See also Benzimidazoles

General information

The benzimidazole antihelminthic drugs albendazole and mebendazole (qv) are commonly used to treat soil-transmitted helminth infections, such as gastrointestinal roundworms, hydatid disease, neurocysticercosis, larva migrans cutanea, and strongyloidiasis [ ]. They bind to nematode β tubulin and inhibit parasite microtubule polymerization, which causes death of adult worms after a few days. Although both albendazole and mebendazole are broad-spectrum antihelminthic drugs, their use differs substantially in clinical practice. Both are effective against ascariasis in a single dose. In hookworm infections, however, a single dose of mebendazole is associated with a low cure rate and albendazole is more effective. Conversely, a single dose of albendazole is not effective in many cases of trichuriasis. For both trichuriasis and hookworm infection, several doses of benzimidazoles are commonly needed. Provided that an adequate concentration is attained within the cyst, it is scolicidal. In high doses given for prolonged periods or cyclically, it is effective in echinococcosis, in which it is given in a dosage of 10 mg/kg/day for 4 weeks, repeated in six cycles with 2-week rest periods between each cycle, although even with this high dose only about one-third of patients enjoy a complete cure, some 70% having a partial response. Albendazole is also active against Pneumocystis jirovecii , and is effective in prophylaxis and treatment in immunosuppressed mice [ ]. In hydatid disease a combination of albendazole and praziquantel is effective when either agent has failed when used alone [ ].

Another important difference between albendazole and mebendazole is that mebendazole is poorly absorbed from the gastrointestinal tract. For this reason the therapeutic action is largely directed at intraluminal (adult) worms. Albendazole is better absorbed, especially when it is taken with a fatty meal. It is metabolized in the liver to a sulfoxide derivative, which is highly distributed to the tissues. It is therefore used to treat disorders caused by tissue-migrating larvae, such as visceral larva migrans caused by Toxocara canis . Systemic adverse effects, such as those on the liver and bone marrow, are usually rare with benzimidazoles in the doses used to treat soil-transmitted helminth infections. However, transient abdominal pain, diarrhea, nausea, dizziness, and headache can occur. Since deworming programmes in endemic regions clearly improve child health and education as well as reducing the burden of disease attributed to soil-transmitted helminths, the use of these drugs is not limited to treatment of symptomatic infections, but also for prevention by mass deworming programmes of morbidity in children living in endemic areas. Concerns about the sustainability of periodic deworming with benzimidazoles and the emergence of resistance have prompted efforts to develop and test new control tools (such as plant cysteine proteinases from various sources of latex-bearing plants and fruits).

Drug studies

Observational studies

Ankylostomiasis

Albendazole has been used in the treatment of human hookworm and trichuriasis. In a mass-treatment report from Western Australia 295 individuals in a remote rural area were treated with albendazole 400 mg/day for 5 days because of possible Giardia lamblia and hookworm infections [ ]. The 37% prevalence of Giardia fell to 12% between days 6 and 9, but rose again to 28% between days 18 and 30. The effect on hookworms ( Ankylostoma duodenale ) was more pronounced and more sustained with a reduction of the pretreatment prevalence of hookworm infections from 76% before treatment to 0% after 3–4 weeks. The tolerability of the drug was judged to be excellent by 89%, good by 1%, and moderately good by 1%, while 9% gave no response. Adverse effects were reported by five individuals and consisted of mild abdominal pain (n = 2), mild or moderate diarrhea (n = 2), moderate fever (n = 1), and weakness (n = 1).

Ascariasis

The efficacy of 2 years of mass chemotherapy against ascariasis has been evaluated in Iran [ ]. A single dose of albendazole 400 mg was given at 3-month intervals for 2 years to every person, except children under 2 years of age and pregnant women. After 2 years of treatment the prevalences, based on 2667 post-treatment samples, had fallen ( Table 1 ). There were no adverse effects of mass treatment with albendazole.

