Anthelmintic agents

1. CHEMOTHERAPY OF HELMINTHES
 Infections with helminths, or parasitic worms, affect more than two billion people
worldwide.
 Immature forms invade humans via the skin or gastrointestinal (GI) tract and
mature into adult worms with characteristic tissue distributions; with few
exceptions, such as Strongyloides and Echinococcus, which cannot complete
their life cycle unless they replicate themselves within the human host.
 Anthelmintics are drugs that act locally to expel worms from the GI tract or
systemically to eradicate adult helminths or developmental forms that invade
organs and tissues.
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2. TREATMENT OF HELMINTH INFECTIONS
Pathogenic worms are classified into;
1) Roundworms (nematodes)
2) Flatworms;
a) Tapeworms (cestodes).
b) Flukes (trematodes)
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3. NEMATODES (ROUNDWORMS)
 The major nematode parasites of humans include the soil-transmitted
helminths (STHs) and the filarial nematodes. These include;
1. Ascariasis
2. Trichuriasis
3. Hookworm
4. Strongyloides Stercoralis
5. Enterobius Vermicularis
6. Trichinella Spiralis
7. Filarisis;
• Wuchereria Bancrofti and Brugia Species
(Lymphatic Filariasis)
• Loa Loa (Loiasis)
• Onchocerca Volvulus
(Onchocerciasis or River Blindness)
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4.  The most widely used agents for reducing morbidity are the benzimidazole
anthelmintics (BZAs), either albendazole or mebendazole.
 Anthelmintics that eliminate lymphatic filariasis (LF) and onchocerciasis (river
blindness) include;
I. Combination therapy with either diethylcarbamazine and albendazole (in
LF-endemic regions.
II. Ivermectin and albendazole (in LF regions where onchocerciasis and/or
loiasis are co-endemic).
 These drugs target the microfilarial stages of the parasite, which circulate
in blood and are taken up by arthropod vectors where further parasite
development occurs.
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5. ASCARIS LUMBRICOIDES AND TOXOCARA CANIS
 A. lumbricoides, known as the “roundworm,” affects up to 90% of persons in
some tropical regions but also is seen in temperate climates.
 Mebendazole, albendazole, and pyrantel pamoate are preferred drugs; all
infected persons should be treated.
 Mebendazole and albendazole are preferred for therapy of asymptomatic-to-
moderate ascariasis. Both compounds should be used with caution to treat
heavy ascaris infections, alone or with hookworms.
 Pyrantel is safe for use in pregnancy, whereas BZAs should be avoided during
the first trimester.
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6.  Toxocariasis is common in North America and Europe. Major syndromes caused
by T. Canis infection are visceral larva migrans (VLM), ocular larva migrans
(OLM), and covert toxocariasis (CT). Treatment of VLM is reserved for patients
with severe, persistent, or progressive symptoms. Albendazole is the drug of
choice. The role of anthelmintic drugs for OLM and CT is controversial and
surgical management often is indicated, sometimes accompanied by
glucocorticoids.
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7. HOOKWORM
Necator americanus, Ancylostoma duodenale
 Hookworm species infect 740 million people. N americanus is the
predominant hookworm worldwide,whereas A. duodenale is focally
endemic in Egypt, India, and China.
 Hookworm larvae live in the soil and penetrate exposed skin. After
reaching the lungs, larvae migrate to the oral cavity and are swallowed.
After attaching to the jejunal mucosa, the adult worms feed on host blood.
 There is a direct correlation between the hookworm burden and fecal blood
loss.
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8.  The major treatment goal is to remove blood-feeding adult hookworms from the
intestines.
 Albendazole and mebendazole are preferred agents against both A. duodenale
and N. Americanus
 As a single dose, albendazole is superior to mebendazole at removing adult
hookworms from the GI tract.
 Oral albendazole is the drug of choice for treating cutaneous larva migrans or
“creeping eruption,” due to skin migration by larvae.
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9. STRONGYLOIDES STERCORALIS
 S. stercoralis, sometimes called the threadworm, can replicate and cause cycles
of larval reinfection entirely within the human host.
 Infective larvae in contaminated soil penetrate the skin or mucous membranes,
travel to the lungs, and ultimately mature into adult worms in the small intestine,
where they reside.
