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Anthelmintics
Peter Andrews, Bayer AG, Wuppertal, Federal Republic of Germany
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.
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.
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].
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.
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
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).
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