C H A P T E R e 2 6
Amodiaquine has been widely used in the treatment of malaria for >40 years. Like chloroquine (the other major 4-aminoquinoline), amodiaquine is now of limited use because of the spread of resis-tance. Amodiaquine interferes with hemozoin formation through complexation with heme. Although rapidly absorbed, amodiaquine behaves as a prodrug after oral administration, with the principal plasma metabolite monodesethylamodiaquine as the predomi- nant antimalarial agent. Amodiaquine and its metabolites are all excreted in urine, but there are no recommendations concerning dosage adjustment in patients with impaired renal function. Severe adverse events can occur, albeit rarely (1 case in 2000 treatment courses), with amodiaquine administration. Agranulocytosis and This chapter deals exclusively with the pharmacologic properties hepatotoxicity can develop with repeated use; therefore, this drug of the agents used to treat infections due to parasites. Specific should not be used for prophylaxis. Despite widespread resistance, treatment recommendations for the parasitic diseases of humans amodiaquine has been shown to be effective in some areas when are listed in the chapters on those diseases. Information on these combined with other antimalarial drugs. Its use with artesunate agents’ major toxicities, spectrum of activity, and safety for use dur- in a fixed-dose combination with a soluble formulation creates an ing pregnancy and lactation is presented in Chap. 208. Many of the
antimalarial specifically designed for children. Amodiaquine is not agents discussed herein are approved by the U.S. Food and Drug Administration (FDA) but are considered investigational for the
treatment of certain infections (see Table 208-1 ). Drugs marked in
Amphotericin B
the text with an asterisk (∗) are available only through the Centers See Table 208-1 and Chap. 198.
for Disease Control and Prevention (CDC) Drug Service (tele-phone: 404-639-3670 or 404-639-2888; www.cdc.gov/ncpdcid/dsr/). Antimonials*
Drugs marked with a dagger (†) are available only through their Despite associated adverse reactions and the need for prolonged manufacturers; contact information for these manufacturers may parenteral treatment, the pentavalent antimonial compounds (designated Sb v ) have remained the first-line therapy for all forms of leishmaniasis throughout the world, primarily because they Albendazole
are affordable, are effective, and have survived the test of time. Like all benzimidazoles, albendazole acts by selectively binding to Although they have been used for almost 100 years, their mecha- free β-tubulin in nematodes, inhibiting the polymerization of tubulin nism of action against Leishmania species has only recently come and the microtubule-dependent uptake of glucose. Irreversible to light. Pentavalent antimonials are active only after bioreduction Pharmacology of Agents Used to Treat Parasitic Infections damage occurs in gastrointestinal (GI) cells of the nematodes, to the trivalent Sb(III) form. This form inhibits trypanothione resulting in starvation, death, and expulsion by the host. While reductase, a critical enzyme involved in the oxidative stress manage- highly injurious to nematodes, this fundamental disruption of ment of Leishmania species. The fact that Leishmania species use cellular metabolism also offers treatment for a wide range of parasitic trypanothione rather than glutathione (which is used by mammalian cells) may explain the parasite-specific activity of antimonials. The Albendazole is poorly absorbed from the GI tract. Administration drugs are taken up by the reticuloendothelial system, and their activity with a fatty meal increases its absorption by two- to sixfold. Poor against Leishmania species may be enhanced by this localization. absorption may be advantageous for the treatment of intestinal Sodium stibogluconate is the only pentavalent antimonial available helminths, but successful treatment of tissue helminth infections in the United States; meglumine antimoniate is principally used in (e.g., hydatid disease and neurocysticercosis) requires that a sufficient amount of active drug reach the site of infection. The metabolite Resistance is a major problem in some areas. Although low- albendazole sulfoxide is responsible for the drug’s therapeutic level unresponsiveness to Sb v was identified in India in the 1970s, effect outside the gut lumen. Albendazole sulfoxide crosses the incremental increases in both the recommended daily dosage (to blood-brain barrier, reaching a level significantly higher than that 20 mg/kg) and the duration of treatment (to 28 days) satisfactorily achieved in plasma. The high concentrations of albendazole sulfoxide compensated for the growing resistance until around 1990. There attained in cerebrospinal fluid (CSF) probably explain the efficacy has since been a steady erosion in the capacity of Sb v to induce of albendazole in the treatment of neurocysticercosis. long-term cure in patients with kala-azar who live in eastern India. Albendazole is extensively metabolized in the liver, but there are Foremost among the many factors that have probably contributed few data regarding the drug’s use in patients with hepatic disease. to this failure is the provision of suboptimal treatment for years, Single-dose albendazole therapy in humans is largely without side which led to the development of drug resistance among parasites. effects (overall frequency, ≤1%). More prolonged courses (e.g., as Co-infection with HIV impairs the treatment response. administered for cystic and alveolar echinococcal disease) have Sodium stibogluconate is available in aqueous solution and is been associated with liver function abnormalities and bone marrow administered parenterally. Antimony appears to have two elimina- toxicity. Thus, when prolonged use is anticipated, the drug should tion phases. When administered IV, the mean half-life of the first be administered in treatment cycles of 28 days interrupted by phase is <2 h; the mean half-life of the terminal elimination phase 14 days off therapy. Prolonged therapy with full-dose albendazole is nearly 36 h. This slower phase may be due to conversion of pen- (800 mg/d) should be approached cautiously in patients also receiving tavalent antimony to a trivalent form that is the likely cause of the drugs with known effects on the cytochrome P450 system. side effects often seen with prolonged therapy. Copyright 2012 The McGraw-Hill Companies, Inc. All rights reserved.
Artemisinin derivatives*
Artesunate, artemether, arteether, and the parent compound See Table 208-1 and Chap. 198.
