Nematodes Infections

Chapter 4

Abstract

1. Introduction

33

Filariasis

Sharba Kausar

Filariasis is one of the most debilitating tropical neglected diseases with high morbidity rate and less rate of mortality with various clinical symptoms. According to the World Health Organization (WHO) reports, about 120 million people from 81 countries are infected at present, and an estimated 1.34 billion people live in areas endemic to filariasis and are at risk of infection. Currently available drugs are only effective against the larval stage of the worms with side effects, and their repetitive use gives rise to drug resistance. Till date, no effective vaccine is available for the treatment of filariasis; to fulfill this need, new drug development becomes the priority for the researchers. This chapter reviews different synthetic and natural origin drugs, drug targets, and use of bioinformatics to discover new antifilarial agents which can control this debilitating disease, including the types of filariasis,

A variety of parasitic diseases which are associated with morbidity and mortality have received less attention worldwide. Among these, filariasis is one of the most debilitating neglected tropical diseases. Filariasis is a vector-borne disease transmitted by arthropod vector which is endemic in the tropics and subtropics that results in social stigma. It is a group of human and animal infectious diseases caused by nematode parasites generally called "filariae" that include several hundred species of worms that are slender and elongated and are parasitic in tissues of various vertebrate hosts. This parasite known to cause human infections belongs mainly to the genera Wuchereria, Brugia, Onchocerca, Dipetalonema, Mansonella, and Loa. They reside either in lymphatics or muscles, connective tissues, body cavities, etc. of vertebrate hosts. They may be classified into three main groups based on the habitat of the adult worm, i.e., the cutaneous group, the lymphatic group, and the body cavity group. Based on the habitat of the adult worm, a few of the filarial species infecting man and the disease caused by them with their intermediate hosts are listed in Table 1. The infection is transmitted by intermediate hosts which are always blood-sucking arthropods of the order Diptera. Only two genera, Wuchereria and Brugia, are mainly responsible for human lymphatic filariasis. The common animal parasites are Setaria digitata and S. cervi (bovine), Dirofilaria immitis (dog), D. uniformis (rabbit), Litomosoides carinii and Dipetalonema vitae (gerbils), Brugia

According to recent surveys, about 120 million people in 81 countries of the world are infected from this disease, and 1.34 billion people who live in endemic areas are at high risk of this life-threatening infection [1]. To eradicate filariasis

their prevalence, and eradication programs which are discussed.

Keywords: filariasis, drug targets, antifilarials, bioinformatics

pahangi (cat), and Acanthocheilonema viteae (jird).

## Chapter 4 Filariasis

Sharba Kausar

## Abstract

Filariasis is one of the most debilitating tropical neglected diseases with high morbidity rate and less rate of mortality with various clinical symptoms. According to the World Health Organization (WHO) reports, about 120 million people from 81 countries are infected at present, and an estimated 1.34 billion people live in areas endemic to filariasis and are at risk of infection. Currently available drugs are only effective against the larval stage of the worms with side effects, and their repetitive use gives rise to drug resistance. Till date, no effective vaccine is available for the treatment of filariasis; to fulfill this need, new drug development becomes the priority for the researchers. This chapter reviews different synthetic and natural origin drugs, drug targets, and use of bioinformatics to discover new antifilarial agents which can control this debilitating disease, including the types of filariasis, their prevalence, and eradication programs which are discussed.

Keywords: filariasis, drug targets, antifilarials, bioinformatics

## 1. Introduction

A variety of parasitic diseases which are associated with morbidity and mortality have received less attention worldwide. Among these, filariasis is one of the most debilitating neglected tropical diseases. Filariasis is a vector-borne disease transmitted by arthropod vector which is endemic in the tropics and subtropics that results in social stigma. It is a group of human and animal infectious diseases caused by nematode parasites generally called "filariae" that include several hundred species of worms that are slender and elongated and are parasitic in tissues of various vertebrate hosts. This parasite known to cause human infections belongs mainly to the genera Wuchereria, Brugia, Onchocerca, Dipetalonema, Mansonella, and Loa. They reside either in lymphatics or muscles, connective tissues, body cavities, etc. of vertebrate hosts. They may be classified into three main groups based on the habitat of the adult worm, i.e., the cutaneous group, the lymphatic group, and the body cavity group. Based on the habitat of the adult worm, a few of the filarial species infecting man and the disease caused by them with their intermediate hosts are listed in Table 1. The infection is transmitted by intermediate hosts which are always blood-sucking arthropods of the order Diptera. Only two genera, Wuchereria and Brugia, are mainly responsible for human lymphatic filariasis. The common animal parasites are Setaria digitata and S. cervi (bovine), Dirofilaria immitis (dog), D. uniformis (rabbit), Litomosoides carinii and Dipetalonema vitae (gerbils), Brugia pahangi (cat), and Acanthocheilonema viteae (jird).

According to recent surveys, about 120 million people in 81 countries of the world are infected from this disease, and 1.34 billion people who live in endemic areas are at high risk of this life-threatening infection [1]. To eradicate filariasis


the blood of an infected gardener and thus reported that filariasis is transmitted by the mosquito. In 1960 and 1977, two other filarial worm species were identified and

Among all the filariasis, lymphatic filariasis is the most debilitating which causes disability in humans. Wuchereria bancrofti and Brugia malayi or B. timori are the main cause of lymphatic filariasis, each of which is transmitted by the bite of a specific insect vector. The various vectors that cause LF belong to the genera Anopheles, Culex, Aedes, and Mansonia. According to the WHO, increase in the microfilarial density in the infected individuals and the feeding rate of vector population are the causes of high transmission rates of filariasis in a particular area. Onchocerca volvulus and Loa loa are the two other filarial worms that reside in the cutaneous and subcutaneous tissues of the host and cause onchocerciasis and loaiasis, respectively. Wuchereria bancrofti and O. volvulus are the two filarial worms

Data collected from the survey depicted the picture of depressive illness of an individual caused by LF and estimated 5.09 million disability-adjusted life years (DALYs) [3–5]. In infants microfilaremia starts at the age of 5 after acquiring infection, but the actual signs of filariasis (including hydroceles) appear during puberty. Previous survey reports indicated that once the individual acquired infec-

Filarial worms inhabiting the lymphatic system live up to 8 years and release millions of microfilariae into the bloodstream. The WHO started the Global Alliance to Eliminate Lymphatic Filariasis (GPELF) in 2000 with the goal of eradicating this disease by 2020 through the use of MDA [7]. In the history of public health, GPELF is the most successfully expanding global health program. Fifty-three out of the 81 endemic countries have started mass drug administration to halt the transmission of filariasis. Two strategies have been developed to achieve the target of eliminating filariasis. According to the first strategy, single annual doses of diethylcarbamazine or ivermectin plus albendazole will be provided to the entire endemic area to prevent the disease. The second strategy is to reduce disability rate by providing knowledge about how to maintain hygiene and skin care, to those with lymphedema and performing surgery in patients with hydrocele. The investment for chemotherapy to control this disease is approximately US\$ 105–208 million per year during 2015–2020. The WHO determined two objectives, which include "70% of endemic countries demanding MDA will have to enter post-intervention surveillance by 2016" and "all other endemic countries have to complete the post-intervention surveillance by 2020" [8, 9]. The abovementioned antifilarial drugs are only effective against the microfilariae and have no effect on the adult worms which therefore provide a partial treatment to the infected individuals. Repetitive use of these drugs resulted in drug resistance. Till date no vaccines are developed, and treatment depends only on the antifilarial. Researchers are developing various new antifilarials

Man is the definitive host of filarial worm, in whose lymphatic system, the adult worms reside. Adult females discharge the live embryo called microfilariae (290 μ). Microfilariae flow in the peripheral blood and can survive for a considerable time

named as Brugia malayi and B. timori, respectively.

DOI: http://dx.doi.org/10.5772/intechopen.89454

which do not require an animal host as reservoir.

tion chances of cure becomes very low [6].

and combination therapies to overcome this disease [10].

4. General life cycle of filarial worm

35

3. Filariasis: an overview

Filariasis

#### Table 1.

List of filarial worms with their habitats and intermediate host infecting humans.

globally, research plans are needed to design effective drugs and drug targets, new vector control strategies, and diagnostic techniques. At the same time, the treatment of filariasis also requires disease-specific clinical care and patient education with counseling to eradicate this disease. Moreover, statistical analysis along with bioinformatics tools of the mass drug administration (MDA) surveillance reports should be carried out which could provide new opportunities to get an insight into the proteins or genome which may contribute to its inhibition process.

In current surveillance report, five World Health Organization (WHO) regions are endemic with lymphatic filariasis (LF). Worldwide, 1.39 billion people require preventive chemotherapy. In Southeast Asia region, 877 million people of 9 countries and 432 million people of 39 countries in the Africa region are brutally affected from this disease and require proper treatment. From the Western Pacific Region which includes the Mekong Plus region and the Pacific region, nearly 40 million people are at a risk of lymphatic filariasis. Cambodia, China, Cook Islands, Niue, the Marshall Islands, Palau, the Republic of Korea, Tonga, Vanuatu, Viet Nam, and Wallis and Futuna are the countries of this region that successfully eradicated this disease, whereas American Samoa, Brunei Darussalam, Fiji, French Polynesia, Kiribati, Lao People's Democratic Republic, Malaysia, Federated States of Micronesia, New Caledonia, Papua New Guinea, Philippines, Samoa and Tuvalu are the 13 countries where lymphatic filariasis remains endemic [1, 2].

#### 2. History of filariasis

In India first, ancient documented evidence of filariasis was reported in Sushruta Samhita (approximately 600 BC) by the famous physician Sushruta. According to some records, the first reliable documentation of filariasis was reported in the late fifteenth and early sixteenth centuries. In 1849 William Prout explained the pathological condition of chyluria in which the passage of lymph occurs in urine, a condition associated with lymphatic filariasis. The French surgeon Jean Nicolas in 1863 was the first person who observed the microfilariae in the hydrocele fluid. For the first time, in 1872 Timothy Lewis observed the microfilariae in the human blood in India. In 1876, Joseph Bancroft recovered female filarial worms and named them Filaria bancrofti, which later merged in the genus Wuchereria. In 1877, Sir Patrick Manson discovered the main cause of transmission of filariasis, by studying the parasitic development of microfilariae in the mosquito stomach that was fed on the blood of an infected gardener and thus reported that filariasis is transmitted by the mosquito. In 1960 and 1977, two other filarial worm species were identified and named as Brugia malayi and B. timori, respectively.

## 3. Filariasis: an overview

globally, research plans are needed to design effective drugs and drug targets, new vector control strategies, and diagnostic techniques. At the same time, the treatment of filariasis also requires disease-specific clinical care and patient education with counseling to eradicate this disease. Moreover, statistical analysis along with bioinformatics tools of the mass drug administration (MDA) surveillance reports should be carried out which could provide new opportunities to get an insight into

Onchocerca volvulus Skin Simulium sp. (S. damnosum)—black flies Onchocerciasis

Filarial worm Habitat Intermediate host Disease

Brugia malayi Lymphatics Mosquito sp. Malayan

Loa loa Connective tissue Chrysopsis sp. (C. dimidiata)—Horse flies

List of filarial worms with their habitats and intermediate host infecting humans.

membranes

B. timori Lymphatics Mosquito sp. Timor fever

Lymphatics Mosquito sp. Elephantiasis

Culicoides sp. (C. furens)—biting midges Ozzard's filaria

filariasis

Loaiasis

In current surveillance report, five World Health Organization (WHO) regions are endemic with lymphatic filariasis (LF). Worldwide, 1.39 billion people require preventive chemotherapy. In Southeast Asia region, 877 million people of 9 countries and 432 million people of 39 countries in the Africa region are brutally affected from this disease and require proper treatment. From the Western Pacific Region which includes the Mekong Plus region and the Pacific region, nearly 40 million people are at a risk of lymphatic filariasis. Cambodia, China, Cook Islands, Niue, the Marshall Islands, Palau, the Republic of Korea, Tonga, Vanuatu, Viet Nam, and Wallis and Futuna are the countries of this region that successfully eradicated this disease, whereas American Samoa, Brunei Darussalam, Fiji, French Polynesia,

In India first, ancient documented evidence of filariasis was reported in Sushruta Samhita (approximately 600 BC) by the famous physician Sushruta. According to some records, the first reliable documentation of filariasis was reported in the late fifteenth and early sixteenth centuries. In 1849 William Prout explained the pathological condition of chyluria in which the passage of lymph occurs in urine, a condition associated with lymphatic filariasis. The French surgeon Jean Nicolas in 1863 was the first person who observed the microfilariae in the hydrocele fluid. For the first time, in 1872 Timothy Lewis observed the microfilariae in the human blood in India. In 1876, Joseph Bancroft recovered female filarial worms and named them Filaria bancrofti, which later merged in the genus Wuchereria. In 1877, Sir Patrick Manson discovered the main cause of transmission of filariasis, by studying the parasitic development of microfilariae in the mosquito stomach that was fed on

the proteins or genome which may contribute to its inhibition process.

Kiribati, Lao People's Democratic Republic, Malaysia, Federated States of Micronesia, New Caledonia, Papua New Guinea, Philippines, Samoa and Tuvalu

are the 13 countries where lymphatic filariasis remains endemic [1, 2].

2. History of filariasis

34

Wuchereria bancrofti

Helminthiasis

Table 1.

