ABSTRACT
It has been demonstrated that continuous exposure to amodiaquine (AQ) alone elicits <i>in vitro</i> antischistosomal activities at concentrations of 1–10 μg/ml. However, orally administered drugs reach a peak blood concentration within one or two hours and then gradually decrease. The blood concentration does not remain at a constant level over several days as <i>in vitro</i> concentration of continuous drug exposure. <i>In vitro</i> activities by one day exposure to AQ better reflect the actual antischistosomal activities after oral administration than those elicited by continuous exposure.The objective of the present study is to compare the antischistosomal potential of one-day exposure to AQ with that to praziquantel (PZQ), a current antischistosomal drug. <i>Schistosoma mansoni</i> adult worm pairs were incubated with 0 (control), 1, 2, 5 and 10 μg/ml AQ as well as 0.01, 0.02, 0.05 and 0.1 μg/ml PZQ for the first day, and were subsequently incubated in drug-free media for a period of 14 days. The one-day exposure to AQ significantly reduced the daily egg output of the worm pairs at 1–10 μg/ml. The inhibitory effect on egg production continued at 5 and 10 μg/ml but proved temporary at 1 and 2 μg/ml. Furthermore, AQ-induced specific morphological alterations (severe swelling and/or localization of hemozoin) were observed in the worms at 5 and 10 μg/ml. The AQ-specific appearance of the male worms gradually faded during subsequent incubation in drug-free media, although the female worms showed elongation. Meanwhile, PZQ inhibited the egg output of adult worm pairs at concentrations of 0.01–0.1 μg/ml during exposure. The inhibitory effect on egg production continued at 0.05 and 0.1 μg/ml but proved temporary at 0.01 and 0.02 μg/ml. Furthermore, PZQ induced a visible contraction and shortening of the male and female worms at 0.05 and 0.1 μg/ml during exposure, but the PZQ-specific alterations quickly disappeared during subsequent incubation in drug-free media. To our knowledge, this is the first report showing that one-day exposure to AQ inhibits the egg production of adult worm pairs at 1–10 μg/ml and induces specific morphological alterations in the worms at 5 and 10 μg/ml. The present findings have important implications for the evaluation of the therapeutic effects of both AQ monotherapy and combination therapy with artesunate on schistosomiasis in clinical field trials.
ABSTRACT
It has been demonstrated that continuous exposure to amodiaquine (AQ) alone elicits <i>in vitro</i> antischistosomal activities at concentrations of 1 - 10 µg/ml. However, orally administered drugs reach a peak blood concentration within one or two hours and then gradually decrease. The blood concentration does not remain at a constant level over several days as <i>in vitro</i> concentration of continuous drug exposure. <i>In vitro</i> activities by one day exposure to AQ better reflect the actual antischistosomal activities after oral administration than those elicited by continuous exposure.The objective of the present study is to compare the antischistosomal potential of one-day exposure to AQ with that to praziquantel (PZQ), a current antischistosomal drug. <i>Schistosoma mansoni</i> adult worm pairs were incubated with 0 (control), 1, 2, 5 and 10 µg/ml AQ as well as 0.01, 0.02, 0.05 and 0.1 µg/ml PZQ for the first day, and were subsequently incubated in drug-free media for a period of 14 days. The one-day exposure to AQ significantly reduced the daily egg output of the worm pairs at 1 - 10 µg/ml. The inhibitory effect on egg production continued at 5 and 10 µg/ml but proved temporary at 1 and 2 µg/ml. Furthermore, AQ-induced specific morphological alterations (severe swelling and/or localization of hemozoin) were observed in the worms at 5 and 10 µg/ml. The AQ-specific appearance of the male worms gradually faded during subsequent incubation in drug-free media, although the female worms showed elongation. Meanwhile, PZQ inhibited the egg output of adult worm pairs at concentrations of 0.01 - 0.1 µg/ml during exposure. The inhibitory effect on egg production continued at 0.05 and 0.1 µg/ml but proved temporary at 0.01 and 0.02 µg/ml. Furthermore, PZQ induced a visible contraction and shortening of the male and female worms at 0.05 and 0.1 µg/ml during exposure, but the PZQ-specific alterations quickly disappeared during subsequent incubation in drug-free media. To our knowledge, this is the first report showing that one-day exposure to AQ inhibits the egg production of adult worm pairs at 1 - 10 µg/ml and induces specific morphological alterations in the worms at 5 and 10 µg/ml. The present findings have important implications for the evaluation of the therapeutic effects of both AQ monotherapy and combination therapy with artesunate on schistosomiasis in clinical field trials.
ABSTRACT
@#Intestinal helminth infections caused by soil-transmitted helminths and schistosomes bring about the greatest burden of disease in poverty-stricken areas in the developing world. The most vulnerable group and the most significant contributors to disease transmission are the school-age children. While awaiting major improvements on sanitation, the recommended strategy for helminth control is school-based, teacher assisted, mass drug administration (MDA). However, millions of individuals worldwide remain afflicted with these diseases, and the Philippines is no different from many of the developing countries. The overall objective of this paper is to review current Philippine control programs and initiatives and offer evidence based recommendations for improvement. Discrepancies between parasitologic parameters and drug coverage rates pose significant challenges in the control and prevention of helminth infections in the country. School-based MDA may be scaled up after successful local initiatives, where teachers have direct participation in drug administration. There is also a need to involve the social science sector to help address the behavioral aspects of helminth control. Moreover, monitoring and evaluation of interventions through identification of success parameters will contribute to the optimization of school-based helminth control, and to strategies towards effective control of intestinal helminth infections as a public health problem in the country.
Subject(s)
Ascaris , Trichuris , SchistosomiasisABSTRACT
Genetic crosses between phenotypically resistant and sensitive schistosomes demonstrated that resistance to hycanthone and oxamniquine behaves like a recessive trait, thus suggesting that resistance is due to the lack of some factor. We hypothesized that, in order to kill schistosomes, hycanthone and oxamniquine need to be converted into an active metabolite by some parasite enzyme wich, if inactive, results in drug resistance. Esterification of the drugs seemed to be the most likely event as it would lead to the production of an alkylating agent upon dissociation of the ester. An artificial ester of hycanthone was indeed active even in resistant worms, thus indirectly supporting our hypothesis. In addition, several lines of evidence demonstrated that exposure to hycanthone and oxamniquine results in alkylation of worm macromolecules. Thus, radioactive drugs formed covalent bonds with the DNA of sensitive (but not of resistant) schistosomes; an antiserum raised against hycanthone detected the presence of the drug in the purified DNA fraction of sensitive (but not of resistant) schistosomes; a drug-DNA adduct was isolated from hycanthone-treated worms and fully characterized as hycanthone-deoxyguanosine.