Old drugs – new uses (2007)

In 1949 Henri Laborit, a French surgeon, used the antihistamine promethazine to treat surgical shock in the belief that inhibition of the autonomic nervous system would prevent adverse cardiovascular responses to hypotension [1]. He found that it had some beneficial action and combined it with other drugs, in a so-called ‘lytic cocktail’, to prevent its adverse effects. The manufacturers of promethazine, Rhône–Poulenc, became interested and examined a range of phenothiazines that Paul Charpentier had synthesized as potential antihistamines [2]. A chlorinated derivative of promazine showed great promise in animal experiments, but when he tried it in patients undergoing surgery Laborit noticed that they became relaxed and unperturbed by the prospect of the operation. This serendipitous observation led him to persuade the psychiatrists at the Val de Grace military hospital in Paris to use it. The director of neuropsychiatry, Joseph Hamon, gave it to a patient with acute mania, who became calm. Although derided by some as a ‘liquid cosh’[3], chlorpromazine, marketed as Largactil in France and elsewhere and as Thorazine in the USA, was enthusiastically espoused by such psychiatrists as William Sargant. It transformed the management of schizophrenia overnight, paving the way for the eventual introduction of community psychiatry, as the need for hospital management diminished. Because chlorpromazine has a large range of pharmacological actions (hence ‘Largactil’), alternatives were sought, by the traditional method of side-chain substitution, yielding such compounds as fluphenazine, perphenazine, prochlorperazine, trifluperazine, and thioridazine [4]. All shared the extrapyramidal adverse effects of chlorpromazine, but in the 1980s a new adverse effect of thioridazine began to emerge – QT interval prolongation, with a risk of the polymorphous ventricular tachycardia called torsade de pointes [5, 6]. Following renewed warnings in 2000 [7], the then Committee on Safety of Medicines in the UK restricted the use of thioridazine to patients with a diagnosis of schizophrenia and then only as a second-line drug [8, 9]. The Committee also introduced a requirement for regular monitoring of the QTc interval in patients taking thioridazine and contraindicated the concomitant use of thioridazine with other drugs that cause QT interval prolongation. Branded versions of thioridazine were voluntarily withdrawn worldwide by Novartis in June 2005. It is no longer listed, for example, in the British National Formulary, although generic formulations are still available in some places. However, as Thanacoody points out in a review in this issue of the Journal, thioridazine, in common with other phenothiazines, also has antimicrobial properties [10]. It is active in vitro against organisms such as methicillin-susceptible and methicillin-resistant Staphylococcus aureus, enterococci, Mycobacterium tuberculosis, Plasmodium falciparum, and Trypanosoma cruzi. This opens the way for the potential development of novel antimicrobial drugs based on the phenothiazine structure. Thioridazine is by no means the only drug whose multiple actions may make it an old drug with new uses. Acetylsalicylic acid, which has been used for over a century as an analgesic [11], has for several years been used for its antiplatelet activity in cardiovascular disease, so much so that this can no longer be regarded as a new action of this very old drug. However, its more recent potential use in colorectal cancer has yet to be fully realised [12]. There are many other examples, of which the following is a small selection: Arsenic, first introduced for the treatment of syphilis in the form of arsphenamine (Salvarsan, ‘compound 606’) by Paul Ehrlich [13], is now being used, in the form of arsenic trioxide, to treat promyelocytic leukaemia [14]. Duloxetine, a serotonin and noradrenaline reuptake blocker, developed for the treatment of depression, is being used in the management of detrusor instability [15]. Ethacrynic acid, long abandoned as a loop diuretic, has apoptotic effects through actions on glutathione transferase, which could be harnessed in the development of new anticancer drugs [16]. Miltefosine, initially developed for breast cancer [17], is now being used to treat visceral leishmaniasis [18]. Nitric oxide, the effector in the treatment of angina pectoris with glyceryl trinitrate and related compounds, first used in the nineteenth century, is now being used to treat pulmonary hypertension [19]. Thalidomide, originally developed as a hypnotic in the 1950s and taken off the market because of its teratogenic effects [20], inhibits the synthesis of tumor necrosis factor-alfa and other cytokines and is now being used as an immunomodulator in a variety of diseases, such as multiple myeloma [21] and erythema nodosum leprosum [22]. Tretinoin (all-trans retinoic acid), a standby in the treatment of severe acne, is now also being used in the management of acute promyelocytic leukemia [23]. Other examples have been given and referred to elsewhere [24]. Nor is this principle limited to drug treatments. For example, beta radiation, which has long been used in ophthalmology, for example in the treatment of pterygium, has recently had its indications expanded to include age-related macular degeneration and trabeculectomy and has also been used in the prevention of restenosis following coronary balloon angioplasty or stenting [25]. It has been estimated that it takes about 15 years to bring a drug to the market, at a cost of about £400 million [26], although the true costs have been disputed [27]. Innovation in drug development is also at an ebb [28]; only 20–30 new drugs are approved by the Food and Drug Administration in the USA each year [29]. We should look hard at old drugs for new indications, so that they can be used themselves, or, if their newly discovered effects are inadequate for routine therapy or their adverse effects unacceptable, so that novel compounds can be developed from them. It has been estimated that nearly 9000 drugs are off patent and available for such investigation [23]. The article on the potential new uses of drugs related to thioridazine that we publish in this issue of the Journal is the first in what we hope will be a series of such articles.