Chapter 51: Chemotherapy of Helminth Infections

Single dose therapy with a BZ reduces worm burden to a varying degree, with greatest efficacy for ascariasis, followed by whipworm and hookworm (Keiser and Utzinger, 2008) and subsequently reduces morbidity attributable to the parasite. Treatment improves host iron stores and hemoglobin levels, physical growth, cognition, educational achievement, and school absenteeism, as well as having a positive influence on the entire community by reducing transmission (Bethony et al., 2006). In 2001, the World Health Assembly adopted a resolution urging that by 2010 member states should regularly administer anthelmintics to at least 75% of all school-age children at risk for morbidity (WHO, 2002). Concerns with this recommendation have included:

• The scope of the undertaking

• The high rate of post-treatment reinfection that occur in areas of high transmission

• Documented drug failures against hookworm with mebendazole

• The possibility that widespread treatment will lead to the emergence of BZ drug resistance

• The possibility that by focusing exclusively on school-aged children, other groups and vulnerable populations, such as preschool children and women of reproductive age, will be omitted

In addition to targeting STH infections among school-aged children, there are ongoing programs to eliminate lymphatic filariasis (LF) and onchocerciasis (river blindness) over the next 10-20 years (Molyneux and Zagaria, 2002; Molyneux et al., 2003). The term elimination, as opposed to eradication, refers to the reduction of disease incidence to zero or close to zero, with a requirement for ongoing control efforts (Hotez et al., 2004). The major goals for the LF elimination program (and to some extent, the onchocerciasis elimination programs) are to interrupt arthropod-borne transmission by administering combination therapy with either diethylcarbamazine (DEC; hetrazan; available from CDC in the U.S.) and albendazole (in LF-endemic regions such as India and Egypt), or ivermectin (stromectol) and albendazole (in LF regions where onchocerciasis and/or loiasis are co-endemic). For onchocerciasis, ivermectin also reduces the microfilarial load in the skin, leading to reductions in so-called troublesome itching and ultimately, in preventing river blindness. DEC and ivermectin target the microfilarial stages of the parasite, which circulate in blood and are taken up by arthropod vectors where further parasite development takes place. Both control programs rely heavily on the generosity of major drug companies that donate ivermectin and albendazole, respectively (Burnham and Mebrahtu, 2004; Molyneux et al., 2003).

Effective and safe anthelmintics have replaced the older ascaricides. The preferred agents are the benzimidazoles (BZ), mebendazole and albendazole, and the broad spectrum drug pyrantel pamoate. Cure with any of these drugs can be achieved in nearly 100% of cases. Mebendazole and albendazole are preferred for therapy of asymptomatic to moderate ascariasis, as well as for mass drug administration campaigns because those agents have a broad spectrum of activity against GI nematodes. Both compounds should be used with caution to treat heavy Ascaris infections, alone or with hookworms. In rare instances, following chemotherapy hyperactive ascarids may migrate to unusual loci and cause serious complications such as appendicitis, occlusion of the common bile duct, and intestinal obstruction and perforation with peritonitis. For this reason, some clinicians recommend the use of pyrantel for heavy Ascaris infections because this agent paralyzes the worms prior to their expulsion. Surgery may be required to alleviate obstructive complications. Pyrantel is considered safe for use during pregnancy, whereas BZ should be avoided during the first trimester. Albendazole is available off-label for treatment of ascariasis in the U.S.

Three major syndromes are caused by T. canis infection: visceral larva migrans (VLM), ocular larva migrans (OLM), and covert toxocariasis (CTox). CTox may represent an under-appreciated cause of asthma and seizures (Sharghi et al., 2001). Specific treatment of VLM is reserved for patients with severe, persistent, or progressive symptoms (Bethany et al., 2006). Albendazole is the drug of choice. In contrast, anthelmintic therapy for treatment of OLM and CT is controversial. In the case of OLM, surgical management often is indicated, sometimes accompanied by systemic or topical steroids (Sabrosa and de Souza, 2001).

N. americanus is the predominant hookworm worldwide, especially in the Americas, sub-Saharan Africa, South China, and Southeast Asia, whereas A. duodenale is focally endemic in Egypt and in parts of northern India and China. Infection also occurs farther north in unusual but relatively warm settings such as mines and large mountain tunnels, hence the terms miner's disease and tunnel disease. Hookworm larvae live in the soils and penetrate exposed skin. After reaching the lungs, the larvae migrate to the oral cavity and are swallowed. After attaching to the small intestinal mucosa, the derived adult worms feed on host blood. There is a general relationship between the number of hookworms (hookworm burden) as determined by quantitative fecal egg counts and fecal blood loss. In individuals with low iron reserves, the correlation extends to hookworm burden and degree of iron-deficiency anemia. Unlike heavy Ascaris and Trichuris infections, which occur predominantly in children, heavy hookworm infections also occur in adults, including women of reproductive age. In some endemic areas, the heaviest hookworm burdens occur exclusively in adult populations.

Although iron supplementation (and transfusion in severe cases) often is helpful in individuals with severe iron-deficiency anemia, the major goal of treatment is to remove blood-feeding adult hookworms from the intestines. Albendazole is the agent of first choice against both A. duodenale and N. americanus. This drug has the advantage of activity against other GI nematodes (Hotez, 2009). Mebendazole is also commonly used; however, especially when used in a single dose, albendazole is considered far superior to mebendazole at removing adult hookworms from the GI tract (Keiser and Utzinger, 2008). Oral albendazole is the drug of choice for treating cutaneous larva migrans, or "creeping eruption," which is due most commonly to skin migration by larvae of the dog hookworm, A. braziliense. Oral ivermectin or topical thiabendazole also can be used.

Mebendazole and albendazole are the most effective agents for treatment of whipworm, either as a single agent or together with Ascaris and hookworm infections. Both drugs provide significant reductions in host worm burdens even when used in a single dose, such as what might be used in mass drug administration campaigns (Hotez, 2009). However, single-dose therapy with either drug is often ineffective for achieving "cure" (i.e., total worm burden removal), so that a 3-day course of therapy is typically required (Keiser and Utzinger, 2008).

Infective larvae in fecally 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. Many infected individuals are asymptomatic, but some experience skin rashes, nonspecific GI symptoms, and cough. Life-threatening disseminated disease, known as the hyperinfection syndrome, can occur in immunosuppressed persons, even decades after the initial infection when parasite replication in the small intestine is unchecked by a competent immune response. Most deaths caused by parasites in the U.S. probably are due to Strongyloides hyperinfection. Ivermectin is the drug of choice for treatment of strongyloidiasis. Hyperinfection may require prolonged or repeated therapy. Although the BZ drugs show some efficacy, they are less effective than ivermectin.

Pyrantel pamoate, mebendazole, and albendazole are highly effective. Single oral doses of each should be repeated after 2 weeks. When their use is combined with rigid standards of personal hygiene, a very high proportion of cures can be obtained. Treatment is simple and almost devoid of side effects.

Severe infection can be fatal, but more typically causes marked muscle pain and cardiac complications. Fortunately, infection is readily preventable. All pork, including pork sausages, should be thoroughly cooked before being eaten. The encysted larvae are killed by exposure to heat of 60°C for 5 minutes.

Albendazole and mebendazole are effective against the intestinal forms of T. spiralis that are present early in infection. The efficacy of these agents or any anthelmintic agent on larvae that have migrated to muscle is questionable. Glucocorticoids may be of considerable value in controlling the acute and dangerous manifestations of established infection, although steroids can alter the metabolism of albendazole.

