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Anthelmintics 1

Anthelmintics
Peter Andrews, Bayer AG, Wuppertal, Federal Republic of Germany

Achim Harder, Bayer AG, Wuppertal, Federal Republic of Germany

1. Introduction . . . . . . . . . . . . . . 1 2.3.1. Roundworm . . . . . . . . . . . . . . . 6


2. Parasitic Worms . . . . . . . . . . . . 1 2.3.2. Hookworms . . . . . . . . . . . . . . . 6
2.1. Trematodes (Flukes) . . . . . . . . . 2 2.3.3. Pinworm . . . . . . . . . . . . . . . . . 6
2.1.1. Blood Flukes . . . . . . . . . . . . . . . 2 2.3.4. Whipworm . . . . . . . . . . . . . . . . 7
2.1.2. Lung Flukes . . . . . . . . . . . . . . . 2 2.3.5. Threadworm . . . . . . . . . . . . . . . 7
2.1.3. Liver Flukes . . . . . . . . . . . . . . . 3 2.3.6. Trichina . . . . . . . . . . . . . . . . . . 7
2.1.4. Giant Intestinal Fluke . . . . . . . . . 3 2.3.7. Larvae of Toxocara canis, Toxocara
2.1.5. Lesser Intestinal Flukes . . . . . . . . 3 cati, Ancylostoma brasiliense and
2.2. Cestodes (Tapeworms) . . . . . . . . 4 Ancylostoma caninum . . . . . . . . . 8
2.2.1. Broad or Fish Tapeworm . . . . . . . 4 2.3.8. Guinea Worm . . . . . . . . . . . . . . 8
2.2.2. Beef Tapeworm . . . . . . . . . . . . . 4 2.3.9. Lymphatic Filariae . . . . . . . . . . . 8
2.2.3. Pork Tapeworm . . . . . . . . . . . . . 5 2.3.10. Convoluted Filaria . . . . . . . . . . . 8
2.2.4. Dwarf Tapeworm . . . . . . . . . . . . 5 2.3.11. African Eye Worm . . . . . . . . . . . 9
2.2.5. Dog Tapeworm . . . . . . . . . . . . . 5 3. Anthelmintic Drugs . . . . . . . . . . 9
2.3. Nematodes (Roundworms) . . . . . 5 4. References . . . . . . . . . . . . . . . . 15

1. Introduction taken as an endorsement. Chapter 2 describes


the helminth parasites of humans and the dis-
Parasitism is a special form of intimate relation- eases they cause, and Chapter 3 describes the
ship between two species. One species, the host, drugs that may be used to control the parasites.
is to some degree injured through the activities
of the other species, the parasite. The parasite
need not be parasitic through all stages of its 2. Parasitic Worms
existence. Parasites living within the host are
distinguished as endoparasites, e.g., helminths, Helminths are the wormlike organisms clas-
from those found on the surface of the body, the sified in two phyla, the flatworms (Platy-
ectoparasites, e.g., arthropods. There are forms helminthes), comprising the flukes (or trema-
of close biologic relationships other than par- todes) and the tapeworms (or cestodes), and the
asitism. Commensalism denotes an association roundworms (Nemathelminthes). The round-
beneficial to one partner and at least not dis- worms are also called nematodes. Therefore,
advantageous to the other. Mutualism (or sym- “helminth” refers to three morphologically dif-
biosis) denotes an association that is mutually ferent groups: flukes, tapeworms, and round-
beneficial. worms. Most flatworms are hermaphroditic,
This article describes only the helminth having both male and female reproductive or-
infections of humans. Infections caused by gans within the same individual, and are para-
other parasitic organisms, such as protozoa sites. In contrast, the roundworms have separate
and ectoparasites, are described elsewhere sexes and are overwhelmingly free living. Nev-
(→ Chemotherapeutics, → Dermatotherapeutic ertheless, a number of roundworm species are
Agents), as are the veterinary parasitoses parasitic, affecting humans, animals, and plants.
(→ Veterinary Drugs).
This article is not intended to be a guide
to therapy, and mention of a drug is not to be

c 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim


10.1002/14356007.a02 329
2 Anthelmintics

2.1. Trematodes (Flukes) locate human skin exposed to water and pene-
trate it. Within another 6 – 12 weeks the juvenile
2.1.1. Blood Flukes (Schistosoma spp.) schistosomes migrate through the vascular sys-
tem and lungs to their predilected sites, mature,
Three species of schistosomes cause most hu- pair, and start laying eggs. The normal lifespan
man schistosomiasis infections: Schistosoma of schistosomes is 2 – 7 years. However, some
mansoni and S. japonicum (locally also S. in- parasites can survive and produce eggs for as
tercalatum and S. mekongi) cause the intestinal long as thirty years.
form of the disease, whereas S. haematobium
(rarely S. mattheii) causes the urinary form. Clinical Features. Severe itching (cercarial
dermatitis) may occur at the site of skin penetra-
Distribution. S. haematobium: all over tion, and fever may occur during the migration
Africa, in the Near East (Syria to Iran and phase of the parasite. In established infections,
Yemen), islands off East Africa. S. mansoni: the egg incites an inflammatory reaction around
throughout most of Africa southeast of a line the site where it is deposited in the tissues. This
from Gambia to Libya, Arabian peninsula, leads to fibrosis and calcification of the blad-
Brazil, Venezuela, Surinam, some Antilles Is- der, hematuria, uretric and renal involvement,
lands. S. japonicum: southern half of continen- and bladder cancer (S. haematobium). In the in-
tal China, the Philippines; however, virtually ex- testinal form of the disease (S. mansoni and S.
tinct in Japan. S. mekongi: Laos, Cambodia. S. japonicum) symptoms encountered are diarrhea,
intercalatum: Cameroun to the Congo Basin. S. weakness, abdominal pain, splenomegaly, hep-
mattheii: restricted to southern Africa. About atic and portal fibrosis, portal hypertension, as-
270 million people are infected [13]. Annually, cites, and carcinoma of the colon. Severe infec-
about one million deaths are caused by schisto- tions with S. japonicum can interfere with nor-
somiasis [14]. mal growth and mental development.

Development. The schistosomes differ in Therapy: praziquantel, oxamniquine, metr-


many aspects from all other human flukes. They ifonate, niridazole, hycanthone.
are elongate, wormlike, and live within the blood
vessels. They have separate sexes. The adult par-
asites S. mansoni and S. japonicum are found as 2.1.2. Lung Flukes (Paragonimus spp.)
pairs in the mesenteric veins, whereas S. haema-
tobium inhabits the veins of the vesical plexus. Distribution. P. westermani: East Asia (Ko-
Adult males are 10 – 15 mm long and 0.5 – 1 mm rea, Japan, China, Philippines, Indonesia). P. kel-
wide. Their lateral body seams are folded down- licotti: North America. P. africanus: Gabon to
wards, forming a tube, the gynecophoric canal, Zaire; several other species ranging from Mex-
which holds the female, which can be up to ico to Peru. About 20 million people are infected
28 mm long. The females deposit eggs, a few [15].
dozen to several thousand per day, depending on
the species. About three fourths of the eggs laid Development. The adult parasites measure
are retained in the tissues of the body – mainly 8 – 16 mm by 4 – 6 mm. They are found in pul-
the liver and the intestinal and bladder walls – monary cysts that are formed by destroyed tissue
where they die within three weeks. The other and that connect to the respiratory passages of
eggs pass through the tissues into the lumen of the lung. Eggs are voided with the sputum or the
the intestine or the bladder. They contain a larva, feces. Once eggs reach fresh water, a larva, the
the miracidium, which hatches as soon as the miracidium, develops within 2 – 4 weeks. The
eggs are voided into fresh water. The miracid- miracidium hatches from the egg, actively pene-
ium swims through the water in search of an trates into specific aquatic snails, and multiplies.
appropriate snail (its intermediate host), pene- After 8 – 10 weeks, cercariae begin to be re-
trates the snail’s tissues, and begins to multiply. leased from the snail. They locate crabs or cray-
After 4 – 7 weeks another type of larva, the cer- fish, penetrate them, and encyst in the muscula-
caria, is released from the snail. These cercariae ture as metacercariae. The crustaceans can also
Anthelmintics 3

