Heterogeneity in the in vitro susceptibility of Loa loa microfilariae to drugs commonly used in parasitological infections

Njouendou, Abdel Jélil; Fombad, Fanny Fri; O’Neill, Maeghan; Zofou, Denis; Nutting, Chuck; Ndongmo, Patrick Chounna; Kengne-Ouafo, Arnaud J.; Geary, Timothy G.; Mackenzie, Charles D.; Wanji, Samuel

doi:10.1186/s13071-018-2799-3

Cited by 16 publications

(18 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, mefloquine was active against Opisthorchis viverrini in vitro and in hamsters ( Keiser et al, 2009b ), but not in human patients ( Soukhathammavong et al, 2011 ). Against nematodes, mefloquine was active in vitro against adults and microfilariae of Brugia patei and B. malayi ( Walter et al, 1987 ), against Onchocerca gutturosa ( Townson et al, 1990 ), against microfilariae of Loa loa ( Njouendou et al, 2018 ), and against Mansonella perstans microfilariae ( Njouendou et al, 2019 ). Overall, mefloquine shows activity against a variety of helminth parasite species.…”

Section: Mefloquinementioning

confidence: 99%

Drug repurposing applied: Activity of the anti-malarial mefloquine against Echinococcus multilocularis

Lundström‐Stadelmann

Rufener

Hemphill

2020

International Journal for Parasitology: Drugs and Drug Resistan

View full text Add to dashboard Cite

The current chemotherapeutical treatment against alveolar echinococcosis relies exclusively on benzimidazoles, which are not parasiticidal and can induce severe toxicity. There are no alternative treatment options. To identify novel drugs with activity against Echinococcus multilocularis metacestodes, researchers have studied potentially interesting drug targets (e.g. the parasite's energy metabolism), and/or adopted drug repurposing approaches by undertaking whole organism screenings. We here focus on drug screening approaches, which utilize an in vitro screening cascade that includes assessment of the drug-induced physical damage of metacestodes, the impact on metacestode viability and the viability of isolated parasite stem cells, structure-activity relationship (SAR) analysis of compound derivatives, and the mode of action. Finally, once in vitro data are indicative for a therapeutic window, the efficacy of selected compounds is assessed in experimentally infected mice. Using this screening cascade, we found that the anti-malarial mefloquine was active against E. multilocularis metacestodes in vitro and in vivo . To shed more light into the mode of action of mefloquine, SAR analysis on mefloquine analogues was performed. E. multilocularis ferritin was identified as a mefloquine-binding protein, but its precise role as a drug target remains to be elucidated. In mice that were infected either intraperitoneally with metacestodes or orally with eggs, oral treatment with mefloquine led to a significant reduction of parasite growth compared to the standard treatment with albendazole. However, mefloquine was not acting parasiticidally. Assessment of mefloquine plasma concentrations in treated mice showed that levels were reached which are close to serum concentrations that are achieved in humans during long-term malaria prophylaxis. Mefloquine might be applied in human AE patients as a salvage treatment. Future studies should focus on other repurposed anti-infective compounds (MMV665807, niclosamide, atovaquone), which showed stronger in vitro activity against E. multilocularis than mefloquine.

show abstract

Section: Mefloquinementioning

confidence: 99%

Drug repurposing applied: Activity of the anti-malarial mefloquine against Echinococcus multilocularis

Lundström‐Stadelmann

Rufener

Hemphill

2020

International Journal for Parasitology: Drugs and Drug Resistan

View full text Add to dashboard Cite

show abstract

“…Loiasis remains an important public health issue, and treatment options are limited due to severe adverse events [4, 5]. However, it has been shown that FLBZ, know essentially as a macrofilaricidal agent drug [16, 17], exhibits little or no microfilaridal activity against several filarial species, such as Brugia pahangi [18], Onchocerca lienalis [19] and L. loa [20], and its capacity in eliminating adult worms has been elucidated in many studies for filarial species such as B. pahangi [18, 21], Breinlia booliati [22] and Onchocerca ochengi [23]. In this study, we showed that FLBZ reduces worm motility from 80.5% to 14.5% by 9 days after incubation at concentrations of 0.05–10 μg/ml, using the recently published filarial in vitro culture system that has been shown to promote development and moulting of infective stages of L. loa [13] and M. perstans [12].…”