In LF, host reaction to the adult worms initially cause lymphatic inflammation manifested by fevers, lymphangitis, and lymphadenitis. This can progress to lymphatic obstruction and is often exacerbated by secondary attacks of bacterial cellulitis, leading to lymphedema manifested by hydrocele and elephantiasis. An accentuated immune reaction to microfilariae, termed tropical pulmonary eosinophilia, also occurs in some persons.

The Global Program for the Elimination of LF recommends that all at-risk individuals be treated once yearly with an oral two-drug combination (Molyneux and Zagaria, 2002). Today, >500 million people are treated annually (Hotez, 2009). For most countries, the WHO recommends diethylcarbamate (DEC) for its micro- and macrofilaricidal effect in combination with albendazole to enhance macrofilaricidal activity. The exceptions are in many parts of sub-Saharan Africa and Yemen, where either loiasis or onchocerciasis are co-endemic. In these regions, ivermectin is substituted for DEC (Molyneux et al., 2003). DEC and ivermectin clear circulating microfilariae from infected subjects (Molyneux and Zagaria, 2002), thereby reducing the likelihood that mosquitoes will transmit LF to other individuals. The number of serious adverse events from LF-control chemotherapy programs has been remarkably low, 1 out of 4.5 million subjects treated (Molyneux et al., 2003).

DEC is the drug of choice for specific therapy directed against adult worms. However, the anthelmintic effect on the adult worms is variable. Although chemotherapy decreases the incidence of filarial lymphangitis, it is unclear whether it reverses lymphatic damage or other chronic manifestations of LF. In longstanding elephantiasis, surgical measures may be required to improve lymph drainage and remove redundant tissue.

DEC currently is the best single drug for the treatment of loiasis, but it is advisable to start with a small initial dose to diminish host reactions that result from destruction of microfilariae. Glucocorticoids may be administered to ameliorate post-treatment acute reactions. In rare instances, life-threatening encephalopathy follows the treatment of loiasis, probably due to the inflammatory reaction to dead or dying microfilariae lodged in the cerebral microvasculature. Guidelines have been developed aimed at screening out populations with heavy infection so that they are not administered ivermectin, which has also been associated with fatal encephalopathy. The potential complications of unmonitored DEC treatment of loiasis are a major reason why this agent is not recommended for mass chemoprophylaxis of LF in regions of sub-Saharan Africa where L. loa is co-endemic.

Ivermectin is the drug of choice for control and treatment of onchocerciasis. DEC is no longer recommended because ivermectin produces far milder systemic reactions and few if any ocular complications. Ivermectin treatment clears microfilariae in the tissues, prevents the development of blindness, and interrupts transmission. It also results in delayed resumption of production of microfilariae in the uterus of female worms. The African Programme for Onchocerciasis Control coordinates treatment of river blindness in Central and West Africa (www.who.int/pbd/blindness/onchocerciasis). Although suramin (Chapter 50) kills adult O. volvulus worms, treatment with this relatively toxic agent is generally not advised.

There is no effective anthelmintic for treatment of D. medinensis infection. Traditional treatment for this disabling condition is to draw the live adult female worm out day by day by rolling it onto a small piece of wood. This procedure risks significant secondary bacterial infection. Metronidazole, 250 mg given three times a day for 10 days, may provide symptomatic and functional relief by facilitating removal of the worm through indirect suppression of host inflammatory responses.

Praziquantel (biltricide) is the drug of choice for treatment of infection by T. saginata, although niclosamide can also be used. Both drugs are very effective, simple to administer, and comparatively free from side effects. Assessment of cure can be difficult because the worm (segments as well as scolex) usually is passed in a partially digested state. If the parasitological diagnosis is uncertain, niclosamide (not available in the U.S.) is the preferred drug because of the danger of an inadvertent secondary inflammatory response to occult cysticercosis.

Niclosamide is preferred for treatment of intestinal infections with T. solium because it will have no effect on occult neurocysticercosis. Albendazole is the drug of choice for treating cysticercosis. The advisability of chemotherapy for neurocysticercosis is controversial (Salinas and Prasad, 2000), being appropriate only when it is directed at live cysticerci and not against dead or dying cysticerci (as evidenced by neuroimaging using contrast agents) or in settings where cerebral imaging reveals a large burden of parasites. Pretreatment with glucocorticoids is strongly advised in this situation to minimize inflammatory reactions to dying parasites (Evans et al., 1997). Anthelmintic treatment can shrink brain cysts but also can have adverse consequences leading to seizures and hydrocephalus especially if corticosteroids are not administered beforehand. Some experts advocate use of albendazole therapy for patients with multiple cysts or viable cysts (as determined by absence of ring enhancement on contrast neuroimaging studies).

Therapy with praziquantel readily eliminates the worm and ensures hematological remission.

Praziquantel is effective against H. nana infections, but higher doses than used for other tapeworm infections usually are required. In addition, therapy may have to be repeated. Treatment failure or reinfection is indicated by the appearance of eggs in the stool ~4 weeks after the last dose. Albendazole is partially efficacious against H. nana; in 277 cases from 11 studies, 69.5% of patients were cured by albendazole (400 mg daily for 3 days) (Horton, 2000).

Prolonged regimens of albendazole, either alone or as an adjunct to surgery, are reportedly of some benefit. However, some patients are not cured despite multiple courses of therapy, especially in alveolar echinococcosis where lifelong therapy with albendazole may be required. Treatment of infected dogs with praziquantel eradicates adult worms and interrupts transmission of these infections. New treatment methods, such as percutaneous puncture, aspiration, injection of scolicidal agents, and re-aspiration–based techniques, have received much attention, and they yield rates of cure and relapse equivalent to those following surgery. Benzimidazole treatment should be administered in the perioperative period (Kern, 2003).

Praziquantel is the drug of choice for treatment of schistosomiasis. The drug is safe and effective when given in single or divided oral doses on the same day. These properties make praziquantel especially suitable for population-based chemotherapy. Moreover, repeated chemotherapy with praziquantel is thought to accelerate protective immune responses by increasing exposure to antigens released from dying worms that induce a T_H2 response (Mutapi et al., 1998). In sub-Saharan Africa, praziquantel is typically administered in mass drug administration campaigns for populations infected with schistosomiasis, with the use of a height pole as a guide to drug dosage. Sadly, even the modest cost of US $0.08 per tablet is beyond the health budgets of many sub-Saharan African countries (Hotez, 2009). Although not effective clinically against S. haematobium and S. japonicum, oxamniquine is effective for treatment of S. mansoni infections, particularly in South America, where the sensitivity of most strains may permit single-dose therapy. However, resistance has been reported and higher doses of the drug are required to treat African strains than to treat Brazilian strains of S. mansoni. Metrifonate (trichlorfon) has been used with considerable success in the treatment of S. haematobium infections, but the drug is not effective against S. mansoni and S. japonicum. Metrifonate is relatively inexpensive and can be combined with oxamniquine for treatment of mixed infections with S. haematobium and S. mansoni.

The artemisinin derivative artemether (Chapter 49) shows promise as an anti-schistosomal agent. Artemether targets the larval schistosomula stages of the parasite. Clinical trials confirmed that artemether (administered in an oral dose of 6 mg/kg once every 2-3 weeks) significantly reduced the incidence and intensity of schistosome infections without adverse reactions. In animals harboring juvenile and adult schistosome worms, the combination of artemether and praziquantel resulted in significantly reductions of worm burden than each drug administered singly (Xiao et al., 1985). There is concern, however, that widespread use of artemether as an anthelmintic may induce drug-resistant malaria in areas where multidrug resistant plasmodia still respond to artemether therapy.