 Life-threatening disease due to massive larval hyperinfection can occur in
immunosuppressed persons, even decades after the initial infection.
 Ivermectin is the best drug for treating intestinal strongyloidiasis.
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10. ENTEROBIUS VERMICULARIS
 Enterobius, probably the most common helminth infections in temperate
climates, typically causes pruritus in the perianal and perineal regions.
 Because the infection is easily spread, the clinician must decide whether to
treat all close contacts and more than one course of therapy may be required.
 Pyrantel, mebendazole, and albendazole are highly effective. Single oral doses
of each should be repeated after 2 weeks.
 When combined with fastidious personal hygiene, a high cure rate can be
obtained.
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11. TRICHINELLA SPIRALIS
 T. spiralis infection results from eating insufficiently cooked flesh of infected
animals, especially pigs.
 When released, encysted larvae mature into adult worms in the intestine, which
then produce infectious larvae that invade tissues, especially skeletal muscle and
heart.
 Severe infection cause marked muscle pain and cardiac complications.
 Albendazole and mebendazole appear to be effective against the intestinal forms
of T. Spiralis that are present early in infection.
 Their efficacy on larvae that have migrated to muscle is questionable.
Glucocorticoids are of considerable value in controlling the acute manifestations
of infection.
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12. FILARIASIS
1) Wuchereria Bancrofti and Brugia Species (Lymphatic Filariasis)
 Adult worms that cause human filariasis dwell either in the lymphatics or
other tissues.
 Spread by the bites of infected mosquitoes, lymphatic filariasis (LF) affects
~120 million people in sub-Saharan Africa, India, Southeast Asia, the Pacific
region, and tropical America.
 In LF, host reactions to adult worms initially cause lymphatic inflammation
manifested by fever, lymphangitis, and lymphadenitis; this can progress to
lymphatic obstruction.
 A reaction to microfilariae, tropical pulmonary eosinophilia, may occur.
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13.  Recommended treatment is yearly combined therapy with albendazole and
diethylcarbamazine (DEC), which clears circulating microfilariae from infected
subjects, thereby reducing the likelihood that mosquitoes will transmit LF to other
individuals.
 Diethylcarbamazine is the drug of choice for the treatment of LF adult worms,
but the effect is variable; best results are achieved if therapy is started before
lymphatic obstruction has occurred.
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14. 2) Loa Loa (Loiasis)
 L. loa is a tissue-migrating filarial parasite found in river regions of Central
and West Africa.
 worms in subcutaneous tissues typically cause episodic swellings and
allergic reactions.
 Rarely, encephalopathy, cardiomyopathy, or nephropathy occurs.
 Diethylcarbamazine is the best single drug for the treatment of loiasis,
initially in small initial doses to diminish host reactions that result from
destruction of microfilariae (Mazzotti test).
 Glucocorticoids often are required to control acute reactions.
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15. 3) Onchocerca Volvulus (Onchocerciasis or River Blindness)
 Transmitted by blackflies, O. volvulus infects ~17 million people in sub-
Saharan Africa, and <100,000 people in parts of Mexico, Guatemala, and
South America.
 Inflammatory reactions, primarily to microfilariae rather than adult worms,
affect the subcutaneous tissues, lymph nodes, and eyes.
 Onchocerciasis is a leading cause of infectious blindness worldwide.
 Ivermectin is the best single drug for control and treatment of
onchocerciasis. It kills only microfilariae of O. volvulus, while producing few
if any ocular complications.
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16. CESTODES (FLATWORMS)
These include;
1. Taenia Saginata
2. Taenia Solium
3. Diphyllobothrium Latum
4. Hymenolepis Nana
5. Echinococcus Species
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17. TAENIA SAGINATA
 Humans are the definitive hosts for T. saginata, the beef tapeworm.
 This most common tapeworm usually is detected after passage of
proglottids from the intestine.
 It is cosmopolitan, occurring most commonly in sub-Saharan Africa and the
Middle East, where undercooked beef is consumed.
 Praziquantel is the drug of choice for T. saginata infection.
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18. TAENIA SOLIUM
 T. solium, or pork tapeworm, causes two types of infection.
 The intestinal form with adult tapeworms results from eating undercooked meat
containing cysticerci.
 Invasive larval forms cause Cysticercosis, the more dangerous systemic
infection.
