The curious stories of drugs with two lives: a new paradigm in drug development

Conventional drug development resulted in the synthesis of drug molecules with specific targets and responses in mind. However, in recent years there has been a rise in the number of drugs that have been redeveloped to be used in a range of disease states far removed from their original indications. Initially, these discoveries were mainly as a result of serendipitous case reports or occasionally by astute scientific observation. Drug developers are now actively investigating hundreds of ‘old’ drugs to ascertain if they have another life ahead of them. This is being done using complex scientific and computer-aided technologies, not relying on luck and uncertainty. The advantages and cost benefits that are attached to such processes may be significant. Most drugs in use today have been developed as exogenous ligands that bind to specific receptor sites. The resulting effect either through agonism or antagonism generally results in a narrow set of responses. Therefore, most drugs tend to have a fairly selective set of actions following administration. This selectivity is, of course, exactly what Erlich was alluding to almost a century ago when he referred to the need to develop therapeutic agents with a specific target in mind – the so-called ‘magic bullets’. It came as somewhat of a sensation therefore, to find some years ago, that thalidomide, a mild sedative and anti-emetic that had been withdrawn from use many years earlier for its now well-known teratogenic effects was showing promise in the treatment of multiple myeloma. Since then, a wide variety of agents, many of which have been in clinical use for prolonged periods, have been redeveloped to treat an entirely new and unsuspecting host of disease states. In many cases, this represents treatment of pathological states so far removed from their original use as to defy belief that somebody could have even suspected that they might have any effects. The discovery that drugs can have uses removed from their original indications is not entirely new, with clonidine and amantadine being such examples from the 1960s. Clonidine was initially developed as a nasal decongestant by the pharmaceutical manufacturer Boehringer Ingelheim. Following its administration to a department secretary, it caused her to ‘fall asleep for 24 hours, develop low blood pressure, bradycardia, and a dry mouth’. As a result, focus changed, and it has since been used initially as an anti-hypertensive and anti-migraine product and more latterly in anaesthesia. In the case of amantadine, the discovery that this drug initially developed as an anti-viral agent possessed mild activity in the management of Parkinson’s disease was likewise a serendipitous discovery that occurred when a patient with advanced Parkinson’s disease noted a transient improvement in her symptoms after a few weeks of taking the drug for its intended use. Although rarely used, nowadays it provided a useful adjunct in the management of the disease during the years when therapeutic options were limited. The list of drugs that have been given a ‘second life’ has now grown significantly over the last 10 years, and now numbers are approaching a 100. A selection of some of the more noteworthy examples is given below.