In Vitro Activity of Novel Metronidazole Derivatives on Larval Stages of Echinococcus Granulosus (original) (raw)
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Parasitology, 2020
In this study, we evaluated the efficacy, expressed as a mean weight decrease of the whole echinococcal cyst mass, of novel benzimidazole salt formulations in a murineEchinococcus granulosusinfection model. BALB/c mice were intraperitoneally infected with protoscoleces ofE. granulosus(genotype G1). At 9 months post-infection, treatment with albendazole (ABZ), ricobendazole (RBZ) salt formulations, and RBZ enantiomer salts (R)-(+)-RBZ-Na and (S)-(−)-RBZ-Na formulations were initiated. Drugs were orally applied by gavage at 10 mg kg−1body weight per day during 30 days. Experimental treatments with benzimidazole sodium salts resulted in a significant reduction of the weight of cysts compared to conventional ABZ treatment, except for the (S)-(−)-RBZ-Na enantiomer formulation. Scanning electron microscopy and histological inspection revealed that treatments impacted not only the structural integrity of the parasite tissue in the germinal layer, but also induced alterations in the laminat...
Parasitology Research, 2013
Alveolar echinococcosis (AE) caused by the cestode Echinococcus multilocularis (E. multilocularis) is endemic in wide areas of the Northern hemisphere. Untreated AE progresses and leads to death in more than 90 % of cases. Until the advent of benzimidazoles, no antihelminthic drugs were available to cure AE. Benzimidazoles have greatly improved the prognosis of patients with AE. However, benzimidazoles have only a parasitostatic effect on E. multilocularis. Albendazole (ABZ) must sometimes be withdrawn because of adverse events. Alternative drugs are urgently needed. The antihelminthic triclabendazole (TCZ) and clorsulon (CLS) are more effective than ABZ to cure infections by the liver flukes Fasciola spp. The efficacy of TCZ and CLS was investigated on an in vitro culture of E. multilocularis larval tissue. E. multilocularis vesicles were evaluated for their morphology before and after adding TCZ, TCZ sulfoxide (TCZSX) and CLS to the larval tissue culture. TCZ at the concentrations of 20 μg/ml culture solution led to maximum vesicle damage within 12 days and of 25 μg/ml within 13 days, and TCZSX at the concentrations of 20 μg/ml within 20 days and of 25 μg/ml within 14 days. Contrary, CLS added at 5, 10 and 15 μg/ml to culture solution did not lead to any vesicle damage. TCZ is a promising further candidate drug for the treatment of AE.
Parasite, 2003
Two different preparations, solution and suspension, of three benzimidazole carbamate drugs, mebendazole, albendazole and ricobendazole, were compared by analyzing their in vivo activity against Echinococcus granulosus cysts in a mouse model. Polyvinylpyrrolidone was used for the elaboration of drug solutions and these formulations manifested better results in terms of reduction of number of viable hydatid cysts in mice than the reference drug suspensions. The effect was more prominent on mebendazole-treated mice, at doses of 25-50 mg/kg. There was a correlation between ED50 and pharmacokinetical parameters of AUC0 and CMAX, showing that a significant improvement on solubility affects the in vivo activity of these drugs.
Echinococcus granulosus: EVALUATION OF PROTOSCOLICIDAL ACTIVITY OF SEVERAL SUBSTANCES
Revista de Patologia Tropical, 2011
Surgical treatment of hydatid disease requires the use oi" protoscolicidal substances Io preveni secondary infection of the patients. The most comrnonly used substance ín Chile is Na Cl (20%) due to its low frequency oí' adverse effects. W e tested the protoscolicidal activity of two benzimidazole drugs, albendazole and mebendazole, currently used tòr chemotherapy of hydatidosís disease in humans. Bovine and human protoscolices were used in the test. Vitality of protoscolices was evaluated by Evans blue vital staining. Isolated protoscolices were exposed to several concentrations of albendazole and mebendazole lòr 10 min. Protoscolices were a!so exposed to hypertonic NaCl (20°ó) solulion for the same time. In protoscolices obtained from cattle, mebendazole at 300 |i£/ml produced lhe nighest mortalily (72.5%), followed by albendazole at 120 p-g/ml with a mortality oi" 69.5%. Hypertonic NaCl produced a 3.8% mortality. Protoscolices obtained from two patients were less susceptible to the treatments. Mebendazole at 600 ng/ml produced a 12% mortality. and albendazole at 120 ng/ml produced the highest mortality (14%). Untreated protoscolices remained viable during the test (98 to 100%). Under these conditions, the benzoimidazolic drugs were better protoscolicidal agents than Na Cl 20% and they were also more effective on the bovine cysts protoscolex than on those isolated trom humans. Further evaluation of benzimidazoles and other protoscolicidal substances should be carried out on parasites obtained from human patients.
