Albendazole and Mebendazole as Anti-Parasitic and ...

The use of albendazole and mebendazole, i.e., benzimidazole broad-spectrum anthelmintics, in treatment of parasitic infections, as well as cancers, is briefly reviewed. These drugs are known to block the microtubule systems of parasites and mammalian cells leading to inhibition of glucose uptake and transport and finally cell death. Eventually they exhibit ovicidal, larvicidal, and vermicidal effects on parasites, and tumoricidal effects on hosts. Albendazole and mebendazole are most frequently prescribed for treatment of intestinal nematode infections (ascariasis, hookworm infections, trichuriasis, strongyloidiasis, and enterobiasis) and can also be used for intestinal tapeworm infections (taeniases and hymenolepiasis). However, these drugs also exhibit considerable therapeutic effects against tissue nematode/cestode infections (visceral, ocular, neural, and cutaneous larva migrans, anisakiasis, trichinosis, hepatic and intestinal capillariasis, angiostrongyliasis, gnathostomiasis, gongylonemiasis, thelaziasis, dracunculiasis, cerebral and subcutaneous cysticercosis, and echinococcosis). Albendazole is also used for treatment of filarial infections (lymphatic filariasis, onchocerciasis, loiasis, mansonellosis, and dirofilariasis) alone or in combination with other drugs, such as ivermectin or diethylcarbamazine. Albendazole was tried even for treatment of trematode (fascioliasis, clonorchiasis, opisthorchiasis, and intestinal fluke infections) and protozoan infections (giardiasis, vaginal trichomoniasis, cryptosporidiosis, and microsporidiosis). These drugs are generally safe with few side effects; however, when they are used for prolonged time (>14&#;28 days) or even only 1 time, liver toxicity and other side reactions may occur. In hookworms, Trichuris trichiura, possibly Ascaris lumbricoides, Wuchereria bancrofti, and Giardia sp., there are emerging issues of drug resistance. It is of particular note that albendazole and mebendazole have been repositioned as promising anti-cancer drugs. These drugs have been shown to be active in vitro and in vivo (animals) against liver, lung, ovary, prostate, colorectal, breast, head and neck cancers, and melanoma. Two clinical reports for albendazole and 2 case reports for mebendazole have revealed promising effects of these drugs in human patients having variable types of cancers. However, because of the toxicity of albendazole, for example, neutropenia due to myelosuppression, if high doses are used for a prolonged time, mebendazole is currently more popularly used than albendazole in anti-cancer clinical trials.

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The present study aimed to review briefly recent trends in use of albendazole and mebendazole not only as anti-parasitic agents but also as new promising anti-cancer agents. In addition, the increasing reports on the hepatotoxicity of these drugs as well as drug resistance in parasites are also briefly reviewed.

Albendazole and mebendazole are generally safe without significant side effects when used in recommended doses just for 1&#;3 days [ 2 , 4 , 9 , 13 ]. However, when these drugs are used for prolonged periods to treat tissue helminthiases [ 36 ], cancers [ 37 , 38 ], or even when they are used just for once as preventive chemotherapy for intestinal helminths [ 39 ], liver toxicity, allergic reactions, and rarely severe myelosuppression (in particular, neutropenia) may occur. In addition, the occurrence of drug resistance to albendazole and mebendazole with treatment failure was reported recently in hookworm infections, trichuriasis, ascariasis, and lymphatic filariasis [ 40 &#; 42 ] which has become a significant emerging issue.

Meanwhile, albendazole and mebendazole have been shown to suppress tumor growth in vitro and in vivo and thus have been repositioned as anti-cancer agents [ 32 &#; 35 ]. For example, albendazole induces oxidative stress promoting DNA fragmentation and triggering apoptosis and inducing death of breast cancer cells [ 33 ]. Mebendazole disrupts microtubule functions by preventing polymerization of tubulin in cancer cells, such as glioblastoma and melanoma, and leads to cell death [ 32 ]. In addition, mebendazole would synergize with a range of other anti-cancer drugs, including the existing ones [ 32 ].

Since albendazole and mebendazole were first used for treatment of several intestinal helminth species infecting humans [ 2 , 4 ], numerous studies have been performed on their anthelmintic efficacies against a variety of nematodes, trematodes, cestodes, and even protozoans [ 1 , 3 , 5 &#; 12 ]. The examples of nematode infections included ascariasis, hookworm infections, trichuriasis, strongyloidiasis, enterobiasis, larva migrans (visceral, ocular, neural, and cutaneous), anisakiasis (anisakidosis), trichinosis, angiostrongyliasis (cerebral and abdominal), gnathostomiasis, capillariasis (hepatic and intestinal), thelaziasis, lymphatic filariasis, onchocerciasis, and dirofilariasis [ 8 , 9 ]. Trematode infections that can be treated with albendazole and/or mebendazole are fascioliasis, clonorchiasis, opisthorchiasis, and intestinal fluke infections [ 13 &#; 20 ]. Cestode diseases responsive to albendazole and/or mebendazole include cysticercosis, hydatidosis, and intestinal taeniases [ 21 &#; 25 ]. Protozoan diseases for which albendazole and/or mebendazole have been tried were giardiasis, vaginal trichomoniasis, cryptosporidiosis, and microsporidiosis, although the efficacies against some of these infections need to be further evaluated [ 12 , 26 &#; 31 ].

Albendazole, methyl [5-(propylthio)-1H-benzimidazol-2-yl] carbamate, is a broad- spectrum anti-parasitic agent, first introduced in for treatment of liver flukes, tapeworms, lung and gastrointestinal nematodes in sheep and cattle [ 1 ]. It was subsequently approved for human use in [ 2 , 3 ]. Mebendazole, methyl 5-benzoyl-1H-benzimidazol-2-yl-carbamate, is also a broad-spectrum anthelmintic, applied first to human subjects in [ 4 ]. Both drugs are relatively insoluble in water and most organic solvents and poorly absorbed from the gastrointestinal tract unless administered with high-fat meals [ 5 ]. The absorption rate of oral albendazole and mebendazole in human intestine is about 1&#;5% [ 3 ]. It is assumed that these drugs act directly on luminal parasites in the gastrointestinal tract, and after first-pass in the intestinal wall and liver their metabolites are active against parasites in internal organs and tissues [ 3 , 4 ]. For example, albendazole sulfoxide, among 5 metabolites of albendazole detected in human urine, is considered the major metabolite responsible for the anthelmintic activity [ 3 , 6 ]. In mebendazole, 2 forms of metabolites are known in the plasma, i.e., aminometabolite and hydroxymetabolite, which are excreted in urine as decarboxylated forms [ 6 ]. Albendazole and mebendazole are known to block microtubule functions of parasites and mammalian cells through inhibition of polymerization of ß-tubulin into microtubules followed by inhibition of glucose uptake and transport which eventually lead parasites to be in shortage of glycogen [ 7 ].

The therapeutic efficacy of albendazole against human Hymenolepis nana infection has been variable [ 53 ]. Whereas Rossignol and Maisonneuve [ 70 ] reported the CR of only 29.4% using 400 mg albendazole daily for 3 days, Rim et al. [ 13 ] reported the CR of 66.7% using 800 mg daily for 2 days ( ). Horton [ 53 ] reviewed the CR of human H. nana infection using 400 mg albendazole daily for 3 days in 13 trials from until March to be in the range between 28.5% and 100% (av. 69.5%). However, shorter courses, particularly 400 mg single dose, do not appear to produce a significant cure of the disease [ 53 ].

