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Review on Anthelmintic Drugs

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Review Article

Review on Anthelmintic Drugs

DEOKATE U.A., SANDHYA BHIMRAO LAHANE, AHIRE SUJEETKUMAR
Government College Of Pharmacy, Aurangabad, Maharashtra, INDIA, 431005.

ABSTRACT
Anthelmintic Drugs-used against invasion of parasitic worms (Helminthiasis) Roundworms, pinworms,
whipworms, hookworms and tapeworms. Broad spectrum anthelmintics are effective against parasitic flat
worms and nematodes. However, the majority of drugs are more limited in their action e.g., praziquantel, a drug
used in the treatment of schistosomiasis and thought to act by disrupting calcium homeostasis, has no activity
against nematodes. Anthelmintics are drugs that are used to treat infections with parasitic worms. This includes
both flat worms, e.g., flukes and tapeworms and round worms, i.e., nematodes. It is extremely hard to eradicate
helminthiases because of the close association between these diseases and poverty. They are of huge importance
for human tropical medicine and for veterinary medicine. Helminth infections resulting to diseases such as
ascariasis, hookworm infection and schistosomiasis constitute the bulk of the 13 diseases classified as neglected
tropical diseases (NTDs) by the WHO. Despite the prevalence of parasitic worms, anthelmintic drug discovery
is the poor relation of the pharmaceutical industry. The search for novel anthelmintics has traditionally involved
two approaches, the empirical and the selective methods .The simple reason is that the nations which suffer
most from these tropical diseases have little money to invest in drug discovery or therapy.

Keywords: Helminth infection, Schistosomiasis, Anthelmintic Drugs, parasites, veterinary medicine, tropical
disease.

INTRODUCTION ubiquitous infections is such that they are

Helminth infections are one of the most
prevalent diseases in developing and devel-
oped countries [1]. Globally, an estimated 2
billion people are infected by intestinal nema-
todes [2]. Anthelmintic drugs are used for
the control of parasitic infection caused by
helminths. The demand for new and effective
anthelmintic is immense, as the chemically
drugs currently employed in the control of
helminth is expensive and most of them lose
their efficacy in 20 years due to the problem
of resistance. It is extremely hard to eradicate
helminthiases because of the close association
between these diseases and poverty. The
clinical development of these common and
generally neglected until they become manifest.
They are more frequent in hot climates and
in places with poor sanitary conditions, the
presence of large water tanks and carriers of
parasites, and contaminated food and water.
This does not mean, however, that good
economic conditions constitute a complete
safeguard against such infections. Moreover,
individuals from more affluent countries might
well acquire such infections during travel to
more endemic regions. Until such time as
effective vaccines can be discovered,
antihelminthic chemotherapy is the only effec-
tive, practical, and inexpensive way of keeping
such infections under control. Helminth infec-

 Address for correspondence:

Sandhya Bhimrao Lahane, Government College of Pharmacy, Aurangabad, Maharashtra, INDIA, 431005.
E-mail address: sandhyabl.lahane@gmail.com, Phone: +91-9021823446
Received: 18/04/2014, Revised: 10/05/2014, Accepted: 25/05/2014

International Journal of Pharmaceutical Research | July-September 2014 | Volume 6 | Issue 3

