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1.
Exp Parasitol ; 207: 107780, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31629699

RESUMO

Plant extracts used for the treatment of helminth infections in sheep are an alternative to chemical anthelmintic drugs. Previous studies have reported the anthelmintic activity of acetone leaf extracts of Leucosidea sericea. For this study, we evaluate the ultrastructure changes induced by the acetone leaf extract of L. sericea and the component agrimol G (AG) that was isolated for the first time on adult haemonchus parasites. Adult haemonchus parasites harvested from sheep were incubated with the plant extract and AG for 3 h and evaluated by both scanning and transmission electron microscopy in comparison and in combination with albendazole or ivermectin. In all cases the method of evaluation shows ultrastructural changes, with albendazole inducing mitochondrial damage and ivermectin inducing muscle degeneration, both as previously described. Incubation with the plant extract and AG resulted in the formation of numerous non-membrane bound multi-vesicular like bodies and evenly spread disruptions/erosion in the epicuticle. Combining AG with ivermectin or albendazole resulted in an absence of effect of AG. Based on the structural changes induced by AG, together with the absence of an effect in combination with ivermectin and albendazole would suggest a disrupted microtubular network. The latter does however require biochemical confirmation.


Assuntos
Anti-Helmínticos/farmacologia , Haemonchus/efeitos dos fármacos , Floroglucinol/química , Extratos Vegetais/farmacologia , Rosaceae/química , Abomaso/parasitologia , Albendazol/farmacologia , Animais , Quimioterapia Combinada , Fixadores , Glutaral , Hemoncose/parasitologia , Hemoncose/veterinária , Haemonchus/ultraestrutura , Ivermectina/farmacologia , Microscopia Eletrônica de Varredura/veterinária , Microscopia Eletrônica de Transmissão/veterinária , Extratos Vegetais/química , Ovinos , Doenças dos Ovinos/parasitologia
2.
Exp Parasitol ; 206: 107769, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31580876

RESUMO

BACKGROUND: Mansonellosis arises from infections with threadlike filarial nematodes in millions of individuals, especially in sub-Saharan Africa. Since infections present no overt clinical symptoms but attenuate immune responses that might lead to increased susceptibility and worsened disease course of concomitant infections, it is truly a neglected tropical disease. Nevertheless, only few studies focus on identifying suitable safe drugs for its control and little is known about the requirements for in vitro maintenance of the Mansonella perstans transmission stage. This study, therefore, evaluated the survival of M. perstans microfilariae (mf) using in vitro conditions that have been shown to promote survival of Loa loa, a closely related filarial nematode. Furthermore, the in vitro microfilaricidal effect of 15 agents was assessed on this helminth. METHODS: The ability of two basic culture media; Dulbecco's Modified Eagle's Medium (DMEM) and Roswell Park Memorial Institute (RPMI-1640) supplemented with 10% fetal bovine serum (FBS) and a monkey kidney epithelial cell line (LLC-MK2) to support the survival of M. perstans microfilariae was investigated. Subsequently, 6 anti-helminthics, 5 anti-malarials, 1 anti-microbacterial, 2 trypanocidals and 1 anti-cancer agent were tested in vitro against mf. The suitability of the culture media as well as the effect of the anti-infective agents on mf survival was assessed by scoring their motility. RESULTS: FBS supplement and additional LLC-MK2 cells significantly improved the survival of mf in DMEM and RPMI-1640 culture. In detail, RPMI-1640 supplemented with 10% FBS and LLC-MK2 cells sustained the maintenance of mf for at least 20 days (100.00 ±â€¯0.00% survival). In co-cultures with LLC-MK2 cells without serum, M. perstans mf were maintained in DMEM and RPMI-1640 medium with a motility above 99% by day 5. Mefloquine displayed the highest microfilaricidal effect in vitro followed by artesunate. CONCLUSION: Both RPMI and DMEM in the presence of LLC-MK2 cells are suitable for the maintenance of M. perstans mf in vitro. In absence of the feeder cells, the addition of 10% FBS to RPMI-1640 medium improved the parasite survival rate and motility. The microfilaricidal activity of mefloquine and artesunate on M. perstans mf was documented for the first time in this study and can therefore be considered as reference for further screening of agents against this parasite stage.