In Vitro Parasiticidal Effect of Nitazoxanide against Echinococcus multilocularis Metacestodes
Antimicrobial Agents and Chemotherapy, 2003
) may result from the expanding parasite metacestode in visceral organs, mostly in the liver. Benzimidazole carbamate derivatives such as mebendazole and albendazole are used for chemotherapeutic treatment of AE. However, these treatments are, in most cases, parasitistatic rather than parasiticidal. As treatment is discontinued, a recurrence of parasite growth has been observed in many AE patients with nonradical resections. The only curative treatment for AE is radical surgical resection of the parasite tissue and support by chemotherapy. As there is a need for new treatment options for AE, the in vitro efficacy of nitazoxanide (NTZ), a broad-spectrum drug used against intestinal parasites and bacteria, was investigated. We showed that in vitro treatment of E. multilocularis metacestodes with NTZ induced high levels of alkaline phosphatase activity in the medium. Concurrently, distinct morphological and ultrastructural alterations were detected.
Antimicrobial Agents and Chemotherapy, 2011
The need to identify improved therapy against cystic echinococcosis (CE) has motivated pharmacology-based research. The comparative pharmacological performances of the benzimidazole compounds flubendazole (FLBZ) and albendazole (ABZ) were addressed here. The goals of the work were as follows: (i) to evaluate the ex vivo activities of FLBZ, ABZ, and their respective metabolites against Echinococcus granulosus protoscoleces, (ii) to compare the plasma and cyst disposition kinetics for the two drugs in infected mice, and (iii) to compare the clinical efficacies of FLBZ and ABZ against CE in mice. For the ex vivo study, E. granulosus protoscoleces were incubated with FLBZ, reduced FLBZ (R-FLBZ), ABZ, and ABZ-sulfoxide (ABZSO) (10 nmol/ml). Protoscolex viability was monitored by the methylene blue exclusion test and scanning electron microscopy (SEM). For the pharmacokinetic study, BALB/c mice with CE were allocated to two different groups and orally treated with either FLBZ or ABZ (5 mg...
In vitro effects of nitazoxanide on Echinococcus granulosus protoscoleces and metacestodes
Objectives: Infection of humans and domestic ruminants with the larval stage (metacestode) of Echinococcus granulosus results in cystic echinococcosis (CE). The metacestode causes a space-occupying lesion in visceral organs, most commonly in the liver. Benzimidazole carbamate derivatives, such as mebendazole and albendazole, are currently used for chemotherapeutic treatment of CE. In human patients, benzimidazoles have to be applied in high doses for extended periods of time, and adverse side effects are frequently observed. In order to evaluate alternative treatment options, the in vitro efficacy of nitazoxanide, a broad-spectrum drug used against intestinal parasites and bacteria, was investigated.
An experimental in vitro model for evaluating drugs against protoscoleces of Echinococcus granulosus
Journal of Helminthology, 1990
ABSTRACTPharmacological studies carried out on protoscoleces in vitro to standardize conditions that would permit a preliminary estimate of the efficacy of drugs with potential activity against Echinococcus granulosus are reported. Media such as PBS and Hanks solution, maintenance temperature, different pH values and concentrations of various solvents have been tested to check the effects on protoscolex survival in tubes in vitro. Mebendazole has been used as the pharmacological standard reference. Changes in the viability of protoscoleces have been used to demonstrate pharmacological activity. Best conditions were obtained employing Hanks solution and propylene glycol at low concentrations. Mebendazole was not completely effective at the concentrations achievable in human therapy. Linear, reproducible results demonstrated that Hanks solution provides an ideal medium for pharmacological studies. Among tested solvents, propylene glycol and dimethyl sulphoxide showed no lethal activit...