| 1
 Lahane et al / A review on anthelmintic drugs
tions resulting to diseases such as ascariasis,
hookworm infection and schistosomiasis consti-
tute the bulk of the 13 diseases classified as
neglected tropical diseases (NTDs) by the
WHO. The search for novel anthelmintics has
traditionally involved two approaches, the em-
pirical and the selective methods [3]. The
empirical approach involves the screening of
large numbers of chemicals, quite unrelated to
each other, possessing no known anthelmintic
activity, and screened in the hope that one or
more of them may exhibit sufficient activity to
constitute a chemical lead. This method is
most commonly used in large-scale drug de-
velopment programs [4].The selective ap-
proach involves biological investigation of the
activity of chemicals allied structurally to those
known to possess activity against a particular
organism. The major objective of this ap-
proach is increased activity or decreased tox-
icity through chemical modification of the par-
ent compound. This approach has recently
been used in a drug development program
funded by a Primate Foundation.
CLASSES OF ANTHELMINTIC DRUGS
Benzimidazole
The first of this class, thiabendazole, was
discovered in 1961 and subsequently a num-
ber of further benzamidazoles were introduced
as broad spectrum anthelmintics. There is an
extensive literature on these compounds re-
porting a number of different biochemical ef-
fects. Nonetheless, it is clear that their an-
thelmintic efficacy is due to their ability to
compromise the cytoskeleton through a selec-
tive interaction with β-tubulin [5-6]. BZD
anthelmintics are extensively metabolized in all
mammalian species studied [7]. Albendazole a benzimidazole carbamate (me-
Thiabendazole, mebendazole, and albendazole
belong to this class of drugs.
Mechanism of Action [5]
It inhibits the microtubule formation. So the
parasite loses its cytoskeleton and motility and
dies. It also impairs glucose uptake and ↓
ATP formation. However, beside the tubulin,
2 | International Journal of Pharmaceutical Research | July-September 2014 | Volume 6 | Is-
sue 3
other mechanisms of action have been de-
scribed for the BZs including disruption of the
energy metabolism of the host. In fact initial
studies of the mode of action of BZs focused
on their role in carbohydrate metabolism as
these compounds have been shown to inhibit
glucose uptake both in vitro and in vivo in
many helminth species. Albendazole has been
shown to block glucose uptake by larval and
adult stages of susceptible Parasites, depleting
their glycogen stores and decreasing formation
of ATP leading to the death of the parasite
[8]. Mebendazole [5-9] and flubendazole
[9] induce the loss of cytoplasmic microtu-
bules of the tegumental and intestinal cells of
cestodes and nematodes, and this is followed
by loss of transport of secretary vesicles, a
decreased glucose uptake and an increased
utilization of stored glycogen. The literature
survey recently, shown that mebendazole
(MBZ), a marketed benzimidazole (BZ)
antihelminthic, is an effective anti-melanoma
agent given its ability to disrupt microtubule
stability at clinically achievable concentrations,
thereby inducing apoptosis.
Albendazole (ABZ)
Albendazole acts by blocking the glucose
uptake of larvae. The adult worm stored De-
pletes of glycogen hence, Decreases the for-
mation of ATP, as a result the parasite is
immobilized and dies [10].It is another mar-
keted antihelminthic that is structurally related
to MBZ. ABZ, however, has the unique ad-
vantage of crossing the BBB, a characteristic
that is used to treat parasitic infections of the
central nervous system and may be harnessed
to potentially target brain metastasis.
thyl 5- propylthio-1H-benzimidazole-2-yl
carbamate) is a broad spectrum antiparasitic
which is used worldwide against a variety of
parasites [11-12]. Studies conducted on the
mechanism of action of BZs have demonstrat-
ed that, by binding to tubulin, these drugs
inhibit micro- tubule polymerization [5-13].
Inhibitors of microtu-bule polymerization have
 Lahane et al / A review on anthelmintic drugs
been shown to exhibit experimentally and clin-
ically, useful antitumor activity [14].
Albendazole (ABZ) is a benzimidazole
(BZD) methylcarbamate molecule which ex-
hibits high efficacy against a broad-spectrum
of helminth parasites, including lung- worms,
adult and larval stages of most gastrointestinal
(GI) nematodes, cestodes and trematodes
[15]. Anthelrnintic Activity in Man numerous
clinical trials have been conducted to deter-
mine the efficacy of albendazole against
nematodes and cestode infections in man
[16-19]. The results of these studies indicate
that albendazole appears to be an effective
single dose treatment for use against Ascaris
lumbricoides, Necator americanus, Ancylostoma
duodenale, and Trichuris and Enterobius
vermicularis. Lesser levels of activity against
Strongyloides stercoralis were also observed.
The drug was only fairly active against the
cestodes, Hymenolepis nana and Taenia
saginata. The dose indication for hydatid and
neurocysticercosis is shown in table no. 1.
Ovicidal effect was observed against the eggs
of Ascaris, hookworm and trichuris, and
against the migrating larval stage of N.
americanus.
Thiabendazole
The benzimidazole drugs bind selectively to
beta-tubulin of nematodes, cestodes and
fluke, and inhibit microtubule for-
mation. Thiabendazole is effective against:
 Strongyloidiasis
 cutaneous Larva Migrans
 Trichinosis
Thiabendazole affects microtubular aggregation.
Among the anthelminthics available for the
treatment of human strongyloidosis, the
benzimidazole compound, thiabendazole is
considered effective in 75–96% of cases, alt-
hough with considerable adverse effects[20] ;
while its therapeutic alternative, albendazole
has a cure rate of 42–100%, depending on
the dose schedule and length of follow-up. At
International Journal of Pharmaceutical Research | July-September 2014 | Volume 6 | Issue 3