Mansonella ozzardi Serous

Among all the filariasis, lymphatic filariasis is the most debilitating which causes disability in humans. Wuchereria bancrofti and Brugia malayi or B. timori are the main cause of lymphatic filariasis, each of which is transmitted by the bite of a specific insect vector. The various vectors that cause LF belong to the genera Anopheles, Culex, Aedes, and Mansonia. According to the WHO, increase in the microfilarial density in the infected individuals and the feeding rate of vector population are the causes of high transmission rates of filariasis in a particular area. Onchocerca volvulus and Loa loa are the two other filarial worms that reside in the cutaneous and subcutaneous tissues of the host and cause onchocerciasis and loaiasis, respectively. Wuchereria bancrofti and O. volvulus are the two filarial worms which do not require an animal host as reservoir.

Data collected from the survey depicted the picture of depressive illness of an individual caused by LF and estimated 5.09 million disability-adjusted life years (DALYs) [3–5]. In infants microfilaremia starts at the age of 5 after acquiring infection, but the actual signs of filariasis (including hydroceles) appear during puberty. Previous survey reports indicated that once the individual acquired infection chances of cure becomes very low [6].

Filarial worms inhabiting the lymphatic system live up to 8 years and release millions of microfilariae into the bloodstream. The WHO started the Global Alliance to Eliminate Lymphatic Filariasis (GPELF) in 2000 with the goal of eradicating this disease by 2020 through the use of MDA [7]. In the history of public health, GPELF is the most successfully expanding global health program. Fifty-three out of the 81 endemic countries have started mass drug administration to halt the transmission of filariasis. Two strategies have been developed to achieve the target of eliminating filariasis. According to the first strategy, single annual doses of diethylcarbamazine or ivermectin plus albendazole will be provided to the entire endemic area to prevent the disease. The second strategy is to reduce disability rate by providing knowledge about how to maintain hygiene and skin care, to those with lymphedema and performing surgery in patients with hydrocele. The investment for chemotherapy to control this disease is approximately US\$ 105–208 million per year during 2015–2020. The WHO determined two objectives, which include "70% of endemic countries demanding MDA will have to enter post-intervention surveillance by 2016" and "all other endemic countries have to complete the post-intervention surveillance by 2020" [8, 9]. The abovementioned antifilarial drugs are only effective against the microfilariae and have no effect on the adult worms which therefore provide a partial treatment to the infected individuals. Repetitive use of these drugs resulted in drug resistance. Till date no vaccines are developed, and treatment depends only on the antifilarial. Researchers are developing various new antifilarials and combination therapies to overcome this disease [10].

## 4. General life cycle of filarial worm

Man is the definitive host of filarial worm, in whose lymphatic system, the adult worms reside. Adult females discharge the live embryo called microfilariae (290 μ). Microfilariae flow in the peripheral blood and can survive for a considerable time

drugs, drugs preventing exsheathment in microfilariae and drugs that can cause hindrance in the movement of microfilariae. Different biochemical pathways are summarized in Table 2 which are used in designing new drugs. On the other hand,

> Contribute to the nucleotide pool of nematodes

Bacteria-specific filamenting temperature-sensitive protein (important in bacterial cytokinesis) that was expressed in all

developmental stages of B.

a 14-carbon unsaturated fatty acid, to the N-terminus of glycine in a subset of proteins via myristoyl-CoA:protein Nmyristoyltransferase (NMT) promotes their binding to cell

Free amino acids are required for intracellular osmoregulation and

Are required for the conversion of methionine to homocysteine in

malayi

membrane

protein synthesis

the methionine

Play a vital role in the biosynthesis of this collagen

growth, development, and maturation of the nematode

Myristoyltransferase (NMT) The addition of myristic acid,

Transaminoglutamase Play a significant role in the

Tetracycline was resulted in the depletion of these Wolbachia resulting in the upregulation of phosphate permease gene, required for nucleotide synthesis Another study with doxycycline showed that Wolbachia depletion was associated with a reduction in the levels of vascular endothelial growth factors (VEGFs) that are essential for lymphangiogenesis (18)

E. coli FtsZ inhibitor berberine, a natural alkaloid, was examined by researchers against GTPase activity of FtsZ in B. malayi, and it was observed that at 10–40 mM concentration, berberine had adversely affected production of microfilariae as well as motility of adult females of B. malayi

A known NMT enzyme inhibitor in tripanosomatids, DDD85646, and its analog DDD100870, were tested against B. malayi NMT proteins and provided IC50 values of 10 nM and

2.5 nM, respectively

A pseudosubstrate,

parasite

monodansylcadaverine (MDC), and active site inhibitors cystamine or iodoacetamide were found to inhibit L3-stage parasite mobility in a dose-dependent manner that was associated with irreversible biochemical lesions, resulting in the death of the

Wolbachia bacteria

Filariasis

Wolbachia cell division protein FtsZ a GTPase

N-Myristoyltransferase

Proteins and amino acids

S-adenosylmethionine methyltransferase, methionine adenosyltransferase, and S-adenosylhomocysteine

Enzyme prolyl-4-hydroxylase has been reported to

hydrolase

37

Wolbachia are proteobacteria 61 potential drug targets (outer membrane proteins, ribosomal proteins, DNA polymerases, mutases, ligases, isomerases, cell division proteins, transferases, synthetases, reductases, etc.) and four potential vaccine extracellular targets such as putative peptidoglycan lipid II flippase, deoxycytidine triphosphate deaminase, GTP cyclohydrolase II, and RNA pyrophosphohydrolase

DOI: http://dx.doi.org/10.5772/intechopen.89454

Figure 1. Life cycle of filarial worm Setaria cervi given by Prof. Wajihullah and Dr. Sharba Kausar.

without undergoing metamorphosis until they are taken up by the intermediate host, i.e., the culicine mosquitoes during their blood meal. After reaching in the mosquitoes, microfilariae undergo development and become infective-stage larvae as described in Figure 1.

## 5. Diagnosis of lymphatic filariasis

LF is primarily diagnosed using the immunochromatographic card test kit via antigen detection methods (which also detects latent infections). The traditional diagnosis of LF is performed by microscopy to detect circulating microfilariae. Molecular xenomonitoring of parasites in mosquitoes, serological testing, ultrasonography, PCR tests, lymphoscintigraphy, detection of exposure to transmission in children via antibody detection, and the recently introduced filariasis test strip (FTS) are some of the other diagnostic approaches that are currently used.

## 6. Biological point for designing new drug

A clear knowledge of parasite physiology is very important to identify drug targets for understanding the mode of action of antifilarial drug. Sometimes compounds are also tested, without prior knowledge of the target. Compounds which are effective against the whole parasite are defined as hits, while compounds that are found to be active in vivo are considered as leads. Lead compounds require standardization for increasing their efficacy. Once a compound is optimized, it can be tested clinically in patients and defined as a "drug candidate." Based on the physiological processes and symptoms, a drug should be formulated and designed to combat the disease. To overcome filariasis a number of drug targets should be covered for developing new antifilarial, viz., macrofilaricidal and microfilaricidal

drugs, drugs preventing exsheathment in microfilariae and drugs that can cause hindrance in the movement of microfilariae. Different biochemical pathways are summarized in Table 2 which are used in designing new drugs. On the other hand,


without undergoing metamorphosis until they are taken up by the intermediate host, i.e., the culicine mosquitoes during their blood meal. After reaching in the mosquitoes, microfilariae undergo development and become infective-stage larvae

Life cycle of filarial worm Setaria cervi given by Prof. Wajihullah and Dr. Sharba Kausar.

LF is primarily diagnosed using the immunochromatographic card test kit via antigen detection methods (which also detects latent infections). The traditional diagnosis of LF is performed by microscopy to detect circulating microfilariae. Molecular xenomonitoring of parasites in mosquitoes, serological testing, ultrasonography, PCR tests, lymphoscintigraphy, detection of exposure to transmission in children via antibody detection, and the recently introduced filariasis test strip (FTS) are some of the other diagnostic approaches that are currently used.

A clear knowledge of parasite physiology is very important to identify drug targets for understanding the mode of action of antifilarial drug. Sometimes compounds are also tested, without prior knowledge of the target. Compounds which are effective against the whole parasite are defined as hits, while compounds that are found to be active in vivo are considered as leads. Lead compounds require standardization for increasing their efficacy. Once a compound is optimized, it can be tested clinically in patients and defined as a "drug candidate." Based on the physiological processes and symptoms, a drug should be formulated and designed to combat the disease. To overcome filariasis a number of drug targets should be covered for developing new antifilarial, viz., macrofilaricidal and microfilaricidal

as described in Figure 1.

Figure 1.

Helminthiasis

36

5. Diagnosis of lymphatic filariasis

6. Biological point for designing new drug


vaccine development and mosquito repellent practices such as the use of insecticide nets, body lotions, insecticides spray, coils, etc. along with good knowledge of sanitization can prevent vector development which together helps in combating filarial worm infection in a community. The pathology associated with lymphatic filariasis like elephantiasis, hydrocoele, and lymphedema is due to the hyporesponsiveness of D4+ T cells of the host immune system [11–13]. Therefore, immunological studies are also playing an important role in the field of drug development. Drugs are also designed to combat symptoms associated with filariasis, viz., drugs used for the treatment of lymphatic filariasis (drugs effective against adenolymphadenitis, funiculitis, epididymo-orchitis, lymphedema, hydrocele, chyluria,

Lipid metabolism

Filariasis

limiting enzyme

Folate metabolism

HMG-CoA reductase is a rate

Enzymes, such as reductases, transferases, synthases, dehydrogenases, hydrolases, mutases, ligases, and deaminases

10-Formyl FH4 dehydrogenase

enzyme

Glutathione

Glutamate-cysteine ligase (rate-g-glutamyl transpeptidase)

Glutathione-transferases

Antifilarial targets for designing drugs.

(GSTs)

Table 2.

39

Juvenile hormones Regulators of larval development Dolichols Required for glycoprotein

DOI: http://dx.doi.org/10.5772/intechopen.89454

Isopentyl pyrophosphate IPP constituent of filarial tRNA

synthesis

Involved in the isoprenoid pathway of filaria

Are involved in the interconversation of folate analogs observed in the synthesis of different tetrahydrofolate cofactors by macrofilariae. Specifically, dihydrofolate reductase activity, which is commonly observed in macrofilariae, was found to be absent in the microfilariae of

B. pahangi

mammals

peroxidation

Which was found to play a vital role in the regulation of the endogenous FH4 cofactor concentrations, was more active in B. pahangi than in

Glutathione has been proposed to constitute the antioxidant system (g-glutamyl cycle) that extends the survival of filarial parasites in mammalian hosts, thereby protecting them from hostmediated membrane lipid

The major detoxifying systems in filarial parasites and can detoxify cytotoxic products of lipid peroxidation via the conjugation of glutathione (GSH) to various endogenous xenobiotic electrophiles

Inhibited by mevinolin

folate metabolism

Arsenicals depletes filarial glutathione (262–264) Phytocompounds such as plumbagin, curcumin, and a phenoxyacetic acid derivative were found to inhibit filarial GST In a report of a homology modeling approach via in silico analysis of the filarial GST of B. malayi, albendazole, and a methyl-substituted chalcone showed non-competitive type of inhibition of GST activity

DEC and suramin were found to inhibit some enzymes involved in Proteins and amino acids Retinoic acid-binding proteins

Biogenic amines and polyamines

Norepinephrine (NE), histamine, 5-

and dopamine

Octopamine

spermidine

aldolase

hydroxytryptamine (5-HT),

Monoamine oxidase (i.e., MAO), acetylcholinesterase, and dopamine-b-hydroxylase

Dopamine-b-hydroxylase

Putrescine, spermine, and

S-adenosylmethionine decarboxylase (SAMDC)

Carbohydrate metabolism Fructose 1,6-diphosphate

Phosphoenolpyruvate carboxykinase

Lipid metabolism

38

Parasitic nematodes require lipophilic retinol for various biological processes, such as embryogenesis, differentiation, Ivermectin(II) was found to compete efficiently with retinol for the retinol-binding sites on RBP of the parasite but not for

the host RBP sites

DEC, levamisole, and centperazine were found to inactivate these enzymes

Berenil and aromatic methylglyoxal bis

(guanylhydrazone) analogs are inhibitors of an important regulatory enzyme

geraniol and dolichols was inhibited by mevinolin

For inter- as well as intracellular

Biogenic amines play a role in neuromuscular activity and behavioral coordination in

Are required for growth, differentiation, and

macromolecular synthesis in all living organisms as constituents of the polyamine salvage

Which is required for polyamine

Its immunogenic component in filarial worms is distinguishable from that of mammals, thus identifying it as possible vaccine

in B. pahangi and L. carinii when compared to isofunctional mammalian enzyme

Geranyl geraniol Unknown role The biosynthesis of genanyl

and growth

movement

nematodes

pathway

biosynthesis

target238

Fumarate reductase Inhibited by DEC and

Phosphofructokinase Blocked by antimonial stibophen

Glucose uptake Altered by DEC, amoscanate, and arsenicals

Utilization of glucose Decreased by levamisole

Quinones Play a role in filarial electron

transport

Succinate dehydrogenase Inhibited by DEC

Inhibited by DEC

benzimidazoles

(RABPs)

Helminthiasis


#### Table 2.

Antifilarial targets for designing drugs.

vaccine development and mosquito repellent practices such as the use of insecticide nets, body lotions, insecticides spray, coils, etc. along with good knowledge of sanitization can prevent vector development which together helps in combating filarial worm infection in a community. The pathology associated with lymphatic filariasis like elephantiasis, hydrocoele, and lymphedema is due to the hyporesponsiveness of D4+ T cells of the host immune system [11–13]. Therefore, immunological studies are also playing an important role in the field of drug development. Drugs are also designed to combat symptoms associated with filariasis, viz., drugs used for the treatment of lymphatic filariasis (drugs effective against adenolymphadenitis, funiculitis, epididymo-orchitis, lymphedema, hydrocele, chyluria,

chylocele, lymph scrotum) and drugs used in the treatment of other manifestations like asymptomatic microfilaremia, occult filariasis, onchocerciasis, and loaiasis.

