Benzimidazoles

Ankylostomiasis

In 13 British soldiers with cutaneous larva migrans after a 2-week jungle training exercise in Belize the median incubation period was 10 (range 4–38) days; in 12 there were skin lesions on the calves or shins, and only two had foot or ankle lesions [ ]. Ten received oral thiabendazole, one oral mebendazole, one oral albendazole, and one topical thiabendazole. All those treated with oral thiabendazole complained of unpleasant reactions, predominantly nausea, vomiting, and dizziness. The one patient treated with topical thiabendazole returned with a new lesion 12 months later. He was then treated with systemic albendazole, with rapid resolution of symptoms. A 45-year-old woman developed larva migrans 20 days after lying on a beach in Singapore and was treated with thiabendazole 50 mg/kg in two doses for one day; she had no adverse reactions [ ].

The treatment of cutaneous larva migrans in 56 Italian patients aged 2–60 years has been retrospectively reviewed [ ]. All 13 patients treated with cryotherapy reported that it was painful, but none had recurrent disease or scarring. A further six patients were treated with oral thiabendazole 25–50 mg/kg/day for 2 days, and one had both thiabendazole and cryotherapy. In all cases there was regression of itching and skin lesions, but they had nausea, diarrhea, and dizziness while taking oral thiabendazole. No adverse reactions were reported in 36 patients who were treated with albendazole 400 mg/day for 3 days (two were also treated with cryotherapy). Despite the low dose, larval migration was stopped in 1–2 days. Although a prompt and definitive cure was achieved in all 56 patients, albendazole was considered the treatment of choice given its minimal adverse reactions. Until about 1980, surgery was the only treatment available for larval infections with Echinococcus granulosus or Echinococcus multilocularis . However, cysts are not always amenable to surgical removal, and operation is associated with the risk of rupture, leading to anaphylactic shock and re-infection; a proportion of cases are in any case not fit enough for surgery. The benzimidazoles have been used in varying high dosages over extended periods, initially to treat inoperable hydatid cysts and before surgery in attempts to sterilize cysts.

Echinococcosis

The epidemiology, clinical presentation, and treatment of alveolar echinococcosis of the liver have been described in French patients followed between 1972 and 1993 [ ]. From 1982 benzimidazoles were used. Of 117 patients, 72 took either albendazole or mebendazole for 4–134 months. The most common adverse effect was an increase in alanine transaminase activity to more than five times the top of the reference range (in six patients taking albendazole and in three taking mebendazole). Neutropenia (leukocyte count below 1.0 × 10 ⁹ /l) occurred in two patients taking albendazole. Alopecia occurred in four patients taking mebendazole. Minor adverse reactions to albendazole included malaise, anorexia, and digestive intolerance in one patient each. In 13 patients treatment had to be withdrawn because of adverse reactions (n = 10) or non-adherence to therapy (n = 3).

While mebendazole is used in continuous therapy of human alveolar echinococcosis, albendazole has been used in cyclic treatment. One treatment cycle consists of 28 days followed by a washout phase of 14 days without treatment, intended to reduce toxicity. Whether albendazole can also be used on a continuous basis has recently been studied in an open observational study in 35 patients with alveolar echinococcosis (in seven of 35 patients a curative operation was performed) [ ]. The outcome (lack of progression) was compared with the results obtained with continuous treatment with mebendazole or cyclic albendazole. Albendazole 10–15 mg/kg/day and mebendazole 40–50 mg/kg/day were equally effective. Seven patients were treated with continuous albendazole for an average of 28 (range 13–50) months. All patients taking continuous albendazole had stable or even regressive disease. The continuous dosing regimen was well tolerated without increased toxicity or higher rates of adverse reactions. Therefore, continuous dosing of albendazole is a promising alternative in cases of inoperable or progressive alveolar echinococcosis.

Prolonged cyclic albendazole treatment (for more than 9 years) was safe and effective in a patient with isolated cervical spine echinococcosis in whom surgery was performed without preoperative antihelminthic therapy because of a delay in diagnosis [ ].

There have been several studies of the efficacy of albendazole in preventing recurrences of hydatid disease and cyst fluid spillage complications after surgery. In one Turkish study 22 of 36 patients with echinococcosis were treated with albendazole after surgical intervention [ ]. There was no significant benefit of perioperative albendazole over operation alone, although the recurrence rate of hepatic echinococcosis was lower than in historical controls. In contrast, in another study in 22 patients with hepatic echinococcosis there was a clear benefit of peri- and postoperative cyclic albendazole (12–15 mg/kg/day in four divided doses) [ ]. There were no cases of secondary hydatid disease or recurrence after a mean follow-up of 20 months. In two cases there were liver function abnormalities, which normalized after withdrawal.

