Effect of a single dose of diethylcarbamazine, albendazole or both on the clearance of Wuchereria bancrofti microfilariae and antigenaemia among microfilaria carriers: A randomized trial.

Background. Lymphatic filariasis is a major vector-borne parasitic disease. The global programme to eliminate lymphatic filariasis was launched in 1997 and currently over 570 million people are covered under it in 48 countries. Mass annual single-dose drug administration of diethylcarbamazine (DEC), co-administrated with albendazole for 5–6 years and mass distribution of diethylcarbamazine-fortified salt are the two strategies for elimination of filariasis. Methods. Asymptomatic volunteers residing in Puducherry, India were screened for microfilaria (mf) by examining nocturnal thick blood smears. Those testing positive were randomly assigned to receive a single dose of DEC (6 mg/kg body weight) or albendazole 400 mg or both. Participants were hospitalized for 5 days. Membrane filtration count was used to assess microfilaraemia and ELISA (Og4C3) assay to measure circulating filarial antigens (CFA). Measurements were done before treatment and at 1, 2 and 3 years post-treatment. Viability of the adult worms was assessed by looking for the filarial dance sign (FDS) using ultrasound examination of the scrotum in men with hydrocele. Results. Fifty-four microfilaraemic individuals were studied. The mf prevalence started decreasing only by day 180 posttreatment in the DEC group but much earlier in the other two groups (day 30 in the albendazole and day 90 in the DEC with albendazole group). The decrease in mf was marginal (17.6%, 26.3% and 27.8%, respectively) by the end of year 1 posttreatment, but significant (96.7%, 78.6% and 93.3%, respectively) by the end of year 2 post-treatment (p<0.05). By the end of year 3, the level decreased to 80% in the DEC, 90% in the albendazole and to 100% in the DEC and albendazole groups. However, the mf intensity decreased © The National Medical Journal of India 2010 Vector Control Research Centre, Department of Health Research (ICMR), Indira Nagar, Puducherry 605006, India S. L. HOTI, S. P. PANI, P. VANAMAIL, K. ATHISAYA MARY, L. K. DAS, P. K. DAS Correspondence to S. L. HOTI; slhoti@yahoo.com significantly (by 39%; p<0.05) by day 7 post-treatment in both the DEC and DEC with albendazole groups, but only by day 30 in the albendazole group. In all the drug groups, the prevalence as well as intensity of CFA returned to pretreatment levels by the end of year 3 post-treatment. Conclusion. Annual single-dose administration of all the 3 drug regimens significantly reduced antigenaemia levels. There were no significant differences in the efficacy and overall pattern of CFA clearance between the 3 drug regimens.

An allele specific PCR assay for screening for drug resistance among Wuchereria bancrofti populations in India.

Background & objectives: Albendazole, a commonly used anthelminthic drug that targets the polymerization of α- and β-tubulin dimer is currently co-administered with the antifilarial drug, diethylcarbamazine citrate (DEC) in the ongoing Global Programme for Elimination of Lymphatic Filariasis (GPELF). The experience in veterinary field has shown that there can be a rapid development of resistance to this drug, which therefore, needs to be monitored regularly in GPELF. Hence, we investigated the nucleotide polymorphism in the albendazole-binding domain of the isotype 1 β-tubulin gene from several populations of Wuchereria bancrofti and developed an AS-PCR assay useful in screening for sensitive/resistance alleles among parasite populations and also evaluated its utility. Methods: For studying the polymorphism of isotype 1 β-tubulin gene, a 475 bp fragment spanning exon 5 and 6 of the gene was amplified and sequenced from the genomic DNA of W. bancrofti collected from six geographic regions of India. An allele specific (AS) PCR for screening albendazole sensitivity/resistance was developed and a total of 55 mf samples from blood smears on slides collected from Thiruvannamalai, Thanjavur and Puducherry were screened. Selective therapy with DEC was in place in three areas, mass drug administration (MDA) with DEC alone was implemented in four areas, while DEC plus albendazole was administered in one district. Results: The analysis of the nucleotide sequence of the fragment from 20 W. bancrofti populations showed the domain to be highly conserved. An allele-specific PCR assay developed was used to detect sensitive/ resistance alleles among 55 isolates of W. bancrofti and no albendazole resistance alleles were detected among the populations tested. Interpretation & conclusion: The drug-binding domain of isotype 1 β-tubulin gene of W. bancrofti from different geographical locations was highly conserved. The AS-PCR developed showed potential application as a tool for monitoring albendazole sensitivity/resistance alleles among W. bancrofti populations, in areas where combination therapy of DEC-albendazole is being mass administered in the LF elimination programme.