## 7. Currently used antifilarial drugs

#### 7.1 Diethylcarbamazine (DEC)

Diethylcarbamazine (DEC), a piperazine derivative, is the most common and widely used drug over many decades. The antifilarial activity of DEC was first tested against Litomosoides carinii- and Dirofilaria immitis-infected cotton rats and dogs, respectively [8]. The observations revealed DEC as a potential microfilaricidal agent. Clinical trial of DEC was started in 1947 against human filariasis. Later, strong antimicrofilarial activity of DEC was also observed against W. bancrofti, B. malayi, O. volvulus, and Loa loa infection in humans [14–17]. DEC acts rapidly by stimulating the host immune system. In some reports macrofilaricidal effect of DEC was also recorded along with its antimicrofilarial activity [18–21]. Peixoto et al. [22] described the direct mechanism of action of this drug during their in vitro and in vivo studies; they observed apoptosis and organelle damage of W. bancrofti microfilariae by DEC [22]. To enhance the effect of DEC against microfilariae, nitric oxide was induced by some researchers and was found to be a good synergist [23]. However, DEC combined with albendazole [24] revealed an effective killing of W. bancrofti microfilariae, but the combination therapy increased the development of hydroceles in the treated patient [25].

#### 7.2 Ivermectin (IVM)

It is a broad-spectrum anthelmintic and an effective macrofilaricidal drug introduced in 1981 also known as Mectizan [2], which was the first commercially available macrocyclic lactone. Chemically, it is a 22,23-dihydro semisynthetic derivative of avermectin B1, which is a fermentation product of actinomycetes S. avermitilis discovered by Merck in the mid-1970s [11–32]. IVM alone or in combination with DEC [8] resulted in long-term suppression of microfilariae in both bancroftian and brugian filariasis [20, 33, 34].

#### 7.3 Suramin

Suramin [35] initially was a drug used to cure trypanosomiasis and onchocerciasis. Chemically it is an 8,80-(carbonylbis[imino-3,1-phenylenecarbonylimino(4 methyl-3,1-phenylene)carbonylimino])bis-1,3,5-naphthalenetrisulfonic acid hexasodium salt. Presently it is the only macrofilaricidal drug that is effective against W. bancrofti and O. volvulus.

#### 7.4 Albendazole

This anthelmintic drug is [24] a benzimidazole derivative. Recently this has been used in a clinical trial to check out its efficacy as antifilarial drug [36]. Its efficacy was increased when administered in combination with either DEC [8] or IVM [2].

Antifilarial

41

Diethyl

6 mg/kg for 12 days (individual

treatment)

carbamazine

(piperazine

6 mg/kg in 24 hours

single annual dose in mass treatment)

treating W. bancrofti infection

3–6 mg/kg for 6–12 days (individual

treatment)

3–6 mg/kg in 24 hours (6 times at weekly

or monthly in mass treatment)

treating B. malayi and B. timori

8 mg/kg for 14 days For the treatment of occult filariasis

> Table salt +

0.1% for 6 months treatment of LF

Diethylcarbamazine

0.3% for 3–4 months B. malayi is endemic

Ivermectin

400 mg/kg single dose treatment

Oral

Targets glutamate gated Cl- and K+ ion

channels in nematodes,

hyperpolarization

the body wall muscle and pharynx. The

drug also affects

channels gated by GABA. It competes

with retinol for the

retinol-binding

parasite only

> Suramin

66.7 mg/kg in 6 incremental

(3.3, 6.7, 10.0, 13.3, 16.7, 16.7 mg/kg for

the first and sixth weeks,

 weekly doses

Intravenous

It adversely affects enzymes associated

W. bancrofti, O.

Fatal collapse,

albuminuria,

 ulceration,

volvulus

and persistent high fever; polyuria,

tiredness, tenderness, increased thirst; among others are some

of the milder side effects

 anorexia, and

with glucose catabolism and destabilizes

DNA and protein kinase enzymes in

filarial worms

(10% solution

respectively)

in water)

 proteins (RBPs) in the

retinol-binding

 site on

ligand-gated

 chloride ion

 that causes paralysis of

 results in

4800 mg/kg for 6 months treatment of B.

malayi and single dose remove

microfilariae W. bancrofti

(macrocyclic

lactone)

 for infections

(weekly/monthly/

 for

derivative)

 agent

Recommended

 dose

Route of

Mechanism

 of action

Filarial worm

 Side effects

administration

Oral

Alterations

metabolism

 of host endothelial

microfilariae,

constriction

platelet aggregation;

nelle damage

 apoptosis and org

 and host granulocyte

 and

 resulting in blood vessel

 cells and

 in arachidonic

 acid

W. bancrofti

Encephalitis

Increasing dose include systemic reaction:

nausea, GIT upset, malaise, body aches,

and anorexia. Localized reactions: abscess

formation, lymphedema

> B. malayi and

B. timori infections

Occult filariasis

W. bancrofti

(lymphatic

filariasis)

B. malayi Bancroftian

Same as DEC, and special care must be

considered,

 such as avoiding its use in

and brugian

filariasis

cases of pregnancy and in children

younger than 5 years old

lymphadenitis,

 and transient

DOI: http://dx.doi.org/10.5772/intechopen.89454

 and retinal

hemorrhage.

Filariasis

infection


chylocele, lymph scrotum) and drugs used in the treatment of other

and loaiasis.

Helminthiasis

patient [25].

7.3 Suramin

7.4 Albendazole

or IVM [2].

40

7.2 Ivermectin (IVM)

brugian filariasis [20, 33, 34].

against W. bancrofti and O. volvulus.

7. Currently used antifilarial drugs

7.1 Diethylcarbamazine (DEC)

manifestations like asymptomatic microfilaremia, occult filariasis, onchocerciasis,

Diethylcarbamazine (DEC), a piperazine derivative, is the most common and widely used drug over many decades. The antifilarial activity of DEC was first tested against Litomosoides carinii- and Dirofilaria immitis-infected cotton rats and dogs, respectively [8]. The observations revealed DEC as a potential microfilaricidal agent. Clinical trial of DEC was started in 1947 against human filariasis. Later, strong antimicrofilarial activity of DEC was also observed against W. bancrofti, B. malayi, O. volvulus, and Loa loa infection in humans [14–17]. DEC acts rapidly by stimulating the host immune system. In some reports macrofilaricidal effect of DEC was also recorded along with its antimicrofilarial activity [18–21]. Peixoto et al. [22] described the direct mechanism of action of this drug during their in vitro and in vivo studies; they observed apoptosis and organelle damage of W. bancrofti microfilariae by DEC [22]. To enhance the effect of DEC against microfilariae, nitric oxide was induced by some researchers

and was found to be a good synergist [23]. However, DEC combined with

albendazole [24] revealed an effective killing of W. bancrofti microfilariae, but the combination therapy increased the development of hydroceles in the treated

It is a broad-spectrum anthelmintic and an effective macrofilaricidal drug introduced in 1981 also known as Mectizan [2], which was the first commercially available macrocyclic lactone. Chemically, it is a 22,23-dihydro semisynthetic derivative of avermectin B1, which is a fermentation product of actinomycetes S. avermitilis discovered by Merck in the mid-1970s [11–32]. IVM alone or in combination with DEC [8] resulted in long-term suppression of microfilariae in both bancroftian and

Suramin [35] initially was a drug used to cure trypanosomiasis and onchocerciasis. Chemically it is an 8,80-(carbonylbis[imino-3,1-phenylenecarbonylimino(4 methyl-3,1-phenylene)carbonylimino])bis-1,3,5-naphthalenetrisulfonic acid hexasodium salt. Presently it is the only macrofilaricidal drug that is effective

This anthelmintic drug is [24] a benzimidazole derivative. Recently this has been used in a clinical trial to check out its efficacy as antifilarial drug [36]. Its efficacy was increased when administered in combination with either DEC [8]


Table 3.

Antifilarial

43

 agent

Trisubstituted

amino group and

the second position plays an important role

in exerting antifilarial activity)

2-Sulfanyl-6-methyl-1,4-

dihydropyrimidines

Indole derivatives

b-Carbolines

indoles)

Quinoline and related compounds

4-(substituted

3-Nitro-4-quinolones

Quinolones

(substituted

3-Nitro-4-quinolones

Glycoside cinnamoyl glycosides

Cinnamoyl glycosides Dioxocine 3,6-epoxy dioxocines

Chromatin fragmentation;

damaged the cuticular sheath of the

microfilariae

B. malayi–M. coucha

IC50 values (0.4 mg/ml and 1.8 mg/ml, with

selectivity indices (SI) of 100 and 22.2 with

respect to

respectively

macrofilariae

 and

microfilariae,

[49]

 this compound also

condensation

 and DNA

W. bancrofti

amino)quinolines

 compound 7-chloro-4-

 via

ipso-nitration

Thymidylate

Evaluation against DNA

enzyme, compound

Brugia malayi

activity

thymidylate

 kinase inhibitory

B. malayi

S. cervi

topoisomerase

 II

Screened in vivo against A. viteae

 kinase inhibitory activity

Brugia malayi

IC50 2.9 mM 200 mg/kg for 5 days

IC50 2.9 mM

MIC (3.40 nM), IC50 (6.90 nM) and LC50

[48]

(25 nM) values, CC50 value of

approximately

MIC and IC50 values were 4.4 nM/ml and

8.96 nM/ml, respectively

 103 nM

amino)quinolines

 7-chloro-

 (substituted

9Hpyrido[3,4-b]

 B-carboline

 pyrimidine

 derivatives

4-aminophenyl

 group at

 (the

ATP-dependent

inhibitory activity

 DNA

topoisomerase

 II

S. cervi B. malayi (in vitro)

B. L. carinii–S. hispidus (cotton rats)

A. viteae–M. natalensis

L. carinii, A. viteae and B. malayi in a

M. coucha model

A. viteae

malayi–Mastomys

 coucha

25 and 50 μM

100 mg/kg 30 mg/kg for 5 days

[40–43]

DOI: http://dx.doi.org/10.5772/intechopen.89454

[44–47]

50 mg/kg for 5 days

50 mg/kg for 5 days

Action

Parasite

Dose 10–40 mg/ml

Reference

[38, 39]

Filariasis

Summary of the recommended doses of currently used antifilarials.


#### Filariasis DOI: http://dx.doi.org/10.5772/intechopen.89454

Antifilarial

42

Levimazol

An initial dose of 100 mg followed by the

same dose twice daily for 10 days was

found to be as effective as the total oral

dosage of DEC at 126 mg per kg body

weight

Albendazole

Albendazole

(benzimidazole)

(400 mg) +

diethylcarbamazine

 (DEC)

Oral

Block tubulin inhibiting microtubule

inhibits parasite intestinal cells,

preventing glucose uptake leading to the

death of the parasite

polymerization,

 formation. It also

 thereby

Macrofilaricidal

Embryotoxicity

 and

teratogenicity

Albendazole+

Albendazole+

Albendazole

(150–200 mg/kg)

 (400 mg) + ivermectin

ivermectin

Table 3. Summary of the

recommended

 doses of currently used antifilarials.

 DEC

(6 mg/kg)

 agent

Recommended

 dose

Route of

Mechanism

 of action

Filarial worm

W. bancrofti, B.

No side effects at

recommended

 doses

Helminthiasis

malayi

 Side effects

administration

Oral

Acts as nicotinic receptor agonist that

causes prolonged activation of the

excitatory nicotinic

receptors on the body wall muscle of

parasites, leading to spastic muscle

paralysis in the worm

acetylcholine

 (nACh)


Antifilarial

45

Butylated hydroxy anisole (BHA) Piperazine benzoyl piperazine derivatives

(two compounds, compound (35) containing a 4-chloro

(para) substituent

substituent

Pyrrolidine

containing the

Diaminoalkane

diaminoalkanes

Secondary amines

Glycyrrhetinic

benzylamide

 analog

 acid derivatives

 and the

N1,Nn-xylofuranosylated

pyrrolidine-methoxy

 group the

macrofilariae

concentration

 of 3 mM in vitro

B. malayi–M. coucha

At 50 mg kg 1 provided

38.7% recovery of

sterilization

The same compound also showed 33.5%

adulticidal action along with 50%

sterilization

At a dose of 200 mg/kg for 5 days exhibited

100% compound elicited a

response of

Killing and 25 mM, respectively The IC50 values were found to be 2.2 mM

against macrofilariae

At a dose of 100 mg/kg for 5 days exhibited

40% adulticidal activity

B. malayi–jirid

 of the worm

microfilariae

 and 8.8 mM against

microfilariae

 and

macrofilariae

 at 50

[60]

B. malayi

approximately

 93%

macrofilaricidal

 activity, whereas

[59]

microfilaricidal

A. viteae

 of female worms

 of female parasites

approximately

[58]

macrofilariae

 and 63.80%

B. malayi–jirid

 of female S. cervi at a

glutathione-S-transferase

 (GST) activity in

Showed a significant suppression

 of

S. cervi

100% inhibition

 chalcone derivative (36)

 on the aromatic ring)

 and 3-methyl (meta)

 viz., compound (34) and

 agent

Action Oxidative found to be its major killing mechanism

(135)

stress-induced

 apoptosis was

S. cervi S. cervi

Parasite

Dose At 100 mM was found to be a potent

adulticide

Worms were immotile following treatment

with these two compounds

concentration

 of 8 mg ml 1

 at a

[16, 17,

57]

DOI: http://dx.doi.org/10.5772/intechopen.89454

Reference

[15]