Praziquantel is effective, as is triclabendazole (egaten), in a dose of 10 mg/kg daily for 3 days (Gao et al., 2003). Bithionol is considered a second-line agent; it is available in the U.S. through the Centers for Disease Control and Prevention (CDC).

One-day therapy with praziquantel is highly effective against these parasites.

Triclabendazole, given as a single oral dose of 10 mg/kg, or in cases of severe infection 20 mg/kg divided into two doses, is the drug of choice for treatment of fascioliasis. In the U.S., this agent is available only from the manufacturer (Novartis). The cure rate among a cohort of Turkish patients was 78%, and the addition of another course(s) increased this to 90%. No significant side effects were reported (Saba et al., 2004). Bithionol was previously the recommended drug.

Infections with all the intestinal trematodes respond well to single-day therapy with praziquantel.

History. The discovery by Brown and coworkers that thiabendazole possessed potent activity against GI nematodes sparked development of the benzimidazoles as broad-spectrum anthelmintic agents against parasites of importance in both veterinary and human medicine. Of the hundreds of derivatives tested, those most therapeutically useful have modifications at the 2 and/or 5 positions of the benzimidazole ring system. Three compounds, thiabendazole, mebendazole, and albendazole, have been used extensively for the treatment of human helminth infections. The chemical structures of these drugs are shown in Table 51–1.

Thiabendazole, which contains a thiazole at position 2, is active against a wide range of nematodes that infect the GI tract. However, its clinical value against these organisms has declined markedly because of thiabendazole's toxicity (particularly unwanted central nervous system [CNS], liver, hypersensitivity, and visual side effects) relative to that of other equally effective drugs. Mebendazole, the prototype benzimidazole carbamate, was introduced for the treatment of intestinal roundworm infections as a result of research carried out >30 years ago. Albendazole is a newer benzimidazole carbamate that is used worldwide, both for treatment of intestinal nematodes and cestodes, but also because of the systemic bioavailability of its sulphoxide metabolite against tissue-dwelling nematodes and cestodes (Venkatesan, 1998). Albendazole has become the drug of choice for treating cysticercosis (Garcia and Del Brutto, 2000) and cystic hydatid disease (Horton, 1997). When used in single dose in conjunction with either ivermectin or DEC, it has shown additive effect in the control of lymphatic filariasis and related tissue filarial infections (Molyneux and Zagaria, 2002; Molyneux et al., 2003). Of note, albendazole lacks activity against the liver fluke F. hepatica.

Studies of BZ resistance by site-directed mutagenesis of the β-tubulin gene in the free-living nematode Caenorhabditis elegans (Driscoll et al., 1989) and of BZ resistance in the sheep nematode Haemonchus contortus have provided insights into the mechanisms of action of BZ drugs and of the mechanism of resistance (Prichard, 1994) In drug-resistant isolates of H. contortus, BZ drugs display reduced affinity binding to β-tubulin and specific mutations occur in the β-tubulin gene (Kwa et al., 1995; Roos, 1997). The major mechanism of drug resistance in nematodes involves selection of a naturally occurring "resistant" genotype entailing a Phe → Tyr change at position 200 of β-tubulin (Sangster and Gill, 1999). Evidence for the emergence of β-tubulin gene mutations associated with resistance among human nematodes is confined to T. trichuria (Diawara et al., 2009) and W. bancrofti (Schwab et al., 2005). Drug treatment failures have been reported in hookworm infections (Flohr et al., 2007), but there is little evidence of widespread dissemination of resistant forms. However, these recent observations, and the increasing use of BZs in parasite control programs, suggest that monitoring for BZ resistance is critically important, especially as veterinary experience indicates that drug-resistant helminths can persist even after selection pressure is withdrawn.

The BZs, exemplified by mebendazole and albendazole, are versatile anthelmintic agents, particularly against GI nematodes, where their action is not limited by a requirement for absorption. Appropriate doses of mebendazole and albendazole are highly effective in treating most of 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 that cause these infections, and they are ovicidal for Ascaris and Trichuris. Immobilization and death of susceptible GI parasites occur slowly, and their clearance from the GI tract may not be complete until several days after treatment.

Removal of STHs in children by a single-dose treatment with either albendazole or mebendazole improves their health, as evidenced by post-treatment catch-up growth and replenishment of iron stores (Hotez et al, 2004, 2009). In addition, BZ treatment of STH infections results in improvements in childhood intellectual and cognitive development (Drake et al., 2000). These observations have led to advocacy for the implementation of large-scale STH control programs that target school-aged children (Hotez et al., 2009; WHO, 2002).

Albendazole is superior to mebendazole in curing hookworm and trichuriasis infections in children (de Silva et al., 2003), especially when used as a single dose (Keiser and Utzinger, 2008). Moreover, albendazole is more effective than mebendazole against strongyloidiasis (Liu and Weller, 1993) and is superior to mebendazole against all tissue-dwelling helminths due to its active metabolite albendazole sulfoxide. It is therefore the drug of choice against cystic and alveolar hydatid disease caused by Echinococcus granulosus and E. multilocularis (Davis et al., 1989; Horton, 1997), and neurocysticercosis caused by larval forms of Taenia solium (Evans et al., 1997; Garcia and Del Brutto, 2000). The BZs probably are active against the intestinal stages of Trichinella spiralis in humans but probably do not affect the larval stages in tissues. Albendazole is highly effective against the migrating forms of dog and cat hookworms that cause cutaneous larval migrans, although thiabendazole can be applied topically for this purpose. Microsporidial species that cause intestinal infections in HIV-infected individuals respond partially (Enterocytozoon bieneusi) or completely (Encephalitozoon intestinalis and related Encephalitozoon species) to albendazole. The sulfoxide metabolite of albendazole appears to be especially effective against these parasites in vitro (Katiyar and Edlind, 1997). Albendazole also has efficacy against anaerobic protozoa such as Trichomonas vaginalis and Giardia lamblia (Ottesen et al., 1999). Although BZs exert antifungal activity in vitro, they have no clinical utility in human mycoses.

Both the (+) and (−) enantiomers of albendazole sulfoxide are formed, but the (+) enantiomer reaches much higher peak plasma concentrations in humans and is cleared much more slowly than the (−) form (Marques et al., 1999). Albendazole sulfoxide is ~70% bound to plasma proteins and has a highly variable plasma t_1/2 of 4-15 hours (Marques et al., 1999). It is well distributed into various tissues including hydatid cysts, where it reaches a concentration of ~20% that in plasma (Morris et al., 1987). The bioavailability of parent drug and activity of albendazole sulfoxide explain why albendazole is more effective than mebendazole for treatment of tissue-dwelling helminths. Oxidation of the sulfoxide derivatives to the nonchiral sulfone metabolite of albendazole, which is pharmacologically inactive, is probably rate limiting in determining the clearance and plasma t_1/2 of the bioactive (+) sulfoxide metabolite. In animal models, BZs can induce their own metabolism (Gleizes et al., 1991). Albendazole metabolites are excreted mainly in the urine.

