Pharmacovigilance through consumer feedback (reporting) in the mass treatment of lymphatic filariasis using diethylcarbamazine and albendazole in two districts of Sri Lanka

Objective  To document the types and severity of adverse drug reactions to diethylcarbamazine and albendazole in randomly selected urban populations from Colombo and rural populations from Gampaha, Sri Lanka.
Methods  Interviewers administered a pre-tested questionnaire to elicit information about the type and severity of adverse drug reactions experienced by recipients. Seeking medical treatment and requiring hospital admission for the adverse drug reactions were used as indicators for severity. The sample population was selected using the cluster sampling method.
Results  Two thousand three hundred and nineteen persons aged 10 to 90 years (median 40.0) responded to the questionnaire; 63.9% of them had received and ingested the drugs. 12.6% reported that they had experienced adverse drug reactions, the proportion being similar in urban and rural areas (χ² = 0.05; p = 0.82). Commonly reported reactions were drowsiness (34.7%), headache (23.1%), gastrointestinal symptoms (18.7%) and dizziness or faintness (11.9%). However, most symptoms were mild (96.3%) and did not interfere with daily activities or require medical attention. 3.2% said that they sought medical advice for their symptoms; one person (0.5%) who had severe abdominal pain was hospitalized.
Conclusions  Fewer people experienced adverse drug reactions than in previous years, possibly due to lower microfilariaemia prevalence after several rounds of mass drug administration against filariasis. Community awareness of adverse drug reactions is essential for improving compliance and for the success of the filariasis elimination programme.     

Treatment of the microfilaraemia of asymptomatic brugian filariasis with single doses of ivermectin, diethylcarbamazine or albendazole, in various combinations

Several new chemotherapeutic tools are now available for the control of lymphatic filariasis. Combinations of single doses of antifilarial drugs are generally superior to single drugs. The efficacy and safety of albendazole in combination with diethylcarbamazine (DEC) or ivermectin, for the treatment of Brugia malayi infection, were investigated, for the first time, in an open, hospital-based study. Fifty-one asymptomatic microfilaraemics (with 108-4034 microfilariae/ml; median = 531) of both sexes and aged 14-70 years were randomly allocated to receive single-dose treatments of ivermectin (200 micrograms/kg) with diethylcarbamazine (DEC; 6 mg/kg), ivermectin (200 micrograms/kg) with albendazole (400 mg), DEC (6 mg/kg) with albendazole (400 mg), or albendazole (400 mg) alone. Albendazole alone had no effect on the microfilarial levels at the 1-year follow-up but both groups given DEC had significantly lower microfilaraemias (P < 0.015 and P < 0.02) than that given ivermectin with albendazole. Overall, 47%-64% of those given DEC but only 14% of those given ivermectin with albendazole appeared to be amicrofilaraemic 1 year post-treatment. The adverse reactions seen in the study were mild, transient and qualitatively similar to those seen earlier with ivermectin and DEC. The combination of DEC and albendazole, both well tested drugs, offers a new option for countries such as India where there is no onchocerciasis or loiasis and where ivermectin may not be immediately available. The direct and indirect effects of albendazole on intestinal helminths would be additional benefits.     

A comparative trial of albendazole alone versus combination of albendazole and praziquantel for treatment of Trichuris trichiura infection

A randomized clinical trial was conducted to compare the effectiveness of albendazole alone and albendazole combined with praziquantel in the treatment of Trichuris trichiura infection. The drug regimens consisted of single dose of albendazole 400 mg (A1, n=34), 3 days of albendazole 400 mg daily (A3, n=34), 5 days of albendazole 400 mg daily (A5, n=35), single dose of albendazole 400 mg plus praziquantel 40 mg/kg (AIP1, n=34), and 3 days of albendazole 400 mg plus praziquantel 40 mg/kg daily (A3P3, n=36). It was found that treatment with 3 or more consecutive days of albendazole with or without praziquantel resulted in a significant reduction in density of Trichuris eggs in stools while a single dose of such drug did not. Praziquantel was not shown to have synergistic or antagonistic effects with albendazole. A regimen of 400 mg of albendazole daily for 3 days was found to be the most suitable therapy for Trichuris infection.     