Filariasis


#### Filariasis DOI: http://dx.doi.org/10.5772/intechopen.89454

Antifilarial

44

Compound

Alcohols

propanol

Cyclooctanol

Triazine

DHFR good inhibitory activity

74%) against PARP

diphosphate

Benzopyran

Naphthalene

 derivative 1,4-

1,3-Dimethyl

butylamino

lipophilicity

binding to the active site, which results in

elevated

Thiazolidine

compounds

(32)

 compound (31) and compound

 heterocyclic

 thiazolidine

macrofilaricidal

 activity (133)

B. malayi

IC50 values of 5.2 mM and 1.78 mM

[14]

LD50 values of 349 mM and 17.59 mM,

respectively

 with potentially improved

 side chain favors an increased

 substitution

 on the

Setaria digitata

naphthoquinones

 (coumarin)

 ribose

(dihydrofolate

 reductase) inhibitors,

B. malayi

(approximately

(polyadenosine

polymerase)enzyme

 derivatives

cyclohexanol,

 2- substituted

 agent

Action

Parasite

B. malayi in jirid

Dose Found to be potent in terms of both in vitro

(IC50 1.6 mg/ml and 3.5 mg/ml for

macrofilariae

respectively)

activity, 200 mg/kg

100%

200 mg/kg for 5 days)

81% sterilization of 100 mg/kg for 5 days) against Almost 100% loss of motility of filarial

[51, 52]

> worms at 20 mg/ml showed better activity

(IC50 10.90 mM) when compared with

standard antifolate (positive control)

compounds,

12.92 mM) and

20.10 mM

When

300 mg/kg for 5 days showed 53.6%

macrofilaricidal

activity

At a dose of 100 mg/ kg for 5 days, showed

75% adulticidal and 50%

activity

ED50 value of 2.6 mM after a 24 h

[56]

incubation and 0.91 mM after a 48 h

incubation

microfilaricidal

 and 46%

microfilaricidal

administered

 orally at a dose of

[53–55]

B. malayi–M. coucha

B. malayi–jirid

 model

 i.e.,

trimethoprim

pyrimethamine

 (IC50

 (IC50

 of female worms (at a dose

macrofilaricidal

 activity (at a dose of

[50]

A. viteae and L. carinii in rodents

A. viteae in rodent

 and in vivo antifilarial

 and

microfilariae,

Reference


Antifilarial

47

 agent

Benzimidazole

mebendazole,

Flubendazole

2,20-Dicarbomethoxyamino-5,50-

dibenzimidazolyl

Silver

Table 4.

List of synthetic and naturally originated antifilarials.

 ketone

 derivatives

 HOE 33258

At 5 � 2.5 mg/kg and 1 � 25 mg/kg in jirds

and 1 � 100 mg/kg in cats when

administered

A dose of 3 mg/kg (i.p.) and 50 mg/kg

(oral) � 5 days of Comp. 82/437

At a dose of 150 and 200 mg/kg for 5 days

Nanosilver

 by

subcutaneous

 injection

Action

Parasite L. carinii and D. immitis Evaluated in jirds (Meriones

unguiculatus)

infected with Brugia pahangi

L. carinii in cotton rats

Dipetalonema

malayi in

B. malayi

LD50 exclusion) of 101.2 mM and an IC50 value of

50.6 mM (complete population found immotile). At 4.6 mM

only, nanosilver caused a 50% decrease in

the motility of the parasite

microfilariae

concentration

 (by trypan blue

[80]

DOI: http://dx.doi.org/10.5772/intechopen.89454

Mastomys natalensis

 viteae and Brugia

 and cats (Felis catus)

Dose Macrofilaricidal.

larvae in jirds. It was not

Eliminated almost 100% of adult worms

and

It killed 100% of the

of the

microfilariae

macrofilariae

 and 97%

microfilariae

 It also killed developing microfilaricidal

Reference

[68–79]

Filariasis


Antifilarial

46

Nitazoxanide

 and tizoxanide

 agent

Action The researchers

compounds

production

female worms. They also suggested that

mitochondria

possible target of NTZ (41) and TZ (42)

because in addition to damaged worm

tissues, they found alterations in the

mitochondria

Nitazoxanide

Nitazoxanide

Anthraquinone

substitution

Sulfonamide

Benzothiazole

benzothiazole

Thiazole

chalcone–thiazole

 derivatives

 hybrids

 novel chalcone–

It showed higher binding interactions

active site of BmTMK (B. malayi

thymidylate

nucleotide metabolism

 in B. malayi).

B. malayi–jirid

B. malayi–M. coucha

 kinase, an essential enzyme for

 at the

B. malayi

 sulfonamide

 chalcones

 of acylium ions

3-methylcatechol

 with a

Marked effects on intrauterine

parasite

 embryos of

B. malayi infection in humans

 + silver

nanoparticles

Inhibit TCA cycle enzymes

S. cervi

 in the worms may be a

 and impaired

embryogenesis

 in

 reduced microfilarial

 further reported that both

Parasite

B. malayi

Dose Macrofilariae

immotile after 6 days when cultured with

these two compounds

20 mg/ml On day 8 of culture at

2.5 mg/ml, both drugs also caused a 50%

decrease in worm viability

Microfilarial

these compounds exceeding 5 mg/ml, and the worms were

completely immotile following treatment

with 20 mg/ml (after 48 h)

100% mortality of

100 μg/ml 100% mortality of

 At 5 ppm (18–19 mM) showed 100%

mortality within 1, 5, and 3 days against

microfilariae

worms

IC50 value was found to be 4.4 mM, LD50

value of 188 mMt 500 mM

after 48 h of incubation

IC50 values of 2.12 mM and 1.63 mM,

[66]

respectively,

microfilariae

MIC value of 5 mM for both the forms

IC50 value was 95.3 mM

At a dose of 100 mg/kg for 5 days showed

[67]

100% Exerted macrofilaricidal

 activity and

approximately

 49%

embryostatic

 activity

 for adult worms as well as

concentration

[65]

B. malayi

 and adult male and female

microfilariae

 at 30 μg/ml [64]

microfilariae

 at

[62, 63]

 motility was also hampered by

 at

concentrations

concentrations

 of

 at

concentrations

 of

 were found completely

Reference

[61]


Plant

49

Azadirachta

 indica

Extract Alcoholic extract of flowers

Aqueous extract of flowers

Methanolic

Ethanolic extract of leaves Ethanolic extract of A. indica leaves

> Eucalyptus tereticornis

Senecio nudicaulis Hibiscus sabdariffa

n-Butanol insoluble fraction of leaf extract

At a dose of 500 mg/kg 5 days

1 g/kg 5 days

Trachyspermum

 ammi

Methanolic

The active component Its positional isomer (i.e.,

carvacrol,)

showed promising result

2-Isopropyl-5-methyl

5 days

 phenol at a dose of 50 mg/ kg for

B. malayi–M. coucha

 also

5-isopropyl-2-methyl

 phenol,

2-isopropyl-5-methyl

 phenol (thymol) was the

 extract of fruit

B. malayi B. malayi–jirid B. malayi–M. coucha model

S. digitata

 model

Showed 30%

Showed 57% IC50 0.067 and 0.019 mg/ml after 24 h and 48 h,

respectively

IC50 were 0.024 mg/ml and 0.002 mg/ml after 24 h and

48 h incubation,

 respectively

Macrofilaricidal

0.004 mg/ml after 24 h and 48 h incubation,

respectively.

Macrofilarial

 mortality of 58.93%

 IC50 values were 0.025 mg/ml and

macrofilaricidal

macrofilaricidal

 activity [92]

 activity

Aqueous leaf extract

Alcoholic leaf extract

Ursolic acid obtained from the leaves

 extract of leaves

S. cervi S. cervi

B. malayi

Target S. cervi

Antifilarial

Mf(LC50 of 15 ng/ml)

(LC90 ¼ 23 ng/ ml),

mf(LC50 of 18 ng/ml)

(LC90 ¼ 25 ng/ ml)

Mf 100% mortality at 200 μg/ml in 135 min

Mf 90% mortality at 200 μg/ml in 135 min

Showed significant worm reduction at 25 lg/ml and

highest mortality at 100 lg/ml after 24 h of incubation

when applied against the

LC100 50 mM and IC50 8.84 mM against and LC100 100 mM and IC50 35.36 mM against adult

worms

Both the extracts exhibited

LC50 10 ng/ml and LC90 15 ng/ml

LC50 5 ng/ml and LC90 12 ng/ml

At 250 mg/ml

microfilarial

 motility

concentration

demonstrated

 a high

[91]

macrofilaricidal

 activity

[90]

Setaria cervi

microfilariae

microfilariae,

[89]

DOI: http://dx.doi.org/10.5772/intechopen.89454

 efficiency

Author

[86–88]

Filariasis


#### Filariasis DOI: http://dx.doi.org/10.5772/intechopen.89454

Plant

48

Streptomyces sp. 17,944

Streptomyces sp. 9078

Streptomyces sp. 4875

Lantana camara

 Four adipostatins

compounds

Crude extract

Chloroform,

Fractions of n-hexane oleanonic acid

Oleanonic acid Crude extract 1 g/kg 5 days

> Taxodium distichum

A001 (crude ethanolic extract of aerial part)

F001 (hexane fraction) K003(labda-8(20),13-diene-15-oic

(metasequoic

SF1 (fraction)

SF4 A001 (500 mg/kg 5 days; orally) K003 (100 mg/kg 5 days) exerted

At 100 mg/kg dose, both K003 and K004

K003 (100 mg/kg 5 days)

(fraction)

 acid A)

 acid) and K004

 n-butanol and aqueous

 (alkyl resorcinols)

 potent among the

Depsipeptide

 Three new

tirandamycins

Extract

Target

B. malayi B. malayi B. malayi

A. viteae B. malayi

B. malayi

B. malayi A. viteae/M. coucha model

B. malayi M. unguiculatus

B. malayi

mf (LC100 3.91 μg/ml) than adult worms

[85]

(LC100 15.63 μg/ml) IC50 values for the respective parasite stages were found

to be 1.95 and 10.00 μg/ml

mf (LC100 7.83 μg/ml) adult worms (LC100 31.25 μg/ml) mf (LC100 31.25 μg/ml) and adult worms

(LC100 125 μg/ml) mf (LC100 7.83 μg/ml) than adult (LC100 31.25 μg/ml)

mf (LC100 62.5 μg/ml) adult (LC100 125 μg/ml)

100% effective against Adult

>95%; remarkable

activity

Produced >25%

activity

Exerted 53.94%

macrofilaricidal

macrofilaricidal

embryostatic

B. malayi/M. unguiculatus B. malayi/M. coucha model

transplanted/

80% effective against adult

LC100 62.5 μg/ml LC100 500 mg/ml

LC100 250 μg/ml

LC100 31.25 μg/ml LC100 62.5 μg/ml

 95.05% reduction in Mf 23.65% effective against adult

Antifilarial

Inhibit the

enzyme at an IC50 value of 30 mM

IC50 value of 50 mM Kill the worms at 1 mM

concentrations

asparaginyl-tRNA-synthetase

 (BmAsnRS)

[81]

Helminthiasis

[82]

[83]

[84]

 efficiency

Author


Plant

51

Diospyros peregrina

Cajanus Ficus racemosa

Botryocladia

 leptopoda

The crude ethanolic extract from the marine red alga B.

leptopoda

At a dose of 200 mg/kg for 5 days

> Haliclona oculata

The methanolic

Chloroform

fraction

At a dose of 100 mg/kg for 5 days the methanol extract,

chloroform

(contain four major alkaloids:

araguspongin-C,

respectively

Methanol extract, the

Chloroform

 fraction

Araguspongin

 C

n-butanol-soluble

 fraction

B. malayi

(LC100 31.25 mg/ml)

[106]

(LC100 15.6 mg/ml)

Macrofilaricidal

 activity at 15.6 mg/ml

Haliclona exigua

mimosamycin,

 and

xestospongin-D),

 fraction, and

chromatographic

 fraction

B. malayi–jirid

xestospongin-C,

 fraction and its one

chromatographic

 extract

scarabaeoides (L)

 The the stem part Alcoholic and aqueous extract of fruits of F. racemosa

polyphenol-rich

 ethanolic extract obtained from

Extract n-Butanol extract (NBE) of D. peregrina stem bark on

Setaria cervi

Target S. cervi S. cervi

 Setaria cervi

A. viteae

L. sigmodontis Brugia malayi

L.

