**3. History of antimalarial drug use in vivax malaria**

#### **3.1 Quinine**

Originally extracted from a Peruvian tree bark in South America, quinine was initially named cinchona in 1742 by Linnaeus. In 1820, two French chemists isolated quinine from the cinchona bark and this compound became a treatment of reference for intermittent fever throughout the world [24, 25] until the resistance of *P. falciparum* was first reported in Brazil in 1910 [26]. Quinine is also used for malaria prophylaxis. It was not clear as to whether the resistance rendered complete inefficacy of quinine to cure the falciparum malaria nor that it also occurred in other species, including *P. vivax* but it was evident that quinine was still widely used as the antimalarial mainstay until the second world war when the new antimalarial, chloroquine was introduced. As the advance in parasite biology provide more insight into parasite species diversity in human and other primates, the resistance phenomenon has attracted attention to investigate in animal model but the results were not conclusive [27]. At the end of 1930s, pamaquine, a new compound targeted at *P. vivax* liver stage was introduced, but 20 years later it was replaced by primaquine, a new 8-aminoquinoline compound. Primaquine is also still used until now as anti-hypnozoites for *P. vivax* [28] and malaria prophylactic [29] and anti-gametocyte drug for *P. falciparum* [30].

In response to the resistance to quinine in 1910 [26], scientists across the globe explore to find alternative treatment. Mepacrine was first synthesised in 1931 at Bayer, Germany. The product was one of the first synthetic substitutes for quinine although later superseded by chloroquine. Mepacrine (Atabrine) was used extensively during the second World War by Allied forces fighting in North Africa and the Far East to prevent malaria. This compound is also used for the treatment of giardiasis (an intestinal parasite) and has been researched as an inhibitor of phospholipase A2. Establishment of mepacrine-resistant strain in rodent plasmodia model indicated that the drug interfere with the haemozoin formation as that of quinine-resistant and primaquine-resistant strain [31]. The major breakthrough achieved during this period is the establishment of testing platform to raise drugresistant malarial parasites in rodent model [32].

#### **3.2 Primaquine (8-aminoquinoline)**

Primaquine has long been used for radical cure to prevent relapse of malaria due to *P. vivax* and *P. ovale*. Primaquine kills hypnozoites, the dormant liver stage of the parasite. However, primaquine is known to cause severe haemolysis in patients with G6PD deficiency, a genetic disorder present in approximately 8% of the population in malaria endemic countries [33]. To prevent relapses, the World Health Organisation recommends the co-administration of CQ and standard- (total, 3.5 mg/kg) or high-dose PQ (total, 7.0 mg/kg) distributed over 14 days to patients aged >6 months with normal G6PD activity who are neither pregnant nor breastfeeding [34]. Nevertheless, adherence to such prolonged course in malaria endemic areas is poor and coupled with the fear of G6PD deficiency, prescription of this drug is mostly inadequate. Following reports of primaquine resistance in *P. vivax* in several geographic areas [35–40]. Collins and Jeffrey in1996 conducted a review and concluded that the data on the efficacy of primaquine as an anti relapse remains few and inconclusive. Therefore, the need for a standardised tool to determine primaquine resistance status should be developed [41, 42]. Primaquine is also known to possess blood schizontocidal activity as well as gametocytocidal activity in *P. falciparum.* In the context of anti-relapse activity in *P. vivax*, it is important

#### Plasmodium vivax *and Drug Resistance DOI: http://dx.doi.org/10.5772/intechopen.97320*

to distinguish as to whether the observed recurrent parasite following a radical cure indeed originates from reactivated hypnozoites or recrudescence. Attempts to prescribe safer and shorter dose of primaquine rendered several improvements but dependence on G6PD screening could not be excluded [34]. Review on primaquine use in *P. vivax* concluded that the currently suggested indications in relation to vivax malaria, namely; causal prophylaxis, terminal prophylaxis, and radical cure is still highly effective [43, 44]. With regard to primaquine treatment failure in some areas, the presence of host genetic factors, such as single nucleotide polymorphisms (SNPs) in the gene encoding enzyme involved in primaquine metabolism, CYP2D6, may also be considered before claiming primaquine resistance [45, 46].

A new compound of 8-aminoquinoline class, tafenoquine was introduced following clinical trials in several countries [47, 48]. Despite single dose prescription, tafenoquine did not show any superiority to primaquine [49]. Therefore, development of a novel compound for anti-hypnozoites that does not depend on G6PD status still has to be prioritised.