 Invasion of the brain (neurocysticercosis) can result in epilepsy, meningitis, and
increased intracranial pressure.
 Praziquantel is preferred for intestinal infections with T. solium, while
albendazole is the drug of choice for cysticercosis.
 Chemotherapy is appropriate only when it is directed at live cysticerci causing
pathology; pretreatment with glucocorticoids is advised.
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19. DIPHYLLOBOTHRIUM LATUM
 D. latum, the fish tapeworm, is acquired by eating inadequately cooked,
infested fish.
 Most infected individuals are asymptomatic; frequent manifestations include
abdominal symptoms and weight loss; megaloblastic anemia may occur due to
vitamin B12 deficiency.
 Praziquantel eliminates the worm.
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20. HYMENOLEPIS NANA
 H. nana, the dwarf tapeworm, is the most common tapeworm parasitizing
humans. Infection is more prevalent in tropical than temperate climates and most
common among institutionalized children.
 Cysticerci develop in the villi of the intestine and then regain access to the
intestinal lumen where larvae mature into adults.
 Praziquantel is effective against H. nana infections; relatively high doses usually
are required, and therapy may need to be repeated.
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21. ECHINOCOCCUS SPECIES
 Humans are one of several intermediate hosts for larval forms of Echinococcus
species that cause “cystic” (E. granulosus) and “alveolar” (E. multilocularis and E.
vogeli) hydatid disease.
 Parasite eggs from canine stools are a major source in associated livestock (e.g.,
sheep and goats).
 Ecchinococcus produces slowly growing cysts, most often in liver and lung.
 Surgical removal of the cyst is the preferred treatment, but leakage may spread
disease to other organs.
 Prolonged regimens of albendazole, either alone or combined with surgery, may
be beneficial, but some patients are not cured despite multiple courses of
therapy.
 Adjunct treatment with BZAs is the cornerstone of the interdisciplinary approach
to controlling cystic echinococcosis.
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22. TREMATODES (FLUKES)
These include;
1) Schistosoma Haematobium, Schistosoma Mansoni, Schistosoma
Japonicum
2) Paragonimus westermani and Other Paragonimus Species
3) Clonorchis sinensis, Opisthorchis viverrini, Opisthorchis felineus
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23. SCHISTOSOMA HAEMATOBIUM, SCHISTOSOMA MANSONI, SCHISTOSOMA
JAPONICUM
 These are the main species of blood flukes that cause human schistosomiasis.
 Schistosomiasis is widely distributed over South America (S. mansoni), much of
Africa and the Arabian Peninsula (S. mansoni and S. haematobium), and China
and Southeast Asia (S. japonicum).
 Infected snails are intermediate hosts for freshwater transmission.
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24.  Schistosomiasis primarily involves the liver, spleen, and GI tract (S. mansoni and
S. japonicum) or the lower genitourinary tract (S. haematobium).
 Heavy infections with S. haematobium are associated with bladder carcinoma.
 Chronic infections can cause portosystemic shunting due to periportal fibrosis in
the liver.
 Praziquantel is the drug of choice for schistosomes.
 The artemisinin derivative artemether targets the larval schistosomula stages of
the parasite.
 Combined treatment of animals harboring juvenile and adult schistosome worms
with artemether and praziquantel resulted in significantly higher worm burden
reductions than either drug administered singly.
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25. PARAGONIMUS WESTERMANI AND OTHER PARAGONIMUS SPECIES
 Called lung flukes, a number of Paragonimus species, of which P. westermani is
the most common, are pathogenic for humans.
 Found in the Far East and on the African and South American continents, these
parasites have two intermediate hosts: snails and crustaceans.
 Humans become infected by eating raw or undercooked crabs or crayfish.
Disease is caused by reactions to adult worms.
 First line treatment is praziquantel which is effective but with occasional
resistance being seen.
 Bithionol is considered a second-line agent.
 Triclabendazole also recently was shown to be efficacious.
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26. CLONORCHIS SINENSIS, OPISTHORCHIS VIVERRINI, OPISTHORCHIS
FELINEUS
 These closely related trematodes exist in the Far East (C. sinensis, “the
Chinese liver fluke,” and O. viverrini) and parts of Eastern Europe (O. felineus).
 Metacercariae released from poorly cooked infected fish mature into adult
flukes that inhabit the human biliary system.