A. viteae–M. coucha and

B. malayi–M. coucha

B. malayi

Mf (IC50 5 mg/ml)

[105]

Adult (1.88 mg/ml)

Showed

1.62 mg/ml,

1.72 mg/ml and 1.19 mg/ml were effective against

microfilariae

Revealed 51.3%, 64% and 70.7%

activities in the methanol extract, chloroform

and

chromatographic

 fraction,

respectively.

macrofilaricidal

 fraction,

respectively,

 whereas

concentrations

 of

antimacrofilarial

 activity IC50 1.80 mg/ml and

sigmodontis–cotton

 rats

Exhibited 71.6% 63.2% (ethanolic extract) and 45%

(hexane fraction)

macrofilaricidal

 activity, respectively

Antifilarial

Mf (IC50 56.1 μg/ml, (IC50), adult (IC50 57.6 μg/ml)

Mf (LD100 187.17 μg/ml) after 24 h of treatment

LD50 values were 2.5, 10 and 35 μg/ml, against the

oocytes, LC50 and LC90 were 21 and 35 ng/ml, alcoholic, while for aqueous extracts were 27 and 42 ng/

ml, respectively

LC100 of 62.5 mg ml1

LC100 of 31.25 mg ml1

LC100 of 125 mg ml1

respectively,

 for

[103]

DOI: http://dx.doi.org/10.5772/intechopen.89454

[104]

microfilariae

 (Mf) and adults, respectively

 efficiency

Author

[101]

Filariasis

[102]


#### Filariasis DOI: http://dx.doi.org/10.5772/intechopen.89454

Plant

50

Bauhinia racemosa (B.

racemosa)

Extract Galactolipid

ethanolic extraction of the leaves

50 mg/kg 5 days

Crude methanolic

 at a dose of 100 mg/kg

Piper betel

Hibiscus mutabilis

Caesalpinia

Melaleuca cajuputi Xylocarpus granatum

Aqueous–ethanolic

fruit extract The ethyl acetate soluble fraction

At a dose of 50 mg/kg for 5 days

Gedunin (64) Photogedunin

Gedunin at a dose of 100 mg/kg for 5 days

B. malayi–M. coucha

B. malayi

Photogedunin

The root extract from V. negundo and the leaf extract

from A. marmelos

Vitex negundo (V. negundo)

and Aegle marmelos (A.

marmelos)

Aegle marmelos

Methanolic

leaves

 extracts of Aegle marmelos Corr. (Rutaceae)

S. cervi

(IC50) was 0.168 mg/ml

 at a dose of 100 mg/kg for 5 days

demonstrated B. malayi–M. coucha

 extract

 bonducella

Crude extract from the seed kernel

The flower extract

Active ferulic acid, from the leaves

B. malayi infection B. malayi–M. coucha

S. cervi B. malayi

B. pahangi

B. malayi

 (n-butanol fraction) obtained from

Target

B. malayi

Antifilarial

The MIC values against adult worms 3.9 mg/ml and

15.6 mg/ml against The IC50 values were 1.25 mg/ml and 1.607 mg/ml,

respectively,

58.3% adult worm mortality

Suppress mf most effectively and showed 26% efficacy

[94]

[95]

[96]

[97]

[98]

against adult worm

Approximately

microfilariae

96% Halted the release of mf and worm mobility after 6 days

at 1000 mg/ml

IC50 value of 15.46 and 13.17 mg/ml against

macrofilariae

An IC50 value of 8.5 and 6.9 mg ml1 against

macrofilariae

53% Mf (IC50 2.03 mg/ml) Adult (IC50 0.239 mg/ml)

Mf (IC50 2.23 mg/ml) Adult (IC50 0.213 mg/ml)

Killed 80.0% of the 70.0% adult worm mortality

At a of microfilarial

concentration

 of 100 ng/ml caused a complete loss

[99]

[100]

 motility after 48 h of incubation

transplanted

 adult worms

macrofilaricidal

 and 63%

embryostatic

 effects

 and

microfilariae,

 respectively

 and

microfilariae,

 respectively

macrofilaricidal

 activity

 and adult worms, respectively

 97 and 90%, of reductions in viability of

 against adult worms and

microfilariae

microfilariae

 efficiency

Author

[93]


#### Table 5. List of naturally originated antifilarials are summarized below.

7.5 Levamisole

Filariasis

bancrofti and Brugia malayi [37].

DOI: http://dx.doi.org/10.5772/intechopen.89454

8. Role of bioinformatics in filarial research

8.1 Genomic approach in filarial research

8.2 Proteomic approach in filarial research

cytochrome oxidase-I (COI).

mass spectroscopy.

53

This is an ascaricidal drug with no side effects at the recommended doses. It has also been found as a microfilaricidal drug against the microfilariae of Wuchereria

Unfortunately, most of the chemical antifilarials are characterized by adverse side effects. The list of currently used antifilarials with their side effects is summarized in Table 3. Hence, researches on exploring new therapeutic drugs, especially less hazardous drugs of natural origin, are highly recommended. The application of biomedicines to treat disease is among the oldest forms of therapy. These biomedicines including plant extracts and their secondary metabolites were believed to exert their bioefficacy through immunomodulatory elicitation of Th1/Th2 response, either by single (Th1, Th2) or mixed adjuvant activity. Therefore, in the context of filariasis, synthetic and naturally originated antifilarials are summarized in Tables 4 and

Bioinformatics is a science of computer-based analysis for the biological datasets in which biology and computer science are mutually helping and influencing each other in the field. Bioinformatics has increased the understanding of molecular mechanism of various cellular processes. Nowadays bioinformatics covers several fields of biological sciences and drug discovery to overcome biological problems.

Genomic research in bioinformatics is a useful technique used to understand the structure and function of all the genes within an organism. Genomics help to find the particular gene and other biological aspects in the entire genome sequence of the organism. Screening of drug targets can also be done using the genomics approach. Casiraghi et al. [115] had carried out phylogenetic analysis using bioinformatics of 11 filarial and Spirurida nematodes and identified the sequence of mitochondrial

Hoerauf et al. [116] detected the mutual interaction between the intracellular bacteria (endobacteria) and filarial nematodes, which is further used as antifilarial drug targets. Nuchprayoon et al. [117] identified the genetic diversity using phylogenetic analysis parsimony tool (PAUP) between the DNA sequences of two strains of Wb found in Myanmar and Thailand. Ghedin et al. [118] reported the nuclear genome draft of Bm (95-Mb), which contains 88,363,057 bp sequences with 17.84%

NEMBASE4 database. Investigators identified a variety of filarial parasite genes and their novel functions that are involved in miRNA regulation and processing.

Proteomics approach involved highly efficient methods of protein separation like two-dimensional-poly acrylamide gel electrophoresis (2DPAGE) and detection, using modern tools of bioinformatics. Proteomic analysis of the several stages of Bm has identified 557 Bm proteins and 11,508 protein coding genes which helps to define various proteins by using reverse-phase liquid chromatography-tandem

Afterwards Bennuru et al. [119] have also done the same in identifying the excretory/secretory (ES) and somatic proteins of adult, mf, and infective stages of

protein coding sequence [118]. The full genome sequences are available at

5 .

## 7.5 Levamisole

This is an ascaricidal drug with no side effects at the recommended doses. It has also been found as a microfilaricidal drug against the microfilariae of Wuchereria bancrofti and Brugia malayi [37].

Unfortunately, most of the chemical antifilarials are characterized by adverse side effects. The list of currently used antifilarials with their side effects is summarized in Table 3. Hence, researches on exploring new therapeutic drugs, especially less hazardous drugs of natural origin, are highly recommended. The application of biomedicines to treat disease is among the oldest forms of therapy. These biomedicines including plant extracts and their secondary metabolites were believed to exert their bioefficacy through immunomodulatory elicitation of Th1/Th2 response, either by single (Th1, Th2) or mixed adjuvant activity. Therefore, in the context of filariasis, synthetic and naturally originated antifilarials are summarized in Tables 4 and 5.

## 8. Role of bioinformatics in filarial research

Bioinformatics is a science of computer-based analysis for the biological datasets in which biology and computer science are mutually helping and influencing each other in the field. Bioinformatics has increased the understanding of molecular mechanism of various cellular processes. Nowadays bioinformatics covers several fields of biological sciences and drug discovery to overcome biological problems.

## 8.1 Genomic approach in filarial research

Genomic research in bioinformatics is a useful technique used to understand the structure and function of all the genes within an organism. Genomics help to find the particular gene and other biological aspects in the entire genome sequence of the organism. Screening of drug targets can also be done using the genomics approach. Casiraghi et al. [115] had carried out phylogenetic analysis using bioinformatics of 11 filarial and Spirurida nematodes and identified the sequence of mitochondrial cytochrome oxidase-I (COI).

Hoerauf et al. [116] detected the mutual interaction between the intracellular bacteria (endobacteria) and filarial nematodes, which is further used as antifilarial drug targets. Nuchprayoon et al. [117] identified the genetic diversity using phylogenetic analysis parsimony tool (PAUP) between the DNA sequences of two strains of Wb found in Myanmar and Thailand. Ghedin et al. [118] reported the nuclear genome draft of Bm (95-Mb), which contains 88,363,057 bp sequences with 17.84% protein coding sequence [118]. The full genome sequences are available at NEMBASE4 database. Investigators identified a variety of filarial parasite genes and their novel functions that are involved in miRNA regulation and processing.

### 8.2 Proteomic approach in filarial research

Proteomics approach involved highly efficient methods of protein separation like two-dimensional-poly acrylamide gel electrophoresis (2DPAGE) and detection, using modern tools of bioinformatics. Proteomic analysis of the several stages of Bm has identified 557 Bm proteins and 11,508 protein coding genes which helps to define various proteins by using reverse-phase liquid chromatography-tandem mass spectroscopy.

Afterwards Bennuru et al. [119] have also done the same in identifying the excretory/secretory (ES) and somatic proteins of adult, mf, and infective stages of

Plant

52

Eucalyptus globulus

Extract The leaf extract from E. globulus was active in vitro

At a dose of 100 mg/kg for 5 days

Terminalia

Terminalia

Terminalia

Moringa oleifera

The gum extract obtained from M. oleifera showed at a

dose of 500 mg/kg for 5 days In contrast, at a dose of 1000 mg/kg for 5 days

> Butea monosperma

The leaf and root extract

Methanol and

extract

Methanolic

 extract of the seed

Ricinus communis Rutin and hesperetin

Naringenin

At 50 mg/kg

Flavone

Chrysin

Table 5.

List of naturally originated antifilarials

 are summarized

 below.

hexane–ethanol

 fraction of the leaf

B. malayi

S. cervi B. malayi S. digitata

B. malayi

B

malayi–Meriones

malayi-M. coucha

 and B.

Eliminate adult worms 73 and 31%, respectively

Exhibit inhibit the adult motility at 31.2 mg/ml

Showed

macrofilaricidal

 activity at 2.50 mg/ml

macrofilaricidal

 activity at 62.5 mg/ml and

 catappa

 chebula,

 bellerica,

Leaf extracts in different solvents

Target

B. malayi

B. malayi–M. coucha model

and transplanted

jirid

Setaria cervi

The methanol extract exhibited more than 80% activity

at the highest dose level of 10 mg/ml. The IC50 in methanol extracts are 2.7, 1.96 and 2.58 mg/ml

Mf (LC100 1000 mg/ml) Adult (LC100 125 mg/ml) Mf (IC50 > 1000 mg/ml) Adult (IC50 74.33 mg/ml) Extract showed 69% adulticidal activity and sterilized

83% of the female worms

Extract showed 44% adulticidal activity

Microfilarial

Showed IC50 values of 1.25 and 3.6 mg/ml,

against 90% death in the

Showed Showed value at2.5 mg/ml

macrofilaricidal

 activity at 125 mg/ml IC50

macrofilaricidal

 activity a 500 mg/ml

developmental

 stages of the parasite

 [112–114]

macrofilariae

 motility in a

dose-dependent

 manner

[110, 111]

respectively,

B. malayi B. malayi–jirid B. malayi–M. coucha

obtained

[109]

[108]

 B. malayi

Antifilarial

IC50 values 62.5 and 31.2 mg/ml,

adult worms and Exhibited 66.7% adulticidal activity and an

embryostatic

 effect

microfilariae

respectively,

 against

[107]

Helminthiasis

 efficiency

Author

larvae of Brugia malayi. Some workers gathered the molecular information of the particular protein of interest through 3D structure which plays a significant role in drug designing and vaccine development for lymphatic filariasis. In 2005 Bhargavi et al. [120] analyzed the 3D model of GST of Wuchereria bancrofti and Brugia malayi for better drug development. For the development of potential drugs, novel drug targets are modeled using bioinformatics approach including either ligand-based drug designing (LBDD) or structure-based drug designing (SBDD). LBDD provides crucial understanding of the interaction between the drug target and ligand molecule and provides information about the biologically active molecules [121]. Currently 3D quantitative structural activity relationship (QSAR) and pharmacophore modeling of small molecules are carried out to define their minimum necessary structural characteristics through which it inhibits the target. These 3D structure analyses of a protein were designed from the experimental-based method such as Xray crystallography, NMR, electron microscopy, etc. If an experimental data are not available for the target proteins, homology modeling is carried out to build the 3D structure using target protein sequence [122].

8.3 Web-based available resources for LF

DOI: http://dx.doi.org/10.5772/intechopen.89454

have been discussed below.

tute, NEB, and TIGR.

Filariasis

contain:

9. Conclusions

55

Web-based biological data plays a significant role in bioinformatics which plays

NEMBASE: It contains databases containing information of filarial nematodes such as filarial biology and pathology, nomenclature of filarial genome, mapping of filarial gene, and Bm genome survey sequencing (GSS). Recently, genome sequencing of wBm and Onchocerca volvulus (Ov) was also included with the Sanger Insti-

WormBase: It's an open access database repository for nematode biology which contains the genome browser for Bm, C. elegans, H. contortus, etc., and the gene predictions and orthology assignments from a range of related nematodes. FilaDB: It is a database for screening filarial patients with the objective of providing information on the incidence of mf and types of acute, chronic, and occult manifestations and age, sex, and distribution area of filariasis cases for

Filarial worm database at broad institute: This database used to study the minute phenotypic difference between the closely related filarial species of Loa loa, Wb, and Ov (http://www.filariasiscenter.org/brugia-malayigenomics-and-bioinformatics-re sources). Filarial worm database also has the sequence data on Wolbachia endosymbionts of Wb, Ov, and Bm. Filarial diseases are still remaining as a major public health concern in India. There is a need of comprehensive database, which should

a. Curated links between genes relevant to filariasis and their sequences in

e. Expressed sequence tagged (EST) sequences from different filarial species.

g. Bioinformatics tools to analyze those data. Database should also contain the epidemiological data on age and gender-wise incidences of disease, remission,

Filariasis is one of the most disabling and disfiguring neglected tropical diseases with various clinical manifestations and a high morbidity rate. Repetitive use of antifilarials has given rise to drug resistance. Most of them are effective against

b. Sequence homology between different filariasis causing genes.

c. Primary and secondary information of pathogens.

f. Supporting references from published literatures.

and transition rates of disease sequelae.

d. Availability of various drugs and their targets.

clinico-immuno monitoring and management of filariasis.