become infected by feeding on infected snails. the small intestine, migrate into the bile ducts,
Humans acquire the infection by ingesting raw and mature within four weeks. They may then
or improperly cooked crab meat or juice. The live for several decades. Dogs, cats, and pigs are
juvenile flukes excyst in the small intestine, pen- important reservoir hosts.
etrate the gut wall, and migrate through the di-
aphragm into the pleural cavity, where they pen- Clinical Features. Mild infections: gener-
etrate the serosal layers of the lungs. Finally they ally asymptomatic. Severe infections: dilation
arrive in the vicinity of the bronchioles. Within and fibrosis of the bile ducts, hemorrhage, diges-
six weeks they develop into adult worms in tis- tive disturbances. Chronic infections: epigastric
sue capsules that rupture and thus connect with pain, anorexia, cholangitis, liver necrosis, bile
the air ducts. These parasites can live for up to duct and pancreas carcinoma, intrahepatic cal-
twenty years. Many mammals can act as carri- culi.
ers for human lung flukes. However, their im-
portance as reservoir hosts is largely unknown. Therapy: praziquantel, bithionol.

Clinical Features. Mild infections: fever and


cough. Severe infections: dry cough, violent 2.1.4. Giant Intestinal Fluke (Fasciolopsis
blood spitting, weight loss, fever, pleural effu- buski)
sion, chest pain.
Distribution. South China, Southeast Asia,
Indonesia, and the Indian subcontinent. Two to
Therapy: praziquantel, bithionol.
ten million people are infected [15].

Development. The eggs of the giant intesti-


2.1.3. Liver Flukes
nal fluke are voided with the feces. In fresh
water a miracidium develops in 3 – 7 weeks,
Infections are caused by Clonorchis sinensis,
hatches, locates an aquatic snail, penetrates it,
Opisthorchis viverrini, or O. felineus. Infections
and begins multiplying. After 4 – 8 weeks cer-
with the cosmopolitan liver flukes of ruminants
cariae begin to be released, and they encyst as
(Fasciola hepatica, Dicrocoelium dendriticum)
metacercariae on aquatic plants. Infection is ac-
may be important locally.
quired when such plants (water caltrop, Trapa
spp.; water chestnut, Eleocharis sp.) are peeled
Distribution. C. sinensis: Korea, China,
with the teeth. The metacercarial cysts are thus
Southeast Asia, Japan, Taiwan, Philippines, In-
freed, are swallowed, and develop to sexually
donesia. O. viverrini: Laos, Thailand, Indian
mature flukes (5 – 7 cm long) in the small intes-
subcontinent. O. felineus: USSR and some Euro-
tine within about three months. Pigs, dogs, and
pean foci. About 50 million people are infected
rabbits are important reservoir hosts.
[15].
Clinical features. Mild infections are often
Development. Adult C. sinensis and O.
asymptomatic. In severe infections there are
viverrini (10 – 20 and 8 – 12 mm long, respec-
generalized toxic and allergic symptoms, di-
tively) live in the intrahepatic bile ducts.
arrhea, weakness, malabsorption, edema, as-
Their eggs contain fully developed larvae, the
cites, abdominal pain, and gastrointestinal hem-
miracidia, which are voided with the feces and
orrhage.
ingested by aquatic snails. The parasitic larva
(miracidium) hatches in the intestine of the snail, Therapy: praziquantel, niclosamide.
enters its tissues, and starts multiplying. After
some time cercariae are released into the water.
They infect cyprinid fish percutaneously, encyst 2.1.5. Lesser Intestinal Flukes
in the fish musculature, and become infective
metacercariae in about four weeks. Infection is Several species of these small flukes (2 – 7 mm
acquired through the consumption of raw or im- in length) are found in humans: Echinostoma ilo-
properly cooked fish. The young flukes excyst in canum, E. lindoense, Heterophyes heterophyes,
4 Anthelmintics

Metagonimus yokogawai, Gastrodiscoides ho- Clinical Features. Infections are generally


minis, Watsonius watsoni. asymptomatic. When they do appear, symptoms
include abdominal discomfort, dizziness, and fa-
Distribution. East and South Asia, West tigue. About 4 % of those infected develop clin-
Africa, Mediterranean countries, especially ical symptoms of a vitamin B12 deficiency in-
Egypt (Heterophyes). About 16 million people distinguishable from pernicious anemia.
are infected [13].
Therapy: praziquantel, niclosamide.
Development. These parasites live in the Several related species that cannot develop
small intestine. They have typical trematode life to maturity in humans, but do so in other mam-
cycles, with a single intermediate host (Gas- mals, may infect humans accidentally. They can
trodiscoides and Watsonius; metacercariae on proliferate and cause painful inflammatory tis-
aquatic plants) or two intermediate hosts. The sue reactions. This rare condition, sparganosis,
second host can be fish (Heterophyes and Metag- can be treated only by surgical removal. Prazi-
onimus) or snails and mussels (Echinostoma). quantel may prove to be effective.
Infection is acquired through the consumption
of raw or improperly cooked plants, fish, or mol-
lusks. The lesser intestinal flukes live and pro- 2.2.2. Beef Tapeworm (Taenia saginata =
duce eggs for several months. Taeniarhynchus saginatus)
Clinical Features. Mild infections are of- Distribution. Cosmopolitan, about 77 mil-
ten asymptomatic or show only nonspecific lion people are infected [13].
symptoms: diarrhea, abdominal discomfort, and
headache.
Development. Adult beef tapeworms gen-
Therapy: praziquantel, thiabendazole, erally measure 3 – 10 m. Each day about ten
niclosamide, bephenium. proglottids of the ribbonlike body, the strobila,
are shed, containing several hundred thousand
eggs. When these eggs are ingested by cattle,
2.2. Cestodes (Tapeworms) a larva, the oncosphere, hatches from the egg
and reaches the musculature (presumably by the
2.2.1. Broad or Fish Tapeworm circulatory system), where an infective larva, the
(Diphyllobothrium latum) cysticercus, develops within 10 – 12 weeks. Cat-
tle may carry infective cysticerci in their muscles
Distribution. Northern temperate zone (Fin- up to three years. Humans acquire the infection
land, USSR, Alaska, Canada; small foci in north- by consuming raw or improperly cooked beef.
ern Italy, Switzerland, and Chile). D. pacificum: Within 3 – 4 months the parasite reaches matu-
coastal regions of Peru. There are several re- rity in the intestine. It may live up to twenty
lated species that infect humans (e.g., Diplo- years.
gonoporus in Japan). About 2 – 9 million people
are infected [6]. Clinical Features. Infections often go un-
noticed. In symptomatic cases: vague abdomi-
Development. D. latum is a typical rib- nal pain, nausea, weakness, loss of weight, in-
bonlike tapeworm of extreme length (up to creased or decreased appetite, headache.
10 – 15 m) living in the small intestine. After the
eggs are voided with the feces into fresh water, Therapy: niclosamide, praziquantel,
a larva, the coracidium, is released. Larvae are mebendazole.
ingested by small copepod crustaceans. When
these are ingested by cyprinid fish, the parasites
penetrate into the musculature of the fish and de-
velop into the infective stage, the plerocercoid.
Humans acquire the infection by consuming raw
or improperly cooked fish.
Anthelmintics 5