 Heavy infections can cause obstructive liver disease, inflammatory gallbladder
pathology associated with pancreatitis.
 One-day therapy with praziquantel is highly effective.
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27. BENZIMIDAZOLES (BZA’s)
 These include; Thiabendazole, mebendazole, and albendazole
 The BZAs have been developed as broad-spectrum anthelmintic agents.
 Thiabendazole, mebendazole, and albendazole have been used extensively
for the treatment of human helminth infections.
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28. 1) Thiabendazole;
• Thiabendazole is active against a wide range of nematodes that infect
the GI tract, but its clinical use has declined markedly because of its
toxicity relative to other equally effective drugs.
2) Mebendazole;
• Mebendazole has supplanted thiabendazole for the treatment of
intestinal roundworm infections.
3) Albendazole;
• Albendazole is used primarily against a variety of intestinal and tissue
nematodes but also against larval forms of certain cestodes.
• Albendazole is the drug of choice for cysticercosis and cystic hydatid
disease. When used yearly in conjunction with either ivermectin or
diethylcarbamazine, single doses of albendazole have shown
considerable promise for global control of lymphatic filariasis and other
filarial infections.
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29. Anthelmintic action
 The BZAs inhibit microtubule polymerization by binding to b-tubulin.
 The selective toxicity of these agents likely results because the BZAs bind
parasite b-tubulin with much higher affinity than they do the mammalian protein.
 The BZAs are versatile anthelmintic agents, particularly against GI nematodes
(round worms), where their action is not dictated by systemic drug
concentration.
 Mebendazole and albendazole are highly effective in treating the major STH
infections; ascariasis, enterobiasis, trichuriasis and hookworm as well as less
common human nematode infections.
 These drugs are active against both larval and adult stages of nematodes
(round worms) and they are ovicidal for Ascaris and Trichuris.
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30. Absorption, metabolism and excretion;
1) Thiabendazole;
• Thiabendazole is absorbed rapidly after oral ingestion and reaches
peak plasma concentrations after 1 hour.
• Most of the drug is excreted in the urine within 24 hours as
5- hydroxythiabendazole, conjugated either as the glucuronide or the
sulfate.
2) Mebendazole;
• Tablet formulations of mebendazole are poorly and erratically
absorbed. It has a low systemic bioavailability of 22% as a result of a
combination of poor absorption and rapid first-pass hepatic
metabolism.
• Mebendazole is ~95% bound to plasma proteins and is extensively
metabolized. Conjugates of mebendazole and its metabolites have
been found in bile, but little unchanged mebendazole appears in the
urine. 30

31. 3) Albendazole;
• Albendazole is variably absorbed after oral administration. A fatty
meal enhances absorption.
• After a 400-mg oral dose, albendazole cannot be detected in
plasma, because the drug is rapidly metabolized in the liver to its
sulfoxide, which has potent anthelmintic activity.
• It is well distributed into various tissues including hydatid cysts,
probably explaining its greater efficacy for tissue-dwelling
helminths.
• Albendazole metabolites are excreted mainly in the urine.
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32. Toxicity, side effects;
 BZAs generally have excellent safety profiles. Side effects, primarily mild
gastrointestinal symptoms. treatment should be avoided during the first
trimester of pregnancy.
1) Thiabendazole;
• The clinical utility of thiabendazole in adults is compromised by its toxicity,
which has diminished its clinical use.
• Frequent side effects include GI upset, fatigue, drowsiness, and
headache. Occasional fever, rash, erythema multiforme, hallucinations, and
sensory disturbances, angioedema, shock, tinnitus, convulsions, transient
leucopenia and intrahepatic cholestasis.
• Thiabendazole is hepatotoxic and should be used with caution in patients
with hepatic disease.
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33. 2) Mebendazole;
• Mebendazole does not routinely cause significant systemic toxicity,
even in the presence of anemia and malnutrition.
• Transient symptoms of abdominal pain, distention, and diarrhea
have occurred with massive infestation and expulsion of worms.
• Rare side effects in patients treated with high doses of
mebendazole include allergic reactions, alopecia, reversible
neutropenia.
• Agranulocytosis, and oligospermia.
• Reversible elevation of serum transaminases may occur.
• Occipital seizures.
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34. 3) Albedazole;
• Albendazole is well tolerated by most patients.
