Biology Reference
In-Depth Information
of the bipyridines such as amrinone (Wetzel and Hauel
1988
). Having established
the biochemical PDE assay, it turned out that these compounds were PDE inhibitors.
In the already existing isolated organ models and in vivo models for bronchocon-
striction, it was demonstrated that these compounds were more potent than theophyl-
line and showed bronchodilatory activity in vitro and in vivo. Byk Gulden at that
time marketed Euphylong - a long duration preparation of theophylline which could
be dosed individually in order to avoid the well-known toxic effects of theophylline.
This administration, however, was complicated and a development of a new medi-
cation could be a task for the young (and small) research team. Taking all arguments
together a decision was drawn in the early 1980s to identify a new candidate
substance for treatment of asthma and the new medication should be identified
following certain (negative) criteria: it should (1) not be a xanthine, (2) not be an
adenosine antagonist, (3) be less toxic than theophylline and (4) have a better
therapeutic window than theophylline. If PDE inhibition was a relevant mechanism
of theophylline, and many arguments were in favour of this assumption, then a more
selective compound could be expected to have a better therapeutic window.
Asthma at that time was treated mainly with ß2-agonists, oral and inhaled
glucocorticoids and by cromoglycate. It was accepted that ß2-agonists relaxed the
bronchial muscle without an influence on inflammation whereas glucocorticoids
reduced the chronic inflammatory process in the lung without influencing bronch-
oconstriction directly. Glucocorticoids - in particular the oral but also the inhaled
forms - were met with scepticism. Since patients after oral steroid treatment
suffered from loss of bone density and were at high risk for bone fractures, a
so-called “steroidophoby” oppressed public opinion. Also, possible retardation of
the growth of children who were taking steroids was discussed. This was a further
argument to develop alternative anti-inflammatory agents to replace the “dangers”
associated with use of the steroids. The available knowledge indicated that smooth
muscle contraction as well as activation of inflammatory cells might be simulta-
neously reduced in the presence of PDE inhibitors.
6.2 Animal Models for Asthma
Animal disease models that somehow reflect the contemporary view about the
pathomechanisms of a disease and for asthma are listed in Table
6
. Since 1962
asthma was defined by the American Thoracic Society by (1) variable obstruction
of airflow and (2) airway hyper-reactivity (American Thoracic Society
1962
;
Hargreave
1989
). Obstruction of airways was attributed to a reduction of the airway
lumen by brochoconstriction which could be measured non-invasively. The main-
stay model was the anaesthetised, mechanically ventilated guinea pig. The jugular
vein, carotid artery and trachea were cannulated with catheters for drug and
spasmogen administration, blood pressure monitoring and mechanical ventilation,
respectively. During bronchospasms the airflow decreased while the airway
pressure and respiratory rate increased dramatically, and, from these parameters,