GenBank and Swiss-Prot.

a significant role in analyzing biological data for large amount of nucleotide sequences, amino acid sequences, and 2D or 3D structures for the broad range of organisms and their drug targets. Currently, there are only few databases available for LF (Table 6), but the specified database for LF is not available, which is an urgent need in the field of drug development and to overcome the emerging drug resistance. Some of the important databases which are available for LF research

Potential inhibitor can be designed on the basis of their binding sites or can be identified from the small-sized molecule databases such as Cambridge Structural Database [123], ChemBank [124], DrugBank [125], PubChem [126], and ZINC database [127] and databases that are available at Lignad.Info: molecule database [128] to inspect the biological activity of the particular protein.


#### Table 6.

List of online databases for lymphatic filariasis are as follows.

larvae of Brugia malayi. Some workers gathered the molecular information of the particular protein of interest through 3D structure which plays a significant role in drug designing and vaccine development for lymphatic filariasis. In 2005 Bhargavi et al. [120] analyzed the 3D model of GST of Wuchereria bancrofti and Brugia malayi for better drug development. For the development of potential drugs, novel drug targets are modeled using bioinformatics approach including either ligand-based drug designing (LBDD) or structure-based drug designing (SBDD). LBDD provides crucial understanding of the interaction between the drug target and ligand molecule and provides information about the biologically active molecules [121]. Currently 3D quantitative structural activity relationship (QSAR) and pharmacophore modeling of small molecules are carried out to define their minimum necessary structural characteristics through which it inhibits the target. These 3D structure analyses of a protein were designed from the experimental-based method such as Xray crystallography, NMR, electron microscopy, etc. If an experimental data are not available for the target proteins, homology modeling is carried out to build the 3D

Potential inhibitor can be designed on the basis of their binding sites or can be identified from the small-sized molecule databases such as Cambridge Structural Database [123], ChemBank [124], DrugBank [125], PubChem [126], and ZINC database [127] and databases that are available at Lignad.Info: molecule database

> http://ideas.repec.org/p/ess/ wpaper/id2032.html

http://www.jbtdrc.org/FilaDb.

http://www.nematodes.org/ne matodeESTs/nembase.html

http://www.wormbase.org

http://www.who.int/topics/fila

http://umis.doh.gov.ph/fila

http://www.who.int/tdrold/d iseases/lymphfil/default.htm

http://www.broadinstitute.org/ annotation/genome/filarial\_ worms/MultiHome.html

om/ddb4824.htm

htm

riasis/en/

structure using target protein sequence [122].

the literature survey

the filarial infection

other nematodes

FilaDB Database on filaria detection, clinico-immuno

NEMBASE2 Contains the EST sequence for Brugia malayi and

Wormbase It is an online database for the biology and genome of the Ce and related nematodes

WHO It contains the related publication of filariasis, reports

diseases and some important links

applied genomics and bioinformatics

This database provides the genome sequence of organisms rapidly and broadly available to the

PHIS It contains the news and updated from filariasis

elimination program

scientific community.

List of online databases for lymphatic filariasis are as follows.

DBEMFDD diseases database

Helminthiasis

Disease database

TDRlymphatic filariasis

Filarial worms database

Table 6.

54

[128] to inspect the biological activity of the particular protein.

Name Description URL

It is an annotated bibliography for filariasis, malaria, dengue, and diarrhea. It also contains the findings of

monitoring, and management has been developed for Kasturba Hospital and private practitioners to screen

of elimination program, control of neglected tropical

It contains knowledge about the parasite genomes for African lymphatic filariasis and other diseases TDR is now focusing on providing capacity to use the parasite genome data and on supporting developments in

Filaria Journal Full and freely access journal of filariasis http://www.filariajournal.com/

It contains the general information regarding diseases http://www.diseasesdatabase.c

## 8.3 Web-based available resources for LF

Web-based biological data plays a significant role in bioinformatics which plays a significant role in analyzing biological data for large amount of nucleotide sequences, amino acid sequences, and 2D or 3D structures for the broad range of organisms and their drug targets. Currently, there are only few databases available for LF (Table 6), but the specified database for LF is not available, which is an urgent need in the field of drug development and to overcome the emerging drug resistance. Some of the important databases which are available for LF research have been discussed below.

NEMBASE: It contains databases containing information of filarial nematodes such as filarial biology and pathology, nomenclature of filarial genome, mapping of filarial gene, and Bm genome survey sequencing (GSS). Recently, genome sequencing of wBm and Onchocerca volvulus (Ov) was also included with the Sanger Institute, NEB, and TIGR.

WormBase: It's an open access database repository for nematode biology which contains the genome browser for Bm, C. elegans, H. contortus, etc., and the gene predictions and orthology assignments from a range of related nematodes.

FilaDB: It is a database for screening filarial patients with the objective of providing information on the incidence of mf and types of acute, chronic, and occult manifestations and age, sex, and distribution area of filariasis cases for clinico-immuno monitoring and management of filariasis.

Filarial worm database at broad institute: This database used to study the minute phenotypic difference between the closely related filarial species of Loa loa, Wb, and Ov (http://www.filariasiscenter.org/brugia-malayigenomics-and-bioinformatics-re sources). Filarial worm database also has the sequence data on Wolbachia endosymbionts of Wb, Ov, and Bm. Filarial diseases are still remaining as a major public health concern in India. There is a need of comprehensive database, which should contain:


#### 9. Conclusions

Filariasis is one of the most disabling and disfiguring neglected tropical diseases with various clinical manifestations and a high morbidity rate. Repetitive use of antifilarials has given rise to drug resistance. Most of them are effective against

## Helminthiasis

microfilariae and have no effect on the adult worms. Till date numbers of antifilarial targets have been explored, but their evaluation with reference to assay feasibility, target validation, drugability, toxicity, resistance potential, and structural information needs to be discovered in the future. There is a need to explore the mechanism through which drug resistance occurs so that new effective combination therapy could be discovered at an early stage.

References

Filariasis

2010. pp. 1-78

[1] World Health Organization. Global programme to eliminate lymphatic filariasis. In: Lymphatic Filariasis, Progress Report 2000–2009 and Strategic Plan 2010–2020; Geneva.

DOI: http://dx.doi.org/10.5772/intechopen.89454

Neglected Tropical Diseases. Geneva:

[10] Liu LX, Weller PF. Antiparasitic drugs. The New England Journal of Medicine. 1996;334:1178-1184

[11] Pink R, Hudson A, Mouriès MA, Bendig M. Opportunities and challenges in antiparasitic drug discovery. Nature Reviews Drug Discovery. 2005;4(9):

[12] Hewitt RI, Kushner S, Stewart H, White E, Wallace W, Subbarow Y. Experimental chemotherapy of filariasis. III. Effect of 1-diethylcarbamyl-4-methylpiperazine hydrochloride against naturally

acquired filarial infections in cotton rats and dogs. Journal of Laboratory and Clinical Medicine. 1947;32:1314-1329

[13] Babu S, Nutman TB. Immunology of

[14] Mandvikar A, Hande SV, Yeole P, Goswami K, Reddy MVR. Therapeutic

thiazolidine compounds against human lymphatic filarial parasite: An in vitro study. International Journal of

Pharmaceutical Sciences and Research.

[15] Rathaur S, Yadav M, Singh N, Singh A. Effect of diethylcarbamazine, butylated hydroxy anisole and methyl substituted chalcone on filarial parasite Setaria cervi: proteomic and biochemical approaches. Journal of Proteomics. 2011;

[16] Saxena R, Sharma S, Iyer RN, Anand N. Potential filaricides. 5.3- Ethyl-8-methyl-1,3,8-triazabicyclo [4.4.0]decan-2-one, a new antifilarial agent. Journal of Medicinal Chemistry.

lymphatic filariasis. Parasite Immunology. 2014;36(8):338-346

potential of novel heterocyclic

2016;7(4):1480-1492

74(9):1595-1606

1971;14(10):929-931

WHO; 2015

727-740

[2] World Health Organization. Three more countries eliminate lymphatic filariasis. 2018. Available from: https:// www.who.int/westernpacific/news/ detail/08-10-2018-three-more-

countries-eliminate-lymphatic-filariasis

[3] World Health Organization. Global Programme to eliminate lymphatic filariasis: Progress report, 2013. Weekly Epidemiological Record. 2014;89:409-418

[4] Ramaiah KD, Das PK, Michael E, Guyatt H. The economic burden of lymphatic filariasis in India.

[5] Ton TG, Mackenzie C,

Parasitology Today. 2000;16(6):251-253

Molyneux DH. The burden of mental health in lymphatic filariasis. Infectious

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communities in north-eastern Tanzania.

[7] Molyneux DH, Zagaria N. Lymphatic filariasis elimination: Progress in global programme development. Annals of Tropical Medicine and Parasitology.

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2002;96:S15-S40

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57

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[8] World Health Organization. Sustaining the drive to overcome the global impact of neglected tropical diseases. In: Second WHO Report on Neglected Tropical Diseases, Geneva.

[9] Third WHO Report on Neglected Tropical Diseases, Investing to Overcome the Global Impact of

## Author details

Sharba Kausar

Department of Microbiology, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, UP, India

\*Address all correspondence to: sharbakausar@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## References

microfilariae and have no effect on the adult worms. Till date numbers of antifilarial targets have been explored, but their evaluation with reference to assay feasibility, target validation, drugability, toxicity, resistance potential, and structural information needs to be discovered in the future. There is a need to explore the mechanism through which drug resistance occurs so that new effective combination therapy

Department of Microbiology, Jawaharlal Nehru Medical College, Aligarh Muslim

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: sharbakausar@gmail.com

could be discovered at an early stage.

Helminthiasis

Author details

University, Aligarh, UP, India

provided the original work is properly cited.

Sharba Kausar

56

[1] World Health Organization. Global programme to eliminate lymphatic filariasis. In: Lymphatic Filariasis, Progress Report 2000–2009 and Strategic Plan 2010–2020; Geneva. 2010. pp. 1-78

[2] World Health Organization. Three more countries eliminate lymphatic filariasis. 2018. Available from: https:// www.who.int/westernpacific/news/ detail/08-10-2018-three-morecountries-eliminate-lymphatic-filariasis

[3] World Health Organization. Global Programme to eliminate lymphatic filariasis: Progress report, 2013. Weekly Epidemiological Record. 2014;89:409-418

[4] Ramaiah KD, Das PK, Michael E, Guyatt H. The economic burden of lymphatic filariasis in India. Parasitology Today. 2000;16(6):251-253

[5] Ton TG, Mackenzie C, Molyneux DH. The burden of mental health in lymphatic filariasis. Infectious Diseases of Poverty. 2015;4:1-8

[6] Meyrowitsch DW, Simonsen PE, Magesa SM. A 26-year follow-up of bancroftian filariasis in two communities in north-eastern Tanzania. Annals of Tropical Medicine and Parasitology. 2004;98:155-169

[7] Molyneux DH, Zagaria N. Lymphatic filariasis elimination: Progress in global programme development. Annals of Tropical Medicine and Parasitology. 2002;96:S15-S40

[8] World Health Organization. Sustaining the drive to overcome the global impact of neglected tropical diseases. In: Second WHO Report on Neglected Tropical Diseases, Geneva. 2013. pp. 1-137

[9] Third WHO Report on Neglected Tropical Diseases, Investing to Overcome the Global Impact of

Neglected Tropical Diseases. Geneva: WHO; 2015

[10] Liu LX, Weller PF. Antiparasitic drugs. The New England Journal of Medicine. 1996;334:1178-1184

[11] Pink R, Hudson A, Mouriès MA, Bendig M. Opportunities and challenges in antiparasitic drug discovery. Nature Reviews Drug Discovery. 2005;4(9): 727-740

[12] Hewitt RI, Kushner S, Stewart H, White E, Wallace W, Subbarow Y. Experimental chemotherapy of filariasis. III. Effect of 1-diethylcarbamyl-4-methylpiperazine hydrochloride against naturally acquired filarial infections in cotton rats and dogs. Journal of Laboratory and Clinical Medicine. 1947;32:1314-1329

[13] Babu S, Nutman TB. Immunology of lymphatic filariasis. Parasite Immunology. 2014;36(8):338-346

[14] Mandvikar A, Hande SV, Yeole P, Goswami K, Reddy MVR. Therapeutic potential of novel heterocyclic thiazolidine compounds against human lymphatic filarial parasite: An in vitro study. International Journal of Pharmaceutical Sciences and Research. 2016;7(4):1480-1492

[15] Rathaur S, Yadav M, Singh N, Singh A. Effect of diethylcarbamazine, butylated hydroxy anisole and methyl substituted chalcone on filarial parasite Setaria cervi: proteomic and biochemical approaches. Journal of Proteomics. 2011; 74(9):1595-1606

[16] Saxena R, Sharma S, Iyer RN, Anand N. Potential filaricides. 5.3- Ethyl-8-methyl-1,3,8-triazabicyclo [4.4.0]decan-2-one, a new antifilarial agent. Journal of Medicinal Chemistry. 1971;14(10):929-931

## Helminthiasis

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[20] Ismail MM, Weil GJ, Jayasinghe KSA, Premaratne UN, Abeyewickreme W, Rajaratnam HN, et al. Prolonged clearance of microfilaraemia in patients with Bancroftian filariasis after multiple high doses of ivermectin of diethylcarbamazine. Transactions of the Royal Society of Tropical Medicine and Hygiene. 1996;90:684-688

