Dataset Information

Repurposing auranofin as a lead candidate for treatment of lymphatic filariasis and onchocerciasis.

ABSTRACT: Two major human diseases caused by filariid nematodes are onchocerciasis, or river blindness, and lymphatic filariasis, which can lead to elephantiasis. The drugs ivermectin, diethylcarbamazine (DEC), and albendazole are used in control programs for these diseases, but are mainly effective against the microfilarial stage and have minimal or no effect on adult worms. Adult Onchocerca volvulus and Brugia malayi worms (macrofilariae) can live for up to 15 years, reproducing and allowing the infection to persist in a population. Therefore, to support control or elimination of these two diseases, effective macrofilaricidal drugs are necessary, in addition to current drugs. In an effort to identify macrofilaricidal drugs, we screened an FDA-approved library with adult worms of Brugia spp. and Onchocerca ochengi, third-stage larvae (L3s) of Onchocerca volvulus, and the microfilariae of both O. ochengi and Loa loa. We found that auranofin, a gold-containing drug used for rheumatoid arthritis, was effective in vitro in killing both Brugia spp. and O. ochengi adult worms and in inhibiting the molting of L3s of O. volvulus with IC50 values in the low micromolar to nanomolar range. Auranofin had an approximately 43-fold higher IC50 against the microfilariae of L. loa compared with the IC50 for adult female O. ochengi, which may be beneficial if used in areas where Onchocerca and Brugia are co-endemic with L. loa, to prevent severe adverse reactions to the drug-induced death of L. loa microfilariae. Further testing indicated that auranofin is also effective in reducing Brugia adult worm burden in infected gerbils and that auranofin may be targeting the thioredoxin reductase in this nematode.

SUBMITTER: Bulman CA

PROVIDER: S-EPMC4336141 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Repurposing auranofin as a lead candidate for treatment of lymphatic filariasis and onchocerciasis.

Bulman Christina A CA Bidlow Chelsea M CM Lustigman Sara S Cho-Ngwa Fidelis F Williams David D Rascón Alberto A AA Tricoche Nancy N Samje Moses M Bell Aaron A Suzuki Brian B Lim K C KC Supakorndej Nonglak N Supakorndej Prasit P Wolfe Alan R AR Knudsen Giselle M GM Chen Steven S Wilson Chris C Ang Kean-Hooi KH Arkin Michelle M Gut Jiri J Franklin Chris C Marcellino Chris C McKerrow James H JH Debnath Anjan A Sakanari Judy A JA

PLoS neglected tropical diseases 20150220 2

Two major human diseases caused by filariid nematodes are onchocerciasis, or river blindness, and lymphatic filariasis, which can lead to elephantiasis. The drugs ivermectin, diethylcarbamazine (DEC), and albendazole are used in control programs for these diseases, but are mainly effective against the microfilarial stage and have minimal or no effect on adult worms. Adult Onchocerca volvulus and Brugia malayi worms (macrofilariae) can live for up to 15 years, reproducing and allowing the infecti ...[more]

PMID: 25700363

Similar Datasets

Project description:In Burkina Faso, onchocerciasis was no longer a public health problem when the WHO Onchocerciasis Control Programme in West Africa closed at the end in 2002. However, epidemiological surveillance carried out from November 2010 to February of 2011, showed a recrudescence of infection in the Cascades Region. This finding was made at a time when ivermectin, a drug recommended for the treatment of both onchocerciasis and lymphatic filariasis, had been distributed in this area since 2004 for the elimination of lymphatic filariasis. It was surprising that ivermectin distributed for treating lymphatic filariasis had not prevented the recrudescence of onchocerciasis. Faced with this situation, the aim of our study was to evaluate the effectiveness of ivermectin on the onchocerciasis parasite. The percentage reduction in microfilarial load after treatment with ivermectin was used as a proxy measure for assessing possible resistance. A cohort study was carried out with 130 individuals who had tested positive for microfilariae of Onchocerca volvulus in 2010 using microscopic examination of skin-snip biopsies from five endemic villages. Subjects were followed from July 2011 to June 2012. The microfilarial load of each individual was enumerated by skin-snip biopsy in 2010, prior to the first ivermectin treatment against onchocerciasis under community guidelines. All individuals received two ivermectin treatments six months apart. In 2012, the microfilarial loads were determined again, six months after the second round of ivermectin and the reductions in parasite loads were calculated to measure the impact of the drug. The percentage reduction of the microfilarial loads ranged from 87% to 98% in the villages. In all villages, there was a statistically significant difference between the average microfilarial loads in 2010 and 2012. The level of reduction of microfilarial loads suggests that ivermectin is effective against the recrudescent population of O. volvulus in Cascades Region of Burkina Faso. Further investigations would be necessary to determine the causes of the recrudescence of onchocerciasis. (For French language abstract, see S1 Alternative Language Abstract-Translation of the Abstract into French by the authors.).

