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The first clinical trial of Mesna was conducted in the early 1970s by UBC Pharmaceuticals to test its mucolytic efficacy for bronchial diseases (Figure 4.1). After successful results, it was launched as an inhaled dosage form (Mistabron®_{) in France}

for treatment of respiratory disorders such as cough and chronic bronchitis, especially for children. The free thiol group of Mesna is suggested to disrupt the disulfide bonds between the mucus glycoproteins, rendering the secretion less viscous and more readily able to be eliminated from the respiratory airways (Shaw and Graham, 1987). This suggested that the sulfhydryl group of Mesna is prerequisite for its activity. Intriguingly, it has also been shown that Mesna is a co-enzyme in bacterial methanogenesis and is responsible for methyl transfer (Taylor and Wolfe, 1974).

Figure 4.1 Chemical structure of 2-mercaptoethanesulfonate sodium (Mesna).

S

O

O

O

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In the early 1980s, Brock and colleagues carried out a comprehensive study to identify the causative agent of haemorrhagic cystitis during oxazophosphorine cancer therapy, notably with cyclophosphamide and ifosfamide. They later reported in their seminal paper that the main causative factor was the renal excretion of the two urotoxic metabolites of oxazophosphorine, namely 4-hydroxy-oxazaphosphorines and acrolein (Brock et al., 1981a). The level of GSH in urine is very low which makes the bladder and the efferent urinary ducts vulnerable for these reactive chemicals that are renally excreted. Brock et al. (1981b) then conducted a comparative study using different thiol–containing compounds as potential adjunct therapies to oxazophosphorines without interfering with the anticancer activity. This screening study was the first to report uroprotection by Mesna and showed that Mesna can interact with the urotoxic chemicals, by virtue of the free sulfhydryl group, forming a nontoxic compound. The anticancer activity of oxazophosphorines was not affected by co-administration of Mesna as the latter does not enter most of the body tissues and has a small volume of distribution (Brock et al., 1982). This unique pharmacokinetic profile endorsed the addition of Mesna to the standard regimen of oxazophosphorine therapy which was confirmed by later clinical trials (Brock and Pohl, 1983). Since then, Mesna has revolutionized the use of high doses of oxazophosphorines in cancer therapy by abolishing the main adverse effect (i.e. haemolytic cystitis). Moreover, it has been demonstrated that Mesna can also prevent the chronic nephrotoxicity as well as the acute urotoxicity (Kempf and Ivankovic, 1987). Although it has small volume of distribution, Mesna has also shown potential to mitigate the systemic adverse effects of doxorubicin in vitro (Aluise et al., 2011).

Another form of Mesna-induced uroprotection was first demonstrated by Mashiach et al. (2001) where they reported that Mesna can protect against acute renal failure in

rat through its antioxidant activity. They showed that a bolus dose of Mesna (180 mg kg-1_{, i.v.) 5 minutes before reperfusing ischaemic renal tissue restored 90-100% of}

glomerular filtration rate (GFR) with 75% improvement in the fractional sodium excretion (FENa). Later work by Kabasakal et al. (2004) demonstrated that Mesna

protected the kidney against renal ischaemia/reperfusion injury via enhancing endogenous antioxidant capacity to attenuate the oxidative stress. Similarly, Sener et al. (2004) found that Mesna restored the GSH level and reduce the oxidative stress- induced damage in a rat model of burn-induced renal injury. The antioxidant effect of Mesna has also been tested against other types of ischaemia/reperfusion injury. Ypsilantis et al. (2006) reported that pre-ischaemia Mesna therapy protected the intestinal mucosa against intestinal ischaemia/reperfusion injury in a time-dependant manner. In addition to being directly antioxidant, later work by Ypsilantis’s group (Ypsilantis et al., 2008) showed that Mesna could indirectly inhibit oxidative stress by targeting NF-КB, which is involved in the inflammatory and immune responses, and

inhibiting its activity following intestinal ischaemia/reperfusion. They also reported that a bolus dose of Mesna (400 mg kg-1_{, i.p.) ameliorated the peritoneal puncture-induced}

oxidative stress in other splanchnic organs (stomach, liver, and kidney) in a rat model (Ypsilantis et al., 2009b). The protective effect of Mesna was also investigated against hepatic ischaemia/reperfusion injury. Sener and colleagues (Sener et al., 2005b) showed that administration of two bolus doses of Mesna (150 mg kg-1_{, i.p.), one before}

ischaemia and the other at reperfusion, can improve hepatic function and structure by reducing the tissue damage in a rat model of hepatic ischaemia/reperfusion mediated via its antioxidant action. Later work by Ypsilantis’s group (2009a) reported that Mesna also protected the liver against the anti-mitotic effect of Pringle-manoeuvre, inducing hepatic ischaemia by interrupting the blood flow through the hepatic artery

and the portal vein, by suppressing the activity of NF-КB and scavenging of generated

ROS. Interestingly, the protective effects of Mesna have also been shown in other pathologies. For instant, Shusterman et al. (2003) demonstrated that intrarectal administration of Mesna was protective against trinitrobenzene sulfonic acid-induced colitis in rat.

To our best knowledge, the first work investigating the potential cardioprotective action of Mesna against myocardial ischaemia/reperfusion injury was carried out in our laboratory in 2009, by David Elsey (Elsey, 2009). Elsey was exploring the cardioprotective properties of hydrogen sulfide (H2S). As a part of his PhD work,

Mesna was selected for comparison as an alternative sulfhydryl-containing compound and potentially a donor of H2S. He reported a significant reduction in infarct size when

Mesna (50 µM) was perfused through the heart either pre-ischaemically or at reperfusion in an isolated buffer-perfused rat heart preparation. Further mechanistic study revealed that the cardioprotection established by Mesna was abrogated in the presence of the PI3K inhibitor, LY294002, suggesting that Mesna’s cardioprotection might be mediated by triggering the RISK pathway.

In view of the significant contribution of oxidant stress to the development of lethal reperfusion injury and the preceding evidence suggesting that Mesna ameliorates oxidant stress, we sought to characterise the potential protective effect of Mesna as an adjunct to reperfusion against myocardial ischaemia/reperfusion injury in vivo. These studies are important because Mesna represents a drug with potential to be repurposed for clinical use as an adjunct to PPCI.