artemisinin are sesquiterpene lactones derived from the worm-wood plant Benznidazole
more potent in vivo than other antimalarial drugs and presently This oral nitroimidazole derivative is used to treat Chagas’ disease, show no cross-resistance with known antimalarial drugs; thus, they with cure rates of 80–90% recorded in acute infections. Benznidazole have become first-line agents for the treatment of severe falciparum is believed to exert its trypanocidal effects by generating oxygen malaria. The artemisinin compounds are rapidly effective against radicals to which the parasites are more sensitive than mamma- the asexual blood forms of Plasmodium species but are not active lian cells because of a relative deficiency in antioxidant enzymes. against intrahepatic forms. Artemisinin and its derivatives are Benznidazole also appears to alter the balance between pro- and highly lipid soluble and readily cross both host and parasite cell anti-inflammatory mediators by downregulating the synthesis of membranes. One factor that explains the drugs’ highly selective nitrite, interleukin (IL) 6, and IL-10 in macrophages. Benznidazole toxicity against malaria is that parasitized erythrocytes concentrate is highly lipophilic and readily absorbed. The drug is extensively artemisinin and its derivatives to concentrations one hundredfold metabolized; only 5% of the dose is excreted unchanged in the higher than those in uninfected erythrocytes. The antimalarial effect urine. Benznidazole is well tolerated; adverse effects are rare and of these agents results primarily from dihydroartemisinin, a com- usually manifest as gastrointestinal upset or pruritic rash. pound to which artemether and artesunate are both converted. In the presence of heme or molecular iron, the endoperoxide moiety Bithionol*
of dihydroartemisinin decomposes, generating free radicals and Bithionol is a chlorinated bisphenol with activity against trema- other metabolites that damage parasite proteins. The compounds todes. Fasciola hepatica uses fumarate reduction coupled to rhodo- are available for oral, rectal, IV, or IM administration, depending quinone for anaerobic energy metabolism. Bithionol competitively on the derivative. In the United States, IV artesunate is avail- inhibits electron transfer to fumarate by rhodoquinone; the result able for the treatment of severe, quinidine-unresponsive malaria is impaired anaerobic energy metabolism and trematode death. through the CDC malaria hotline (770-488-7788, M-F, 0800-1630 Bithionol is parasite specific for two reasons: (1) fumarate reductase EST; 770-488-7100 after hours). Artemisinin and its derivatives catalyzes the reverse of the reaction of mammalian succinic dehy- are cleared rapidly from the circulation. Their short half-lives limit drogenase in the Krebs cycle, and (2) the rhodoquinone respiratory their value for prophylaxis and monotherapy. These agents should chain link is unique to the parasite. In the mammalian respiratory be used only in combination with another, longer-acting agent chain, the quinone electron carrier is ubiquinone. Bithionol is read- (e.g., artesunate-mefloquine, dihydroartemisinin-piperaquine). A ily absorbed from the GI tract. It is no longer produced, but limited combined formulation of artemether and lumefantrine is now avail- able for the treatment of acute uncomplicated falciparum malaria acquired in areas where Plasmodium falciparum is resistant to chlo- Chloroquine
This 4-aminoquinoline has marked, rapid schizonticidal and game-tocidal activity against blood forms of P. ovale and Plasmodium Atovaquone
malariae and against susceptible strains of P. vivax and P. falci- Atovaquone is a hydroxynaphthoquinone that exerts broad- parum . It is not active against intrahepatic forms ( P. vivax and spectrum antiprotozoal activity via selective inhibition of para- ). Parasitized erythrocytes accumulate chloroquine in site mitochondrial electron transport. This agent exhibits potent significantly greater concentrations than do normal erythrocytes. activity against toxoplasmosis and babesiosis when used with Chloroquine, a weak base, concentrates in the food vacuoles pyrimethamine and azithromycin, respectively. Atovaquone pos- of intraerythrocytic parasites because of a relative pH gradient sesses a novel mode of action against Plasmodium species, inhibit- between the extracellular space and the acidic food vacuole. Once ing the electron transport system at the level of the cytochrome bc1 it enters the acidic food vacuole, chloroquine is rapidly converted complex. The drug is active against both the erythrocytic and the to a membrane-impermeable protonated form and is trapped. exoerythrocytic stages of Plasmodium species; however, because Continued accumulation of chloroquine in the parasite’s acidic it does not eradicate hypnozoites from the liver, patients with food vacuoles results in drug levels that are 600-fold higher at this Plasmodium vivax or Plasmodium ovale infections must be given site than in plasma. The high accumulation of chloroquine results in an increase in pH within the food vacuole to a level above that Malarone is a fixed-dose combination of atovaquone and progua- required for the acid proteases’ optimal activity, inhibiting parasite nil used for malaria prophylaxis as well as for the treatment of acute, heme polymerase; as a result, the parasite is effectively killed with its uncomplicated P. falciparum malaria. Malarone has been shown own metabolic waste. Compared with susceptible strains, chloro- to be effective in regions with multidrug-resistant P. falciparum . quine-resistant plasmodia transport chloroquine out of intrapara- Resistance to atovaquone has yet to be reported. sitic compartments more rapidly and maintain lower chloroquine The bioavailability of atovaquone varies considerably. Absorption concentrations in their acid vesicles. Hydroxychloroquine, a conge- after a single oral dose is slow, increases two- to threefold with a fatty ner of chloroquine, is equivalent to chloroquine in its antimalarial meal, and is dose-limited above 750 mg. The elimination half-life is efficacy but is preferred to chloroquine for the treatment of auto- increased in patients with moderate hepatic impairment. Because immune disorders because it produces less ocular toxicity when of the potential for drug accumulation, the use of atovaquone is generally contraindicated in persons with a creatinine clearance rate Chloroquine is well absorbed. However, because it exhibits <30 mL/min. No dosage adjustments are needed in patients with extensive tissue binding, a loading dose is required to yield effec- tive plasma concentrations. A therapeutic drug level in plasma is reached 2–3 h after oral administration (the preferred route). Chloroquine can be administered IV, but excessively rapid Azithromycin
parenteral administration can result in seizures and death from See Table 208-1 and Chap. 133.
cardiovascular collapse. The mean half-life of chloroquine is 4 days, Copyright 2012 The McGraw-Hill Companies, Inc. All rights reserved.
but the rate of excretion decreases as plasma levels decline, making such as metronidazole or tinidazole. Diloxanide furoate is rapidly once-weekly administration possible for prophylaxis in areas with absorbed after oral administration. When coadministered with a sensitive strains. About one-half of the parent drug is excreted in 5-nitroimidazole, only diloxanide appears in the systemic circulation; urine, but the dose should not be reduced for persons with acute levels peak within 1 h and disappear within 6 h. About 90% of an oral dose is excreted in the urine within 48 h, chiefly as the glucuronide metabolite. Diloxanide furoate is contraindicated in pregnant and Ciprofloxacin
breast-feeding women and in children <2 years of age. See Table 208-1 and Chap. 133.
