Ivermectin Treatment of Cutaneous Gnathostomiasis

Previous studies have revealed that ivermectin treatment for gnathostomiasis can reduce parasitic loads in animals and make recurrent subcutaneous swelling subside in 76% of patients. Our study aimed to evaluate the efficacy of ivermectin for cutaneous gnathostomiasis treatment in a placebo-controlled trial. This study was a prospective randomized placebo-controlled study performed at The Bangkok Hospital for Tropical Diseases, Mahidol University, Thailand. Thirty patients with a serologically confirmed diagnosis of cutaneous gnathostomiasis were enrolled. Seventeen patients in the ivermectin treated group received a single dose of 12 mg ivermectin (200 μg/kg bodyweight), while 13 patients in the control group received a single dose of 40 mg of vitamin B1. The follow-up period was 1 year. Of the 17 patients, 7 (41.2%) responded to ivermectin, while no patient responded to placebo. The mean (95% CI) time to the first recurrence of subcutaneous swelling with ivermectin and in the placebo groups were 257 (184-331) and 146 (42-250) days, respectively, (p=0.102). Although this study revealed no significant difference in the mean time to first recurrence of swelling between the ivermectin and placebo groups, there was a trend towards ivermectin efficacy against gnathostomiasis in previous animal and human studies. Further studies with different doses of ivermectin and larger sample sizes, and close monitoring for ivermectin tolerability and treatment response are necessary to confirm an efficacy of ivermectin. ment regimen for cutaneous gnathostomiasis has not been well established. Current treatment at the Bangkok Hospital for Tropical Diseases is albendazole, 400 mg twice daily for 14 days or 400 mg once a day for 21 days. However these regimens provide low efficacy and transient elevations of liver enzymes occurs at a dosage of 800 mg daily for 14 days (Inkatanuwat et al, 1998). The treatment resulted in cutaneous outward migration of the parasite in only 7.3% and 21%, respectively, in patients treated with twicedaily albendazole for 14 days (Suntharasamai et al, 1992) and once or twice daily dose for 21 days (Kraivichian et al, 1992). Albendazole resulted in a reduction in the frequency of recurrent subcutaneous swelling when given at a dosage of 400 mg once or twice daily compared to the non-treated group (Kraivichian et al, 1992). Ivermectin is a macro-cyclic lactone causing paralysis of nematodes and arthropods through an influx of chloride ions across the cell membrane (Ottesen and Campbell, 1994). At a dose of 150-200 μg/kg, it reaches a maximum SOUTHEAST ASIAN J TROP MED PUBLIC HEALTH 434 Vol 37 No. 3 May 2006 concentration at 2.7-4.3 hours with an elimination half-life of 28±10 hours. It is metabolized by the cytochrome p 450 systems in the liver and excreted almost entirely in feces within 12 days (Ett et al, 1990). This drug has been shown to be effective for mass treatment of onchocerciasis with a good safety record since 1987 (Pacque et al, 1989). It has also been shown to be effective in the treatment of many intestinal helminthiases including strongyloidiasis (Aziz et al, 1982; Coulaud et al, 1983; Kumaraswami et al, 1988; De Sole et al, 1989; Pacque et al, 1989; Shikiya et al, 1992; Coutinho et al, 1994; Datry et al, 1994; Bockarie et al, 1998; Kombila et al, 1998) and scabies, especially in the elderly and children (Huffam and Currie, 1998; Meinking et al, 1995). Severe adverse events noted after using ivermectin treatment included hypotension, breathing discomfort, high fever, hematuria, and abnormal complete blood counts and liver enzymes. However, the laboratory abnormalities were transient and occurred uncommonly (Ett et al, 1990). Ivermectin has been shown to be effective against the larvae of Gnathostoma spinigerum in experimental animals (Anantaphruti et al, 1992). When infected rabbits were treated with subcutaneous ivermectin, either as a single dose of 0.2 mg/kg or up to 3 doses of 2 mg/kg, these resulted in 74.2% and 84.2% reductions in worm load by 28 weeks of treatment, respectively. A clinical study of ivermectin to treat human cutaneous gnathostomiasis was conducted with single oral doses of 50, 100, 150 and 200 μg/kg bodyweight. These regimens demonstrated ivermectin was well tolerated (Bussaratid et al, 2005). Another study showed that a single dose (200 μg/kg) of ivermectin was effective in the treatment of gnathostomiasis with cure rates of up to 76% during 120 days of follow-up. This study aimed to assess the safety, tolerability, and efficacy of ivermectin compared to placebo in a randomized placebo-controlled trial. MATERIALS AND METHODS This study was carried out prospectively between July 2001 and July 2004 at the OutPatient Department of the Bangkok Hospital for Tropical Diseases, Mahidol University, Thailand. The study was reviewed and approved by the Ethics Committee on Clinical Research of the Faculty of Tropical Medicine, Mahidol University. Thirty patients, age 20-65 years, having at least one episode of subcutaneous swelling during the past 12 months with positive antibodies against a speci f ic 24 kDa ant igen of G. spinigerum third stage larva by immunoblot analysis (Nopparatana et al, 1991; Tapchaisri et al, 1991) were enrolled with informed consent. Patients were excluded if pregnant, lactating, or if they had taken any anti-parasitic agents during the previous 14 days. Patients with underlying diseases, including pulmonary disease (especially asthma), renal disease (especially hematuria), a history of seizures, liver disease (elevated liver function test), cardiovascular disease (especially tachycardia with a heart rate >100/ minute or having an abnormal electrocardiogram at baseline), hematological disorders, such as anemia (hematocrit < 25%), leukopenia (WBC < 3,500/mm3), or thrombocytopenia (platelet < 100,000/mm3), and hypotension (blood pressure <90/60 mmHg) were also excluded. After providing informed consent, each patient was randomly assigned to receive a single dose of ivermect in 200 μg/kg (4 tablets of 3 mg ivermectin) or placebo (4 tablets of 10 mg-vitamin B1). Clinical assessment was performed before treatment, on days 7 and 28, at months 3, 6 and 12. The laboratory tests included a CBC, liver enzymes (AST, ALT), BUN, creatinine and urinalysis were performed before treatment and on day 7. If any abnormality occurred, the laboratory tests were repeated on day 28 and at months 3, 6, and 12, or until they returned to normal. Safety and tolerability Each patient was observed for immediate adverse reactions for 30 minutes after taking the study drug at the Out-Patient Department. Other symptoms were self recorded for 7 days by each patient using a diary card. The severity of any symptoms was classified as follows. A “mild symptom” was defined as self-limited without needing treatment. A “moderate symptom” was defined as a symptom that was relieved with IVERMECTIN TREATMENT OF CUTANEOUS GNATHOSTOMIASIS Vol 37 No. 3 May 2006 435 medication or an outpatient visit was required. A “severe symptom” was defined as a symptom which led to hospitalization of the patient. Causality evaluation of adverse events Adverse events were considered as to whether they were related to the study drug and classified as follows: none, remotely related, possibly related, probably related, and definitely related (Stark et al, 1999; Gait et al, 2000).