• The most common side effect is an increase in serum
aminotransferases, which return to normal upon drug cessation; rarely
jaundice or cholestasis may occur.
• Transient mild GI symptoms (epigastric pain, diarrhea, nausea, and
vomiting) occur in ~1% of treated individuals. Dizziness and headache
occur occasionally.
• Other side effects during extended therapy include; alopecia,
leukopenia, and thrombocytopenia.
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35. DIETHYLCARBAMAZINE (DEC)
 Diethylcarbamazine is a first-line agent for control and treatment of lymphatic
filariasis and for therapy of tropical pulmonary eosinophilia caused by W.
bancrofti and Brugia malayi.
 Although partially effective against onchocerciasis and loiasis, it can cause
serious adverse reactions. For this reason, ivermectin has replaced
diethylcarbamazine for onchocerciasis.
 Despite its toxicity, diethylcarbamazine remains the best drug available to treat
loiasis.
 Annual single doses of both diethylcarbamazine and albendazole show
considerable promise for the control of lymphatic filariasis in regions where
onchocerciasis and loiasis are not endemic.
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36. Anthelmintic action
 Microfilarial forms of susceptible species are most affected by
diethylcarbamazine, which elicits rapid disappearance from blood for W.
bancrofti, B. malayi, and L. loa.
 The drug kills microfilariae of O. volvulus in skin but not in nodules that
contain the adult (female) worms.
 It does not affect the microfilariae of W. bancrofti in a hydrocele.
 Diethylcarbamazine appears to exert a direct toxic effect on W. bancrofti
microfilariae; it also kills worms of adult L. loa and probably adult W. bancrofti
and B. malayi.
 Diethylcarbamazine may impair intracellular processing and transport of
certain macromolecules to the helminth plasma membrane.
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37. Absorption, metabolism, and excretion of diethylcarbamazine;
 Diethylcarbamazine is absorbed rapidly from the GI tract.
 Peak plasma levels occur within 1–2 hours, and the plasma t1/2 varies from 2 to
10 hours, depending on urinary pH.
 Metabolism is rapid and extensive. A major metabolite, diethylcarbamazine- N-
oxide, is bioactive.
 Diethylcarbamazine is excreted by both urinary and extraurinary routes.
 Alkalinizing the urine can elevate plasma levels, prolong the plasma t1/2, and
increase both therapeutic effect and toxicity of diethylcarbamazine.
 Dosage reduction may be required in people with renal dysfunction or sustained
alkaline urine.
 Therapeutic uses recommended regimens for filarial infections differ according to
whether the drug is used singly or in combination with albendazole.
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38. Toxicity and side effects
 At 8–10 mg/kg/day, direct toxic reactions to diethylcarbamazine, including
anorexia, nausea, headache, and vomiting, are rarely severe and usually
disappear within a few days despite continued therapy.
 Major adverse effects result from host response to destruction of parasites,
primarily microfilariae.
 Ocular complications include; keratitis, uveitis, and atrophy of the retinal
pigment epithelium.
 In patients with bancroftian or brugian filariasis, nodular swellings may occur
along the course of the lymphatics, often with an accompanying lymphadenitis
that also subsides within a few days.
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39. IVERMECTIN
 Ivermectin (dihydroavermectin B1a) is FDA-approved for treatment of
onchocerciasis and for therapy of intestinal strongyloidiasis.
 Ivermectin taken as a single oral dose every 6–12 months continues to serve
as the mainstay of major programs to control onchocerciasis.
 In addition, annual oral doses of ivermectin, either taken alone or combined
with annual oral doses of albendazole, markedly reduce microfilaremia in
lymphatic filariasis due to W. bancrofti or B. malayi.
 Current recommendations advocate diethylcarbamazine (6 mg/kg b.w) plus
albendazole (400 mg).
 The two-drug regimen is preferred in regions where lymphatic filariasis (LF)
coexists with either onchocerciasis or loiasis.
 Ivermectin is the drug of choice against intestinal strongyloidiasis and is
effective against several other human infections caused by intestinal
nematodes.
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40. Absorption, metabolism, and excretion
 Peak plasma levels of ivermectin are achieved within 4–5 hours after oral
administration.
 Ivermectin is ~93% bound to plasma proteins.
 The drug is extensively converted by hepatic CYP3A4 to at least 10
metabolites, mostly hydroxylated and demethylated derivatives.