Eflornithine †
Eflornithine (difluoromethylornithine, or DFMO) is a fluorinated See Table 208-1 and Chap. 133.
analogue of the amino acid ornithine. Although originally designed as an antineoplastic agent, eflornithine has proven effective against some trypanosomatids. At one point, the production of this effec-tive agent ceased despite the increasing incidence of human African See Table 208-1 and Chap. 168.
trypanosomiasis; however, production resumed after eflornithine was discovered to be an effective cosmetic depilatory agent. Dehydroemetine
Eflornithine has specific activity against all stages of infection Emetine is an alkaloid derived from ipecac; dehydroemetine is with Trypanosoma brucei gambiense ; however, it is inactive against synthetically derived from emetine and is considered less toxic. T. b. rhodesiense . The drug acts as an irreversible suicide inhibitor Both agents are active against Entamoeba histolytica and appear to of ornithine decarboxylase, the first enzyme in the biosynthesis work by blocking peptide elongation and thus inhibiting protein of the polyamines putrescine and spermidine. Polyamines are synthesis. Emetine is rapidly absorbed after parenteral administra- essential for the synthesis of trypanothione, an enzyme required tion, rapidly distributed throughout the body, and slowly excreted for the maintenance of intracellular thiols in the correct redox in the urine in unchanged form. Both agents are contraindicated in state and for the removal of reactive oxygen metabolites. However, polyamines are also essential for cell division in eukaryotes, and ornithine decarboxylase is similar in trypanosomes and mam-mals. The selective antiparasitic activity of eflornithine is partly CHAPTER e26
A derivative of the antihelminthic agent piperazine with a long explained by the structure of the trypanosomal enzyme, which history of successful use, diethylcarbamazine (DEC) remains the lacks a 36-amino-acid C-terminal sequence found on mammalian treatment of choice for lymphatic filariasis and loiasis and has ornithine decarboxylase. This difference results in a lower turn- also been used for visceral larva migrans. While piperazine itself over of ornithine decarboxylase and a more rapid decrease of has no antifilarial activity, the piperazine ring of DEC is essential polyamines in trypanosomes than in the mammalian host. The for the drug’s activity. DEC’s mechanism of action remains to be diminished effectiveness of eflornithine against T. b. rhodesiense fully defined. Proposed mechanisms include immobilization due appears to be due to the parasite’s ability to replace the inhibited to inhibition of parasite cholinergic muscle receptors, disruption of enzyme more rapidly than T. b. gambiense . Pharmacology of Agents Used to Treat Parasitic Infections microtubule formation, and alteration of helminthic surface mem- Eflornithine is less toxic but more costly than conventional therapy. branes resulting in enhanced killing by the host’s immune system. It can be administered IV or PO. The dose should be reduced in DEC enhances adherence properties of eosinophils. The develop- renal failure. Eflornithine readily crosses the blood-brain barrier; ment of resistance under drug pressure (i.e., a progressive decrease CSF levels are highest in persons with the most severe central nervous in efficacy when the drug is used widely in human populations) has not been observed, although DEC has variable effects when admin-istered to persons with filariasis. Monthly administration provides Fumagillin†
effective prophylaxis against both bancroftian filariasis and loiasis. Fumagillin is a water-insoluble antibiotic that is derived from the DEC is well absorbed after oral administration, with peak plasma fungus Aspergillus fumigatus and is active against microsporidia. concentrations reached within 1–2 h. No parenteral form is available. This drug is effective when used topically to treat ocular infections The drug is eliminated largely by renal excretion, with <5% found in due to Encephalitozoon species. When given systemically, fumagil- feces. If more than one dose is to be administered to an individual lin was effective but caused thrombocytopenia in all recipients in with renal dysfunction, the dose should be reduced commensurate the second week of treatment; this side effect was readily reversed with the reduction in creatinine clearance rate. Alkalinization of the when administration of the drug was stopped. The mechanisms urine prevents renal excretion and increases the half-life of DEC. by which fumagillin inhibits microsporidial replication are poorly Use in patients with onchocerciasis can precipitate a Mazzotti reac- understood, although the drug may inhibit methionine aminopep- tion, with pruritus, fever, and arthralgias. Like other piperazines, tidase 2 by irreversibly blocking the active site. DEC is active against Ascaris species. Patients co-infected with this nematode may expel live worms after treatment. Furazolidone
This nitrofuran derivative is an effective alternative agent for the Diloxanide furoate
treatment of giardiasis and also exhibits activity against Isospora Diloxanide furoate, a substituted acetanilide, is a luminally active belli . Since it is the only agent active against Giardia that is available agent used to eradicate the cysts of E. histolytica . After ingestion, in liquid form, it is often used to treat young children. Furazolidone diloxanide furoate is hydrolyzed by enzymes in the lumen or undergoes reductive activation in Giardia lamblia trophozoites—an mucosa of the intestine, releasing furoic acid and the ester dilox- event that, unlike the reductive activation of metronidazole, involves anide; the latter acts directly as an amebicide. an NADH oxidase. The killing effect correlates with the toxicity of Diloxanide furoate is given alone to asymptomatic cyst passers. reduced products, which damage important cellular components, For patients with active amebic infections, diloxanide is gen- including DNA. Although furazolidone had been thought to be erally administered in combination with a 5-nitroimidazole largely unabsorbed when administered orally, the occurrence of Copyright 2012 The McGraw-Hill Companies, Inc. All rights reserved.
