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Trichuris suis and Oesophagostomum dentatum show different sensitivity and accumulation of fenbendazole, albendazole and levamisole in vitro.

Hansen TV, Nejsum P, Friis C, Olsen A, Thamsborg SM - PLoS Negl Trop Dis (2014)

Bottom Line: The total drug concentrations (pmol/mg dry worm tissue) were significantly lower within T. suis than O. dentatum whether killed or alive when incubated in all tested drugs (except in living worms exposed to fenbendazole).Relatively high proportions of the anthelmintic inactive metabolite fenbendazole sulphone was measured within T. suis (6-17.2%) as compared to O. dentatum (0.8-0.9%).Furthermore, the relatively high occurrence of fenbendazole sulphone suggests a higher detoxifying capacity of T. suis as compared to O. dentatum.

View Article: PubMed Central - PubMed

Affiliation: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark.

ABSTRACT

Background: The single-dose benzimidazoles used against Trichuris trichiura infections in humans are not satisfactory. Likewise, the benzimidazole, fenbendazole, has varied efficacy against Trichuris suis whereas Oesophagostomum dentatum is highly sensitive to the drug. The reasons for low treatment efficacy of Trichuris spp. infections are not known.

Methodology: We studied the effect of fenbendazole, albendazole and levamisole on the motility of T. suis and O. dentatum and measured concentrations of the parent drug compounds and metabolites of the benzimidazoles within worms in vitro. The motility and concentrations of drug compounds within worms were compared between species and the maximum specific binding capacity (Bmax) of T. suis and O. dentatum towards the benzimidazoles was estimated. Comparisons of drug uptake in living and killed worms were made for both species.

Principal findings: The motility of T. suis was generally less decreased than the motility of O. dentatum when incubated in benzimidazoles, but was more decreased when incubated in levamisole. The Bmax were significantly lower for T. suis (106.6, and 612.7 pmol/mg dry worm tissue) than O. dentatum (395.2, 958.1 pmol/mg dry worm tissue) when incubated for 72 hours in fenbendazole and albendazole respectively. The total drug concentrations (pmol/mg dry worm tissue) were significantly lower within T. suis than O. dentatum whether killed or alive when incubated in all tested drugs (except in living worms exposed to fenbendazole). Relatively high proportions of the anthelmintic inactive metabolite fenbendazole sulphone was measured within T. suis (6-17.2%) as compared to O. dentatum (0.8-0.9%).

Conclusion/significance: The general lower sensitivity of T. suis towards BZs in vitro seems to be related to a lower drug uptake. Furthermore, the relatively high occurrence of fenbendazole sulphone suggests a higher detoxifying capacity of T. suis as compared to O. dentatum.

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Mean concentration of LEV (± SD, n = 3) measured in living Trichuris suis and Oesophagostomum dentatum after incubation in 10 or 200 µM LEV for 24 and 72 hours.Statistically different concentration between species when exposed to either 10 or 200 µM LEV for 24 and 72 hours, respectively are indicated with: *P<0.05, **P<0.01 and ***P<0.001. Statistically different concentration values within the species between 24 and 72 hours are indicated with: ▵P<0.05 and ▵▵P<0.01.
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pntd-0002752-g004: Mean concentration of LEV (± SD, n = 3) measured in living Trichuris suis and Oesophagostomum dentatum after incubation in 10 or 200 µM LEV for 24 and 72 hours.Statistically different concentration between species when exposed to either 10 or 200 µM LEV for 24 and 72 hours, respectively are indicated with: *P<0.05, **P<0.01 and ***P<0.001. Statistically different concentration values within the species between 24 and 72 hours are indicated with: ▵P<0.05 and ▵▵P<0.01.

Mentions: The concentration of FBZ and ALB inside living T. suis and O. dentatum after incubation in 0.01, 0.1, 1, 10 and 30 µM of FBZ and ALB for 24 and 72 hours is shown in Fig. 3. The Kd and Bmax values for each species at 24 and 72 hours are given in Table 1. For both anthelmintic drugs no significant difference in the Kd – values were observed between the species neither after 24 or 72 hours of incubation. The Bmax – values were similar for the two species after 24 hours exposure to both BZs, but after 72 hours incubation, these were significantly lower for T. suis than O. dentatum when exposed to FBZ (P<0.0001) and ALB (P = 0.033). The concentrations of LEV found within the worms after exposure to 0.01, 0.1, 1, 10 and 200 µM LEV for 24 and 72 hours were only above the detection limit when exposed to the two highest concentrations (Fig. 4). The concentrations of LEV found within the worms were significantly lower in T. suis than O. dentatum when incubated in 10 and 200 µM for 24 hours (P = 0.01, P = 0.0009). When incubated in 200 µM for 72 hours the concentration of LEV was higher in T. suis (452.5 ng/mg dried worm tissue) than in O. dentatum (187.9 ng/mg dried worm tissue) (P<0.0001). The concentration of LEV within T. suis thus increased significantly with incubation time (P<0.0001) when incubated in 200 µM LEV, whereas the concentration was lower after 72 hours than 24 hours incubation within O. dentatum (P = 0.02).