Therapeutic Uses. The introduction of thiabendazole (mintezol) was a major advance in anthelmintic chemotherapy, but its clinical use is now limited, due to the better tolerability and generally better activity of mebendazole and albendazole. Thiabendazole remains a useful drug when applied topically for treatment of cutaneous larva migrans (creeping eruption). Most patients thus treated experience marked relief of symptoms of creeping eruption, and a high percentage of cures are achieved after topical treatment with an extemporaneously compounded 15% thiabendazole in a water-soluble cream base applied to the affected area two to three times daily for 5 days (Davies et al., 1993). For treatment of strongyloidiasis, thiabendazole has been replaced by ivermectin.

Mebendazole is an effective drug for treatment of GI nematode infections. It is only administered orally, with the same dosage schedule applying to adults and to children >2 years of age. For treatment of enterobiasis, a single 100-mg tablet is taken; a second dose should be given after 2 weeks. For control of ascariasis, trichuriasis, or hookworm infections, the recommended regimen is 100 mg of mebendazole taken in the morning and evening for three consecutive days (or a single 500-mg tablet administered once). If the patient is not cured 3 weeks after treatment, a second course should be given. The 3-day mebendazole regimen is more effective than single doses of either mebendazole (500 mg) or albendazole (400 mg). A single dose of albendazole is superior to a single dose of mebendazole against hookworms and trichuriasis (Keiser and Utzinger 2008).

Like mebendazole, albendazole is a safe and highly effective therapy for infections with GI nematodes, including A. lumbricoides, T. trichuria, and hookworms. For treatment of STH infections (enterobiasis, ascariasis, trichuriasis, and hookworm), albendazole is taken as a single oral 400-mg dose by adults and children >2 years of age. In children between the ages of 12 and 24 months, the WHO recommends a reduced dose of 200 mg. Cure rates for light to moderate Ascaris infections typically are >97%, although heavy infections may require therapy for 2-3 days. A 400-mg dose of albendazole appears to be superior to a 500-mg dose of mebendazole for curing hookworm infections and reducing egg counts (Keiser and Utzinger, 2008). When administered at a dose of 400 mg daily for 3 days, albendazole shows some efficacy in treatment of strongyloidiasis but is less effective than ivermectin for treatment of this infection (Marti et al., 1996).

Albendazole is the drug of choice for treating cystic hydatid disease due to Echinococcus granulosus. Although the drug provides only a modest cure rate when used alone, it is a useful adjunctive treatment in the perioperative period to reduce the risk of disseminated infection resulting from spillage of cyst contents at the time of surgery, or with nonoperative puncture, aspiration, injection, and re-aspiration (PAIR) procedures (Horton, 1997; Schantz, 1999). A typical dosage regimen for adults is 400 mg given twice a day (for children, 15 mg/kg per day with a maximum of 800 mg) for 1-6 months. Although it is the only drug available with useful activity against alveolar echinococcosis caused by E. multilocularis (Venkatesan, 1998), it is parasiti-static rather than -cidal, and lifelong therapy with or without surgical intervention is usually required to control the infection.

Albendazole also is the preferred treatment of neurocysticercosis caused by larval forms of Taenia solium (Evans et al., 1997; Garcia and Del Brutto, 2000). The recommended dosage is 400 mg given twice a day for adults for 8-30 days, depending on the number, type, and location of the cysts. For children, the dose is 15 mg/kg per day (maximum: 800 mg) in two doses for 8-30 days. For both adults and children, the course can be repeated as necessary, as long as liver and bone marrow toxicities are monitored. Glucocorticoid therapy is usually begun before initiating albendazole therapy and continued for several days after institution of therapy to reduce the incidence of side effects resulting from inflammatory reactions to dead and dying cysticerci. Glucocorticoids increase plasma levels of albendazole sulfoxide. Prior to initiating chemotherapy of neurocysticercosis, physicians should consult with a neurologist and/or neurosurgeon regarding anticonvulsant therapy, the possible development of complications of arachnoiditis, vasculitis, or cerebral edema, and the need for surgical intervention should obstructive hydrocephalus occur.

Albendazole, 400 mg per day, also has shown efficacy for therapy of microsporidial intestinal infections in patients with AIDS. Infection with Capillaria philippinensis can be treated with a 10-day treatment regimen with albendazole (400 mg/day).

Albendazole has been combined with either DEC or ivermectin in programs directed toward controlling LF (Molyneux and Zagaria, 2002; Ottesen et al., 1999). The strategy is annual dosing with combination therapy for 4-6 years to maintain the microfilaremia at such low levels that transmission cannot occur. The period of therapy is estimated to correspond to the duration of fecundity of adult worms. Albendazole is given with DEC to control LF in most parts of the world. However, to avoid serious reactions to dying microfilariae, the albendazole/ivermectin combination is recommended in locations where filariasis co-exists with either onchocerciasis or loiasis. Recently, the benefits of adding albendazole to either DEC or ivermectin for LF control were evaluated (Addiss et al., 2004); there currently is insufficient reliable research to confirm or refute whether adding albendazole has an effect on LF.

Less frequently, diarrhea, fatigue, drowsiness, giddiness, or headache occur. Occasional fever, rashes, erythema multiforme, hallucinations, sensory disturbances, and Stevens-Johnson syndrome have been reported. Angioedema, shock, tinnitus, convulsions, and intrahepatic cholestasis are rare complications of therapy. Some patients excrete a metabolite that imparts an odor to the urine much like that occurring after ingestion of asparagus. Crystalluria without hematuria has been reported on occasion; it promptly subsides with discontinuation of therapy. Transient leukopenia has been noted in a few patients on thiabendazole therapy. Because CNS side effects occur frequently, activities requiring mental alertness should be avoided during therapy. Thiabendazole has hepatotoxic potential and should be used with caution in patients with hepatic disease or decreased hepatic function. The effects of thiabendazole in pregnant women have not been studied adequately, so it should be used in pregnancy only when the potential benefit justifies the unknown risk.

Rare side effects in patients treated with high doses of mebendazole include allergic reactions, alopecia, reversible neutropenia, agranulocytosis, and hypospermia. Reversible elevation of serum transaminases has been observed when the drug was given in long courses for treatment of hydatid disease. Mebendazole treatment has been associated with occipital seizures (Wilmshurst and Robb, 1998). Mebendazole is a potent embryo toxin and teratogen in laboratory animals; effects may occur in pregnant rats at single oral doses as low as 10 mg/kg. However, there is no evidence for teratogenicity in humans, probably due to its poor systemic bioavailability. Although the general advice is that mebendazole should not be given to pregnant women or to children <2 years of age, it has been safely used after the first trimester of pregnancy for its beneficial effect on anemia due to clearance of hookworm (WHO, 2006). Because the soil-transmitted helminths are important causes of maternal and child morbidity during pregnancy, the WHO recommends its use for infected pregnant women in the second or third trimester.

Even in long-term therapy of cystic hydatid disease and neurocysticercosis, albendazole is well tolerated by most patients. The most common side effect is liver dysfunction, generally manifested by an increase in serum transaminase levels; rarely jaundice may be noted, but enzyme activities return to normal after therapy is completed.

A pharmaco-epidemiological analysis concluded that long-term treatment of echinococcosis or cysticercosis with high-dose albendazole accounted for most of the adverse drug reactions attributed to anthelmintic therapy (Bagheri et al., 2004). Therefore, liver function tests should be monitored during protracted albendazole therapy, and the drug is not recommended for patients with cirrhosis (Davis et al., 1989). Especially if not pretreated with glucocorticoids, some patients with neurocysticercosis may experience serious neurological sequelae that depend on the location of inflamed cysts with dying cysticerci. Other side effects during extended therapy include GI pain, severe headaches, fever, fatigue, loss of hair, leukopenia, and thrombocytopenia. Albendazole is teratogenic and embryotoxic in animals, and it should not be given to pregnant women. The safety of albendazole in children < 2 years of age has not been established.

