DEVELOPMENT AND INNOVATION IN CARDIOVASCULAR MEDICINE - Innovation in the Biopharmaceutical Industry - page 37

of tissue-specific structure-functional relationships. In addition, as is so often the
case, the drug most widely used in clinical practice today is a refinement of the
initial prototype; a result of innovations leading to more specific action and more
favourable pharmacodynamics.
ACE inhibitors
The renin angiotensin aldosterone system (RAAS) is a powerful regulator of
the circulation. Angiotensin II, formed from angiotensin I by the action of the
angiotensin-converting enzyme (ACE), is a potent vasoconstrictor. It enhances
adrenergic stimulation and causes the release of aldosterone (Kang et al. , 1994).
Inhibition of ACE was recognised as a potentially important therapeutic target, and
a large series of ACE inhibitors have been developed. ACE inhibitors have been
shown to be effective antihypertensive agents with particular benefits for diabetic
patients. They have also been shown to reduce mortality in patients with chronic
heart failure (CONSENSUS Trial Study Group, 1987), a substantial therapeutic
breakthrough since prognosis in heart failure is similar to many forms of cancer
and is resistant to treatment. The vascular complications of type II diabetes and
metabolic syndrome are some of the greatest therapeutic challenges for cardiovas-
cular medicine. Clinical trials showing that ACE inhibition confers cardiovascular
protection in diabetes are important, not only in establishing new therapies, but also
in pointing the way towards a better understanding of this complex syndrome.
At present, classification of ACE inhibitors is based on pharmacokinetic charac-
teristics. Class 1 consists of captopril-like compounds that are already active, but are
metabolised by the liver into products, some of which also have pharmacological
activity, and all of which are excreted by the kidney. Class 2, the largest series, are
pro-drugs converted to active forms in the liver. Class 3 are water-soluble active
molecules which are excreted in the urine unchanged. Two potentially troublesome
side-effects of ACE inhibitors are persistent cough and angio-oedema. The precise
mechanisms responsible for these adverse effects are not clear. However, accumula-
tion of endogenous vasodilator substances such as bradykinin is a possible mediator
(Ferner et al. , 1987), since the ACE is also responsible for their catabolism. In terms
of innovation and development, the ACE inhibitors might not yet be fully evolved.
They have made a profound impact on the treatment of hypertension, particularly
in diabetic subjects (Yusef et al. , 2000), in reducing mortality due to chronic heart
failure (CONSENSUS Trial Study Group, 1987),and in preserving left ventricular
function following myocardial infarction. However, the full complexity of the role
of the RAAS and bradykinin systems in vascular pathology remains to be fully
elucidated. Therapeutic advances to date indicate that this system is likely to have
a powerful role in mediating the complex interactions between abnormal glucose