Chloroquine has a quick onset of action, it is cheap with tolerable adverse effects and very efficacious. Since its synthesis in 1940s, it has been the first line of drug. The emergence of chloroquine resistance, and a world-wide scarcity of quinine, has resulted in a search for newer antimalarial drugs. Resistance began in the 1960s and by 1979, 43 different chemical compounds and 4 combinations were selected for clinical trials (WHO 1973. Cited by Black et al 1981). A perfect replacement for chloroquine must have all the qualities of chloroquine and if possible more. Artemisinin is the only compound that has come top of the list in terms of efficacy, low toxicity, resistance, cost, rapidly acting and first order pharmarcokinetics.
 
 

Artemisinin is the most rapid-acting class of antimalarial drugs for both uncomplicated and severe malaria. It acts against the asexual stages, gametocytes and blocks sporogony (heppner and Ballou 1998), that is it acts at all sites on the life cycle (fig 6). At the moment, mefloquine (Larium) so far is the first in line, in terms of effectiveness. In a study in West African at the camp of US Peace Corps volunteers, mefloquine was compared with chloroquine alone and chloroquine + proguanil for prophylaxis (Lobel et at 1993). A weekly regimen of mefloquine was found to be 56 % more effective than chloroquine and 37 % than chloroquine combined with proguanil. Karbwang et al 1992, found that in patients with a uncomplicated P. falciparum, artemether gave a 97 % cure rate (mean parasite clearance = 34) at day 28 compared to mefloquine with 73 % (mean parasite clearance = 64) p value = 0.00006.
Mefloquine was also found to be better than sulfadoxine- pyrimethamine, but not as good as Artemisinin with100% cure as to 43 % mefloquine and14 % with sulfadoxine- pyrimethamine in Nigerian children with severe, non-cerebral P. falciparum malaria (Sowunmi and Oduola 1998). In another study (Sowunmi and Oduola 1998), Artemether shows greater therapeutic effectiveness than sulfadoxine- pyrimethamine (table 2).
 
 

Adverse reaction of drugs involves damage of cellular constituents (proteins, membrane lipid or DNA) resulting from covalent reactions with reactive metabolite of the parent compound or the parent compound itself. Of’ course, all drugs are associated with some adverse reactions (Davis T. M. E. 1997). Chloroquine toxicity is said to be few and mild at the low doses used in malaria (Sisooya et al 1998). Most serious side effect for chloroquine is cardiovascular toxicity. Quinine (Davis T. M. E. 1997) has high incidence of unwanted effects, its use is limited by poor compliance and usually used in the hospitals under supervision. Sulfadoxine- pyrimethamine causes serious blood discrasias and if given iron supplement, the efficacy of the drug is reduced (Nwanyanwu et al 1996). Halofantrine has a narrow therapeutic index. 72 mg/Kg caused a dose-related lengthening of the PR and QT intervals in all 61 patients treated in an experiment (Noste et al.1993). Relatively, 25 mg/Kg in the same trials did not have that effect. Its variable absorption pattern makes it even more dangerous for used. It is a teratogen in rats at 30 mg/Kg, therefore contraindicated in pregnant women. Also there is a recrudescence if used in short term only. Mefloquine has neuropsychiatric side effects and is contraindicated in patients with history of psychiatric disorder (Hellgren et al 1997). Other side effects experienced in table 3 were shown to be significantly higher than for Artemether except for bradycardia. This was in a randomised clinical study of 46 patients in Bangkok with P. falciparum malaria. Total doses over 5 days for mefloquine was 1250 mg and for Artemether, 700 mg. Artemisinin is relatively the safest antimalarial in terms of toxicity. Ten years of clinical trials in China and Thailand has not noted any serious adverse reactions. Tests in rodents have shown a brain stem toxicity, which is now being debated. Risks of convulsion in children after treatment from cerebral malaria has been observed too. This may be due to the dosing procedure, or other complication involved in cerebral malaria which Artemisinin formulation has not taken into consideration. Also the derivatives are semi-synthetics, and these need further investigation as to their total safety.
 