Assuntos
Artesunato/farmacologia , Filaricidas/farmacologia , Mansonella/efeitos dos fármacos , Mansonella/crescimento & desenvolvimento , Mefloquina/farmacologia , Amodiaquina/farmacologia , Animais , Antimaláricos/farmacologia , Antinematódeos/farmacologia , Área Sob a Curva , Bovinos , Linhagem Celular , Meios de Cultura/química , Haplorrinos , Ivermectina/farmacologia , Mansonella/fisiologia , Microfilárias/efeitos dos fármacos , Microfilárias/crescimento & desenvolvimento , Microfilárias/fisiologia , Movimento/efeitos dos fármacos , Rifampina/farmacologia
3.
Anticancer Res ; 39(9): 4837-4843, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519586

RESUMO

BACKGROUND/AIM: The antiparasitic drug, ivermectin (IVM), exerts anticancer activities in diverse cancer types. However, its anticancer activity against cholangiocarcinoma (CCA), especially the drug-resistant phenotype, has not yet been explored. MATERIALS AND METHODS: IVM was tested for its anticancer activity against gemcitabine-sensitive (KKU214) and gemcitabine-resistant (KKU214GemR) CCA cell lines in vitro using the sulforhodamine B and clonogenic assays as well as cell-cycle analysis. RESULTS: IVM treatment inhibited cell proliferation and colony formation of both KKU214 and KKU214GemR in a dose- and time-dependent manner. KKU214GemR cells were more sensitive than KKU214 to IVM treatment. IVM treatment caused S-phase cell-cycle arrest and also cell death as indicated by an increase of sub-G0/G1 population in KKU214GemR cells treated with IVM for 48 h. CONCLUSION: IVM exerts anti-CCA activities and gemcitabine-resistant KKU214GemR cells are more sensitive to IVM treatment. Thus, IVM might be useful as an alternative treatment for CCA, especially in patients who do not respond to gemcitabine.


Assuntos
Antiparasitários/farmacologia , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Ivermectina/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Desoxicitidina/farmacologia , Relação Dose-Resposta a Droga , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo
4.
Pestic Biochem Physiol ; 159: 144-153, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400776

RESUMO

Ivermectin is a pesticide that has been used for over 30 years in livestock. Although there are a number of studies on the therapeutic potential of ivermectin, little is known about the effects of the drug during the early stage of pregnancy. In this study, we investigated the detrimental effects of ivermectin on porcine trophectoderm (pTr) and uterine luminal epithelial (pLE) cells. Ivermectin not only inhibited the proliferation of both cells via the regulation of cell cycle-associated genes, but also induced apoptosis in pTr and pLE cells. We also verified its effect on mitochondrial dysfunction as shown by loss of mitochondrial membrane potential, mitochondrial Ca2+ overload, and reactive oxygen species (ROS) generation in pTr and pLE cells. As a mechanistic approach, we evaluated ivermectin-mediated cell signaling interactions including PI3K, AKT and MAPK pathways. Overall, our results suggest that constant exposure to and accumulation of ivermectin may cause abnormal fetal morphogenesis and placentation during the early stages of pregnancy. Our results may further provide a comprehensive understanding of the detrimental effects of ivermectin during pregnancy and will contribute to the establishment of a complete safety profile for ivermectin and its association with environmental pollution and public health in humans and livestock.


Assuntos
Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Ivermectina/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Útero/citologia , Animais , Proliferação de Células/efeitos dos fármacos , Feminino , Suínos , Trofoblastos/citologia , Trofoblastos/efeitos dos fármacos
5.
Parasit Vectors ; 12(1): 401, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31409391

RESUMO

BACKGROUND: Combination doxycycline/macrocyclic lactone (ML) protocols have been shown to provide a more rapid adulticidal and microfilaricidal effect than either MLs or doxycycline alone, although female worms were reported to have a higher tolerance to treatments compared to male worms. The present study aimed to evaluate how ABC transporters may be involved in the synergic effect of the combination treatment. Adult worms of D. immitis were treated in vitro for 24 hours with doxycycline (DOXY), ivermectin (IVM) and a combination of both, and changes in the modulation of ABC transporter genes were measured. Levels of doxycycline inside different treatment media, post-treatment, were determined through HPLC analysis. RESULTS: Quantitative RT-PCR analysis showed the presence of changes in the modulation of ABC transporter genes evaluated in this study. In particular, in female worms, the combination treatment induced a substantial increase in gene expressions, especially of Dim-pgp-10 and Dim-haf-4; whereas in male worms, the greatest increase in gene expression was observed for Dim-pgp-10 and Dim-pgp-11 when treated with DMSO + IVM and DMSO + DOXY/IVM. HPLC analysis of the DOXY concentrations in the media after in vitro treatments of male worms showed a slight difference between the DMSO + DOXY samples and the combination (DMSO + DOXY + IVM), while no difference was observed among females. CONCLUSIONS: Further studies are required to explain whether the modulation of cellular efflux plays a role, even partially, in the adulticide effect of doxycycline/macrocyclic lactone combinations in heartworm-infected dogs. To the authors' knowledge, this is the first study to evaluate P-gp expression in adult D. immitis.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Dirofilaria immitis/efeitos dos fármacos , Dirofilaria immitis/genética , Doxiciclina/farmacologia , Ivermectina/farmacologia , Animais , Dirofilariose/parasitologia , Cães , Combinação de Medicamentos , Feminino , Masculino
6.
J Agric Food Chem ; 67(36): 9989-9999, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31430135