The effectiveness of 3, 5 or 7 days of albendazole for the treatment of Trichuris trichiura infection

A randomized clinical trial was carried out to study the relationship between the duration of albendazole therapy, at 400 mg/day, and its effectiveness in the treatment of Trichuris trichiura infection. The 168 patients were treated for three (N=56), five (N=56) or seven (N=56) consecutive days. Compared with both of the shorter regimens, treatment for 7 days resulted in a significantly higher cure 'rate' and significantly greater reductions in the level of egg excretion. The advantage of using the longer (5- or 7-day) regimens was most apparent among the patients who had heavy infections (at least 1000 Trichuris eggs/g faeces) when treated. It is therefore suggested that albendazole be given for at least 3 days to those with light infections and for 5-7 days to patients with heavy infections.     

Treatment with a single dose of albendazole improves growth of Kenyan schoolchildren with hookworm, Trichuris trichiura, and Ascaris lumbricoides infections

We studied the growth of primary schoolchildren with hookworm (87%), T. trichiura (97%), and A. lumbricoides (49%) who received a single 400 mg dose of albendazole or an identical placebo. Children were allocated at random to placebo (PL, n = 72) or albendazole (A, n = 78) groups, treated, and re-examined 6 months later. The A group gained significantly more than the PL group in weight (1.3 kg), percent weight for age (4.5% age points), percent height for age (0.5% age points), percent weight for height (4.3% age points), percent arm circumference (2.9% age points), and in triceps and subscapular skinfold thicknesses (1.2 mm). The PL group showed significant decreases between exams in percent weight for age, percent height for age, percent weight for height, percent arm circumference for age, and skinfold thicknesses for age. The A group had highly significant increases (P less than 0.0002) in all of these parameters except height for age. From Exam 1 to 2, the A group exhibited decreases (P less than 0.0002) in geometric means eggs per gram of feces (epg): for hookworm, means = 1,183 epg at Exam 1 vs. 136 epg at Exam 2 (67% egg reduction); for T. trichiura, means = 2,857 epg at Exam 1 vs. 1,061 epg at Exam 2 (28% egg reduction); and for A. lumbricoides, means = 86 epg at Exam 1 vs. 2 epg at Exam 2 (91% egg reduction). The PL group had a borderline increase in geometric means hookworm egg count, no significant change in T. trichiura egg count, and a small but significant decrease in A. lumbricoides egg count. Decreases in intensities of all infections were significant predictors of growth improvement. Hookworm egg count entered the equations for all 6 measurements, and A. lumbricoides and T. trichiura entered 4/6 equations. Single dose treatment with albendazole, despite continual exposure to infection, can permit improved growth rates in areas where intestinal helminths and protein-energy malnutrition are highly prevalent.     

Follow-up of Ascaris lumbricoides and Trichuris trichiura infections in children living in a community treated with ivermectin at 3-monthly intervals.

Ivermectin treatment was administered every 3 months over a 1-year period (April 1993-April 1994) to the whole eligible population of a village in South Cameroon where both Ascaris lumbricoides and Trichuris trichiura were hyper-endemic. A parasitological stool examination was performed before each treatment. Thirty children, aged 5-15 years, were not only found egg-positive for A. lumbricoides and/or T. trichiura before the first treatment but were also each treated and examined in each treatment round. Among these children, the intensity of infection with A. lumbricoides decreased significantly following the first treatment but thereafter remained steady. In contrast, the repeated ivermectin treatments had no significant impact on the intensity of the T. trichiura infections or on the prevalence of infection with T. trichiura or A. lumbricoides among the 30 children.     

Two-year follow-up of the microfilaraemia of asymptomatic brugian filariasis, after treatment with two, annual, single doses of ivermectin, diethylcarbamazine and albendazole, in various combinations

Repeated, single, oral doses of combinations of ivermectin, diethylcarbamazine (DEC) or albendazole are recognized as important tools for parasite control in lymphatic filariasis. In order to assess the effects of re-treatment using these combinations in Brugia malayi infections, 40 asymptomatic microfilaraemics were re-treated at the end of the first year, with an additional, single, dose of the combination they had previously received. They were then followed-up for another year. The subjects, of both sexes and aged 14-70 years, each received a two-drug combination: ivermectin (200 micrograms/kg) with DEC (6 mg/kg); ivermectin (200 micrograms/kg) with albendazole (400 mg); or DEC (6 mg/kg) with albendazole (400 mg). The kinetics of microfilarial clearance were similar to that seen during the first treatment, the members of the two groups given DEC having less intense microfilaraemias, 1 year after the re-treatment, than those given ivermectin with albendazole (P < 0.001 for each comparison). At this time, the two DEC groups also had a higher proportion of amicrofilaraemic individuals (22 of 26) than the ivermectin + albendazole group (three of nine). There were fewer adverse reactions in all the groups after re-treatment than seen after the first treatment. In countries such as India, where there is no co-endemicity of onchocerciasis or loiasis, the options for control programmes in areas where brugian filariasis is endemic are DEC alone or DEC in combination with ivermectin or albendazole. Where there is no access to ivermectin, transmission control must be based on DEC alone or in combination with albendazole.     