 

Chloroquine has been the mainstream of malaria chemotherapy for nearly 60 years, but widespread resistance now limits its usefulness. Resistance began in the early 1960s. Resistance increases the prevalence of P. falciparum gametocytes and infectivity to anopheles mosquito (Koella. J.C.1998). Resistance is either from a recrudescence or recurrences. Recrudescence is a short-term relapse due to surviving erythrocytic parasites. Recurrence is a long-term relapse, due to hypnozoites of P. vivax. Bearing in mind that sometimes, it is difficult to determined relapses from re-infections. Resistance is classified as:

Mechanisms of chloroquine resistance have a few hypotheses. Increase metabolism of the drug, decrease uptake, efflux of the drug from parasitic vesicles. Increased in metabolism is due to increased parasite’s metabolising enzymes, an isoenzyme of the cytochrome P-450 that includes aryl hydrocarbon hydroxylases. Resistant parasites have the genetic ability to initiates these induction (Salganik et al., cited by Ward S.A. 1988). Rapid drug efflux has been designated to two genes; pfmdr 1 and pfmdr 2. The second hypothesis put forward for parasite resistivity to drugs, is the ferriprotoporphyrin (haem) metabolism. Since chloroquine and some other few drugs are said to inhibit the breakdown of toxic haem to non-toxic haemozin (red pigment of malaria) by the parasite enzyme, haem polymerase, thereby allowing the build up of haem in the parasite’s food vacuole, which kills it. Mutant plasmodia are able to metabolised haem by an alternative pathway in the presence of chloroquine. Resistance to chloroquine took years to developed, whereas for the others it was almost instant. Apart from the folate antagonists, all the ‘classic’ anti-malarials adopts the Quinoline moeity, which is recognisable by the mutant plasmodium.

Quinoline moeity

However, There is a suggestion that different mechanisms for drug resistance exist for chloroquine, mefloquine, and quinine (Zalis et al 1998). Resistance to proguanil (Hoskins et al 1998) and pyrimethamine was instant (Duraisingh et al. 1998) and also Sulfadoxine-pyrimethamine (Karbwang et al 1992, Basco et al1998) with RI RII RIII- 3/7 patients (Sowunmi and Oduola 1998). In S. E. Asia, multi-drug resistance means the loss of therapeutics; chloroquine, sulfadoxine-pyrimethamine (fansidar), mefloquine, quinine. However, these still have operational efficacy elsewhere.

WHO envisage that for the Rl and Rll resistance, a slight increase in the dose of the drug can bring efficacy from 1 % to 99% and all the parasites may be killed at doses well within the tolerated dose (Black et al 1981). Other efforts to revive chloroquine sensitivity have been tried too. Calcium ion blockers verapamil (L-type) are thought to be reversants of the drug resistance of malarial parasites (Solomone and Godfraid 1990). Allopurinol is a suggested additive to quinine to bring about faster eradication of Plasmodium falciparum and clinical remission than with quinine alone (Sarma et al 1998).

In view of resistance to chloroquine, epidemic is set to keep on rising, especially in South East Asia and New Guinea where resistance of P. vivax to primaquine is already widespread. To stop these rise and disease transmission, Artemisinin derivatives should be used along with primaquine or WR 238605 for a radical cure (Heppner and Ballou 1998).
 
 

Malaria is the leading cause of disease in most parts of the world. The consequences of the disease are further compounded by extremely low living conditions in some of these poorest nations. Amodiaquine is still being used to treat uncomplicated chloroquine-resistant P. falciparum malaria in Sub-Saharan Africa, for the sole reason of its cost (Heppner and Ballou 1998), since its use is no more recommended due to its sides effects (agranulocytosis and hepatic toxicity). Raw materials accounts for only about 10 % of the retail price of a brand name anti-malarial. Brand names cost 6 times more than ordinary unlabelled drugs. Malarone (Atovaquone-proguanil) was too expensive and incidentally GlaxoWellcome donated it to Asia, South America and Africa for a year (Ridley & Hudson 1998). Halofantrine, Mefloquine, Quinine, Sulfadoxin / Pyrimethamine, Chloroquine Order of cost of drugs. It is not yet established where in this table, Artemisinin stands. It is easy to envisage that if the drug is taken as infusion of the wild dried leaves (fig. 7), then certainly at the bottom of the table. Big pharmaceutical company’s large-scale production might leave its cost souring high. Purification process is expensive, cultivation too, with a yield of about 15 Kg/hectare. It is reckoned that not all species of the plant contains the active ingredient, for example the one found in the UK.
 
