Biology Reference
In-Depth Information
and after injection into the corpus cavernosum an erection of the patient's penis was
observed (Virag et al.
1981
). The description of this accidental observation and the
knowledge of Kukovetz's experiments stimulated GS Brindley to intensively study
the effects of intracavernosal injection of papaverine and several other vasoactive
drugs (Brindley
1982
,
1986
). The results of this engaged investigation was published
in 1983 in an unusual, unique presentation (Klotz
2005
).
Clinical success of sildenafil in treatment of coronary artery disease was limited
due to the relatively short half-life of 4 h and limiting adverse effects such as “blue
vision”, flushing and headache at doses above 50 mg. Improved erectile function
had been reported incidentally among men participating in the clinical trials of
sildenafil conducted by Pfizer. These reports along with the realisation that PDE5
inhibitors such as sildenafil can amplify the naturally intended sexual functions was
in accord with the reports by Ignarro that naturally derived NO released from nerves
upon sexual stimulation or from exogenous NO donors increases cGMP synthesis
and thereby works as a mediator of erection (Ignarro et al.
1990
). It was 1992 when
gears were changed for sildenafil development to focus on treatment of erectile
dysfunction excellently described by Campbell (Campbell
2000
) and a recent
review (Ghofrani et al.
2006
).
Pharmacological studies of PHT models had already shown that the relief of
symptoms elicited by inhaled prostacyclin could be potentiated by PDE 3/4 and/or
PDE5 inhibitors (Schermuly et al.
1999
), and these medications could be trans-
ferred to clinical studies (Ghofrani et al.
2002a
,
b
). Later, the NO-regulated hypoxic
vasoconstriction in the lung, which protects against mismatch of ventilation and
perfusion within the lung microcirculation, indicated that sildenafil alone may
amplify the action of NO whose local release has been pathologically downregu-
lated, thereby improving pulmonary microcirculation and ventilation/perfusion
matching (V/Q ratio) (Grimminger et al.
1995
). Finally, these results led to the
successful introduction of sildenafil (Revatio
TM
) into PHT therapy. The same
principle of selective demand-dependent regulation of microperfusion seems to
be embodied by NO-mediated neuro-vascular coupling in the brain which has been
investigated in animal models (Rosengarten et al.
2006
). Application of the PDE5-
selective inhibitors in treatment of a number of other maladies related to dysfunc-
tion in vascular and non-vascular systems continues to emerge.
6 New PDE Inhibitors Against Airway Diseases
Without Vomiting
6.1 The First Goal: An Improved Bronchodilator
with Anti-inflammatory Potential
The starting point of the new anti-asthma drug program in the company of the authors
(originally Byk Gulden, later Altana and today Nycomed) was a running cardiovas-
cular program with dihydro-pyridazinone compounds, which were chemical relatives
