Antiprotozoal Drug Discovery: A Challenge That Remains

PREFACE

Protozoan parasites are a worldwide public health problem that challenge the immune system of millions of humans and non-humans animals, resulting in devastating social and economic consequences. Until now, chemotherapy is central to the control of most of the infections caused by these parasites in both medical and veterinary practice. Chemotherapy control, has been mainly compromised by the development of parasite drug resistance, drugs severe side-effects and toxicity, low to medium efficacy, high cost drugs, and the introduction of counterfeit drugs that are a threat to public health with many overwhelming effects for patients; consequently, the search for new antiprotozoal drugs is an urgent need.

The development of new drugs against these parasites, has been largely neglected because they mainly affect people living in extreme poverty with limited or non-marketing possibilities; for these reasons, in some endemic countries, herbal medicine has become an important and sustainable source of control.

This eBook is an effort of researches who work in the field of antiparasitic experimental chemotherapy and medical parasitology and it summarizes the progresses made in the field of chemotherapy and drug research against protozoan diseases. Synthetic and natural treatments to control Chagas disease, malaria, toxoplasmosis and other parasitic diseases, are discussed in order to open the possibility for applying these scientific progress in the field of antiprotozoal chemotherapy.

The editor and the authors would like to thank Bentham Science Publishers for providing the opportunity to bring this knowledge to the scientific community and to the general public.

Norma Rivera

Laboratory of Malariology

Department of Microbiology and Parasitology

Faculty of Medicine

UNAM

Mexico

Protozoal Diseases: Importance and Prophylaxis

Filiberto Malagón*, Elba Carrasco

Laboratory of Malariology, Department of Microbiology and Parasitology, Faculty of Medicine, National Autonomous University of Mexico (UNAM), Mexico City, 04510, Mexico

Abstract

This chapter focuses on the effect that five parasitic diseases, produced by five protozoa, have on human health, namely: malaria, toxoplasmosis, Chagas disease, leishmaniasis and trichomoniasis. Our approach is the following: An analysis of the epidemiological components of these diseases in the context of the parasite’s life cycle; an analysis of the modifications in the natural history of these diseases introduced by human activities such as: migration, iatrogenesis and increased human mobility due to technological advances in the transportation of merchandise and persons; an analysis of how immune suppression produced by other living agents and chemotherapy affects these diseases, and their dispersion by tissue grafts; an analysis of the impact that these diseases have on the society, communities and family economies of countries affected by them, as well as what is being done to prevent them. In conclusion we find that research on new drugs is absolutely necessary to alleviate suffering, but given that these diseases are inextricably linked to poverty, we have to think of poverty as a disease, and as such we have an obligation to prevent it and eradicate it, as in the many other diseases and ills that befall mankind.

Keywords: Chagas disease, Chemotherapy, Leishmaniasis, Malaria, New drugs, Parasitic diseases, Poverty, Prohylaxis, Protozoa, Toxoplasmosis, Trichomoniasis.

* Corresponding author Filiberto Malagón: Laboratory of Malariology, Department of Microbiology and Parasitology, Faculty of Medicine, National Autonomous University of Mexico (UNAM), Mexico City, 04510, Mexico; Tel: 55 56232465; Fax: 55 56232386; E-mail: [email protected]

INTRODUCTION

The simplest forms of life among the eukaryote are the protozoa, just formed by one cell. The first protozoa probably evolved from the fusion of two bacteria 1.45 to 2.5 billion years ago [1]. These primogenital protozoa, diversified, organized,

and evolved into multicellular creatures from the trilobites to man. When studding protozoan parasites of man, I suggest not to lose the perception that we, humans, descend from those primogenital protozoa. If we think of humans in this fashion, it is not difficult to recognize that when the cells that conform us face a pathogen protozoa they initiate a relation or confrontation eukaryote to eukaryote and if the balance favors the host the infection is eradicated, but if it favors the parasite, the infection is established [2]. However, in this interaction both may come to an understanding, i.e. if the parasite doesn’t behave as a parasite then the host will tolerate it. This mutual acceptance is possibly the most common.

Of all the protozoa in nature a minuscule number have learned to use humans as substrate, and of all these, only five are discussed in this book because they are of special significance to human health. The five protozoa referred to in this chapter are: Plasmodium spp., Toxoplasma gondii, Trypanosoma cruzi, Leishmania spp. and Trichomonas vaginalis. We will systematically discuss each one of these parasites in the following chapters. In this first chapter we will have a general discussion about all five regarding issues which we find of particular relevance to better understand their importance. The reader will find that in some sections the five parasites are addressed together, while in others we will deal with one parasite or disease specifically.

