Biology Reference
In-Depth Information
2.2 Xanthines for Medical Remedies
Three xanthines (caffeine, theobromine and theophylline) had been isolated from
beans of coffee and cacao and from tea leaves in 1820, 1842 and 1888, respectively,
but it was not until 1895 that the chemical structures were analysed and finally proven
via chemical synthesis (Fischer and Ach
1895
). The first pharmacological investiga-
tion using these compounds was performed in an animal model for urine production
and was published in 1887 by the pharmacologist Schroeder (
1887
). He canulised the
urether of anaesthetised rabbits and observed that after intravenous administration of
theobromine, urine production increased nearly tenfold. This discovery was the birth
of the xanthines as “diuretics”. This observation was highly relevant, and its clinical
application met an important medical need because it gave relief to patients with
leg and lung edema (called “dropsy”) caused by heart failure. This early pharmaco-
logical research success stimulated entrepreneurs in chemical industry to launch
products containing xanthine mixtures such as “Diuretin” (Knoll is the company
that sold that product from 1889), “Agurin” (Bayer1901) or “Theocin” (Byk Gulden
1902) (Rau
2001
). One of the major drawbacks of theobromine and theophylline was
their low solubility in water. A freshly employed chemist at Byk Gulden (Grueter
1910
) solved the problem by creating a complex containing theophylline and ethy-
lenediamine. This formulation resulted in the first preparation of theophylline for oral
and parenteral application and was called “Euphylline”. Heinrich Byk, an entrepre-
neur who had founded a chemical company in 1873, instantly decided to build a new
pharmaceutical factory where Euphylline was produced in various forms, e.g., as an
infusion, tablet and suppositories. Although this was a provocation for established
pharmacists, who had the privilege and responsibility to mix medications with their
own competence, this new drug conquered the market in Europe and USA and was
prescribed for the treatment of angina, coronary sclerosis and so-called “hydrops”.
By around 1900, 16 of 10,000 Americans in USA received a prescription of one of
the available popular xanthine medications. A historical summary is given in Table
2
.
Table 2 Early historical milestones of PDE inhibitor research
1820 Isolation of caffeine, theobromine (1842) and theophylline (1888)
1860 H.H. Salter discovers coffee as effective treatment against asthma
1887 W.v. Schroeder determines diuretic function of theobromine in pharmacological
experiments
1889 Mixtures of theophylline and theobromine are used as treatment for cardiac insufficiency
1895 O. Langendorff establishes isolated perfused heart
1899 K. Hedbom describes increased contractility of rabbit hearts after caffeine
1912 J. Pilcher finds inotropic function of xanthines
1912 P. Trendelenburg establishes isolated bronchi from the cow
1922 S. Hirsch compares clinical efficacy with pharmacological results and defines xanthines
as bronchodilators
1936 G. Herrmann and P. Greene rediscover successful treatment of status asthmaticus with
theophylline
1958 T. Rall and E. Sutherland discover PDEs and identify theophylline as PDE inhibitor
Discovery of xanthines, their pharmacological and clinical applications are listed