 

Various drug combinations have been made in malarial chemotherapy. Combined drugs act in synergism and potentiate the action of one another. Sulfadoxine-pyrimethamine was effective, low-cost, but there is resistance to it now and also too toxic (Nwanyanwu et al 1996). The combination of chloroquine plus promethazine (1 x 10(-6) M) reversed chloroquine resistance in standard P. falciparum clones and patients' parasites isolates from Nigeria. Atovaquone-quinone inhibits mitochodrial electron transport processes and is effective for resistant P. falciparum, but recrudescence happens. Atovaquone-proguanil (malarone) is effective orally for treatment and for prophylaxis. A 3-day course gives 100 % for multi-drug resistant malaria, though causes vomiting. Long term safety of these huge chemically combinations are worrying. The rationale that if individual drugs have so much side effects, combining them might have a devastating consequences. Still, all of these drug combinations must have been through rigorous testing before being granted a market licence.
Nowadays the popular combinations are with Artemisinin derivatives. Laveran conference (1998) in Annecy, France, an expert in malaria panel talked about combination of Artemisinin derivatives to retard the emergence of resistance, enhance efficacy and reduced the duration of treatment. Artesunate plus mefloquine or benflumetol is claimed to give 94% cure. May be the rush for its combination should be halted and proper treatment regimens of its monotherapy be negotiated instead.
 
 

There are now few efforts to develop new antimalarial compounds by the major pharmaceutical companies and new substances are scarce. Some promising new therapeutics have been developed and tested clinically by small groups and companies throughout the world. Pyronaridine was first developed in China. In mice studies, ED50 (mg/Kg) was found to be 6.8 + 1.4 compared to chloroquine, 45.6 + 6.3 after oral administration. Its therapeutic index, 201.2 was also found to be far greater than chloroquine' s, 14.5(Fu and Xiao 1991). Pyronaridine was concluded to be very effective in P. vivax and P. falciparum malaria and well tolerated. In another randomized, unblinded study, the safety, tolerance, and clinical efficacy of pyronaridine in Cameroonian children with acute uncomplicated falciparum malaria was established (Ringwald et al 1998). It is highly efficacious in Africa, where chloroquine resistance is well established. Pyronaridine is also found to treat P. ovale and P. malariae in 4 days. Limitations here is the lack of established pharmacokinetic and problem with recrudescence. Pyronaridine adopts the quinine moiety and so resistance to it will become inevitable. The biggest issue was that the pharmaceutical giants were not interested and it is too expensive.
Etaquine (WR238605) is an experimental agent developed at the Walter Reed Army Institute of Research, USA. It is a long acting primaquine analogue. Affects all stages of the parasitic life cycle to prevent relapse, efficacy is 90 % and it is safe with G-6-PD. Allopurinol causes virtually complete inhibition of purine biosynthesis of malaria parasites, which may prove lethal to the parasites

 In areas of high infection, primary Health care is usually lacking, familiarity of symptoms and self-diagnosis is quiet common. Anti-malarials are usually purchase in the open market where there is little or no control. Cost is taken into account when purchasing these drugs. A survey in Zaire indicated that 92 % of children presented at a hospital emergency ward had detectable levels of chloroquine or quinine in their blood at the time they were seen by a health worker (WHO 1990). Risks of toxicity this way is high, mainly from over dose, but also misused. Since education is poor or insufficient, knowledge of adverse effects or risk assessment and determination of any contraindications can not be made. A safe drug is needed, one that would be safe even at very high doses. Chemoprophylaxis has its problems too. Compliance is the biggest one, logistics of impairment of acquisition of immunity and adverse reactions

Most serious side effect for chloroquine is cardiovascular toxicity, otherwise it is of low toxicity. It has a rapid on set, efficient disposition and most importantly, low expense, which made it accessible to Third World countries where malaria is endemic (Ward .S. A. 1988). It has outlived its usefulness and now has to be replaced by the new competent Artemisinin. Artemisinin is a new era in malaria chemotherapy. To overcome the malaria challenge, there is a need for concentrated efforts by the health services, the private sector, and the communities, both locally and internationally and use Artemisinin and derivatives and mosquito control.