ECONOMIC IMPORTANCE

When we talk about the economic importance of a disease, we normally talk about the burden that the disease creates at a local, national or global level. Most measurements take into account the premature mortality, morbidity, impairment and disability caused by the disease in study. The study of the global burden of diseases has developed a tool to quantify and compare health between populations, using a joint measure of both mortality and disability called disability-adjusted life year or DALY that measures the loss expressed in years of life due to death or disability caused by a disease [3, 4]. There are however other values that can also give us an idea of the burden produced by a disease.

A general rule created by Sachs and Malaney states that where malaria prospers more, human societies will prosper less. There is an unmistakable correlation between malaria and poverty. A comparison between the gross domestic product (GDP) of malarial and non malarial countries of similar development showed a GDP of US$1,526 for the malarial countries while in the non malarial countries it was US$8,268. This represents a five-fold difference between the two, which suggests that malaria exerts a considerable pressure on the economic development of populations. In a study of the rate of economic growth over a period of 25 years (1965-1990), countries with large populations living in areas of high malarial transmission were compared with countries of similar socioeconomic status but with a lower rate of malaria transmission. The results showed that the former countries had an annual per capita growth of 0.4% while for the latter it was 2.3%. [5].

In a study examining the burden of neglected tropical diseases within the framework of the global burden of disease, malaria was listed as the 9th cause of human death at global level, with 39 million DALYs, and held 1st place in the mortality burden among the tropical diseases of the world in the year 2002 [3].

An analysis of malarial deaths in the sub-Saharan region of Africa, made in 2010, showed a mortality between 655,000 and 1.24 million, with an estimated 82.69 million years lost by disability and death (DALYs), and an associated economic cost of 5.8% of the total GDP of the African Sub-Saharan region. Very important improvements have been achieved in the control of malaria in this region, with the use of residual insecticides impregnated in bed-nets and sprayed in houses, in conjunction with the artemisinin-based combination therapy. However, Anopheles resistance to the four classes of insecticides used has been documented, including pyrethroids, the only insecticides used to impregnate bed-nets; the resistance of P. falciparum to artemisinin has also been documented [6].

Among human infections caused by parasites, toxoplasmosis is one of the more prevalent, affecting 30 to 50% of the human population. Despite the fact that the infection is long-lived, the vast majority of people remain asymptomatic. The lowest prevalence of toxoplasmosis, of about 1% occurs in some countries in the Far East, and the highest rates, above 90% are found in European and South-American countries. A study of ocular toxoplasmosis in 1042 patients in Southern Brazil showed a prevalence 30 times higher than in any other part of the world [7]. While in another study on toxoplasmosis in 70,123 individuals from different parts of Mexico, conducted by Galvan-Ramirez from 1951 to 2012, a prevalence of 28.9% was found [8].

In the Netherlands, Kortbeek and colleagues detected 2 cases of infection by T. gondii per 10000 live births, and they calculated that 388 children were born infected nationally in 2006, which puts an estimated Toxoplasma burden at 2,300 DALYs [9]. In another study performed in the same country in 2009 to calculate the burden produced by 14 foodborne pathogens, Havelaar and colleagues concluded that in conjunction, they created a total burden of 13,500 DALYs and that T. gondii was the most important parasite of this group [10].

We think it of interest to note that some studies have found a correlation between latent asymptomatic toxoplasma infections and the development of several diseases, suggesting the existence of cause and effect between those latent infections and the development of cancer and other diseases [11]. In fact, some observations made in France statistically correlate an association between T. gondii infections and the development of malignant brain tumors, mainly in males, observations that suggest the need to research the existence of these processes in individual patients [12].

American trypanosomiasis exists in its natural form in the American Continent, from Texas in USA to Patagonia in Argentina. However, it is not limited to this continent. One of the effects of globalization has been the spread of Chagas disease to all continents due to people travelling from endemic countries, some of them manifesting late face cardiomyopathy of chronic infections, even after 30 years of residence in the host countries [13]. 1 to 1000 cases of Chagas disease have been detected in eleven countries in Europe; In Canada, five European countries, Australia and Japan, 1000 to 10,000 cases have been found; In Spain and 8 countries of Central and South America 10,000 to 100,000 cases have been detected; In USA and 10 countries from Central and South America, 100,000 to one million cases are found; and in Argentina, Brazil and Mexico more than one million cases occur [14].

The annual cost per person to treat Chagas diseases is of US$4,660, the per person lifelong expense of US$27,684, and the annual global cost of US$7.19 billion and of $188.80 billion for lifelong expenses of the total Chagas disease patients [15]. In the global mortality burden of tropical diseases in the world measure in 2002, Chagas disease occupied the place 18th among the most important tropical neglected diseases, with a DALYs of 667,000 [3].