Awareness of health personnel about lymphatic filariasis and mass drug administration in Kerala State.

The mass drug administration programme to eliminate lymphatic filariasis with DEC in Kerala was started in 1997, extended to all the 11 endemic districts by 2005. Since the beginning of Mass drug Administration, the drug consumption rate was found to be not satisfactory. The reasons for noncompliance indicated that the community is not fully convinced about the programme. The knowledge of the medical and para medical workers is certainly a factor in the success of implementation of the programme and is vital. To ascertain the knowledge, a study was undertaken and found not satisfactory. Hence intensive training on all aspects of lymphatic filariasis and the Mass drug Administration programme to achieve the requisite drug consumption rate to meet the goal is needed.

Short-term effects of treatment with 300 mg oral-dose diethylcarbamazine on nocturnally periodic Wuchereria bancrofti microfilaremia and antigenemia.

Seven microfilaremic Myanmar patients were treated with a single 300 mg dose of diethylcarbamazine (DEC) orally, as part of a case-finding survey in Ranong Province, Southern Thailand. This was conducted in order to evaluate the short-term effects of single-dose DEC on Wuchereria bancrofti microfilaremia and antigenemia during a 12-week course of treatment. Analysis of microfilarial periodicity on initial treatment revealed the microfilarial peak density (k) was at 52 minutes after midnight (0052). The periodicity index was then 103.26%. Single-dose DEC treatment did not affect the k values. A linear model of W. bancrofti microfilarial density reduction predicts a sharp decrease in the mean microfilarial density 2 weeks after DEC intake (Z = -2.197, p = 0.028). Over a longer period, a non-linear model predicts an increase in the mean microfilarial density to pre-treatment levels, having little or no macrofilaricidal effects. We reconfirmed the existence of nocturnally periodic W. bancrofti infection in Myanmar migrants in Ranong Province, and the short-term microfilaricidal activity of 300 mg single-dose DEC treatment used for biannual mass treatment and the DEC provocative test. Without an adequate DEC treatment dose, recrudescence can occur. A rational approach to the management of introduced nocturnally periodic W. bancrofti in Myanmar migrants, who came for short periods of stay in transmission-prone areas, is needed.

Border and imported bancroftian filariases: baseline seroprevalence in sentinel populations exposed to infections with Wuchereria bancrofti and concomitant HIV at the start of diethylcarbamazine mass treatment in Thailand.

Border bancroftian filariasis caused by Wuchereria bancrofti nocturnally subperiodic mainly exists in Karens residing alongside the Thailand-Myanmar border. Imported bancroftian filariasis caused by W. bancrofti nocturnally periodic mainly exists in cross-border Myanmar migrants. We analyzed seroprevalence data based on W. bancrofti adult worm antigen (Ag) loads and human immunodeficiency virus (HIV) immunoglobulins in the sentinel population samples which were studied prior to the start of the diethylcarbamazine (DEC) mass treatment phase in the PELF during fiscal years 2002-2006. In the Karens, the cumulative infection prevalence (36.8% serological antigen positivity or SAP) was specific for age (p < 0.001) but universal for gender (p = 0.77). The infection intensity (median Ag load = 60,827 antigen units or AU/ml) was specific for age (p = 0.031) and for males (p = 0.016). In the Myanmars, infection prevalence (24.0% SAP) was universal for age (p = 0.961) and for gender (p = 0.676). The infection intensity (median Ag load = 19,068 AU/ml) was universal for age (p = 0.433) but specific for females (p = 0.027). Overall, the Ag loads between the groups were significantly different (p = 0.014). In analysis of concomitant HIV and W. bancrofti infections, 7 (3.2%) Myanmars infected with HIV 1 and 3 (5.7%) with concomitant infections, subjected to biannual DEC treatment with 300 mg oral-dose FILADEC, were prevalent. The antigenemia clearance in the concomitant infections (r = -0.732, p = 0.039) as well as in the single W. bancrofti infection (r = -0.781, p = 0.022) was correlated with time required to clear antigenemias. We reemphasize that W. bancrofti adult worm Ag loads in the sentinel population samples would be beneficial for the PELF's implementers at the provincial level to probe the disease burdens in target areas and to evaluate and monitor the DEC treatment efficacy and effectiveness in those sentinel populations, including those with concomitant HIV eligible for the DEC mass treatment phase in the PELF.

