RESUMO
Fasciolosis is a food and waterborne disease caused by Fasciola spp., representing a global health burden to various hosts, including humans and other animals. This study investigates the in vitro activity of tellurium- and selenium-containing diaryl dichalcogenides: diacetal ditelluride (LQ07), diacetal diselenide (LQ62), and diacetyl diselenide (LQ68) alone and in combination with ivermectin (IVM) against eggs of Fasciola hepatica. The eggs were exposed for 12 h with each organochalcogen (OC) (0.1 - 2 mmol l-1) and IVM (0.01 - 2 mmol l-1) following an incubation of 15 days, allowing embryonation. The inhibitory concentration of 50 % (IC50) of each OC or IVM was tested with the IC10, IC30, and IC50 of IVM or each OC, respectively. LQ07, LQ62, and LQ68, as well as IVM, demonstrated a concentration-dependent ovicidal activity. The peak ovicidal activity of 99.74 % was achieved when IVM was tested at 2.0 mmol l-1. LQ62 and LQ68 demonstrated greater ovicidal activity, having an IC50 < 0.32 mmol l-1 being 6.25-fold more toxic than IVM alone. The percentage of dead eggs was significantly higher in the IVM group (early mortality), as Se-containing OCs led to the (miracidia) embryonation of the eggs with no hatching (late mortality). Blending Se-containing OCs and IVM showed an additive effect of up to 27 % against F. hepatica eggs. The present data contribute to the potential use of blending-based therapeutic strategies to combat F. hepatica infections in eradication programs worldwide. The combinations may also act against multidrug-resistant strains, reinstating drug-based parasite control.
Assuntos
Fasciola hepatica , Ivermectina , Animais , Fasciola hepatica/efeitos dos fármacos , Ivermectina/farmacologia , Anti-Helmínticos/farmacologia , Concentração Inibidora 50 , Óvulo/efeitos dos fármacos , Calcogênios/farmacologia , Calcogênios/química , Fasciolíase/tratamento farmacológico , Fasciolíase/parasitologia , Fasciolíase/veterináriaRESUMO
Fasciola hepatica is a parasitic trematode that infects livestock animals and humans, causing significant health and economic burdens worldwide. The extensive use of anthelmintic drugs has led to the emergence of resistant parasite strains, posing a threat to treatment success. The complex life cycle of the liver fluke, coupled with limited funding and research interest, have hindered progress in drug discovery. Our group has been working in drug development against this parasite using cathepsin proteases as molecular targets, finding promising compound candidates with inâ vitro and inâ vivo efficacy. Here, we evaluated hybrid molecules that combine two chemotypes, chalcones and quinoxaline 1,4-di- N-oxides, previously found to inhibit F.â hepatica cathepsin Ls and tested their inâ vitro activity with the isolated targets and the parasites in culture. These molecules proved to be good cathepsin inhibitors and to kill the juvenile parasites at micromolar concentrations. Also, we performed molecular docking studies to analyze the compounds-cathepsins interface, finding that the best inhibitors interact at the active site cleft and contact the catalytic dyad and residues belonging to the substrate binding pockets. We conclude that the hybrid compounds constitute promising scaffolds for the further development of new fasciolicidal compounds.
Assuntos
Catepsinas , Fasciola hepatica , Simulação de Acoplamento Molecular , Quinoxalinas , Quinoxalinas/farmacologia , Quinoxalinas/química , Quinoxalinas/síntese química , Animais , Fasciola hepatica/efeitos dos fármacos , Fasciola hepatica/enzimologia , Relação Estrutura-Atividade , Catepsinas/antagonistas & inibidores , Catepsinas/metabolismo , Estrutura Molecular , Flavonoides/farmacologia , Flavonoides/química , Flavonoides/síntese química , Relação Dose-Resposta a Droga , Fasciolíase/tratamento farmacológico , Testes de Sensibilidade Parasitária , Anti-Helmínticos/farmacologia , Anti-Helmínticos/síntese química , Anti-Helmínticos/química , HumanosRESUMO
Fasciolosis is an important zoonotic disease caused by the trematode Fasciola hepatica, and it causes great losses in bovine production. The anthelmintic resistance is a major problem in the control of fasciolosis. In this study, the F. hepatica egg development and hatching test (EDHT) was used for the evaluation of the ovicidal activity of commercial drugs, commonly used for treating infected cattle, which reflects F. hepatica anthelminthic resistance in infected bovines, according to recent literature. Bile samples from F. hepatica naturally parasitized cattle were obtained from slaughterhouses in the cities of Lages and Otacílio Costa, Santa Catarina State, Brazil. The bile was washed, the eggs were recovered, quantified, and distributed in universal collectors, with a minimum of 1,000 eggs per vial. Four commercial drugs were used in this study, containing albendazole sulfoxide (ABDZ), closantel (CSTL), nitroxynil (NTXL), and triclabendazole with fenbendazole (TBZF). The drugs were diluted according to the manufacturer instructions. All drugs, and the respective control, were tested in triplicates, with the quantity of recovered eggs determining the number of drugs to be tested. The vials were incubated for 28 days at 27 °C, and the eggs were classified according to their degree of development under a stereomicroscope. In total, 121 egg samples were analyzed. Two samples were identified as resistant to TBZF. Undetermined resistance/susceptibility has been found in two isolates treated with ABDZ, one treated with NTXL and six treated with TBZF. CSTL did not present ovicidal activity and cannot be used in EDHT. This is the first time that commercial drugs were used in F. hepatica EDHT.