Mebendazole was also proved to be effective against Taenia spp. infection if used in multiple doses, for example, 100 mg b.i.d. for 3 days [ 67 ], 300 mg b.i.d. for 3 days [ 68 ], or 500 mg daily for 3 days [ 23 ]. In particular, the CR of multiple doses, 500 mg daily for 3 days, was 100%, whereas that of 500 mg single dose was only 50.0% [ 23 ].

Albendazole was used for treatment of taeniases due to Taenia spp. (T. saginata and T. solium) for the first time by Rim et al. [ 13 , 21 ]. Whereas single dose regimens (400 mg or 800 mg) were almost ineffective, the dosage showing therapeutic efficacy was 400 mg b.i.d. or t.i.d. for 2&#;3 days (total 1,600&#;3,600 mg) [ 13 , 21 ]. Using this dosage regimen, slightly better efficacy was obtained against T. saginata (90.0&#;95.0% CR) than against T. solium (70.0&#;92.9% CR) infection [ 13 , 21 ] ( ). Thereafter, based on 8 trials performed until March using a reduced dosage regimen of 400 mg daily for 3 days (total 1,200 mg), CR of 75.7&#;100% was obtained [ 53 ]. In other trials, a single dose of 400 mg for adults and 200 mg for children showed low efficacy with 50.0&#;58.8% CR, whereas triple doses repeated for 3 days brought about 100% CR [ 23 , 66 ].

Mebendazole was first used in clinical trial for enterobiasis in [ 4 ]. This drug, in a standard dose of 100 mg single dose [ 45 ], was reported to have been satisfactory for treatment of E. vermicularis infection in adults (88% CR) as well as children (91%) [ 4 ]. Higher doses, 100 mg b.i.d. for 3 days (total 600 mg) or 200 mg or 400 mg in a single dose, revealed similar therapeutic effects [ 4 , 54 , 63 ]. It is notable that the anthelmintic efficacy of mebendazole against young/juvenile worms of E. vermicularis was higher than that of pyrvinium pamoate or pyrantel pamoate [ 64 ]. Thus, the rate and timing of egg positive conversion (due to limited drug efficacy) after MDA were low and delayed in a highly endemic group of children if mebendazole (100 mg single dose) was used but the rate and timing of egg positive conversion were high and rapid if pyrvinium pamoate or pyrantel pamoate was used [ 64 ]. For chemotherapeutic control of enterobiasis using mebendazole 100 mg single dose in a group of children, MDA should be repeated at least 2&#;3 times at 3-week intervals [ 65 ].

Both albendazole and mebendazole have been shown to be highly effective against Enterobius vermicularis infection. The first clinical trial of albendazole was performed in the early s [ 53 ]. Thereafter until March , many clinical trials (at least 26 trials) were performed using 400 mg single dose of albendazole (recommended dose by WHO [ 45 ]) [ 53 ]. In most trials, the CR at day 14&#;17 post-treatment ranged from 93.3 to 100% [ 53 ]. In South Korea, Rim et al. [ 13 ] reported 98.1% CR when follow-up examinations were done on day 14 and 28 post-treatment ( ). Also, Chai et al. [ 62 ] obtained 100% CR at day 14 post-treatment using 400 mg single dose of albendazole. Reduced doses, 100 mg or 200 mg in a single dose, of albendazole were as effective as the recommended dose [ 63 ]. For chemotherapeutic control of enterobiasis using MDA with albendazole in a family or a group of people, treatment should be repeated at least 2 or more times every 2&#;3 weeks [ 8 , 45 ].

An alternative drug, ivermectin (200 μg/kg daily for 2 days), resulted in more people cured than albendazole, and equally tolerated [ 59 ]. In northwestern Argentina, albendazole plus ivermectin was tried to control. Stercoralis and hookworm infections and was found to be effective for reduction of the prevalence as well as the morbidity due to these parasite infections [ 61 ].

Albendazole was evaluated to be partially effective for treatment of Strongyloides stercoralis infection, whereas mebendazole was never shown to be effective for strongyloidiasis [ 59 ]. In , albendazole (400 mg daily for 3 days) was reported to have some effects against S. stercoralis infection, 48.0% in CR [ 51 ]. The ERR for this infection was not calculated because the diagnosis of strongyloidiasis is usually based on detection of larvae by a concentration method [ 53 ]. In addition, higher doses of albendazole, 400 mg b.i.d. for 3 or 7 days, revealed 100% CR [ 14 ] ( ). WHO [ 45 ] recommended the regimen of albendazole for strongyloidiasis as 400 mg daily for &#;3 days. Horton [ 53 ] reviewed the efficacy of albendazole (400 mg daily for 3 days) against S. stercoralis infection, and the average CR was 62.2% (16.7&#;100% in range) calculated from 19 studies performed until March . However, in immunocompromised patients with S. stercoralis hyperinfection syndrome, even 5 courses of albendazole (400 mg daily for 3 days) failed to cure the disease [ 60 ].

Mebendazole was first tried to treat T. trichiura infection in the early s [ 48 ]. A single dose of 300 mg or 200 mg showed 44.4% or 70.0% CR and 96.4% and 98.3% ERR, respectively, and 100 mg b.i.d. for 2&#;4 days increased the efficacies, 75.0&#;90.0% in CR and 99.3&#;99.6% in ERR [ 48 ]. However, Seo et al. [ 54 ] obtained a poor efficacy of 100 mg mebendazole twice daily for 3 days against T. trichiura infection only as 27.3% CR and 65.5% ERR. Kim [ 57 ] used 2 dosage regimens (total 600 mg), 100 mg b.i.d. for 3 days and 300 mg daily for 2 days, and obtained different results, 36.1% CR and 79.3% ERR for the former and 71.0% CR and 85.4% ERR for the latter regimen. Abadi [ 50 ] reported fairly good results using 500 mg single dose of mebendazole, 77.6% CR and 92.8% ERR. WHO [ 45 ] set 100 mg b.i.d. for 3 days as the recommended dose of mebendazole for treatment of T. trichiura infection with a 500 mg single dose as an alternative regimen. It is of note that Seo et al. [ 58 ] reported a satisfactory effect in long-term control of T. trichiura infection in Korea by repeated MDA using the recommended 3-day regimen of mebendazole, from 40.0% pre-control prevalence to 5.6% post-control prevalence a year later. Recently, however, the 500 mg single dose regimen showed lower efficacies, 27.9% CR and 66.0% ERR in [ 44 ] ( ), 42.1% CR and 66.0% ERR in [ 43 ], and 44.4% CR and 80.7% ERR in [ 42 ]. Moser et al. [ 42 , 43 ] reported a more remarkable (compared with albendazole) temporal decrease of ERR in T. trichiura which was 91.4% in that became 54.7% in . They considered this temporal decrease of the drug efficacy to be in part due to an emergence of drug resistance of worms.

