak indication" ("schwache Andeutung") of Domagh's "preparation" being effective at Domagh's clinic. A few months later, Dr. Berthold Mikat spoke about the "definite improvement" ("eindeutige Besserung") of 49 from 66 tuberculosis patients, who were treated with TB-1, the precursor of conteben.^[2]

Structure

Chemical formula

The molecular formula of Conteben is C₁₀H₁₂N₄OS.^[3]

Molecular weight

Molecular weight is measured as g/mol (grams per molecule.) The most common units of molar mass are g/mol because in those units the numerical value equals the average molecular mass in units of u. One "unified atomic mass unit" u is equal to 1/12 of the mass of one isotope of carbon12.^[4][5]

The mass of the molecule may be estimated as approximately 236 atomic mass units,^[6] or 236 u, called molecular mass. Therefore, the molecular weight must be about 236 g/mol.^[7]

Mechanism of action

Conteben has been used against Tuberculosis,^[8] an infectious disease caused by bacteria (usually "Mycobacterium tuberculosis" in humans.) Most infections in humans result in an asymptomatic, latent infection, and about one in ten latent infections eventually progresses to active disease, which can be fatal. If left untreated during the active stage, the illness kills more than 50% of its victims.

M. tuberculosis divides every 15–20 hours. This rate is extremely slow compared to other bacteria, which tend to have division times measured in minutes. For example, "Escherichia coli" (E. coli) can divide roughly every 20 minutes.^[9]

Instead of the short course of antibiotics typically used to cure other bacterial infections, TB requires much longer periods of treatment (around 6 to 24 months).^[10]

M. tuberculosis is highly aerobic and requires high levels of oxygen. [Theoretically, a chemical that interferes with the bacteria's absorption of oxygen will defeat it.] It is primarily a pathogen of the mammalian respiratory system, infecting the lungs.^[11]

Adverse effects

One of the documented adverse effects of conteben is the excessive accumalation of serum (or blood plasma) in the brain. Another is weakening of the thyroid glands. These were found in a treatment combining conteben with PAS acid (p-amino-salicylic acid.)^[12]

Synonyms

Variants in clinical use

Diasan, Diazan and many others.^[3] (Since the prefix "az" refers to containing nitrogen,^[13] perhaps "Di"-"az"-an refers to the four nitrogen atoms in the molecule.)

History

Discovery

In 1950, German scientists named Belmisch, Mietzsch and Domagh (Gerhard Domagk) improved Domagh's "preparation" and produced Conteben.

Medical application

Domagh operated a clinic for treating tuberculosis. In November 1947, Professor Dr. Ludwig Heilmeyer noted improvements in Domagh's patients.^[2]

By 1947, both a vaccine and a treatment already existed for tuberculosis. A vaccine had existed for TB since 1921 but mass vaccination with Bacillus Calmette-Guérin (BCG) did not start until after World War II. A treatment for TB also existed since 1945 called Streptomycin. It was the first antibiotic for tuberculosis.

In the beginning of 1948, Dr. Berthold Mikat spoke about the "definite improvement" of 49 from 66 tuberculosis patients who were treated with the precursor of conteben, called TB-1.^[14]

In 1952, Domagh contributed to the discovery of isoniazid which is one of the two antibiotics most commonly used as treatment for tuberculosis. The other is called rifampicin.

Historical background

There were few discoveries in Europe, in the field of chemistry, during the decade after World War Two. Although many were discovered by Americans, the significant discovery of Conteben as a treatment for the deadly tuberculosis, was made by Gerhard Domagk.

Domagk, the son of a school headmaster, was born in Lagow, Brandenburg. He studied medicine at the University of Kiel. During World War I, he volunteered to serve as a soldier and was wounded in December 1914. The rest of the war he served as a medic.

Domagk was also involved in the discovery of Izoniazid or Isoniazid in 1952, with Hoffman-La Roche of the U.S. This too was used against tuberculosis and became one of the two antibiotics most commonly used in TB treatment. It also led to the first anti-depressant drug.

