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Malaria is a vector borne disease which is responsible for approximately 400 thousand deaths world wide annually, resulting in an enormous public health burden on many of the tropical and subtropical countries. In the last Century, during colonization of Africa, malaria was dreadful disease which affected the life of inhabitants of Africa. It was observation by inhabitants and colonizers that the water from a big pond had curative properties of malaria. They took a sample of water to Germany to chemically analyze the content of water. They found it was Quinine, an alkaloid from Cinchona tree, which had fallen into the pond accidentally has leached Quinine in the pond water. After establishing the chemical structure of Quinine, there was no delay in making antimalarial drugs like chloroquine and many more. Now, it is well understood that malaria is caused by a single-celled parasite of the genus plasmodium. There are mainly five varieties of plasmodium that causes malaria in human being.
The plasmodium causing malaria are P. Falsipuram , P. vivax, P. Malariae, P. ovule and P. knowelsi. The parasite is transmitted to humankind through mosquito bites.
Malaria is an infectious, hematologic disease causing death and illness in children and adults, especially in tropical countries. Malaria control requires an integrated approach, including prevention, primarily (mosquito) vector control, and prompt treatment with effective antimalarial drugs. Malaria even today is among the most devastating and wide spread tropical parasitic diseases in most of the developing countries. Malaria is caused by the plasmodium parasite, which is transmitted by the bite of a mosquito vector. The parasite P. falciparum causes the most dangerous, with the highest rates of complications and death. Antimalarial drug resistance results in a global resurgence of malaria making a major threat to malaria control.
Widespread and indiscriminate use of antimalarial drugs contributes to malaria parasites to evolve mechanisms of resistance. The malaria life cycle is very complex which requires two organisms as host, mosquito, and human being. The most common symptoms of malaria (chills, high fever, sweating, malaise, headache, and muscle aches). Symptoms usually manifest one to four weeks after infection which depends on type of plasmodium. In relapsing cases plasmodium parasites may live in humans for five to eight years, but these signs and symptoms may also have seen in other diseases.
Malaria can be confirmed by diagnostic tools for identification of plasmodium species in blood samples of humans. They are microscopy (light or fluorescence) which is considered as gold standard method. The other methods available are immunochromatographic lateral flow assays which is also known as rapid diagnostic tests (RDT). In addition to it, serology based, nucleic acid amplification techniques (NATs) that include polymerase chain reaction (PCR) and isothermal amplification are also available for diagnostics of malaria.
Therapeutic agents available for treatment of malaria disease are broadly classified into three classes. The Aryl amino alcohol compounds including quinine, quinidine, halofantrine, lumefantrine, chloroquine, amodiaquine, mefloquine, cycloquine, etc.
Antifolate compounds are proguanil, pyrimethamine, trimethoprim, etc. Third category includes Artemisinin compounds like artemisinin, dihydroartemisinin, artesunate, artemether, arteether, etc.
Before discussing malaria drug resistance, it is better to know the terminologies of malaria drug resistance which are called 4R’s viz, Recurrence, Recrudescence, Relapse, and Resistance (4R’s). Recurrence is the recurrence of asexual parasite following treatment (for example P. vivax and P. ovale infections only) or a new infection. Recrudescence is the reinfection of asexual plasmodium after the treatment of the infection with the same infection that caused the original illness. Relapse is the reinfection of asexual plasmodium of P. vivax and P. ovale malaria due to persisting liver stages hypnozoites. Resistance is the ability of a plasmodium strain to survive and/or multiply despite the proper administration of antimalarial drugs in the dose normally recommended. Plasmodium vivax is continued to put a substantial burden on the malaria-endemic world with the morbidity and mortality due to its tendency to cause repeated infections. Plasmodium vivax forms dormant liver stages (hypnozoites), which causes relapses of infection weeks to months after the first attack.
Recurrent infections can occur as often as every three weeks, with relapses the main cause of vivax illness. Chloroquine is the first-line treatment for P. vivax malaria in most endemic countries and chloroquine drug resistance is the main problem in different parts of the world. In Africa and South America chloroquine resistance to plasmodium falciparum first appeared in 1978 and 1996 respectively. Chloroquine-resistant Plasmodium vivax was first reported in 1989 from Papua New Guinea. High-grade chloroquine-resistant plasmodium vivax is prevalent in Indonesia and Oceania (regarded as epicenters of chloroquine resistance). Both the acute illness and relapses from hypnozoites can be effectively prevented by the administration of a combination of chloroquine with primaquine (radical cure). Primaquine has activity against both blood and liver stages, including against chloroquine-resistant strains. Severe P. vivax infections can cause cerebral malaria with generalized convulsions and status epilepticus, severe anemia, hepatic dysfunction and jaundice, acute lung injury, pulmonary edema, splenic rupture, acute renal failure, and severe thrombocytopenia with or without bleeding from different parts of the body.
Primaquine is active against both asexual and sexual blood stages of the parasite as well as the liver stage schizonts and hypnozoites. One major cause for concern is the Primaquine can cause significant hemolysis in people with glucose-6-phosphate dehydrogenase deficiency (G6PDd). Due to gene malfunction glucose-6-phosphate dehydrogenase deficiency is the most common in the world, with a prevalence range of 2 per cent to 40 per cent. The World Health Organization for radical cure of vivax malaria currently recommends the use of a daily dose of 0.25 mg/kg/day (3.5 mg/kg total dose) primaquine taken with food once daily, which can be either co-administered with chloroquine or artemisinin.