systemic adverse reactions indicates that this is not the case. More hookworms. Widespread use of ivermectin for treatment of intesti- than 65% of the drug dose can be recovered from the urine as nal nematode infections in sheep and goats has led to the emergence colored metabolites. Omeprazole reduces the oral bioavailability of of drug resistance in veterinary practice; this development may Furazolidone is a monoamine oxidase (MAO) inhibitor; thus Data suggest that ivermectin acts by opening the neuromuscular caution should be used in its concomitant administration with membrane-associated, glutamate-dependent chloride channels. other drugs (especially indirectly acting sympathomimetic amines) The influx of chloride ions results in hyperpolarization and muscle and in the consumption of food and drink containing tyramine dur- paralysis—particularly of the nematode pharynx, with consequent ing treatment. However, hypertensive crises have not been reported blockage of the oral ingestion of nutrients. Because these chloride in patients receiving furazolidone, and it has been suggested that— channels are present only in invertebrates, the paralysis is seen only since furazolidone inhibits MAOs gradually over several days—the risks are small if treatment is limited to a 5-day course. Because Ivermectin is available for administration to humans only as an hemolytic anemia can occur in patients with glucose-6-phosphate oral formulation. The drug is highly protein bound; it is almost dehydrogenase (G6PD) deficiency and glutathione instability, fura- completely excreted in feces. Both food and beer increase the bio- zolidone treatment is contraindicated in mothers who are breast- availability of ivermectin significantly. Ivermectin is distributed widely throughout the body; animal studies indicate that it accumu-lates at the highest concentration in adipose tissue and liver, with Halofantrine
little accumulation in the brain. Few data exist to guide therapy in This 9-phenanthrenemethanol is one of three classes of arylamino- hosts with conditions that may influence drug pharmacokinetics. alcohols first identified as potential antimalarial agents by the World Ivermectin is generally administered as a single dose of 150–200 War II Malaria Chemotherapy Program. Its activity is believed to be μg/kg. In the absence of parasitic infection, the adverse effects of similar to that of chloroquine, although it is an oral alternative for ivermectin in therapeutic doses are minimal. Adverse effects in the treatment of malaria due to chloroquine-resistant P. falciparum . patients with filarial infections include fever, myalgia, malaise, Although the mechanism of action is poorly understood, halofantrine lightheadedness, and (occasionally) postural hypotension. The is thought to share mechanism(s) with the 4-aminoquinolines, severity of such side effects is related to the intensity of parasite forming a complex with ferriprotoporphyrin IX and interfering infection, with more symptoms in individuals with a heavy parasite burden. In onchocerciasis, skin edema, pruritus, and mild eye irrita-tion may also occur. The adverse effects are generally self-limiting Halofantrine exhibits erratic bioavailability, but its absorption is significantly enhanced when it is taken with a fatty meal. The elimi- and only occasionally require symptom-based treatment with anti- nation half-life of halofantrine is 1–2 days; it is excreted mainly in pyretics or antihistamines. More severe complications of ivermectin therapy for onchocerciasis include encephalopathy in patients heavily feces. Halofantrine is metabolized into N -debutyl-halofantrine by the cytochrome P450 enzyme CYP3A4. Grapefruit juice should be avoided during treatment because it increases both halofantrine’s bioavailability and halofantrine-induced QT interval prolongation Lumefantrine
by inhibiting CYP3A4 at the enterocyte level. Lumefantrine (benflumetol), a fluorene arylaminoalcohol deriva-tive synthesized in the 1970s by the Chinese Academy of Military Iodoquinol
Medical Sciences (Beijing), has marked blood schizonticidal activity Iodoquinol (diiodohydroxyquin), a hydroxyquinoline, is an effective against a wide range of plasmodia. This agent conforms structurally luminal agent for the treatment of amebiasis, balantidiasis, and infec- and in mode of action to other arylaminoalcohols (quinine, meflo- tion with Dientamoeba fragilis . Its mechanism of action is unknown. quine, and halofantrine). Lumefantrine exerts its antimalarial effect It is poorly absorbed. Because the drug contains 64% organically as a consequence of its interaction with heme, a degradation prod- bound iodine, it should be used with caution in patients with thyroid uct of hemoglobin metabolism. Although its antimalarial activity is disease. Iodine dermatitis occurs occasionally during iodoquinol slower than that of the artemisinin-based drugs, the recrudescence treatment. Protein-bound serum iodine levels may be increased dur- rate with the recommended lumefantrine regimen is lower. The ing treatment and can interfere with certain tests of thyroid function. pharmacokinetic properties of lumefantrine are reminiscent of These effects may persist for as long as 6 months after discontinua- those of halofantrine, with variable oral bioavailability, consider- tion of therapy. Iodoquinol is contraindicated in patients with liver able augmentation of oral bioavailability by concomitant fat intake, disease. Most serious are the reactions related to prolonged high-dose and a terminal elimination half-life of ~4–5 days in patients with therapy (optic neuritis, peripheral neuropathy), which should not occur if the recommended dosage regimens are followed. Artemether and lumefantrine have synergistic activity, and clini- cal studies of several hundred patients in China show the combina- Ivermectin
tion to be safe and well tolerated. The combined formulation of artemether and lumefantrine has been developed for the treatment Ivermectin (22,23-dihydroavermectin) is a derivative of the mac- rocyclic lactone avermectin produced by the soil-dwelling actino- to chloroquine and antifolates. This combination has now been mycete Streptomyces avermitilis . Ivermectin is active at low doses against a wide range of helminths and ectoparasites. It is the drug of choice for the treatment of onchocerciasis, strongyloidiasis, cutane-ous larva migrans, and scabies. Ivermectin is highly active against Mebendazole
microfilariae of the lymphatic filariases but has no macrofilaricidal This benzimidazole is a broad-spectrum antiparasitic agent widely activity. When ivermectin is used in combination with other agents used to treat intestinal helminthiases. Its mechanism of action is such as DEC or albendazole for treatment of lymphatic filariasis, similar to that of albendazole; however, it is a more potent inhibi- synergistic activity is seen. While active against the intestinal helm- tor of parasite malic dehydrogenase and exhibits a more specific inths Ascaris lumbricoides and Enterobius vermicularis , ivermectin and selective effect against intestinal nematodes than the other is only variably effective in trichuriasis and is ineffective against Copyright 2012 The McGraw-Hill Companies, Inc. All rights reserved.
Mebendazole is available only in oral form but is poorly absorbed shown to exert variable effects on ritonavir pharmacokinetics that from the GI tract; only 5–10% of a standard dose is measurable in are not explained by hepatic CYP3A4 activity or ritonavir protein plasma. The proportion absorbed from the GI tract is extensively binding. Vaccinations with attenuated live bacteria should be com- metabolized in the liver. Metabolites appear in the urine and bile; pleted at least 3 days before the first dose of mefloquine. impaired liver or biliary function results in higher plasma mebenda- Women of childbearing age who are traveling to areas where zole levels in treated patients. No dose reduction is warranted in malaria is endemic should be warned against becoming pregnant patients with renal function impairment. Because mebendazole and encouraged to practice contraception during malaria prophy- is poorly absorbed, its incidence of side effects is low. Transient laxis with mefloquine and for up to 3 months thereafter. However, abdominal pain and diarrhea sometimes occur, usually in persons in the case of unplanned pregnancy, use of mefloquine is not con- sidered an indication for pregnancy termination. Mefloquine