Tolerability and efficacy of single dose diethylcarbamazine (DEC) alone or co-administration with Ivermectin in the clearance of Wuchereria bancrofti microfilaraemia in Pondicherry, South India.

The tolerability and efficacy of single dose DEC (12mg/kg body weight) or co-administration of DEC (6mg/kg body weight) with Ivermectin (200 or 400 mcg/kg of body weight) was studied in 60 asymptomatic W. bancrofti microfilariae (Mf) carriers following a double blind randomized design. The drugs were tolerated well. The incidence of adverse reactions of DEC (85.0%), DEC + Ivermectin 200mcg (95.0%) and DEC + Ivermectin 400mcg (100%) did not vary significantly (P>0.05). The mean score of adverse reaction intensity due to DEC + Ivermectin 200mcg (1.41) was significantly higher compared to DEC (0.61) (P<0.05). However, there was no significant difference between and DEC +Ivermectin 400mcg (0.89) and DEC + Ivermectin 200mcg (1.41) and DEC + Ivermectin 400mcg and DEC. The major adverse reactions were fever, headache and myalgia in all groups. The incidence and intensity of the adverse reactions were maximum between 24 to 48 hours of post therapy. The haematological and biochemical parameters did not vary significantly between pre and 7-day post therapy values in any of the study groups (P>0.05). Efficacy was measured in terms of proportion of cases clearing microfilaraemia completely and reduction in geometric mean parasite density in comparison to pre therapy levels. At the end of one year, DEC with Ivermectin 400mcg group showed significantly higher efficacy in complete clearance of Mf (94.4%) than that of DEC with Ivermectin 200mcg (60.0%) or DEC alone (52.6%) (P<0.05). However, no significant difference was observed in reduction of geometric mean Mf density (99.9%, 99.7%, 99.5% respectively). In all the groups, the tolerability and efficacy of the drugs were independent of host age and gender.

Treatment of microfilaraemics with DEC and its effect on vector infection and infectivity in tribal and non-tribal areas of Bankura district, West Bengal, India.

Single course DEC treatment (6 mg/kg body weight/day for 12 days) was administered to 66 tribal and 442 non-tribal microfilaria (mf) carriers detected through a Filariasis survey in Bankura district, West Bengal, India. All the mf carriers remained amicrofilaraemic on 22nd, 180th and 365th post-treatment day. As a result of DEC treatment to the mf carriers, vector (Culex quinquefasciatus) infection rate in tribal study areas reduced from 2.06% to 1.07%. Infectivity rate was "nil" both before and after treatment. In non-tribal study areas, vector infection rate reduced from 4.33% to 2.22% and infectivity rate from 0.51% to 0.29%.

Efficacy of a single dose treatment of Wuchereria bancrofti microfilaria carriers with diethylcarbamazine in Matara, Sri Lanka.