this stage there was little knowledge of the
mechanisms of action of the benzimidazoles in
echinococcosis, and experimental work was
limited. The therapeutic arsenal available at
present for the treatment of human
strongyloidosis is limited to thiabendazole and
its alternative, albendazole. Thiabendazole
therapy is however, frequently associated with
considerable adverse reactions. This has ne-
cessitated the need for better and safer ther-
apeutic alternatives.
Levamisole, Butamisole, Pyrantel,
Morantel, Oxantel, Bephenium and
Thenium
Levamisole
Although levamisole has been on the market
as long as the benzimidazole drugs, and has
also been widely used, it has been shown
that H. contortus has not developed resistance
against levamisole to the same extent as it
has to the benzimidazoles. There are the
imidazothiazoles (levamisole and butamisole);
the tetrahydropyrimidines (pyrantel, morantel
and oxantel); the quaternatT ammonium
salts (bephenium and theniuna) and tile
pyrimidines (methyridine). These compounds
act selectively as agonists at synaptic and
extra synaptic nicotinic acetylecholine receptors
on nematode muscle cells and produce con-
traction and spastic paralysis. These
anthelmintics are nicotinic receptor agonists
[21-22] and elicit spastic muscle paralysis
due to prolonged activation of the excitatory
nicotinic acetylcholine (nACh) receptors on
body wall muscle. Their precise mode of ac-
tion has been carefully studied at the single-
channel level on the body wall muscle prepa-
ration of A. suum [23]. Pharmacological analy-
sis has provided evidence for subtypes of
nACh receptor [24], an N-type (preferentially
activated by nicotine), a B-type (preferen-
tially activated by bephenium) and an L-type
(preferentially activated by levamisole and as-
sociated with levamisole resistance).
Pyrantel and its analogues
They produce depolarization, increased spike
| 3
 Lahane et al / A review on anthelmintic drugs
activity and contraction when applied to
Ascaris muscle [22] suggesting that these
compounds have a common mode of action
pyrantel pomoate Causes depolarizing type of
paralysis (spastic paralysis) of the hel-
minthes. So, cannot retain original position
and comes out through stool with normal
peristalsis.
Macrocyclic Lactones and Milbemycins
Avermectin
The discovery of a chemically distinct group of
anthelmintics, the avermectins [25], provided
a welcome alternative. However, since their
introduction in the early 1980s sheep nema-
todes resist- ant to one of these compounds,
ivermectin, have been identified. The
avermectins are a group of broad- spectrum,
macrocyclic, lactone antibiotic anthel- mintics
used to control nematode parasites in man
and animals [26], and assumed to have the
same mode of action in both [27]. They are
used to control onchocerciasis (river blind-
ness) in humans and gastrointestinal, cardiac
and respiratory nematode parasites of domestic
animals. The mode of action of the
avermectins is to selectively paralyse the par-
asite by increasing muscle CI- permeability,
but the identity of the channel targeted by the
avermectins has been controversial [29]. The
avermectins increase the opening of gluta-
mate-gated chloride (glucose) channels and
produce paralysis of pharyngeal pumping. The
effects of avermectins, at low concentrations,
are to potentiate the effect of glutamate, and
at higher concentrations, the avermectins open
the glutamate gated channel directly.
Ivermectin
lvermectin (22.23-dihydroavermectin Bl), a
derivative of avermectin A, is a member of
the family of substances produced by Strepto-
myces avermitilis [27]. Ivermectin was first
introduced for use against internal parasites of
equids in1981. Ivermectin was introduced as
an anthelmintic in the 1980s by Merck. It is
a semi-synthetic derivative of avermectin
4 | International Journal of Pharmaceutical Research | July-September 2014 | Volume 6 | Is-
sue 3
which is a large macrocyclic lactone fermenta-
tion product of the micro-
organism Streptomyces avermitilis. Anthelmintic
Activity Ivermectin is active against many
nematode species (has stage specificity),
insects and acarine parasites. Preliminary tests
indicate that the drug is not active against
trematodes and cestodes [16-27-31].
Ivermectin has not been tested against gas-
trointestinal nematodes in humans. Ivermectin
appears to paralyze nematodes and arthropods
by intensifying GABA mediated transmission of
signals in the peripheral nerves. In
Onchcerciasis, Ivermectin is microfilaricidal and
affects embryogenesis. Ivermectin elicits a po-
tent and persistent paralysis of nematode
pharyngeal [32-33] and body wall muscula-
ture [34-35]. It has been shown to interact
with a range of ligandgated ion channels in-
cluding α7 nACh receptors [36], acetylcholine-
gated chloride channels [37], GABA-gated
chloride channels [38-39], histamine-gated
chloride channels [40], glycine receptors [41]
and P2X4 receptors [42]. However, it is its
high affinity for nematode glutamate-gated
chloride channels (Glucose) that correlates
with its potent anthelmintic activity.
Other drugs
Amino acetonitrile derivatives and
spiroindoles
We are fortunate that two new anthelmintic
classes have been introduced, the Amino-
Acetonitrile Derivatives (aads) and the
spiroindoles, with monepantel (Zolvix®) and a
derquantel/abamectin combination (Startect®),
as the initial products. It is important that
strategies be developed to ensure that the
anthelmintics available (old and new) remain
effective as long as possible and livestock
producers must recognize the need for both
parasites control a sustainability of production.
It is obvious that there are numerous other
compounds in early developmental stages
which deserve discussion in an article such as
the present one, however limitation on length
of this presentation precludes a full considera-
 Lahane et al / A review on anthelmintic drugs