Mefloquine is the preferred drug for prophylaxis of chloroquine- Melarsoprol has been used since 1949 for the treatment of human resistant malaria; high doses can be used for treatment. Despite the African trypanosomiasis. This trivalent arsenical compound is indi- development of drug-resistant strains of P. falciparum in parts of cated for the treatment of African trypanosomiasis with neurologic Africa and southeast Asia, mefloquine is an effective drug through- involvement and for the treatment of early disease that is resistant out most of the world. Cross-resistance of mefloquine with halo- to suramin or pentamidine. Melarsoprol, like other drugs contain- fantrine and with quinine has been documented in limited areas. ing heavy metals, interacts with thiol groups of several different Like quinine and chloroquine, this quinoline is active only against proteins; however, its antiparasitic effects appear to be more specific. the asexual erythrocytic stages of malarial parasites. Unlike quinine, Trypanothione reductase is a key enzyme involved in the oxidative however, mefloquine has a relatively poor affinity for DNA and, as a result, does not inhibit the synthesis of parasitic nucleic acids and cies, helping to maintain an intracellular reducing environment by proteins. Although both mefloquine and chloroquine inhibit hemo- reduction of disulfide trypanothione to its dithiol derivative dihy- zoin formation and heme degradation, mefloquine differs in that it drotrypanothione. Melarsoprol sequesters dihydrotrypanothione, forms a complex with heme that may be toxic to the parasite. depriving the parasite of its main sulfhydryl antioxidant, and inhibits Mefloquine HCl is poorly water soluble and intensely irritating trypanothione reductase, depriving the parasite of the essential CHAPTER e26
when given parenterally; thus it is available only in tablet form. enzyme system that is responsible for keeping trypanothione reduced. Its absorption is adversely affected by vomiting and diarrhea but These effects are synergistic. The selectivity of arsenical action against is significantly enhanced when the drug is administered with or trypanosomes is due at least in part to the greater melarsoprol affinity after food. About 98% of the drug binds to protein. Mefloquine of reduced trypanothione than of other monothiols (e.g., cysteine) on is excreted mainly in the bile and feces; therefore, no dose adjust- which the mammalian host depends for maintenance of high thiol ment is needed in persons with renal insufficiency. The drug and levels. Melarsoprol enters the parasite via an adenosine transporter; its main metabolite are not appreciably removed by hemodialysis. drug-resistant strains lack this transport system. No special chemoprophylactic dosage adjustments are indicated for Melarsoprol is always administered IV. A small but therapeuti- the achievement of plasma concentrations in dialysis patients that cally significant amount of the drug enters the CSF. The compound Pharmacology of Agents Used to Treat Parasitic Infections are similar to those in healthy persons. Pharmacokinetic differences is excreted rapidly, with ~80% of the arsenic found in feces. have been detected among various ethnic populations. In practice, Melarsoprol is highly toxic. The most serious adverse reaction is however, these distinctions are of minor importance compared reactive encephalopathy, which affects 6% of treated individuals and with host immune status and parasite sensitivity. In patients with usually develops within 4 days of the start of therapy, with an average impaired liver function, the elimination of mefloquine may be pro- case-fatality rate of 50%. Glucocorticoids are administered with melar- longed, leading to higher plasma levels. soprol to prevent this development. Because melarsoprol is intensely Mefloquine should be used with caution by individuals par- irritating, care must be taken to avoid infiltration of the drug. ticipating in activities requiring alertness and fine-motor coordi-nation. If the drug is to be administered for a prolonged period, Metrifonate
periodic evaluations are recommended, including liver function Metrifonate has selective activity against Schistosoma haematobium . tests and ophthalmic examinations. Sleep abnormalities (insomnia, This organophosphorous compound is a prodrug that is converted abnormal dreams) have occasionally been reported. Psychosis nonenzymatically to dichlorvos (2,2-dichlorovinyl dimethylphos- and seizures occur rarely; mefloquine should not be prescribed to phate, DDVP), a highly active chemical that irreversibly inhibits the patients with neuropsychiatric conditions, including depression, acetylcholinesterase enzyme. Schistosomal cholinesterase is more generalized anxiety disorder, psychosis, schizophrenia, and seizure susceptible to dichlorvos than is the corresponding human enzyme. disorder. If acute anxiety, depression, restlessness, or confusion The exact mechanism of action of metrifonate is uncertain, but the develops during prophylaxis, these psychiatric symptoms may be drug is believed to inhibit tegumental acetylcholine receptors that considered prodromal to a more serious event, and the drug should Metrifonate is administered in a series of three doses at 2-week Concomitant use of quinine, quinidine, or drugs producing intervals. After a single oral dose, metrifonate produces a 95% β-adrenergic blockade may cause significant electrocardiographic decrease in plasma cholinesterase activity within 6 h, with a fairly abnormalities or cardiac arrest. Halofantrine must not be given rapid return to normal. However, 2.5 months are required for simultaneously with or <3 weeks after mefloquine because a poten- erythrocyte cholinesterase levels to return to normal. Treated per- tially fatal prolongation of the QTc interval on electrocardiography sons should not be exposed to neuromuscular blocking agents or may occur. No data exist on mefloquine use after halofantrine use. organophosphate insecticides for at least 48 h after treatment. Administration of mefloquine with quinine or chloroquine may increase the risk of convulsions. Mefloquine may lower plasma levels of anticonvulsants. Caution should be exercised with regard Metronidazole and other nitroimidazoles
to concomitant antiretroviral therapy, since mefloquine has been See Table 208-1 and Chap. 133.
Copyright 2012 The McGraw-Hill Companies, Inc. All rights reserved.
absorbed and undergoes rapid and extensive biotransformation; In the early 1990s, miltefosine (hexadecylphosphocholine), origi- <0.5% of the original drug is excreted in urine. nally developed as an antineoplastic agent, was discovered to have significant antiproliferative activity against Nitazoxanide