Assuntos
Anti-Helmínticos , Doenças dos Bovinos , Fasciola hepatica , Fasciolíase , Bovinos , Animais , Resistência a Medicamentos , Anti-Helmínticos/farmacologia , Anti-Helmínticos/uso terapêutico , Triclabendazol , Fasciolíase/tratamento farmacológico , Fasciolíase/veterinária , Nitroxinila/uso terapêutico , Fenbendazol/uso terapêutico , Doenças dos Bovinos/tratamento farmacológico , FezesRESUMO
In the fall of 2022, decreased triclabendazole (TCBZ) efficacy against F. hepatica was suspected in a sheep farm located in the Santa Cruz province, Argentinian Patagonia. Since TCBZ-resistance in F. hepatica has never been reported in this province, this study aimed to confirm potential TCBZ-resistance in F. hepatica and to evaluate the efficacy of closantel (CLO) and nitroxinil (NTX), through faecal egg count reduction test (FECRT), and the efficacy of albendazole (ABZ) through the in vitro egg hatch test (EHT) in sheep. Sixty-eight (68) animals were selected from a herd of eighty (80) female Merino naturally infected with F. hepatica based on eggs per gram of F. hepatica (EPGFh) counts and assigned into four (4) groups (n = 17 per group): Group Control, animals did not receive anthelmintic treatment; Group TCBZ, animals were orally treated with TCBZ (12 mg/kg); Group CLO, animals were orally treated with CLO (10 mg/kg); and Group NTX, animals were subcutaneously treated with NTX (10 mg/kg). The fluke egg output was monitored on days 0 and 21 post-treatment. For the EHT, liver fluke eggs were isolated from faecal samples (approx. 50 g) collected from animals of the control group. TCBZ efficacy against liver fluke was 53.4%, confirming the presence of TCBZ-resistant isolates on the farm. CLO and NTX were highly effective (100%) for the treatment of F. hepatica on this farm. The EHT was carried out in two different laboratories, in which was observed an ABZ efficacy of 95.8 (Bariloche) and 96.5% (Tandil). These results indicate the ABZ susceptibility of this F. hepatica isolate and the inter-laboratory precision of the test.
Assuntos
Fasciola hepatica , Fasciolíase , Doenças dos Ovinos , Feminino , Ovinos , Animais , Triclabendazol/uso terapêutico , Fasciolíase/tratamento farmacológico , Fasciolíase/veterinária , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Resistência a Medicamentos , Doenças dos Ovinos/tratamento farmacológico , Albendazol/farmacologia , Albendazol/uso terapêutico , Nitroxinila , Carneiro DomésticoRESUMO
About a third of the world population is infected by helminth parasites implicated in foodborne trematodiasis. Fascioliasis is a worldwide disease caused by trematodes of the genus Fasciola spp. It generates huge economic losses to the agri-food industry and is currently considered an emerging zoonosis by the World Health Organization (WHO). The only available treatment relies on anthelmintic drugs, being triclabendazole (TCBZ) the drug of choice to control human infections. The emergence of TCBZ resistance in several countries and the lack of an effective vaccine to prevent infection highlights the need to develop new drugs to control this parasitosis. We have previously identified a group of benzochalcones as inhibitors of cathepsins, which have fasciolicidal activity in vitro and are potential new drugs for the control of fascioliasis. We selected the four most active compounds of this group to perform further preclinical studies. The compound's stability was determined against a liver microsomal enzyme fraction, obtaining half-lives of 34-169 min and low intrinsic clearance values (<13 µL/min/mg), as desirable for potential new drugs. None of the compounds were mutagenic or genotoxic and no in vitro cytotoxic effects were seen. Compounds C31 and C34 showed the highest selectivity index against liver fluke cathepsins when compared to human cathepsin L. They were selected for in vivo efficacy studies observing a protective effect, similar to TCBZ, in a mouse model of infection. Our findings strongly encourage us to continue the drug development pipeline for these molecules.