2.2.3. Pork Tapeworm (Taenia solium) Clinical Features. Mild infections are
asymptomatic. Severe infections: abdominal
Distribution. Almost cosmopolitan, wher- pain, diarrhea, headache, dizziness, anorexia.
ever people eat improperly cooked pork. About
3 – 5 million people are infected with adult T. Therapy: praziquantel, niclosamide.
solium [15].
Development, clinical features, and therapy
are all similar to those of the beef tapeworm. 2.2.5. Dog Tapeworm (Echinococcus
granulosus, E. multilocularis)
Cysticercosis. Although pigs usually are the
intermediate hosts in the life cycle of the pork Distribution. E. granulosus: cosmopolitan,
tapeworm, humans can also become infected especially in sheep-rearing countries. E. multi-
with the larvae of this parasite by ingesting the locularis: small foci in North, Central, South,
eggs, which remain viable in the soil for many and East Europe, northern United States. About
weeks. The resulting infection, cysticercosis, oc- 100000 people are infected [15].
curs in Central and South America, South and
East Asia, East Africa, and eastern Europe and Development. Many mammals (humans,
may afflict more people than are infected with sheep, goats, cattle, pigs, dromedaries, horses,
the adult tapeworm [15]. This condition is often rodents) serve as intermediate hosts of these
accompanied by myositis and high fever. When small (3 – 5 mm long) tapeworms that live as
the brain is involved (neurocysticercosis, devel- adults in the intestine of dogs or other canines.
oping in 1 – 5 % of the infected persons), this When humans ingest the eggs, larvae hatch, pen-
condition is often accompanied by epileptic at- etrate the gut wall, and generally lodge in the
tacks, meningoencephalitis, and intracranial hy- liver or lungs, although all other tissues can also
pertension. In South America alone, there are be affected. The larvae grow extremely quickly,
about 350000 cases [16]. forming unilocular (E. granulosus) or multiloc-
Formerly, the only treatment for cysticercosis ular (E. multilocularis) cysts. The cysts con-
was surgical removal of larval cysts. tain many protoscolices, which mature to adult
worms when offal containing cystic material is
Therapy: praziquantel, niclosamide, fed to dogs.
mebendazole.
Clinical Features. Cysts are often asymp-
tomatic until they grow large, but then the symp-
2.2.4. Dwarf Tapeworm (Hymenolepis nana) toms become progressively severe. Symptoms
depend on the location of the cysts. Liver cysts
Distribution. Cosmopolitan, about 45 – 50 can cause symptoms resembling a mucoid car-
million people, mainly children, are infected cinoma. Lung cysts give rise to coughing and
[15]. chest pain, whereas cerebral cysts can cause se-
rious neurological damage.
Development. The dwarf tapeworm is
unique in that the adult can develop following Therapy: surgical removal, in inoperable
ingestion of the eggs by humans. The larva, the cases, mebendazole, which does not kill the par-
oncosphere, that hatches from the egg develops asite but arrests the progressive course of the
to the cysticercoid stage in the intestinal mu- disease.
cosa within 4 – 7 days. Alternatively, infections
may be acquired through accidental ingestion of
grain beetles containing infective cysticercoid 2.3. Nematodes (Roundworms)
larvae. The adult tapeworm, developing from the
cysticercoid to maturity in 1 – 2 weeks, grows The parasitic nematodes are conveniently di-
up to 40 cm long. vided into two groups: the intestinal nematodes,
including the roundworm, hookworm, pinworm,
whipworm, threadworm, and trichina, and the
6 Anthelmintics

extra-intestinal nematodes, including the guinea nale: from the Mediterranean through India to
worm and several species of filariae. The second China and Southeast Asia, Brazil. A. ceylanicum
group live in the tissues of fluids of the body and is of local importance. About 930 million people
require an arthropod vector for the completion are infected and about 60000 deaths are caused
of their life cycles. by hookworm infections each year [13], [14].

Development. The mature worms (≈ 10 mm


2.3.1. Roundworm (Ascaris lumbricoides) long) attach to the gut mucosa and suck blood
(Necator 5 – 10 times less than Ancylostoma).
Distribution. Cosmopolitan, common in hu- Each female produces 10000 (Necator) or 20000
mid tropical climates. About 1300 million peo- (Ancylostoma) eggs per day. These are voided
ple are infected [13]. with the feces and release larvae that develop in
the soil within seven days to the infective stage,
Development. This large parasite which is able to survive up to one month. In-
(20 – 40 cm long) lives in the small intestine fection is percutaneous (Ancylostoma also oral).
and feeds on gut contents. Each female pro- The larvae migrate to the heart and lungs. Subse-
duces over 200000 eggs per day. The eggs are quent development is as described for the round-
passed with the feces, become infective in about worm (Ascaris).
one month, and can remain infective in the soil
for up to fifteen years. After infective eggs have Clinical Features. Mild, cutaneous reac-
been ingested, e.g., with vegetables, larvae are tion to the infective larvae and lung reac-
released, penetrate the duodenal wall, and mi- tions (cough, wheezing) to the migratory larvae.
grate through the liver and the blood vessels to Chronic phase: epigastric pain, tenderness, pep-
the lungs. There they break through the alveolae tic symptoms, iron-deficiency anemia, protein-
into the air passages, ascend the trachea, are loss enteropathy, hypoproteinemia. Severe in-
swallowed, and attain maturity in the gut about fections: high-output cardiac-failure dyspnea,
8 – 10 weeks later. The females live about one edema. The symptoms of hookworm infections
year. are often aggravated by malnutrition and sec-
ondary bacterial or other parasitic infections.
Clinical Features. The majority of infec-
tions are light and asymptomatic. Larvae in the Therapy: pyrantel, thiabendazole, mebend-
lungs may cause pneumonitis (cough, wheezing, azole, bephenium, levamisole, tetrachloro-
dyspnea). Complications are intestinal obstruc- ethylene, bitoscanate.
tion and worm irritation after medication, caus-
ing hepatic duct obstruction, appendicitis, and 2.3.3. Pinworm (Enterobius vermicularis)
intestinal perforation.
Distribution. Cosmopolitan, common in the
Therapy: levamisole, pyrantel, piperazine, developed countries of the northern hemisphere.
mebendazole, thiabendazole, albendazole. Iver- About 350 million people are infected [13].
mectin is in clinical development
Development. The pinworm, which is more
commensal than parasitic, lives in the lumen of
2.3.2. Hookworms the colon and feeds on gut contents. Gravid fe-
males migrate out of the anus to deposit their
Two species, Ancylostoma duodenale (common eggs (5000 – 10000), which are fully embry-
or Old World hookworm) and Necator amer- onated and infective within a few hours. Infec-
icanus (American or New World hookworm), tions and reinfections are acquired through ac-
parasitize humans, causing one of the most im- cidental oral intake of eggs. Larval development
portant tropical diseases. occurs in the intestine within about six weeks.

Distribution. N. americanus: the Americas, Clinical features. Perianal itching. Compli-


tropical Africa, South and East Asia. A. duode- cations caused by ectopic migration are rare.
Anthelmintics 7

Therapy: pyrantel, piperazine, mebend- Clinical Features. Infections may be asymp-


azole, pyrvinium. tomatic, but gastrointestinal symptoms (diar-
rhea, katarrhal enteritis, central epigastric pain)
are common. In cases of severe infection the
2.3.4. Whipworm (Trichuris trichiura) prognosis is poor, and the mortality rate is high.