The BZs as a group display remarkably few clinically significant interactions with other drugs. The most versatile member of this family, albendazole, probably induces its own metabolism, and plasma levels of its sulfoxide metabolites can be increased by co-administration of glucocorticoids and possibly praziquantel. Caution is advised when using high doses of albendazole together with general inhibitors of hepatic CYPs. As indicated earlier, co-administration of cimetidine can increase the bioavailability of mebendazole.

Use in Pregnancy. Because of the ongoing and anticipated widespread use of BZs in global control programs for both STH and filarial infections, there is a high level of interest about their use in young children and in the second and third trimesters of pregnancy.

As indicated earlier, both albendazole and mebendazole are embryotoxic and teratogenic in pregnant rats, and they are not generally recommended for use in pregnancy (Bethony et al., 2006). However, in postmarketing surveys on women who inadvertently consumed mebendazole during the first trimester, the incidence of spontaneous abortion and malformations did not exceed that of the general population; comparable studies with albendazole are not available. A review of the risk of congenital abnormalities from BZs concluded that their use during pregnancy was not associated with an increased risk of major congenital defects; nonetheless, it is recommended that treatment should be avoided during the first trimester of pregnancy (Urbani and Albonico, 2003).

Hookworm occurs in many pregnant women in developing countries, including up to one-third of pregnant women in sub-Saharan Africa (Brooker et al., 2008). Because some of these infected women may develop iron-deficiency anemia leading to adverse pregnancy outcomes, BZ treatment would be beneficial during the second and third trimesters of pregnancy (WHO, 2002, 2006). There is no evidence that maternal BZ therapy presents a risk to breast-fed infants (Urbani and Albonico, 2003).

Use in Young Children. The BZs have not been extensively studied in children <2 years of age. The WHO concluded that BZs may be used to treat children >1 year if the risks from adverse consequences caused by STHs are justified. The recommended dose is 200 mg of albendazole in children between the ages of 12 and 24 months (WHO, 2006).

Chemistry. Diethylcarbamazine (hetrazan) is formulated as the water-soluble citrate salt containing 51% by weight of the active base. Because the compound is tasteless, odorless, and stable to heat, it also can be taken in the form of fortified table salt containing 0.2-0.4% by weight of the base. The drug is available outside the U.S.; in the U.S., it is supplied by the CDC.

Microfilarial forms of susceptible filarial species are most affected by DEC. These developmental forms of W. bancrofti, B. malayi, and L. loa rapidly disappear from human blood after consumption of the drug. Microfilariae of O. volvulus rapidly disappear from skin after DEC administration, but the drug does not kill microfilariae in nodules that contain the adult (female) worms. The drug has some activity against the adult lifecycle stages of W. bancrofti, B. malayi, and L. Loa but negligible activity against adult O. volvulus.

W. bancrofti, B. malayi, and B. timori. The standard regimen for the treatment of LF traditionally has been a 12-day, 72-mg/kg (6 mg/kg per day) course of DEC. In the U.S., it is common practice to administer small test doses of 50-100 mg (1-2 mg/kg for children) over a 3-day period prior to beginning the 12-day regimen. However, a single dose of 6 mg/kg had comparable macrofilaricidal and microfilaricidal efficacy to the standard regimen (Addiss and Dreyer, 2000). Single-dose therapy may be repeated every 6-12 months, as necessary.

Although DEC does not usually reverse existing lymphatic damage, early treatment of asymptomatic individuals may prevent new lymphatic damage. In men, the effect of the drug can be monitored by scrotal ultrasound ~2-4 weeks following treatment. Repeat treatment sometimes is recommended if microfilariae remain in the circulation or if motile adult worms remain visible on the ultrasound (Addiss and Dreyer, 2000). Expanded use of ultrasound also has facilitated the identification of infected individuals who are microfilaria negative on blood examination. These individuals also benefit from DEC treatment. During acute episodes of lymphangitis, treatment with DEC is not recommended until acute symptoms subside (Addiss and Dreyer, 2000).

For mass treatment with the objective of reducing microfilaremia to levels whereby transmission is interrupted, effective strategies have included the introduction of DEC into table salt (0.2-0.4% by weight of the base) (Gelband, 1994). DEC, given annually as a single oral dose of 6 mg/kg, is most effective in reducing microfilaremia when co-administered with either albendazole (400 mg) or ivermectin (0.2-0.4 mg/kg) (Ottesen et al., 1999). Although the adverse reactions to microfilarial destruction are greater after the oral therapy with DEC tablets than when the mass drug administration is administered by medicated table salt, therapy is usually well tolerated.

O. volvulus and L. loa. DEC is contraindicated for the treatment of onchocerciasis because it causes severe reactions related to microfilarial destruction, including worsening ocular lesions. Thus use of DEC for control is considered contraindicated in areas where onchocerciasis is endemic (Molyneux et al., 2003). Such reactions are far less severe in response to ivermectin, the preferred drug for this infection. Despite its drawbacks, DEC remains the best available drug for therapy of loiasis. Treatment is initiated with test doses of 50 mg (1 mg/kg in children) daily for 2-3 days, escalating to maximally tolerated daily doses of 9 mg/kg in three doses for a total of 2-3 weeks.

In patients with high-grade microfilaremia, low test doses are used, often accompanied by pretreatment with glucocorticoids or antihistamines, to minimize reactions to dying microfilariae. Such reactions may manifest as severe allergic reactions, and occasionally meningoencephalitis and coma likely caused by CNS effects of dying microfilariae. Repeated courses of DEC treatment, separated by 3-4 weeks, may be required to cure loiasis. Although ivermectin is not a good alternative to DEC for treatment of loiasis, albendazole may be useful in patients who either fail therapy with DEC or who cannot tolerate the drug (Klion et al., 1999).

DEC is clinically effective against microfilariae and adult worms of Dipetalonema streptocerca, but filariasis due to Mansonella perstans, M. ozzardi, or Dirofilaria immitis responds minimally to this agent. DEC is no longer recommended as a first-line drug for the treatment of toxocariasis.

Delayed reactions to dying adult worms may result in lymphangitis, swelling, and lymphoid abscesses in bancroftian and brugian filariasis, and small skin wheals in loiasis. Reactions typically are most severe in patients heavily infected with O. volvulus, less serious in B. malayi or L. loa infections, and mild in bancroftian filariasis. As noted, the drug occasionally causes severe side effects in heavy L. loa infections, including retinal hemorrhages and severe encephalopathy. In patients with onchocerciasis, the Mazzotti reaction typically occurs within a few hours after the first dose, and it manifests as intense itching, a papular rash, enlargement and tenderness of the lymph nodes, and sometimes fever, tachycardia, arthralgia, and headache. This reaction persists for 3-7 days and then subsides. Ocular complications include limbitis, punctate keratitis, uveitis, and atrophy of the retinal pigment epithelium (Dominguez-Vazquez et al., 1983). DEC appears to be safe for use during pregnancy

Precautions and Contraindications. Population-based therapy with DEC should be avoided where onchocerciasis or loiasis is endemic, although the drug can be used to protect foreign travelers from these infections. Pretreatment with glucocorticoids and antihistamines often is undertaken to minimize indirect reactions to DEC that result from release of antigen by dying microfilariae. Dosage reduction may be appropriate for patients with impaired renal function or persistent alkaline urine.

