Biology Reference
In-Depth Information
3.3.4 Predictions Are Not Always Unequivocal
In the therapeutically relevant tissue of human bronchi, the contributions of PDE3
and PDE4 inhibitors were assessed in biochemical and pharmacological experi-
ments by various investigators, however, with results that varied substantially. Rabe
et al. (
1993
) found no significant contribution of the PDE4 inhibitor to relaxation in
bronchi of human origin. Similarly, low efficacy and potency of rolipram was
shown by Torphy et al. (
1993
). In contrast, in the papers of Cortijo et al. (
1993
),
Tomkinson et al. (
1993
), Naline et al. (
1996
), PDE4 inhibitors rolipram and
piclamilast showed high potency and efficacy in relaxation of human bronchi.
These contradictory results demonstrate that in vitro experiments do not always
provide unequivocal answers. Pretreatment of the preparations and the presence of
endogenous agonists (in this case leukotrienes, adenosine) may have considerable
influences. The above conflicting results were reconciled by experiments conducted
in the clinic. In clinical studies, neither of the two PDE4 inhibitors (cilomilast in
doses of 15 mg in COPD patients) (Grootendorst et al.
2003
) nor roflumilast at
doses of 500 and 1,000
m
g in asthma patients (Engelstaetter et al.
2005
) evoked any
acute improvement of FEV1 (a measure of bronchodilation).
3.3.5 Disease-Relevant Models Are Possible on the Level
of Isolated Organs
The influence of an allergic challenge on tracheal contraction can be determined
if the tracheal tissue is derived from animals that have been previously sensitised.
Thus, isolated tracheal rings from guinea pigs that had been sensitised with ovalbu-
min (OVA) were established in parallel to routine in vivo experiments with non-
sensitised animals. Contraction in this preparation is induced by addition of the
allergen (OVA) in order to mimic the bronchoconstriction that occurs during an
allergic episode (preparations that have been denuded loose antigen sensitivity).
Preincubation with a PDE4 inhibitor was shown to maximally inhibit the resulting
antigen-induced contraction by 80%. PDE3 inhibition was not effective against
mediator release from the sensitised tracheal mucosa (Underwood et al.
1993
;
Bundschuh et al.
2001
). Similarly, very early non-specific inhibitors had been
found to suppress histamine and leukotriene release from lung strips of allergic
animals or men (Orange et al.
1971
), and the PDE4 specificity was established by
rolipram inhibition of histamine release from human basophils (Frossard et al.
1981
).
3.3.6 PDE Inhibitors Do Not Always Inhibit via PDE Inhibition
In order to demonstrate the functional and causal relationship between biochemical
and pharmacological IC50 and ED50, these data can be examined in correlation
diagrams for several available PDE inhibitors. For PDE3 inhibitors, a sufficient
correlation was obtained for the potency of PDE3 inhibition and the corresponding