Project description:BackgroundLymphatic filarial parasites survive within the lymphatic vessels for years despite the complex immune environment surrounding them. Parasites possibly accomplish this by adopting various immunomodulatory strategies, which include release of glutathione-S-transferases (GSTs) that counteract the oxidative free radicals produced by the host. Since GSTs produced by parasites appear to be critical for the survival of parasites in the host, several studies evaluated the potential of parasite GSTs as vaccine candidates especially against schistosomiasis, fascioliasis and Seteria cervi. However, vaccine potential of GSTs of lymphatic filarial parasites has not been evaluated before.Methods/principal findingsIn the present study, the GST gene was cloned from the third stage larval (L3) cDNA libraries of Wuchereria bancrofti, and recombinant GST (WbGST) was expressed and purified. Serum samples from individuals living in an endemic area were analyzed for their reactivity with rWbGST. These findings showed that sera from endemic normal individuals (EN) carry significant levels of anti-WbGST IgG antibodies compared to subjects who are microfilaraemic (Mf) or show symptoms of clinical pathology (CP). Isotype analysis of the anti-WbGST IgG antibodies showed a predominance of IgG1 and IgG3 antibodies in EN individuals. Subsequent functional analysis of the rWbGST showed that the rWbGST protein retained the enzymatic activity of GST and the antibodies in EN sera could inhibit this enzymatic activity. Similar results were obtained when anti-rWbGST antibodies raised in mice were used in the neutralization assay. Brugia malayi GST and WbGST show significant sequence similarity. Therefore, to evaluate the vaccine potential of rWbGST, we used B. malayi L3 as challenge parasites. Vaccine potential of rWbGST was initially evaluated by confirming the role of human and mice WbGST antibodies in an antibody dependent cellular cytotoxicity (ADCC) assay. Subsequent vaccination studies in a jird model showed that approximately 61% protection could be achieved against a B. malayi L3 challenge infection in jirds immunized with rWbGST.ConclusionsResults of this study show that rWbGST is a potential vaccine candidate against lymphatic filariasis. Nearly 61% protection can be achieved against a B. malayi challenge infection in a jird model. The study also showed that the WbGST protein retained the enzymatic activity of GST and this enzymatic activity appears to be critical for the survival of the parasite in the host.

Project description:BackgroundLoiasis is a filarial disease caused Loa loa. The main vectors are Chrysops silacea and C. dimidiata which are confined to the tropical rainforests of Central and West Africa. Loiasis is a mild disease, but individuals with high microfilaria loads may suffer from severe adverse events if treated with ivermectin during mass drug administration campaigns for the elimination of lymphatic filariasis and onchocerciasis. This poses significant challenges for elimination programmes and alternative interventions are required in L. loa co-endemic areas. The control of Chrysops has not been considered as a viable cost-effective intervention; we reviewed the current knowledge of Chrysops vectors to assess the potential for control as well as identified areas for future research.ResultsWe identified 89 primary published documents on the two main L. loa vectors C. silacea and C dimidiata. These were collated into a database summarising the publication, field and laboratory procedures, species distributions, ecology, habitats and methods of vector control. The majority of articles were from the 1950-1960s. Field studies conducted in Cameroon, Democratic Republic of Congo, Equatorial Guinea, Nigeria and Sudan highlighted that C. silacea is the most important and widespread vector. This species breeds in muddy streams or swampy areas of forests or plantations, descends from forest canopies to feed on humans during the day, is more readily adapted to human dwellings and attracted to wood fires. Main vector targeted measures proposed to impact on L. loa transmission included personal repellents, household screening, indoor residual spraying, community-based environmental management, adulticiding and larviciding.ConclusionsThis is the first comprehensive review of the major L. loa vectors for several decades. It highlights key vector transmission characteristics that may be targeted for vector control providing insights into the potential for integrated vector management, with multiple diseases being targeted simultaneously, with shared human and financial resources and multiple impact. Integrated vector management programmes for filarial infections, especially in low transmission areas of onchocerciasis, require innovative approaches and alternative strategies if the elimination targets established by the World Health Organization are to be achieved.