RESUMO

Zein's prevalent hydrophobic character is one of the major challenges associated with ineffective utilization as an aqueous nanocarrier for pesticides. Herein, we report an effective approach to hydrophilic modification of zein by phosphorylation using nontoxic sodium tripolyphosphate (STP), thereby improving the water-solubility, foliage wettability, and adhesion ability of zein as a nanocarrier for sustained release of pesticides. The procedure relied on zein grafted with STP via N- and O- phosphate bonds and encapsulation of avermectin (AVM) as a hydrophobic model drug using phosphorylated zein (P-Zein), which achieved pH sensitivity to controlled release of AVM in various applicable environments. The chemical interaction between zein and STP was confirmed by Fourier transform infrared, thermogravimetric analysis, and differential scanning calorimetric. Scanning electron microscopy, dynamic light scattering, and zeta potential technique were applied to investigate their structural characteristics and stability, from which it was found that AVM encapsulated in P-Zein (AVM@P-Zein) formed uniform nanoparticles with average sizes in the range of 174-278 nm under different conditions, and had an excellent stability in aqueous solution. Besides, AVM@P-Zein facilitated the wettability on the foliage surface evidenced from contact angle values owing to the amphiphilic character after phosphorylation as well as enhanced the adhesion ability between liquid and leaf, restricting the pesticide runoff. Ultraviolet-visible spectroscopy was employed to explore the anti-UV property and encapsulation as well as release behavior, which revealed that the presence of P-Zein like a shell protects AVM from UV photolysis with encapsulation efficiency of approximately 81.52%, and the release of AVM from P-Zein showed pH-responsive behavior ascribed to protonation and deprotonation of phosphate under various pH conditions fitting to Elovich kinetic model, achieving the relatively more rapid release under acidic conditions. More importantly, AVM@P-Zein retained the toxicity for insecticidal effect.


Assuntos
Preparações de Ação Retardada/química , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Inseticidas/química , Ivermectina/análogos & derivados , Nanopartículas/química , Zeína/química , Animais , Preparações de Ação Retardada/farmacologia , Portadores de Fármacos/efeitos da radiação , Composição de Medicamentos/instrumentação , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Inseticidas/farmacologia , Ivermectina/química , Ivermectina/farmacologia , Cinética , Mariposas/efeitos dos fármacos , Mariposas/crescimento & desenvolvimento , Nanopartículas/efeitos da radiação , Fosforilação , Polifosfatos/química , Raios Ultravioleta , Zeína/efeitos da radiação
7.
BMC Vet Res ; 15(1): 297, 2019 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31420047

RESUMO

BACKGROUND: Raising cattle on pastures is known to be beneficial for animal welfare and cost reduction. However, grazing is associated with the risk of contracting tick-borne diseases, such as theileriosis. Here, the efficacy of ivermectin against these diseases and associated clinical symptoms were evaluated. RESULTS: A total of 68 cattle from a grazing cattle farm were selected and divided into two groups: the control group (17 cattle) with no preventive treatment and the ivermectin-treated group (51 cattle) in which cattle were treated with pour-on ivermectin prior to grazing. The infection rates of Theileria orientalis and the red blood cell (RBC) profile (e.g., RBC count, hematocrit value, and hemoglobin concentration) were compared in the spring (before grazing) and summer (during grazing) between the two groups. Based on PCR amplification of the major piroplasm surface protein (MPSP) gene, 12 cattle were positive for T. orientalis infection. Phylogenetic analysis revealed that the isolates identified in this study consisted of three MPSP types (1, 2, and 7). The T. orientalis infection rate in the control group during grazing was 3-fold higher than that in the ivermectin-treated group. Moreover, differences in RBC parameters during grazing were greater in the control group than in the ivermectin-treated group. In particular, the hematocrit value was significantly reduced in the control group. CONCLUSIONS: The results of this study demonstrated that ivermectin had protective effects against T. orientalis infection and RBC hemolysis in grazing cattle.