Distribution. Cosmopolitan, especially Therapy: thiabendazole, mebendazole,


common in warm and humid climates. About albendazole. Ivermectin is in clinical devel-
690 million people are infected [13]. opment.
Infections with other nematodes (e.g., Angio-
Development. The parasites (3 – 5 mm long) strongylus, Anisakis, Capillaria, Dipetalonema,
live attached to the cecal mucosa. The eggs are Gnathostoma, Oesophagostomum, Tri-
voided with the feces and require a period of at chostrongylus) are less important and generally
least three weeks to become infective. Eggs re- respond to thiabendazole and/or mebendazole.
main infective in the soil for over one year. The Thiabendazole is also effective against migrat-
larvae hatch after eggs have been ingested, e.g., ing larvae of nematodes that normally mature
with vegetables or dirt, and mature in the intes- in other mammals (cutaneous and visceral larva
tine within 2 – 3 months. The adults live 3 – 10 migrans). About 5 – 10 million people are in-
years. fected [15].

Clinical Features. Infections are generally


asymptomatic; occasionally, abdominal discom- 2.3.6. Trichina (Trichinella spiralis)
fort and, in children, diarrhea occur.
Distribution. Cosmopolitan except Aus-
Therapy: oxantel, mebendazole, thiabenda- tralia. About 46 million people are infected [13].
zole, albendazole. Ivermectin is in clinical de-
velopment. Development. Infection is initiated by the
consumption of raw or improperly cooked meat
(especially pork) containing the encysted lar-
2.3.5. Threadworm (Strongyloides vae. These excyst in the gut and mature to adult
stercoralis) worms in the gut wall within 3 – 4 days. Sexes
mate in the gut lumen, and each female then pro-
Distribution. Tropical and subtropical cli- duces up to 2000 larvae within two weeks. The
mates, extending into southern Europe and larvae penetrate the gut wall, enter the lymphatic
southern United States. About 80 million peo- vessels, disseminate via the circulatory system
ple are infected [15]. throughout the body, develop in the muscle, and
finally encyst in muscle fibers.
Development. The female worms live at-
tached to the mucosa of the small intestine, on Clinical Features. Infections are generally
which they feed. They produce, usually partho- asymptomatic during the intestinal phase. The
genetically, larvae that are infective shortly after muscle infection causes myositis, eosinophilia,
passage of the feces and infect humans percuta- leukocytosis, and occasional fever.
neously. Their further development to maturity
takes about 17 days and resembles that of hook- Therapy: thiabendazole, mebendazole,
worms. Autoinfection is possible when larvae albendazole. Ivermectin is in clinical devel-
mature in the gut and infections may be perpet- opment.
uated up to twenty years. When environmental
conditions are favorable, threadworms can exist
for some time as free-living nematodes, com-
pleting several generations in the soil.
8 Anthelmintics

2.3.7. Larvae of Toxocara canis, Toxocara asymptomatic for one year. Specific signs of the
cati, Ancylostoma brasiliense and disease are painful blisters and ulcerations of
Ancylostoma caninum the skin where the females penetrate the skin.
Secondary bacterial infections often cause addi-
Distribution. Cosmopolitan. tional complications.

Development. Humans, especially children Therapy: Careful mechanical extraction,


are the “wrong hosts“ for these larvae. Human thiabendazole. Both niridazole and metronida-
infection are rare and occur through oral inges- zole reduce the inflammatory tissue reactions
tion of larvae following contact with contami- without affecting the parasites.
nated faeces of Toxocara canis infected dogs or
T. cati infected cats or with contaminated soil,
sand, or playgrounds. The larvae of Ancylostoma 2.3.9. Lymphatic Filariae (Wuchereria
brasiliense or Ancylostoma caninum penetrate bancrofti, Brugia malayi)
the skin (“creeping eruption“) following contact
with contaminated dog or cat faeces. Distribution. Wuchereria: throughout the
tropics and subtropics. Brugia malayi: from In-
Clinical Features. The disease is determined dia to Korea and Indonesia. B. timori: Timor.
by the site where larvae reside. Larvae migrantes About 380 million people are infected [13].
viscerales of T. canis and cati are mostly ob-
served in liver and lungs, occasionally in eyes Development. The adult parasites, the
or brain. Larvae of Ancylostoma brasiliense macrofilariae, live in lymphatic ducts and nodes.
are called larvae migrantes cutaneae, larvae of The females deposit eggs, from which larvae,
Ancylostoma caninum are called epidermis lar- the microfilariae, hatch. The larvae are dis-
vae. tributed with the blood throughout the body
but congregate in the peripheral vasculature
Therapy: Thiabendazole, during the night. From there they are taken up
diethylcarbamazine. by mosquitoes and mature to infective larvae
in their musculature. They then enter the pro-
boscis of the mosquito, and when it takes another
2.3.8. Guinea Worm (Dracunculus blood meal they enter the human skin through
medinensis) the puncture. In the new host, they mature and
mate, and the females start producing the next
Distribution. Focally in West, North, and generation of microfilariae.
East Africa, the Middle East, from Iran through
Pakistan into Indonesia. About 50 – 100 million Clinical Features. Infections generally are
people are infected [15]. asymptomatic, but chronic lesions, presumably
of an allergic nature, can cause lymphangitis
Development. The parasites develop in the and obstruction of lymphatic drainage, leading
body cavity and deeper connective tissue for to elephantiasis and hydrocele.
about 12 – 14 months. The mature females then
migrate to the subcutaneous tissues, mainly of
Therapy: diethylcarbamazine.
the legs. There they cause blisters and ulcera-
tion, through which large numbers of larvae are
discharged when the skin contacts water. If taken
2.3.10. Convoluted Filaria (Onchocerca
up by copepod crustaceans, the larvae develop
volvulus)
in the body cavity and become infective in 2 – 3
weeks. Humans acquire the infection by drink-
Distribution. Africa south of the Sahara,
ing water containing infected copepods. Dogs
Yemen, Mexico to Venezuela. About 40 million
are known reservoir hosts.
people are infected [14].
Clinical Features. Infections are usually
Anthelmintics 9

Development. The adult worms (macrofilar-


iae) live in subcutaneous nodules. The larvae
(microfilariae) collect in the superficial layers
of the skin and are transmitted by black flies
(Simulium), in which they develop to the infec- The compound is synthesized in a five step syn-
tive stage. Humans are infected when the fly thesis. 4-chloro-2-nitroaniline is first acetylated
takes another blood meal. with acetic anhydride to give 1-acetamido-4-
Clinical Features. Microfilariae may cause chloro-2-nitrobenzene. Treatment of this inter-
chronic cutaneous lesions. Invasion of the eye: mediate compound with potassium thiocyanate
conjunctivitis, keratitis, iridocyclitis, choriore- furnishes the key intermediate 1-acetamido-2-
tinitis, glaucoma, opacity of the lens, leading to nitro-4-thiocyanatobenzene. Conversion of the
optic atrophy and blindness. thiocyanato group into the required n-propyl-
thio analogue, with a simultaneous conversion
Therapy: diethylcarbamazine (microfilari- of the acetamido group to the free amine, is
cidal), suramin (macrofilaricidal), ivermectin effected by treating the last intermediate with
(microfilacricidal). 1-bromopropane in the presence of a base. Fur-
ther reduction of the nitro group provides the
diamine, which is subsequently ring closed to
2.3.11. African Eye Worm (Loa loa) albendazole [20].
Distribution. Rain forests of West and Cen- Albendazole is used against nematode infec-
tral Africa. More than 10 million people are in- tions: Ascaris, Necator, Ancylostoma, Trichuris,
fected [15]. Enterobius, and systemic nematodes such as
Trichinella spiralis, Gnathostoma spinigerum,
Development. The adult parasites (macro- and larval Angiostrongylus cantonensis. In ad-
filariae) actively migrate through the subcuta- dition it is used against the larval stages of the
neous tissue. The microfilariae are found in the cestodes Echinococcus granulosus and E. multi-
peripheral blood during the day and are trans- locularis and for treatment of neurocysticercosis
mitted by flies (Chrysops). caused by Taenia solium [21].
Occasional adverse effects include fever, re-
Clinical Features. Allergic swelling of the versible leucopenia, headache, nausea, dizzi-
skin. ness, sleeplessness, epigastric pain and diar-
Therapy: diethylcarbamazine. rhoea. When higher dosages are given over a
long period elevated levels of transaminases
are observed, seldom hepatitis and occasion-
3. Anthelmintic Drugs ally alopecia. Contraindications are pregnancy
and liver cirrhosis. Albendazole interferes se-
The anthelmintic drugs are listed alphabeti- lectively with the polymerization of β-tubulin
cally. The mechanism of action of the older an- to microtubuli. The microtubules play a crucial
thelmintics can be found in [17]. The numer- role in several important cell functions such as
ous trade names for the older drugs are given material transport within cells and neurotrans-
for some twenty countries in [18]. A number of mission [22].
trade names are given in [19]. The national drug Trade names: Eskadole (Smith Kline Beech-
directories can also be consulted. am), Valbazen (Pfizer).