Trypanosoma cruzi , and T. brucei parasites in vitro and in experi- Nitazoxanide is a 5-nitrothiazole compound used for the treatment mental animal models. Miltefosine is the first oral drug that has of cryptosporidiosis and giardiasis; it is active against other intestinal proved to be highly effective and comparable to amphotericin B protozoa as well. The drug is approved for use in children 1–11 years against visceral leishmaniasis in India, where antimonial-resistant cases are prevalent. Miltefosine is also effective in previously The antiprotozoal activity of nitazoxanide is believed to be due to untreated visceral infections. Cure rates in cutaneous leishmaniasis interference with the pyruvate-ferredoxin oxidoreductase (PFOR) are comparable to those obtained with antimony. enzyme–dependent electron transfer reaction that is essential to The activity of miltefosine is attributed to interaction with anaerobic energy metabolism. Studies have shown that the PFOR cell signal transduction pathways and inhibition of phospholipid enzyme from G. lamblia directly reduces nitazoxanide by trans- and sterol biosynthesis. Resistance to miltefosine has not been fer of electrons in the absence of ferredoxin. The DNA-derived observed clinically. The drug is readily absorbed from the GI PFOR protein sequence of Cryptosporidium parvum appears to be tract, is widely distributed, and accumulates in several tissues. similar to that of G. lamblia . Interference with the PFOR enzyme– The efficacy of a 28-day treatment course in Indian visceral dependent electron transfer reaction may not be the only pathway leishmaniasis is equivalent to that of amphotericin B therapy; by which nitazoxanide exerts antiprotozoal activity. however, it appears that a shortened course of 21 days may be After oral administration, nitazoxanide is rapidly hydrolyzed to an active metabolite, tizoxanide (desacetyl-nitazoxanide). General recommendations for the use of miltefosine are limited Tizoxanide then undergoes conjugation, primarily by glucuroni- by the exclusion of specific groups from the published clinical trials: dation. It is recommended that nitazoxanide be taken with food; persons <12 or >65 years of age, persons with the most advanced however, no studies have been conducted to determine whether the disease, breast-feeding women, HIV-infected patients, and indi- pharmacokinetics of tizoxanide and tizoxanide glucuronide differ viduals with significant renal or hepatic insufficiency. in fasted versus fed subjects. Tizoxanide is excreted in urine, bile, and feces, and tizoxanide glucuronide is excreted in urine and bile. Niclosamide
The pharmacokinetics of nitazoxanide in patients with impaired Niclosamide is active against a wide variety of adult tapeworms but hepatic and/or renal function have not been studied. Tizoxanide not against tissue cestodes. It is also a molluscicide and is used in is highly bound to plasma protein (>99.9%). Therefore, caution should be used when administering this agent concurrently with snail-control programs. The drug uncouples oxidative phospho- rylation in parasite mitochondria, thereby blocking the uptake of other highly plasma protein–bound drugs with narrow therapeutic glucose by the intestinal tapeworm and resulting in the parasite’s indices, as competition for binding sites may occur. death. Niclosamide rapidly causes spastic paralysis of intestinal cestodes in vitro. Its use is limited by its side effects, the necessar- Oxamniquine
ily long duration of therapy, the recommended use of purgatives, This tetrahydroquinoline derivative is an effective alternative agent and—most important—limited availability (i.e., on a named-patient for the treatment of Schistosoma mansoni , although susceptibility to this drug exhibits regional variation. Oxamniquine exhibits anti- Niclosamide is poorly absorbed. Tablets are given on an empty cholinergic properties, but its primary mode of action seems to rely stomach in the morning after a liquid meal the night before, on ATP-dependent enzymatic drug activation generating an inter- and this dose is followed by another 1 h later. For treatment of mediate that alkylates essential macromolecules, including DNA. In hymenolepiasis, the drug is administered for 7 days. A second treated adult schistosomes, oxamniquine produces marked tegumen- course is often prescribed. The scolex and proximal segments of tal alterations that are similar to those seen with praziquantel but that the tapeworms are killed on contact with niclosamide and may be develop less rapidly, becoming evident 4–8 days after treatment. digested in the gut. However, disintegration of the adult tapeworm Oxamniquine is administered orally as a single dose and is well results in the release of viable ova, which theoretically can result in absorbed. Food retards absorption and reduces bioavailability. autoinfection. Although fears of the development of cysticercosis About 70% of an administered dose is excreted in urine as a mix- in patients with Taenia solium infections have proved unfounded, ture of pharmacologically inactive metabolites. Patients should be it is still recommended that a brisk purgative be given 2 h after the warned that their urine might have an intense orange-red color. Side effects are uncommon and usually mild, although hallucina-tions and seizures have been reported. Nifurtimox*
This nitrofuran compound is an inexpensive and effective oral Paromomycin (aminosidine)
agent for the treatment of acute Chagas’ disease. Trypanosomes First isolated in 1956, this aminoglycoside is an effective oral agent lack catalase and have very low levels of peroxidase; as a result, for the treatment of infections due to intestinal protozoa. Parenteral they are very vulnerable to by-products of oxygen reduction. When paromomycin appears to be effective against visceral leishmaniasis nifurtimox is reduced in the trypanosome, a nitro anion radical is formed and undergoes autooxidation, resulting in the generation of Paromomycin inhibits protozoan protein synthesis by binding the superoxide anion O − , hydrogen peroxide (H O ), hydroperoxyl to the 30S ribosomal RNA in the aminoacyl-tRNA site, causing radical (HO ), and other highly reactive and cytotoxic molecules. misreading of mRNA codons. Paromomycin is less active against Despite the abundance of catalases, peroxidases, and superoxide G. lamblia than standard agents; however, like other aminoglycosides, dismutases that neutralize these destructive radicals in mammalian paromomycin is poorly absorbed from the intestinal lumen, and the cells, nifurtimox has a poor therapeutic index. Prolonged use is high levels of drug in the gut compensate for this relatively weak required, but the course may have to be interrupted because of drug activity. If absorbed or administered systemically, paromomycin can toxicity, which develops in 40–70% of recipients. Nifurtimox is well cause ototoxicity and nephrotoxicity. However, systemic absorption Copyright 2012 The McGraw-Hill Companies, Inc. All rights reserved.
is very limited, and toxicity should not be a concern in persons with been used most effectively for eradication of the hepatic stage of normal kidneys. Topical formulations are not generally available. these parasites. Despite its toxicity, it remains the drug of choice for radical cure of P. vivax infections. Primaquine must be metabolized Pentamidine isethionate
by the host to be effective. It is, in fact, rapidly metabolized; only a This diamidine is an effective alternative agent for some forms of small fraction of the dose of the parent drug is excreted unchanged. leishmaniasis and trypanosomiasis. It is available for parenteral and Although the parasiticidal activity of the three oxidative metabo- aerosolized administration. While its mechanism of action remains lites remains unclear, they are believed to affect both pyrimidine undefined, it is known to exert a wide range of effects, including synthesis and the mitochondrial electron transport chain. The interaction with trypanosomal kinetoplast DNA; interference with metabolites appear to have significantly less antimalarial activity polyamine synthesis by a decrease in the activity of ornithine decar- than primaquine; however, their hemolytic activity is greater than boxylase; and inhibition of RNA polymerase, ribosomal function, and the synthesis of nucleic acids and proteins. Primaquine causes marked hypotension after parenteral admin- Pentamidine isethionate is well absorbed, is highly tissue bound, istration and therefore is given only by the oral route. It is rapidly and is excreted slowly over several weeks, with an elimination and almost completely absorbed from the GI tract. half-life of 12 days. No steady-state plasma concentration is attained Patients should be tested for G6PD deficiency before they receive in persons given daily injections; the result is extensive accumula- primaquine. The drug may induce the oxidation of hemoglobin tion of pentamidine in tissues, primarily the liver, kidney, adrenal, into methemoglobin, irrespective of the G6PD status of the patient. and spleen. Pentamidine does not penetrate well into the CNS. Pulmonary concentrations of pentamidine are increased when the drug is delivered in aerosolized form. Proguanil (chloroguanide)