Trichuris suis and Oesophagostomum dentatum show different sensitivity and accumulation of fenbendazole, albendazole and levamisole in vitro.

Hansen TV, Nejsum P, Friis C, Olsen A, Thamsborg SM - PLoS Negl Trop Dis (2014)

Mean concentration of LEV (± SD, n = 3) measured in living Trichuris suis and Oesophagostomum dentatum after incubation in 10 or 200 µM LEV for 24 and 72 hours.Statistically different concentration between species when exposed to either 10 or 200 µM LEV for 24 and 72 hours, respectively are indicated with: *P<0.05, **P<0.01 and ***P<0.001. Statistically different concentration values within the species between 24 and 72 hours are indicated with: ▵P<0.05 and ▵▵P<0.01.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3974671&req=5

pntd-0002752-g004: Mean concentration of LEV (± SD, n = 3) measured in living Trichuris suis and Oesophagostomum dentatum after incubation in 10 or 200 µM LEV for 24 and 72 hours.Statistically different concentration between species when exposed to either 10 or 200 µM LEV for 24 and 72 hours, respectively are indicated with: *P<0.05, **P<0.01 and ***P<0.001. Statistically different concentration values within the species between 24 and 72 hours are indicated with: ▵P<0.05 and ▵▵P<0.01.
Mentions: The concentration of FBZ and ALB inside living T. suis and O. dentatum after incubation in 0.01, 0.1, 1, 10 and 30 µM of FBZ and ALB for 24 and 72 hours is shown in Fig. 3. The Kd and Bmax values for each species at 24 and 72 hours are given in Table 1. For both anthelmintic drugs no significant difference in the Kd – values were observed between the species neither after 24 or 72 hours of incubation. The Bmax – values were similar for the two species after 24 hours exposure to both BZs, but after 72 hours incubation, these were significantly lower for T. suis than O. dentatum when exposed to FBZ (P<0.0001) and ALB (P = 0.033). The concentrations of LEV found within the worms after exposure to 0.01, 0.1, 1, 10 and 200 µM LEV for 24 and 72 hours were only above the detection limit when exposed to the two highest concentrations (Fig. 4). The concentrations of LEV found within the worms were significantly lower in T. suis than O. dentatum when incubated in 10 and 200 µM for 24 hours (P = 0.01, P = 0.0009). When incubated in 200 µM for 72 hours the concentration of LEV was higher in T. suis (452.5 ng/mg dried worm tissue) than in O. dentatum (187.9 ng/mg dried worm tissue) (P<0.0001). The concentration of LEV within T. suis thus increased significantly with incubation time (P<0.0001) when incubated in 200 µM LEV, whereas the concentration was lower after 72 hours than 24 hours incubation within O. dentatum (P = 0.02).

Bottom Line: The total drug concentrations (pmol/mg dry worm tissue) were significantly lower within T. suis than O. dentatum whether killed or alive when incubated in all tested drugs (except in living worms exposed to fenbendazole).Relatively high proportions of the anthelmintic inactive metabolite fenbendazole sulphone was measured within T. suis (6-17.2%) as compared to O. dentatum (0.8-0.9%).Furthermore, the relatively high occurrence of fenbendazole sulphone suggests a higher detoxifying capacity of T. suis as compared to O. dentatum.

View Article: PubMed Central - PubMed

Affiliation: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark.

ABSTRACT

Background: The single-dose benzimidazoles used against Trichuris trichiura infections in humans are not satisfactory. Likewise, the benzimidazole, fenbendazole, has varied efficacy against Trichuris suis whereas Oesophagostomum dentatum is highly sensitive to the drug. The reasons for low treatment efficacy of Trichuris spp. infections are not known.

Methodology: We studied the effect of fenbendazole, albendazole and levamisole on the motility of T. suis and O. dentatum and measured concentrations of the parent drug compounds and metabolites of the benzimidazoles within worms in vitro. The motility and concentrations of drug compounds within worms were compared between species and the maximum specific binding capacity (Bmax) of T. suis and O. dentatum towards the benzimidazoles was estimated. Comparisons of drug uptake in living and killed worms were made for both species.

Principal findings: The motility of T. suis was generally less decreased than the motility of O. dentatum when incubated in benzimidazoles, but was more decreased when incubated in levamisole. The Bmax were significantly lower for T. suis (106.6, and 612.7 pmol/mg dry worm tissue) than O. dentatum (395.2, 958.1 pmol/mg dry worm tissue) when incubated for 72 hours in fenbendazole and albendazole respectively. The total drug concentrations (pmol/mg dry worm tissue) were significantly lower within T. suis than O. dentatum whether killed or alive when incubated in all tested drugs (except in living worms exposed to fenbendazole). Relatively high proportions of the anthelmintic inactive metabolite fenbendazole sulphone was measured within T. suis (6-17.2%) as compared to O. dentatum (0.8-0.9%).

Conclusion/significance: The general lower sensitivity of T. suis towards BZs in vitro seems to be related to a lower drug uptake. Furthermore, the relatively high occurrence of fenbendazole sulphone suggests a higher detoxifying capacity of T. suis as compared to O. dentatum.

Show MeSH
Related in: MedlinePlus