Albendazole [54965–21–8], methyl- Bephenium [3818-50-6], benzyldimethyl-


(5-(propylthio)-2-benzimidazol)carbamate, (2-phenoxyethyl)ammonium 3-hydroxy-2-
C12 H15 N3 O2 S, M r 265.3, mp 208 – 210 ◦ C, is naphthoate, C28 H29 NO4 , M r 443.5, mp
a colorless crystalline solid. It is insoluble in wa- 170 – 171 ◦ C, is a bitter tasting, odorless, yel-
ter, sparingly soluble in dimethylformamide or low crystalline solid. It is insoluble in water and
dimethylsulfoxide, and soluble in formic acid. slightly soluble in ethanol.
10 Anthelmintics

The compound is synthesized by the reaction


of diethylcarbamoyl chloride with methylpiper-
azine [25].
Diethylcarbamazine dihydrogen citrate is
The compound is synthesized by the reaction used against the microfilarial stage of filar-
of dimethyl(2-phenoxyethyl)amine with benzyl iae. It also kills the adult filariae of Wuchere-
halide [23]. ria, Brugia, and Loa. Occasional adverse reac-
Bephenium can be used against Ascaris, tions are anorexia, nausea, vomiting, headache,
Ancylostoma, and Trichostrongylus infections; and drowsiness. Allergic reactions occur, espe-
it is less effective against Necator. Occasional cially in onchocercosis patients: intense pruritus,
adverse reactions occur: nausea, diarrhea, vom- edema, lymphadenitis, dermatitis, papular rash,
iting, headache, vertigo. fever, tachycardia.
Trade names: Alcopar(a) (Wellcome, Tan- The most likely mechanism of action is a
abe); Befen (Andromaco); Lecibis (Andromaco, rapid effect on the surface of the microfilar-
Columbia); Debephenium (ICN Usafarma); iae. Previously hidden antigenic determinants
Fedal Uncin (Hosbon-Fedal); Hebe (Farmacon); become accessible to the immune system of
Befeval (Valmorca); Befenium (Laquifa). the host, which then eliminates the microfilar-
iae from the circulating blood [8].
Bithionol [97-18-7], 2,2 -thiobis(4,6-di- Trade names: Hetrazan and Hetrazan 1949
chlorophenol), C12 H6 Cl4 O2 S, M r 356.1, mp (Lederle); Banocide (Wellcome); Notezine
188 ◦ C, is a tasteless, colorless, crystalline solid. (Specia); Supatonin (Tanabe); Carbilazine (Wil-
It is insoluble in water but soluble in ethanol. lows Francis); Caricide (Am. Cyanamid).

Ivermectin (synonyms: 5-O-Demethyl-


22,23-dihydroavermectin A1a , 22,23-Dihydro-
abamectin, 22,23-Dihydroavermectin B1 )
Ivermectin B1a [71827–03–7], C48 H74 O15 ,
Bithionol is synthesized by the reaction of M r 891.1, mp 155 – 157 ◦ C; ivermectin B1b
chlorophenol with sulfur dichloride and sulfuryl [70209–81–3], C47 H72 O15 , M r 877.1, is a white
chloride [24]. powder and forms crystals from ethanol – water.
Bithionol can be used against liver, lung, It is soluble in methyl ethyl ketone, propylene
and intestinal flukes. Frequent adverse reactions glycol, and poly(ethylene glycol).
are abdominal pain, diarrhea, anorexia, nausea,
vomiting, dizziness, headache, skin rashes, ur-
ticaria. Hepatic and renal involvement are rare
complications.
Trade names: Actamer (Monsanto); Bitin (Tan-
abe); Bitin S (Tanabe), which contains the sulf-
oxide of bithionol.
Ivermectin

Diethylcarbamazine [1642-54-2], N,N-di- Ivermectin is a mixture of at least 80 % iver-


ethyl-4-methyl-1-piperazinecarboxamide cit- mectin B1a (R = CH3 ) and not more than 20 %
rate, C16 H29 N3 O8 , M r 391.4, mp141 – 143 ◦ C, ivermectin B1b (R = H).
is a white, odorless, crystalline solid with a bit- Ivermectin is a semisynthetic compound de-
ter acid taste. It is freely soluble in water or hot rived from abamectin (avermectin B1 ) a fer-
ethanol but insoluble in acetone, chloroform, mentation product of Streptomyces avermitilis
ether, or dioxane. by selective hydration with chlorotris(triphenyl-
phosphin)rhodium (I) (Wilkinson catalyst) [26–
28].
In human medicine ivermectin is the drug of
choice for onchocerciasis (river blindness) al-
though it only kills Onchocerca volvulus micro-
Anthelmintics 11

filariae and not the adults. Although the drug has abdominal discomfort, headache, dizziness, hy-
no curative effect, a single dose of 0.2 mg per pertension.
kilogram body weight every 6 – 12 months con- Levamisole causes rapid spastic contrac-
trols the disease [29]. The drug is under clinical tion in nematodes by persistently depolariz-
development for treatment of intestinal nema- ing the muscle-cell membrane. It also acts
tode infections (Ascaris, Enterobius, Trichuris, as a ganglion-stimulating compound [35].
Strongyloides, and Trichinella spiralis). The paralyzed nematodes are then elim-
In veterinary medicine ivermectin is used in inated from the intestine. Levamisole is
cattle against a wide variety of nematodes and likely to be hydrolyzed to l(−)−2-oxo-3-(2-
arthropods. It is inactive against cestodes and mercaptoethyl)−5-phenylimidazoline under al-
trematodes. kaline conditions. This metabolite is a strong
Occasional adverse effects in humans include and stereospecific inhibitor of the enzyme fu-
headache, fever, pruritus, oedema, and arthral- marate reductase through its interaction with
gies. However, as ivermectin is used only 1 – 2 −SH groups of the active center.
times a year at low dosages, side effects are Trade names: Ascaridil, Decaris, and Stimami-
rare. Veterinary usage has shown that collies are zol (Johnson & Johnson, Janssen); Ketrax (ICI);
particular sensitive in developing gabergic side Solaskil (Specia).
effects (CNS depression with dizziness, ataxia,
tremor, salivation, mydriasis, and coma with ex- Mebendazole [31431-39-7], methyl(5-
itus). benzoyl-1H-benzimidazol-2-yl)carbamate,
Presumably, ivermectin exerts its mode of ac- C16 H13 N3 O3 , M r 295.3, mp 288.5 ◦ C, is an
tion by interfering with GABA, glutamate or off-white amorphous powder. It is insoluble in
glycine gated chloride channels, all of which are water, sparingly soluble in dimethylformamide
inhibitory neurotransmitters [30–32]. This ac- or dimethyl sulfoxide, and soluble in formic
tion leads to an increased permeation of chloride acid.
ions, followed by a hyperpolarization of nerve-
muscle membranes and a flaccid paralysis of the
parasites. The action of ivermectin can be antag-
onised by bicuculline and picrotoxin [33].
Trade names: Mectizan in France (MSD),
Ivomec (MSDAGVET). The compound is synthesized by the re-
action of 3,4-diaminobenzophenone hydro-
Levamisole [16595-80-5], l(−)−2,3,5,6- chloride with N-carboxymethyl-S-methyliso-
tetrahydro-6-phenylimidazo[2,1-b]thiazole thiourea [36].
hydrochloride, C11 H12 N2 S · HCl, M r 240.8, Mebendazole is used against nematode in-
mp227 – 229 ◦ C, is a colorless, odorless, crys- fections: Ascaris, Trichuris, Enterobius, Ancylo-
talline solid. It is soluble in water and slightly stoma, Necator, Capillaria. It is also effective
soluble in chloroform. against tapeworms (Taenia). Occasionally ad-
verse reactions, abdominal pain and diarrhea,
occur. A rare complication is leukopenia. Preg-
nancy is a contraindication.
Mebendazole interferes with glucose uptake
by nematodes and cestodes in vivo and in vitro.
This interference occurs by the selective inter-
The compound is synthesized by the reaction action with intracellular tubulin and subsequent
of 4-phenyl-2-thioimidazoline with dibromo- inhibition of the assembly of microtubules. The
ethane [34]. microtubules participate in several important
Levamisole is used against roundworm (As- cell functions, e.g., the transport of materials
caris) infections. It is less effective against within cells [37].
Ancylostoma, Necator, or Strongyloides. Occa- Trade name [18]: Vermox (Janssen, Ortho).
sional adverse reactions are nausea, vomiting,
12 Anthelmintics