Table 1
Changes in prevalences of helminthic infections in patients treated with albendazole [ ]
Helminth Number (%) of positive tests before treatment (n = 3098) Number (%) of positive tests after treatment (n = 2667)
Ascaris lumbricoides 1198 (39%) 196 (7.4%)
Trichuris trichiura 22 (0.7%) 5 (0.2%)
Hymenolepis nana 63 (2%) 49 (1.8%)

Echinococcosis

Hydatid disease is a common zoonosis caused by the larval cysts of Echinococcus granulosus . Hydatid cysts most commonly form in the liver, but can occur in any organ. The management and operative complications in 70 patients with hydatid disease aged 10–78 years have been studied retrospectively to assess the impact of albendazole and praziquantel compared with surgery [ ]. In all, 39 patients received albendazole and praziquantel in combination and 19 received albendazole alone; none was treated with praziquantel alone. The combined use of albendazole and praziquantel preoperatively significantly reduced the number of cysts that contained viable protoscolices. During the 12-year follow-up period an initial 3 months of drug treatment (albendazole throughout and praziquantel for 2 weeks), re-assessment, followed by either surgery or continuation with chemotherapy was found to be a rational treatment algorithm. In 11 patients albendazole, given for a median of 3 months at a dose of 400 mg bd, had adverse effects: five patients developed nausea and six had abnormal liver function tests. Therapy was withdrawn in two patients owing to altered liver function.

The efficacy of albendazole emulsion has been studied in 212 patients with hydatid disease of the liver, aged 4–82 years [ ]. Two regimens of albendazole were given for a variable period (3 months to more than 1 year); 67 adults received albendazole 10 mg/kg/day and 145 adults received 12.5 mg/kg/day. The overall cure rate was 75%. In the follow-up study the recurrence rate was 10%. The highest cure rate was observed in those who received albendazole 12.5 mg/kg/day for 9 months. At the start of therapy about 15% of the patients had mild pruritus, rash, and transient gastric pain, which resolved without specific therapy. Two patients had alopecia. There were frequent rises in serum transaminase activities in both groups but not to above 30–50 IU/l, except in six patients, who had values above 200 IU/l. In two patients albendazole was withdrawn because of vomiting. In one patient who took 12.5 mg/kg/day severe adverse effects, such as anorexia, jaundice, anemia, edema, and hypoproteinemia, developed, necessitating withdrawal. Reintroduction of albendazole 10 mg/kg/day was uneventful.

The use of albendazole and mebendazole in patients with hydatidosis has been evaluated in 448 patients with E. granulosis hydatid cysts who received continuous treatment with albendazole 10–12 mg/kg/day for 3–6 months daily orally in a total dose of (323 patients) twice or mebendazole 50 mg/kg/day [ ]. At the end of treatment, 82% of the cysts treated with albendazole and 56% of the cysts treated with mebendazole showed degenerative changes. During long-term follow-up 25% of these cysts showed relapse, which took place within 2 years in 78% of cases. Further treatment with albendazole induced degenerative changes in over 90% of the relapsed cysts, without induction of more frequent or more severe adverse effects, as observed during the first treatment period. Adverse effects during the first treatment period consisted of raised transaminases with albendazole (67 of 323 patients) and mebendazole (16 of 125 patients), and abdominal pain in 12% and 11% respectively. With both drugs, occasional patients experienced headache, abdominal distension, vertigo, urticaria, jaundice, thrombocytopenia, fever, or dyspepsia, but most of these are known manifestations of Echinococcus infection. Six of 323 patients taking albendazole withdrew because of adverse effects compared with eight of 125 patients taking mebendazole. It appears that albendazole is more effective than mebendazole in the treatment of hydatid cysts caused by E. granulosis and that both the intensity and frequency of the usually mild adverse effects are comparable.

Filariasis

Treatment of patients with high Loa loa microfilaremia is sometimes complicated by an encephalopathy, suggested to be related to a rapid killing of large number of Loa loa microfilariae. If the Loa loa microfilarial count could be reduced more slowly, before ivermectin is distributed, ivermectin-related encephalopathy might be prevented. In 125 patients with Loa loa microfilariasis the effect of albendazole (800 mg/day for three consecutive days) or multivitamin tablets on Loa loa microfilarial load and the occurrence of encephalopathy were studied [ ]. Loa loa microfilarial loads were followed for 9 months. There was no significant change in the overall microfilarial loads among those treated with albendazole, although the loads in patients with more than 8000 microfilariae/ml tended to fall more progressively during the first 3 months of follow-up. There were no cases of encephalopathy. The main adverse effects reported were itching (in eight patients taking albendazole and seven taking multivitamins), abdominal pain (two taking albendazole), and diarrhea (one taking albendazole, two taking multivitamins); overall analysis showed no significant difference in these events between the groups. Albendazole was associated with modest but significantly raised plasma transaminase activities.

