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12.1 Introduction

Chemotherapy remains one of the most important tools for the management and control of malaria. However, the rapid selection of malaria parasite resistant to antimalarial drugs can hamper this strategy. To slow the pace of selection of resistance, the World Health Organization has recommended the use of artemisinin combination therapies (ACTs) as first-line treatments of uncomplicated malaria [1]. In Africa, the combinations of lumefantrine/artemether (Coartem®) and amodiaquine/artesunate are currently the two main ACTs used to treat uncomplicated malaria [1–4]. However, recent reports indicate that resistance to artemisinin is emerging in South East Asia, and thus there is concern that this resistance could spread to Africa [5], a scenario which will not only render the current ACTs ineffective, but will also compromise the efficacy of pyronaridine/artesunate and piperaquine/dihydroartemisinin, the two next ACTs that are now in phase III/IV clinical development [6]. Intravenous artesunate has recently become the drug of choice in the treatment of severe malaria [7]. Unfortunately, the spread of artemisinin resistance will also affect the management of severe malaria. Thus, to counterbalance this burgeoning drug resistance problem, new drugs are urgently needed.

One of the strategies to discover new drugs is to reposition, repurpose or find new uses for drugs that have already been used for other indications. This approach, which has the advantage of reducing the cost and shortening the time of drug development, has become an important area of research by the pharmaceutical industry [8, 9]. For instance, in 2004, almost 40% of drugs registered by the Food and Drug Administration (FDA) found new uses in the treatment of various conditions in humans [8]. It is interesting to note, among the few available antimalarials, that some of them have been repositioned. For instance, quinine is used to treat muscle cramps [10], and chloroquine (CQ) (preferably hydroxyl-chloroquine) is used for the management of rheumatoid arthritis and systemic lupus erythematosus [11]. Artemisinin is being investigated for the treatment of schistosomiasis and cancer [12–14].

12.2 In Vitro Antimalarial Activities of MTX

Several reports indicate that MTX is potent against Plasmodium falciparum, including those resistant to the antifolate pyrimethamine (PM), which carry the Ileu-164-Leu dhfr codon (dihydrofolate reductase), the mutation associated with higher levels of antifolate resistance, with MTX IC50 < 80 nM (inhibitory concentration that kills 50% of parasitaemia) [15–18], and IC90/99 (inhibitory concentration that kills 90–99% of parasitaemia) falling between 150 and 350 nM. Thus, if such concentration can be achieved in vivo with an acceptable toxicity profile, MTX could potentially become a useful antimalarial drug [18]. However, anticancers are perceived to be toxic, thus not suitable for the malaria treatment. Yet the literature is replete with examples of new uses of anticancers in the treatment of non-neoplastic diseases.

12.3 Anticancer May Be Safe at Low Dose

Most anticancers are used at high dose to block tumour cells, leading to the inhibition of the growth of normal cells. Affected most specifically are cells that multiply actively such as bone marrow cells, e.g. leukocytes; cells of the gastrointestinal mucosa; and hair follicle cells, explaining why bone marrow suppression, mucositis and alopecia (hair loss) are among the most salient side effects of anticancers. However, according to Paracelsus’ Law, it is well known that for any drug (including anticancers), there is always a dose range at which the drug is safe.

Paracelsus’ Law states “Sola dosis facit venenum (only dose makes the poison),” meaning that all substances are poisons, and there are none which are not. The right dose differentiates a poison from a remedy; this principle is also known as the “dose–response effect” [19, 20]. For any drug, there is always a dose range (concentration) that is without any effect, one with a pharmacological effect but with minimal toxicity (or acceptable safety profile) and another with pharmacological and toxic effects. Thus, a molecule becomes a drug if the dose required to treat a complication falls in the second range: pharmacologically active with minimal toxicity. Most drugs used in the treatment of human diseases fall in this group [21].