 Virtually no ivermectin appears in human urine in either unchanged or
conjugated form.
 Extremely low levels are found in brain; a P-glycoprotein efflux pump in the
blood–brain barrier prevents ivermectin from entering the central nervous
system (CNS).
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41. Therapeutic uses of Ivermectin;
1) Onchocerciasis ;
• Single oral doses of ivermectin (150 μg/kg) given every 6–12 months are
considered effective, safe, and practical for reducing the number of
circulating microfilariae in adults and children 5 years of age or older;
widespread use of ivermectin is a mainstay of onchocerciasis control
programs.
• Marked reduction of microfilariae in the skin and ocular tissues is noted
within a few days and lasts for 6–12 months; the dose then should be
repeated.
• Cure is not attained, because ivermectin has little effect on adult O.
volvulus. Ivermectin has been widely used for onchocerciasis control
programs in Africa, the Middle East, and Latin America.
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42. 2) Lymphatic Filariasis;
 Single annual doses of ivermectin (400 μg/kg) are effective and safe for mass
therapy of infections with W. bancrofti and B. malayi. The duration of treatment
is for at least 5 years based on the estimated fecundity of the adult worms.
 Ivermectin is as effective as diethylcarbamazine for controlling lymphatic
filariasis and can be used in regions where onchocerciasis, loiasis, or both are
endemic. The duration of treatment required to eliminate LF presumably would
be >6 years.
 A single dose of ivermectin (200 μg/kg) and a single dose of albendazole (400
mg) annually are even more effective in controlling lymphatic filariasis.
 This dual-drug regimen also reduces infections with intestinal nematodes.
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43. 3) Infections with Intestinal Nematodes;
 The finding that a single dose of 150–200 μg/kg of ivermectin can cure
strongyloidiasis is encouraging, because this drug also is effective against
coexisting ascariasis, trichuriasis, and enterobiasis.
 A single dose of 100 μg/kg of ivermectin is as effective as traditional
treatment of intestinal strongyloidiasis with thiabendazole, and less toxic.
 In Japan, almost all S. stercoralis–infected patients were cured by 200
μg/kg of ivermectin orally twice at an interval of 2 weeks.
 In Strongyloides hyperinfection syndrome, ivermectin has been used
successfully, including cases unresponsive to thiabendazole.
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44. 4) Other Indications
 Taken as a single 200-μg/kg oral dose, ivermectin is a first-line drug for
treatment of cutaneous larva migrans.
 Similar doses also are safe and highly effective against human head lice and
scabies, even in HIV-infected individuals.
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45. Toxicity, Side Effects, and Precautions
 Ivermectin generally is well tolerated.
 In infected humans, ivermectin toxicity nearly always results from reactions to
dying microfilariae; the intensity and nature of these reactions relate to the
microfilarial burden and the duration and type of filarial infection.
 Adverse effects include; pruritus and swollen, tender lymph nodes, fever,
tachycardia, hypotension, prostration, dizziness, headache, myalgia, arthralgia,
diarrhea, and edema These may respond to glucocorticoids.
 Ivermectin induces milder side effects than does diethylcarbamazine, and
unlike the latter, seldom exacerbates ocular lesions in onchocerciasis.
 Serious side effects include marked disability and encephalopathies in patients
coinfected with heavy burdens of L. loa microfilaria.
 Loa encephalopathy is associated with ivermectin treatment of individuals
with high levels of Loa microfilaremia.
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46. METRIFONATE
 Metrifonate is an organophosphorus compound used as an insecticide and
then as an anthelmintic, especially for S. haematobium.
 Metrifonate is a prodrug that is converted nonenzymatically to dichlorvos
(2,2-dichlorovinyl dimethyl phosphate, DDVP), a potent cholinesterase
inhibitor.
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47. OXAMNIQUINE
 Oxamniquine is a second-line drug to praziquantel for the treatment of
schistosomiasis.
 Most strains of S. mansoni are highly susceptible to oxamniquine, but S.
haematobium and S. japonicum are virtually unaffected by therapeutic doses.
 Because of a low incidence of mild side effects together with normally high
efficacy after a single oral dose, oxamniquine continues to be used in S. mansoni
control programs, especially in South America.