Assuntos
Anti-Helmínticos , Chalconas , Fasciola hepatica , Fasciolíase , Animais , Camundongos , Humanos , Fasciolíase/tratamento farmacológico , Fasciolíase/parasitologia , Chalconas/farmacologia , Chalconas/uso terapêutico , Triclabendazol/farmacologia , Triclabendazol/uso terapêutico , Anti-Helmínticos/farmacologia , Anti-Helmínticos/uso terapêutico , CatepsinasRESUMO
Fasciola hepatica, the liver trematode, infects ruminants and causes economic loss. Because parasites are developing resistance to commercial drugs, the negative effects of parasitism are increasing. In this study, we aimed to evaluate the efficacy of cumin (Cuminum cyminum) essential oil against F. hepatica eggs and adults. The eggs were incubated with eight concentrations of the essential oil (0.031125-4.15 mg/mL), and viable eggs were counted after 14 days and classified as embryonated or non-embryonated. Adult flukes were incubated in Roswell Park Memorial Institute medium to ensure their viability and then incubated in essential oil. They were observed for 24 h after treatment. The adults were assessed with the two lowest effective oil concentrations used in the ovicidal test. Three controls were used for both tests: nitroxynil, a negative control, and Tween®80. After incubation in oil, the adult specimens were processed for histological analysis and stained with hematoxylin-eosin. In addition, the oil was tested for cytotoxicity using Madin-Darby bovine kidney cells to assess any possible effect on them. The oil was effective in ovicidal and adulticidal inhibition of the trematode, with statistically significant results. All concentrations assessed in the ovicidal test were 100% effective. The adult test was effective within 15 h and inactivated all the specimens at the highest concentration evaluated (0.06225 mg/mL). Histological analysis showed that cumin essential oil resulted in marked areas of vacuolization. The spines showed no structural changes but were surrounded by microvesicles. These findings indicated that cumin oil could be a potential compound in the control of fasciolosis.
Assuntos
Anti-Helmínticos , Cuminum , Fasciola hepatica , Fasciolíase , Óleos Voláteis , Bovinos , Animais , Fasciolíase/tratamento farmacológico , Fasciolíase/veterinária , Fasciolíase/parasitologia , Cuminum/química , Anti-Helmínticos/farmacologia , Anti-Helmínticos/uso terapêutico , Óleos Voláteis/químicaRESUMO
The biliary pathology, is undoubtedly one of the most frequent surgical pathologies in Chile, statistical data establish the incidence of biliary pathology in over 20 years 30% of women have biliary lithiasis, of these 10% will present some complication as it is coledocolithiasis. On the other hand, hepatic fascioliasis or dystomatosis is a disease caused by hepatic fasciola, or duela, sabuaypé or Distomun hepaticum, corresponds to a flatworm, trematode of the digenea class, with affinity to stay in liver tissue, which when performing the biological cycle of the parasite can be the cause of choledocholithiasis, cholecystitis, cholangitis, pancreatitis, among others. We present a clinical case of chronic intracholedocianfasciolitis diagnosed by ERCP3,4. METHODS: Descriptive observational study, in addition to a systematic review in databases such as Pub-Med/MEDLINE, Elsevier, Cochrane and manually through the Internet in journals and public bodies. This work seeks to collect information from different authors regarding its incidence, management and established treatments. RESULTS: Inclusion and exclusion criteria were defined to analyze the characteristics of the selected articles. We present the clinical case of a 47-year-old female patient, with a history of hypertension, type 2 diabetes mellitus and egg allergy who went to the Emergency Department due to a picture characterized by epigastralgia of 3 days of evolution. During endoscopic retrograde cholangio-pancreatography (ERCP), 2 suggestive images of lyte are seen inside that finally result in 2 apparent live parasites.
Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Doenças do Ducto Colédoco/parasitologia , Doenças do Ducto Colédoco/diagnóstico por imagem , Endossonografia/métodos , Fasciolíase/diagnóstico por imagem , Colangiopancreatografia Retrógrada Endoscópica/métodos , Doenças do Ducto Colédoco/tratamento farmacológico , Técnicas de Laboratório Clínico , Fasciola hepatica , Fasciolíase/tratamento farmacológicoRESUMO
The intensive use of anthelmintic drugs to control Fasciola hepatica infections in dairy cattle has resulted in the emergence of anthelmintic resistance. Cases of resistance to triclabendazole (TCBZ) have been reported worldwide. The main goal of this research was to evaluate the main five fasciolicides to control fasciolosis in dairy cattle in the Mantaro Valley, Peru. Two fecal egg count reduction tests were performed. In a first study, 24 naturally F. hepatica infected cattle were randomly grouped into three experimental groups (n = 8). Groups were treated with either TCBZ, nitroxynil (NTX) or closantel (CLOS). In a second experiment, 55 naturally infected cows were grouped into three experimental groups and treated with either TCBZ (n = 18), rafoxanide (RFX) + albendazole (ABZ) (n = 19) or clorsulon (CLN) + ivermectin (IVM) (n = 18). Therapeutic efficacy was determined following the WAAVP guidelines by measuring reduction in fluke egg output at days 15 and 30 post-treatment. Bootstrapping method was used to obtain the 95% confidence intervals. The efficacy of TCBZ was inadequate in both studies (≤80.8%). Closantel showed high efficacy (≥ 90%) at both days, while NTX showed 92.9% (83-100) and 82.1% (53.6-100), efficacy, at days 15 and 30, respectively. Efficacy for RFX were 92.1% (79.6-98.9) and 97.4% (94.1-99.4); and for CLN, 98.8% (97.6-100) and 80.1% (44.7-99.4), at days 15 and 30, respectively. The outcome of this study indicates reduced therapeutic efficacy of TCBZ against F. hepatica in an important dairy area of the Peruvian central highlands but also demonstrates the validity of four alternatives.
Assuntos
Anti-Helmínticos , Fasciola hepatica , Fasciolíase , Animais , Bovinos , Feminino , Anti-Helmínticos/uso terapêutico , Fasciolíase/tratamento farmacológico , Fasciolíase/veterinária , Nitroxinila/uso terapêutico , Peru , Rafoxanida/uso terapêutico , Triclabendazol/uso terapêuticoRESUMO
Fasciola hepatica, a worldwide-distributed liver fluke, is one of the causative agents of fasciolosis, a zoonotic disease that affects livestock and humans. In livestock, fasciolosis causes huge economic losses worldwide, reducing animal fertility, milk production, weight gain and condemnation of livers. In spite of the availability of drugs, such as triclabendazole (TCZ), for the treatment of fasciolosis, they do not necessarily prevent liver damage or parasite reinfection and can eventually increase parasite resistance. The aim of this research was to relate the hepatic function, haematological parameters, leukocyte counts in circulation and parasite egg shedding during F. hepatica acute and chronic phases of infection in cattle as well as to determine how these parameters change with TCZ-treatment of chronically infected cattle. Our results show that increased levels of serum aspartate aminotransferase (AST) and gamma glutamyltransferase (GGT) were detected in early stages of the experimental infection. Moreover, high circulating eosinophil count and plateletcrit levels were correlated with fluke number in livers from infected cattle. On the other hand, although TCZ-treatment in the chronic phase of infection reduced parasite burden and damage in the liver, it was not able to completely avoid them. In conclusion, our work sheds light into the physiopathological mechanisms induced during fluke infection in cattle, revealing the complexity of the host response to the infection, together with the effects of TCZ-treatment in chronically infected animals.