Assuntos
Doenças dos Bovinos/parasitologia , Ivermectina/farmacologia , Theileria/efeitos dos fármacos , Theileriose/tratamento farmacológico , Criação de Animais Domésticos , Animais , Antiparasitários/uso terapêutico , Bovinos , Doenças dos Bovinos/tratamento farmacológico , Filogenia , Theileriose/parasitologia
8.
Vet Parasitol ; 273: 24-31, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31442889

RESUMO

Haemonchus contortus, one of the most pathogenic of all small ruminant parasites, have developed resistance to all used anthelmintics. Detoxification enzymes, e.g. cytochromes P450 (CYPs) and efflux transporters P-glycoproteins (P-gps), which represent the main defense system against harmful xenobiotics, have been suggested to contribute to drug resistance development. The present study was designed to compare the constitutive expression of individual CYPs and P-gps in females and males of H. contortus adults and to follow up on the changes in expression of these genes in nematodes exposed to sub-lethal concentrations of ivermectin (IVM), which might occur during inaccurate treatment. The adults of inbred susceptible-Edinburgh strain (ISE, MHco3) of H. contortus were used for this purpose. The nematodes were incubated ex vivo with or without IVM (1, 10 and 100 nM) in culture medium for 4, 12 and 24 h. After incubation, total RNA was isolated and expression levels of individual CYPs and P-gps were analyzed using qPCR. Our results showed a great variability in the constitutive expression of individual CYPs and P-gps in H. contortus adults. The constitutive expression as well as the inducibility of CYPs and P-gps significantly differed in males and females. Contact of adult nematodes with sub-lethal IVM concentrations led to only minor changes in expression of CYPs, while expression of several P-gps, particularly pgp-9.2 in males and pgp-10, pgp-11 in females was increased significantly in IVM-exposed nematodes. In conclusion, inaccurate treatment of sheep with IVM might contribute to drug resistance development via increased expression of efflux transporters in H. contortus adults.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Sistema Enzimático do Citocromo P-450/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Haemonchus/efeitos dos fármacos , Ivermectina/farmacologia , Animais , Resistência a Medicamentos/genética , Feminino , Haemonchus/genética , Masculino
9.
Molecules ; 24(15)2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374818

RESUMO

Using nanotechnology to develop new formulations of pesticides is considered a possible option in enhancing the efficiency, safety, and photostability of pesticides under various climatic conditions. In the present study, two novel nanoformulations (NFs) were successfully prepared based on nano-delivery systems for emamectin benzoate (EMB) by loading it on cellulose nanocrystals (CNCs) and silicon dioxide nanoparticles (SNPs) as carriers through a freeze-drying method. The synthesized nanoformulations were examined using field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and dynamic light scattering (DLS). The results showed that SNPs and CNCs had a loading efficiency of 43.31% and 15.04% (w/w) for EMB, respectively, and could effectively protect EMB from photolysis under UV radiation. The LC50 values for EMB + SNPs, EMB + CNCs, and EMB commercial formulation against Phenacoccus solenopsis were 0.01, 0.05, and 0.31 µg/mL, respectively, indicating that both NFs were more effective than the EMB commercial formulation. This work seeks to develop new nano-carriers for potential applications of pesticides in plant protection, which will reduce the recommended dose of pesticides and thereby decrease the amount of pesticide residue in food and the environment.


Assuntos
Hemípteros/efeitos dos fármacos , Ivermectina/análogos & derivados , Nanopartículas/química , Animais , Celulose/química , Hemípteros/patogenicidade , Ivermectina/síntese química , Ivermectina/química , Ivermectina/farmacologia , Microscopia Eletrônica de Transmissão , Nanopartículas/ultraestrutura , Controle de Pragas/métodos , Dióxido de Silício/química , Espectroscopia de Infravermelho com Transformada de Fourier
10.
BMC Vet Res ; 15(1): 276, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375107

RESUMO

BACKGROUND: Mammary gland tumor is the most common spontaneous tumor in intact female dogs, and its poor prognosis remains a clinical challenge. Ivermectin, a well-known anti-parasitic agent, has been implicated as a potential anticancer agent in various types of human cancer. However, there are no reports evaluating the antitumor effects of ivermectin in canine mammary tumor. Here, we investigated whether ivermectin was able to inhibit canine mammary tumor development and explored the related mechanisms. RESULTS: Ivermectin inhibited the growth of canine mammary tumor cell lines in a dose- and time-dependent manner. The antitumor effects induced by ivermectin were associated with cell cycle arrest at G1 phase via down-regulation of CDK4 and cyclin D1 expression, with no significant induction of apoptosis. Furthermore, significantly reduced ß-catenin nuclear translocation was observed after treatment with ivermectin, resulting in the inactivation of WNT signaling. Consistent with the results in vitro, a significant suppression of tumor growth by ivermectin was observed in canine mammary tumor xenografts. CONCLUSION: Ivermectin, as a promising anti-cancer agent, inhibits the growth of canine mammary tumor by regulating cell cycle progression and WNT signaling.