The efficacy of albendazole for Trichuris trichiura was first studied in the early s [ 2 , 51 , 52 , 56 ]. Some of these studies reported quite satisfactory results using 200 mg twice (400 mg in total) with CR of 80.0&#;88.0% and ERR of 98.0&#;99.0% [ 51 , 56 ]. However, some others using 400 mg in a single dose or 200 mg twice reported lower efficacies, 50.0&#;61.5% in CR and 76.5&#;95.0% in ERR [ 2 , 13 , 52 ]. WHO [ 45 ] recommended 400 mg single dose as the recommended dose for moderate T. trichiura infection, but in heavy infections 3-day course (total 1,200 mg) has been recommended. Horton [ 53 ] summarized the effects of albendazole (400 mg single dose) for T. trichiura reported until March worldwide (58 studies) to be highly variable, from 4.9% to 100% (av. 47.7%) in CR and 28.0% to 99.0% (av. 75.4%) in ERR. However, the therapeutic efficacy of albendazole against trichuriasis seemed to be progressively lowered. A study in Lao PDR in reported only 33.3% CR and 67.0% ERR [ 44 ]. In 2 publications in [ 43 ] and [ 42 ], the CRs were reported as 30.7% and 32.1%, and the ERRs were 49.9% and 64.3%, respectively. Moser et al. [ 42 , 43 ] put an emphasis on a temporal decrease of ERR which was 72.6% in and 43.4% in and considered this temporal decrease of albendazole efficacy against T. trichiura to be in part due to an emergence of drug resistance. Chai et al. [ 46 ] tried to control A. lumbricoides and T. trichiura infections among schoolchildren in Myanmar by MDA using a 400 mg single dose of albendazole but difficulties were experienced in short-term control of trichuriasis seemingly because of limited drug efficacy against T. trichiura.

Mebendazole showed poor efficacy for hookworms if used 500 mg only 1 time. Keiser and Utzinger [ 10 ] and Soukhathammavong et al. [ 44 ] reported the CRs of 500 mg single dose of mebendazole to be 15.0% and 17.6% and ERR 0&#;98.0% and 76.3%, respectively. In comparison, 100 mg twice daily for 3 days (total 600 mg), the recommended dose by WHO [ 45 ], showed fairly higher efficacies of 80.0% CR and 41.0&#;100% ERR according to reports from 27 trials [ 10 ]. However, the efficacy of mebendazole was variable depending on the species of hookworms. For example, using the recommended dose of mebendazole, the CR of A. duodenale was 71.4% and the ERR was 97.3% as reported by Seo et al. [ 54 ], whereas the CR of N. americanus was lower 52.0% and the ERR was 91.2% as reported by Sinniah et al. [ 55 ].

The use of albendazole for treatment of hookworm infections in humans, i.e., Ancylostoma duodenale and Necator americanus in most cases, started in the early s [ 2 , 51 , 52 ]. Pene et al. [ 2 , 51 ] reported that the CR and ERR using 400 mg single dose were 80.7&#;94.3% and 97.0%, respectively, whereas Soula and Siopathis [ 52 ] reported lower effects, 74.0% and 97.5%, respectively. Thereafter, until March , at least 68 articles reported the efficacy of albendazole (400 mg single dose; the recommended dose by WHO [ 45 ]) against hookworm infections (A. duodenale or N. americanus), with CR ranging from 33.3 to 100% (av. 77.7%), and ERR from 29.6 to 100% [ 53 ]. The efficacy was markedly different between the species of hookworms and between adults and children age groups. The average CR for A. duodenale was higher (91.8%) than that for N. americanus (75.0%), and those for adults and children in A. duodenale were similar, 91.7% and 90.8%, respectively, whereas those for adults and children in N. americanus were 80.9% and 67.0%, respectively [ 53 ]. These results represent lower efficacy of albendazole in treatment of N. americanus hookworm infections especially in children. Similar efficacies were reported after , for example, Keiser and Utzinger [ 10 ] reported that the CR of albendazole for hookworms using 400 mg single dose was 72.0% and the ERR was 64.0&#;100% ( ), and Moser et al. [ 43 ] reported 79.5% CR and 89.6% ERR.

The effect of mebendazole against intestinal nematodes, including A. lumbricoides, was reported at an earlier time in from schoolchildren in Brazil using the dose of 100 or 200 mg twice daily for 3&#;4 consecutive days or 100 mg daily for 6 days [ 47 ]. The cure rate for ascariasis was 100% [ 47 ]. However, these regimens (repeated doses for 3&#;6 days) were inconvenient especially for MDA. Therefore, reduced single doses were tried by various researchers [ 48 &#; 50 ]. The study using a 200 or 300 mg single dose in Costa Rica reported 93&#;100% cure rates of A. lumbricoides infection and almost 100% ERR [ 48 ]. Another study in South Korea reported that a single dose of 200&#;300 mg revealed 93.8&#;96.7% CR and 98.6&#;99.9% ERR [ 49 ]. A lower dose, 100 mg once, was almost equally effective as 200&#;300 mg, showing 89.7% CR and 98.6% ERR [ 49 ]. On the other hand, a trial using 500 mg single dose of mebendazole was reported to be highly effective for ascariasis with 93.4% CR and 99.0% ERR [ 50 ]. In view of the efficacy and safety, the recommended dose of mebendazole for ascariasis has been set at 500 mg single dose by WHO [ 45 ]. The therapeutic efficacy of mebendazole against A. lumbricoides seems unchanged until recently (); it was reported to be 96.2% in CR and 98.0% in ERR [ 43 ].

Among various species of intestinal nematodes infecting humans, Ascaris lumbricoides is the most highly susceptible parasite species to albendazole and mebendazole [ 1 , 8 &#; 10 , 42 &#; 44 ] ( ). The earliest clinical study in using albendazole (400 mg in a single dose) reported the cure rate (CR) (=egg negative conversion rate; NCR) to be 96%, and the egg reduction rate (ERR) almost 100% [ 2 ]. A reduced dose, i.e., 200 mg in a single dose, was also found to be equally effective against A. lumbricoides infection showing 92.3% CR and 98.3% ERR [ 8 ]. However, viewing from the drug efficacy and safety, the recommended dose of albendazole for A. lumbricoides has been set at 400 mg single dose by World Health Organization (WHO) [ 45 ]. The therapeutic efficacy of albendazole against A. lumbricoides seems unchanged until recently (); it was reported to be 95.7&#;96.5% in CR and 98.5&#;99.7% in ERR [ 42 , 43 ]. Albendazole (400 mg single dose) was shown to be useful for short-term control (4 months) of ascariasis using mass drug administration (MDA) in schoolchildren in Yangon Region, Myanmar [ 46 ].

TISSUE HELMINTHIASES

Visceral, ocular, and neural larva migrans

Human toxocariasis or visceral, ocular, and neural larva migrans are most commonly caused by the larvae of Toxocara canis (dog ascarid) and less commonly Toxocara cati (cat ascarid) [72]. Albendazole was experimentally shown to be effective against the larval stage of T. canis in mice [73]. Subsequently, albendazole began to be used for treatment of human toxocariasis (visceral or ocular larva migrans) with the dosage regimen of 5 mg/kg b.i.d. for 5 days; however, only 6 (31.6%) of 19 patients were clinically cured, and 11 (57.9%) showed excellent or good drug tolerability [74]. In ocular toxocariasis (5 patients involving 7 eyes), treatment with a higher dose for longer days, 800 mg b.i.d. for 14 days, produced good results with no relapse and no side effects [75]. In the United States, the regimen of albendazole to treat visceral larva migrans was set at 800 mg daily for 5 days [76] ( ). However, for neural toxocariasis albendazole should be given 800 mg daily (15 mg/kg for children) for longer duration, 21&#;28 days [77&#;79]. Moreover, in Japan, even an additional second course of 28-day treatment, following the first 28-day course treatment with albendazole (10&#;15 mg/kg daily) and 14 days of drug free, was needed to obtain cure of 192 (78.0%) of 246 patients with larva migrans syndrome [80].

