RESUMO
Wheat bran is an abundant yet underutilized agricultural byproduct. Herein, the insoluble dietary fiber from wheat bran (WBIDF) was ultra-milled to investigate its impact on physicochemical properties and gastrointestinal emptying. SEM and CLSM showed that the laminar structure of WBIDF was disrupted as the particle size was significantly reduced. In the similar characteristic peaks appearing at 3410, 2925, 1635, 1041, and 895 cm-1 in the FT-IR spectra and at 2940, 1593, 1080, and 526 cm-1 in the Raman spectra, the peak intensity was increased as the particle size decreased. It may be that the hydrogen bonding between cellulose, hemicellulose, or other macromolecules was enhanced. X-ray diffraction showed cellulose type I results for all five samples. Correspondingly, the water-holding, swelling, and oil-holding capacities increased by 75.33 %, 52.62 %, and 75.00 %, respectively, in WBIDF-CW1.8 compared with WBIDF-CWy. Additionally, smaller particle sizes had lower viscosity, thereby enhancing intestinal propulsion and gastric emptying rates. Enhanced contact of the cecal tissue growth factor with the intestinal mucosa delayed ghrelin secretion and stimulated the secretion of motilin, gastrin, and cholecystokinin. In conclusion, the particle sizes of WBIDF were reduced through ultramicro-grinding, leading to altered structure, enhanced hydration and oil-holding capacities, decreased viscosity, and improved gastrointestinal emptying capacity.
Assuntos
Fibras na Dieta , Esvaziamento Gástrico , Tamanho da Partícula , Fibras na Dieta/análise , Animais , Camundongos , Cinética , Solubilidade , Masculino , ViscosidadeRESUMO
Background and aim: Sarcopenia has gained considerable attention in the context of hepatocellular carcinoma, as it has been correlated with a poorer prognosis among patients undergoing sorafenib or lenvatinib treatment for hepatocellular carcinoma (HCC). The clinical significance of sarcopenia in first-line advanced HCC patients treated with lenvatinib and programmed death-1 (PD-1) inhibitors needs to be clarified. Methods: Sarcopenia was diagnosed using CT (Computed tomography) or MRI (Magnetic Resonance Imaging), with the psoas muscle index (PMI) as the surrogate marker. Patients were grouped based on sarcopenia presences, and a comparative analysis examined characteristics, adverse events, and prognosis. The Cox regression analysis was applied to identify independent prognostic factors for survival, while nomograms were constructed to predict 1-year survival. Results: Among 180 patients, 46 had sarcopenia. Patients with baseline sarcopenia demonstrated significantly inferior median progression-free survival (mPFS) (3.0 vs. 8.3 months) and median overall survival (mOS) (7.3 vs. 21.6 months). The same results for mPFS (3.3 vs. 9.2 months) and mOS (9.4 vs. 24.2 months) were observed in patients who developed sarcopenia after treatment. Furthermore, significantly higher grade 3 or higher adverse events (AEs) (73.91% vs 41.79%, p<0.001) were recorded in the sarcopenia group compared to the non-sarcopenia group. In the multivariate analysis, distant metastasis, elevated PLR and CRP levels, and low PMI remained independent predictive factors for poor OS. Additionally, skeletal muscle loss remained a significant independent risk factor for PFS. We developed a nomogram incorporating these four indicators, which predicted 12-month survival with a C-index of 0.853 (95% CI, 0.791 - 0.915), aligning well with actual observations. Conclusion: The prognosis of patients with HCC and sarcopenia is significantly worse when treated with lenvatinib and PD-1 inhibitors. The combination regimen of lenvatinib plus PD-1 inhibitors should be cautiously recommended due to the inferior prognosis and higher AEs.
