Fortified anti-proliferative activity of niclosamide for breast cancer treatment: In-vitro and in-vivo assessment.

Breast cancer represents one of the top lethal cancer types among the females worldwide. Several factors manipulate the clinical outcome of the treatment as the stage of the cancer upon detection, genetic and hormonal factors, drug resistance and metastasis. Accordingly, drug's repositioning, enhancing the bioavailability and encapsulation into nanoparticles (NPs) are among the predilected pathways for enhanced therapeutic outcome. Niclosamide (NIC) is an anthelmintic drug and has been repositioned as anticancer agent after revealing its anti-neoplastic activity. Piperine (PIP) was used as food spice until its anticancer activity was discovered. However, their hydrophobicity constrains their therapeutic efficiency. The cytotoxicity of both drugs in the free form was tested on MCF-7 cells, and the results indicated a NIC cytotoxicity enhancement by PIP. Then, NIC and PIP were encapsulated successfully into F127-NPs with entrapment efficiency of 97 % and 82 %, respectively. Particle size, zeta potential, TEM and FTIR confirmed the micellization process and drug encapsulation. The developed NIC-NPs and PIP-NPs exerted potent anticancer effect as compared to the free forms. Accordingly, the mixture; NIC-NPs/PIP-NPs was tested and its cytotoxicity exceeded the individually encapsulated drugs. Flowcytometry assessment was performed and demonstrated an induced cell death through the apoptotic stage. Additionally, in-vivo therapeutic efficiency of NIC-NPs/PIP-NPs was assessed through Ehrlich ascites tumor and the nanocombination therapy exerted superior additive anticancer effect when compared to NIC-NPs which is attributed to the PIP-NPs induced bioavailability. The study can be considered the first one investigating the PIP role in bioenhancing the anti-proliferative activity of NIC to combat breast cancer.

[Effectiveness and cost analysis of two chemical molluscicides in hilly schistosomiasis-endemic regions].

OBJECTIVE: To investigate the effectiveness and cost of 50% and 80% wettable powder of niclosamide ethanolamine salt (NESWP) and 26% metaldehyde and niclosamide suspension concentrate (MNSC) in hilly schistosomiasis-endemic regions, so as to provide insights into the selection of chemical molluscicides in hilly regions. METHODS: In September 2020, a wasteland in Guanshanqiao Village, Yanrui Township, Yushan County of Jiangxi Province was selected as the experimental region, which was sectioned into five blocks and defined as four experimental groups (A1, A2, B, C) and a blank control group (D). 80% NESWP were given at doses of 1 g/m2 and 1.5 g/m2 in groups A1 and A2 using the spraying method, 50% NESWP was given at a dose of 2 g/m2 in Group B using the spraying method, and 26% MNSC was at a dose of 4 g/m2 in Group C using the spraying method, while no chemical treatment was given in Group D. Snail survey was performed using a systematic sampling method before chemical treatment and 1, 3, 7 d and 15 d post-treatment to examine the molluscicidal effect, and all molluscicidal costs were estimated to calculate the cost of chemical treatment per 1 m2 and the cost of the reduction in the mean density of living snails per 1%. RESULTS: The highest mortality of snails was 78.95% and the lowest density of living snails was 0.2388 snails/0.1 m2 in the experimental groups within 7 d of chemical treatment, and the highest mortality of snails was 94.74% and the lowest density of living snails was 0.058 0 snails/0.1 m2 7 d post-treatment. There were no significant differences in the snail mortality among the A1, A2, B and C groups 1 (χ2 = 2.250, P > 0.05), 3 (χ2 = 1.779, P > 0.05) or 15 d post-treatment (χ2 = 2.286, P > 0.05), while a significant difference was detected in the snail mortality among the four groups 7 d post-treatment (χ2 = 7.990, P = 0.046). In addition, there were no significant differences in the snail mortality between A1 and A2 groups 1 (χ2 = 0.724, P > 0.05), 3 (χ2 = 0.584, P > 0.05), 7 (χ2 = 0.400, P > 0.05) or 15 d post-treatment (χ2 = 0.251, P > 0.05). The costs of chemical treatment per 1 m2 were 0.58, 0.60, 0.64 Yuan and 0.73 Yuan in groups A1, A2, B and C, and the costs of the mean density of living snail per 1% reduction were 19.29, 20.44, 21.68 Yuan and 23.53 Yuan in groups A1, A2, B and C, respectively. CONCLUSIONS: 80% NESWP shows a high molluscicidal efficacy and low cost in hilly schistosomiasis-endemic regions.

[Comparison of molluscicidal cost and effectiveness between 5% niclosamide ethanolamine salt granules and 26% suspension concentrate of metalaldehyde and niclosamide ethanolamine salt].

OBJECTIVE: To compare the molluscicidal effects and cost-effectiveness of 5% niclosamide ethanolamine salt granules (NEG) and 26% suspension concentrate of metalaldehyde and niclosamide ethanolamine salt (MNSC) . METHODS: Two plots with high Oncomelania hupensis snail density were selected as research areas in Nanjing Chemical Industry Zone, and 5% NEG (40 g/m2) and 26% MNSC (40 g/m2) were used by the spraying method for snail control in the two plots, and their molluscicidal effects and cost-effectiveness were investigated and statistically analyzed. RESULTS: There was no significant difference between 5% NEG and 26% MNSC in the molluscicidal effects. The cost of 5% NEG was 1.25 times higher than that of 26% MN-SC per ten thousand square meters in snail control. CONCLUSIONS: The cost of 5% NEG is higher than that of 26% MNSC per ten thousand square meters in snail control. Their molluscicidal effects are similar.