Table 2

DrugDisease & parasiteRegimenEfficacyRemarkReferencesAlbendazoleVisceral larva migrans (Toxocara canis)800 mg/day×5 daysFairly effectiveIn USA[76]800 mg/day×21&#;28 daysFairly effectiveNeural toxocariasis[77&#;79]800 mg/day×14 daysEffectiveOcular toxocariasis[75]Cutaneous larva migrans (Ancylostoma spp.)400 mg/day×5 daysSatisfactory15 of 18 patients[82]400 mg/day×10&#;21 daysSatisfactoryButtock, perianal[83]Anisakiasis400 mg b.i.d.×21 daysSatisfactorySupplementary to endoscopic removal of larvae or surgery[88]Trichinosis800 mg/day×8&#;15 daysEffectiveCombined with methimazole to increase drug absorption[76,98&#;101]Hepatic capillariasis400 mg/day×21&#;100 daysSatisfactoryCombined with steroids[110]Intestinal capillariasis400&#;800 mg/day×10&#;30 daysSatisfactoryAs effective as mebendazole[112&#;114,118]Angiostrongyliasis200&#;1,000 mg/day×7&#;14 daysEffectiveCombined with dexamethasone[124&#;126]Gnathostomiasis400&#;1,200 mg/day×21 daysSatisfactoryCR; 93.9&#;94.1%[133,138]Gongylonemiasis400 mg/day×30 daysEffectiveEsophageal infection[148]Thelaziasis400 mg/day×3 daysRemains to be determinedSupplementary to surgical extraction of worms[152]DracunculiasisPoor drug candidate for this disease--- MebendazoleVisceral larva migrans (Toxocara canis)100&#;200 mg b.i.d.×5 daysEffective-[76]20&#;25 mg/kg/day×21 daysEffective-[81]Cutaneous larva migrans (Ancylostoma spp.)Clinical trial seldom done-Albendazole better than mebendazole[85]Anisakiasis100 mg b.i.d.×3 daysFairly effectiveSupplementary to surgery[92]Trichinosis5 mg/kg/day×10&#;15 daysEffective-[99]200&#;400 mg t.i.d.×3 days, and then 400&#;500 mg t.i.d.×10 daysEffective-[76,100]Hepatic capillariasisClinical trial needed---Intestinal capillariasis200&#;400 mg/day×20&#;30 daysSatisfactoryAs effective as albendazole[115,120]Angiostrongyliasis10 mg/kg/day×14 daysEffectiveSteroid needs to be combined[129]Gnathostomiasis200 mg/day×21 daysEffectiveAfter surgery[142]GongylonemiasisClinical trial needed---ThelaziasisClinical trial needed---DracunculiasisPoor drug candidate for this disease---Open in a separate window

Mebendazole was tried to treat visceral larva migrans. At least 20&#;25 mg/kg daily for 21 days was needed to treat human toxocariasis [81]. However, The Medical Letter [76] recommended 100&#;200 mg b.i.d. for 5 days for human visceral larva migrans due to Toxocara spp.

Cutaneous larva migrans

Cutaneous larva migrans is most commonly caused by the larvae of Ancylostoma brasiliense (dog and cat hookworm) and less commonly Ancylostoma caninum (dog hookworm). Albendazole at the dose of 400 mg daily for 5 days showed fairly good results in 15 of 18 patients with cutaneous larva migrans [82]. However, longer period use of oral albendazole (400 mg daily), for 10&#;21 days, was reported in 5 cases of cutaneous larva migrans over buttocks and perianal regions in children [83]. Topical application of 4% albendazole cream (office-made with Vaseline) on the affected skin lesions of 3 cutaneous larva migrans cases also showed effects in 2 adults and 1 child patient [84].

Mebendazole has seldom been tried to treat cutaneous larva migrans because it seems less efficacious than albendazole. A 47-year-old man having erythematous, serpiginous burrows on both feet and right thigh and buttock received 2 courses of mebendazole therapy (3 days each, drug dosage not described), and 70% resolution of skin lesions was obtained [85]. However, he developed pulmonary infiltrates with Löffler syndrome (shortness of breath, wheezing, and chest discomfort), and was prescribed with albendazole and intravenous hydrocortisone for 5 days and then completely cured [85].

Anisakiasis (anisakidosis)

Human anisakiasis (or anisakidosis) is mainly caused by Anisakis simplex, Anisakis pegreffii, Anisakis physeteris, and Pseudoterranova decipiens, and the treatment of choice is gastroendoscopic removal of the larvae or surgical excision of the affected lesion [86,87]. However, albendazole or mebendazole may be prescribed as a supplementary therapy [9,88&#;90] or in cases where the larvae have penetrated the thickness of the stomach or intestinal wall [91]. The use of albendazole (400 mg b.i.d for 21 days) in human anisakiasis was first reported by Moore et al. [88] which was followed by several workers [89]. However, the use of albendazole alone is controversial regarding its efficacy for treatment of this disease [91].

Mebendazole was rarely tried for treatment of human anisakiasis. Maggi et al. [92] used mebendazole 100 mg b.i.d for 3 days in 2 anisakiasis patients, i.e., mebendazole alone in 1 case and supplementary to surgery in another case. The results were satisfactory in both cases. Moschella et al. [93] used the same dosage of mebendazole for post-operative treatment of a patient with intestinal anisakiasis. Of considerable interest to note is that mebendazole was recently highlighted to be a more effective drug than albendazole and flubendazole in reducing lesion occurrence in experimentally infected rats [94].

Trichinosis

The efficacy of albendazole against Trichinella spiralis infection was first confirmed by McCracken [95] in experimental mice; treatment with 50 mg/kg for 5 consecutive days reduced the number of muscle larvae by 67% compared to controls. However, this efficacy of albendazole was worse than that of mebendazole (at the same dosage regimen) which revealed 96% reduction rate of muscle larvae [95]. The therapeutic usefulness of albendazole for human patients in combination with steroids was investigated during an outbreak of trichinosis in France by Fourestie et al. [96]. The regimen of albendazole was 400 mg daily for 3 days and then 800 mg daily for 15 days. Another study in France reported use of albendazole at the dose of 13±2.6 mg/kg daily for 8 days with satisfactory therapeutic effects with no side effects [97]. Thereafter, the recommended regimen of albendazole for treatment of human trichinosis has been settled at 800 mg (15 mg/kg) daily for 8&#;14 days [76,98] or 10&#;15 days [99,100] Albendazole is poorly absorbed through the intestinal tract especially in humans [3]. Thus, in order to increase the bioavailability of the drug in the plasma and enhance the therapeutic efficacy, trials have been made by co-administration with methimazole [101], using solid dispersion and cyclodextrin complexation techniques [102] or chitosan coated nanostructured lipid carriers [103].

Mebendazole at the dose of 50 mg/kg daily for 8&#;14 days was shown to be effective against migrating larvae of T. spiralis in experimental mice [104]. The clinical trial of mebendazole (1,000 mg daily for 14 days) for human trichinosis was reported in , and no side effects were observed [105]. Use of prolonged (2 courses) and a higher dose of mebendazole was reported in a human patient unresponsive to steroid therapy [106]. In experimental mice, mebendazole showed better effects to kill muscle larvae than albendazole [95]. However, the effect of mebendazole was limited in human trichinosis because it was effective only on newborn larvae in lymph and blood vessels but not on encapsulating larvae in muscle cells [107]. The dosage of mebendazole for trichinosis has now been settled at 5 mg/kg daily for 10&#;15 days [99] or 200&#;400 mg t.i.d. for 3 days followed by 400&#;500 mg t.i.d. for 10 days [76,98,100].