OBJECTIVE: To test the efficacy of diethylcarbamazine DEC single dose regimen of 6 mg/kg body weight (bw) on a sample of Wuchereria bancrofti microfilaria (mf) carriers in Matara. DESIGN: 6 mg/kg bw DEC dose in 50 mg tablets given under direct observation to the subjects at 23.00 hours after pre-treatment blood collection for mf counts. Post-treatment mf counts were at 1, 2 weeks and 1, 3, 6, 12 months. SUBJECTS: 31 asymptomatic mf carriers, 14 males, age range 6 to 62 years. RESULTS: Treatment resulted in 89 to 97% success rate, 19 to 28% cure rates and 74 to 80% reduction in mf density. There was no difference statistically in the success rate and cure rate at 6 and 12 months. The effect of DEC treatment at 6 and 12 months compared by sex, age group and pre-treatment mf level showed no difference. 64.5% of the carriers treated had at least one mild adverse reaction. Rates of the common reactions were 41.9% fever, 22.6% headache and 16.1% joint pains. CONCLUSION: A new mass treatment program has been initiated by the national Antifilariasis Campaign using the single dose DEC 6 mg/kg bw regimen. The satisfactory reduction in mf density at 6 and 12 months following DEC single dose treatment we observed provides support for this program.

Dietilcarbamazina no tratamento da filariose bancroftiana / Diethylcarbamazine in the treatment of Bancroft's filariasis

Os autores realizaram uma ampla revisão sobre o tratamento da filariose bancroftiana com a droga dietilcarbamazina. Os aspectos interessantes sobre o histórico de sua descoberta e os conceitos básicos de sua farmacologia foram relatados de forma resumida. Ênfase especial, por outro lado, foi dada às especulações feitas pelos diversos autores sobre os achados intrigantes descritos na literatura. Foram trazidos os novos avanços sobre o conhecimento da doença, como por exemplo, a visualização pela ultra-sonografia do verme vivo de Wuchereria bancrofti, no seu hospedeiro natural, o homem. Isso possibilitou a compreensão de muitos dos achados aparentemente paradoxais encontrados na literatura sobre o tratamento da infeção com a DEC. Assim, devido à inexistência de uma droga sucessora que reunisse efeitos micro e macrofilaricidas ideais e aos novos conhecimentos sobre a bancroftose e sobre a própria dietilcarbamazina, foi-lhe conferido um novo realce. Esses aspectos a colocaram numa posição de destaque no cenário da infecção, à época do seu quase cinqüentenário de existência.

The authors presented a detailed review about the treatment of bancroftian filariasis with diethylcarbamazine. The interesting aspects about the drug discovery and the basic concepts about its pharmacology were reported in a summarised form. On the other hand, emphasis was made about the speculation done by several authors about the intriguing findings regarding its efficacy reported in the literature. Latter, it was brought the new advances about the disease, as for example, the visualization by ultrasound of living Wuchereria bancrofti adult worm on its natural host--the human being. This made possible the comprehension of several paradoxical issues reported, focusing the treatment of infection using diethylcarbamazine. So far, because of the lack of ideal drug with micro and macrofilaricidal properties, together with the new understand about the disease and the new parameters for monitoring the efficacy of the drug, diethylcarbamazine has back its importance conquered at the begin of its discovery, almost fifth years ago.

Effect of two single doses of ivermectin in treatment of asymptomatic bancroftian filariasis in two villages in the Nile delta, Egypt

To evaluate the efficacy and longitudinal effect of two single [100 mug/kg] doses of ivermectin, 3 months apart, 240 asymptomatic male subjects from 2 endemic Egyptian villages were enrolled in a one- year double-blind study. Subjects aged 15 - 55 years were randomly assigned to placebo [40] or ivermectin [200]. Microfilaria [MF] density in 1 ml blood was measured by membrane filtration before and every 3 months after treatment. Initial mean MF density was 462 [range 14 - 2869/ml]. Clinical examination performed daily for 3 days after each treatment revealed brief, mild side effects [fever, headache, weakness, nausea, and epigastric pain] with no adverse physical or laboratory findings. Three months after initial dose, 31% of MF counts had completely cleared, in the remaining, mean MF density was 11.0 [2.4% of pretreatment level]. At 3, 6 and 9 months after the second Dose, there was complete MF clearance in 60%, 45% and 47%. In those who still infected, MF densities were 1.7, 4.6 and 6.1% of the pretreatment level. Therefore, treatment with 2 doses of ivermectin reduced microfilaremia, without inducing severe side effects. Prolonged suppression of microfilaremia may indicate an effect of ivermectin on the adult worms and may reduce the potential for MF acquisition by mosquitos, reducing transmission of lymphatic filariasis. It was concluded that ivermectin is a useful drug for public health measure, including asymptomatic filariasis patients