Assuntos
Carcinoma Hepatocelular , Inibidores de Checkpoint Imunológico , Neoplasias Hepáticas , Compostos de Fenilureia , Quinolinas , Sarcopenia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/mortalidade , Relevância Clínica , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/uso terapêutico , Prognóstico , Quinolinas/uso terapêutico , Quinolinas/efeitos adversos , Estudos Retrospectivos , Sarcopenia/tratamento farmacológico , Sarcopenia/etiologiaRESUMO
The burgeoning development of railway construction in plateau regions of southwest China necessitates innovative and environmentally sustainable approaches, particularly in the realm of tunnel construction, where the transfer of muck poses significant operational and environmental challenges. This research, pivoting around the application and configuration of electric muck transfer equipment in plateau railway tunnels, seeks to dissect the potentialities and impediments of transitioning from conventional diesel-powered machinery to electric alternatives, with a spotlight on mitigating environmental impacts and enhancing operational efficiency. Through an analytical lens, the study employs a case study methodology, leveraging data and insights from existing electric equipment models and their applications, provided by major manufacturers in China, to weave a comprehensive narrative around the practicalities, specifications, and challenges embedded in the adoption of electric machinery in plateau environments. The findings unveil a nuanced landscape, where the environmental and operational advantages of electric equipment are juxtaposed against a backdrop of technological, financial, and infrastructural hurdles, thereby crafting a complex tapestry of opportunities and challenges. The research further extrapolates policy recommendations and practical guidelines, advocating for a harmonized amalgamation of governmental policies, technological advancements, and strategic planning to navigate through the identified challenges and optimize the integration of electric equipment in tunnel construction practices. Envisaging future research pathways, the study underscores the criticality of perpetuating technological innovations, policy adaptations, and interdisciplinary research to further refine and enhance the application of electric muck transfer equipment in plateau railway tunnel projects, thereby contributing to the broader narrative of sustainable construction practices in challenging terrains.
RESUMO
Background: This research aimed to comprehensively assess the prognostic role of fibrinogen to prealbumin ratio (FPR) in BCLC A-C HCC patients treated by TACE and RFA. Methods: The research included 240 patients at stage BCLC A-C treated by TACE and RFA at Beijing Ditan Hospital of Capital Medical University from May 2011 to November 2018. Results: The results showed that the size of the tumor, vascular invasion, α-foetoprotein, cirrhosis, NLR, LMR, and PLR showed prognostic value in predicting 5-year OS. Besides, FPR (95% confidence interval: 1.006-1.013, hazard ratio: 1.009) was a prognostic factor for the prediction of 5-year OS in HCC. Conclusion: Our research indicated that FPR was a potential indicator for patients with BCLC A-C hepatocellular carcinoma after treatment of RFA and TACE.
RESUMO
BACKGROUND: This cohort study aimed to investigate the influence of fibrinogen on progression-free survival and overall survival in unresectable HCC cases treated by PD-1 and lenvatinib. METHODS: A total of 57 unresectable HCC cases who received lenvatinib and PD-1, such as toripalimab, camrelizumab, or sintilimab, in Beijing Ditan Hospital Affiliated to Capital Medical University were enrolled in this study. RESULTS: Vascular invasion, high FIB (>2.83g/L), and metastasis were highly correlated with low PFS. There was a significant correlation between a raised risk of death and metastasis and increased FIB (>2.83g/L). CONCLUSION: FIB is associated with outcomes of unresectable HCC cases treated by PD-1 and lenvatinib.
RESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) portends a worse prognosis. The objective of this study was to compare the efficacy of percutaneous radiofrequency ablation (RFA) combined with transarterial chemoembolization (TACE) plus sorafenib to that of the most commonly utilized regimen of TACE plus sorafenib in large HCCs with type I/II PVTT. METHODS: An open-label, single-center, prospective, randomized trial of participants with tumors ≥5 cm and type I/II PVTT was performed. Participants with previously untreated HCCs were divided into two groups: RFA + cTACE + sorafenib (study group, n = 40) and cTACE + sorafenib (control group, n = 40). The primary endpoint was the objective response rate (ORR), the secondary endpoints included the overall survival (OS); time to progression (TTP); and toxicity. Prognostic factors were analyzed using cox-regression analysis. RESULTS: 80 patients were enrolled into this study with integrated clinical data. Under a median follow-up of 506 days, the median age was 57.5 years (range: 28-80 years). The ORR of study group was higher than control group (70% vs 22.5%, p<0.001). Furthermore, the median OS of study group was superior to that of control group (468 days vs 219 days, HR: 0.44 [95% CI: 0.25-0.78], P = 0.005). Adverse events occurred with 100% probability in both groups (p>0.99), but no treatment-related deaths were recorded. Tumor encapsulation and attaining treatment response predict favorable OS in a multivariate Cox model. The rates of adverse events in both groups were 100% (p>0.99). There were no treatment-related deaths. CONCLUSIONS: RFA combined with TACE plus sorafenib is a safe, well-tolerated three-modality treatment for large HCCs with types I/II PVTT, and it demonstrated better efficacy than TACE plus sorafenib alone.