Hepatic capillariasis

Albendazole and mebendazole were tried for treatment of hepatic capillariasis (frequently fatal especially in children), due to Capillaria hepatica, by observing reduction of egg deposition in the liver of experimental mice [108]. Both drugs were found to be effective, although mebendazole appeared to be more useful as the effects could be obtained using dosage regimens within the range recommended for humans; 10 times higher dosage was required for albendazole to obtain the same results [108]. However, clinical trial has been reported only in albendazole but not in mebendazole.

The first clinical use of albendazole (10&#;20 mg/kg daily for 20 days) was reported in a child case with only a limited success, which was followed by thiabendazole (25 mg/kg daily for 27 days) and prednisolone (10 mg daily) therapy with final survival of the patient [109]. Albendazole was again used in 2 patients; 400 mg daily for 21 days and 100 days (in combination with steroids) each, and the results were both satisfactory [110]. Thus, the drug of choice for hepatic capillariasis is currently thiabendazole or albendazole for 21 days [111]. The clinical use of mebendazole for human hepatic capillariasis remains to be tried.

Intestinal capillariasis

Human intestinal capillariasis due to Capillaria philippinensis has been treated with albendazole or mebendazole. In , Cross and Basaca-Sevilla [112] used albendazole (400 mg daily for 10 days) in 16 intestinal capillariasis patients, and 15 were completely cured. One treatment failure case was retreated with mebendazole 400 mg daily for 20 days with success; however, they recommended albendazole as the drug of choice [112]. Thereafter, many workers used albendazole for treatment of this disease, including Lee et al. [113], Hong et al. [114], Bair et al. [115], Soukhathamvong et al. [116], Rana et al. [117], and Sadaow et al. [118]. The dosage regimen of albendazole has been 400&#;800 mg daily for 10&#;30 days.

The use of mebendazole for human intestinal capillariasis seems to be first tried by Alcantara et al. [119] in . The patient experienced an obstinate course of the disease, including 16 episodes in 12 years, and was treated with thiabendazole, mebendazole, and flubendazole. The final treatment with mebendazole (200 mg daily) for a total of 8.5 months resulted in clinical and parasitological cures without further relapses [119]. Thereafter, mebendazole (200&#;400 mg daily for 20&#;30 days) was recommended as the drug of choice for intestinal capillariasis [115,120&#;122]. However, after albendazole was proved to be also effective, both drugs have been recommended as the drug of choice for human intestinal capillariasis by The Medical Letter [76].

Angiostrongyliasis

Use of anthelmintics in eosinophilic meningoencephalitis due to Angiostrongylus cantonensis infection (cerebral angiostrongyliasis in humans) has been controversial. Most patients have a self-limited course and recover completely, and analgesics, corticosteroids, and careful removal of cerebrospinal fluid at frequent intervals can relieve symptoms from increased intracranial pressure [76]. However, Hwang and Chen [123] suggested the usefulness of albendazole for treatment of A. cantonensis infection in children. Thereafter, a combination therapy of albendazole (200&#;1,000 mg daily for 7&#;14 days) with dexamethasone (or prednisolone) effectively treated eosinophilic meningoencephalitis patients [124&#;126]. Federspiel et al. [127] reviewed the literature of 22 A. cantonensis cases reported since , and found that 12 of the 22 cases were treated with albendazole in combination with corticosteroids. Some studies [125,126] agreed that albendazole was useful for reducing the clinical symptoms, including headache. However, others do not recognize the superiority of using albendazole in combination with corticosteroids over corticosteroid treatment alone [127].

Mebendazole, combined with glucocorticosteroids, was reported to be effective in treatment of A. cantonensis infection; it appeared to shorten the course of infection though not the number of relapses [128]. Chotmongkol et al. [129] used mebendazole (10 mg/kg daily for 14 days) in combination with prednisolone in 41 patients, and headache completely disappeared in 37 (90.2%) patients within 14 days of treatment. However, Leone et al. [130] could not continue mebendazole treatment in a patient because of accentuation of the symptoms after the first dose of mebendazole; the patient was switched to steroid therapy. The usefulness of mebendazole for eosinophilic meningoencephalitis remains to be further defined.

In abdominal angiostrongyliasis due to infection with Angiostrongylus costaricensis, anthelmintics such as albendazole and mebendazole have not proven to be efficient, since the worms can cause lesions after their death inside the blood vessels [131].

Gnathostomiasis

Five species of Gnathostoma, including G. spinigerum, G. hispidum, G. doloresi, G. nipponicum, and G. binucleatum, have been reported to infect humans [132]. The first use of albendazole for treatment of human gnathostomiasis was reported in by Chitchang S. in a local journal (Thai) [133]. Subsequently, its usefulness (400&#;800 mg daily for 21 days) was confirmed with 93.9&#;94.1% CR in 100 gnathostomiasis patients in Thailand [133]. Similar results were reported either using albendazole alone (the same regimen) or ivermectin alone (0.2 mg/kg single or double doses) [134&#;137]. Chai et al. [138] used albendazole (1,200 mg daily for 21 days) in combination with ivermectin (0.2 mg/kg single doe) in 38 Korean patients who immigrated to Myanmar with satisfactory results. However, superiority of albendazole alone or ivermectin alone for treatment of human gnathostomiasis has been controversial [139,140]. However, albendazole stimulates the outward migration of the gnathostome larva, thus making it more accessible and possibly amenable to excision [141].

Mebendazole has seldom been used for treatment of human gnathostomiasis. However, in a recent report from Madagascar, a G. spinigerum 3rd-stage larva was surgically extracted from an eye of a woman, and then mebendazole (200 mg daily for 21 days) was prescribed to treat probable further infection by Gnathostoma parasites and also to cure a wide spectrum of intestinal nematode infections [142].

Gongylonemiasis

Human gongylonemiasis, due to Gongylonema pulchrum, occurs on the lips, gums, tongue, and palate eliciting the sensation of a moving worm (s) in the buccal cavity [143]. Removal of the parasite may be curative; however, because of possible additional worms, anthelmintic drugs, including albendazole (400 mg daily for 3 days), have been prescribed [143&#;147]. However, in a patient having esophageal symptoms, this albendazole regimen failed to prevent recurrence, and a prolonged administration of albendazole (400 mg daily for 30 days) was needed to obtain a complete cure [148].

In experimental rabbits, mebendazole (70 mg/kg daily for 3 days) showed 22.8% reduction of worm burdens of G. pulchrum; however, levamisole (8 mg/kg single) revealed a higher reduction of 63.2% [149]. Clinical trials for mebendazole in human patients have been unavailable.

Thelaziasis

Human thelaziasis is mostly due to infection with Thelazia callipaeda and less frequently by Thelazia californiensis [150]. Mechanical removal of worms directly from the eyes of humans or animals is the first treatment of choice [150]. Nonetheless, this does not guarantee complete extraction of all parasites from the eyes; therefore, anti-parasitic medication is sometimes necessary [150]. Moxidectin and milbemycin oxime are the drugs of choice for thelaziasis; but mebendazole (20 mg/kg daily for 3 days) was also shown to be effective for cure of the infection in dogs [151]. In a human patient complaining of foreign body sensation in the right eye, 3 T. callipaeda worms were retrieved, and albendazole (400 mg daily for 3 days) was prescribed for a supplementary purpose; this treatment was repeated 1 more time 2 weeks later [152]. However, the efficacy of albendazole and mebendazole in treating hidden T. callipaeda infection in the eyes remains to be further clarified.