Proguanil inhibits plasmodial dihydrofolate reductase and is used Piperazine
with atovaquone for oral treatment of uncomplicated malaria or The antihelminthic activity of piperazine is confined to ascariasis with chloroquine for malaria prophylaxis in parts of Africa without and enterobiasis. Piperazine acts as an agonist at extrasynaptic widespread chloroquine-resistant P. falciparum . γ-aminobutyric acid (GABA) receptors, causing an influx of chlo- Proguanil exerts its effect primarily by means of the metabolite ride ions in the nematode somatic musculature. Although the initial cycloguanil, whose inhibition of dihydrofolate reductase in the parasite disrupts deoxythymidylate synthesis, thus interfering with CHAPTER e26
result is hyperpolarization of the muscle fibers, the ultimate effect is flaccid paralysis leading to the expulsion of live worms. Patients a key pathway involved in the biosynthesis of pyrimidines required should be warned, as this occurrence can be unsettling. for nucleic acid replication. There are no clinical data indicating that folate supplementation diminishes drug efficacy; women of Praziquantel
childbearing age for whom atovaquone/proguanil is prescribed This heterocyclic pyrazinoisoquinoline derivative is highly active should continue taking folate supplements to prevent neural tube against a broad spectrum of trematodes and cestodes. It is the mainstay of treatment for schistosomiasis and is a critical part of Proguanil is extensively absorbed regardless of food intake. The drug is 75% protein bound. The main routes of elimination Pharmacology of Agents Used to Treat Parasitic Infections All of the effects of praziquantel can be attributed either directly are hepatic biotransformation and renal excretion; 40–60% of the or indirectly to an alteration of intracellular calcium concentrations. proguanil dose is excreted by the kidneys. Drug levels are increased Although the exact mechanism of action remains unclear, the major and elimination is impaired in patients with hepatic insufficiency. mechanism is disruption of the parasite tegument, causing tetanic contractures with loss of adherence to host tissues and, ultimately, Pyrantel pamoate
disintegration or expulsion. Praziquantel induces changes in the Pyrantel is a tetrahydropyrimidine formulated as pamoate. This antigenicity of the parasite by causing the exposure of concealed safe, well-tolerated, inexpensive drug is used to treat a variety of antigens. Praziquantel also produces alterations in schistosomal intestinal nematode infections but is ineffective in trichuriasis. glucose metabolism, including decreases in glucose uptake, lactate Pyrantel pamoate is usually effective in a single dose. Its target is release, glycogen content, and ATP levels. the nicotinic acetylcholine receptor on the surface of nematode Praziquantel exerts its parasitic effects directly and does not need somatic muscle. Pyrantel depolarizes the neuromuscular junction to be metabolized to be effective. It is well absorbed but under- of the nematode, resulting in its irreversible paralysis and allowing goes extensive first-pass hepatic clearance. Levels of the drug are increased when it is taken with food, particularly carbohydrates, Pyrantel pamoate is poorly absorbed from the intestine; >85% or with cimetidine. Serum levels are reduced by glucocorticoids, of the dose is passed unaltered in feces. The absorbed portion is chloroquine, carbamazepine, and phenytoin. Praziquantel is com- metabolized and excreted in urine. Piperazine is antagonistic to pletely metabolized in humans, with 80% of the dose recovered as pyrantel pamoate and should not be used concomitantly. metabolites in urine within 4 days. It is not known to what extent Pyrantel pamoate has minimal toxicity at the oral doses used praziquantel crosses the placenta, but retrospective studies suggest to treat intestinal helminthic infection. It is not recommended for pregnant women or for children <12 months old. Patients with schistosomiasis who have heavy parasite burdens may develop abdominal discomfort, nausea, headache, dizziness, Pyrimethamine
and drowsiness. Symptoms begin 30 min after ingestion, may When combined with short-acting sulfonamides, this diaminopy- require spasmolytics for relief, and usually disappear spontaneously rimidine is effective in malaria, toxoplasmosis, and isosporiasis. Unlike mammalian cells, the parasites that cause these infections cannot utilize preformed pyrimidines obtained through salvage Primaquine phosphate
pathways but rather rely completely on de novo pyrimidine synthe- Primaquine, an 8-aminoquinoline, has a broad spectrum of activity sis, for which folate derivatives are essential cofactors. The efficacy against all stages of plasmodial development in humans but has of pyrimethamine is increasingly limited by the development of Copyright 2012 The McGraw-Hill Companies, Inc. All rights reserved.
resistant strains of P. falciparum and P. vivax . Single amino acid Serious reactions to spiramycin are rare. Of the available mac- substitutions to parasite dihydrofolate reductase confer resistance rolides, spiramycin appears to have the lowest risk of drug interac- to pyrimethamine by decreasing the enzyme’s binding affinity for tions. Complications of treatment are rare but, in neonates, can include life-threatening ventricular arrhythmias that disappear with Pyrimethamine is well absorbed; the drug is 87% bound to human plasma proteins. In healthy volunteers, drug concentrations remain at therapeutic levels for up to 2 weeks; drug levels are lower Sulfonamides
See Table 208-1 and Chap. 133.
At the usual dosage, pyrimethamine alone causes little toxicity except for occasional skin rashes and, more rarely, blood dyscrasias. Suramin*
Bone marrow suppression sometimes occurs at the higher doses This derivative of urea is the drug of choice for the early stage used for toxoplasmosis; at these doses, the drug should be adminis- of African trypanosomiasis. The drug is polyanionic and acts by forming stable complexes with proteins, thus inhibiting multiple enzymes essential to parasite energy metabolism. Suramin appears Quinacrine*
to inhibit all trypanosome glycolytic enzymes more effectively than Quinacrine is the only drug approved by the FDA for the treatment it inhibits the corresponding host enzymes. of giardiasis. Although its production was discontinued in 1992, Suramin is parenterally administered. It binds to plasma proteins quinacrine can be obtained from alternative sources through the and persists at low levels for several weeks after infusion. Its metab- CDC Drug Service. The antiprotozoal mechanism of quinacrine olism is negligible. This drug does not penetrate the CNS. has not been fully elucidated. The drug inhibits NADH oxidase—the same enzyme that activates furazolidone. The differing rela- Tafenoquine
tive quinacrine uptake rate between human cells and G. lamblia Tafenoquine is an 8-aminoquinoline with causal prophylactic activ- may explain the selective toxicity of the drug. Resistance corre- ity. Its prolonged half-life (2–3 weeks) allows longer dosing intervals when the drug is used for prophylaxis. Tafenoquine has been well Quinacrine is rapidly absorbed from the intestinal tract and is tolerated in clinical trials. When tafenoquine is taken with food, its widely distributed in body tissues. Alcohol is best avoided due to a absorption is increased by 50% and the most commonly reported adverse event—mild GI upset—is diminished. Like primaquine, tafenoquine is a potent oxidizing agent, causing hemolysis in Quinine and quinidine
patients with G6PD deficiency as well as methemoglobinemia. When combined with another agent, the cinchona alkaloid quinine is effective for the oral treatment of both uncomplicated, chloroquine- Tetracyclines
resistant malaria and babesiosis. Quinine acts rapidly against the See Table 208-1 and Chap. 133.