The discovery that filarial parasites, including W. bancrofti and O. volvulus, harbor bacterial symbionts of the genus Wolbachia led to studies that have established the efficacy of courses of doxycycline of duration ≥6 weeks in bancroftian filariasis and onchocerciasis (Taylor and Hoerauf, 2001). A 6-week regimen of doxycycline (100 mg daily), by killing the Wolbachia, leads to sterility of adult female Onchocerca worms (Hoerauf et al., 2000). Studies using shorter treatment courses and alternative antibiotics including rifampicin are in progress. The pharmacology of doxycycline is discussed in Chapter 55.

History. In the mid-1970s, surveys of natural products revealed that a fermentation broth of the soil actinomycete Streptomyces avermitilis ameliorated infection with Nematospiroides dubius in mice. Isolation of the anthelmintic components from cultures of this organism led to discovery of the avermectins, a novel class of 16-membered macrocyclic lactones (Campbell, 1989). Ivermectin (mectizan; stromectol; 22,23-dihydroavermectin B_1a) is a semisynthetic analog of avermectin B_1a (abamectin), an insecticide developed for crop management. Ivermectin now is used extensively to control and treat a broad spectrum of infections caused by parasitic nematodes (roundworms) and arthropods (insects, ticks, and mites) that plague livestock and domestic animals (Campbell, 1993).

Chemistry. Ivermectin exists as an odorless off-white powder with high lipid solubility but poor solubility in water. It is a mixture of at least 80% 22,23-dihydroavermectin B_1a and no more than 20% 22,23-dihydroavermectin B_1b. B_1a and B_1b have nearly identical antiparasitic activities. The hydrogenation of avermectin B₁ at the C22-23 linkage confers increased activity against Haemonchus contortus, an important veterinary parasite, and against the cattle parasite Onchocerca cervicalis.

Several different avermectin-"resistant" developmental and physiological phenotypes have been described, but definitive relationships among these phenotypes and native avermectin receptor subtypes, locations, numbers, and binding affinities require clarification (Hejmadi et al., 2000; Sangster and Gill, 1999). Alterations in genes encoding ATP-dependent P-glycoprotein transporters that bind avermectins and in those encoding putative components of the glutamate-gated Cl⁻ channel have been associated with the development of resistance in Haemonchus contortus (Xu et al., 1998). A significant increase in low-affinity glutamate binding has been detected in ivermectin-resistant nematodes, but how this relates to drug resistance is unclear (Hejmadi et al., 2000).

Glutamate-gated Cl⁻ channels probably are one of several sites of ivermectin action among invertebrates (Zufall et al., 1989). Avermectins also bind with high affinity to γ-aminobutyric acid (GABA)-gated and other ligand-gated Cl⁻ channels in nematodes such as Ascaris and in insects, but the physiological consequences are less well defined. Lack of high-affinity avermectin receptors in cestodes and trematodes may explain why these helminths are not sensitive to ivermectin (Shoop et al., 1995). Avermectins also interact with GABA receptors in mammalian brain, but their affinity for invertebrate receptors is ~100-fold higher (Schaeffer and Haines, 1989).

In humans infected with O. volvulus, ivermectin causes a rapid, marked decrease in microfilarial counts in the skin and ocular tissues that lasts for 6-12 months (Newland et al., 1988). The drug has little discernible effect on adult parasites, even at doses as high as 800 μg/kg (Molyneux et al., 2003) but affects developing larvae and blocks egress of microfilariae from the uterus of adult female worms (Court et al., 1985). By reducing microfilariae in the skin, ivermectin decreases transmission to the Simulium black fly vector (Cupp et al., 1989). Regular treatment with ivermectin also has been conjectured to act prophylactically against the development of Onchocerca infection (Molyneux et al., 2003).

Ivermectin also is effective against microfilaria but not against adult worms of W. bancrofti, B. malayi, L. loa, and M. ozzardi. The drug exhibits excellent efficacy in humans against Ascaris lumbricoides, Strongyloides stercoralis, and cutaneous larva migrans. Other GI nematodes are either variably affected (Trichuris trichura and Enterobius vermicularis), or unresponsive (Necator americanus and Ancylostoma duodenale).

Absorption, Fate, and Excretion. In humans, peak levels of ivermectin in plasma are achieved within 4-5 hours after oral administration. The long terminal t_1/2 (~57 hours in adults) primarily reflects a low systemic clearance (~1-2 L/hour) and a large apparent volume of distribution. 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 (Zeng et al., 1998). Virtually no ivermectin appears in human urine in either unchanged or conjugated form (Krishna and Klotz, 1993). Studies in transgenic mice lacking a P-glycoprotein efflux pump showed neurotoxicity, indicating that this drug transporter, located in the endothelium of brain microvasculature, reduces ivermectin penetration to the CNS (Schinkel et al., 1994). This, and the relatively lower affinity of ivermectin for mammalian CNS receptors, may explain the paucity of CNS side effects and the relative safety of this drug in humans.

Therapeutic Uses.

Onchocerciasis. Ivermectin administered as a single oral dose (150 to 200 μg/kg) given every 6-12 months is the drug of choice for treatment of onchocerciasis, in adults and children ≥5 years of age (Goa et al., 1991). Ivermectin given in mass drug administration programs has become a critical component of onchocerciasis control programs in the Americas and in sub-Saharan Africa. Equally important, such therapy results in reversal of inflammatory changes in ocular tissues and arrests the development of further ocular pathology due to microfilariae. Marked reduction of microfilariae in the skin results in major relief of the intense pruritus that is a feature of onchocerciasis. Clearance of microfilariae from skin and ocular tissues occurs within a few days and lasts for 6-12 months; the dose then should be repeated. The drug is not curative, however, because ivermectin has little effect on adult O. volvulus. Ivermectin has been used since 1987 as the mainstay for onchocerciasis control programs in all of Africa and in the Middle East and Latin America, where the disease is endemic. Nearly 20 million people have received at least one dose of the drug, and many have received six to nine doses (Dull and Meredith, 1998). The Onchocerciasis Elimination Programme in the Americas (OEPA) has effectively reduced transmission in the endemic nations of the Americas, Brazil, Colombia, Ecuador, Guatemala, Mexico, and Venezuela through biannual treatment with ivermectin (Molyneux et al., 2003), and there is interest in extending biannual ivermectin coverage to the endemic regions of sub-Saharan Africa. Annual doses of the drug are quite safe and substantially reduce transmission of this infection (Boatin et al., 1998; Brown, 1998). How long such therapy should continue is unknown.

Resistance to ivermectin and the related agent moxidectin have been reported in a variety of parasites of veterinary importance, as have poor parasitological responses to ivermectin in the onchocerciasis control program (Osei-Atweneboana et al., 2007). Recent laboratory work with C. elegans has shown that exposure to increasing doses of ivermectin resulted in the development of a stable multidrug resistance phenotype with cross-resistance to the related drug moxidectin and to other antihelmintics, levamisole and pyrantel, but not albendazole (James and Davey, 2009). The potential for the development of similar resistance in human parasites exists, particularly in the setting of mass treatment campaigns.