Dracunculiasis

The treatment of dracunculiasis (due to Dracunculus medinensis) is largely dependent upon mechanical removal of worms (winding the emerging worm around a stick) from the subcutaneous tissue [153]. Medical treatment is usually not necessary, and drugs attacking the worm inside the host body may cause anaphylactic reaction due to the death of larvae [153]. However, dracunculiasis typically occurs in remote areas without easy access to medical attention, and anthelmintic drugs may be beneficial for such cases and also in mass, community-based control trials [154]. Nevertheless, albendazole, thiabendazole, metronidazole, ivermectin, and DEC showed no significant effects in managing this disease in animals, thus were poor candidates for clinical trials [153,154].

Cerebral and subcutaneous cysticercosis

Albendazole began to be used for treatment of human neurocysticercosis caused by the metacestode of Taenia solium in by Escobedo et al. [155]. They observed that albendazole (15 mg/kg daily for 30 days) was highly effective for treatment of patients with brain parenchymal cysticercosis; it was also effective in patients who had shown poor therapeutic response to praziquantel [155]. Sotelo et al. [156] recommended starting a course of albendazole (15 mg/kg daily for 30 days) therapy, and 3 months later, if parenchymal cysts are still detected, a course of praziquantel should be tried. Even a shorter course of treatment with albendazole (15 mg/kg daily for 3 days) was as effective as the 30-day course treatment [157]. Currently, the recommended regimen of albendazole for treatment of neurocysticercosis is 15 mg/kg daily for 8 days (7&#;15 days) in combination with steroids if necessary [22,158,159] ( ). Albendazole was also found to be effective for subarachnoid and ventricular cysticercosis [160]. The antiparasitic activity of albendazole is closely related to bioavailability of its active compound, albendazole sulfoxide; in this form, the drug passes through the blood-brain barrier and reaches the central nervous system where it exerts its therapeutic effects [161].

Table 3

DrugDisease & parasiteRegimenEfficacyRemarkReferencesAlbendazoleNeurocysticercosis (metacestode of Taenia solium)15 mg/kg/day×7&#;15 daysEffectiveParenchymal, subarachnoid, and ventricular cysticerci Combined with steroids[22,158,159]Cutaneous cysticercosis (metacestode of Taenia solium)15 mg/kg/day×28 daysSatisfactoryCombined with steroids[163]Cystic echinococcosis (hydatid of Echinococcus granulosus)400 mg b.i.d.×3&#;6 months with 14 days of breakFairly goodCombined with PAIRa[174]Alveolar echinococcosis (hydatid of Echinococcus multilocularis)400 mg b.i.d.×2&#;3 years with 14 days of breakFairly goodMinimum 2&#;3 years, but probably lifelong[174] MebendazoleNeurocysticercosis (metacestode of Taenia solium)Mebendazole plus praziquantel recommended--[164]Cutaneous cysticercosis (metacestode of Taenia solium)Mebendazole plus praziquantel recommended[164]Cystic echinococcosis (hydatid of Echinococcus granulosus)50&#;70 mg/kg/day× 6&#;24 monthsFairly goodLower efficacy than albendazole[172,186]Alveolar echinococcosis (hydatid of Echinococcus multilocularis)45&#;48 mg/kg/day×13 yearsSeemingly goodMay be parasiticidal[189]Open in a separate window

Albendazole (15 mg/kg daily for 30 days) was highly effective against dermal and cutaneous cysticercosis; most subcutaneous nodules disappeared or were markedly reduced in size [162]. Almost the same dose of albendazole (15 mg/kg daily for 28 days), in combination with steroids tapered over a period of 28 days, brought about complete recovery of ptosis due to extraocular muscle cysticercosis in the right eye [163]. However, it is of note that using corticosteroids in experimental cysticercosis by Taenia crassiceps negatively affected the efficacy of cysticidal activity of albendazole [164].

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Mebendazole was assessed for use in treatment of cysticercosis in humans [165] and animals [166]. Some cures were documented but the results were equivocal and temporary inhibition of cyst growth or absence of a detectable effect were the more likely sequelae [165]. Thus, mebendazole alone is not recommended for human cysticercosis. However, mebendazole in combination with praziquantel has been proposed to be a promising alternative for treatment of human or animal cysticercosis [167].

Echinococcosis

The primary choice of treatment for human cystic echinococcosis (=cystic hydatidosis) due to Echinococcus granulosus infection is surgery unless the cyst is multiple or inoperable [168]. Chemotherapy with anthelmintics, including albendazole, mebendazole, praziquantel, or nitazoxanide, is an alternative to surgery and for a pre-operative or post-operative treatment, as well as management of inoperable alveolar echinococcosis due to Echinococcus multilocularis by long-term chemotherapy [168,169]. Albendazole has been used since [170,171]. A great number of case studies were performed, and valuable results were obtained [7,168,169,172&#;175]. The dosage regimen of albendazole in the first 2 pilot studies was 10&#;14 mg/kg daily for 2&#;39 days [170] and 10 mg/kg daily for 5&#;8 days [171]. Currently the recommended dose is 400 mg twice daily for 3&#;6 months with 14 days of break for cystic echinococcosis and 400 mg twice daily for minimum 2&#;3 years for alveolar echinococcosis [174]. In the meantime, combined albendazole and praziquantel treatment was tried with good results [176,177]. However, because of toxicity issues the use of this drug combination needs further research [175]. On the other hand, percutaneous drainage method was introduced as an alternative therapy for patients with hepatic hydatid cysts who cannot undergo surgery [175,178&#;182]. The procedure consists of puncture (P), aspiration (A), injection of scolicidal agent (I), and reaspiration (R), so-called PAIR, and this method (PAIR) in combination with albendazole or mebendazole has been evaluated as a highly useful strategy for managing cystic hydatidosis [174,175,181,182]. Now, 4 treatment options for human cystic echinococcosis have been proposed; 1) surgery, 2) PAIR, 3) chemotherapy with albendazole, mebendazole or other anthelmintics, and 4) watch-and-wait for inactive or silent cysts [169].

Mebendazole was first shown to be effective in killing hydatid cysts (E. granulosus) in experimental mice [183]. Human cystic echinococcosis began to be treated with mebendazole (400&#;600 mg t.i.d. for 21&#;30 days), and regression of the cysts and clinical improvement were observed [184]. However, it often remained speculative whether the regressed cysts were completely destroyed [185]. Higher dose (50&#;70 mg/kg daily) of mebendazole with longer duration (6&#;24 months) was tried in human cystic echinococcosis, and its efficacy was compared with that of albendazole (10 mg/kg daily for 5.5 months) [172]. The treatment was partially or completely successful in 16 (57.1%) of 28 patients treated with mebendazole and in 20 (87.0%) of 23 patients treated with albendazole [172]. Other studies also supported superiority of albendazole over mebendazole for medical treatment of human cystic hydatid disease [169]. However, in children, mebendazole (50 mg/kg daily for 9&#;18 months) was appropriate to use due to the lack of side effects, high therapeutic effects, and low risk of recurrence [186]. In addition, a combination of mebendazole (3,000 mg daily for 30 days) with praziquantel (1,800 mg daily for 15 days) with variable resting periods was suggested to be a good pharmacological alternative in the medical management of cystic echinococcosis [187]. The regimen of mebendazole in human cystic echinococcosis was studied by Vutova et al. [188]; it was concluded that the CR was increased both with dosage (from 30 to 70 mg/kg daily) and duration (from 6 to 24 months). PAIR plus pre- or post-operative mebendazole therapy brought about greater clinical and parasitological efficacy compared with surgery alone [168,181,182]. In alveolar echinococcosis, long-term mebendazole therapy (45&#;48 mg/kg daily for 13 years) was suggested to have a good effect [189].