[21] McCarthy JS, Guinea A, Weil GJ, Ottesen EA. Clearance of circulating filarial antigen as a measure of the macrofilaricidal activity of diethylcarbamazine in Wuchereria bancrofti infection. The Journal of Infectious Diseases. 1995;172(2):521-526

[22] Peixoto CA, Rocha A, Aguiar-Santos A, Florencio MS. The effects of diethylcarbamazine on the ultrastructure of microfilariae of Wuchereria bancrofti in vivo and in vitro. Parasitolology Research. 2004;92(6): 513-517

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[39] Singh BK, Mishra M, Saxena N, Yadav GP, Maulik PR, Sahoo MK, et al. Synthesis of 2-sulfanyl-6-methyl-1,4 dihydropyrimidines as a new class of antifilarial agents. European Journal of Medicinal Chemistry. 2008;43(12):

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disubstituted-9H-pyrido[3,4-b] indoles as new lead compounds in antifilarial chemotherapy. Journal of Medicinal Chemistry. 1999;42(9):1667-1672

[42] Hewitt RI, Kushner S, Stewart H, White E, Wallace WS, Subbarow Y. Experimental chemotherapy of filariasis. III. Effect of 1-

diethylcarbamyl-4-methylpiperazine hydrochloride against naturally

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Chemistry Letters. 2000;10(13): 1409-1412

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[50] Agarwal A, Awasthi SK, Murthy PK. In vivo antifilarial activity of some cyclic and acylic alcohols. Medicinal Chemistry Research. 2011;20(4): 430-434

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[52] Bag S, Tawari NR, Sharma R, Goswami K, Reddy MV, Degani MS. In vitro biological evaluation of biguanides and dihydrotriazines against Brugia malayi and folate reversal studies. Acta Tropica. 2010;113(1):48-51

Secondary amines as new

Filariasis

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high-affinity chalcone-benzothiazole hybrids as Brugia malayi thymidylate kinase inhibitors: In vitro validation and docking studies. European Journal Medicinal Chemistry. 2015;103:418-428

Kushwaha V, Modukuri RK, Verma R, Murthy PK. Synthesis and antifilarial activity of chalcone–thiazole derivatives against a human lymphatic filarial parasite, Brugia malayi. European Journal of Medicinal Chemistry. 2014;

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Secondary amines as new pharmacophores for macrofilaricidal drug design. Bioorganic & Medicinal Chemistry Letters. 2000;10(4):313-314

Chemistry Letters. 2000;10(13):

[52] Bag S, Tawari NR, Sharma R, Goswami K, Reddy MV, Degani MS. In vitro biological evaluation of biguanides and dihydrotriazines against Brugia malayi and folate reversal studies. Acta

[53] Tripathi RP, Tripathi R, Bhaduri AP, Singh SN, Chatterjee RK, Murthy PK. Antifilarial activity of some 2H-1 benzopyran-2-ones (coumarins). Acta

Tropica. 2010;113(1):48-51

Tropica. 2000;76(2):101-106

Bhattacharya S, Tyagi K,

Chemistry. 2015;94:211-217

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diaminoalkanes. Bioorganic & Medicinal Chemistry. 2003;11(8):1789-1800

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N1,Nn-xylofuranosylated

1-one: Effect on glutathione-Stransferase, a phase II detoxification enzyme. American Journal of Tropical Medicine and Hygiene. 2009;80(5):

87(2):215-224

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malayi thymidylate kinase. RSC Advances. 2015;5(100):82208-82214

[46] Srivastava SK, Chauhan PMS, Agarwal SK, Bhaduri AP, Singh SN, Fatima N, et al. Syntheses and antifilarial profile of 5-amino and 5,8-diamino-isoquinoline derivatives: A

new class of antifilarial agents. Bioorganic & Medicinal Chemistry Letters. 1996;6(22):2623-2628

[47] Srivastava SK, Chauhan PMS, Bhaduri AP, Fatima N, Chatterjee AK. Quinolones: Novel probes in antifilarial chemotheraphy. Journal of Medicinal Chemistry. 2000;43(11):2275-2279

[48] Roy P, Dhara D, Parida PK, Kar RJ, Bhunia A, Jana K, et al. C-cinnamoyl glycosides as a new class of anti-filarial agents. European Journal of Medicinal

[49] Sashidhara KV, Kumar A, Rao KB, Kushwaha V, Saxena K, Murthy PK. In vitro and in vivo antifilarial activity evaluation of 3,6-epoxy [1,5]

dioxocines: A new class of antifilarial agents. Bioorganic & Medicinal

Chemistry Letters. 2012;22(4):1527-1532

[50] Agarwal A, Awasthi SK, Murthy PK. In vivo antifilarial activity of some cyclic

and acylic alcohols. Medicinal Chemistry Research. 2011;20(4):

as potential antifilarial agents. Parasitology. 2013;140(8):959-965

[51] Sharma RD, Bag S, Tawari NR, Degani MS, Goswami K, Reddy MVR. Exploration of 2,4-diaminopyrimidine and 2,4-diamino-s-triazine derivatives

430-434

60

Chemistry. 2016;114:308-317

1409-1412

Helminthiasis

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[61] Rao RU, Huang Y, Fischer K, Fischer PU, Weil GJ. Brugia malayi: Effects of nitazoxanide and tizoxanide on adult worms and microfilariae of filarial nematodes. Experimental Parasitology. 2008;121(1):38-45

[62] Kausar S, Khan W, Azam A. The effect of DEC, NTZ and NTZ + AgNPs on the TCA cycle enzymes of the microfilariae of Setaria cervi in vitro. Asian Journal of Pharmacy and Pharmacology. 2016;2(6):154-161

[63] Kausar S, Khan W. Comparative efficacy of diethylcarbamazine, nitazoxanide and nanocomposite of nitazoxanide and silver nanoparticles on the dehydrogenases of TCA cycle in Setaria cervi, in vitro. Iranian Journal of Parasitology. 2018;13(3):399-405

[64] Dhananjeyan MR, Milev YP, Kron MA, Nair MG. Synthesis and activity of substituted anthraquinones against a human filarial parasite, Brugia malayi. Journal of Medicinal Chemistry. 2005;48(8):2822-2830

[65] Bahekar SP, Hande SV, Agarwal NR, Chandak HS, Bhoj PS, Goswami K, et al. Sulfonamide chalcones: Synthesis and in vitro exploration for therapeutic potential against Brugia malayi. European Journal Medicinal Chemistry. 2016;124:262-269

[66] Sashidhara KV, Avula SR, Doharey PK, Singh LR, Balaramnavar VM, Gupta J, et al. Designing, synthesis of selective and high-affinity chalcone-benzothiazole hybrids as Brugia malayi thymidylate kinase inhibitors: In vitro validation and docking studies. European Journal Medicinal Chemistry. 2015;103:418-428

[67] Sashidhara KV, Rao KB, Kushwaha V, Modukuri RK, Verma R, Murthy PK. Synthesis and antifilarial activity of chalcone–thiazole derivatives against a human lymphatic filarial parasite, Brugia malayi. European Journal of Medicinal Chemistry. 2014; 81:473-480

[68] Raether W, Lammler G. The filaricidal effect of basically substituted 2,6-bis-benzimidazoles in Litomosoides carinii infection of the cotton rat (Sigmodon hispidus). Annals of Tropical Medicine and Parasitology. 1971;65(1): 107-115

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[97] Al-Abd NM, Nor ZM, Mansor M, Hasan MS, Kassim M. Antifilarial and antibiotic activities of methanolic extracts of Melaleuca cajuputi flowers. Korean Journal of Parasitology. 2016;

[98] Misra S, Verma M, Mishra SK, Srivastava S, Lakshmi V, Misra-Bhattacharya S. Gedunin and

photogedunin of Xylocarpus granatum possess antifilarial activity against human lymphatic filarial parasite Brugia malayi in experimental rodent host. Parasitology Research. 2011;109:

[99] Sahare KN, Anandhraman V, Meshram VG, Meshram SU, Reddy MV, Tumane PM, et al. Anti-microfilarial activity of methanolic extract of Vitex negundo and Aegle marmelos and their phytochemical analysis. Indian Journal of Experimental Biology. 2008;46(2):

[100] Sahare KN, Singh V. In-vitro antifilarial activity of methanol extract of Aegle marmelos. Indo American Journal of Pharmaceutical Research.

[101] Saini P, Mukherjee N, Mukherjee S,

Diospyros perigrena bark extract induced apoptosis in filarial parasite Setaria cervi through generation of reactive oxygen species. Pharmaceutical Biology. 2015;

[102] Ray AS, Joardar N, Mukherjee S, Rahaman CH, Babu SPS. Polyphenol

Roy P, Gayen P, Kumar D, et al.

520-531

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1351-1360

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53(6):813-823

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[90] Singh R, Khan NU, Singhal KC. In vitro antifilarial activity of Sencio nudicaulis Buch. Ham.—Effect on Setaria cervi (Nematoda Filarioidea). Indian Journal of Physiology and Pharmacology. 1996;40(3):231-236

[91] Saxena K, Dube V, Kushwaha V, Gupta V, Lakshmi M, Mishra S, et al. Antifilarial efficacy of Hibiscus

sabdariffa on lymphatic filarial parasite Brugia malayi. Medicinal Chemistry Research. 2011;20(9):1594-1602

[92] Mathew N, Misra-Bhattacharya S, Perumal V, Muthuswamy K. Antifilarial

Trachyspermum ammi. Molecules. 2008;

[93] Sashidhara KV, Singh SP, Misra S, Gupta J, Misra-Bhattacharya S.

Galactolipids from Bauhinia racemosa as a new class of antifilarial agents against human lymphatic filarial parasite, Brugia malayi. European Journal of Medicinal Chemistry. 2012;50:230-235

[94] Singha M, Shakya S, Soni VK, Dangi A, Kumar N, Misra-Bhattacharya S. The n-hexane and chloroform fractions of Piper betle L. trigger different arms of immune responses in BALB/c mice and exhibit antifilarial activity against human lymphatic filarid

Brugia malayi. International Immunopharmacology. 2009;9(6):

[95] Saini P, Gayen P, Nayak A, Kumar D, Mukherjee N, Pal BC, et al. Effect of ferulic acid from Hibiscus mutabilis on filarial parasite Setaria cervi:

716-728

63

lead molecules isolated from

13(9):2156-2168

PLoS One. 2014;9:1-13

Filariasis

[82] Yu Z, Vodanovic-Jankovic S, Kron M, Shen B. New WS9326A congeners from Streptomyces sp. 9078 inhibiting Brugia malayi asparaginyltRNA synthetase. Organic Letters. 2012; 14(18):4946-4949

[83] Rateb ME, Yang D, Vodanovic-Jankovic S, Yu Z, Kron MA, Shen B. Adipostatins A–D from Streptomyces sp. 4875 inhibiting Brugia malayi asparaginyl-tRNA synthetase and killing adult Brugia malayi parasites. The Journal of Antibiotics. 2015;68:540-542

[84] Misra N, Sharma M, Raj K, Dangi A, Srivastava S, Misra-Bhattacharya S. Chemical constituents and antifilarial activity of Lantana camara against human lymphatic filariid Brugia malayi and rodent filariid Acanthocheilonema viteae maintained in rodent hosts. Parasitology Research. 2007;100(3): 439-448

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14(18):4946-4949

439-448

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[92] Mathew N, Misra-Bhattacharya S, Perumal V, Muthuswamy K. Antifilarial lead molecules isolated from Trachyspermum ammi. Molecules. 2008; 13(9):2156-2168

[93] Sashidhara KV, Singh SP, Misra S, Gupta J, Misra-Bhattacharya S. Galactolipids from Bauhinia racemosa as a new class of antifilarial agents against human lymphatic filarial parasite, Brugia malayi. European Journal of Medicinal Chemistry. 2012;50:230-235

[94] Singha M, Shakya S, Soni VK, Dangi A, Kumar N, Misra-Bhattacharya S. The n-hexane and chloroform fractions of Piper betle L. trigger different arms of immune responses in BALB/c mice and exhibit antifilarial activity against human lymphatic filarid Brugia malayi. International Immunopharmacology. 2009;9(6): 716-728

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[96] Gaur RL, Sahoo MK, Dixit S, Fatima N, Rastogi S, Kulshreshtha DK, et al. Antifilarial activity of Caesalpinia bonducella against experimental filarial infections. Indian Journal of Medical Research. 2008;128(1):65-70

[97] Al-Abd NM, Nor ZM, Mansor M, Hasan MS, Kassim M. Antifilarial and antibiotic activities of methanolic extracts of Melaleuca cajuputi flowers. Korean Journal of Parasitology. 2016; 54(3):273-280

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[99] Sahare KN, Anandhraman V, Meshram VG, Meshram SU, Reddy MV, Tumane PM, et al. Anti-microfilarial activity of methanolic extract of Vitex negundo and Aegle marmelos and their phytochemical analysis. Indian Journal of Experimental Biology. 2008;46(2): 128-131

[100] Sahare KN, Singh V. In-vitro antifilarial activity of methanol extract of Aegle marmelos. Indo American Journal of Pharmaceutical Research. 2013;3(6):1-7

[101] Saini P, Mukherjee N, Mukherjee S, Roy P, Gayen P, Kumar D, et al. Diospyros perigrena bark extract induced apoptosis in filarial parasite Setaria cervi through generation of reactive oxygen species. Pharmaceutical Biology. 2015; 53(6):813-823

[102] Ray AS, Joardar N, Mukherjee S, Rahaman CH, Babu SPS. Polyphenol

enriched ethanolic extract of Cajanus scarabaeoides (L.) Thouars exerts potential antifilarial activity by inducing oxidative stress and programmed cell death. PLoS One. 2018;13(12):e0208201

