An alternative mebendazole formulation for cystic echinococcosis: the treatment efficacy, pharmacokinetics and safety in mice

Liu, Congshan; Zhang, Haobing; Lei, Wen; Zhang, Chao-Wei; Jiang, Bin; Zheng, Qi; Yin, Jun; Han, Xiumin

doi:10.1186/preaccept-1360059003131120

Cited by 3 publications

(4 citation statements)

References 19 publications

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“…MBZ's low solubility is hypothesized to be due, at least in part, to its planar structure causing strong stacking interactions in the crystal lattice, which are reinforced by intermolecular hydrogen bonds. 17 Previous studies have attempted to increase MBZ's bioavailability using oil-based formulations, 29 nanoformulations, 48,49 and prodrug strategies, 33,34 although with varied success. Our work extends and improves upon prior MBZ prodrug efforts by exploring alternative N-linked substituents including acyloxymethyl, aminoacyloxymethyl, and substituted phosphonooxymethyl promoieties.…”

Section: ■ Discussion and Conclusionmentioning

confidence: 99%

N-Substituted Prodrugs of Mebendazole Provide Improved Aqueous Solubility and Oral Bioavailability in Mice and Dogs

et al. 2018

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Mebendazole (MBZ) was developed as a broad-spectrum anthelmintic but has recently shown efficacy as an anticancer agent. The use of MBZ for cancer, however, is challenging due to its poor solubility leading to poor bioavailability. Herein, we developed a prodrug approach with various N-linked promoieties including acyloxymethyl, aminoacyloxymethyl, and substituted phosphonooxymethyl in attempt to improve these characteristics. Compound 12, containing an (((((isopropoxycarbonyl)oxy)methoxy)phosphoryl)oxy)methyl promoiety, showed a >10 000-fold improvement in aqueous solubility. When evaluated in mice, 12 displayed a 2.2-fold higher plasma AUC and a 1.7-fold improvement in brain AUC with a calculated oral bioavailability of 52%, as compared to 24% for MBZ-polymorph C (MBZ-C), the most bioavailable polymorph. In dogs, 12 showed a 3.8-fold higher plasma AUC with oral bioavailability of 41% compared to 11% for MBZ-C. In summary, we have identified a prodrug of MBZ with better physicochemical properties and enhanced bioavailability in both mice and dog.

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Section: ■ Discussion and Conclusionmentioning

confidence: 99%

N-Substituted Prodrugs of Mebendazole Provide Improved Aqueous Solubility and Oral Bioavailability in Mice and Dogs

et al. 2018

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“…Although the initial phase of the infection is always asymptomatic for many years or even permanently [ 2 ]. Without efficient treatment, the continuous development of the cyst will ultimately result in organ malfunction and even death in many cases [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

In Vitro Scolicidal Effects of <i>Salvadora persica</i> Root Extract against Protoscolices of <i>Echinococcus granulosus</i>

et al. 2016

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It has been known that Arak, Salvadora persica, has a number of medicinal properties. We tried to investigate in vitro scolicidal effect of root extracts of this plant against protoscolices from hydatid cysts of Echinococcus granulosus. Protoscolices were aseptically collected from sheep livers containing hydatid cysts. S. persica root extract was used in 10, 30, and 50 mg/ml concentration for 10, 20, and 30 min. The viability of protoscolices was ascertained by 0.1% eosin staining. Scolicidal activity of S. persica extract at a concentration of 10 mg/ml was 36.3%, 50.3%, and 70.8% after 10, 20, and 30 min of exposure, respectively. The scolicidal effect of this extract at a concentration of 30 mg/ml was 52.9%, 86.7%, and 100% after 10, 20, and 30 min of exposure, respectively. S. persica extract at a concentration of 50 mg/ml, meanwhile, killed 81.4%, 100%, and 100% of protoscolices after 10, 20, and 30 min, respectively. Also, the cytotoxic potential of S. persica was assessed on human liver cells (HepG2) using trypan blue exclusion test. No cytotoxic effect was observed on HepG2 cell line. The present study confirmed for the first time that the ethanolic extract of S. persica has high scolicidal power in vitro. However, in vivo effect of this material remains to be studied for treatment of echinococcosis in humans and herbivorous animals.

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“…Besides, the effects of some natural compounds, such as honey and vinegar, on these parasites have been evaluated and approved in vitro (21,22). The WHO only recommends albendazole and mebendazole for CE treatment (23). These benzimidazole drugs are used to treat many parasitic worm diseases.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, the MR of protoscolices was 100% in exposure to 75 mg/mL of VPA; even a VPA concentration of 50 mg/mL led to the death of 82% of protoscolices. Liu et al (2014Liu et al ( , 2015 found that the MR of protoscolices, exposed to 10 µg/mL of mebendazole during 24 hours, was 86%. These studies also showed that the incubation of protoscolices with higher concentrations of mebendazole in a longer exposure time increased the mortality of protoscolices, which is consistent with the present results (23,24).…”

Section: Discussionmentioning

confidence: 99%

Anti-hydatidosis Potential of Sodium Valproate: Evaluating New Therapeutic Potential for Sodium Valproate

Rezaie

Rahimi

Eslamirad

2022

Arch Clin Infect Dis

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Background: Larval stage of Echinococcus granulosus is the main cause of the hydatid cyst. Surgery, which is both aggressive and high-risk, is the most common treatment for this type of cyst. Some medicines, such as mebendazole, are also used as a complementary approach to preventing the recurrence of hydatid cysts. Objectives: Considering the approved antiparasitic effects of sodium valproate (VPA) on some parasites, this research intended to examine the potential of VPA against protoscolices and hydatid walls. Methods: Liver hydatid cysts caused by E. granulosus were collected from a slaughterhouse. Protoscolices and hydatid cysts were exposed to RPMI and dimethyl sulfoxide (DMSO) media (control groups) or different concentrations of VPA and mebendazole in vitro. The viability of protoscolices was evaluated via light microscopy. Also, tissue changes and expression of apoptotic caspase-3 were examined in hydatid cyst walls (HCWs) using histological and immunohistochemical methods, respectively. Results: The mortality rates of VPA-treated and mebendazole-treated protoscolices were dose- and time-dependent. There was a significant difference between the intervention and control groups (P < 0.05). Tissue changes and apoptosis were observed in VPA-treated and mebendazole-treated HCWs. Conclusions: Valproate and mebendazole had significant effects on protoscolices and HCWs, although VPA exerted its effects more rapidly. It seems that VPA can be a new promising protoscolicidal agent and anti-hydatid medicine.

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An alternative mebendazole formulation for cystic echinococcosis: the treatment efficacy, pharmacokinetics and safety in mice

Cited by 3 publications

References 19 publications

N-Substituted Prodrugs of Mebendazole Provide Improved Aqueous Solubility and Oral Bioavailability in Mice and Dogs

N-Substituted Prodrugs of Mebendazole Provide Improved Aqueous Solubility and Oral Bioavailability in Mice and Dogs

In Vitro Scolicidal Effects of <i>Salvadora persica</i> Root Extract against Protoscolices of <i>Echinococcus granulosus</i>

Anti-hydatidosis Potential of Sodium Valproate: Evaluating New Therapeutic Potential for Sodium Valproate

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