Although projects are ongoing in World Health Organization, pharmaceutical companies and foundations, basic university-based research is also essential against for treatment and drug resistance in malaria. Antimalarial drug resistance is the ability of a parasite strain to survive and/or to multiply despite the administration and absorption of medicine given in doses equal to or higher than those usually recommended. Among the factors which facilitate the emergence of resistance to existing antimalarial drugs.
For radical cure of P. vivax combination therapy was tried depending on chloroquine sensitivity. Current guidelines recommend a 14 days course of primaquine administered either once or twice daily to reduce the risk of hemolysis and improve tolerability from gastrointestinal disturbance. In Ethiopia, in 1995, P. falciparum and P. vivax chloroquine treatment failure was reported. It was due to extracellular merozite invasion of human red blood cells by Plasmodium falciparum which is central to the pathogenesis. In the present time control of multidrugresistant P. falciparum malaria has become a very difficult task due to endogenous allelic exchanges occurred in P. falciparum which have increased the therapeutic failures and significantly increased the levels of resistance worldwide. Usually higher mean parasitemia index is seen in infected individuals with P. falciparum but P. vivax infection generally exhibits low parasitemia index due to its preference to invade reticulocytes rather than erythrocytes.
Vaccines are among the most successful and cost-effective public health tools. Millions of human lives have been saved and a substantial reduction in morbidity has been associated with vaccine scale-up implementation against other diseases. Vaccines in the malaria pipeline have many challenges/limitations due in part to the complex biology and life cycle of plasmodium and the immunological interplay between the parasite and host. At the same time, every malaria infection can be considered unique in terms of antigenic aggregation and host, frequency of exposure, age, access to treatment, and presence of comorbidity. RTS,S (registered as Mosquirix), based on the sporozoite protein, is thus far the only vaccine that has progressed beyond phase 3 clinical study and is now in a World Health Organization recommended and sponsored pilot implementation. RTS,S is a pre-erythrocytic vaccine directed at the sporozoite stage or at the infected hepatocyte.
The existing antimalarial drugs were identified based on the major metabolic pathway differences of the parasite with its host. The key metabolic pathways of the plasmodium species, including oxidative stress, heme detoxification, fatty acid synthesis, and nucleic acid synthesis are some of the novel targets for antimalarial drug discovery and development. Though most of the antimalarial drugs used for many years, presently the use of such drugs is limited as a result of drug resistance. There is an increasing need to develop new antimalarial drugs, identifying countermeasures either to delay or minimize the development of resistance against new drugs is an important phenomenon. New approaches include targeting glucose transporter PfHT1.
Glucose is a source of energy for intra-erythrocytic malarial parasites in which infected erythrocytes consume higher energy than normal erythrocytes. P. falciparum almost fully depend on glycolysis for energy production and is deprived of energy stores.
Targeting the parasite protein Kinases is another interesting approach
Kinases are involved in phosphorylation, transcriptional control, post-transcriptional control, and protein degradation in the plasmodium parasite life cycle. So, it could be the important targets for the development of antimalarial drugs.
The most studied Cyclin-dependent kinases (CDKs) are protein kinase, and compounds, flavopiridol and lomoucine have shown inhibition of PfPK5, by decreasing DNA synthesis and changing total RNA synthesis and parasite growth.
Food vacuole in human erythrocyte can be an attractive target. Malarial parasite receives its nutrition by food vacuoles The plasmodium mitochondrial electron transport chain is produced from non-proton motive quinone reductases, such as malate quinone oxidoreductase (MQO), etc.The pool of electron transport chain and carbon metabolism antimalarial targets that have been under the scanner because promising new avenue for the validation of novel drug targets for the treatment of malaria Apicoplast as drug targets is under consideration by blocking the P. falciparum ribosome and other parts of the transnational machinery accountable for protein synthesis. Plasmodium proteases are a regulatory and ubiquitous catalytic enzyme that play an important role in the survival of the plasmodium parasite and responsible for the hydrolysis of the peptide bond. The role of plasmodium proteases in the pathogenesis of malaria disease includes activation of inflammation, cell/tissue penetration, invasion of erythrocyte, development of the parasite, immune evasion, autophagy, and hemoglobin and other proteins breakdown. Amino peptidases catalyze the cleavage of amino acids from the amino terminus of peptides and proteins and are distributed widely in prokaryotes and eukaryotes as either integral membrane or cytosolic proteins. The amino peptidases are important target for development of novel drugs for malaria.
Conclusion
Present and future therapeutic targets for the discovery and development of novel antimalarial agents are promising. The frequently emerging antimalarial drug resistance including combination therapies globally forces the scientists to search and develop antimalarial drugs with novel mechanisms of action. Resistance to two highly dominant species Plasmodium falciparum and Plasmodium vivax is highly predominant in South East Asia, Africa, and South America. The complex life cycle of malaria parasite provoke obstacle in the discovery of new therapeutic agents.
(Author is with Bahara University, Kandaghat, District, Waknaghat, Himachal Pradesh 173 234)
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