Biology Reference
In-Depth Information
2.3 Rationale for Pharmacology
Driven by the widespread medical use of xanthines and their success in treatment of
cardiac insufficiency, the influence of these compounds on cardiac functions were
studied in the emerging pharmacological models of the time. Isolated, perfused
heart preparations were established by Langendorff (
1895
), and the xanthine-
induced increase of contractile power of the left ventricle was demonstrated using
this model (Pilcher
1912
; Plant
1914
). Furthermore, in vitro isolated smooth muscle
tissue preparations including blood vessels and segments of intestinal wall (Magnus
1904
) were used to demonstrate the effect of xanthines to decrease contractile force
and promote relaxation. These effects contributed a further rationale for the use of
xanthines for treatment of cardiovascular diseases.
Around 1920, Euphylline was the mainstay for treatment of cardiovascular
diseases, and it was Samson Hirsch, MD who shifted the focus to airway patho-
physiology (Hirsch
1922
). Using suppositories containing a mixture of theobromine
and theophylline (ratio 1:2 and called “spasmopurin”), he treated patients experi-
encing bronchospasms from various origins. He discriminated between young
patients with “endogenous asthma” from elderly patients with concomitant “bron-
chitis”, “circulatory and cardiac insufficiency” and peripheral edema, which were
called “cardiac and/or renal asthma”. In both conditions, he observed that Euphyl-
line produced fast relief of dyspnea and bronchospasms as well as a long-term
amelioration of the general condition of the patient. He recommends the diuretin/
spasmopurin treatment for both (1) “antispasmodic bronchodilatation” and also (2)
for “prophylactic treatment” and thereby recognises that a chronic disease underlies
the acute symptoms.
Being already familiar with the pharmacological experiments of Trendelenburg
using isolated tracheal muscles (Trendelenburg
1912
), Hirsch then reinforced
his clinical observations by conducting in vitro experiments. He measured the
influence of the xanthine mixture on isolated bovine bronchial muscle preparations.
In the summary of his unique publication on the combined clinical and pharmaco-
logical investigations of bronchospasms, he states that (1) theobromine and
theophylline are bronchodilators, and (2) bronchi are relaxed independent of their
spasmogenic origin. Moreover, he recommends that both drugs should be used not
only as “diuretics” but also as “bronchodilators”. This was Hirsch's only published
paper with pharmacological results, and although carefully described, these dis-
coveries did not gain general acceptance or clinical application (May
1974
). The
reason that such an important discovery was not recognised seems to be twofold: (1)
within the title of this paper the terms “asthma” and “theophylline” were not
included and thus it may have missed public recognition; (2) apparently, there
were no pharmacological societies or clinical opinion leaders available to spread
these observations to those in clinical practice. Similar pharmacological results had
been obtained by Macht and Ting but without accompanying clinical results
(Macht and Ting
1921
). It took another 15 years until the bronchospasmolytic
potential of theophylline in the status asthmaticus was reinvented in clinical studies
