Drug repurposing and it’s implications in therapy: An overview

Drug Repurposing is finding new use of an already existing drug. It offers affordable, cheap and faster treatment. Drug repurposing has an additional advantage over new drug development because it lowers drug development costs as toxicity and other measures, including clinical trials, have already gone through them. However, there are few barriers which need to over-come like legal and economic barriers. Alternative drug development strate-gies are now being explored, such as the repurposing of existing drugs used to treat other diseases. This can save a considerable amount of time and money since the pharmacokinetics, pharmacodynamics and safety profiles of these drugs are already established, effectively enabling pre-clinical studies to be bypassed. Awareness and encouragement can promote the flourish-ing of drug repurposing, which holds a great future in the modern medical sector. Improvements in health care and nutrition have caused impressive improvements in life expectancy worldwide. Repurposing is an accelerated drug development path since existing drugs have clinical and pharmacokinetic evidence. New approaches to drug discovery, such as the re-use of patented medicines that are used to cure other diseases, are under debate. This can save significant time and money because these drugs’ pharmacokinetics, pharma-codynamics, and safety profiles are already known, potentially enabling pre-clinical studies to override.


INTRODUCTION
The repurposing (repositioning, therapeutic switching, drug re-tasking or re-pro iling) of medicines is the technique of inding new healing targets for present drugs. Drug re-pro iling has advantages over typical drug development because it reduces the actual price for the medication, as a result of the that they have already undergone tests and clinical trials. Need already been undergone toxicity and alternative tests like clinical trials. The prospect of further marketing and extending the patent life of a drug is one reason behind repositioning drugs. Another aim is to treat rare or neglected diseases; such conditions are typically dif icult to address for inancial reasons, yet some safe and active molecules already produced for other indications may exist.
Drug repositioning is potentially one of the most signi icant tools to enhance our discovery and understanding of new biology. It can be an important research strategy, as many new drugs have high absorption, distribution, metabolism and excretion data, previously passed clinical trial data and postmarketing surveillance data (Ashburn and Thor, 2004;Tobinick, 2009). These are expensive and time-consuming to obtain.

The bene its of drug repositioning
Finding new indications for the existing drugs will bene it patients who will see a potential new therapy sooner. Repositioning is usually done by accident and in a limited manner. Drug repositioning is often studied beyond inancial sense in terms of its patent protection scenarios and potential intrinsic restriction due to off-label use of such products in their new indications.
Often, when repositioning a drug, it is always a good idea to include a new dosage, formulation or route of administration, if medically necessary. These systematic approaches could also be divided into method approaches and experimental approaches, every of that is additional and more obtaining used synergistically.
Discovery of a candidate molecule for a given indication (generation of the hypothesis); mechanical assessment of the drug's effects by pre-clinical models; and ef icacy review in phase II trials are the three steps involved in drug repurposing process.
Drug Repositioning has two pro iles: on target and off-target. In 'off-target', the drugs bind to targets that are not always the ones they were initially designed for. But in reality, the drugs are completely 'on target', binding precisely to what they are capable of binding.

MINOCYCLINE
Minocycline has been in use since 1972, and it is a semi-synthetic tetracycline analogue having broad-spectrum activity against a wide range of gram-positive and gram-negative bacteria. Its clinical applications include susceptible microorganism infections and rheumatoid arthritis (Ochsendorf, 2010).
Many research studies showed its non-antibiotic role, such as anti-in lammatory, antioxidant, anti-apoptotic, neuroprotective, and anti-cancer properties. The signi icant anti-in lammatory and immunomodulatory effects of minocycline in the management of COVID-19 patients can offer potential bene its, especially for its respiratory complications, such as acute respiratory distress syndrome and multiorgan damage. Minocycline prevented the human immunode iciency virus (HIV) induced cytopathic effects in a study conducted by Lemaître et al. (1990). Minocycline reduced HIV replication as well as reactivation in primary human CD4+ T cells in a study by Szeto et al. In this study, anti-HIV effects of minocycline were found to be mediated by the modi ication of cellular environment rather than direct drug-induced antiviral effects (Szeto et al., 2010).