RESUMO
Human-wildlife conflict (HWC) has become a conservation focus for both protected area management and local communities in many parts of the world. The incidence and mediation of HWCs are rooted in coupled environmental and socioeconomic contexts. A systematic analysis of HWCs was undertaken in 2016 in the Wolong Nature Reserve located in Sichuan Province, southwestern China. Semi-structured interviews were conducted with 201 local households to understand the occurrence of wildlife damage, the wildlife species involved, the typical losses incurred, and the mitigation measures employed. The results revealed that local HWC has increased rapidly in recent years due to effective biodiversity conservation and ecological restoration policies. Despite the widespread occurrence of HWCs, with nearly all respondents stating that they had suffered a financial loss, appropriate compensation schemes are lacking. Local respondents' expected compensation amount and style were investigated, and it was concluded that integrated compensation and community development plans are needed to mediate and resolve HWC. In particular, greater attention should be given to reduce local households' dependence on agriculture and transform local livelihood strategies to alternative economic activities not related to farming, such as ecotourism development and migrating employment.
RESUMO
OBJECTIVE: To investigate the distribution and spreading speed of niclosamide spreading oil, as well as its effect against cercariae of Schistosoma japonicum. METHODS: The foamed plastic with a diameter of 4 mm served as a buoyage, which was placed at the center of the still water surface. The niclosamide spreading oil was dropped at 0.5 cm from the buoyage, the floating distance of the buoyage was observed, and the spreading speed and area of the niclosamide spreading oil were measured. A cylindrical bucket (at a diameter of 40 cm and height of 50 cm) was filled with de-chlorinated water at a temperature of 25 +/- 1 degrees C, and then 60 microl of the spreading oil was dropped at the center of the water surface. At 10 cm and 20 cm from the center, 1 ml water was sampled at water depths of 10, 20, 30, 40 cm and 50 cm, respectively, and the niclosamide concentrations were determined by using high-performance liquid chromatography in each sample. The niclosamide spreading oil was diluted into solutions at effective concentrations of 1.25 mg/L and 0.63 mg/L with ethanol, and then 10 microl of each solution was added to 24-well plates which contained S. japonicum cercariae to yield the niclosamide concentration of 6.25 x 10(-3) mg/L and 3.13 x 10(-3) mg/L per well, respectively. The survival of the cercariae was observed at different time. RESULTS: The spreading speeds and areas were 59, 55, 71, 90, 111, 122 cm/s and 153 cm/s, and 5.31, 5.89, 7.07, 10.06, 12.56, 15.20 m2 and 16.61 m2, respectively, while dropping 20, 30, 40, 50, 60, 70 microl and 80 microl of the niclosamide spreading oil on water surface. The spreading showed an accelerating trend with the increasing dropping volume, and there was a good linear relationship observed between them. In addition, the spreading area also enlarged with the increase in the dropping volume. After dropping 60 microl of the niclosamide spreading oil on water surface, the peak concentration of niclosamide reached 1.27 mg/L on water surface, and remained more than 0.07 mg/L 2 h later. However, the concentration of niclosamide was all lower than 0.04 mg/L at 10 cm under surface or more. Following the treatment with 6.25 x 10(-3) mg/L of niclosamide spreading oil for 1 min, all the cercariae were dead, while the mortality rates of the cercariae were 0, 1.39%, 13.89%, 19.44%, 43.06%, 69.44% and 79.17% at 1, 2, 3, 5, 10, 20 min and 30 min, respectively, after the treatment with 3.13 x 10(-3) mg/L of the drug. CONCLUSIONS: The niclosamide spreading oil is fast to spread and is kept retention for a long time on water surface, and exhibits high activity against S. japonicum cercariae, and it can be used for killing the cercariae on water surface and interrupting the transmission of schistosomiasis in the endemic field.