Assuntos
Doenças dos Bovinos , Fasciola hepatica , Fasciolíase , Animais , Bovinos , Doenças dos Bovinos/tratamento farmacológico , Doenças dos Bovinos/parasitologia , Fasciolíase/tratamento farmacológico , Fasciolíase/parasitologia , Fasciolíase/veterinária , Triclabendazol/uso terapêuticoRESUMO
In this work, we present an evaluation of the fasciolicidal efficacy of a new injectable formulation of fosfatriclaben in comparison with the subcutaneous closantel and oral triclabendazole formulations currently used in veterinary practice as fasciolicides. The study was carried out in vivo on Fasciola hepatica at 2, 4, 6 and 8 weeks of age in experimentally infected sheep. To evaluate the formulation, the percent reduction of the parasite load was measured and the number of fluke eggs. Fosfatriclaben was used at 6 mg/kg/IM (dose equivalent to triclabendazole content), closantel at 5% at 10 mg/kg/SC, and triclabendazole at 10 mg/kg/PO; the control group received no treatment. Fosfatriclaben showed fasciolicidal efficacies of 95.5 %, 100 %, 100 % and 100 %, and triclabendazole showed similar efficacies of 97.4 %, 100 %, 100 % and 100 %, at the different treatment weeks (P > 0.05). Closantel showed limited efficacy against 2-, 4- and 6-week-old flukes but 100 % efficacy in adult flukes. All three evaluated formulations eliminated all 8-week-old F. hepatica trematode eggs. Although fosfatriclaben and triclabendazole showed similar fasciolicidal efficacy, the intramuscular administration of fosfatriclaben has several advantages over the oral administration of triclabendazole, such as ease of administration for veterinary use and a reduced risk of accidents for both the operator and the animals. In addition, the dose used in this injectable formulation is only 60 % of the oral dose, which reduces environmental contamination.
Assuntos
Anti-Helmínticos , Fasciola hepatica , Fasciolíase , Pró-Fármacos , Doenças dos Ovinos , Animais , Anti-Helmínticos/administração & dosagem , Fasciolíase/tratamento farmacológico , Fasciolíase/veterinária , Pró-Fármacos/administração & dosagem , Ovinos , Doenças dos Ovinos/tratamento farmacológico , Resultado do TratamentoRESUMO
OBJECTIVES: Triclabendazole (TCBZ) is the recommended anthelmintic against Fasciola hepatica at a dose of 10 mg/kg body weight administered as a single or double dose. However, treatment failures to TCBZ standard-of-care (SOC) doses have been reported in humans. The aim of this study was to describe the effectiveness and tolerability of alternative TCBZ regimens in those patients who failed the SOC regimen for fascioliasis in Peru. METHODS: A retrospective study was conducted at a major referral centre for fascioliasis in Peru between 2002 and 2018. Inclusion criteria were cases with chronic F. hepatica infection who failed the SOC regimen for human fascioliasis with TCBZ at 10 mg/kg orally as single dose with food. RESULTS: A total of 27 cases (59% female; mean age 39.4 years, range 6-71 years) with chronic fascioliasis failed at least once the current SOC regimen of TCBZ. Of 27 cases, 21 failed a second treatment regimen. Multiple regimens of TCBZ were given to these patients until three consecutive stool examinations were negative for Fasciola eggs. The overall cure rate was 74%. TCBZ was well tolerated with minimal side effects. CONCLUSION: According to the results of this study, patients labelled as having 'TCBZ resistance' may respond to multiple regimens of TCBZ with a cure rate of 74%. Thus, the term 'TCBZ resistance' should be re-evaluated using biomarkers.
Assuntos
Fasciola hepatica , Fasciolíase , Adolescente , Adulto , Idoso , Animais , Criança , Fasciolíase/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Peru , Estudos Retrospectivos , Triclabendazol , Adulto JovemRESUMO
The objective of this study was to evaluate the effectiveness of the main anthelmintics used for the control of trematodes in cattle in an endemic area in the humid Mexican tropics. A diagnostic study was carried out in nine cattle farms to determine the prevalence of flukes through faecal examination. Only three farms with more than 20 cows positive to trematodes were chosen to determine the effectiveness of commercial anthelmintics (triclabendazole, TCBZ; ivermectin + closantel, (IVM + CLOS); IVM + clorsulon, (CLORS); nitroxynil, NITROX). The prevalence of Fasciola hepatica was 27.1% and 29.6% of paramphistomes. The faecal egg count of trematodes ranged from 0.0 to 12.2 eggs per gram of faeces. The highest effectiveness against F. hepatica was 96.7%, and 92.7% against paramphistomes. NITROX was the most effective in the control of trematodes, while other products, such as IVM + CLORS and TCBZ obtained values lower than 90%, which puts sustainable trematode control at risk. The presence of trematodes was observed on most farms, although the prevalence per herd was highly variable, which indicates that the trematodes F. hepatica and paramphistomes are endemic to the region and a suitable management programme is suggested to control infections caused by these parasites.