Assuntos
Ciclo Celular/efeitos dos fármacos , Doenças do Cão , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ivermectina/farmacologia , Neoplasias Mamárias Animais , Proteínas Wnt/metabolismo , Animais , Antiparasitários/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cães , Feminino , Camundongos , Camundongos Nus , Neoplasias Experimentais/tratamento farmacológico , Proteínas Wnt/genética , beta Catenina/genética , beta Catenina/metabolismo
11.
J Fish Dis ; 42(10): 1351-1357, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31309582

RESUMO

Pseudocapillaria tomentosa is a pathogenic nematode parasite, causing emaciation and severe inflammatory lesions in the intestines in zebrafish Danio rerio (Hamilton 1822). Emamectin benzoate is commercially available analogue of ivermectin used for treating salmon for sea lice, under the brand name SLICE® , and we have used this for treating zebrafish with the P. tomentosa. Here, SLICE® , 0.2 per cent active emamectin benzoate, was used for oral treatments at 0.35 mg emamectin benzoate/kg fish/day for 14 days starting at 7 days post-exposure (dpe). Another experiment entailed initiating treatment during clinical disease (starting at 28 dpe). Early treatment was very effective, but delaying treatment was less so, presumably due to inappetence in clinically affected fish. We evaluated emamectin benzoate delivered in water, using Lice-Solve™ (mectinsol; 1.4% active emamectin benzoate) in two experiments. Application of four 24-hr treatments, space over 7 days was initiated at 28 dpe at either 0.168 or 0.56 mg emamectin benzoate/L/bath, and both treatments completely eradicated infections. This was 3 or 10 times manufacture's recommended dose, but was not associated with clinical or histological side effects.


Assuntos
Antinematódeos/farmacologia , Infecções por Enoplida/veterinária , Enoplídios/efeitos dos fármacos , Doenças dos Peixes/tratamento farmacológico , Ivermectina/análogos & derivados , Peixe-Zebra , Animais , Relação Dose-Resposta a Droga , Infecções por Enoplida/tratamento farmacológico , Feminino , Ivermectina/farmacologia , Masculino
12.
Vet Parasitol ; 270: 1-6, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31213235

RESUMO

In 2016 suspected reduced ivermectin (IVM) efficacy in Oesophagostomum species in pigs was reported in England. Following this initial report, APHA raised awareness amongst private pig veterinary practitioners of the need to monitor the efficacy of the worm control on pig units. In 2017 another veterinary practitioner highlighted a potential in-field lack of IVM efficacy in treating Oesophagostomum species in sows on another breeder-finisher unit. In this trial, the efficacy of IVM against Oesophagostomum species worms has been investigated to determine whether suspected reduced efficacy (52% reduction in mean faecal egg count 14 days post ivermectin administration) on a mixed indoor and outdoor breeder-finisher pig farm in England reflected true IVM resistance under controlled experimental conditions. On days 0 and 40 of the trial, twenty helminth-naive pigs were artificially infected per os with 5000 Oesophagostomum L3 obtained from the farm under investigation. The pigs were allocated to treatment or control groups (n = 10 per group). Treatment group pigs received IVM (0.3 mg kg body weight) by sub-cutaneous injection as per manufacturer's instructions on day 44. Control group animals were left untreated. Faecal worm egg counts were monitored throughout the trial from day 15 post infection to determine time to patency. On day 50 all pigs were euthanased to assess the worm burdens. Resistance to IVM was confirmed in Oesophagostomum dentatum based on the results of a faecal egg count reduction test (FECRT) and a controlled efficacy test (CET). Efficacy based on mean reduction in faecal egg count of IVM-treated pigs compared to untreated control pigs was 86%. Mean reduction in IVM-treated pig worm burdens was 5% against an adult worm population and 94% against an L3/L4 population. The apparent discrepancy between FECRT and CET efficacy results appears to be due to egg development and/or oviposition suppression in IVM-treated female worms. The detection of IVM resistance in Oesophagostomum species worms for the first time in UK pigs is particularly important considering the global situation where resistance to pyrantel, levamisole and benzimidazole anthelmintics in Oesophagostomum species in pigs have already been reported. The results also provide an opportunity to discuss the wider issue of anthelmintic usage and efficacy on pig farms and highlight the need for wider surveillance for the occurrence of anthelmintic resistance in pigs.