Efficacy of single-dose diethylcarbamazine compared with diethylcarbamazine combined with albendazole against Wuchereria bancrofti infection in Papua New Guinea

The efficacy of diethylcarbamazine alone was compared with diethylcarbamazine plus albendazole in residents of an island in Papua New Guinea endemic for Wuchereria bancrofti. There was no statistically significant difference between the two drug regimens in decreasing the microfilaria positive rate at 12 and 24 months after a single-dose treatment with either regimen, e.g., 50.0% clearance of microfilaria at 24 months for diethylcarbamazine alone versus 65.7% clearance of microfilaria for diethylcarbamazine plus albendazole (P > 0.05). In contrast, diethylcarbamazine plus albendazole resulted in a significant decrease in Og4C3 antigen prevalence (17%; P = 0.003) at 24 months whereas diethylcarbamazine did not (10%; P = 0.564). These data showed no statistically significant difference in the efficacy of the two drug regimens in lowering the microfilaria reservoir, but they support the use of diethylcarbamazine combined with albendazole in mass treatment programs on the basis of greater activity against adult worms.     

Efficacy of ivermectin for control of microfilaremia recurring after treatment with diethylcarbamazine. II. Immunologic changes following treatment

We compared the effect of a single dose of ivermectin with that of a standard course of diethylcarbamazine (DEC) on several parameters of the host's antifilarial immune response in 60 patients with bancroftian filariasis enrolled in a double-blind drug trial. All participants had measurable serum levels of antifilarial antibodies and parasite antigens at the onset of the study. Drug-induced clearance of microfilaremia was associated with a temporary increase in HC 11 antigenemia and a decrease in serum levels of antibodies to soluble filarial antigens. Antigenemia progressively declined in patients who remained amicrofilaremic after treatment, but declined and then increased in persons with recurrent microfilaremia. Treatment triggered a sustained increase in serum levels of interleukin-1, tumor necrosis factor, and interleukin-6 in all patients studied. Although ivermectin and DEC are believed to exert their antiparasite activity via different mechanisms, the same pattern of serologic changes was observed in patients treated with either drug.     

Prevalence of strongyloides in Northern Thailand and treatment with ivermectin vs albendazole

The stools of 697 cases were examined by agar plate technique at Tambon Makam Luang, Sun Pa Tong district, Chiang Mai; there were Strongyloides stercoralis 15.9%,Opisthorchis viverrini 5.1%, intestinal fluke 0.1%. Treatment with ivermectin 78 cases and albendazole 33 cases of strongyloidiasis gave cure rates at 98.7% and 78.7%, respectively. Alkaline phosphatase in some patients were increased at mild level after treatment. Side effects in ivermectin group were anorexia, nausia, diarrhea, diffuse itching and drowsiness; and in albendazole group were nausia and diarrhea. The efficacy of single dose and mild side effects suggest ivermectin as drug of choice for strongyloidiasis treatment.     

Alterations in filarial antigen-specific immunologic reactivity following treatment with ivermectin and diethylcarbamazine.

The presence of circulating microfilariae has been associated with alterations in B and T cell functions. In this study, we compared the influence of diethylcarbamazine (DEC) and ivermectin on filarial antigen-specific immune responses in a Haitian population. Both drugs were effective at reducing microfilaremia levels to less than 10% of pretreatment levels for up to one year. This reduction in microfilaremia was associated with two phases of altered cellular responsiveness monitored with in vitro assays. Five days post-treatment, cellular proliferation in response to both filarial and nonfilarial antigens was significantly increased, as was the background response in the absence of any antigen. At both nine months and one year post-treatment, the filarial antigen-specific reactivity of both DEC- and ivermectin-treated patients was significantly increased over baseline levels. No differences were observed between the two treatment groups in terms of humoral or cellular reactivity to filarial antigens, despite evidence suggesting a role for DEC in adult worm killing. These results provide additional evidence that microfilariae modulate antifilarial immune reactivity.