title: Secondary and primary murine alveolar echinococcosis: combined albendazole/nitazoxanide chemotherapy exhibits profound anti-parasitic activity.
abstract: In this study, the efficacies of chemotherapy employing nitazoxanide (NTZ), albendazole (ABZ), and a NTZ/ABZ-combination against alveolar echinococcosis (AE) were investigated in an experimental murine model. Following secondary infection, meaning i.p. injection of 20 Echinococcus multilocularis metacestodes, the drugs were administered by intragastric inoculation on a daily bases for a period of 5 weeks. Treatment was started either immediately on the day of infection, or at 2 months p.i., respectively. Application of the NTZ/ABZ-combination starting at 2 months p.i. was proven to be most effective in terms of reducing parasite weight (from 4.42+/-1.03 to 1+/-0.05 g; P=0.01). Inspection of treated parasites by transmission electron microscopy showed that ABZ- and NTZ-treated metacestode tissues, respectively, were heterogeneous in that both largely intact parasites as well as severely altered metacestodes could be observed. NTZ/ABZ-combination treatment induced the most severe ultrastructural alterations, including massive reduction in length and number of microtriches, severely damaged tegumental architecture, and progressive loss of viability of the germinal layer, associated with encapsulation by host connective tissue. A comparative pharmacokinetic study in mice revealed that the application of ABZ and NTZ in combination resulted in a two- to four-fold increase of albendazole sulfoxide serum levels for the period of 4-8 h following drug uptake compared to application of ABZ alone. In a third experiment, mice were orally infected with E. multilocularis eggs, and treated with NTZ starting at 2 months p.i. This resulted in a significantly lower lesion number in treated versus untreated mice (P=0.01). This investigation indicates the potential value for NTZ and/or a combined ABZ/NTZ chemotherapy against AE.
authors.affiliation: Faculties of Veterinary Medicine and Medicine, Institute of Parasitology, University of Berne, Langgass-Strasse 122, CH-3012 Bern, Switzerland.
authors.forename: Marianne
authors.initials: M
authors.lastname: Stettler
authors.forename: Jean François
authors.initials: JF
authors.lastname: Rossignol
authors.forename: Renate
authors.initials: R
authors.lastname: Fink
authors.forename: Mirjam
authors.initials: M
authors.lastname: Walker
authors.forename: Bruno
authors.initials: B
authors.lastname: Gottstein
authors.forename: Michael
authors.initials: M
authors.lastname: Merli
authors.forename: Regula
authors.initials: R
authors.lastname: Theurillat
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Thormann
authors.forename: Eric
authors.initials: E
authors.lastname: Dricot
authors.forename: Rudi
authors.initials: R
authors.lastname: Segers
authors.forename: Andrew
authors.initials: A
authors.lastname: Hemphill
mesh_terms: D015766:Albendazole / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D000977:Antiparasitic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D004443:Echinococcosis / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008854:Microscopy, Electron; D009574:Nitro Compounds; D011650:Pulmonary Alveoli / Q000469:parasitology* / Q000473:pathology; D013844:Thiazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000977:Antiparasitic Agents; D009574:Nitro Compounds; D013844:Thiazoles; D015766:Albendazole; C041747:nitazoxanide