Two regimens of albendazole emulsion were used in 264 patients with hepatic cystic echinococcosis [ ]. In 71 albendazole emulsion was given in a dose of 10 mg/kg/day by mouth for 6 months to over 1 year (group A). In 62 cases follow-up extended to 3–4 years after treatment. In 193 cases albendazole emulsion was given in a dose of 12.5 mg/kg/day for 3 months to over 1 year (group B). The follow-up study in 139 cases extended for 2–4 years after treatment. In 38 there were mild, self-limiting reactions: mild pruritus (n = 20), rash (n = 14), transient liver pain (n = 9), gastric pain (n = 11), alopecia (n = 2), anorexia (n = 4), nausea (n = 3), vomiting (n = 3), and headache (n = 2). These adverse reactions gradually resolved over 2 weeks without any treatment. In two patients with anorexia, nausea, and vomiting treatment was stopped. There were slight rises in serum transaminases in both groups. In group A there were increases in 43% (aspartate transaminase) and 49% (alanine transaminase) after 3 months. In group B increases occurred 2 weeks after starting treatment in 64% (aspartate transaminase) and 43% (alanine transaminase).

In a retrospective study of 30 patients with echinococcosis [ ], four took albendazole. In two cases albendazole could not be tolerated because of gastrointestinal adverse reactions in one case and abnormal liver function tests in the other. The liver function tests normalized after withdrawal of albendazole.

Fascioliasis

In 165 patients with fascioliasis (n = 35) or supposed fascioliasis (based on clinical and laboratory data but without detectable fasciola eggs in stools, n = 130), who were randomly allocated to oral triclabendazole 10 mg/kg for 1, 2, or 3 days, there were mild drug complications, such as nausea, vomiting, weakness, pruritus, epigastric pain, and liver enlargement in five, eight, and five patients who took one, two, and three doses respectively [ ]. In the triple dose group, there was an increase in one or both transaminases in seven patients, which normalized in four of five patients on day 60.

Neurocysticercosis

Cysticercosis is caused by the larval stage of the pork tapeworm Tenia solium . Neurocysticercosis is the most severe and common clinical manifestation in humans and probably the most frequent parasitic infection of the central nervous system. T. solium is endemic in Latin America, Asia, and sub-Saharan Africa. However, with the advent of computerized neuroradiology and improved serological tests, neurocysticercosis is increasingly being diagnosed throughout the world.

Controversies in the management of neurocysticercosis have been described [ ]. The management of the neurological complications of cysticercosis and in particular the role of antiparasitic drugs are issues of debate. It is commonly believed that the use of antiparasitic drugs and steroids should be individualized, based on the presence of active or inactive disease, the location of the cysts, and the presence or absence of complications such as hydrocephalus.

Some imidazoles have been used to treat parenchymal brain cysticerci. Initially, flubendazole (40 mg/kg for 10 days) was given to 13 patients with neurocysticercosis, with promising results. However, owing to its poor intestinal absorption, the use of flubendazole is limited. Albendazole is usually well absorbed and well tolerated, and albendazole serum concentrations are not significantly affected by glucocorticoids or anticonvulsants. Albendazole was given in daily doses of 15 mg/kg for 30 days. Further studies, however, showed that a treatment course could be shortened from 30 to 8 days without affecting efficacy. Direct comparative trials have shown that albendazole usually destroys 75–90% of parenchymal brain cysts, whereas praziquantel destroys 60–70%. The advantage of albendazole over praziquantel is limited not to its better efficacy, but also to better penetration of the subarachnoid space, allowing destruction of meningeal cysticerci. It also costs less than praziquantel.

Paragonimiasis

Five patients, aged 7–38 years, with Paragonimus skrjabini infections, were treated with oral triclabendazole (10 mg/kg bd for 3 consecutive days), an antihelminthic benzimidazole derivative used in the treatment of fascioliasis in sheep [ ]. One patient had cerebral involvement and received two courses. All five were cured. Blood eosinophilia completely disappeared. There were no adverse reactions. Hepatic and renal function tests were unaffected. These data suggest that Paragonimus skrjabini infections can be safely treated with triclabendazole.

Trichuriasis

In a randomized trial in 168 patients the duration of albendazole therapy (400 mg/day) for 3, 5, or 7 days was studied in relation to its effectiveness in the treatment of Trichuris trichiura infection [ ]. Treatment with albendazole for 7 days resulted in a significantly higher cure rate, in particular in patients who had heavy infections (at least 1000 Trichuris eggs/g of feces). The authors therefore suggested that albendazole should be given for at least 3 days to those with light infections and for 5–7 days to patients with heavy infections. All reported adverse reactions were mild. One patient (treated for 3 days) reported headache. Two patients (one treated for 3 days the other for 7 days) reported dizziness. Insomnia was reported in two patients treated for 7 days. Jaundice was not detected at any time.

To test the efficacy of albendazole against the for school-based deworming 150 children with whipworm ( Trichuris trichiura ) infections were randomized to albendazole 400, 800, or 1200 mg, each repeated four times, and 50 randomized to placebo; there were no adverse drug-related events [ ].