Metrifonate [52-68-6], O,O-dimethyl- tack of the tapeworm by host digestive enzymes


2,2,2-trichloro-1-hydroxyethylphosphonate, [41].
C4 H8 Cl3 O4 P, M r 257.4, mp 83 – 84 ◦ C, is a Trade names: Yomesan, Cestocide, and Nasemo
colorless, crystalline solid. It is soluble in water, (Bayer); Niclocide (Miles); Trédémine (Roger
chloroform, or ether and very slightly soluble in Bellon); Radeverm (VEB Arzneimittelwerk
pentane or hexane. Dresden); Sulqui (Ella); Atenase (ICN Usa-
farma); Teniarene (Amsa); Teniamida (Bial);
Fedal Telmin (Hosbon-Fedal); Copharten
(Cophar). Some preparations contain niclos-
amide monohydrate.
The compound is synthesized by reaction of
chloral with dimethyl phosphite [38]. Niridazole [61-57-4], 1-(5-nitro-2-thiazol-
Metrifonate is used against the blood fluke yl)-2-imidazolidinone, C6 H6 N4 O3 S, M r 214.2,
Schistosoma haematobium. The occasional ad- mp 260 – 262 ◦ C, is a yellow, crystalline solid.
verse reactions are nausea, vomiting, bron- It is almost insoluble in water and most organic
chospasm, weakness, diarrhea, and abdominal solvents, but it is soluble in dimethylformamide.
pain.
In vivo, metrifonate rapidly rearranges to
O,O-dimethyl O-(2,2-dichlorovinyl) phosphate,
which is a potent inhibitor of schistosome acetyl-
cholinesterase. This paralyzes the parasites be-
cause of the accumulation of acetylcholine, The compound is synthesized by reaction of
which functions as inhibitory transmitter [39]. 2-amino-5-nitrothiazole and β-chloroethyliso-
Trade name: Bilarcil (Bayer). cyanate [42].
Niridazole can be used against blood flukes,
Niclosamide [50-65-7], 2 ,5-dichloro-4 - especially Schistosoma haematobium. Toler-
nitrosalicylanilide, C13 H8 Cl2 N2 O4 , M r 327.5, ance and efficacy are reduced in S. mansoni
mp 225 – 230 ◦ C, is a tasteless, pale yellow, and especially in S. japonicum infections. It is
crystalline solid. It is almost insoluble in wa- also used in Dracunculus infections. Immuno-
ter; sparingly soluble in ethanol, chloroform, or suppression, vomiting, cramps, dizziness, and
ether; and soluble in acetone. headache are among the frequent adverse re-
actions. Occasional adverse reactions are di-
arrhea, electrocardiographic changes, rash, in-
somnia, and paresthesia. Psychosis, hemolytic
anemia, and convulsions are rare. Contraindi-
cations are impaired liver function, glucose-6-
The compound is synthesized by condensa- phosphatedehydrogenase deficiency, epilepsy,
tion of 5-chlorosalicylic acid with 2-chloro-4- and severe heart diseases.
nitroaniline [40]. Niridazole causes a depletion of glycogen
Niclosamide is used against all kinds of tape- in schistosomes by inducing a reduced rate of
worms. It is also effective against intestinal conversion of active glycogen phosphorylase
flukes. Occasional adverse reactions are abdom- to its inactive form. This is achieved through
inal pain and nausea. inhibition of the enzyme phosphorylase phos-
Niclosamide causes uncoupling of oxidative phatase, which normally inactivates glycogen
phosphorylation and respiration. It also activates phosphorylase. It is possible that the active moi-
ATPases, and this disturbs the energy balance of ety is not niridazole, but its 5-imino analog,
cestodes, which degrade endogenous glycogen, which can be formed by schistosomes in vitro
and impairs glucose uptake. Protein synthesis under anaerobic conditions [43].
is also affected; e.g., a trypsin inhibitor is no Trade names: Ambilhar (Ciba-Geigy); Ambil-
longer formed, which facilitates proteolytic at- har Ciba (Biogalenica Q Farm).
Anthelmintics 13

Oxamniquine [21738-42-1], 1,2,3,4-tetra- much like the closely related pyrantel.


hydro-2-[(isopropylamino)methyl]−7-nitro-6- Trade name: Telopar (Pfizer).
quinolinemethanol, C14 H21 N3 O3 , M r 279.3,
mp 151 – 152 ◦ C, is a light orange, crystalline Piperazine [110-85-0], piperazine hexa-
solid. It is slightly soluble in water and soluble hydrate, C4 H10 N2 · 6 H2 O, M r 194.2, mp
in methanol, acetone, or chloroform. 43 – 45 ◦ C, is a colorless salty tasting crystalline
solid. It is soluble in water and insoluble in ether.

Piperazine is used against roundworms (As-


The compound is manufactured by fermen-
caris) and pinworms (Enterobius). Adverse re-
tative oxidation of its 6-methyl analog by As-
actions are nausea, vomiting, diarrhea, abdom-
pergillus scleroticum [44].
inal pain, headache, and paresthesia. Urticaria
Oxamniquine is used against the blood fluke
may occur occasionally. Contraindications are
Schistosoma mansoni. The adverse reactions ob-
impaired renal or hepatic function. Various salts
served are vertigo, vomiting, nausea, abdomi-
are also used: Calcium ethylenediaminetetra-
nal pain, anorexia, dizziness, drowsiness, and
acetate (edetate), calcium citrate, citrate, tar-
somnolence. Hallucinations are occasional, and
trate, maleate, phosphate, adipate, sebacate, sul-
epileptiform convulsions are rare. Intramuscular
fate. Piperazine increases the resting potential
injection causes severe pain at the site of injec-
of the somatic musculature of nematodes, espe-
tion.
cially in the syncytial region, by increasing the
The antischistosomal effect of oxamniquine
permeability of the membrane to chloride ions.
as a function of time correlates well with the ac-
This results in flaccid paralysis of the parasites,
tivity of the enzyme ornithine-δ-transaminase.
which are expelled from the intestine [17].
The enzyme may interfere with normal arginine
Trade names [18]: Uvilon (Bayer); Antepar
formation and the maintenance of a normal ni-
1953 (Wellcome); Helmazine (Midy); Mul-
trogen balance in the parasite [43].
tifuge (Glaxo); Neox (Rocador).
Trade names: Mansil, Vansil, and Vancil (all
Pfizer). Praziquantel [55268-74-1], 2-cyclo-
hexylcarbonyl-1,2,3,6,7,11 b-hexahydro-4H-
Oxantel [68813-55-8], (E)−3-[2-(1,4,5,6- pyrazino[2,1-a]isoquinolin-4-one, C19 H24 N2 O2 ,
tetrahydro-1-methyl-2-pyrimidinyl)ethenyl]- M r 312.4, mp 136 – 140 ◦ C, is a bitter tasting,
phenol 4,4 -methylenebis(3-hydroxy-2- colorless, crystalline solid. It is sparingly solu-
naphthalenecarboxylate), C36 H32 N2 O7 , M r ble in water and soluble in ethanol, chloroform,
604.7, mp 207 – 208 ◦ C (hydrochloride), is a or dimethyl sulfoxide.
yellow crystalline solid. It is practically insolu-
ble in water.