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Single&#;dose of albendazole, mebendazole, and ivermectin all appeared effective against Ascaris lumbricoides infection, yielding high parasitological cure and large reductions in eggs excreted, with no differences detected between them. The drugs appear to be safe to treat children and adults with confirmed Ascaris infection. There is little to choose between drugs and regimens in terms of cure or adverse events.

No included trials reported complication or serious adverse events. Other adverse events were apparently similar among the compared anthelmintic groups (moderate&#; to low&#;certainty evidence). The most commonly reported other adverse events were nausea, vomiting, abdominal pain, diarrhoea, headache, and fever.

The egg reduction rate (ERR) measured up to 60 days after the treatment was high in all treated groups, regardless of the anthelmintic used (range 96% to 100%). It was not possible to evaluate parasitological cure by classes of infection intensity.

Across all the studies, failure after single dose of albendazole ranged from 0.0% to 30.3%, mebendazole from 0.0% to 22.2%, and ivermectin from 0.0% to 21.6%.

Single dose of albendazole (four trials), mebendazole (three trials) or ivermectin (one trial) was compared to placebo. Parasitological cure at 14 to 60 days was high in all the studies (illustrative cure of 93.0% in the anthelmintic group and 16.1% in the placebo group; RR 6.29, 95% CI 3.91 to 10.12; 8 trials, participants; moderate&#;certainty evidence). Single dose of albendazole is as effective as multiple doses of albendazole (illustrative cure of 93.2% with single dose, 94.3% with multiple doses; RR 0.98, 95% CI 0.92 to 1.05; 3 trials, 307 participants; high&#;certainty evidence); or as single dose of mebendazole (illustrative cure of 98.0% with albendazole, 96.9% with mebendazole; RR 1.01, 95% CI 1.00 to 1.02; 6 trials, participants; high&#;certainty evidence). Studies did not detect a difference between a single dose of albendazole and a single dose of ivermectin (cure rates of 87.8% with albendazole, 90.2% with ivermectin; RR 0.99, 95% CI 0.91 to 1.08; 3 trials, 519 participants; moderate&#;certainty evidence).

We included 30 parallel&#;group RCTs, which enrolled participants from 17 countries across Africa, Asia, Central America and the Caribbean, and South America. Participants were from 28 days to 82 years of age, recruited from school, communities, and health facilities. Twenty studies were funded or co&#;funded by manufacturers, while 10 studies were independent of manufacturer funding. Twenty&#;two trials had a high risk of bias for one or two domains (blinding, incomplete outcome data, selective reporting).

Two review authors independently assessed studies for inclusion, assessed risk of bias, and extracted data from the included trials. A third review author checked the quality of data extraction. We used the Cochrane 'Risk of bias' assessment tool to determine the risk of bias in included trials. We used risk ratios (RRs) with 95% confidence intervals (CIs) to compare dichotomous outcomes in treatment and control groups. We used the fixed&#;effect model for studies with low heterogeneity and the random&#;effects model for studies with moderate to high heterogeneity. We assessed the certainty of the evidence using the GRADE approach. We used the control rate average to provide illustrative cure rates in the comparison groups.

Ascaris lumbricoides is a common infection, and mainly affects children living in low&#;income areas. Water and sanitation improvement, health education, and drug treatment may help break the cycle of transmission, and effective drugs will reduce morbidity.

No difference in ascariasis cure was found in comparisons between single dose albendazole with single doses of either mebendazole or ivermectin; and no difference was found between single dose albendazole compared with giving multiple doses.

We included 30 randomized controlled trials (clinical studies where people are randomly put into one of two or more treatment groups), enrolling children and adults aged from 28 days to 82 years, with Ascaris infection. Twenty studies were funded or co&#;funded by manufacturers (which may introduce bias), while 10 were independent of manufacturer funding.

Ascaris lumbricoides, also known as roundworm, is a soil&#;transmitted worm that can infect people. Ascariasis is common worldwide and mainly affects children living in low&#;income areas. Interventions against ascariasis include water and sanitation improvement, health education, and medicine treatment for infected individuals. Treatment with medications removes adult worms from the gastrointestinal tract reducing morbidity (illness) and infection transmission. Although many medicines exist to treat people who have worms (anthelmintic drugs), the most effective regimen and the optimal doses are not well known. We assessed studies that compared the use of anthelmintic medications in adults and children, as a single or a combined therapy, and in single or multiple dose regimens.

We aimed to compare the effect of different medications for treating people with Ascaris infection. Albendazole and mebendazole are most commonly used to treat ascariasis. Ivermectin can also be used. We wanted to know if there was anything to choose between these drugs for eradicating the worms and their eggs in stool samples. We included 30 relevant studies.

Background

Ascaris lumbricoides, also known as roundworm, is a soil&#;transmitted helminth (STH) that infects humans and animals. It is common worldwide and affects mainly tropical and subtropical areas, such as sub&#;Saharan Africa and Southeast Asia (Bethony ; WHO ). The most affected groups are preschool&#; and school&#;age children living in low&#;income areas (Xu ). A modelling study showed that the prevalence of A lumbricoides declined in some parts of the world after , probably as a result of improvements in living conditions and deworming programmes (Pullan ). However, ascariasis remains one of the most prevalent diseases affecting around 738 million to 872 million people worldwide (GBD ).

A lumbricoides infection rarely causes direct mortality, but it contributes to chronic lifetime morbidity. The morbidity attributable to Ascaris infection is difficult to measure considering the non&#;specificity of clinical manifestation (Campbell ; Pullan ). Complications related to Ascaris infection may cause up to 60,000 deaths annually (WHO ).

Ascariasis is transmitted through the faecal&#;oral route. Infection occurs when embryonated eggs that contaminate food, utensils, or hands are ingested. The eggs hatch in the small intestine, releasing the larvae that pass through the intestinal wall and migrate through the liver and heart, up to the lungs. In the lung passage, the larvae are expectorated and swallowed, passing through the gastrointestinal tract until they arrive at the small intestine, where they mature into adult worms and produce new eggs which are expelled with faeces contaminating the environment (CDC ; WHO ; WHO ). Reinfection occurs only when contaminated eggs are ingested, since these parasites do not multiply in the human host (WHO ). The distribution of A lumbricoides in the community can be either aggregated or over dispersed, with most people who are infected harbouring few worms, and a small proportion of people who are infected harbouring a very high number of worms (Holland ).

The relationship between A lumbricoides infection and socioeconomic variables is intense, as STH infections are linked to a lack of sanitation and poverty (Stepek ; WHO ). Other factors such as unhygienic housing conditions, precarious health care, and poor educational or financial resources result in difficulties in ascariasis management, especially among economically disadvantaged groups (Bethony ; WHO ; WHO ; WHO ; WHO ).

Description of the intervention

Interventions against worm infection include deworming using anthelmintic drugs, water and sanitation improvement, and health education. The WHO recommends three public health drug treatment policies (WHO ; WHO a).

• Selective: individual deworming based on a diagnosis of infection.

• Targeted: group deworming where a specific risk group is treated without prior diagnosis.

• Universal: population deworming in which the whole community is treated irrespective of infection status.

The WHO considers the target groups for drug treatment to be preschool&#;age children (aged between one and five years), school&#;age children (aged between six and 15 years), women of childbearing age including pregnant women in the second and third trimesters and breastfeeding women, and adults in certain high&#;risk occupations (such as tea&#;pickers and miners).

