‘Old Drugs for New Applications’ : Can Orthopedic Research Benefit from This Strategy?

Abstract

New drug exploration is difficult in a clinical setting and the development of new drugs may be costly and time consuming. With further research into the pathological mechanisms and etiology of diseases as well as the rapid development of biological techniques, many ‘old drugs’ that have been applied in clinics may have new therapeutic functions which may shed light on clinical management. Based on this, we have investigated the ‘old drugs for new applications’ strategy in pharmacology which may be less expensive and more efficient in the clinical setting. In this paper we have explored and illustrated the potential applications of ‘old drugs’ for the treatment of orthopedic diseases, especially in arthritis and osteoporosis therapy.

Introduction

It has been reported that to introduce a new drug to the market can cost an average of US$897 million and can also be a very time-consuming process (it may take more than 15 years before a drug receives approval) [Dickson and Gagnon, 2004]. Moreover, some newly discovered drugs in developmental stage are unable to receive US Food and Drug Administration (FDA) approval due to undesirable adverse reactions or even toxicity. Therefore, it is often helpful to explore new indications for already-existing drugs with known adverse drug reactions, an approach that is commonly called ‘old drugs for new applications’.

Many orthopedic diseases such as rheumatoid arthritis (RA), osteoporosis, etc., have become endemic with the trend of an aging population, and the treatment of these diseases can entail enormous expense. The discovery of cheap and efficient drugs is the ultimate goal of pharmacologists and clinicians. With this in mind, it is reasonable to believe that the ‘old drugs for new applications’ strategy will decrease the therapeutic cost for patients and may herald a new era for drug research and development.

The current status of ‘old drugs for new applications’

The ‘old drugs for new applications’ is not an uncommon strategy. A well known application is that of aspirin, a typical nonsteroidal anti-inflammatory drug (NSAID) used to relieve pain and reduce inflammation [Yasuda et al. 2008]. Several studies have also shown a cardioprotective effect and, consequently, aspirin is now widely used in the prophylaxis and management of cardiac diseases [Sciulli et al. 2006; Howard and Delafontaine, 2004]. In addition, an anticancer effect has also been found and studies have shown that even at a 75 mg/day dose, aspirin may reduce colorectal cancer risk after a lag of a year or so [Benamouzig and Uzzan, 2010; Yeomans, 2010]. The application of phosphoantigens for the potential therapy of flu is another classical example which has been investigated by Qin and colleagues [Qin et al. 2009]. Phosphoantigens have been successfully used for decades to treat osteoporosis. However, new properties have been discovered recently. Phosphoantigens can also enhance the function and increase the number of γδ T cells (gamma delta T cells) in the body thus boosting the immune response to influenza and limiting viral production. Another example of ‘new uses for old drugs’ is offered by the antihypertensive drugs, angiotension-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) which have also been found to be useful agents for migraine prophylaxis [Tronvik et al. 2003; Schrader et al. 2001]. Many other clinical examples can be found to support the ‘old drugs for new applications’ strategy.

‘Old drugs’ for the treatment of orthopedic diseases

Focusing on research into the pathological mechanism of orthopedic diseases, new indications and therapeutic roles can be found in ‘old drugs’. RA and osteoporosis will be exemplified and illustrated in detail in this paper.

RA is an autoimmune disease where the immune system attacks the lining of body's joints, which may cause swelling, stiffness, pain and can eventually damage bones, tendons and cartilage, causing deformities and limiting motion [Lindstrom and Robinson, 2010]. Inflammation plays a crucial role in the pathological process of RA and the majority of available drugs were designed to block the inflammatory process. NSAIDs and disease-modifying antirheumatic drugs (DMARDs) are commonly used and widely accepted by rheumatologists and orthopedic surgeons as the gold standard prescription in clinics [Salt and Frazier, 2010]. Since none of the available drugs can cure this disease completely, the exploration of new drugs is needed.

Cholinergic receptor agonists, such as GTS-21 (DMXB-A), that have been used for the treatment of neurological disorders [Olincy et al. 2006; Martin et al. 2004; Kem, 2000] may offer a therapeutic potential in the treatment of RA. This is as a result of the newly discovered cholinergic anti-inflammatory and antinociceptive pathway. GTS-21 acts as a partial agonist of neural nicotinic acetylcholine receptors which may bind to both the α₄β₂ and α₇ subtypes [Meyer et al. 1997]. If we consider the role of the cholinergic receptor in the pathogenesis of RA [van Maanen et al. 2009] and the cholinergic anti-inflammatory pathway (first reported by Tracey [Tracey, 2002]), GTS-21 may have a role as a potential RA therapeutic agent. The cholinergic anti-inflammatory pathway indicates that the α₇ nicotinic acetylcholine receptor (α₇nAChR) represents the molecular dovetail between the cholinergic nervous system and the innate immune system [Wang et al. 2003]. The receptor is mainly expressed on the membrane of immune cells, including monocytes, macrophages, T and B lymphocytes, and dendritic cells [Bendixen et al. 2001]. The activation of α₇ nAChR inhibits, the production of pro-inflammatory cytokines (tumor necrosis factor alpha [TNF-α], interleukin [IL]-1, and IL-18) rather than anti-inflammatory cytokines [Borovikova et al. 2000]. This is due mainly to the activation of JaK₂-STAT₃ signaling transduction pathway and to the inhibition of NF-κB pathway [Altavilla et al. 2006; de Jonge et al. 2005]. In addition to the anti-inflammatory effect, an antinociceptive function of nAChRs was also found [Rowley et al. 2010], which may relieve pain in RA patents. Therefore, the potential application of cholinergic receptor agonists (GTS-21, etc.), which are already used by neurologist for the treatment of diseases such as Alzheimer's [Gu et al. 2009], for the treatment of RA [Pan et al. 2010a, 2010b] seems promising (Figure 1) for the treatment of RA [Pan et al.2010a, 2010b].

