Index

INDUSTRY OVERVIEW

Natural prostaglandins (PGs) are biologically potent, short-lived local hormone metabolites derived, via cyclooxygenase (COX) enzymes, from nutritionally essential precursor polyunsaturated fatty acids (PUFAs) and are present in virtually all mammalian tissues. Dietary insufficiency and/or imbalances of precursor PUFAs can cause corresponding disturbances of prostaglandin levels and this is now accepted to be a major factor in a wide range of human ailments and diseases.

The natural PGs have many useful applications in medicine as indicated below...

Prostaglandin	Biological Properties	Indications
PGE1 (Alprostadil)	vasodilator, anti-aggregatory, tissue protection	Congenital heart disease, peripheral vascular disease, erectile dysfunction, female sexual dysfunction, organ transplantation
PGE2 (Dinoprostone)	smooth muscle contraction, vasodilator, bronchodilator	induction of labour
PGF2a (Dinoprost)	vasoconstrictor, bronchoconstrictor, smooth muscle contraction	fertility control, synchronisation of oestrus (veterinary)
PGI2-Na (Epoprostenol-Na as sodium salt)	anti-aggregatory vasodilator	extracorporeal circulation (eg. in renal dialysis), primary pulmonary hypertension.

While natural PGs are useful pharmaceuticals they are generally rapidly metabolised and can have widespread and unspecific pharmacological actions. For these reasons oral delivery is in general, not feasible and a large number of structurally stabilised analogues of the natural PGs with more specific actions have been been developed over the years. Most notably the orally active (Alprostadil) PGE1 analogues misoprostol and limaprost were introduced for gastrointestinal ulceration and cardiovascular disease respectively; the PGE2 analogues enprostil and arbaprostil were also launched as antiulcer therapies and sulprostone became available for fertility control; the PGF2a analogues carboprost and cloprostenol were marketed for fertility control/post partum haemorrhage and synchronisation of oestrus respectively (the latter for use in veterinary medicine).

The discovery in 1976 of the unstable prostanoid prostacyclin (PGI2) shifted the focus of a number of pharmaceutical companies toward the development of stable analogues of this highly potent vasodilator and antiplatelet aggregatory (anticoagulant) product. Iloprost in Germany and beraprost in Japan were the first stable PGI2 analogue to be marketed. Iloprost is effective for the treatment of ischaemic heart disease and PVD and has been investigated for topical application in skin ulceration. Beraprost is another stable prostacyclin which is widely prescribed in Japan for ischaemic conditions such as angina.

More recently there has been a growing recognition of the versatility of the PGs and research and development in the field has continued, with increasing momentum of late. There are now more than thirty PG drugs (including the 4 natural products alprostadil, - PGE1, dinoprostone - PGE2, dinoprost -PGF2a, and epoprostenol - PGI2) marketed around the world. The top six have a combined and increasing market value, as dosage forms, currently around US$2bn. New stable PG molecules continue to be introduced, sometimes for entirely new uses, and existing PGs are continually being developed for new indications. PG drugs are now established in the key therapeutic areas of cardiovascular, inflammatory and gastrointestinal medicine and are being developed for very large emerging indications such as erectile dysfunction (ED-impotence) and female sexual dysfunction (FSD), glaucoma, osteoporosis There also exists a large and growing market for PG products in veterinary medicine.

A highly significant factor has been the increasing acceptance by the medical profession that the diversity of disorders associated with PG deficiency is wider and of greater pathogenic importance than was earlier recognised. PG imbalances can now be demonstrated in many abnormalities that were earlier described as being of uncertain aetiology. Moreover there is a growing acceptance that total selectivity is not always a prerequisite and that multiple beneficial actions can frequently be utilised to good effect. In tandem with this there is a trend toward the use of combination therapies and novel drug delivery systems and all of these emerging new attitudes, trends and developments have had a positive influence on the PG field. Furthermore the expiry of patent protection on a number of key PG analogues has not missed the attention of the generic and biotechnology industries who are increasingly seeking to add niche, value- added products to their portfolios.

The literature on the PGs is vast and growing with currently around 200 papers a month being published. Thus in addition to those topics referred to above there are a growing number of on-going and new areas of research of relevance to PG drug development. These include

Roles of PGs in pregnancy and parturition.
Involvement of COX enzymes and PGs in cancer of the colon, breast, lung, prostate, skin and brain.
Selective prevention of cytoxicity of anti-cancer drugs.
Involvement of COX enzymes and PGs in Alzheimers disease.
Roles of PGs in sleep wake cycles.
Use of PGs in organ transplantation.
Involvement of isoprostanes as mediators in oxidation injury.
Role of PGs and COX enzymes in the CNS, brain injury and depression.
Roles of PGs in allergic disease.

Conclusion
Endogenous prostaglandins (PGs) are of fundamental importance in human and animal health and have been a focus of attention for drug development for many years. There are now some thirty PG drugs (including natural PGs and prostacyclin and its analogues) marketed throughout the world with many more under development. PGs are now utilised in the key therapeutic areas of cardiovascular, inflammatory, and gastrointestinal medicine and the top half dozen PG products have a combined market value in excess of $2.5bn. Current pre-clinical and clinical research will lead, in the foreseeable future, to the introduction of an increasingly diverse range of innovative PG products for use in many areas of medicine.