New uses for old drugs: Novel therapeutic optionsByline: Ujala. Verma, R. Sharma, P. Gupta, B. Kapoor, G. Bano, V. Sawhney

New uses for old drugs: Novel therapeutic optionsByline: Ujala. Verma, R. Sharma, P. Gupta, B. Kapoor, G. Bano, V. SawhneyIntroducing a new drug to the market now costs an average of US$ 897 million and is a time consuming process. Discovering new uses for the old drugs offers the advantage of providing time tested drugs for the benefit of the patients. Serendipity plays an important role in this. This therapeutic option may provide cost effective treatment, especially for the developing countries with limited resources. This article focuses on the new potential uses of some common drugs. However, these options need to be pursued by more researches so that the potential benefits could be passed on to the patients.

Since decades, the rational discovery of new medicines has depended on the modification of molecular structures. Introducing a new drug to the market now costs an average of US$ 897 million which includes preclinical and clinical costs before the US FDA (Food and Drug Administration) approval and costs associated with studies conducted after a product has gained such approval.[1] Moreover, the process of approval may take up to 15 years. The new drug may prove to be a loss in terms of its high manufacturing costs if it produces any unacceptable adverse reaction or toxicity in early years of marketing. In such prevailing conditions, discovering new uses for the already-existing time tested drugs with known adverse drug reaction profile may prove to be beneficial for the use of patients. Some older drugs have the potential and offer the advantage of extensive clinical experience in other therapeutic areas. They should be considered as potential partners to the products emerging from more recent research and development. Old drugs are resurfacing with new uses (but often off-label) as the underlying mechanism of diseases become understood.[2] The American Medical Association (AMA) estimates that 40% to 60% of all prescriptions in the United States are written for unapproved/unlabelled purpose. An unapproved use merely indicates the lack of FDA approval and does not imply an improper or illegal use. Unlabeled use is a more appropriate term and is defined as the use of a drug product in doses, patient populations, routes of administration or for indications that are not included in FDA-approved product labeling.[3] Many examples can be quoted to prove its benefits. For example, aspirin, approved by the FDA as a pain killer, was used to reduce the mortality rate among heart attack victims; the drug mitomycin, approved for the treatment of gastric and pancreatic cancers, has been found to be useful in the treatment of lung, bladder, breast and cervical cancers, as well as in certain forms of leukemia; trimethoprim, a drug approved to treat pneumonia, has been proved useful as an AIDS management.[4] Moreover, discovering new uses for a new drug that does not work out for its intended use may be another aspect of utilizing the researches and is a valuable strategy because approximately 90% of experimental drugs in the industry fail. In fact, many pharmaceutical companies routinely follow this. The trials of experimental chemotherapy drug pemetrexed were halted following the death of some patients. However, now it is an approved treatment for mesothelioma and is under FDA consideration as a treatment for lung cancer. Pfizer Inc. originally developed the impotence drug sildenafil (viagra) to treat angina. Raloxifene, used for osteoporosis, was a failed contraceptive. Atomoxetine, now used for attention-deficit/hyperactivity disorder failed as an antidepressant.[5] The tenacious effort to develop new and specific agents to treat HIV infection is currently accompanied by a reconsideration of existing drugs on the basis of their known or putative effects on the retroviral life cycle and/or the tuning of immune mechanisms.[2] Owing to the limitations with which the scientists can predict the efficacy in humans, medicines introduced for one disease state have subsequently been observed to be of value in unrelated diseases.[6] In many instances, however serendipity plays an important role in the identification of such new uses for the old drugs. The accidental discovery of the ability of the antihelminthic drug disulfiram to produce toxic breakdown products during the metabolism of ethanol, led to its use in the treatment of chronic alcoholism. Similarly the anticonvulsant property possessed by potential antipsychotic drug carbamazepine became apparent on administering it to a patient of epilepsy suffering from behavioral pathology.[7] Few examples of additional uses of drugs discovered during clinical usage are shown in [Table 1]. The new uses of the old drugs therefore may provide cost-effective treatment, especially in developing countries with limited resources. In the present review, we are presenting the novel potential uses of drugs (in alphabetical order) that are approved by FDA for important clinical conditions.

Studies have suggested that ACEI [8] and ARB [9] might be useful agents for migraine prophylaxis. A few studies have reported the effectiveness of lisinopril and candesartan cilexetil as prophylactic agents. Although the exact mechanism is unknown, the rationale behind the positive effect of lisinopril in migraine prophylaxis is that it decreases the effect of angiotensin II, which might be causing direct vasoconstriction, increased sympathetic discharge, as well as adrenergic medullary catecholamine release. In addition, by acting at AT<sub>1</sub> receptor in brain, angiotensin-II modulates cerebrovascular flow, electrolyte homeostasis, autonomic pathways, and modulates both potassium channels and calcium activity in cells. Moreover, components of renin angiotensin system are present in peripheral tissues, including the eye, and may play a role in controlling aqueous humor production, retinal blood flow, or retinovascular disease. Angiotensin II receptors of the retinal vasculature may play a major role in the autoregulation of blood supply to the retina and optic nerve head. Topical ACEI has been shown to lower the intra ocular pressure in rabbits, monkeys, and humans. These may act by inhibiting breakdown of bradykinin, by promoting formation of endogenous prostaglandins, and by enhancing uveoscleral flow. Therefore, ACEI might be a useful pharmacological agent in the medical therapy of glaucoma.[10]

Anti-TNF-a (tumor necrosis factor-alpha) in dermatology [11], [12]

Infliximab and etanercept, widely used in the treatment of Crohn's disease and rheumatoid arthritis, was recently shown to be effective in the treatment of psoriasis and psoriatic arthritis. Results of a number of research and clinical studies suggest a role of biological agents that is, etanercept, infliximab (antiTNF-a), anakinra (IL-1 [interleukin] receptor antagonist), huOKT3r1 (Anti-CD3 antibody), and alefacept (interference with the CD2/LFA-3 pathway) in psoriatic arthritis. At present, etanercept has been approved for use in psoriatic arthritis. Etanercept has been reported to be useful in conditions like cicatricial pemphigoid, subcorneal pustular dermatosis, toxic epidermal necrolysis, and concurrent sweet syndrome and erythema nodosum. Anti TNF-a was used to treat diseases like Behcet disease, Sjogren syndrome, synovitis-acne-pustulosis hyperostosis-osteomyelitis syndrome, and ankylosing spondylitis. Hidradenitis suppurativa might be added to the growing list of dermatological diseases that respond to anti TNF-a therapy.