Assuntos
Anti-Helmínticos , Coinfecção , Fasciola hepatica , Fasciolíase , Animais , Anti-Helmínticos/farmacologia , Anti-Helmínticos/uso terapêutico , Bovinos , Coinfecção/tratamento farmacológico , Resistência a Medicamentos , Fasciolíase/tratamento farmacológico , Fasciolíase/epidemiologia , Fasciolíase/prevenção & controle , Feminino , México/epidemiologia , Contagem de Ovos de Parasitas/veterináriaRESUMO
Liver fluke Fasciola hepatica remains an important agent of foodborne trematode disease producing great economic losses due to its negative effect on productivity of grazing livestock in temperate areas. The prevailing control strategies based on antihelminthic drugs are not long term sustainable due to widespread resistance. Hence, vaccination appears as an attractive option to pursue for parasite eradication.
Assuntos
Fasciola hepatica/imunologia , Fasciolíase/imunologia , Vacinas/imunologia , Animais , Anti-Helmínticos/farmacologia , Antígenos de Helmintos/imunologia , Bovinos , Doenças dos Bovinos/tratamento farmacológico , Doenças dos Bovinos/imunologia , Doenças dos Bovinos/parasitologia , Fasciola hepatica/efeitos dos fármacos , Fasciolíase/tratamento farmacológico , Fasciolíase/parasitologia , Gado/imunologia , Vacinação/métodosRESUMO
The egg development test is a useful in vitro tool to detect albendazole (ABZ) resistance in Fasciola hepatica. ABZ is the only flukicidal compound with ovicidal activity. The described test is based on the ABZ capacity to affect parasite egg development and hatching in susceptible parasites, while this effect is lost in ABZ-resistant liver fluke isolates. Among many advantages, it is noted that the diagnostic test can be performed on eggs isolated from fecal samples (sheep and cattle), avoiding the sacrifice of animals necessary in controlled efficacy trials. The egg development test described here is a simple, inexpensive, and accessible method, previously employed for diagnosis of ABZ resistance in F. hepatica.
Assuntos
Albendazol/farmacologia , Resistência a Medicamentos/efeitos dos fármacos , Fasciola hepatica/efeitos dos fármacos , Fasciolíase/tratamento farmacológico , Doenças dos Ovinos/tratamento farmacológico , Animais , Bovinos , Ovos/parasitologia , Fasciolíase/parasitologia , Fezes/parasitologia , Ovinos/parasitologia , Doenças dos Ovinos/parasitologiaRESUMO
Trematode infections such as schistosomiasis and fascioliasis cause significant morbidity in an estimated 250 million people worldwide and the associated agricultural losses are estimated at more than US$ 6 billion per year. Current chemotherapy is limited. Triosephosphate isomerase (TIM), an enzyme of the glycolytic pathway, has emerged as a useful drug target in many parasites, including Fasciola hepatica TIM (FhTIM). We identified 21 novel compounds that selectively inhibit this enzyme. Using microscale thermophoresis we explored the interaction between target and compounds and identified a potent interaction between the sulfonyl-1,2,4-thiadiazole (compound 187) and FhTIM, which showed an IC50 of 5 µM and a Kd of 66 nM. In only 4 hours, this compound killed the juvenile form of F. hepatica with an IC50 of 3 µM, better than the reference drug triclabendazole (TCZ). Interestingly, we discovered in vitro inhibition of FhTIM by TCZ, with an IC50 of 7 µM suggesting a previously uncharacterized role of FhTIM in the mechanism of action of this drug. Compound 187 was also active against various developmental stages of Schistosoma mansoni. The low toxicity in vitro in different cell types and lack of acute toxicity in mice was demonstrated for this compound, as was demonstrated the efficacy of 187 in vivo in F. hepatica infected mice. Finally, we obtained the first crystal structure of FhTIM at 1.9 Å resolution which allows us using docking to suggest a mechanism of interaction between compound 187 and TIM. In conclusion, we describe a promising drug candidate to control neglected trematode infections in human and animal health.