Effect of ivermectin on survival and fecundity of culex pipiens the vector of wuchereria bancrofti in Egypt

The effect of two different doses of ivermectin on the survival and fecundity of Culex pipiens was evaluated. Female mosquitoes [50 in each group, same age and generation] were fed once on blood from ivermectin-treated rabbits. Comparative treatments consisted of two different doses of ivermectin [0.1 mg or 0.4 mg/kg of body weight] and mosquito groups were fed on the rabbits at 3 days and 10 days post-treatment, respectively. Mosquitoes were maintained with 10% sucrose solution at 25C and 70% relative humidity. Observations were made at 7, 10, 15, 20, 25 and 30 days post-feeding. These results provided new information about the effect of ivermectin on the vector of lymphatic filariasis and added a new dimension to the use of ivermectin in filariasis control

Arthritis in children: an occult manifestation of Bancroftian filariasis.

A form of unexplained arthritis, not attributable to known causes, seen in children (0-14 yrs) in this endemic zone of Bancroftian filariasis was investigated for its association with filariasis. Nineteen cases of undiagnosed arthritis were screened for filarial IgG antibodies to Wuchereria by Stick Enzyme Linked Immunosorbent Assay (ELISA). All had large joint involvement, the commonest joint affected being the knee joint. Involvement was monoarticular in 10 and binarticular in 9. Joint pain was present in 18 and effusion in 12. Five patients had recurrent episodes. Sixteen (84.2%) showed filarial antibodies of which only one (5.3%) was microfilaraemic. Patients with classical filariasis (16), disease controls (10), endemic normals (15) and non-endemic normals (10) were also subjected to ELISA to ascertain the sensitivity and specificity of the technique. Fifteen (93.8%) cases of classical filariasis and 1 (6.7%) of endemic normal were antibody positive, whereas none of disease controls and non-endemic normals had filarial antibodies. Nine cases of filarial arthritis reviewed after a course of Diethylcarbamazine showed satisfactory response to treatment.

Ivermectin in the treatment of bancroftian filarial infection in Orissa, India.

Ivermectin treatment was evaluated for its efficacy and side reactions in sixty patients of Orissa with Bancroftian filarial infection and microfilaremia. Ivermectin was administered as a single oral dose at four dosage levels (20, 50, 100 and 200 micrograms/kg), and both microfilarial clearance and associated side reactions were monitored in a double blind fashion. Blood microfilariae were cleared in all patients at all dosages within 1 to 14 days. In most patients microfilariae reappeared by third month. The microfilaria appearance by third and sixth month averaged 12.2 to 44 percent of pretreatment values in the four study groups. Side reactions were encountered in almost all patients, the commonest being fever, headache, weakness, myalgia and cough which occurred most prominently 12 to 72 hours after treatment. Side reactions were more frequent and severe in patients with high microfilaria counts. Clinical reaction scores for each group were independent of the dose administered. The 200 micrograms dose group showed significantly more rapid microfilariae clearance and its delayed reappearance as compared with the other dosage groups and without inducing significantly greater clinical reaction scores.

Double blind clinical trial on centperazine & DEC in bancroftian filariasis.

Centperazine, an analogue of DEC, was subjected to a double blind controlled trial, to evaluate its efficacy as a newer antifilarial agent. Centperazine (300 mg/day) along with equivalent quantities of DEC and placebo were administered to different types of filariasis patients. DEC was found to be significantly effective in reducing peripheral microfilaraemia, in different weeks and months of follow-up, except at the end of 6th month, as compared to Centperazine. There was no significant difference between the placebo and Centperazine treated patients, in this respect, revealing that the drugs had no efficacy in eliminating peripheral microfilaraemia. Recurrence of acute attack within 6 months was nearly equal with both Centperazine and DEC, being 28.2 and 24 per cent respectively, whereas in the placebo group the recurrence rate was 48.9 per cent. Centperazine treated patients showed significantly less side effects (8.9%), as compared to DEC treated patients (34%). Giddiness, nausea and vomiting were the common adverse effects observed.