Assuntos
Resistência a Medicamentos , Ivermectina/farmacologia , Esofagostomíase/veterinária , Oesophagostomum/efeitos dos fármacos , Doenças dos Suínos/parasitologia , Animais , Anti-Helmínticos/administração & dosagem , Anti-Helmínticos/farmacologia , Inglaterra , Fezes/parasitologia , Ivermectina/administração & dosagem , Esofagostomíase/tratamento farmacológico , Esofagostomíase/parasitologia , Contagem de Ovos de Parasitas , Suínos , Doenças dos Suínos/tratamento farmacológico
13.
Ticks Tick Borne Dis ; 10(5): 1046-1050, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31175029

RESUMO

Rhipicephalus sanguineus sensu stricto (s.s.), the temperate lineage of the brown dog tick, is the most common tick found on dogs from urban areas in Rio Grande do Sul (RS) state, southern Brazil. Chemical treatments against ticks are important to control this pest, but can lead to selection for acaricide resistance. Unfortunately, little is known about acaricide resistance in this tick species in Brazil, although such information is very important to companion animal clinical practice. The objective of this study was to analyze acaricide susceptibility of R. sanguineus s.s. from the metropolitan area of Porto Alegre, RS. Engorged females ticks were collected in ten different locations, from naturally infested dogs or the environment (homes, shelters and kennels). The progenies were used in toxicological larval tests with deltamethrin, fipronil and ivermectin. Mortality data was used to determine the median lethal concentrations (LC50) for each tick population and resistance was characterized based on relative susceptibility of the different tick populations against each acaricide. Seven samples were considered resistant to deltamethrin, with resistance ratios (RR) ranging from 2.32 to 5.67. From five tick populations tested with fipronil, three were considered resistant, with RR varying from 2.56 to 13.83. For ivermectin, resistance ratios were lower, ranging from 1.54 to 2.97. The results reveal a notable variance of susceptibility to deltamethrin, fipronil and ivermectin in the R. sanguineus s.s. populations studied. This study documents for the first time the existence of acaricide-resistant populations of R. sanguineus s.s. in Brazil.


Assuntos
Acaricidas/farmacologia , Resistência a Medicamentos , Ivermectina/farmacologia , Nitrilos/farmacologia , Pirazóis/farmacologia , Piretrinas/farmacologia , Rhipicephalus sanguineus/efeitos dos fármacos , Animais , Brasil , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Rhipicephalus sanguineus/crescimento & desenvolvimento
14.
Food Chem Toxicol ; 131: 110576, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31199990

RESUMO

Ivermectin, a member of the avermectins, is one of the most used anti-parasitic agents, and acts by binding to glutamate-gated chloride channels in invertebrate nerve cells. There is limited information, however, on the effects of ivermectin in non-neural cell, such as adipocytes. The present work aimed to investigate the role of ivermectin in adipogenesis using 3T3-L1 preadipocytes. Ivermectin inhibited the differentiation of preadipocytes and triglyceride (TG) accumulation. In particular, the treatment of ivermectin at the middle to late adipogenic differentiation period (day 2-8) was correlated with the inhibition of fat accumulation. Ivermectin treatment also significantly modulated the mRNA expression of key markers in adipogenesis, fatty acid synthesis, uptake, and oxidation, and enhanced the gene expression of two subunits of the glycine receptor (GlyR). Specifically, the protein levels of peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), and acetyl-CoA carboxylase (ACC) were reduced. Interestingly, the suppression of TG accumulation by ivermectin was partially abolished by rosiglitazone, a specific PPARγ agonist, but Z-guggulsterone, a selective FXR antagonist, failed to rescue the ivermectin-induced effect on adipogenesis. Lastly, ivermectin prevented adipogenesis induced by permethrin and fipronil. In conclusion, ivermectin inhibits adipogenesis of 3T3-L1 preadipocytes partially via PPARγ & GlyR-dependent, but not FXR-dependent, pathway.


Assuntos
Adipogenia/efeitos dos fármacos , Antiparasitários/farmacologia , Ivermectina/farmacologia , Triglicerídeos/metabolismo , Células 3T3-L1 , Animais , Diferenciação Celular/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Camundongos , PPAR gama/metabolismo , RNA Mensageiro/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores da Glicina/metabolismo
15.
Exp Appl Acarol ; 78(3): 343-360, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31250237

RESUMO

Tetranychus urticae Koch is one of the most common and harmful pests in vegetable production areas. Similar to other countries, control of T. urticae is mainly based on acaricides in Turkey. However, T. urticae rapidly develops resistance and failures in chemical control have occurred frequently. The toxicity of various acaricides was investigated in ten T. urticae populations collected from vegetable crops in Turkey. In addition, populations were screened for the presence of currently known target-site resistance mutations. It was shown that resistance to bifenthrin was the most widespread, but also half of the populations were resistant to abamectin and hexythiazox. Resistance mutations in the voltage-gated sodium channel (VGSC) and chitin synthase 1 were found in various populations. Moreover, for the first time, F1538I and L1024V VGSC mutations were reported for Turkish populations. Mutations that confer resistance to abamectin, bifenazate and METI-I acaricides such as pyridaben were not detected. These results will contribute to the design of an effective resistance management program in Turkey.