Assuntos
Anti-Helmínticos/química , Anti-Helmínticos/farmacologia , Trematódeos/efeitos dos fármacos , Trematódeos/enzimologia , Infecções por Trematódeos/tratamento farmacológico , Triose-Fosfato Isomerase/antagonistas & inibidores , Animais , Anti-Helmínticos/uso terapêutico , Cristalografia por Raios X , Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Fasciola hepatica/efeitos dos fármacos , Fasciola hepatica/enzimologia , Fasciolíase/tratamento farmacológico , Fasciolíase/parasitologia , Feminino , Masculino , Mesocricetus , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Schistosoma mansoni/efeitos dos fármacos , Schistosoma mansoni/enzimologia , Esquistossomose mansoni/tratamento farmacológico , Esquistossomose mansoni/parasitologia , Infecções por Trematódeos/parasitologia , Triose-Fosfato Isomerase/metabolismoRESUMO
Albendazole is a benzimidazole derivative with anthelmintic activity. It is the treatment of choice for fasciolosis. The use of albendazole in South American camelids is common, however, there are no studies about the pharmacokinetics and pharmacodynamics of albendazole in alpacas and llamas. In the present study, a case of fiber loss (alopecia) in alpacas is described because of the suspected use of a high dose of albendazole. In a fasciolosis control program of an alpaca ranch located in the district of Nuñoa in Puno, Peru, 2184 alpacas were oral treated with albendazole (35-40â¯mg/kg). After 2â¯weeks of treatment the alpacas began to show loss of fiber in the abdomen, flanks and neck. The alpacas showed no other sign of disease. The alpacas recovered their fiber after 6â¯months. We suggest studies are needed to determine the safe dose of albendazole in alpacas.
Assuntos
Albendazol/efeitos adversos , Alopecia/veterinária , Anti-Helmínticos/efeitos adversos , Camelídeos Americanos , Fasciolíase/veterinária , Administração Oral , Albendazol/administração & dosagem , Albendazol/uso terapêutico , Alopecia/induzido quimicamente , Animais , Anti-Helmínticos/administração & dosagem , Anti-Helmínticos/uso terapêutico , Camelídeos Americanos/parasitologia , Fasciolíase/tratamento farmacológico , Fasciolíase/prevenção & controle , PeruRESUMO
On a farm with permanent history of fasciolasis a study was performed aimed to know the efficacy of triclabendazole (TCBZ) and then to contrast with that of nitroxynil. Thirty-nine cattle naturally infected with Fasciola hepatica were randomly allocated into 4 experimental groups: Group 1 (control) was left untreated. Group 2 was treated with of 12 mg/kg body weight (bw) of TCBZ by oral route. Group 3 treated with 24 mg/kg bw TCBZ orally. Group 4 was treated with 10 mg/kg bw of nitroxynil subcutaneously. The anthelmintic efficacy was calculated as the percentage of reduction in faecal egg count (FEC) at 14 and 28 d post-treatment. Results indicated that there were no significant differences in the percentage of FEC reduction between control group and the groups treated with 12 or 24 mg/kg of TCBZ. On the contrary, the treatment with nitroxinyl significantly reduced the FEC and decreased the percentage of positive animals. In conclusion, Fasciola hepatica is reported for first time as resistant to TCBZ in Chile, which highlights the need of rotating drugs and assessing the efficacy of the administered drug in order to avoid the selection of resistant worms.
Assuntos
Antiplatelmínticos/uso terapêutico , Fasciolíase/veterinária , Nitroxinila/uso terapêutico , Triclabendazol/uso terapêutico , Animais , Bovinos , Chile , Fasciolíase/tratamento farmacológico , Fezes/parasitologia , Contagem de Ovos de Parasitas , Resultado do TratamentoRESUMO
Abstract On a farm with permanent history of fasciolasis a study was performed aimed to know the efficacy of triclabendazole (TCBZ) and then to contrast with that of nitroxynil. Thirty-nine cattle naturally infected with Fasciola hepatica were randomly allocated into 4 experimental groups: Group 1 (control) was left untreated. Group 2 was treated with of 12 mg/kg body weight (bw) of TCBZ by oral route. Group 3 treated with 24 mg/kg bw TCBZ orally. Group 4 was treated with 10 mg/kg bw of nitroxynil subcutaneously. The anthelmintic efficacy was calculated as the percentage of reduction in faecal egg count (FEC) at 14 and 28 d post-treatment. Results indicated that there were no significant differences in the percentage of FEC reduction between control group and the groups treated with 12 or 24 mg/kg of TCBZ. On the contrary, the treatment with nitroxinyl significantly reduced the FEC and decreased the percentage of positive animals. In conclusion, Fasciola hepatica is reported for first time as resistant to TCBZ in Chile, which highlights the need of rotating drugs and assessing the efficacy of the administered drug in order to avoid the selection of resistant worms.
