Biology Reference
In-Depth Information
5 The Path to the Clinic with Cardiovascular Models
5.1 New Drugs with PDE Inhibitor Function
for Cardiac Rejuvenation
Around 1960, the treatment of heart failure with cardiac glycosides as well as
theophylline had acquired an established place in the clinic. However, both
medications suffered from (1) a narrow therapeutic window, (2) unwanted AEs
such as tachycardia and (3) risk of digitalis intoxication. Research at Sterling-
Winthrop and Warner-Lambert had revealed a variety of new compounds with
the leading compound amrinone in 1975 (Farah and Alousi
1978
; Alousi et al.
1979
). Pharmacological studies were performed predominantly in models of rats
and dogs which were used for determination of blood pressure, heart rate, cardiac
contractility and urine production (Alousi et al.
1979
). In anaesthetised animals,
substances were administered intravenously (iv) whereas in conscious models
oral administration (po) was possible and cardiovascular parameters were not
disturbed by anaesthesia. These cardiovascular models including modifications in
cats and guinea pigs had been previously established for the development of
different classes of antihypertensives such as
a
- and ß-adrenoceptor antagonists,
Ca
2+
-antagonists and ACE inhibitors. For investigation of PDE3 inhibitors, these
models could be used without any major changes (Table
4
).
For amrinone, the in vivo dog model showed an increase in contractile force of
the left ventricle as had been predicted from the measurements in isolated organs
(Alousi et al.
1979
). In the conscious dog dose-escalating studies showed that
pharmacological effects of amrinone started at 0.1 mg/kg iv, side effects were
observed from 3 mg/kg iv and the highest non-toxic dose was 10 mg/kg iv or
50 mg/kg po. These data demonstrate a therapeutic index (TI) of about 100 which
represents a considerable improvement over cardiac glycosides with TI of 2-3.
Amrinone could be administered orally and with an iv/po efficacy ratio of 1:2
revealed a satisfying oral bioavailability. Initial pioneering clinical studies showed
beneficial efficacy in patients (LeJemtel et al.
1979
; Benotti et al.
1978
), which
were later repeated with a variety of different PDE3 inhibitors (Weisshaar et al.
1983
; Wetzel and Hauel
1988
). However, in the PROMISE study for chronic
treatment of severe chronic heart failure with milrinone within a time period of
maximally 12 months the arrhythmogenic potential of PDE3 inhibitors was finally
ascertained. In this study, an increase of mortality and morbidity of 28% was
reported (Packer et al.
1991
). Consequently, further clinical development of
PDE3 inhibitors as cardiotonics was terminated and the reasons for this deleterious
effect will be discussed in two subsequent chapters in this volume (chapter by
Y. Liu, et al, and chapter by M. Movsesian and R. Kukreja). A partial revival of
PDE3 inhibitors occurred when ibudilast was approved and launched for intermit-
tent claudication (Kumar and Bhattacharya
2007
).