Lymphatic Filariasis. Initial studies indicated that single annual doses of ivermectin (400 μg/kg) was both effective and safe for mass chemotherapy of infections with W. bancrofti and B. malayi (Ottesen and Ramachandran, 1995). Ivermectin is as effective as DEC for controlling lymphatic filariasis, and unlike DEC, it can be used in regions where onchocerciasis, loiasis, or both are endemic. Although ivermectin as a single agent can reduce W. bancrofti microfilaremia, the duration of treatment required to eliminate LF at 65% coverage of the affected population presumably would be >6 years (Molyneux et al., 2003). More recent evidence indicates that a single annual dose of ivermectin (200 μg/kg) and a single annual dose of albendazole (400 mg) are even more effective in controlling lymphatic filariasis than either drug alone (www.filariasis.org). The duration of treatment is at least 5 years, based on the estimated fecundity of the adult worms. This dual-drug regimen also reduces infections with intestinal nematodes. Facilitated by corporate donation of ivermectin and albendazole, the drug combination now serves as the treatment standard for mass chemotherapy and control of lymphatic filariasis (Ottesen et al., 1999).

Strongyloidiasis. Ivermectin administered as a single dose of 150 to 200 μg/kg is the drug of choice for treatment of human strongyloidiasis (Marti et al., 1996). It is at least as active as the older drug of choice, thiabendazole, and significantly better tolerated. It is generally recommended that a second dose be administered a week following the first dose. It is more efficacious than a 3-day course of albendazole (Marti et al., 1996). In the life-threatening Strongyloides hyperinfection syndrome where GI absorption of oral dose may be poor, parenteral veterinary ivermectin has been administered "off-label" to human subjects by the subcutaneous route (Chiodini et al., 2000).

Infections with Other Intestinal Nematodes. Ivermectin also is variably effective against other intestinal nematodes. It is more effective in ascariasis and enterobiasis than in trichuriasis or hookworm infection (Keiser and Utzinger, 2008). In the latter two infections, although it is not curative, it significantly reduces the intensity of infection.

Other Indications. Although ivermectin has activity against microfilaria (but not adult worms) of L. loa and M. ozzardi, it is not used clinically to treat infections with these parasites. Taken as a single 200-μg/kg oral dose, ivermectin is a first-line drug for treatment of cutaneous larva migrans caused by dog or cat hookworms. Ivermectin, administered orally in a dose of 200 μg/kg, is an effective treatment of scabies. In uncomplicated scabies, two doses should be administered, 1-2 weeks apart. It should be used in severe (crusted) scabies in repeated doses, with one recommended regimen entailing 7 doses of 200 μg/kg given with food, on days 1, 2, 8, 9, 15, 22, and 29 (Roberts et al., 2005). The drug appears to be effective against human head lice as well.

Toxicity, Side Effects, and Precautions. Ivermectin is well tolerated by uninfected humans.

In filarial infection, ivermectin therapy frequently causes a Mazzotti-like reaction to dying microfilariae. The intensity and nature of these reactions relate to the microfilarial burden. After treatment of O. volvulus infections, these side effects usually are limited to mild itching and swollen, tender lymph nodes, which occur in 5-35% of people, last just a few days, and are relieved by aspirin and antihistamines (Goa et al., 1991). Rarely, more severe reactions occur that include high fever, tachycardia, hypotension, prostration, dizziness, headache, myalgia, arthralgia, diarrhea, and facial and peripheral edema; these may respond to glucocorticoid therapy. Ivermectin induces milder side effects than does DEC, and unlike the latter, it seldom exacerbates ocular lesions in onchocerciasis. The drug can cause rare but serious side effects including marked disability and encephalopathies in patients with heavy L. loa microfilaria (Gardon et al., 1997). Loa encephalopathy is associated with ivermectin treatment of individuals with Loa microfilaremia levels ≥30,000 microfilariae per milliliter of blood (Molyneux et al., 2003). There is little evidence that ivermectin is teratogenic or carcinogenic.

Possible adverse interactions of ivermectin with other drugs that are extensively metabolized by hepatic CYP3A4 have yet to be evaluated. Because of its effects on GABA receptors in the CNS, ivermectin is contraindicated in conditions associated with an impaired blood-brain barrier (e.g., African trypanosomiasis and meningitis). Ivermectin is not approved for use in children <5 years of age or in pregnant women. Lactating women taking the drug secrete low levels in their milk; the consequences for nursing infants are unknown. Currently, the WHO recommends against ivermectin treatments in mass drug administration campaigns for pregnant women, lactating women in the first week after birth, children <90 cm in height (~15 kg in body weight), and the severely ill (WHO, 2006).

The drug shows useful activity against most cestodes and trematodes that infect humans, whereas nematodes generally are unaffected (Andrews, 1985; Symposium, 1981). The drug is best studied and most commonly used for treatment of schistosomiasis, caused by S. mansoni, S. haematobium, and S. japonicum.

The primary site of action of praziquantel is uncertain (Aragon et al., 2009). The drug may act through generation of reactive oxygen species. It also promotes an influx of Ca²⁺, and possibly interacts with the variant Ca²⁺ channel Ca-varβ (Jeziorski and Greenberg, 2006), which is found in schistosomes and other praziquantel-sensitive parasites. However, Ca²⁺ influx does not correlate with sensitivity to the drug an all settings (Pica-Mattoccia et al., 2008). Prazifuantel inhibits adenosine flux (Angelucci et al., 2007), but definitive evidence that this action contributes to the anthelmintic effect is lacking.

Absorption, Fate, and Excretion. Praziquantel is readily absorbed after oral administration, the drug reaching maximal levels in human plasma in 1-2 hours. The pharmacokinetics of praziquantel are dose related. Extensive first-pass metabolism to many inactive hydroxylated and conjugated products limits the bioavailability of this drug and results in plasma concentrations of metabolites at least 100-fold higher than that of praziquantel. The drug is ~80% bound to plasma proteins. Its plasma t_1/2 is 0.8-3 hours, depending on the dose, compared with 4-6 hours for its metabolites; this may be prolonged in patients with severe liver disease, including those with hepatosplenic 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.

Praziquantel is the drug of choice for treating schistosomiasis caused by all Schistosoma species that infect humans. 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 consistently high reductions (>85%) in egg counts. Tablets of 600 mg currently are available from generic manufacturers; on average, treatment of a school-aged child in Africa requires 2.5 tablets (WHO, 2002).

The absence of weighing scales in Africa and elsewhere in developing countries led to the development dosing in proportion to height (WHO 2006; www.who.int/wormcontrol).

Strains of S. mansoni and S. japonicum resistant to praziquantel have been selected in laboratory studies (Fallon et al., 1996). Moreover, decreased clinical efficacy of praziquantel against infections with S. mansoni has been reported in two human populations (Ismail et al., 1999). However, praziquantel-tolerant or -resistant schistosome strains are not currently of clinical importance (Fallon et al., 1996).

Three doses of 25 mg/kg taken 4-8 hours apart on the same day result in high rates of cure for infections with either the liver flukes Clonorchis sinensis and Opisthorchis viverrini, or the intestinal flukes Fasciolopsis buski, Heterophyes heterophyes, and Metagonimus yokogawai. The same three-dose regimen, used over 2 days, is highly effective against infections with the lung fluke, Paragonimus westermani. Of note, the liver fluke Fasciola hepatica is resistant to praziquantel and should be treated with the BZ drug triclabendazole.