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48. PIPERAZINE
 A number of substituted piperazine derivatives have anthelmintic activity, but
none apart from diethylcarbamazine has found a place in human therapeutics.
 Piperazine is highly effective against A. lumbricoides and E. vermicularis. The
predominant effect of piperazine on Ascaris is a temporary paralysis that results
in expulsion of the worm by peristalsis.
 Piperazine acts as a GABA-receptor agonist. By increasing Cl− conductance of
the Ascaris muscle membrane, the drug produces hyperpolarization that leads
to flaccid paralysis.
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49. PRAZIQUANTEL
 Praziquantel (biltricide, distocide) is a pyrazinoisoquinoline derivative.
Infections with many different cestodes and trematodes respond favorably to
this agent, whereas nematodes generally are unaffected.
 Praziquantel treatment of patients coinfected with schistosomes and
hookworms reduces hookworm prevalence and infection intensities (egg
counts) significantly.
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50. Anthelmintic action
 After rapid and reversible uptake, praziquantel has two major effects on adult
schistosomes.
 At low concentrations, it causes increased muscular activity, followed by
contraction and spastic paralysis.
 Affected worms detach from blood vessel walls, resulting in a rapid shift from
the mesenteric veins to the liver.
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51. Absorption, metabolism and excretion;
 Praziquantel is readily absorbed after oral administration, and maximal levels in
human plasma occur in 1–2 hours.
 Extensive first-pass metabolism to inactive hydroxylated and conjugated
products limits drug bioavailability.
 The drug is ~80% bound to plasma proteins. Its plasma t1/2 is 1–3 hours but may
be prolonged in patients with severe liver disease, including those with hepato-
splenic schistosomiasis.
 About 70% of an oral dose of praziquantel is recovered as metabolites in the
urine within 24 hours; most of the remainder is metabolized in the liver and
eliminated in the bile.
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52. Therapeutic uses
 Praziquantel is FDA approved for therapy of schistosomiasis and liver fluke
infections, but also is used to treat infections with many other trematodes and
cestodes.
 Praziquantel is the drug of choice for schistosomiasis caused by all
Schistosoma species.
 Although dosage regimens vary, a single oral dose of 40 mg/kg or three doses
of 20 mg/kg each, given 4–6 hours apart, generally produce cure rates of 70–
95% and consistent reductions (>85%) in egg counts.
 Tablets of 600 mg are available.
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53. Toxicity, precautions, and interactions;
 Abdominal discomfort, nausea, diarrhea, headache, dizziness and drowsiness
These direct effects are transient and dose-related.
 Indirect effects such as fever, pruritus, urticaria, rashes, arthralgia, and myalgia
are noted occasionally and are related to parasite burden.
 In neurocysticercosis, inflammatory reactions to praziquantel may produce
meningismus, seizures, mental changes, and CSF pleocytosis. These effects
usually are delayed in onset, last 2–3 days, and respond to symptomatic therapy
such as analgesics and anticonvulsants.
 Dexamethasone reduces the bioavailability of praziquantel, but the mechanism
is not understood. Under certain conditions, praziquantel may increase the
bioavailability of albendazole.
 Praziquantel is contraindicated in ocular cysticercosis because the host
response can irreversibly damage the eye.
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54. PYRANTEL PAMOATE
 Pyrantel is a broad-spectrum anthelmintic directed against pinworm, roundworm,
and hookworm infections.
 Pyrantel is a depolarizing neuromuscular blocking agent that opens nonselective
cation channels and induces marked, persistent activation of nicotinic
acetylcholine receptors, which results in spastic paralysis of the worm.
 Pyrantel is effective against hookworm, pinworm, and roundworm; unlike its
analog oxantel, it is ineffective against Trichuris trichiura.
 Pyrantel pamoate is poorly absorbed from the GI tract, a property that contributes
to its selective action on GI nematodes.
 Less than 15% is excreted in the urine as parent drug and metabolites. Most of an
administered dose is recovered in the feces.
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55.  High cure rates have been achieved after a single oral dose of 11 mg/kg
(maximum of 1 g).
 Transient and mild GI symptoms occasionally are observed, as are headache,
dizziness, rash, and fever.
 Pyrantel pamoate use in pregnant patients and children <2 years of age is not
recommended.
 Because pyrantel pamoate and piperazine are mutually antagonistic in their
neuromuscular effects on parasites, they should not be used together.
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