Section: Discussionmentioning

confidence: 99%

Effect of flubendazole on developing stages of Loa loa in vitro and in vivo: a new approach for screening filaricidal agents

et al. 2019

Self Cite

View full text Add to dashboard Cite

BackgroundLoiasis, an often-neglected tropical disease, is a threat to the success of lymphatic filariasis and onchocerciasis elimination programmes in rainforest areas of the central and western Africa. Its control and even its elimination might be possible through the use of a safe macrofilaricide, a prophylactic drug, or perhaps a vaccine. This present study evaluated the effect of flubendazole (FLBZ) on the development of Loa loa L3 in vitro and in vivo.MethodsInfective stages of L. loa were isolated and co-cultured in Dulbecco’s Modified Eagle’s Medium in the presence of monkey kidney epithelial cells (LLC-MK2) feeder cells. FLBZ and its principal metabolites, reduced flubendazole (RFLBZ) and hydrolyzed flubendazole (HFLBZ), were screened in vitro at concentrations 0.05, 0.1, 0.5, 1 and 10 μg/ml. The viability of the parasites was assessed microscopically daily for 15 days. For in vivo study, a total of 48 CcR3 KO mice were infected subcutaneously with 200 L. loa L3 and treated with 10 mg/kg FLBZ once daily for 5 consecutive days. Twenty-four animals were used as control and received L3 and vehicle. They were dissected at 5, 10, 15 and 20 days post-treatment for worm recovery.ResultsThe motility of L3 larvae in vitro was reduced from the second day of incubation with drugs at in vivo plasma concentration levels, with a strong correlation found between reduced motility and increased drug concentration (Spearman’s rho = -0.9, P < 0.0001). Except for HFLBZ (0.05 μg/ml and 0.01 μg/ml), all concentrations of FLBZ, HFLBZ and RFLBZ interrupted the moulting of L. loa infective larvae to L4. In vivo, regardless of the experimental group, there was a decrease in parasite recovery with time. However, at each time point this reduction was more pronounced in the group of animals treated with FLBZ compared to equivalent control. Parasites were recovered from the flubendazole-treated groups only on day 5 post-inoculation at an average rate of 2.1%, a value significantly lower (Mann-Whitney U-test, U = 28, P = 0.0156) than the average of 31.1% recovered from the control group.ConclusionsThis study reveals the ability of flubendazole to inhibit the development of L. loa L3 both in vitro and in vivo, and in addition validates the importance of in vitro and animal models of L. loa as tools for the development of drugs against loiasis.Electronic supplementary materialThe online version of this article (10.1186/s13071-018-3282-x) contains supplementary material, which is available to authorized users.

show abstract

“…Whole blood samples (4 ml) were collected from a donor infected with L. loa and MF were obtained using version of a previously described protocol [20,21]. In brief, 2 ml of whole blood was layered onto 2 ml-modified Percoll gradient (Sigma-Aldrich) in a 15-ml tube (Falcon) and centrifuged at 2000× rpm for 20 min without brake using a bench-top centrifuge (Human Diagnostics, Wiesbaden, Germany).…”

Section: Isolation Of Loa Loa Microfilariae From Human Peripheral Bloodmentioning

confidence: 99%

Comparison of immune responses to Loa loa stage-specific antigen extracts in Loa loa-exposed BALB/c mice upon clearance of infection

Chunda¹,

Ritter

Bate³

et al. 2020

Parasites Vectors

Self Cite

View full text Add to dashboard Cite

Background: Different immune mechanisms are capable of killing developmental stages of filarial nematodes and these mechanisms are also likely to vary between the primary and a challenge infection. However, the lack of a detailed analysis of cytokine, chemokine and immunoglobulin levels in human loiasis is still evident. Therefore, detailed analysis of immune responses induced by the different developmental stages of Loa loa in immune-competent BALB/c mice will aid in the characterization of distinct immune responses that are important for the immunity against loiasis. Methods: Different developmental stages of L. loa were obtained from human peripheral blood (microfilariae, MF), the transmitting vector, Chrysops (larval stage 3, L3) and infected immune-deficient BALB/cRAG2γc −/− mice (L4, L5, adult worms). Groups of wildtype BALB/c mice were then injected with the isolated stages and after 42 days postinfection (pi), systemic cytokine, chemokine and immunoglobulin levels were determined. These were then compared to L. loa-specific responses from in vitro re-stimulated splenocytes from individual mice. All parameters were determined using Luminex technology. Results: In a pilot study, BALB/c mice cleared the different life stages of L. loa within 42 days pi and systemic cytokine, chemokine and immunoglobulin levels were equal between infected and naive mice. Nevertheless, L. loa-specific re-stimulation of splenocytes from mice infected with L5, MF or adult worms led to induction of Th2, Th17 and chemokine secretion patterns. Conclusions: This study shows that although host immunity remains comparable to naive mice, clearance of L. loa life-cycle development stages can induce immune cell memory leading to cytokine, chemokine and immunoglobulins secretion patterns which might contribute to immunity and protection against reinfection.

show abstract

Heterogeneity in the in vitro susceptibility of Loa loa microfilariae to drugs commonly used in parasitological infections

Cited by 16 publications

References 47 publications

Drug repurposing applied: Activity of the anti-malarial mefloquine against Echinococcus multilocularis

Drug repurposing applied: Activity of the anti-malarial mefloquine against Echinococcus multilocularis

Effect of flubendazole on developing stages of Loa loa in vitro and in vivo: a new approach for screening filaricidal agents

Comparison of immune responses to Loa loa stage-specific antigen extracts in Loa loa-exposed BALB/c mice upon clearance of infection

Contact Info

Product

Resources

About