Assuntos
Cercárias/efeitos dos fármacos , Niclosamida/farmacologia , Schistosoma japonicum/efeitos dos fármacos , Esquistossomicidas/farmacologia , Animais , Niclosamida/químicaRESUMO
OBJECTIVE: To understand the sensitivity of Oncomelania snails collected from different months to niclosamide, so as to provide the scientific evidence for the standardization of methods for molluscicide screening and efficacy evaluation in laboratory. METHODS: The snails collected from the marshland of Zhenjiang City, Jiangsu Province month by month from June 2010 to May 2011. After being raised in laboratory for 24 h, the snails were randomly grouped, and then immersed in different concentrations of 50% wettable powder formulation of niclosamide ethanolamine salt at (25 +/- 1) degrees C with a humidity of 60%. The dead snails were identified and counted, and the mortality rate of snails and median lethal concentration (LC50) were calculated. RESULTS: When the snails were immersed in the solutions of niclosamide at concentrations of more than 0.5 mg/L for 24 h, all the snails collected from different months were dead, while 60%-100% of the snail mortality was achieved for 0.250 mg/L niclosamide, 3%-27% for 0.125 mg/L niclosamide, and 3%-20% for 0.062 5 mg/L niclosamide. When the concentration was lower than 0.032 mg/L, the niclosamide was not toxic to the snails within 24 h. The LC50 value was 0.140-0.209 mg/L for 24 h. When the snails were immersed in the solutions of niclosamide at concentrations of more than 0.5 mg/L for 48 h, all the snails collected from different months were dead, while 90%-100% of the snail mortality was achieved for 0.250 mg/L niclosamide, 3%-57% for 0.125 mg/L niclosamide, 3%-13% for 0.062 5 mg/L niclosamide, and 0-10% for 0.032 mg/L niclosamide. When the concentration was lower than 0.016 mg/L, the niclosamide was not toxic to the snails within 48 h. The LC50 value was 0.112-0.170 mg/L for 48 h. There were no significant differences in the mortality of snails caused by niclosamide treatment observed at 24 and 48 h (P values = 0.374 and 0.267, respectively). CONCLUSIONS: There are little changes in the sensitivity of snails collected from different months to niclosamide, with minor fluctuations in LC50 values. Such a finding indicates that the snails collected from different months have few effects on screening of molluscicides and efficacy evaluation.
Assuntos
Laboratórios , Moluscocidas/farmacologia , Niclosamida/farmacologia , Caramujos/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Dose Letal Mediana , Niclosamida/análogos & derivados , Fatores de Tempo , MolhabilidadeRESUMO
Dihydroartemisinin, formerly known as an antimalarial drug, is the main metabolite of the mother compound artemisinins, as well as of artemether and artesunate. It has been shown that the drug exhibits antischistosomal efficacy against Schistosoma japonicum. The purpose of the current study was to assess the in vivo effect of dihydroartemisinin against Schistosoma mansoni infection in mice. Drugs at a single oral dose of 300 mg/kg were given to mice to assess the efficacy against different developmental stages of the parasite; juvenile and adult S. mansoni were treated with single doses of dihydroarteminisin with different regimens (at 200, 300, 400 or 600 mg/kg) in the stage of drug sensitivity, and the dose-response relationship was assessed; and the effect of multiple doses (at 200, 300 or 400 mg/kg) on juvenile and adult S. mansoni was also observed. The results showed that a single oral dose (300 mg/kg) of dihydroartemisinin reduced total worm burdens by 13.8-82.1% and female worm burdens by 13-82.8%, and the greatest reductions were seen when treatment was given on day 21 post-infection, with total and female worm burden reductions of 82.1% and 82.8%. Administration of a single oral dose of dihydroartemisinin on day 21 post-infection with different drug dosage (at 200, 300, 400 or 600 mg/kg) reduced total worm burdens by 70.3-87.3% and female worm burdens by 73.5-92.4%, depending on dosage. Similar treatments given on day 49 post-infection reduced total worm burdens by 48.7-68.73% and female worm burdens by 63.25-94.6%. There was obvious dose-response relationship of dihydroartemisinin against the schistosomula and adult worms of S. mansoni observed. Administration with dihydroartemisinin at oral doses of 200, 300 and 400 mg/kg, given once on each of days 20-22 post-infection of three successive days, reduced total worm burdens by 88.5-90.1% and female worm burdens by 89.2-92.1%, depending on dosage. Similar treatments given once on each of days 48-50 post-infection reduced total worm burdens by 60-70.3% and female worm burdens by 77.5-94.9%. It is concluded that dihydroartemisinin exhibits in vivo activity against various developmental stages of S. mansoni, particularly the 21-day schistosomula, and there is obvious dose-response relationship of dihydroartemisinin against the schistosomula and adult worms of S. mansoni observed.