Figure 1.

The diagrammatic illustration of the pathological process of rheumatoid arthritis and the potential application of cholinergic receptor agonists.

The potential role of statins for the treatment of osteoporosis is another good example worth mentioning. Statins are specific inhibitors of 3-hydroxy-3methyl-glutaryl coenzyme A (HMG-CoA) reductase and are some of the most used drugs in the treatment of atherosclerosis and other cardiovascular conditions [Pedersen et al. 1996]. Recent in vitro research has indicated an anabolic effect of these drugs on bone [Yazawa et al. 2005]. Moreover, simvastatin was found to enhance bone formation through induction of BMP-2 and alkaline phosphatase and by the accumulation of bone matrix proteins [Maeda et al. 2001]. The anabolic effect of statins on bone has also been supported by in vivo studies. Oral administration of simvastatin was found to increase the trabecular bone volume and bone formation rate with a concomitant decrease in osteoclast numbers in ovariectomized rats, as well as in rats with intact ovaries, which also minimized the ovariectomy-induced reduction in cancellous bone volume [Oxlund and Andreassen, 2004; Oxlund et al. 2001]. Due to to their liver specificity and very poor distribution to the periphery, the probability of statins reaching the bone microenvironment is very low [Mundy, 2001]. Therefore, it is extremely important to evaluate the potential skeletal effect of statins. Much preliminary research has been done regarding this issue. In vivo studies have indicated that dermal application of statins in rats, compared with oral gavage administration, may have a greater effect in increasing the bone formation and plasma concentration [Gutierrez et al. 2006]. With the recent advances of polymer science, various biocompatible polymers have been developed which are widely used as a novel drug-delivery systems. The controlled delivery of simvastatin, to provide an example, showed a significant effect on bone formation [Thylin et al. 2002]. In addition to the aforementioned, other interestin drug cases can be mentioned in the orthopaedic settings. Erythromycin, which has been used as an antibiotic, has also been used to treat aseptic loosening and osteolysis in animal models [Ren et al. 2006] and most recently in patients [Ren et al. 2009; Zhang and Qin].

How to perform the ‘old drugs for new applications’ strategy?

There are still several challenges to overcome to predict or identify new potential uses of ‘old drugs’. Often serendipity plays an important role in this process.

The discovery of sildenafil citrate (Viagra) is a typical example. Viagra was initially studied for its role in hypertension and angina pectoris. The results of phase I clinical trials showed only a little effect on angina but instead, it was observed a marked induction of penile erection [Boolell et al. 1996]. Based on this discovery, Viagra was patented in 1996 and approved for use in erectile dysfunction by the FDA on 27 March 1998. It soon became a great success. This example clearly shows how the investigation of side effects may lead to the discovery of alternative new treatment indications. However, although serendipity has an important role in research, other approaches are needed to explore new properties and uses from existing old drugs. This strategy can be very convenient as often, when a new indication is discovered, the drug has already undergone preclinical and clinical testing.

Keiser and colleagues' research have shed light on this important issue [Keiser et al. 2009]. Their research was based on the criteria that if a drug and a ligand have similar three-dimensional structures, then there is a good chance that the drug will bind to the same protein as the ligand. Thousands new targets for existing drugs could be identified using computer-aided molecular modelling programs by screening and comparing molecular structures of endogenous compounds with those of existing drugs.

The ‘old drugs for new applications’ strategy can be divided into two stages. In the first stage, serendipity plays an important role and depends on the careful observation of researchers which may find new therapeutic indications from the side effect of the drugs. The use of modern tools and techniques is also important. As we have mentioned above, Keiser and colleagues' research should be further investigated and represents a very promising tool for the investigation of new indications for old drugs.

Future prospects

The ‘old drugs for new applications’ strategy may provide cost-effective treatments especially in developing countries with limited resources and funding. In addition, as the drug has often already undergone preclinical and clinical testing this strategy will greatly reduce the cost of drugs in clinics and more patients will benefit.