Synthesis, Bioactivity Evaluation, and Toxicity Assessment of Novel Salicylanilide Ester Derivatives as Cercaricides against Schistosoma japonicum and Molluscicides against Oncomelania hupensis.

A series of novel salicylanilide ester derivatives were synthesized, characterized, and evaluated for cercaricidal potential against Schistosoma japonicum and molluscicidal potential against Oncomelania hupensis. Four derivatives exhibited remarkable cercaricidal activity superior to that of niclosamide. Among them, the most active compound, 4-chloro-2-((2-methoxy-4-nitrophenyl)carbamoyl)phenyl 4-methoxybenzoate (compound 4c), showed a marked minimum effective cercaricidal concentration as low as 0.43 µM and significant molluscicidal activity, with a 50% lethal concentration (LC50) of 0.206 g/m(2). Particularly, compound 4c displayed 88-fold decreased fish toxicity on Danio rerio and 44-fold reduced cytotoxicity on human kidney HEK293 cells in comparison with the toxicity of niclosamide. The results indicated that 4c could serve as a promising drug candidate, with environmental safety properties, against Schistosoma japonicum at transmission stages. The preliminary molecular mechanism of target compounds in Schistosoma japonicum cercariae was also investigated. Salicylanilide ester derivatives exhibited an inhibitory effect on nitric oxide synthase (NOS) but no effect on lactate dehydrogenase (LDH) and acetylcholinesterase (AChE), and a strong and significant correlation between NOS inhibitory efficacy and cercaricidal activity was observed. In addition, 4c could downregulate the expression of NOS in a dose-dependent manner. These results suggested that NOS was probably one of the drug targets of salicylanilide esters.

[Field evaluation of a novel plant molluscicide "Luo-wei" against Oncomelania hupensis IV molluscicidal effect in field of river beach in Dongzhi County, Anhui Province].

OBJECTIVE: To evaluate the field effect of the plant molluscicide "Luo-wei" (tea-seed distilled saponins, TDS) against the snail Oncomelania hupensis in the river beach in Anhui Province. METHODS: The immersing and spraying experiments were carried out in the river beach in Dongzhi County, Anhui Province, to assess the molluscicidal effect of 4% TDS comparing with 50% wettable powder of niclosamide ethanolamine salt (WPN). The chi(2) test or Fish's exact test was used to examine the differences between or among the molluscicidal effects by different environments, molluscicides, application methods, or days after the intervention. Meanwhile, the cost-effectiveness of the two molluscicides was analyzed. RESULTS: After 1, 2 , 3 d and 7 d of the immersion, the snail death rates in both TDS group and WPN group increased gradually, the snail death rates in the two groups after immersing for 7 d were 94.62% and 99.24%, respectively, and there was no significant difference between them ( chi(2) = 3.30, P > 0.05). After 1 , 3 , 7 d and 15 d of spraying, the snail death rates were 70.82%, 79.75%, 85.11% and 91.65% in the TDS group, and 77.71%, 84.27%, 91.90% and 95.58% in the WPN group, respectively, and the differences among the snail death rates of the two groups at each time point were statistically significant (all P values < 0.05). The costs of spraying were 316.71 yuan per 100 m2 for TDS and 309.71 for WPN. CONCLUSIONS: The molluscicidal effect of TDS has reached the requirements of national standard on nature source pesticides in the river beach of the middle and lower reaches of the Yangtze River. It is necessary to further evaluate its cost-effectiveness in large-scale field experiments in the future.

Optimizing molluscicide treatment strategies in different control stages of schistosomiasis in the People's Republic of China.

BACKGROUND: The application of chemical molluscicides is still one of the most effective measures for schistosomiasis control in P. R. China. By applying diverse molluscicide treatment scenarios on different snail densities in the field, we attempted to understand the cost-effectiveness of molluscicide application so as to prescribe an optimal management approach to control intermediate host snail Oncomelania hupensis under acceptable thresholds based on the goal of the National Schistosomiasis Control Programme. METHODS: The molluscicidal field trial was carried out in the marshland of an island along the Yangtze River, Jiangsu province, P.R. China in October 2010. Three plots in the island representing low-density, medium-density and high-density groups were identified after the baseline survey on snail density. Each snail density plot was divided into four experimental units in which molluscicide (50% niclosamide ethanolamine salt wettable powder) was applied once, twice, trice and four times, respectively. The logistic regression model to correlate snail mortality rate with the covariates of number of molluscicidal treatment and snail density, and a linear regression model to investigate the relationship between cost-effectiveness and number of molluscicidal treatment as well as snail density were established. RESULTS: The study revealed that increase in the number of molluscicide treatments led to increased snail mortality across all three population density groups. The most cost-effective regimen was seen in the high snail density group with a single molluscicide treatment. For both high and low density groups, the more times molluscicide were applied, the less cost-effectiveness was. However, for the median density group, the level of cost-effectiveness for two applications was slightly higher than that in one time. CONCLUSIONS: We concluded that different stages of the national schistosomiasis control/elimination programme, namely morbidity control, transmission control and transmission interruption, should utilize different molluscicide treatment strategies to maximize cost-effectiveness.