Assuntos
Anti-Helmínticos/administração & dosagem , Artemisininas/administração & dosagem , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Administração Oral , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Camundongos , Carga Parasitária , Resultado do TratamentoRESUMO
OBJECTIVE: To investigate the preservation condition of niclosamide in water samples and establish a high performance liquid chromatography (HPLC) method by solid-phase extraction (SPE) which is used for determination and preservation of niclosamide in water samples. METHODS: Under the simulated setting in laboratory, niclosamide was formulated into the solutions of 0.50, 1.00 mg/L and 2.00 mg/L with fishpond water. The solutions were preserved at 25, 4, -40 degrees C and -40 degrees C (repeated freezing and thawing), respectively, or 0.2% acetic acid and twice volume of acetonitrile were added into the water samples, and then the solutions were passed through the activated column, and stored at room temperature, 16 days later, the column was washed, dried and re-dissolved, and niclosamide was determined by using the HPLC method. RESULTS: The concentration of niclosamide in water samples decreased at 25 degrees C or 4 degrees C, and did not change at -40 degrees C, but decreased after repeated freezing and thawing. No decrease of niclosamide was found in water samples for 16 days by using SPE. The recovery rate of HPLC was 98.12%-100.06% and the relative standard deviation (RSD) was less than 5%. CONCLUSIONS: The preservation of niclosamide in water samples is frozen and protected from light without repeated freezing and thawing. The SPE method does not need to be protected from light and freezing, which can simply and effectively purify, concentrate and store niclosamide in water samples.
Assuntos
Moluscocidas/química , Niclosamida/química , Poluentes Químicos da Água/química , Cromatografia Líquida de Alta Pressão , Estabilidade de MedicamentosRESUMO
Artemether and artesunate, derivatives of the antimalarial artemisinin, as well as their main metabolite, dihydroartemisinin, all exhibit antischistosomal activities. The purpose of the current study was to compare the effects of artemether, artesunate and dihydroartemisinin administered orally at multiple doses or combination in treatment of mice infected with Schistosoma japonicum. We carried out experiments with mice, infected with 40 cercariae of S. japonicum, and treated with artemether, artesunate and dihydroartemisinin (all at a single dose of 300 mg/kg, and the dose of the mixed three drugs is also 300 mg/kg) at multiple doses or combination therapy on days 6-8 or 34-36 post-infection. Administration with artemether, artesunate or dihydroartemisinin for 3 successive days reduced total worm burdens by 79.5-86% (30.86 ± 4.98 of mean total worm burden in control), female worm burdens by 79.4-86.7% (11.29 ± 2.63 of mean female worm burden in control) (all P values <0.01 vs. control), depending on different treatment protocols given on days 6-8 post-infection. However, no differences were seen between each treatment group (all P > 0.05). While the same treatment was given on days 34-36 post-infection, total worm burden reductions of 73.8-75.8% were achieved (29.44 ± 3.36 of mean total worm burden in control), which were significant when compared with the untreated control group (all P values <0.01). In all different treatment groups, female worm reductions (ranging from 88.7% to 93.1%, while the mean female worm burden in control is 10.33 ± 1.80) were consistently higher than the total worm reductions, resulting always in significantly lower female worm burdens when compared to the corresponding control (all P values < 0.01). However, there were no significant differences found between each treatment group (all P values >0.05). It is concluded that artemether, artesunate and dihydroartemisinin can be used to control schistosomiasis japonica, as a strategy to prevent S. japonicum infection. Administration with artemether, artesunate and dihydroartemisinin at multiple doses or in combined treatment damages both juvenile and adult S. japonicum, without statistically significant differences among the three drugs at the same dose.