Leishmaniasis is an underreported disease because it has to be notified only in 33 out of the 88 endemic countries; in many of these countries, leishmaniasis is treated by non-governmental organizations or by the private sector. In Sudan, Africa, it is estimated that 91% of all deaths for kala-azar are not registered, and in India as much as 20% of the extremely poor patients infected with L. donovani died with no diagnosis. Leishmaniasis epidemics are associated with wars, ecologic disasters, famine and forced migration. During the civil war in Sudan, Africa, hundreds of thousands of visceral leishmaniasis cases occurred, in some communities causing the death of between 30 to 60% of the population. Possibly the first visceral epidemics occurred in Bengal and Assam in India where a devastating epidemic of a febrile chronic disease with cachexia, hepato-splenomegaly and a high fatality was described. Visceral leishmaniasis produced in South Asia (India, Nepal, Bangladesh) accounts for 60% of the global incidence. The cost of health care for kala-azar patients in these countries goes from US$80 to US$120, this equals or surpasses the annual per capita income of the patients and their families, aggravated by their inability to work and the frequent appearance of post-kala-azar dermal leishmaniasis.

In the Americas, Brazil suffers from 90% of visceral leishmaniasis cases and is regarded as the third most important concentration of visceral leishmaniasis in the world. Kala-azar from endemic countries of South Asia, differs from those of the Americas in that the first is produced by L. donovani and is transmitted only among humans, while the latter is produced by L. chagasi (infantum) and has a zoonotic character, in which dogs play the role of reservoirs. Infection occurs in rural, periurban and urban areas, marked by poverty. The cost of treatment with pentavalent antimony for a person is approximately of US$345. Brazil paid the equivalent of US$2.5 million in the treatment of 35,000 persons, plus $500,000 in the treatment of 95 persons with liposomal amphotericin [16, 17]. In 2002, leishmaniasis occupied the 9th place in mortality rate among the tropical diseases of the world, with 2,090,000 DALYs [3].

Trichomoniasis is the most prevalent sexually transmitted infection. It is estimated that in the USA 3% of the population is infected with Trichomonas vaginalis, with a proportionally higher rate in blacks than whites. Each year, it is calculated that 1.1 million new cases occur. Trichomoniasis is considered a neglected parasitic infection, perhaps because 70 to 85% of infected individuals do not develop symptoms, the infection is curable, and the general public lacks an interest in this disease [18]. Trichomoniasis is the last on the list of lifelong costs for direct medical care of 8 sexually transmitted infections, because it costs the US Government only 24 million dollars per year [19]. However, it is thought by some that trichomoniasis should be given more importance in the USA, because vaginal trichomoniasis in women can increase the risk of adverse effects during pregnancy including preterm delivery and low-birth-weight infants. Some observations also suggest that trichomoniasis in women increases their risk of acquiring HIV. In men trichomoniasis can cause urethritis complicated with prostatitis. These facts suggest that it would be wise to include trichomoniasis among reportable diseases in the USA [20].

EPIDEMIOLOGICAL IMPORTANCE

The Parasite Reservoir of Infection

From the five diseases discussed in this chapter, Chagas disease, leishmaniasis and toxoplasmosis have sylvatic or domestic animals other than man as parasite source of the infection, for which these are consider zoonosis, although, under certain circumstances humans may function also as source of parasites [21, 22, 23]. From the parasites causing these three diseases, T. gondii is the most widely disperse among different animal species (eurixenous) followed by T. cruzi, and Leishmania spp.

Malaria is produced by five parasite species: P. falciparum, P. vivax, P. malariae and P. ovale and P. knowlesi that causes malaria in macaques and humans in Southeast Asia [24]. In malaria knowlesi, Anopheles mosquitos use monkeys as the main source of the parasite to transmit the infection among other monkeys and humans, thus malaria also qualifies as a zoonosis, at least for this Plasmodium species. It is necessary to note that malaria parasites are also widely dispersed in nature in reptiles, birds and mammals, however, it differs from Toxoplasma because the same species of this parasite infects all its species of hosts, while the malaria parasite species are almost strictly specific for a host species [25]. Trichomoniasis is the only disease of the five that has the same animal species, Homo sapiens, as main host and reservoir. Due to its character as a sexually transmitted disease, trichomoniasis infections occurs only among humans, and both men and women may function as reservoir and transmitters.

Processes of Parasite Dispersion

A parasite is regarded as stenoxenous when it infects just one specie of host in nature; however, when a parasite is capable of infecting many host species, we regard it as eurixenous. A parasite that requires a single host to develop its complete life cycle is called a monoxenous parasite, and if it requires of more than one host to complete its life cycle is named polixenous. In a polixenous parasite, the species that hosts the sexual form of the parasite