tion of their potential. A brief summary of worm infections and which inversely damage
some of those compounds are given. proximal segment separating worms from the
intestinal wall and thus expelling them out of
Niclosamide
Niclosamide was the drug of choice for tape- the host body [43].
Table 1: Indication of dose of albendazole for treatment.
Indication Patient Weight Dose Duration

60 kg or greater 400 mg twice daily with meals. 2

Hydatid Disease 28 days cycle followed
15 mg/kg/day given in divided doses twice
Less than 60 kg by a 14 day ALB.
daily with meals.
60 kg or greater 400 mg twice daily with meals.
Neurocysticercosis 15 mg/kg daily given in divided dose twice 8-30 days
Less than 60 kg
daily with meals.
NOTE: When administering ALBENZA in the pre- or Post-surgical setting, optimal killing of cyst
content is achieved when 3 courses of therapy have been given.

Diethylcarbamazine increased Ca `'+ permeability of parasite

A piperazine derivative, it is active in filarial
infections. It has been suggested that it
modifies the parasite so that it becomes sus-
ceptible to the host's normal immune respons-
es. It may also interfere with the parasite's
arachidonate metabolism [43].
Oxamniquine
Active against Schistosoma mansoni, it affects
both mature and immature forms of parasite.
Its mechanism of action may involve intercala-
tion in the DNA and its selective action may
be related to the ability of the parasite to
concentrate the drug [43].
muscle and/or tegumental membranes[47].
Ro I l-3128 Ro 11-3128 [( +)-5-(o-
chlorophenyl)l .3-dihydro-3-methyl-7-nitro-
2H-1.4-benezo-diazepin-2-one]
This is a product of Hoffman-LaRoche, Basel,
Switzerland and was found to be effective
against various strains of S. mansoni and S.
haematobium in animals and man but not
against S. japonicum. In contrast to other
drugs, Ro 11-3128 appears to kill all stages
of immature schistosome equally well when
administered less than a week before expo-
sure as a prophylaxis [48].

