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Chronology of Drug Development for Malaria

Nalini Kurup and Nikhil Rajnani

Principal K. M. Kundnani College of Pharmacy, Department of Pharmaceutics, Mumbai, 400005, India

1.1 Introduction

The deadly malaria parasite is transmitted by mosquitoes and has been documented since earlier times. Malaria still remains an important cause of illness and death in children and adults in countries in which it is endemic. World Health Organization defines malaria as a life-threatening disease caused by parasites that are transmitted to people through the bites of infected female Anopheles mosquitoes, and it is preventable and curable [1]. The name malaria comes from the Italian word mal'aria, meaning "bad air." This was due to the reason that people thought the disease was transmitted via contaminated air (miasmas). Human malaria is caused by four different species of Plasmodium namely P. falciparum, P. malariae, P. ovale, and P. vivax. Of the four, P. falciparum and P. vivax pose the greatest threat. Scientists succeeded in sequencing the P. falciparum genome in 2002, which has permitted researchers to make great progress in comprehending better ways to target it [2].

The history of malaria depicts many attempts to defeat it. Quinine, a substance derived from the bark of the cinchona tree, has been known to be effective against malaria since the 1600s [3]. After discovering the role of mosquitoes in malaria transmission, scientists focused on vector control. They presumed that by killing the vector, they could halt the cycle of infection. As a result, DDT and other insecticides came into vogue in the mid-1900s and have been used ever since. Bed nets to protect sleeping people from mosquito bites are another form of vector control that is not only effective, but also extremely cost-effective [4]. Subsequently, the development of different anti-malaria drugs has changed the way travelers view malaria-endemic countries and the risk associated with traveling. In fact, and likely due to all of the above measures, estimated deaths from malaria fell 13%, from 755?000 in 2000 to 655?000 in 2010 [5]. Cases of the disease fell as well, although less dramatically, from 223?million in 2000 to about 216?million in 2010.

With all of these developments, why does malaria remain a problem? The emergence of resistance to drugs and insecticides is a major concern. Research in recent decades has shed light on many aspects of Plasmodium biology, broadening understanding of how parasites interact with the human immune system, cause human disease, and are transmitted by mosquitoes [6]. The malaria parasite has survived for more than 50?000?years, and natural selection favors strains of the organism with mutations that help them evade threats. Today we are seeing more and more drug-resistant parasites and insecticide-resistant mosquitoes. Global efforts are underway in the next era of malaria prevention: the development of malaria vaccines that have the potential to save countless lives and that could ultimately help eradicate this historic plight.

The World Malaria Report 2019 by WHO pays attention to the burden of malaria in two high-risk groups - children and pregnant women. In 2018, an estimated 228?million cases occurred worldwide and 405?000 deaths were reported. Twenty-seven countries reported less than 100 cases of malaria in 2018 compared with 17 countries in 2010. Inadequate funding being a barrier to future progress renewed R&D agenda is one of the major priorities to achieve a malaria-free world.

The report details on regional and global trends in burden of malaria cases and deaths, maternal, infant, and child health consequences of malaria, high burden to high-impact approach, investments in malaria programs and research, preventing malaria, diagnostic testing and treatment, world malaria report 2019 malaria surveillance systems and responding to biological threats to the fight against malaria [7].

The global technical strategy for malaria 2016-2030 adopted by the World Health Assembly in May 2015 provides a comprehensive framework to guide countries in their efforts to accelerate progress toward malaria elimination. The strategic framework comprising of three major pillars and two supporting elements sets the target of reducing global malaria incidence and mortality rates by at least 90% by 2030. The three major pillars being: (i) ensure universal access to malaria prevention, diagnosis, and treatment; (ii) accelerate efforts toward elimination and attainment of malaria-free status; and (iii) transform malaria surveillance into a core intervention. The two supporting elements are (i) innovation and research and (ii) a strong enabling environment. The program aims at achieving the vision - a world free of malaria [8].

There are many review articles emphasizing on the approaches available for prevention and treatment of malaria. This chapter aims at summarizing the information available on the erstwhile, current, and promising future in the drug development for malaria (Figure 1.1).

1.1.1 Life Cycle of Malaria (Adapted from CDC)

The malaria parasite life cycle involves two hosts [9].

During a blood meal, a malaria-infected female Anopheles mosquito inoculates sporozoites into the human host. Sporozoites infect liver cells and mature into schizonts, which rupture and release merozoites. (Of note, in P. vivax and P. ovale, a dormant stage [hypnozoites] can persist in the liver [if untreated] and cause relapses by invading the bloodstream weeks or even years later.) After this initial replication in the liver (exo-erythrocytic schizogony), the parasites undergo asexual multiplication in the erythrocytes (erythrocytic schizogony). Merozoites infect red blood cells. The ring stage trophozoites mature into schizonts, which rupture releasing merozoites. Some parasites differentiate into sexual erythrocytic stages (gametocytes). Blood stage parasites are responsible for the clinical manifestations of the disease. The gametocytes, male and female, are ingested by an Anopheles mosquito during a blood meal. The parasites' multiplication in the mosquito is known as the sporogonic cycle. While in the mosquito's stomach, the microgametes penetrate the macrogametes generating zygotes. The zygotes in turn become motile and elongated (ookinetes), which invade the midgut wall of the mosquito where they develop into oocysts. The oocysts grow, rupture, and release sporozoites, which make their way to the mosquito's salivary glands. Inoculation of the sporozoites into a new human host perpetuates the malaria life cycle.

Figure 1.1 Life cycle of malaria adapted from CDC.

1.2 Malaria - Erstwhile Memories

1.2.1 Progress Fighting Malaria

Since the dawn of modern microbiology research, beginning in the nineteenth century, scientists have known that the disease is actually caused by a microscopic parasite called Plasmodium, which is spread by mosquitoes common to wet, marshy places. Two of the earliest Nobel Prizes went to the scientists who made these basic discoveries, and at the dawn of the twentieth century, the situation had never seemed brighter. The possibility that malaria would be eliminated or eradicated was exciting and real then. History proved otherwise (Figures 1.2 and 1.3, Table 1.1).

Figure 1.2 Charles Louis Alphonse Laveran first identifies the malaria parasite. Credit: Photo Researchers/Science History Images/Alamy Stock Photo.

Full malaria eradication was a major public health effort in the first half of the twentieth century and was intensively pursued after World War II. Since that effort was launched, 108 countries have eliminated malaria from within their borders, with another 39 countries en route to that goal. Despite those efforts, malaria remains a major cause of illness in many parts of the world. Today almost half the world's population lives in places where the disease is common.

According to the Centers for Disease Control and Prevention, about 1500 cases of malaria still occur in the United States each year, but most are imported when people travel abroad. The real problem exists in several Asian and sub-Saharan African countries, where malaria is both a major leading cause of death and a significant drain on the economy. The World Health Organization estimates that the disease eats up nearly half of all public health expenditures and measurably lowers the gross domestic product of countries where it is common.

Several new approaches to controlling malaria have become available in the last few decades, such as insecticide-treated bed nets, but there remains a dire need for new drugs and for effective vaccines to control it.

There are many references in early history indicating malaria afflicting mankind. In earlier times herbal remedies found importance in treatment of malaria [11]. The first efficacious treatment for malaria was quinine from the bark of the cinchona tree. With the association of spread of malaria to mosquitoes, many control measures such as spraying of insecticides, covering of open water surfaces, insecticide treated nets were initiated.