[103] Mishra V, Khan NU, Singhal KC. Potential antifilarial activity of fruit extracts of Ficus racemosa Linn. against Setaria cervi in vitro. Indian Journal of Experimental Biology. 2005;43:346-350

[104] Lakshmi V, Kumar R, Gupta P, Varshney V, Srivastava MN, Dikshit M, et al. The antifilarial activity of a marine red alga, Botryocladia leptopoda, against experimental infections with animal and human filariae. Parasitology Research. 2004;93:468-474

[105] Gupta J, Misra S, Mishra SK, Srivastava S, Srivastava MN, Lakshmi V, et al. Antifilarial activity of marine sponge Haliclona oculata against experimental Brugia malayi infection. Experimental Parasitology. 2012;130(4): 449-455

[106] Lakshmi V, Srivastava S, Mishra SK, Misra S, Verma M, Misra-Bhattacharya S. In-vitro and in-vivo antifilarial potential of marine sponge, Haliclona exigua (Kirkpatrick) against human lymphatic filarial parasite Brugia malayi. Parasitology Research. 2009; 105(5):1295-1301

[107] Lakshmi V, Misra-Bhattacharya S. Antifilarial activity of Eucalyptus globulus Labill. leaves against Brugia malayi. Bangladesh Pharmaceutical Journal. 2016;19:44-47

[108] Behera DR, Bhatnagar S. Assessment of macrofilaricidal activity of leaf extracts of Terminalia sp. against bovine filarial parasite Setaria cervi. Journal of Infection and Public Health. 2018;11(5):5643-5647

[109] Kushwaha V, Saxena K, Verma SK, Lakshmi V, Sharma RK, Murthy PK. Antifilarial activity of gum from Moringa oleifera Lam. on human lymphatic filaria Brugia malayi. Chronicles of Young Scientists. 2016;2:201-206

[117] Nuchprayoon S, Junpee A, Poovorawan Y. Random amplified polymorphic DNA (RAPD) for differentiation between Thai and Myanmar strains of Wuchereria bancrofti. Filaria Journal. 2007;6:6

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[128] Von Grotthuss M, Koczyk G, Pas J, Wyrwicz LS, Rychlewski L. Ligand: Info

[126] Li Q, Cheng T, Wang Y, Bryant SH. PubChem as a public resource for drug discovery. Drug Discovery Today. 2010;15:1052-1057

Modeling. 2005;45:177-182

small-molecule meta-database. Combinatorial Chemistry & High Throughput Screening. 2004;7:757-761

[118] Ghedin E, Wang S, Spiro D, Caler E, Zhao Q, Crabtree J, et al. Draft genome of the filarial nematode parasite Brugia malayi. Science. 2007;317:

[119] Bennuru S, Meng Z, Ribeiro JM, Semnani RT, Ghedin E, Chan K, et al. Stage-specific proteomic expression patterns of the human filarial parasite Brugia malayi and its endosymbiont Wolbachia. Proceedings of the National Academy of Sciences of the United States of America. 2011;108:9649-9654

[120] Bhargavi R, Vishwakarma S, Murty US. Modeling analysis of GST (glutathione-s-transferases) from Wuchereria bancrofti and Brugia malayi.

Bioinformation. 2005;1:25-27

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[122] Anderson AC. The process of structure-based drug design. Chemical

[123] Allen FH, Taylor R. Research applications of the Cambridge structural database (CSD). Chemical Society

[124] Seiler KP, George GA, Happ MP, Bodycombe NE, Carrinski HA,

Norton S. ChemBank: A small-molecule screening and cheminformatics resource database. Nucleic Acids Research. 2008;

Biology. 2003;10:787-797

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36:D351-D359

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10-22

[110] Sahare KN, Anandharaman V, Meshram VG, Meshram SU, Gajalakshmi D, Goswami K, et al. In vitro effect of four herbal plants on the motility of Brugia malayi microfilariae. Indian Journal of Medical Research. 2008;127(5):467-471

[111] Deshmukh M, Sahare KN, Patidar RK, Mahajan B, Singh V. Antifilarial activity of Butea monosperma L. leaves extracts against Setaria cervi. Trends in Vector Research and Parasitology. 2014;1:1-5

[112] Shanmugapriya R, Ramnathan T. Antifilarial activity of seed extracts of Ricinus communis against Brugia malayi. Journal of Pharmacy Research. 2012; 5(3):1448-1450

[113] Lakshmi V, Joseph SK, Srivastava S, Verma SK, Sahoo MK, Dube V, et al. Antifilarial activity in vitro and in vivo of some flavonoids tested against Brugia malayi. Acta Tropica. 2010;116(2):127-133

[114] Srinivasan L, Mathew N, Muthuswamy K. In vitro antifilarial activity of Glutathione S transferase inhibitors. Parasitology Research. 2009; 105(4):1179-1182

[115] Casiraghi M, Anderson TJ, Bandi C, Bazzocchi C, Genchi CA. Phylogenetic analysis of filarial nematodes: Comparison with the phylogeny of Wolbachia endosymbionts. Parasitology. 2001;122:93-103

[116] Hoerauf A, Nissen-Pahle K, Schmetz C, Henkle-Duhrsen K, Blaxter ML, Buttner DW, et al. Tetracycline therapy targets intracellular bacteria in the filarial nematode Litomosoides sigmodontis and results in filarial infertility. Journal of Clinical Investigation. 1999;103:11-17

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[117] Nuchprayoon S, Junpee A, Poovorawan Y. Random amplified polymorphic DNA (RAPD) for differentiation between Thai and Myanmar strains of Wuchereria bancrofti. Filaria Journal. 2007;6:6

enriched ethanolic extract of Cajanus scarabaeoides (L.) Thouars exerts

potential antifilarial activity by inducing oxidative stress and programmed cell death. PLoS One. 2018;13(12):e0208201

oleifera Lam. on human lymphatic filaria Brugia malayi. Chronicles of Young

[110] Sahare KN, Anandharaman V, Meshram VG, Meshram SU,

Gajalakshmi D, Goswami K, et al. In vitro effect of four herbal plants on the motility of Brugia malayi microfilariae. Indian Journal of Medical Research.

[111] Deshmukh M, Sahare KN, Patidar RK, Mahajan B, Singh V.

Antifilarial activity of Butea monosperma L. leaves extracts against Setaria cervi. Trends in Vector Research and Parasitology. 2014;1:1-5

[112] Shanmugapriya R, Ramnathan T. Antifilarial activity of seed extracts of Ricinus communis against Brugia malayi. Journal of Pharmacy Research. 2012;

Scientists. 2016;2:201-206

2008;127(5):467-471

5(3):1448-1450

105(4):1179-1182

2001;122:93-103

[113] Lakshmi V, Joseph SK,

[114] Srinivasan L, Mathew N, Muthuswamy K. In vitro antifilarial activity of Glutathione S transferase inhibitors. Parasitology Research. 2009;

analysis of filarial nematodes: Comparison with the phylogeny of Wolbachia endosymbionts. Parasitology.

[116] Hoerauf A, Nissen-Pahle K, Schmetz C, Henkle-Duhrsen K, Blaxter ML, Buttner DW, et al. Tetracycline therapy targets intracellular bacteria in the filarial nematode Litomosoides sigmodontis and results in filarial infertility. Journal of Clinical Investigation. 1999;103:11-17

[115] Casiraghi M, Anderson TJ, Bandi C, Bazzocchi C, Genchi CA. Phylogenetic

Srivastava S, Verma SK, Sahoo MK, Dube V, et al. Antifilarial activity in vitro and in vivo of some flavonoids tested against Brugia malayi. Acta Tropica. 2010;116(2):127-133

[103] Mishra V, Khan NU, Singhal KC. Potential antifilarial activity of fruit extracts of Ficus racemosa Linn. against Setaria cervi in vitro. Indian Journal of Experimental Biology. 2005;43:346-350

[104] Lakshmi V, Kumar R, Gupta P, Varshney V, Srivastava MN, Dikshit M, et al. The antifilarial activity of a marine red alga, Botryocladia leptopoda, against experimental infections with animal and human filariae. Parasitology Research.

[105] Gupta J, Misra S, Mishra SK, Srivastava S, Srivastava MN,

[106] Lakshmi V, Srivastava S,

Mishra SK, Misra S, Verma M, Misra-Bhattacharya S. In-vitro and in-vivo antifilarial potential of marine sponge, Haliclona exigua (Kirkpatrick) against human lymphatic filarial parasite Brugia malayi. Parasitology Research. 2009;

[107] Lakshmi V, Misra-Bhattacharya S. Antifilarial activity of Eucalyptus globulus Labill. leaves against Brugia malayi. Bangladesh Pharmaceutical

Assessment of macrofilaricidal activity of leaf extracts of Terminalia sp. against bovine filarial parasite Setaria cervi. Journal of Infection and Public Health.

[109] Kushwaha V, Saxena K, Verma SK, Lakshmi V, Sharma RK, Murthy PK. Antifilarial activity of gum from Moringa

Lakshmi V, et al. Antifilarial activity of marine sponge Haliclona oculata against experimental Brugia malayi infection. Experimental Parasitology. 2012;130(4):

2004;93:468-474

Helminthiasis

105(5):1295-1301

Journal. 2016;19:44-47

2018;11(5):5643-5647

64

[108] Behera DR, Bhatnagar S.

449-455

[118] Ghedin E, Wang S, Spiro D, Caler E, Zhao Q, Crabtree J, et al. Draft genome of the filarial nematode parasite Brugia malayi. Science. 2007;317: 1756-1760

[119] Bennuru S, Meng Z, Ribeiro JM, Semnani RT, Ghedin E, Chan K, et al. Stage-specific proteomic expression patterns of the human filarial parasite Brugia malayi and its endosymbiont Wolbachia. Proceedings of the National Academy of Sciences of the United States of America. 2011;108:9649-9654

[120] Bhargavi R, Vishwakarma S, Murty US. Modeling analysis of GST (glutathione-s-transferases) from Wuchereria bancrofti and Brugia malayi. Bioinformation. 2005;1:25-27

[121] Acharya C, Coop A, Polli JE, Mackerell AD Jr. Recent advances in ligand-based drug design: Relevance and utility of the conformationally sampled pharmacophore approach. Current Computer-Aided Drug Design. 2011;7: 10-22

[122] Anderson AC. The process of structure-based drug design. Chemical Biology. 2003;10:787-797

[123] Allen FH, Taylor R. Research applications of the Cambridge structural database (CSD). Chemical Society Reviews. 2004;33:463-475

[124] Seiler KP, George GA, Happ MP, Bodycombe NE, Carrinski HA, Norton S. ChemBank: A small-molecule screening and cheminformatics resource database. Nucleic Acids Research. 2008; 36:D351-D359

[125] Knox C, Law V, Jewison T, Liu P, Ly S, Frolkis A, et al. DrugBank 3.0: A comprehensive resource for 'omics' research on drugs. Nucleic Acids Research. 2011;39:D1035-D1041

[126] Li Q, Cheng T, Wang Y, Bryant SH. PubChem as a public resource for drug discovery. Drug Discovery Today. 2010;15:1052-1057

[127] Irwin JJ, Shoichet BK. ZINC: A free database of commercially available compounds for virtual screening. Journal of Chemical Information and Modeling. 2005;45:177-182

[128] Von Grotthuss M, Koczyk G, Pas J, Wyrwicz LS, Rychlewski L. Ligand: Info small-molecule meta-database. Combinatorial Chemistry & High Throughput Screening. 2004;7:757-761

**67**

**Chapter 5**

Region

**Abstract**

**1. Introduction**

*Ingrid Papajová and Jindřich Šoltys*

Nematode Infections Spread in

Slovakia, an European Temperate

Nematode parasitic infections in the twenty-first century present a serious problem. They occur not only in developing but also in industrialised countries of temperate regions. It is well-known that these infections are common for communities living in poverty. Large numbers of nematode infections are transmitted via the faecal-oral route, where invasive parasitic eggs are excreted into the environments by the definitive hosts. The aim of this chapter is to investigate the occurrence of the most important nematode infections spread in major populations and population living under low hygienic standard conditions in the Slovak Republic territory. The data are compared with data available within European Union countries. The incidence of nematodes in domestic animals increases the health risks in low-privilege population. Contamination of the environment with nematodes as well as proposed

countermeasures in urban and rural localities are discussed and suggested.

Zoonoses are diseases transmitted by its natural way between man and animals pose a serious health risk. Principally, the zoonoses transmission is accomplished through close contact with domestic animals, especially dogs and cats, with whom we share more than 60 parasitic species [1]. Of about more than 370 parasite species, 40 of them are classified as zoonotic. According to the WHO data [2, 3], more than 2 billion people are affected by parasitic zoonoses. This is happening not only within developing but also in the industrialised countries, including Slovakia. Zoonotic diseases are mainly transmitted through the soil or water. Primarily, they are represented by endoparasites such as protozoa and nematodes [4, 5]. In all of these diseases caused by endoparasites, the most likely route of man infection is oral transmission followed by the contact with infected humans and animals (wild, stray, and domestic), with contaminated food, soil, water, or infected environment. The main sources of the infected environment are faeces from infected animals living in close vicinity with the man. Though the contact with an animal is more intense in the rural than in the urban ecosystems, the likelihood of animal diseases spread is greater between stray animals or in animals without veterinary control. The prevalence of intestinal parasitic diseases in Slovakia is due to its geographical location and relatively low good hygiene conditions. However, it may be easily

**Keywords:** nematodes, Slovakia, temperate region, environment

## **Chapter 5**