Assuntos
Acaricidas/farmacologia , Resistência a Medicamentos/genética , Ivermectina/análogos & derivados , Piretrinas/farmacologia , Tetranychidae/efeitos dos fármacos , Tiazolidinas/farmacologia , Animais , Produtos Agrícolas/crescimento & desenvolvimento , Cadeia Alimentar , Ivermectina/farmacologia , Mutação , Tetranychidae/genética , Turquia , Verduras/crescimento & desenvolvimento
16.
J Exp Clin Cancer Res ; 38(1): 265, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31215501

RESUMO

BACKGROUND: Discovery and development of novel drugs that are capable of overcoming drug resistance in tumor cells are urgently needed clinically. In this study, we sought to explore whether ivermectin (IVM), a macrolide antiparasitic agent, could overcome the resistance of cancer cells to the therapeutic drugs. METHODS: We used two solid tumor cell lines (HCT-8 colorectal cancer cells and MCF-7 breast cancer cells) and one hematologic tumor cell line (K562 chronic myeloid leukemia cells), which are resistant to the chemotherapeutic drugs vincristine and adriamycin respectively, and two xenograft mice models, including the solid tumor model in nude mice with the resistant HCT-8 cells and the leukemia model in NOD/SCID mice with the resistant K562 cells to investigate the reversal effect of IVM on the resistance in vitro and in vivo. MTT assay was used to investigate the effect of IVM on cancer cells growth in vitro. Flow cytometry, immunohistochemistry, and immunofluorescence were performed to investigate the reversal effect of IVM in vivo. Western blotting, qPCR, luciferase reporter assay and ChIP assay were used to detect the molecular mechanism of the reversal effect. Octet RED96 system and Co-IP were used to determine the interactions between IVM and EGFR. RESULTS: Our results indicated that ivermectin at its very low dose, which did not induce obvious cytotoxicity, drastically reversed the resistance of the tumor cells to the chemotherapeutic drugs both in vitro and in vivo. Mechanistically, ivermectin reversed the resistance mainly by reducing the expression of P-glycoprotein (P-gp) via inhibiting the epidermal growth factor receptor (EGFR), not by directly inhibiting P-gp activity. Ivermectin bound with the extracellular domain of EGFR, which inhibited the activation of EGFR and its downstream signaling cascade ERK/Akt/NF-κB. The inhibition of the transcriptional factor NF-κB led to the reduced P-gp transcription. CONCLUSIONS: These findings demonstrated that ivermectin significantly enhanced the anti-cancer efficacy of chemotherapeutic drugs to tumor cells, especially in the drug-resistant cells. Thus, ivermectin, a FDA-approved antiparasitic drug, could potentially be used in combination with chemotherapeutic agents to treat cancers and in particular, the drug-resistant cancers.


Assuntos
Doxorrubicina/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ivermectina/administração & dosagem , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Vincristina/administração & dosagem , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Reposicionamento de Medicamentos , Sinergismo Farmacológico , Receptores ErbB/metabolismo , Feminino , Células HCT116 , Humanos , Ivermectina/farmacologia , Células K562 , Células MCF-7 , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , NF-kappa B/metabolismo , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Vincristina/farmacologia
17.
Vet Parasitol ; 269: 7-12, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31079830

RESUMO

Anthelmintic resistance is widespread in equine cyathostomin populations across the world, and with no new anthelmintic drug classes in the pharmaceutical pipeline, the equine industry is forced to abandon traditional parasite control regimens. Current recommendations aim at reducing treatment intensity and identifying high strongylid egg shedders in a targeted treatment approach. But, virtually nothing is known about the effectiveness of these recommendations, nor their applicability to different climatic regions, making it challenging to tailor sustainable recommendations for equine parasite control. This study made use of a computer model of the entire cyathostomin life-cycle to evaluate the influence of climate and seasonality on the development of anthelmintic resistance in cyathostomin parasites. Furthermore, the study evaluated the impact of recommended programs involving selective anthelmintic therapy on delaying anthelmintic resistance development. All simulations evaluated the use of a single anthelmintic (i.e., ivermectin) over the course of 40 model years. The study made use of weather station data representing four different climatic zones: a cold humid continental climate, a temperate oceanic climate, a cold semi-arid climate, and a humid subtropical climate. Initially, the impact of time of the year was evaluated when a single anthelmintic treatment was administered once a year in any of the twelve months. The next simulations evaluated the impact of treatment intensities varying between 2 and 6 treatments per year. And finally, we evaluated treatment schedules consisting of a combination of strategic treatments administered to all horses and additional treatments administered to horses exceeding a predetermined fecal egg count threshold. Month of treatment had a large effect on resistance development in colder climates, but little or no impact in subtropical and tropical climates. Resistance development was affected by treatment intensity, but was also strongly affected by climate. Selective therapy delayed resistance development in all modelled scenarios, but, again, this effect was climate dependent with the largest delays observed in the colder climates. This study is the first to demonstrate the value of cyathostomin parasite refugia in managing anthelmintic resistance, and also that climate and seasonality are important. This modelling exercise has allowed an illustration of concepts believed to play important roles in anthelmintic resistance in equine cyathostomins, but has also identified knowledge gaps and new questions to address in future studies.


