betadex and Trichinellosis

Albendazole is a benzimidazole carbamate extensively used in oral chemotherapy against intestinal parasites, due to its broad spectrum activity, good tolerance and low cost. However, the drug has the disadvantage of poor bioavailability due to its very low solubility in water; as a consequence, a very active area of research focuses on the development of new pharmaceutical formulations to increase its solubility, dissolution rate, and bioavailability. The primary objective of this study was to prepare randomly methylated β-cyclodextrins inclusion complexes to increase albendazole dissolution rate, in order to enhance its antiparasitic activity. This formulation therapeutic efficacy was contrasted with that of the pure drug by treating Trichinella spiralis infected mice during the intestinal phase of the parasite cycle, on days five and six post-infection. This protocol significantly decreased muscle larval burden measured in the parenteral stage on day 30 post-infection, when compared with the untreated control. Thus, it could be demonstrated that the inclusion complexes improve the in vivo therapeutic activity of albendazole.

Topics: Albendazole; Animals; Antiparasitic Agents; beta-Cyclodextrins; Calorimetry, Differential Scanning; Disease Models, Animal; Macromolecular Substances; Mass Spectrometry; Methylation; Mice; Muscle, Skeletal; Solubility; Trichinellosis; X-Ray Diffraction

Albendazole and mebendazole are widely used in the treatment of trichinellosis; however, chemotherapy failure has been reported. In an effort to develop new anthelminthic compounds, we examined a previously synthesized 2-(trifluoromethyl)-1H-benzimidazole derivative (1) that showed good in vitro activity against Trichinella spiralis muscle larvae but low in vivo efficacy. In order to improve the solubility of compound 1, an inclusion complex with 2-hydroxypropyl-β-cyclodextrin (1/HP-βCD) was prepared. When 1/HP-βCD was tested in vivo, it significantly reduced the ML burden (84%). In addition, a proteomic analysis of T. spiralis ML treated with 1 revealed significant changes in the expression levels of proteins involved in energy metabolism and the cytoskeleton of the parasite. Compound (1) also induced extensive ultrastructural changes in the cuticle, hypodermis and midgut of the parasite.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Anthelmintics; Benzimidazoles; beta-Cyclodextrins; Electrophoresis, Gel, Two-Dimensional; Gene Expression Regulation; Larva; Mass Spectrometry; Mice; Mice, Inbred BALB C; Microscopy, Electron, Transmission; Muscles; Proteomics; Trichinella spiralis; Trichinellosis

The purpose of this work is to study the molecular association that occurs between 2-hydroxypropyl-β-cyclodextrin (HPβCD) and 6-chloro-5-(1-naphthyloxy)-2-(trifluoromethyl)-1H-benzimidazole (RCB20), an antiparasitic compound recently found by our research group, with poor aqueous solubility. The complex stability constant and stoichiometric ratio determined by phase-solubility diagram and Job's plot provided evidence that HPβCD enhanced water solubility of RCB20 through inclusion complex formation. Two-dimensional ¹H NMR spectroscopy is used to study the molecular arrangement of inclusion complex in solution. These results are further supported using molecular modeling studies. In the solid state, the complexation is confirmed by differential scanning calorimetry, powder X-ray diffraction, and scanning electron microscopy. Finally, RCB20/HPβCD complex has better activity than RCB20 against the adult and muscle larvae phase of Trichinella spiralis.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Anthelmintics; Benzimidazoles; beta-Cyclodextrins; Calorimetry, Differential Scanning; Disease Models, Animal; Magnetic Resonance Spectroscopy; Mice; Models, Molecular; Molecular Conformation; Molecular Dynamics Simulation; Trichinellosis; X-Ray Diffraction

We evaluated whether the effectiveness of albendazole against encapsulated larvae increases when 2-hydroxypropyl-beta-cyclodextrin (HP-betaCD) is added to improve bioavailability.. Mice were infected with Trichinella spiralis and treated with albendazole alone, albendazole plus HP-betaCD or not at all (controls) (Experiment I). Both immediately after treatment [76 days post-infection (p.i.)] and later (139 days p.i.) larvae were recovered, and the mean count was expressed in proportion to the larva count for controls. To evaluate the infectivity of the recovered larvae, the larvae recovered at 76 days p.i. and 139 days p.i. were used to infect another three groups (Experiments II and III, respectively).. At 76 days p.i., the percentage of larvae recovered was 77.4% for mice treated with albendazole alone and 61.2% for those treated with albendazole plus HP-betaCD; at 139 days p.i., these percentages were 67.4% and 40.9%, respectively (Experiment I). In Experiments II and III, the percentage of larvae collected from the albendazole group and the combined-treatment group was 55.2% and 27.6%, and 53.1% and 26.6%, respectively. The ABZSO active metabolite was analysed to determine the bioavailability of albendazole. For the combined-treatment group, the area under the plasma concentration-time curve between 0 and 6 h was higher than that for the albendazole group.. These data suggest that HP-betaCD increases the bioavailability and consequently the effectiveness of albendazole against encapsulated Trichinella larvae.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Albendazole; Animals; Anthelmintics; beta-Cyclodextrins; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Excipients; Female; Humans; Larva; Mice; Mice, Inbred BALB C; Treatment Outcome; Trichinella spiralis; Trichinellosis

The bioavailability and anthelmintic activity of albendazole-cyclodextrin complexes (ABZ-CDC) compared to albendazole suspensions in carboxymethylcellulose (ABZ-CMC) was assessed in a mouse model for Trichinella infections. Swiss CD-1 mice experimentally infected with T. spiralis were treated with both formulations against enteral (adult worms) and parenteral (migrating and encysted larvae). Oral bioavailability was assessed in age matched mice treated with 50 mg/kg of both formulations. The anthelmintic effects and plasma concentration of the active metabolite albendazole-sulphoxide (ABZSO) enantiomer (-) were significantly increased following administration of ABZ-CDC in relation to ABZ-CMC.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Administration, Oral; Albendazole; Animals; Anthelmintics; beta-Cyclodextrins; Biological Availability; Cyclodextrins; Excipients; Mice; Stereoisomerism; Time Factors; Trichinella spiralis; Trichinellosis