In this regard, the example of the antimalarial drug chloroquine (CQ) is noteworthy. CQ is used at 10 mg base/kg on days 1 and 2, and 5 mg/kg on day 3 [22]. At this dose, CQ has an acceptable safety profile. However, a dose of 20 mg/kg is considered toxic [22], and fatal cases have been reported from doses as low as 30 mg/kg, only three times higher than the normal dose [23, 24]. This indicates that a slight dose increase shifts CQ’s effect from the second range (acceptable safety profile with a pharmacological effect) to the third (life-threatening toxicity). Thus, CQ has a very low safety margin, and yet it has been used widely and is considered to be one of the safest antimalarials.

12.4 Safety of Low Dose of MTX in Human

MTX is one interesting example that vindicates Paracelsus’ Law. MTX is used at high dose, up to 5,000–12,000 mg/m2 per week (130–300 mg/kg) for several weeks for the treatment of cancer, and this dose can yield serum concentrations >1,000 μM, the concentration range that is associated with MTX life-threatening toxicity [25–27]. On the other hand, a 1,000-fold lower dose of MTX (LD-MTX) [0.1–0.35 mg/kg (7.5–25 mg per adult)] is used once weekly in the treatment of rheumatoid arthritis (RA), and sometimes, for many years. At this dose, MTX is safe and a mainstay in the treatment of RA in the Western world [28]. MTX is also the drug of choice for the treatment of juvenile idiopathic arthritis in children (including infants of less than 1 year old), a common rheumatic disease in the Western world [29].

Worldwide, it is estimated that 0.5–1 million adults and 50,000–100,000 children receive LD-MTX weekly for the treatment of rheumatoid and juvenile idiopathic arthritis, respectively. The drug is now being used in the African population as well, and its safety profile is similar to what has been reported in the Western world [30, 31]. LD-MTX is now considered to be one of the safest drugs used in the treatment of RA, and its safety profile has led to its new repositioning in the treatment of various conditions including multiple sclerosis [32], inflammatory bowel disease [33], urticaria [34], chronic cholestatic disorder [35], Wegener’s granulomatosis [36], primary biliary cirrhosis [36] and systemic lupus erythematosus [37], among others.

12.5 Proof of Concept of MTX as an Antimalarial in Humans

The antimalarial potential of MTX has been established for almost 40 years now. Two relatively small clinical trials, involving seven patients, have demonstrated that doses as low as 2.5 mg/per day for 3–5 days are effective to treat malaria infection in humans (Plasmodium falciparum and/or P. vivax) [38, 39]. However, MTX has not come into widespread use because of concerns over toxicity [40, 41]. At the time of the aforementioned clinical trials (which were in the 1970s), no information was available on the safety of LD-MTX. Indeed, LD-MTX only started to be used for the treatment of arthritis from the 1980s, and before then, it was only used at high doses in cancer treatment, doses associated with toxicity. Thus, its use as an antimalarial was abandoned. At present, we have 30 years’ experience on the safety of LD-MTX in adults and children; thus, this drug could now be reconsidered and evaluated as a potential antimalarial. Unlike its use in immune diseases, in malaria, MTX will not be used on a chronic basis. It will be a “one-off treatment”; as a result, the risk of toxicity should be even lower.

This information on the in vitro activity of MTX, the safety and possible in vivo efficacy of LD-MTX has led us to re-evaluate the potential of MTX as an antimalarial.

12.6 Re-evaluation of the Antimalarial Potential of MTX in Humans

A phase I evaluation of MTX was conducted to assess the safety and pharmacokinetic profile of this drug in healthy adult male Kenyan volunteers [42]. Twenty five adult volunteers were recruited, admitted and received a 5 mg dose of MTX/day/5 days. Pharmacokinetics (PK) blood sampling was carried out at 2, 4, 6, 12 and 24 h following each dose, and patients were followed up to 42 days. The most important known side effects associated with the chronic use of LD-MTX were solicited. These included nausea, vomiting and oral ulcers, among others. The result clearly indicated the absence of drug-associated side effect during the 42-day follow-up [42].

