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but with similar efficacy. In sensitised OVA-challenged guinea pigs, zardaverine
reduced allergic bronchoconstriction and reduced hyper-reactivity induced by Ach
(Kilian et al. 1989 ). These data were confirmed in 1989 when inhibition of
bronchial eosinophilia could be demonstrated in the freshly established guinea
pig BAL model (Table 6 ) (Schudt et al. 1991a , b , c ; Tenor and Schudt 1996 ). The
risk for AEs was tested in rodent models using behavioural effects (Wachtel 1983 )
and for vomiting in dogs (Burkman 1982 ), and since emesis was found to be low in
comparison with rolipram, the results opened the possibility to try both the oral and
the inhalative administration routes. Pharmacologically, the efficacy of inhaled/
instilled and oral zardaverine could be demonstrated in guinea pigs and the pre-
requisites for human studies were provided by oral and inhalation toxicology.
Clinical trials with oral and iv administration started in 1988. Disappointingly,
but not totally surprising, at oral doses that were efficacious for bronchodilation,
AEs involving the central nervous system, and especially vomiting, were
experienced which discouraged further development for oral administration. In
inhalation studies, zardaverine was well tolerated. FEV1 increases of 200-400 ml -
depending on the dose - were shown; however, the duration of dilation was
not sufficient for a long-term protection. The interesting question as to whether
the inflammatory process in the lungs of the asthmatic was influenced could be
qualitatively assessed by studying EAR and LAR after provocation and consider-
able reductions of LAR were reported (Hatzelmann et al. 1996a ). When zardaverine
development was terminated in 1991 due to its fast elimination, 250 patients had
received this drug by inhalation.
Benafentrine or AH 21-132 had been investigated at Sandoz and a bronchodilat-
ing efficacy was demonstrated in volunteers (Foster et al. 1992 ). Benafentrine was
structurally related to papaverine and served as a lead structure for tolafentrine
(Hatzelmann et al. 1996a ). Also tolafentrine was a dual PDE3/4 inhibitor with
bronchodilatory function after mediator or allergen stimulation, however, with
~20-fold higher potency (Beume et al. 1993 ; Schudt et al. 1993 ). In contrast to
zardaverine, tolafentrine was scarcely adsorbed following oral administration. This
characteristic would significantly reduce the expected AEs due to the swallowed
fraction which was 40-50% of the inhaled material after inhalation therapy. The
development of tolafentrine had successfully passed the inhalation studies in normal
volunteers in phase I trials without complications. However, when the first four
asthmatics received the puffs of inhalative tolafentrine, they experienced an unfore-
seen bronchoconstriction. The reason for this effect is not understood even today, but
it led to termination of clinical development of tolafentrine for asthma.
6.4 Early Strategies for Avoiding Nausea and Vomiting
In the pioneering work of Wachtel, a Schering scientist, rolipram was characterised
pharmacologically as a centrally active PDE4 inhibitor (Wachtel 1983 ). In rodents,
rolipram reduced (1) body temperature, (2) locomotor activity, and (3) behavioural
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