Assuntos
Antiprotozoários/administração & dosagem , Artemisininas/administração & dosagem , Schistosoma japonicum/efeitos dos fármacos , Esquistossomose Japônica/tratamento farmacológico , Administração Oral , Animais , Artemeter , Artesunato , Modelos Animais de Doenças , Feminino , Camundongos , Doenças dos Roedores/tratamento farmacológico , Resultado do TratamentoRESUMO
OBJECTIVE: To investigate the possibility of the emergence of praziquantel resistance in Schistosoma japonicum in Mainland China under drug pressure. METHODS: S. japonicum cercaria were released from the infected Oncomelania hupensis snails collected from the marshland in Hunan Province that was endemic for schistosomiasis japonica and raised in the laboratory of Jiangsu Institute of Parasitic Diseases, and mice were infected. O. hupensis snails were infected with miracidia hatched from the schistosome mature eggs that were isolated from the liver of the infected mice. The life cycles of a field isolate and a laboratory passage isolate of S. japonicum were established in laboratory via the cycle of mouse-snail. The mice were infected with 40 cercariae each, 35 days later post-infection, were grouped randomly into control and resistance-induced groups. All the mice in the control group were sacrificed on day 45 post-infection, and any adult S. japonicum worms in the hepatic and portomesenteric veins were recovered and counted, and the worm burdens were calculated. The mice in the resistance-induced group were administered orally with the sub-curative dose of praziquantel, and were sacrificed 22 days post-treatment. Any adult S. japonicum worms in the hepatic and portomesenteric veins were recovered and counted, and the worm burdens and reduction in the worms recovered which were obviously caused by the praziquantel treatment were calculated. The eggs in the liver of the mice in the resistance-induced group were isolated and hatched to yield miracidia, and then the snails were again infected with the newly hatched miracidia to complete the first-passage inducement. After raising in laboratory at 25 degrees C for 60-70 days post-infection, the infected snails were isolated and shed cercaria, and the mice were infected with the newly released cercaria to start a new passage of resistance-inducement. The oral dose of praziquantel for the first-passage inducement was 100 mg/kg, and an additional 100 mg/kg was given every 2-3 passages. The mice were infected with cercariae of the parasite with 8-passge resistance-inducement and the isolate that was not induced, and 35 days post-infection, were administered with praziquantel at a single oral doses of 300 mg/kg and 600 mg/kg respectively. All the mice were sacrificed 14 days post - treatment, and any adult S. japonicum worms in the hepatic and portomesenteric veins were recovered and counted, and the reductions in the worm burdens were calculated to assess the sensitivity of praziquantel in the parasites after 8-passage resistance-inducement. RESULTS: Two isolates of Jiangsu laboratory passage of Jiangsu and field isolate of Hunan were established in the laboratory, and a total 8-passage resistance -inducement was completed. For the laboratory passage isolate, the worm burden reduction was 22.3% post-treatment with 100 mg/kg praziquantel during the first-passage inducement, and 53.7% post-treatment with 300 mg/kg praziquantel during the 8-passage inducement, appearing that the worm burden reduction increased with the increasing dose of praziquantel. For the field-collected isolate, the worm burden reduction was 66.8% post-treatment with 100 mg/kg praziquantel during the first-passage inducement, and 20.6% post-treatment with 300 mg/kg praziquantel during the 8-passage inducement, indicating that the worm burden reduction markedly decreased with the increasing dose of praziquantel. The worm burden reductions were 71.5% and 97.4% respectively for the mice infected with the non-induced laboratory passage isolate, while administered with praziquantel at doses of 300 mg/kg and 600 mg/kg respectively. After 8-passage treatment with sub-curative praziquantel, the corresponding worm burden reductions decreased to 32.6% and 68.1%, respectively. For the field-collected isolate without inducement, the worm burden reductions in the mice were 70.8% and 97.5% respectively post-treatment with praziquantel at doses of 300 mg/kg and 600 mg/ kg respectively, and the corresponding worm burden reductions decreased to 45.7% and 61.9%, respectively after 8-passage treatment. COCLUSIONS: S. japonicum (strain of Mainland China) is able to develop resistance to praziquantel under continuous drug pressure. However, there are variations in the potential of the emergence of resistance due to various susceptibility of praziquantel among different isolates. The successful establishment of praziquantel-resistant strain of S. japonicum (Mainland China) will provide the basis for exploring the mechanism of praziquantel resistance in S. japonicum, and developing related techniques to detect and monitor praziquantel resistance.