asexual blood stages of all forms of human malaria. For severe malaria, only quinidine (the dextroisomer of quinine) is available Thiabendazole
in the United States. Quinine concentrates in the acidic food Discovered in 1961, thiabendazole remains one of the most potent vacuoles of Plasmodium species. The drug inhibits the nonenzymatic of the numerous benzimidazole derivatives. However, its use has polymeri zation of the highly reactive, toxic heme molecule into the declined significantly because of a higher frequency of adverse effects than is seen with other, equally effective agents. Quinine is readily absorbed when given orally. In patients with Thiabendazole is active against most intestinal nematodes that malaria, the elimination half-life of quinine increases according infect humans. Although the exact mechanism of its antihelminthic to the severity of the infection. However, toxicity is avoided by an activity has not been fully elucidated, it is likely to be similar to that increase in the concentration of plasma glycoproteins. The cinchona of other benzimidazole drugs: namely, inhibition of polymerization alkaloids are extensively metabolized, particularly by CYP3A4; only of parasite β-tubulin. The drug also inhibits the helminth-specific 20% of the dose is excreted unchanged in urine. The drug’s metabo- enzyme fumarate reductase. In animals, thiabendazole has anti- lites are also excreted in urine and may be responsible for toxicity in inflammatory, antipyretic, and analgesic effects, which may explain patients with renal failure. Renal excretion of quinine is decreased its usefulness in dracunculiasis and trichinosis. Thiabendazole also when cimetidine is taken and increased when the urine is acidic. The suppresses egg and/or larval production by some nematodes and may inhibit the subsequent development of eggs or larvae passed in Quinidine is both more potent as an antimalarial and more toxic feces. Despite the emergence and global spread of thiabendazole- than quinine. Its use requires cardiac monitoring. Dose reduction is resistant trichostrongyliasis among sheep, there have been no necessary in persons with severe renal impairment. Thiabendazole is available in tablet form and as an oral suspen- Spiramycin †
sion. The drug is rapidly absorbed from the GI tract but can also This macrolide is used to treat acute toxoplasmosis in pregnancy be absorbed through the skin. Thiabendazole should be taken after and congenital toxoplasmosis. While the mechanism of action is meals. This agent is extensively metabolized in the liver before similar to that of other macrolides, the efficacy of spiramycin in ultimately being excreted; most of the dose is excreted within the toxoplasmosis appears to stem from its rapid and extensive intracel- first 24 h. The usual dose of thiabendazole is determined by the lular penetration, which results in macrophage drug concentrations patient’s weight, but some treatment regimens are parasite specific. 10–20 times greater than serum concentrations. No particular adjustments are recommended in patients with renal Spiramycin is rapidly and widely distributed throughout the or hepatic failure; only cautious use is advised. body and reaches concentrations in the placenta up to five times Coadministration of thiabendazole in patients taking theo- those in serum. This agent is excreted mainly in bile. Indeed, in phylline can result in an increase in theophylline levels by >50%. humans, the urinary excretion of active compounds represents only Therefore, serum levels of theophylline should be monitored closely Copyright 2012 The McGraw-Hill Companies, Inc. All rights reserved.
Triclabendazole is rapidly absorbed after oral ingestion; adminis- This nitroimidazole is effective for the treatment of amebiasis, tration with food enhances its absorption and shortens the elimina- giardiasis, and trichomoniasis. Like metronidazole, tinidazole tion half-life of the active metabolite. Both the sulfoxide and the sul- must undergo reductive activation by the parasite’s metabolic fone metabolites are highly protein bound (>99%). Treatment with system before it can act on protozoal targets. Tinidazole inhibits triclabendazole is typically given in one or two doses. No clinical data the synthesis of new DNA in the parasite and causes degradation are available regarding dose adjustment in renal or hepatic insuffi- of existing DNA. The reduced free-radical derivatives alkylate ciency; however, given the short course of therapy and extensive DNA, with consequent cytotoxic damage to the parasite. This hepatic metabolism of triclabendazole, dose adjustment is unlikely damage appears to be produced by short-lived reduction inter- to be necessary. No information exists on drug interactions. mediates, resulting in helix destabilization and strain breakage of DNA. The mechanism of action and side effects of tinidazole are Trimethoprim-sulfamethoxazole
similar to those of metronidazole, but adverse events appear to be See Table 208-1 and Chap. 133.
less frequent and severe with tinidazole. In addition, the signifi-cantly longer half-life of tinidazole (>12 h) offers potential cure FURTHER READINGS
Hoerauf A: New strategies to combat filariasis. Expert Rev Anti Keiser J, Utzinger J: The drugs we have and the drugs we need Triclabendazole
against major helminth infections. Adv Parasitol 73:197, 2010 While most benzimidazoles have broad-spectrum antihelminthic Moore TA: Ivermectin, in Kucer’s Use of Antibiotics , 6th ed, activity, they exhibit minimal or no activity against F. hepatica . In M L Grayson et al (eds). London, Oxford University Press, 2010, contrast, the antihelminthic activity of triclabendazole is highly specific for Fasciola and Paragonimus species, with little activity ———, McCarthy JS: Benzimidazoles, in Antimicrobial Therapy against nematodes, cestodes, and other trematodes. Triclabendazole , 2nd ed, VL Yu et al (eds). Pittsburgh, ESun is effective against all stages of Fasciola species. The active sulfoxide metabolite of triclabendazole binds to fluke tubulin by assuming a unique nonplanar configuration and disrupts microtubule-based Schlagenhauf P et al: The position of mefloquine as a 21st century malaria chemoprophylaxis. Malar J 9:357, 2010 CHAPTER e26
processes. Resistance to triclabendazole in veterinary use has been reported in Australia and Europe; however, no resistance has been World Health Organization: Guidelines for the treatment of Pharmacology of Agents Used to Treat Parasitic Infections Copyright 2012 The McGraw-Hill Companies, Inc. All rights reserved.

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MacArthur Foundation Network on Mental Health Policy Research —Robert Drake, Jonathan Skinner, and Howard Goldman W H Y S O S L O W T O A D O P T C E R T A I N P R O V E N T R E A T M E N T S ? G A I N I N G A B E T T E R U N D E R S T A N D I N G O F H O W A D V A N C E M E N T S I N M E N T A L H E A L T H C A R E A R E D I S S E M I N A T E D The past twenty years

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Learning from a Suicide This is an actual case history. For various reasons, despite the client having died, all names and possibleidentifiers have been changed. Details have been compiled from various sources. I was employed for a while as a psychological therapist in a Clinical Psychology department thatserved a rural area of Scotland, once a thriving mining community, now a little like th

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