The recommended frequency of treatment is once per year for low&#;risk communities with between 20% and 50% infection prevalence, or twice per year for high&#;risk communities with more than 50% infection prevalence (WHO ). Infections of heavy intensity are absent when the prevalence of any STH infection is less than 20% (Montresor ). However, the advantages to recommend universal (also called mass or whole community) deworming or targeted deworming for STHs is still controversial. One systematic review and meta&#;analysis compared the effect of universal and targeted anthelmintic delivery strategies on STH prevalence in school&#;aged children (Clarke ). The results of this meta&#;analysis suggest that universal deworming programmes led to a greater reduction in the prevalence of STHs rather than targeted strategy (Clarke ). According to another systematic review and meta&#;analysis, treating children known to have worm infection may achieve nutritional benefits for the individual. However, universal treatment seems to have little or no effect on haemoglobin levels, nutritional status, school performance, or survival rates among children in endemic area (Taylor&#;Robinson ).

Anthelmintic drugs for treating ascariasis

The current WHO Model List of Essential Medicine for treating intestinal helminths includes seven drugs: albendazole, mebendazole, levamisole, ivermectin, niclosamide, praziquantel, and pyrantel (WHO b). The benzimidazoles drugs (i.e. albendazole and mebendazole), are used to treat a variety of parasitic infestations by interfering with the parasitic worm microtubular system (Utzinger ). They are considered the mainstay drugs for roundworm and hookworm treatment. They are low cost, safe, easily administered, and children do not need to be weighed. Dosage is the same for children and adults. Albendazole 400 mg once a day and mebendazole 100 mg orally twice daily for three days or 500 mg orally once are given.

The accumulated scientific knowledge shows high efficacy, resulting in large&#;scale use of these drugs for treatment and preventive chemotherapy (Bennett ; Keiser ). Albendazole and mebendazole are donated to national ministries of health through WHO in endemic countries for the treatment of school&#;age children (WHO ; WHO a). Single&#;dose albendazole achieves high cure rates againstA lumbricoides infection. However, there are differences in the cure rates obtained among trials (Venkatesan ; Vercruysse a).

Mebendazole is an equivalent alternative to albendazole and may cause the same adverse effects, such as transient gastrointestinal discomfort, headache, and leukopenia. Levamisole and pyrantel pamoate act as nicotinic acetylcholine receptor agonists (Utzinger ). Levamisole has been studied less intensively, and the availability of this drug is limited, but it is currently considered a safe and effective drug. In mass treatment, it showed significant differences pre&#; and post&#;treatment egg count values (Asaolu ). Pyrantel pamoate is cited in the WHO Model List of Essential Medicine for treating intestinal helminths (WHO b). It is considered an effective single&#;dose drug for treating ascariasis in one systematic review and meta&#;analysis (Keiser ). Ivermectin is most commonly used to treat lymphatic filariasis, onchocerciasis, loiasis, and strongyloidiasis. It is also moderately effective against Trichuris trichiura and is approved for treating human ascariasis. It causes paralysis of adult worms and seems to be effective. Piperazine citrate acts by paralyzing the worms, which aids expulsion from the infected person's body (del Castillo ). However, it is now being withdrawn from the market as other alternative drugs are less toxic and more efficacious. Nitazoxanide is a new antiprotozoal drug reported as an effective choice against a broad range of parasites, including A lumbricoides (Galvan&#;Ramirez ). This drug has been listed as a potential candidate for human&#;soil transmitted helminthiasis and further research has been suggested (Diaz ). Anthelmintic drugs not registered for treating ascaris but occasionally compared with these drugs are praziquantel and diethylcarbamazine (Long ; WHO ).

How the intervention might work

Ascariasis causes a high disease burden worldwide. Health education, access to good&#;quality water, and improvements in basic sanitation are crucial to reduce the number of people infected globally. Drug treatment for infected individuals, in combination with other public health measures, is necessary to break the cycle of transmission (Bethony ; WHO ). Infected individuals should be treated with anthelmintic drugs to remove adult worms from the gastrointestinal tract aiming to reduce morbidity and infection transmission (Bethony ). In preventive chemotherapy programmes, the purpose of anthelmintics administration is to control morbidity by maintaining the intensity of the infection low (WHO ).

Some randomized trials suggest that poor cognitive performance, malnutrition, and anaemia may be potentially reversible following treatment with anthelmintic drugs (Hall ; Stepek ). Even when a person has concomitant infections, such as hookworm, T trichiura, or Schistosoma haematobium infection, treatment may improve nutritional status (Stephenson ). One systematic review suggested that selective deworming probably increases weight gain (low&#;quality evidence) and may increase haemoglobin in children confirmed to have worms based on screening. According to this review there is limited evidence of other benefits on selective deworming (Taylor&#;Robinson ).

shows a logic diagram of relationship between anthelmintic use and expected outcomes.

Open in a separate window

Why it is important to do this review

Ascariasis remains a neglected disease despite its global distribution and the high number of infected individuals. It is still one of the most prevalent STH in the world. A lumbricoides, like other helminth infections, can affect the immune system and alter susceptibility to other parasitic diseases, such as malaria. The potential interaction between STH and malaria is complex. Previous studies suggest that large&#;scale deworming programmes can have a protective effect on malaria morbidity in children (Stelekati ). One systematic review and meta&#;analysis suggested that STH infection is associated with an increased prevalence and density of asymptomatic/uncomplicated Plasmodium falciparum infection but with a decreased occurrence of anaemia (Degarege ).

The main goals of deworming programmes are to reduce the number of people who have heavy infections; reduce environmental contamination and risk of infection for other people; reduce micronutrient loss (e.g. iron loss through intestinal bleeding in hookworm infection); and improve nutritional status, cognitive functions, and learning abilities (WHO ).

Some specialists believe that wide&#;scale administration of anthelmintic drugs will exert increasing drug pressure on parasite populations and favour parasite genotypes resistant to anthelmintic drugs (Vercruysse a). Occurrence of resistance to anthelmintic drugs in nematode populations has been described in veterinary medicine. It highlights the potential for selecting drug&#;resistant worms when chemotherapy programmes are widely adopted (Wolstenholme ). For example, reduction in the efficacy of mebendazole compared with historical controls has been documented in studies in Vietnam (Flohr ).

The WHO has highlighted the need to closely monitor anthelmintic drug efficacy (Vercruysse a). Currently, there have been few research&#;based studies about anthelmintic drugs, a very limited number of drugs that do not meet all needs in terms of efficacy, and there are no new anthelmintic drugs in late&#;stage development (Geary ).

One network meta&#;analysis evaluated the efficacy of mebendazole, albendazole, levamisole, and pyrantel pamoate against A lumbricoides, hookworms and T trichiura. It included 55 randomized controlled trials (RCTs) to assess the cure rate and 46 RCTs to assess the egg reduction rates (ERR), with a single&#;dose of anthelmintic drugs (Moser b). In this network meta&#;analysis, all drugs presented high efficacy against Ascaris.

Although using different methodological approaches, these two systematic reviews published with an interval of about 10 years (Keiser ; Moser b) focus on the same anthelmintic drugs. Another meta&#;analysis using individual patient data analysis evaluated the efficacy and safety of co&#;administered ivermectin plus albendazole for treating STH. According to this systematic review, the coadministration resulted in no benefit on cure and ERRs over albendazole alone for A lumbricoides (Palmeirim b).

Some anthelmintic drugs, for example nitazoxanide and ivermectin, potentially effective againstA lumbricoides, have not been evaluated in previous systematic reviews. Although many anthelmintic drugs exist, the most effective regimen and the optimal doses to treat ascariasis are not well known. In this sense, further systematic reviews are necessary to evaluate efficacy and safety of these drugs.

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