VALPROATE
Valproate (VPA) is widely used as a mood-stabilizing and anti-epileptic agent. Being an inhibitor of histone deacetylases (HDAC), VPA is also modulating epigenetic changes.
VPA can inhibit NF-µB, TNF-α, and IL-6 production in human cells stimulated with lipopolysaccharides in vitro studies (Ichiyama et al., 2000). VPA has also been shown to decrease the expression of nitric oxide, down regulate the macrophage response, and block macrophage migration by inhibiting pro-in lammatory cytokines; pathogen-associated molecular pattern receptors of toll-like receptors, retinoic acid-inducible gene-I, phosphatases; and transcriptional modulators (Suliman et al., 2012;Guo et al., 2007). Differentiation of T cells towards Th2 / M2 instead of Th1 / M1 is possible through VPA, and also a generation of regulatory T cells are stimulated through VPA, thereby reducing the percentage of CD8 + T lymphocytes. In another study conducted on rats by Fukudome et al., haemorrhage-induced acute lung injury (ALI) is prevented by VPA in rats by decreasing the expression of cytokine-induced monocyte chemoattractant protein-1 (Fukudome et al., 2012). In response to sepsis-induced lung injury, VPA administration 6 hours before the in lammatory stimulus inhibited NF-yB activation and neutrophil in iltration in the lungs observed by Ji et al. (2013) in a retrospective study on patients with subarachnoid haemorrhage, 521 patients who received VPA for seizures had reduced incidences of pneumonia and sepsis-related ALI compared to the 1042 patients who received other anticonvulsants. The difference in respiratory failure could be due to the epigenetic mediated anti-in lammatory effects of VPA, postulated by the authors (Liao et al., 2018).

ASPIRIN
For the treatment and prevention of atherosclerotic diseases, aspirin is commonly used. COX-1 and COX-2 are the pharmacological targets of aspirin (Smith et al., 1996). Thromboxane A2 (TXA2) in platelets are produced from COX-1, which promotes platelet aggregation and platelet adherence to tumour cells.
Being a rapidly inducing enzyme during in lammation, COX-2 produces prostaglandin E2 (PGE2) primarily in tumour cells compared to COX-1, and it is suspected that PGE2 plays an essential role in promoting cell proliferation and tumour growth. Aspirin administered at low doses (50-100 mg daily), and high doses (>325 mg daily) selectively irreversibly blocks COX-1 and COX-2, respectively. In 1972, the anti-tumour effect of aspirin was irst reported in a tumour bearing mouse (Gasic et al., 1972;Kolenich et al., 1972), a number of subsequent experimental studies have supported this evidence (Thun et al., 2002). In patients taking aspirin at a low dose, showed a signi icant reduction in cancer risk and cancer-associated death as proven by different clinical trials (Rothwell et al., 2010). COX-1 inhibition is the one crucial mechanism of aspirin in the process of tumour suppression. Besides, PGE2 was upregulated in colon cancer (Pugh and Thomas, 1994) and angiogenesis (Shao et al., 2005). PGE2 was signi icantly suppressed in human colons when aspirin was administered even at a low dose (81 mg daily) (Ruf in et al., 1997). In the anti-tumour activity of aspirin, suppression of PGE2 might also be an essential factor.

CHLOROQUINE
To prevent or to treat malarial infections, 4aminoquinoline agent Chloroquine (CQ) have been used, and later it is used for treating discoid and systemic lupus erythematosus and rheumatoid arthritis (Ben-Zvi et al., 2012). The dosage of chloroquine mainly depends on the indication. Chloroquine is often marketed as chloroquine phosphate in tablets of 250 mg, which corresponds to about 150 mg of chloroquine. The usual dose for long-term use (rheumatoid arthritis and lupus) is 250 mg of chloroquine phosphate per day (Olson and Lindsley, 1989).
Bene icial effects of chloroquine administration in cancer are found when beginning with in vivo studies. In response to chloroquine administration, delayed tumour growth in mice with an epidermal growth factor receptor (EGFR) over expressing glioblastoma xenografts was observed by Jutten et al. (2013). These similar indings were reported in another study by Kim et al. (2010) in which xenograft glioblastoma mouse, where chloroquine was injected intracraneously. Substantial reduction in the number of mitotic cells and an increase in apoptotic cells after administration of chloroquine were found in their study (Kim et al., 2010). Besides, in mice bearing liver cancer stem cells, a signi icant reduction of tumour volume and tumour incidence was shown by Song et al. (2013) and signi icant tumour growth and weight reduction in an orthotopic xenograft model of liver cancer after chloroquine administration were observed by Hu et al. (2016). Chloroquine signi icantly reduced both tumour volume and tumour mass in a human melanoma xenograft model study conducted by Lakhter et al. (2013). Jiang et al. (2010) showed that doses of 25 and 50 mg/kg of chloroquine both signi icantly improved survival time and decreased primary tumour vol-ume in mice with a strongly metastasizing breast cancer cell line (Jiang et al., 2010).

METFORMIN
Metformin, the biguanide antidiabetic drug typically prescribed for type 2 diabetes (T2D) Metformin (N, N-dimethyl biguanide) is derived initially from galegine (isoamyleneguanidine), a guanidine derivative found in the French lilac Galegaof icinalis (Bailey, 2017). By increasing peripheral glucose absorption and reducing basal and postprandial glucose, it decreases hepatic gluconeogenesis and improves insulin sensitivity (Zhou et al., 2007). Metformin is orally delivered and has a bioavailability of 40-60 per cent. Metformin is distributed systemically within 6 hours of absorption, which occurs primarily in the upper small intestine, following a single oral dose of 0.5 g, with limited absorption in the large intestine (Graham et al., 2011).