Praziquantel Ro I l-0761 Ro 1 l-0761 [3-(3,5-dinitio-2-

The anthelmintic activity of pyrazinoisoquinoline
derivatives was discovered jointly by E. Merck
and Bayer AG in 1972. Praziquantel has a
selective effect on the tegument of trematodes
and increases permeability of calcium.
Praziquantel has a selective toxic effect on
schistosome parasites, where its mode of ac-
tion has been studied more extensively
[44,45] than in cestodes. However, the
majority of drugs are more limited in their
action, e.g., praziquantel, a drug used in the
treatment of schistosomiasis and thought to
act by disrupting calcium homeostasis (46),
has no activity against nematodes. Many ac-
tions of praziquantel may be explained by an
International Journal of Pharmaceutical Research | July-September 2014 | Volume 6 | Issue 3
thienyl)thiazolidine]
This was developed by Hoffman-LaRoche,
Basel, Switzerland and is active against S.
mansoni, S. haematobium and S. japonicum
in mice, hamsters, and man. The compound
has some activity against Leishmania donovani
in hamsters and against L. tropica in mice
[48] .
IA-4 N-Oxide IA-4 N-oxide (8-chloro-2[2-
diethylamino)ethy1]-2H-(l)-benzothiopyrano
(4,3,2,cd)-indazole 5-methanol
monomethanesul fonate)
This was developed by Parke-Davis, and
Co., Ann Arbor, Michigan. This drug is active
against S. mansoni in mice and monkeys
[49].
| 5
 Lahane et al / A review on anthelmintic drugs
CDRI 81-470 Methyl 5(6)-4-2-pyridyl
piperazino carbamoyl benzimiadazole-2-
carbamate (CDRI Comp. 81-470)
This was developed at the Central Drug Re-
search Institute, Lucknow, India and is active
against adult of A. ceylanicum and A.
caninum in hamsters and dogs respectively.
Nippostrongylus brasiliensis and H. nana in
rats, and Toxocara species from dogs and
cats, among others.
Natural anthelmintic
The synthetic anthelmintics used are not very
safe as they suffer from the problem of side
effects and toxicity and many of them are not
recommended for young children and pregnant
ladies. In the treatment of parasitic diseases,
the anthelmintic drugs are used indiscriminate-
ly.
Hence, the development and discovery of new
substances acting as anthelmintic are being
derived through plants. Various plants were
used in veneral diseases, to promote healing
of wounds, swellings, abscesses, rheumatism
and treating pain in lower extremities, skin
diseases, leucorrhoea, dysentery, dysuria and
fever [50-51].
Natural anthelmintic
 Allium sativum (Lillaceae) [52] :
Garlic has been demonstrated In vitro
to exert activity against multiple patho-
gens, including bacteria including re-
sistant strains, mycobacterium, Helico-
bacter pylori and fungi.
 Adhatoda vesica (Acanthaceae) [53].
 Butea monosperma (Fabaceae) [54-
55].
 Ficus religiosa (Moraceae) [52].
 Trichilia emetic (Meliaceae)
 The extensive traditional use of this
species has encouraged scientists to
explore several biological activities in-
cluding anti-infective, anti-inflammatory,
antischistosomal, antiplasmodial, anti-
6 | International Journal of Pharmaceutical Research | July-September 2014 | Volume 6 | Is-
sue 3
convulsant, antitrypanosomal, antioxi-
dant, antitussive, antimutagenic and
hepatoprotective properties.
Moa: Trichilia substance Tr-B and nymania 1
exhibited selective inhibitory activity towards
DNA repair-deficient yeast mutants and exert-
ed antifungal, bactericidal, antiviral, antifeedant
and growth regulating properties.
CONCLUSION
The anthelmintic drugs currently available are
still relatively few in number. Many of them
are limited in their usefulness because of
narrow spectrum of action, safety, high cost
or impractical delivery systems. Some of these
will be discontinued because of unforseen
problems such as occurrence of drug re-
sistance which needs more attention than it
presently receives. Drug development is costly
and time consuming and requires exacting
interdisciplinary interactions between researchers
using the most stringent quantitative tests to
determine toxicity, safety, mode of action and
pharmacokinetics before a drug is ever used
in clinical trials. A system of universal testing
standards accepted by all involved in drug-
development should be established. Scientists
are beginning to apply rational design to the
development of new compounds and this ap-
proach can be expected to be exploited more
in the future. From the clinical standpoint, the
future is beginning to look brighter for the
millions of persons suffering from helminth
diseases as a result of available broad spec-
trum compounds which can be used in clinics
and mass-treatment programs.
ACKNOWLEGEMENT
I would like to thanks
Dr.S.S.Khadbadi,Dr.U.A.Deokate sir for there
support.I also like to thank specially to my Fa-
ther Bhimrao B.Lahane and all family ,friends
for their love and support.
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