Low doses of praziquantel can be used successfully to treat intestinal infections with adult cestodes, for example, a single oral dose of 25 mg/kg for Hymenolepis nana and 10 to 20 mg/kg for Diphyllobothrium latum, Taenia saginata, or T. solium. Retreatment after 7-10 days is advisable for individuals heavily infected with H. nana. Although albendazole is preferred for therapy of human cysticercosis, praziquantel represents an alternative agent, but its use for this indication is hampered by the important pharmacokinetic interaction with dexamethasone and other corticosteroids that should be co-administered in this condition (Evans et al., 1997). Neither the "cystic" nor "alveolar" hydatid disease caused by larval stages of Echinococcus tapeworms responds to praziquantel, but the drug may have a role in the uncommon setting of perioperative cyst spillage (Horton, 1997; Schantz, 1999).

Toxicity, Precautions, and Interactions. Abdominal discomfort, particularly pain and nausea, diarrhea, headache, dizziness, and drowsiness may occur shortly after taking praziquantel; these direct effects are transient and dose related. Indirect effects such as fever, pruritus, urticaria, rashes, arthralgia, and myalgia are noted occasionally. Such side effects and increases in eosinophilia often relate to parasite burden and are therefore believed to be a consequence of parasite killing and antigen release. In neurocysticercosis, inflammatory reactions to praziquantel may produce meningismus, seizures, mental changes, and cerebrospinal fluid pleocytosis. These effects usually are delayed in onset, last 2-3 days, and respond to appropriate symptomatic therapy such as analgesics and anticonvulsants.

Praziquantel is considered safe in children >4 years of age (or >94 cm in height), who probably tolerate the drug better than adults. Low levels of the drug appear in the breast milk, but there is no evidence that this compound is mutagenic or carcinogenic. High doses of praziquantel increase abortion rates in rats, but a retrospective study showed that treatment of pregnant women in Sudan resulted in no significant differences between treated and untreated women in the rates of abortion or preterm deliveries. Moreover, no congenital abnormalities were noted by clinical examination in any of the infants born to either group (Adam et al., 2004).

The bioavailability of praziquantel is reduced by inducers of hepatic CYPs such as carbamazepine and phenobarbital; predictably, co-administration of the CYP inhibitor, cimetidine, has the opposite effect (Dachman et al., 1994). Dexamethasone reduces the bioavailability of praziquantel. Under certain conditions, praziquantel may increase the bioavailability of albendazole (Homeida et al., 1994).

Praziquantel is contraindicated in ocular cysticercosis because the host response can irreversibly damage the eye. Shortly after taking the drug, driving, operating machinery, and other tasks requiring mental alertness should be avoided. Severe hepatic disease can prolong the t_1/2 of praziquantel, requiring dosage adjustment in such patients (Mandour et al., 1990).

Metrifonate is a prodrug; at physiological pH, it is converted nonenzymatically to dichlorvos (2,2-dichlorovinyl dimethyl phosphate, DDVP), a potent cholinesterase inhibitor (Chapter 10) However, inhibition of cholinesterase alone is unlikely to explain the antischistosomal properties of metrifonate (Bloom, 1981). In vitro, dichlorvos is about equally potent as an inhibitor of both S. mansoni and S. haematobium acetylcholinesterases, yet metrifonate is effective clinically only against infections with S. haematobium. The molecular basis for this species-selective effect is not understood. Trichlorfon is the formulation of metrifonate approved for veterinary purposes in the U.S. More complete information on the pharmacology and therapeutic uses of metrifonate can be found in the tenth edition of this book.

Oxamniquine is a 2-aminomethyltetrahydroquinoline derivative that is used as a second-line drug after praziquantel for the treatment of Schistosoma mansoni infection. S. haematobium and S. japonicum are refractory to this drug. Although it has largely been replaced by praziquantel and is not commercially available in the U.S., it continues to be used in S. mansoni control programs, especially in South America. More details on the pharmacology and therapeutic uses of oxamniquine can be found in the ninth edition of this book.

Niclosamide, a halogenated salicylanilide derivative, was introduced in the 1960s for human use as a taeniacide. This compound was considered as a second-choice drug to praziquantel for treating human intestinal infections with Taenia saginata, Diphyllobothrium latum, Hymenolepis nana, and most other cestodes because it was cheap, effective, and readily available in many parts of the world. However, therapy with niclosamide poses a risk to people infected with T. solium because ova released from drug-damaged gravid worms develop into larvae that can cause cysticercosis, a dangerous infection that responds poorly to chemotherapy. Niclosamide is no longer approved for use in the U.S. More complete information on the pharmacology and therapeutic uses of niclosamide can be found in the ninth edition of this book.

Piperazine, a cyclic secondary amine, has been superseded as a first-line anthelmintic by the better tolerated and more easily administered benzimidazole anthelmintics (BZs). Piperazine is highly effective against Ascaris lumbricoides and Enterobius vermicularis. The predominant effect of piperazine on Ascaris is a flaccid paralysis that results in expulsion of the worm by peristalsis. Affected worms recover if incubated in drug-free medium. Piperazine acts as a GABA-receptor agonist. By increasing chloride ion conductance of Ascaris muscle membrane, the drug produces hyperpolarization and reduced excitability that leads to muscle relaxation and flaccid paralysis (Martin, 1985). Piperazine and dipiperazine are licensed as veterinary medications in the U.S. More complete information on the pharmacology and therapeutic uses of piperazine may be found in the tenth edition of this book.

Antihelmintic Action. Pyrantel and its analogs are depolarizing neuromuscular blocking agents. They open nonselective cation channels and induce persistent activation of nicotinic acetylcholine receptors and spastic paralysis of the worm (Robertson et al., 1994).

Pyrantel also inhibits cholinesterases. It causes a slowly developing contracture of isolated preparations of Ascaris at 1% of the concentration of acetylcholine required to produce the same effect. Pyrantel exposure leads to depolarization and increased spike-discharge frequency, accompanied by increases in tension, in isolated helminth muscle preparations. Pyrantel is effective against hookworm, pinworm, and roundworm but is ineffective against Trichuris trichiura, which responds paradoxically to the analog oxantel.

Absorption, Fate, and Excretion. Pyrantel pamoate is poorly absorbed from the GI tract, a property that confines its action to intralumenal GI nematodes. Less than 15% is excreted in the urine as parent drug and metabolites. The major proportion of an administered dose is recovered in the feces.

Therapeutic Uses. Pyrantel pamoate is an alternative to mebendazole or albendazole in the treatment of ascariasis and enterobiasis. High cure rates have been achieved after a single oral dose of 11 mg/kg, to a maximum of 1 g. Pyrantel also is effective against hookworm infections caused by Ancylostoma duodenale and Necator americanus, although repeated doses are needed to cure heavy infections by N. americanus. The drug should be used in combination with oxantel for mixed infections with T. trichiura. In the case of pinworm, it is wise to repeat the treatment after an interval of 2 weeks. In the U.S., pyrantel is sold as an over-the-counter pinworm treatment (PIN-x, others).

Precautions. When given parenterally to experimental animals, pyrantel can produce complete neuromuscular blockade; only very large oral doses produce toxic effects. Transient and mild GI symptoms occasionally are observed in humans, as are headache, dizziness, rash, and fever. Pyrantel pamoate has not been studied in pregnant women. Thus its use in pregnant patients and children <2 years of age is not recommended. Because pyrantel pamoate and piperazine are mutually antagonistic with respect to their neuromuscular effects on parasites, they should not be used together.