Biology Reference
In-Depth Information
A variety of animal species was investigated to study and predict the emetic
potential in man. Neither (1) dog, nor (2) ferret has been reported to reveal a
significant correlation between (1) blood concentrations for vomiting and (2)
HARBS of PDE4 inhibition for a group of PDE4 inhibitors indicating that no
reliable results were drawn from these models. Recently, with use of PDE4D
knockout mice, the duration of alpha2-adrenoceptor-mediated anaesthesia was
suggested as a correlate of emesis (Robichaud et al.
2002
). This model may be
relevant and sufficient, however, in the historical overview, it occurs that finally the
surrogate for estimation of emetic potential was the IC50 ratio of (1) ROS release
from neutrophils to (2) TNF release from MC. These assumptions guided the
identification the next generation of PDE4 inhibitors which were synthesised on
the basis of the rolipram structure (Christensen et al.
1996
), and the most promising
examples derived from this approach are piclamilast (Souness
1996
), cilomilast
(Barnette et al.
1998
) and roflumilast (Hatzelmann et al. 2010).
6.5 Animal Models for COPD
Chronic bronchitis and emphysema as well as their clinical correlates, named the
“pink puffer” and “blue bloater”, had been discussed since their definition (Filley
1967
) and a variety of pathogenetic concepts had been put forward (Tudor and
Voelkel
2002
). When the increasing worldwide prevalence of COPD was published
in 1997 (Murray and Lopez
1997
), it appeared that this fast-growing disease had
been neglected and a discussion about pathomechanisms and possible new strate-
gies towards treatment of COPD started (Barnes
1998
). COPD was recognised as a
systemic disease with pathogenic changes in the small airways, characterised by (1)
irreversible bronchial obstruction due to remodelling and hypersecretion, (2) muco-
ciliary malfunction with exaggerated mucus production and inhibited transport as
well as (3) reduced exercise tolerance (Barnes
1998
). Smoking is the main environ-
mental factor, but no information existed as to why about 15% of smokers were
susceptible for the disease, whereas about 85% smokers were unaffected. COPD
shows an “anomalous inflammatory process” in the lung with CD8+ and CD68+
cells in bronchial biopsies and macrophages and neutrophils in the induced sputum.
Furthermore, enhanced serum albumin was found in BALs and TNF
a
was the
major cytokine found in sputum. These inflammatory parameters could be imitated
in an animal model which had initially been established for endotoxic shock
(Fischer et al.
1993
). LPS was given intravenously and 4 h later lungs were lavaged
and cells and TNF
a
were quantified. This model in the BAL showed neutrophilia,
increased macrophages, TNF
a
and serum albumin indicating the induced edema
and was used as a screening model for pulmonary and systemic inflammation
(Table
6
). Corresponding cellular models for the characterisation of the various
different pathophysiologies including (1) remodelling, (2) secretory and (3) vascu-
lar functions were established.