Neurocysticercosis

In a report on the use of albendazole 15 mg/kg/day in two divided doses for 14 days in the treatment of persistent neurocysticercosis [ ], adverse reactions were monitored in 43 patients with seizures and a solitary cysticercal cyst, who had not been treated before. In all patients CT scans confirmed the presence of a solitary cyst less than 2 cm in diameter. Antiepileptic treatment was continued. In seven patients dexamethasone 8 mg/day in four divided doses was given for the first 5–7 days after the start of treatment. Follow-up CT scans at 4–10 weeks after the start of treatment showed responses in 20 patients, with complete disappearance in seven patients and a reduction to 50% of the pretreatment size in the other 13. There were adverse effects in 15 patients, with a maximum on the fifth day after the start of treatment. Six patients had severe headaches, 11 had partial seizures, and 2 had epileptic seizures and severe postictal hemiparesis that persisted for a week or more. Because of these serious adverse effects treatment was discontinued in seven patients and dexamethasone was added in those patients who were not already taking it, although its use proved questionable. Adverse effects were seen in three of seven patients who took prophylactic steroid therapy and in 12 of 36 patients who did not.

Albendazole was effective in neurocysticercosis in an optimal dosage of 15 mg/kg/day divided in two doses every 12 hours for 8 days [ ]. It was generally well tolerated, although several patients had adverse reactions during the first few days after the start of treatment, consisting of headache, vomiting, and exacerbation of neurological symptoms caused by an inflammatory reaction to antigens from degenerating cysts, necessitating the concomitant use of glucocorticoids. In very large cysticerci, or cysticerci located in risky areas like the brainstem, these reactions may rarely be life-threatening.

Protozoal infections

The efficacy of albendazole 800 mg bd for 14 days for persistent diarrhea due to cryptosporidiosis (n = 10), isosporiasis (n = 54), or microsporidiosis (n = 23) has been studied in 153 HIV-positive patients [ ]. Albendazole reduced the burden of protozoal infection and promoted mucosal recovery in 87 patients who had a complete clinical response. Two patients reported nausea and vomiting. One patient developed leukopenia (1.9 × 10 9 /l) after treatment and four patients developed thrombocytopenia (51–98 × 10 9 /l).

Toxocariasis

The efficacy of albendazole plus prednisolone has been studied in five patients aged 11–72 years with ocular toxocariasis [ ]. All had uveitis and retinochoroidal granulomas. Their symptoms had persisted for a mean of 14 months (range 3 days to 24 months). The adults were treated with albendazole 800 mg bd for 2 weeks plus prednisolone starting at 1.5 mg/kg/day tapering over 3 months. The children were treated with 400 mg bd for 2 weeks plus prednisolone 1.0 mg/kg/day. All tolerated the therapy well without adverse effects. In particular, there were no significant hypersensitivity reactions to dying Toxocara larvae. The uveitis resolved in all cases and there were no relapses. After treatment, all the granulomas had disappeared, leaving heavily pigmented chorioretinal scars without loss of vision.

Comparative studies

Ascariasis

See below under Trichuriasis

Echinococcosis

Human hydatid disease is caused by the metacestode of Echinococcus granulosus . There are few data on the treatment of pulmonary hydatid disease in children. Mebendazole and albendazole have been evaluated in 82 children with a total of 102 pulmonary hydatid cysts [ ]. Mebendazole was given as 50 mg/kg/day in three divided doses and albendazole was given as 10 mg/kg/day in two divided doses continuously or in cycles consisting of 4 weeks of treatment alternating with 2-week drug-free intervals. The duration of treatment was 1–36 months. While taking benzimidazoles eight patients had raised liver enzymes, three had rash, and one had neutropenia; all were reversible on withdrawal.

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