Year	Discovery	Uses
1945	Streptomycin	the first antibiotic for tuberculosis
1947	Polymyxin	damages the bacterial cell membrane
1947	Chloramphenicol	against typhoid and a wide range of bacteria
1948	Chlortetracycline	in veterinary medicine
1949	Neomycin	kills bacteria in the intestinal tract or topically
1950	Conteben	against tuberculosis
1950	Tetracycline	against cholera
1953	vaccine	to prevent polio
1954	vaccine	to prevent measles

People of U.S. nationality ^[15] discovered (or made discoveries related to):

Bacitracin, a topical antibiotic and Streptomycin the first antibiotic for tuberculosis, in 1945;

Chloromycetin or Chloramphenicol in 1947, which was used against typhoid and is effective against a wide range of bacteria, although it has some adverse side effects and many typhi are presently resistant to it; Aureomycin (or Chlortetracycline, the first tetracycline to be discovered) in 1948; Adrenocorticotropic hormone (ACTH) and Neomycin in 1949; Terramycin or Tetracycline in 1950 which was used against cholera; as well as two of the antibiotics in the category Macrolide: Carbomycin and Erythromycin in 1952.

The vaccines of polio and measles, too, were by discoverers whose nationality was American (U.S.).

During this decade (1945–1955) very few discoveries were made in Europe in this field or in any field of chemistry and physics (not including the Soviet Nuclear test in 1949). The transistor is credited to Americans in 1956. Meanwhile in Europe, only the antibiotic: polymixin or Polymyxin by a British discoverer in 1947, stands out besides the advances of Domagh.

See also

• Isoniazid

References

1. ^ The World Almanac
2. ^ ^{a b} Der spiegel 26.12.1951
3. ^ ^{a b} http://www.chemindustry.com/chemicals/013633964.html
4. ^ http://goldbook.iupac.org/r05271.html
5. ^ http://www.webqc.org/mmcalc.php
6. ^ IUPAC, BSP (The International Union of Pure and Applied Chemistry and Butterworth Scientific Publications.) Atomic weights are based on atomic mass (relative to carbon 12.) (Several atoms in the Conteben molecule are known to be variable and their ranges are marked n ^up to n) carbon 12 (12.01115+/-0.00005=range 12.0111^12.0112) (natural variations in isotopoic composition) hydrogen 1 (1.00797+/-0.00001=range 1.00796^1.00798) nitrogen 14 (14.0067) oxygen 16 (15.9994+/-0.0001=range 15.9993^15.9995) sulfur 32 (32.064+/-0.003=range 32.061^32.067). The mass numbers of C, H, N, O, S, are approximately: 12, 1, 14, 16, 32 respectively, so per molecule: 10*12+12*1+4*14+16+32= 236 atomic mass units.
7. ^ because "The average atomic mass of natural hydrogen is 1.00794 u and that of natural oxygen is 15.9994 u; therefore, the molecular mass of natural water with formula H₂O is (2 × 1.00794 u) + 15.9994 u = 18.01528 u. Therefore, one mole of water has a mass of 18.01528 grams."
8. ^ Martindale, The Extra Pharmacopoeia, 30th ed, p. 217 , http://www3.interscience.wiley.com/journal/122317107/abstract?CRETRY=1&SRETRY=0
9. ^ Murray PR, Rosenthal KS, Pfaller MA (2005). Medical Microbiology. Elsevier Mosby
10. ^ Centers for Disease Control and Prevention (CDC), Division of Tuberculosis Elimination. Core Curriculum on Tuberculosis: What the Clinician Should Know. 4th edition (2000). Updated August 2003
11. ^ Ryan KJ, Ray CG (editors) (2004) Sherris Medical Microbiology (4th ed.). McGraw Hill. ISBN 0-8385-8529-9
12. ^ http://www3.interscience.wiley.com/journal/122317107/abstract?CRETRY=1&SRETRY=0
13. ^ Webster's New Collegiate Dictionary
14. ^ http://www.spiegel.de/spiegel/print/d-20300776.html
15. ^ The World Almanac 1966 p. 294

External links

• Chemindustry
• "Im November 1947 macht der für alles Neue aufgeschlossene Freiburger Internist Professor Dr. Ludwig Heilmeyer, ein Mitschüler des Atomphysikers Heisenberg, die erste schwache Andeutung, daß sich Domagks Präparat in seiner Klinik zu bewähren scheine. Genaue Zahlen gibt aber erst drei Monate später ein bis dahin unbekannter Arzt, Dr. Berthold Mikat, der nur in Vertretung seines Chefs, Dr. Fritz Kuhlmann aus Mölln, spricht: Im Krankenhaus der Landesversicherungsanstalt Schleswig-Holstein ist nach Tb I-Behandlung bei 49 von 66 Patienten mit Lungentuberkulose eindeutige Besserung nachgewiesen worden. Das ist der Start für die Einführung des Tb I, das später den Namen Conteben bekommt."