Based on in vitro data, MTX > 350 nM in blood will be required to clear malaria infection in humans [18]. However, PK analysis of the 25 volunteers showed that the achieved maximum concentration (C max) fell between 160 and 200 nM only, and after 6 h, effective concentration (C eff) was < 150 nM. Thus, at a dose of 5 mg/day/5 days, the achieved MTX blood levels would not be high enough to clear malaria infection. This implies that further studies should be carried out to evaluate the dose range that will yield adequate plasma concentrations and still be well tolerated. One of the approaches would be to reduce the days of treatment from 5 to 3 only and increase the dose to 7.5, 10 or 12.5 mg per day. The total dose for each treatment course should, however, remain around 22.5–37 mg, which is close to the range of doses administered weekly in the treatment of inflammatory diseases (7.5–35 mg per adult). Thus, further studies are warranted to explore the antimalarial potential of MTX.

12.7 Other Anticancers with Antimalarial Potency

Our group has also shown that the anticancer antifolates aminopterin, trimetrexate and pemetrexed are potent against P. falciparum, with activity in the nanomolar range (IC50 < 50 nM) ([18] and unpublished work). Since all these anticancers are inhibitors of DHFR enzymes, we hypothesise that other anticancer inhibitors of DHFR, such as edatrexate, talotrexin, pralatrexate and piritrexim [43], would also be active against P. falciparum. In addition, several other anticancers but non-antifolates have proved potent against P. falciparum, and among these are the inhibitors of the microtubulin assembly tubulozole, vinblastine, docetaxel, paclitaxel and dolastatin [44–48]; the DNA cross-linking agent cisplatin [49]; and the proteasome inhibitor Bortezomib [50, 51]. If these drugs were active in vivo at low and safe doses, they could potentially become antimalarials.

12.8 Anticancer Drugs in the Treatment of Non-neoplastic Diseases

The use of MTX in the treatment of non-neoplastic diseases would not be unusual. Indeed, there are many anticancers that are used in the treatment of various complications other than cancer. For instance, cyclophosphamide is used in Behcet’s syndrome, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), nephritic syndrome, systemic lupus erythematosus (SLE), multiple sclerosis and Wegener’s granulomatosis, among others [52, 53]; 6-mercapto-purine is used in Crohn’s disease and ulcerative colitis [54]; thalidomide is becoming an important drug in Behcet’s syndrome, Crohn’s disease and SLE [52, 55]; and vincristine is used in ITP and thrombotic thrombocytopenic purpura [52, 56]. In relation to tropical diseases, the two anticancer agents miltefosine and eflornithine have been repositioned as drugs of choice in the treatment of leishmaniasis and trypanosomiasis, respectively [57, 58]. The common point in all these repositioned drugs is that they are used at doses lower that those used in the treatment of neoplasma; thus, they have better toxicity profiles. Therefore, the use of anticancers could be extended in the treatment of malarial diseases.

12.9 Conclusion

The pharmaceutical industry have now acknowledged the central importance of drug repositioning in the discovery of new active agents, even against diseases for which there are relatively sizeable human and financial resources such as cancer [59]. The rationale is that the large numbers of available drugs should permit, within a shorter time frame and a smaller financial cost, the discovery and development of new uses for drugs. This rationale is in fact more relevant with poverty related diseases such as malaria.

Among drugs that could be repositioned for malaria treatment are anticancer agents. For instance, many anticancers, including MTX, were shown to be potent against malaria parasite several decades ago; however, their perceived toxicity has prevented their development as antimalarials. Yet, as reported by Paracelsus more than 400 years ago, it is “the dose that makes a drug”; this principle has been exploited in the use of several anticancers (including MTX) at low doses in the treatment of various non-neoplastic diseases. This concept could be extended to anticancer bearing antimalarial activity, such as MTX, as discussed in this chapter. Thus, anticancer pharmacopoeia could provide a good platform for the discovery of new antimalarials.