Blue-chip technology
Authors: David A Flockhart, David J Webb
Journal: The Lancet (1998)

The currency of clinical pharmacology is the development of new drugs and the monitoring of their efficacy and safety. In 1998, the delicacy of the calculations required to balance the promise of efficacy of new drugs against their safety was emphasised once more. Again, the fruits of the labours of scientists around the world have resulted in the appearance of new drugs with entirely novel mechanisms of action. Although in the past few years such pharmaceuticals have included the HIV-protease inhibitors, the bisphosphonates for osteoporosis, and the 5HTID-receptor antagonists for migraine, in 1998 they were dominated by a novel cyclic GMP (cGMP) phosphodiesterase inhibitor, sildenafil, originally intended to treat angina. Effects of nitric oxide (NO) donors on the cardiovascular system in human beings have been documented for more than 80 years. However, only recently have we uncovered the intricate relationship between endothelial function, NO, and the control of vascular tone. Endothelial NO is a potent endogenous stimulator of the guanylate cyclase present in vascular smooth muscle, and the cGMP thus formed is a key mechanism in the relaxation of blood vessels. Sildenafil inhibits cGMP phosphodiesterase type 5, the predominant isoform in the corpus cavernosum, allowing the drug to effect penile turgor. Ready oral bioavailability has made it possible to distribute sildenafil in pill form as Viagra. The huge popularity of Viagra around the world has bought to the fore the multiple dilemmas presented by the practice of "lifestyle" pharmacology: the prescribing of drugs not to prevent death and disability, but to enhance the quality of life—if we can afford it. The drug has presented not only prescribing physicians but insurers and governments with an unprecedented problem: a relatively high-cost, high-volume drug capable of bankrupting drug budgets in order to improve the sexual capacity of the male population. The safety of such a drug must obviously be very high; hence the concern to avoid co-prescription with nitrates and the advice to physicians, in the USA, to avoid using the drug in men with evidence of cardiovascular disease. The focus on the safe prescribing of sildenafil has been particularly intense in the USA, where its introduction came as three drugs were removed from the market for safety reasons in the space of 5 months: terfenadine (Seldane), mibefradil (Posicor), and bromfenac (Duract). In all cases the reason for withdrawal was that prescribers could not be relied on to follow critical prescribing instructions. As a result, terfenadine and mibefradil continued to be co-prescribed with interacting medications, and bromfenac continued to be prescribed for more than 10 days, resulting in an unacceptable incidence of hepatotoxicity. Indeed, adverse drug reactions remain a leading cause of admission to hospital, and potential cause of death, in the USA and UK. Safety concerns obviously apply particularly to drugs for which the perceived benefit is lower, but pharmacologists continue to discover unique mechanisms of drug action, each one presenting a new opportunity for benefit, and risk of toxicity. In 1999, we anticipate the appearance of COX-2 inhibitors, drugs for the treatment of pain and inflammation, that we all hope will be less toxic to the gut and kidney than standard COX-1 non-steroidal anti-inflammatory agents which, as a class, have the highest incidence of adverse reactions. Endothelin antagonists will emerge from the same body of endothelial research as sildenafil, and have the potential to improve the treatment of hypertension and congestive heart failure. Lastly, the chance of benefit and risk of toxicity may both be improved by a product of the molecular biology revolution; the oligonucleotide array or "gene chip" capable of screening simultaneously for thousands of mutations that might identify patients particularly worthy of therapy, or at risk for toxicity (figure). These chips have already been used to rapidly type HIV and tuberculosis strains, and offer the hope that we will be able to individualise therapy using the science of pharmacogenetics to identify key enzyme and receptor types and optimise treatment–if we can afford it.