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Metformin improves the therapeutic efficacy of low-dose albendazole against experimental alveolar echinococcosis.

ABSTRACT: Alveolar echinococcosis (AE) is a severe disease caused by Echinococcus multilocularis. Its chemotherapeutic treatment is based on benzimidazoles, which are rarely curative and cause several adverse effects. Therefore, it is necessary to develop alternative and safer chemotherapeutic strategies against AE. It has previously been shown that metformin (Met) exhibits considerable in vivo activity on an early-infection model of AE when administered at 50 mg kg−1 day−1 for 8 weeks. Here, the challenge is heightened by a 2-fold increase in parasite inoculum or by starting the treatment 6 weeks post-infection. In both cases, only the combination of Met (100 mg kg−1 day−1) together with a sub-optimal dose of albendazole (ABZ) (5 mg kg−1 day−1) led to a significant reduction in parasite weight compared to the untreated group. Coincidentally, drug combination showed the highest level of damage in E. multilocularis metacestodes. Likewise, Met alone or combined with ABZ led to a decrease in parasite glucose availability, which was evidenced as a lower intracystic glucose concentration. Therefore, the results demonstrate that combination therapy with Met and ABZ offers an alternative to improve the efficacy and reduce the toxicity of the high-dose ABZ monotherapy currently employed.

SUBMITTER: Loos JA

PROVIDER: S-EPMC11010535 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Metformin improves the therapeutic efficacy of low-dose albendazole against experimental alveolar echinococcosis.

Loos Julia A JA Coccimiglio Magalí M Nicolao María Celeste MC Rodrigues Christian Rodriguez CR Cumino Andrea C AC

Parasitology 20211020 1

Alveolar echinococcosis (AE) is a severe disease caused by Echinococcus multilocularis. Its chemotherapeutic treatment is based on benzimidazoles, which are rarely curative and cause several adverse effects. Therefore, it is necessary to develop alternative and safer chemotherapeutic strategies against AE. It has previously been shown that metformin (Met) exhibits considerable in vivo activity on an early-infection model of AE when administered at 50 mg kg−1 day−1 for 8 weeks. Here, the challeng ...[more]

PMID: 35184788

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Project description:Alveolar echinococcosis (AE) is a chronic and fatal infectious parasitic disease, which has not been well-researched. Current recommended therapies for AE by the World Health Organization include complete removal of the infected tissue followed by two years of albendazole (ABZ), administered orally, which is the only effective first-line anti-AE drug. Unfortunately, in most cases, complete resection of AE lesions is impossible, requiring ABZ administration for even longer periods. Only one-third of patients experienced complete remission or cure with such treatments, primarily due to ABZ's low solubility and low bioavailability. To improve ABZ bioavailability, albendazole bile acid derivative (ABZ-BA) has been designed and synthesized. Its structure was identified by mass spectrometry and nuclear magnetic resonance. Its physicochemical properties were evaluated by wide-angle X-ray diffraction, differential scanning calorimetry, scanning electron microscopy, and polarizing microscopy; it was compared with ABZ to assess its solubilization mechanism at the molecular level. To avoid the effects of bile acid on the efficacy of albendazole, the inhibitory effect of ABZ-BA on protoscolex (PSCs)s was observed in vitro. The inhibitory effect of ABZ-BA on PSCs was evaluated by survival rate, ultrastructural changes, and the expression of key cytokines during PSC apoptosis. The results showed that ABZ-BA with 4-amino-1-butanol as a linker was successfully prepared. Physicochemical characterization demonstrated that the molecular arrangement of ABZ-BA presents a short-range disordered amorphous state, which changes the drug morphology compared with crystalline ABZ. The equilibrium solubility of ABZ-BA was 4-fold higher than ABZ in vitro. ABZ-BA relative bioavailability (Frel) in Sprague-Dawley (SD) rats was 26-fold higher than ABZ in vivo. The inhibitory effect of ABZ-BA on PSCs was identical to that of ABZ, indicating that adding bile acid did not affect the efficacy of anti-echinococcosis. In the pharmacodynamics study, it was found that the ABZ-BA group had 2.7-fold greater than that of Albenda after 1 month of oral administration. The relative bioavailability of ABZ-BA is significantly better than ABZ due to the transformation of the physical state from a crystalline state to an amorphous state. Furthermore, sodium-dependent bile acid transporter (ASBT) expressed in the apical small intestine has a synergistic effect through the effective transport of bile acids. Therefore, we concluded that the NC formulation could potentially be developed to improve anti-AE drug therapy.

Dataset Information

Metformin improves the therapeutic efficacy of low-dose albendazole against experimental alveolar echinococcosis.

Publications

Metformin improves the therapeutic efficacy of low-dose albendazole against experimental alveolar echinococcosis.

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