Biology Reference
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independently by Herrmann and Greene (Hermann et al.
1937
; Greene and Paul
1937
). They showed that a very slow intravenous injection of 480 mg theophylline
over 2-5 min resulted in a “prompt and persistent relief” from dyspnea. Based on
the publication of these investigations, theophylline was promulgated as a broncho-
dilatory substance and became the mainstay of asthma therapy from 1940 onwards.
In the years following 1980, theophylline treatment for asthma was increasingly
displaced by inhalative glucocorticoids, but the anti-inflammatory activity of the-
ophylline was still intensively investigated in the 1990s, and today further mechan-
isms for the action of low-dose theophylline, i.e., as a PI3K inhibitor and HDAC2
activator, are discussed (Barnes
2003a
). Since, in addition to these effects, theoph-
ylline is also a potent antagonist of the anti-inflammatory A2-receptor-linked
function of endogeneous adenosine, it seems that its characteristic therapeutic
unreliability is based on the counteraction of its endogeneous anti- and pro-inflam-
matory mechanisms.
2.4 Narrow Therapeutic Window
Thus, in the first half of the twentieth century, theophylline had acquired a promi-
nent position in the drug spectrum for use in counteracting various life-threatening
disease states. It combined (1) inotropic, (2) diuretic and (3) bronchospasmolytic
efficacies. However, this broad clinical spectrum was accompanied by severe, in
some instances toxic side effects. Adverse events (AEs) on the cardiac, central
nervous system and gastrointestinal functions such as (1) tachycardia, palpitations,
tremor and arrhythmias, (2) headache and (3) nausea and vomiting were frequently
experienced, but these problems were tolerated since the expectation in the tolera-
bility vs. efficacy ratio in those days was low. Correct dosing was not possible
because of the lack of knowledge of pharmacokinetics for these drugs, and the dose
was determined by trial and error. We know today that proportionality of dose to
blood concentration of theophylline is unusually weak (Ohta et al.
2004
) and that
even at low doses of 2
15 mg/l (in 13% of
patients) followed by toxic AEs may occur. The most severe and frightening AEs
of theophylline were seizures, which had already been published by Allard (
1904
).
He describes two patients who were repeatedly injected with a relatively small dose
of 300 mg theobromine. They had been rescued from dyspnea, increased their
cardiac contractility, and their general condition had been significantly ameliorated.
In spite of this considerable beneficial effect of the medication, these two patients
suddenly and surprisingly were attacked by “epileptic convulsions” and died a
few minutes later. This alarming finding was instantly confirmed in toxicological
experiments with dogs and rabbits. Similar cramp phenomena were observed
after diuretin administration when dogs died and a “lethal dose” of 500 mg/kg
was evaluated. This dose was far greater than the critical doses in man (500 mg
per patient), and a clear correlation from dog to man could not be drawn. Today,
it is well known that blood concentrations established after a constant dose of
200 mg/day blood concentrations of
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