METFORMIN AND CANCER
Cancer is the number one cause of morbidity and death worldwide. A recent lifespan risk assessment by the British population showed, at some point in their lifetime, more than 50 per cent of adults under the age of 65 will be diagnosed with the disease (Ahmad et al., 2015). Various studies show that metformin can change the in lammatory pathways which are known to play a role in the development of cancer. It was stated that metformin blocks the transcription factor nuclear factor activity, which results in reduced pro-in lammatory cytokine secretion by the senescent cells (Moiseeva et al., 2013). A recent mouse model study showed that metformin protects CD8 + lymphocytes that invade the tumour from apoptosis and functional exhaustion (Eikawa et al., 2015). Metformin has been demonstrated to enhance the ef icacy of an experimental anti-cancer vaccine by enabling T-cell survival in memory, also a promising one (Pearce et al., 2009). The ability of metformin to prevent complex I and prevent oxidative phosphorylation has recently been emphasized as a signi icant prerequisite for inhibiting tumorigenesis. Metformin reduces the intermediate cycle of tricarboxylic acids suggesting impaired complex I activity in a metabolomic study of a neoplastictransformed breast epithelial cell line and thus highlights the fact that this enzyme is a primary target.

NELFINAVIR
Nel inavir is used to treat patients with HIV infection in conjunction with other antiretroviral medicines (Moyle et al., 1998). In 1997 it received approval from the US-FDA for an oral dosage scheme of 750 mg three times a day. It was later changed to a twice-daily 1250 mg. All regimens have been proved equally effective (Marzolini et al., 2001).
Nel inavir peak plasma level is around 8 µM, and it is established that the bioavailability is increased when taken with food (Bardsley-Elliot and Plosker, 2000). Since the early 2000s, researchers have been seeking possible anti-cancer activity of nel inavir. The growths of Kaposi's sarcoma (Sgadari et al., 2003), multiple myeloma (Ikezoe et al., 2004), prostate cancer (Yang et al., 2005), and breast cancer (Brüning et al., 2010;Shim et al., 2012) were con irmed to be inhibiting by nel inavir. Nel inavir exhibited wide-spectrum anti-cancer activity in vivo, being successful in several models of preclinical cancer.
Insulin resistance was a common side effect of nelinavir. (Brunner et al., 2008) have recently conducted a Phase I clinical trial of nel inavir and chemoradiation for locally advanced pancreatic cancer (Brunner et al., 2008). In this trial, during patients with pancreatic cancer, nel inavir demonstrated potent radiosensitizing and anti-tumour activities without adding toxicity.

NITROXOLINE
Nitroxoline, an old antibiotic commonly used since the 1960s in countries like Europe, Asia and Africa for treating urinary tract infections (UTI). Nitroxoline is quickly absorbed into the plasma when injected orally and eventually excreted into urine (Mrhar et al., 1979). Due to its ability to chelate divalent metal ions such as Mg2+ and Mn2+ is the possible mechanism of nitroxoline antibacterial activity (Pelletier et al., 1995).
Anti-cancer activity of nitroxoline is initially reported in 2010. Many recent studies have also been supporting nitroxoline's anti-cancer role.
A study conducted by Jiang et al. (2011) showed the anti-cancer activity of nitroxoline against lymphoma, leukaemia, pancreatic cancer and ovarian cancer cells (Jiang et al., 2011). Nitroxoline has been used as a UTI medication in several European countries for over 50 years, and no signi icant human toxicity has been recorded, making the drug an excellent candidate for repositioning of anti-cancer treatment.

CONCLUSION
Drug repositioning may be described as a process for inding and discovering new therapeutic uses for already approved drugs, outside the scope of the original pharmacological indication. Time and expense associated with drug development processes can be substantially reduced through drug repositioning. There are still lots of challenges following Phase II trials. Phase III studies include a signi icantly larger number of patients compared with Phase I and Phase II studies. Because of the size and relatively long duration, Phase III studies are the most expensive and time-consuming trials, and those hurdles have not changed over the years in Phase III studies. Intellectual property (IP) protection of repositioned drugs is another challenge that should be considered for drug repositioning. Especially for those drugs that are off patents. Both pharmaceutical and biotech companies have recognized the advantages of repositioning, and activity in the area has increased dramatically.

ACKNOWLEDGEMENT
No inancial support for this study.

Con lict of interest
Authors declare that there is no con lict of interests in this study.

Statement of human and animal rights
This article does not contain any studies with human or animal subjects performed by any of the authors.