Assuntos
Resistência a Medicamentos , Praziquantel/farmacologia , Schistosoma japonicum/efeitos dos fármacos , Esquistossomose Japônica/parasitologia , Esquistossomicidas/farmacologia , Animais , Cercárias/efeitos dos fármacos , Cercárias/crescimento & desenvolvimento , China , Modelos Animais de Doenças , Feminino , Humanos , Fígado/parasitologia , Masculino , Camundongos , Schistosoma japonicum/crescimento & desenvolvimento , Schistosoma japonicum/fisiologia , Esquistossomose Japônica/tratamento farmacológico , Caramujos/parasitologiaRESUMO
OBJECTIVE: To investigate the changes of sensitivity to praziquantel (PZQ) about PZQ-resistant isolates of Schistosoma japonicum established in laboratory by means of the resistance-inducement method during the stages of adult worms, cercariae and miracidia, so as to provide the basis for establishing the sensitivity-detecting technique to praziquantel. METHODS: A Jiangsu laboratory-maintaining isolate and a Hunan field-collecting isolate of S. japonicum that were never treated with PZQ were as PZQ-susceptible isolates, and two PZQ-induced isolates that were established via drug-treated passage in laboratory were as PZQ-resistant isolates. Mice were infected with S. japonicum cercariae collected from above four isolates each. Thirty-five days after the infection, the mice were divided into 6 groups and administered orally with PZQ at dosages of 0, 37.5, 75, 150, 300 mg/kg and 600 mg/kg, respectively. All the mice were sacrificed two weeks after the treatment, and all the adult worms in the hepatic and portomesenteric veins were recovered and counted. The mean worm burden and reductions were calculated and input into Graphpad Prism 5.0 software, and the PZQ ED50 values of four isolates were calculated by the software. The cercariae of above four isolates were exposed to 10(-5), 5 x 10(-6), 10(-6), 5 x 10(-7), 10(-7) mol/L PZQ solutions for 20, 40, 60, 80, 100 min and the changes of tail shedding were observed under a dissecting microscope, then the tail shedding rates of cercariae were calculated. The miracidia of above four isolates were exposed to 5 x 10(-6), 10(-6), 5 x 10(-7), 10(-7) mol/L PZQ solutions for 1, 3 and 5 min and the morphological changes were observed under a dissecting microscope, then the morphological change rates of miracidia were calculated. RESULTS: The PZQ ED50 values of PZQ-susceptible and PZQ-resistant isolates of Jiangsu were 147.7 mg/kg and 565.5 mg/kg, respectively, and the PZQ ED50 values of PZQ-susceptible and PZQ-resistant isolates of Hunan were 151.8 mg/kg and 467.2 mg/kg, respectively. When the cercariae were exposed to 10(-5) mol/L PZQ solution over 20 min, the tail shedding rate of cercariae from PZQ-susceptible isolate of Jiangsu was 68.8%, and the tail shedding rate of cercariae from PZQ-resistant isolate of Jiangsu was 38.2% (P < 0.01). When the cercariae were exposed to 10(-7) mol/L PZQ solution over 100 min, the tail shedding rate of cercariae from PZQ-susceptible isolate of Jiangsu was 15.9%, and the tail shedding rate of cercariae from PZQ-resistant isolate of Jiangsu was 6.7% (P < 0.01). When the cercariae were exposed to 10(-5) mol/L PZQ solution over 20 min, the tail shedding rates of cercariae from PZQ-susceptible isolate of Hunan was 59.4%, and the tail shedding rates of cercariae from PZQ-resistant isolate of Hunan was 54.6% (P < 0.05). When the cercariae were exposed to 5 x 10(-7) mol/L PZQ solution over 40 min, the tail shedding rates of cercariae from PZQ-susceptible isolate of Jiangsu was 34.3%, and the tail shedding rates of cercariae from PZQ-resistant isolate of Jiangsu was 18.4% (P < 0.01). When the miracidia were exposed to 5 x 10(-7) mol/L and 10(-7) mol/L PZQ solutions for 1, 3 and 5 min respectively, the morphological change rates of miracidia from PZQ-susceptible isolates of Jiangsu and Hunan were significantly higher than those of PZQ-resistant isolates (P < 0.01). CONCLUSIONS: PZQ-resistant isolates of S. japonicum has been established in mice with sub-curative doses of PZQ by artificial selection in laboratory, and their sensitivities to PZQ are significantly lower than those of the isolates never treated with PZQ. The drug-resistance could exhibit in the stages of adult worms, cercariae and miracidia. The PZQ ED50 value of adult worms, the tail shedding rates of cercariae and the morphological change rates of miracidia as quantitative indicators can be used for monitoring the S. japonicum sensitivity to PZQ.