In vitro effects of flubendazole on Echinococcus granulosus protoscoleces
Parasitology Research, 2005
The aim of the present work was to determine the in vitro protoscolicidal effect of flubendazole (FLBZ) against Echinococcus granulosus. Protoscoleces of E. granulosus were incubated with FLBZ at concentrations of 10, 5 and 1 μg/ml. The first signs of FLBZ-induced damage were observed 3 days post-incubation. A clear protoscolicidal effect, reducing the vitality of protoscoleces to 35.6±0.7%, was observed after 18 days of incubation. After 25 days of FLBZ incubation (5 μg/ml), the percentage of vital protoscoleces was 13.9±5.9%. Protoscolex mortality was 100% (10 and 1 μg/ml) and 0.7±0.7% (5 μg/ml) after FLBZ incubation for 30 days. Results of vitality tests were consistent with the tissue damage observed at the ultrastructural level. The primary site of damage was the tegument of the parasite. The morphological changes included contraction of the soma region, formation of blebs on the tegument, rostellar disorganization, loss of hooks and destruction of microtriches. The data reported in this article demonstrate a clear in vitro effect of FLBZ against E. granulosus protoscoleces.
Acta Tropica, 2013
Cyst echinococcosis (CE) is a zoonotic disease caused by the larval stage of the Echinococcus granulosus helminth parasite. The work reported here aimed to compare the efficacy of albendazole (ABZ) and flubendazole (FLBZ) against CE in naturally infected sheep. Additionally, their comparative pharmacokinetic behaviour and the assessment of serum liver enzymes activities were studied. Twelve (12) naturally infected sheep were allocated to the following experimental groups: unmedicated control group, FLBZtreated and ABZ-treated. Treatments were orally performed every 48 h, over 55 days at dose rate of 10 (FLBZ) and 8.5 (ABZ) mg/kg (equimolar dose rates). The efficacy of the drug treatments was based on protoscoleces' vitality/viability. The kinetic disposition assessment included the Initial and Final Kinetic Studies which implicated the collection of blood samples after both the first and the last drug administration. Blood samples were processed to measure drug concentrations by HPLC. The protoscoleces' vitality observed in the untreated control group (98%) was significantly reduced in the presence of both ABZ and FLBZ. 90% of mice inoculated with protoscoleces in the control group developed hydatid cysts in their peritoneal cavity (viability study). However, only 25% (FLBZ) and 33% (ABZ) of mice inoculated with protoscoleces recovered from Q3 treated sheep, developed hydatid cysts in their abdominal cavity. Reduced FLBZ (R-FLBZ) was the main metabolite recovered in the bloodstream after oral administration of FLBZ to sheep. Low plasma concentrations of FLBZ parent drug were measured up to 48 h post-administration. ABZ was not detected in plasma at any time post-treatment, being its metabolites ABZ sulphoxide (ABZSO) and ABZ sulphone Q4 (ABZSO 2) recovered in plasma. Hepatotoxicity due to the continued treatment with either ABZ or FLBZ was not observed. A 3-fold increase ethoxyresorufin O-deethylase activity, a cytochrome P450 1A (CYP1A)dependent enzyme reaction, was observed in liver microsomes obtained from sheep receiving ABZ, compared to those of the unmedicated and FLBZ-treated animals. In conclusion, FLBZ is an available anthelmintic which may be developed into an effective and safe drug for the human CE treatment. Despite the low plasma concentrations measured by FLBZ/R-FLBZ, an important reduction in protoscoleces' vitality was observed in cysts located in sheep liver. Modern pharmaceutical technology may help to greatly improve FLBZ systemic exposure improving its efficacy against CE.