Project description:BackgroundThe World Health Organization has targeted lymphatic filariasis for global elimination by 2020 with a strategy of mass drug administration. This trial tested whether a single dose of a three-drug regimen of ivermectin plus diethylcarbamazine plus albendazole results in a greater sustained clearance of microfilariae than a single dose of a two-drug regimen of diethylcarbamazine plus albendazole and is noninferior to the two-drug regimen administered once a year for 3 years.MethodsIn a randomized, controlled trial involving adults from Papua New Guinea with Wuchereria bancrofti microfilaremia, we assigned 182 participants to receive a single dose of the three-drug regimen (60 participants), a single dose of the two-drug regimen (61 participants), or the two-drug regimen once a year for 3 years (61 participants). Clearance of microfilariae from the blood was measured at 12, 24, and 36 months after trial initiation.ResultsThe three-drug regimen cleared microfilaremia in 55 of 57 participants (96%) at 12 months, in 52 of 54 participants (96%) at 24 months, and in 55 of 57 participants (96%) at 36 months. A single dose of the two-drug regimen cleared microfilaremia in 18 of 56 participants (32%) at 12 months, in 31 of 55 participants (56%) at 24 months, and in 43 of 52 participants (83%) at 36 months (P=0.02 for the three-drug regimen vs. a single dose of the two-drug regimen at 36 months). The two-drug regimen administered once a year for 3 years cleared microfilaremia in 20 of 59 participants (34%) at 12 months, in 42 of 56 participants (75%) at 24 months, and in 51 of 52 participants (98%) at 36 months (P=0.004 for noninferiority of the three-drug regimen vs. the two-drug regimen administered once a year for 3 years at 36 months). Moderate adverse events were more common in the group that received the three-drug regimen than in the combined two-drug-regimen groups (27% vs. 5%, P<0.001). There were no serious adverse events.ConclusionsThe three-drug regimen induced clearance of microfilariae from the blood for 3 years in almost all participants who received the treatment and was superior to the two-drug regimen administered once and noninferior to the two-drug regimen administered once a year for 3 years. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT01975441 .).

Project description:Mass Drug Administration (MDA) programs to eliminate Lymphatic Filariasis (LF) in western Africa use the anthelminthics ivermectin plus albendazole. These drugs have the potential to impact also Soil-Transmitted Helminth (STH) infections, since the drugs have a broad range of anthelminthic activity. Integration of preventive chemotherapy efforts for LF, onchocerciasis and STH is recommended by the World Health Organization (WHO) in order to avoid duplication of MDA and to reduce costs. The objective of the current study was to determine whether five semi-annual rounds of community-wide MDA to eliminate LF and onchocerciasis have a greater impact on STH than three annual rounds of MDA with similar compliance. The effects of MDA using ivermectin (IVM, 0.2 mg/kg) combined with albendazole (ALB, 400 mg) on the prevalence and intensity of hookworm infection were evaluated in the Abengourou (annual MDA) and Akoupé (semi-annual MDA) health Districts in eastern Côte d'Ivoire from 2014 to 2017. A cross-sectional approach was used together with mixed logistic regression, and mixed linear models. Subjects were tested for STH using the Kato-Katz technique before the first round of MDA and 12, 24, and 36 months after the first round of MDA. The mean self-reported MDA compliance assessed during the survey was 65%, and no difference was observed between treatment areas. These results were confirmed by an independent coverage survey as recommended by WHO. Hookworm was the most prevalent STH species in both areas (23.9% vs 12.4%) and the prevalence of other STH species was less than 1%. The crude prevalence of hookworm dropped significantly, from 23.9% to 5.5% (p <0.001, 77% reduction) in the annual MDA treatment area and from 12.4% to 1.9% (p <0.001, 85% reduction) in the semi-annual treatment area. The average intensity of hookworm infection decreased in the annual MDA area (406.2 epg to 118.3 epg), but not in the semi-annual MDA area (804.9 epg to 875.0 epg). Moderate and heavy infections (1% and 1.3% at baseline) were reduced to 0% and 0.4% in the annual and semi-annual treatment areas, respectively. Using a mixed logistic regression model, and after adjusting for baseline prevalence, only the year 2 re-examination showed a difference in prevalence between treatments (OR: 2.26 [95% CI: 1.03, 4.98], p = 0.043). Analysis of intensity of hookworm infection indicated also that treatment differences varied by follow-up visit. In conclusion twelve months after the last treatment cycle, three annual and five semi-annual rounds of community-wide MDA with the combination of IVM and ALB showed strong, but similar impact on hookworm prevalence and intensity in eastern Côte d'Ivoire. Therefore, an annual MDA regimen seems to be an efficient strategy to control hookworm infection in endemic areas with low and moderate infection prevalence. Trial registration: The study was registered at ClinicalTrial.gov under the number NTC02032043.

Dataset Information

Repurposing auranofin as a lead candidate for treatment of lymphatic filariasis and onchocerciasis.

Publications

Repurposing auranofin as a lead candidate for treatment of lymphatic filariasis and onchocerciasis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets