Limits...
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.

Show MeSH

Related in: MedlinePlus

Concentrations of OXF, FBZSO2 and mean concentrations of ALBSO (± SD, n = 3) measured in living Trichuris suis (black columns) and Oesophagostomum dentatum (hatched columns) after incubation in 0.01, 0.1, 1, 10 or 30 µM FBZ (upper three graphs) or ALB (lower two graphs) for 24 and 72 hours.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3974671&req=5

pntd-0002752-g005: Concentrations of OXF, FBZSO2 and mean concentrations of ALBSO (± SD, n = 3) measured in living Trichuris suis (black columns) and Oesophagostomum dentatum (hatched columns) after incubation in 0.01, 0.1, 1, 10 or 30 µM FBZ (upper three graphs) or ALB (lower two graphs) for 24 and 72 hours.

Mentions: The concentrations of the metabolites OXF, FBZSO2 and ALBSO measured within living T. suis and O. dentatum are given in Fig. 5. The concentrations of OXF and FBZSO2 within the two worm species were much lower than ALBSO (Fig. 5). Incubation concentrations below 0.1 µM of FBZ and ALB did not result in detectable levels of metabolites. The concentration of OXF within T. suis did not show a concentration or time dependent increase (3.2–5.4 pmol/mg dry worm tissue and 3.8–5.4 pmol/mg dry worm tissue after incubation periods of 24 and 72 hours, respectively) whereas a clear time dependent increase was observed for O. dentatum (5.4–7.9 pmol/mg dry worm tissue and 14.2–15.6 pmol/mg dry worm tissue after 24 and 72 hours, respectively). After 24 hours incubation the inactive metabolite FBZSO2 was only detected in T. suis. Results were inconsistent and are thus not given. After 72 hours incubation, FBZSO2 was detected within T. suis at an incubation concentration as low as 0.1 µM FBZ whereas FBZSO2 only appeared in O. dentatum when incubated in 10 and 30 µM. After 72 hours a concentration dependent formation of FBZSO2 (0.9–17.5 pmol/mg dry worm tissue) was measured within T. suis where it represented between 6–17.2% of the total drug concentration whereas in O. dentatum it only constituted 0.8–0.9%. For both species, the formation of FBZSO2 appeared to be both time- and concentration-dependent as consistent results only were obtained after 72 hours incubation. The ALBSO metabolite showed a clear tendency to reach a higher concentration within O. dentatum than T. suis when incubated for both 24 and 72 hours. The formation of ALBSO within the worms appeared to be both time- and concentration-dependent at incubation concentrations ranging from 0.1 µM to 30 µM. Incubation in 30 µM ALB resulted in ALBSO concentrations equal to or below the concentrations formed when incubated in 10 µM. The metabolite ALBSO2 was not detected within any of the two species. The metabolites OXF and ALBSO showed a clear tendency to reach a higher concentration level within O. dentatum than T. suis when incubated for both 24 and 72 hours, but in relation to the total drug concentration, the average proportion of the metabolites were approximately the same (OXF: T. suis; 4% at 24 hours and 3.6% at 72 hours; O. dentatum: 5.6% and 4%, ALBSO: T. suis; 11.1% and 13.8%, O. dentatum; 15% and 12.2%).


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)

Concentrations of OXF, FBZSO2 and mean concentrations of ALBSO (± SD, n = 3) measured in living Trichuris suis (black columns) and Oesophagostomum dentatum (hatched columns) after incubation in 0.01, 0.1, 1, 10 or 30 µM FBZ (upper three graphs) or ALB (lower two graphs) for 24 and 72 hours.
© Copyright Policy
Related In: Results  -  Collection

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

pntd-0002752-g005: Concentrations of OXF, FBZSO2 and mean concentrations of ALBSO (± SD, n = 3) measured in living Trichuris suis (black columns) and Oesophagostomum dentatum (hatched columns) after incubation in 0.01, 0.1, 1, 10 or 30 µM FBZ (upper three graphs) or ALB (lower two graphs) for 24 and 72 hours.
Mentions: The concentrations of the metabolites OXF, FBZSO2 and ALBSO measured within living T. suis and O. dentatum are given in Fig. 5. The concentrations of OXF and FBZSO2 within the two worm species were much lower than ALBSO (Fig. 5). Incubation concentrations below 0.1 µM of FBZ and ALB did not result in detectable levels of metabolites. The concentration of OXF within T. suis did not show a concentration or time dependent increase (3.2–5.4 pmol/mg dry worm tissue and 3.8–5.4 pmol/mg dry worm tissue after incubation periods of 24 and 72 hours, respectively) whereas a clear time dependent increase was observed for O. dentatum (5.4–7.9 pmol/mg dry worm tissue and 14.2–15.6 pmol/mg dry worm tissue after 24 and 72 hours, respectively). After 24 hours incubation the inactive metabolite FBZSO2 was only detected in T. suis. Results were inconsistent and are thus not given. After 72 hours incubation, FBZSO2 was detected within T. suis at an incubation concentration as low as 0.1 µM FBZ whereas FBZSO2 only appeared in O. dentatum when incubated in 10 and 30 µM. After 72 hours a concentration dependent formation of FBZSO2 (0.9–17.5 pmol/mg dry worm tissue) was measured within T. suis where it represented between 6–17.2% of the total drug concentration whereas in O. dentatum it only constituted 0.8–0.9%. For both species, the formation of FBZSO2 appeared to be both time- and concentration-dependent as consistent results only were obtained after 72 hours incubation. The ALBSO metabolite showed a clear tendency to reach a higher concentration within O. dentatum than T. suis when incubated for both 24 and 72 hours. The formation of ALBSO within the worms appeared to be both time- and concentration-dependent at incubation concentrations ranging from 0.1 µM to 30 µM. Incubation in 30 µM ALB resulted in ALBSO concentrations equal to or below the concentrations formed when incubated in 10 µM. The metabolite ALBSO2 was not detected within any of the two species. The metabolites OXF and ALBSO showed a clear tendency to reach a higher concentration level within O. dentatum than T. suis when incubated for both 24 and 72 hours, but in relation to the total drug concentration, the average proportion of the metabolites were approximately the same (OXF: T. suis; 4% at 24 hours and 3.6% at 72 hours; O. dentatum: 5.6% and 4%, ALBSO: T. suis; 11.1% and 13.8%, O. dentatum; 15% and 12.2%).

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