The compound is synthesized by reacting


It is synthesized by condensation of 1,2,3,6,7,11 b-hexahydropyrazino[2,1-a]iso-
3-hydroxybenzaldehyde and 1,2-dimethyl- quinolin-4-one with cyclohexylcarbonyl chlo-
1,4,5,6-tetrahydropyrimidine in refluxing ethyl ride in chloroform [46].
formate [45]. Praziquantel is used against all infections
The cation is the active part of the compound. caused by trematode parasites (blood, liver, lung,
Oxantel is used against whipworm (Trichuris). and intestinal flukes) or adult tapeworms. It is
No adverse reactions to this relatively new drug also effective in cysticercosis. Occasional ad-
have been found, but it can be expected to behave verse reactions are epigastric pain, nausea, dizzi-
14 Anthelmintics

ness, diarrhea, and vomiting. Rare adverse re- menta); Antiminth (Roerig); Combantrin,
actions are skin manifestations, headache, and Trilombrin, Cobantril, and Helmex (Pfizer);
tiredness. Tricocel and Piranver (ICN Usafarma); Verdal
Praziquantel causes a very rapid increase (Columbia); Perverme (Biofarma); Piranver and
in the permeability of membranes to divalent Piranver F (ICN Farmaceutica).
cations. In the musculature of trematodes and
cestodes, this permeability increase results in a Pyrvinium [3546-41-6], 6-(dimethyl-amino)-
calcium concentration increase, which initiates 2-[2-(2,5-dimethyl-1-phenyl-1H-pyrrol-3-yl)-
rapid contracture and subsequent spastic con- ethenyl]−1-methylquinolinium 4,4 -methylene-
traction and paralysis. In the tegument, prazi- bis(3-hydroxy-2-naphthalenecarboxylate),
quantel causes rapid and progressive vacuoliza- C75 H70 N6 O6 , M r 1151.4, mp 210 – 215 ◦ C,
tion, which leads to partial disintegration of the is a tasteless, odorless, bright orange to black,
body surface of the parasites. This, in turn, ren- crystalline solid. It is insoluble in water or ether,
ders them susceptible to attacks by the host de- slightly soluble in chloroform, and soluble in
fense system and its digestive enzymes [47]. glacial acetic acid.
Trade names: Biltricide (Bayer, Miles); Cestox,
Cesol, and Cisticid (all E. Merck).

Pyrantel [22204-24-6], (E)−1,4,5,6-


tetrahydro-1-methyl-2-[2-(2-thienyl)vinyl]-
pyrimidinium 4,4 -methylenebis(3-hydroxy-2-
naphthalenecarboxylate), C34 H30 N2 O6 S, M r
594.7, mp 178 – 179 ◦ C (free base), is a tasteless, The compound is synthesized by the reac-
odorless, yellow, crystalline solid. It is insoluble tion of 1,2-dimethyl-6-dimethylaminoquinoline
in water, slightly soluble in dimethylformamide, iodide with 2,5-dimethyl-1-phenyl-3-pyrrol-
and soluble in dimethyl sulfoxide. aldehyde [50].
The cation is the active part of the compound.
Pyrvinium is used against pinworms (Enter-
obius). Occasional adverse reactions are blood
dyscrasia and folic acid deficiency. Rare adverse
reactions are rash, vomiting, convulsion, shock,
photosensitivity, and headache.
The compound is synthesized by react- Trade names: Vanquil, Vanpar, Vanquin, Po-
ing 2-thiophenealdehyde with 1,2-dimethyl- van(yl) Molevac, Povan 1959, Paquil, Polyquil,
tetrahydropyrimidine [48]. and Povanyl (all Parke-Davis and Substantia).
The cation is the active part of the compound.
Pyrantel is used against nematodes: Ascaris, Suramin [129-46-4], hexasodium 8,8 -
Enterobius, Ancylostoma, and Necator. Adverse [carbonylbis[imino-3,1-phenylenecarbonyl-
reactions are anorexia, abdominal cramps, diar- imino(4-methyl-3,1-phenylene)carbonyl-
rhea, nausea, vomiting. Occasional adverse re- imino]]bis-1,3,5-naphthalenetrisulfonate,
actions are headache, dizziness, drowsiness, and C51 H34 N6 Na6 O23 S6 , M r 1429.2, is a pink-
skin rash. Impaired hepatic function is a con- ish white, white, or cream-colored, odorless,
traindication. hygroscopic powder with a slightly bitter taste.
Pyrantel is a depolarizing neuromuscular It is soluble in water and insoluble in chloroform
blocking agent. In nematodes it causes a slowly or ether.
developing contraction and paralysis. The im- The compound is synthesized by condensa-
mobilized parasites are then eliminated from the tion of 1-naphthylamine-4,6,8-trisulfonic acid
intestine. The neuromuscular junction of Ascaris with 3-nitro-4-methylbenzoyl chloride, reduc-
is 100-fold more sensitive to pyrantel than to tion of the product, condensation with 3-nitro-
acetylcholine [49]. benzoyl chloride, renewed reduction, and final
Trade names: Lombpiareu (Areu); Aut (Elea); condensation with phosgene [51].
Aguipiran (Aguilar); Tamoa (North Medica-
Anthelmintics 15