Assuntos
Anti-Helmínticos/farmacologia , Simulação por Computador , Resistência a Medicamentos , Doenças dos Cavalos/parasitologia , Infecções Equinas por Strongyloidea/parasitologia , Strongyloidea/efeitos dos fármacos , Animais , Clima , Doenças dos Cavalos/tratamento farmacológico , Cavalos , Ivermectina/farmacologia , Refúgio , Estações do Ano , Infecções Equinas por Strongyloidea/tratamento farmacológico , Tempo (Meteorologia)
18.
Diagn Microbiol Infect Dis ; 95(1): 38-40, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31097261

RESUMO

The antihelminthic drug ivermectin has been demonstrated to have antiviral activity against the Zika virus and other arboviruses in in vitro studies. The effectiveness of ivermectin for Zika virus infection, however, has never been studied in an animal model. In this study, ivermectin was found to be ineffective for prevention of a lethal infection with the Senegal strain of Zika virus in Ifnar1 knockout mice. In view of several study limitations, evaluation of ivermectin's anti-Zika virus activity in other animal models and against other Zika virus strains would be desirable.


Assuntos
Ivermectina/farmacologia , Infecção por Zika virus/patologia , Zika virus/efeitos dos fármacos , Animais , Antivirais/farmacologia , Modelos Animais de Doenças , Esquema de Medicação , Camundongos , Camundongos Knockout , Falha de Tratamento , Células Vero , Zika virus/fisiologia , Infecção por Zika virus/prevenção & controle
19.
J Biochem Mol Toxicol ; 33(7): e22336, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30958899

RESUMO

Abamectin (ABA) is one of the most widely used compounds in agriculture and veterinary medicine. However, the cytotoxicity of ABA in human gastric cells is utterly unknown. In this study, ABA suppressed the proliferation of MGC803 cells by arresting the cell cycle at the G0/G1-phase. Moreover, ABA induced mitochondrial-mediated apoptosis by inducing the loss of mitochondrial membrane potential, upregulation of Bax/Bcl-2, and activation of caspase-3. ABA significantly improved the LC3-II/LC3-I ratio and reduced P62 protein expression in a dose-dependent manner. Through detection of the reactive oxygen species (ROS) levels, we found ABA induced the accumulation of intracellular ROS and then reduced PI3K/AKT signaling activation related to MGC803 cell apoptosis and autophagy. Our results indicate that ABA exerts cytotoxic effects on human MGC803 cells through apoptosis and autophagy by inhibiting ROS-mediated PI3K/AKT signaling. Furthermore, ABA may be a potential risk to human gastric health.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Ivermectina/análogos & derivados , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular , Humanos , Ivermectina/farmacologia , Espécies Reativas de Oxigênio/metabolismo
20.
Pestic Biochem Physiol ; 156: 56-62, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31027581

RESUMO

Glutamate-gated chloride channels (GluCls) mediate inhibitory synaptic transmission in invertebrate nervous systems, and only one GluCl gene has been found in insects. Therefore, insect GluCls are one of the major targets of insecticides including avermectins. In the present study, a 1347 bp full-length cDNA encoding a 449-amino acid protein (named MsGluCl, GenBank ID: MK336885) was cloned from the oriental armyworm, Mythimna separata, and characterized two alternative splicing variants of MsGluCl. The protein shares 76.9-98.6% identity with other insect GluCl isoforms. Spatial and temporal expression analysis revealed that MsGluCl was highly expressed in the 3rd instar and adult head. Dietary ingestion of dsMsGluCl significantly reduced the mRNA level of MsGluCl and decreased abamectin mortality. Thus, our results reveal that MsGluCl could be the molecular target of abamectin and provide the basis for further understanding the resistance mechanism to abamectin in arthropods.


Assuntos
Processamento Alternativo/genética , Canais de Cloreto/metabolismo , Clonagem Molecular/métodos , Mariposas/genética , Animais , Canais de Cloreto/genética , DNA Complementar/genética , DNA Complementar/metabolismo , Inseticidas/farmacologia , Ivermectina/análogos & derivados , Ivermectina/farmacologia , Mariposas/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
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