Thiabendazole is used against nematodes and


nematode larvae: Enterobius, Ascaris, Strongy-
loides, Necator, Trichinella, Ancylostoma, Cap-
illaria, Dracunculus, and Trichostrongylus. It is
also effective against intestinal flukes. Frequent
adverse reactions are dizziness, anorexia, vom-
iting, and epigastric distress. Diarrhea, fever,
headache, skin rashes, hallucinations, and ol-
factory disturbances occur occasionally. Tinni-
tus, hypotension, and syncope are rare compli-
cations. The mechanism of action is not yet un-
derstood. Thiabendazole inhibits fumarate re-
ductase, an enzyme essential for mitochondrial
energy production in many nematodes, but this
cannot be the primary or sole mechanism. Pos-
sibly thiabendazole, like mebendazole, affects
tubulin polymerization, but there is no good ex-
Suramin is used as a macrofilaricide against perimental evidence for this [43].
Onchocerca. Frequent adverse reactions are Trade names: Mintezol and Minzolum (Merck
nausea, vomiting, colic, and urticaria. Occasion- Sharp & Dohme).
ally, kidney damage, blood dyscrasias, shock,
and optic atrophy occur. Allergic reactions to fi-
larial proteins (pruritus, rash, fever, edema, hy-
peresthesia, photophobia, lachrymation) are also 4. References
encountered.
1. H. Loewe: “Anthelminthica,” in G. Ehrhardt,
The mechanism of action is not well under-
R. Ruschig (eds.): Arzneimittel, Entwicklung,
stood. Suramin inhibits many different enzyme Wirkung, Darstellung, vol. 5, Verlag Chemie,
systems by binding to free cationic amino acid Weinheim 1972, pp. 11 – 110.
residues in the area of the active center. This 2. R. B. Borrows: “Human and Veterinary
appears to lead to a specific, but slight, inter- Anthelmintics,” Progr. Drug. Res. 17 (1973)
ference with the DNA-RNA replication mech- 108 – 209.
anism. The inhibition of protein kinase, an en- 3. P. J. Islip: “Anthelmintic Agents,” in M. E.
zyme intimately involved in intracellular regu- Wolff (ed.): Burger’s Medicinal Chemistry,
lation, also may be involved in the effects of vol. 2, J. Wiley & Sons, New York 1979,
suramin [52]. pp. 481 – 530.
Trade names: Germanin (Bayer); Antrypol 4. R. Cavier (ed.): “Chemotherapy of
(ICI); Moranyl (Specia). Helminthiasis,” Int. Encycl. Pharmacol. Ther.,
section 64, vol. 1, Pergamon, Oxford 1973.
Thiabendazole [148-79-8], 2-(4-thiazolyl)−1H- 5. “Intestinal Protozoan and Helminthic
benzimidazole, C10 H7 N3 S, M r 201.3, mp Infections,” WHO Tech. Rep. Ser. 1981,
304 – 305 ◦ C, is a tasteless, colorless, crystalline no. 666.
solid. It is insoluble in water, slightly soluble in 6. “Parasitic Zoonoses,” WHO Tech. Rep. Ser.
ethanol or chloroform, and soluble in acetone, 1979, no. 637.
7. M. A. Gemmell, P. P. Johnstone: “Cestodes,”
dimethyl sulfoxide, or dimethylformamide.
Antibiot. Chemother. (Basel) 30 (1981)
54 – 114.
8. F. Hawking: “Chemotherapy of Filariasis,”
Antibiot. Chemother. (Basel) 30 (1981)
135 – 162.
9. E. A. Malek (ed.): Snail-Transmitted Parasitic
The compound is synthesized by heating 4- Diseases, CRC Press, Boca Raton, Florida,
thiazolecarboxamide with o-phenylenediamine 1980.
in polyphosphoric acid [53].
16 Anthelmintics

10. A. E. R. Taylor, R. Muller (eds.): “The 33. S. S. Pong, C. C. Wang, L .C. Fritz, J.
Relevance of Parasitology to Human Welfare Neurochem. 34 (1980) 351 – 358.
Today,” Symp. Br. Soc. Parasitol., vol. 16, 34. Janssen, US 3274209, 1966 (A. H. M.
Blackwell Scientific Publications, Oxford Raeymaekers, D. C. J. C. Thienpont, P. J. A. W.
1978. Demoen).
11. E. K. Markell, M. Voge: Medical Parasitology, 35. P. A. J. Janssen: “The Levamisole Story,” Prog.
Saunders, Philadelphia 1981. Drug Res. 20 (1976) 347 – 383.
12. P. E. C. Manson-Bahr, F. I. C. Apted: Manson’s 36. Janssen, US 3657267, 1972 (J. L. H. Van
Tropical Diseases, Baillière Findall, London Gelder, L. F. C. Roevens, A. H. M.
1982. Raeymaekers).
13. W. Peters, in [10], pp. 25 – 40. 37. H. Van den Bossche, F. Rochette, C. Hörig:
14. J. Walsh, K. S. Warren, N. Engl. J. Med. 301 “Mebendazole and Related Anthelmintics,”
(1979) 967 – 974. Adv. Pharmacol. Chemother. 19 (1982)
15. D. Stürchler: Endemiegebiete tropischer
67 – 128.
Infektionskrankheiten, Huber, Bern 1981.
38. Bayer, US 2701225, 1955 (W. Lorenz).
16. H. Schenone in A. Flisser et al. (eds.):
39. B. Holmgren, I. Nordgren, M. Sandoz, A.
Cysticercosis, Present State of Knowledge and
Sundwall: “Metrifonate. Summary of
Perspectives, Academic Press, New York
Toxicological and Pharmacological
1982, pp. 25 – 38.
17. J. del Castillo in M. Florkin, B. T. Scheer Information Available,” Arch. Toxicol. 41
(eds.): Chemical Zoology, vol. 3, Academic (1978) 3 – 29.
Press, New York 1969, pp. 521 – 554. 40. Bayer, GB 824345, 1959.
18. Chemindex International 1983, IMS A.G., 41. P. Andrews, J. Thyssen, D. Lorke: “The
Zug,Switzerland. Biology and Toxicology of Molluscicides,
19. Index Nominum 1984, International Drug Bayluscide,” Pharmacol. Ther. 19 (1983)
Directory, Laboratory of the Swiss 245 – 295.
Pharmaceutical Society, Zürich, Switzerland. 42. Ciba, BE 632989, 1963.
20. L. B. Townsend, D. S. Wise: “The synthesis 43. P. Andrews, A. Haberkorn, H. Thomas:
and chemistry of certain anthelmintic “Antiparasitic Drugs: Mechanism of Action,
benzimidazoles,” Parasitology Today 6 (1990) Pharmacokinetics, and in Vitro and in Vivo
107 – 112. Assays of Drug Activity,” in V. Lorian (ed.):
21. G. C. Cook: “Use of benzimidazole Antibiotics in Laboratory Medicine, 2nd ed.,
chemotherapy in human helminthiases : Williams and Wilkins, Baltimore 1985,
indications and efficacy, Parasitology Today Chap. 9.
6 (1990) 133 – 136. 44. H. C. Richards, R. Forster, Nature (London)
22. E. Lacey: “Mode of action of benzimidazoles,” 222 (1969) 581 – 582.
Parasitology Today 6 (1990) 112 – 115. 45. Pfizer, ZA 6804589, 1967; FR 1584069, 1967
23. Burroughs Wellcome, US 2918401, 1959 (C. (J. W. McFarland).
Copp). 46. E. Merck, US 4113867, 1978.
24. I. G. Farbenind., DE 583055, 1933 (F. Muth). 47. P. Andrews, H. Thomas, R. Pohlke, J. Seubert:
25. American Cyanamid, US 2467893, 1949 (S. “Praziquantel,” Med. Res. Rev. 3 (1983)
Kushner, L. Brancone). 147 – 200.
26. J. C. Chabala et al., J. Med. Chem. 23 (1980)
48. Pfizer, BE 658987, 1965.
1134 – 1136.
27. H. Mrozik et al., Tetrahedron Lett. 23 (1982) 49. M. L. Aubry, P. Cowell, M. J. Davey, S.
2377. Shevde: “Aspects of the Pharmacology of a
28. M. E. Jung, Tetrahedron Lett. 28 (1987) 5977. New Anthelmintic: Pyrantel,” Br. J.
29. H. Bradshaw, Parasitology Today 5 (1989) Pharmacol. 38 (1970) 332 – 344.
63 – 64. 50. Eastman Kodak, US 2515912, 1950 (E. Van
30. D. F. Cully et al., Nature (London) 371 (1994) Lare, L. G. S. Brooker).
707 – 712. 51. I. G. Farbenind., GB 224849, 1924.
31. D. F. Cully et al., J. Biol. Chem. 271 (1996) 52. F. Hawking: “Suramin: With Special
20187 – 20191. Reference to Onchocerciasis,” Adv.
32. W. Forth in W. Forth, D. Henschler, W. Pharmacol. Chemother. 15 (1978) 289 – 322.
Rummel, K. Starke, (eds): Anthelmintika, 53. Merck & Co., US 3017415, 1962 (L. H. Sarett,
Pharmakologie und Toxikologie, H. D. Brown).
Wissenschaftsverlag 1993, 711 – 712.

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