Resumo Em uma fazenda com histórico de fasciolose permanente, foi realizado um estudo com o objetivo de conhecer a eficácia do triclabendazol (TCBZ) e depois contrastar com o do nitroxinil. Trinta e nove bovinos naturalmente infectados com Fasciola hepatica foram distribuídos aleatoriamente em 4 grupos experimentais: Grupo 1 (controle), sem tratamento. O grupo 2 foi tratado com 12 mg/kg de peso vivo (PV) do TCBZ por via oral (VO). Grupo 3 tratado com 24 mg/kg de PV TCBZ por VO. O grupo 4 foi tratado com 10 mg /kg de PV Nitroxinil via subcutânea. A eficácia anti-helmíntica foi calculada comparando a percentagem de redução na contagem de ovos fecais (FEC) 14 e 28 dias pós tratamento. Não houve diferença significativa na porcentagem de redução FEC entre o grupo controle e os grupos tratados com 12 ou 24 mg/kg de TCBZ. Entretanto, o tratamento com nitroxinil reduziu significativamente o FEC e diminuiu a porcentagem de animais positivos. Em conclusão, a Fasciola hepatica é relatada pela primeira vez como resistente ao TCBZ no Chile, o que destaca a necessidade de realizar uma rotação em relação aos medicamentos anti-helmínticos e avaliar a eficácia do mesmo, a fim de evitar a seleção de vermes resistentes.
Assuntos
Animais , Bovinos , Fasciolíase/veterinária , Triclabendazol/uso terapêutico , Nitroxinila/uso terapêutico , Antiplatelmínticos/uso terapêutico , Contagem de Ovos de Parasitas , Chile , Resultado do Tratamento , Fasciolíase/tratamento farmacológico , Fezes/parasitologiaRESUMO
Abstract Currently, albendazole is one of the most commonly used drugs because of its affordability. The objective was to evaluate the histopathology of Fasciola hepatica specimens. For this, the efficacy test was performed on sheep treated with albendazole at the dose recommended for F. hepatica, in which the helminths recovered at necropsy were counted and separated for histology. Spermatogenic cells from parasites recovered from treated and control sheep were examined by microscopy. The fecal egg-count reduction test revealed 97.06% efficacy of albendazole in the treatment of F. hepatica. Changes in testicular tubule cells started 48 hours after treatment and became evident within 72 hours, at which point it became difficult to identify cell types. Primary and secondary spermatogonia became increasingly rare and intercellular vacuolization was more evident. Signs of apoptosis, with pycnotic nuclei and evidence of keriorrexia were observed at all times. Cell debris was identified 96 hours after treatment. The results indicated that parasitic spermatogenesis was severely affected by albendazole and demonstrated the importance of the use of histopathology for the diagnosis of therapeutic efficacy in field strains.
Resumo Na atualidade, o albendazol é uma das drogas mais usadas devido à sua acessibilidade econômica. O objetivo foi avaliar a histopatologia dos espécimes de Fasciola hepatica. Para isso, foi realizado o teste de eficácia em ovinos tratados com albendazol na dose recomendada para Fasciola hepatica, no qual os helmintos recuperados em necropsia foram contabilizados e separados para histologia. As células espermatogênicas de parasitas recuperados de ovinos tratados e controle foram examinadas por microscopia. O teste de redução de ovos por grama de fezes revelou 97,06% de eficácia do albendazol no tratamento de F. hepatica. As alterações nas células dos túbulos testiculares iniciaram-se 48 horas após o tratamento e tornaram-se evidentes em 72 horas, altura em que tornou-se difícil identificar os tipos de células. As espermatogônias primárias e secundárias tornaram-se cada vez mais raras e a vacuolização intercelular foi mais evidente. Sinais de apoptose, com núcleos picnóticos e evidência de cariorrexia foram observados em todos os momentos. Os detritos celulares foram identificados 96 horas após o tratamento. Os resultados indicaram que a espermatogênese parasitária foi severamente afetada pelo albendazol e demonstrou a importância do uso da histopatologia para o diagnóstico de eficácia terapêutica em cepas de campo.
Assuntos
Animais , Masculino , Feminino , Doenças dos Ovinos/tratamento farmacológico , Ovinos/parasitologia , Albendazol/administração & dosagem , Fasciola hepatica/efeitos dos fármacos , Fasciolíase/veterinária , Anti-Helmínticos/administração & dosagem , Contagem de Ovos de Parasitas , Doenças dos Ovinos/parasitologia , Fasciolíase/parasitologia , Fasciolíase/tratamento farmacológico , Fezes/parasitologiaRESUMO
Currently, albendazole is one of the most commonly used drugs because of its affordability. The objective was to evaluate the histopathology of Fasciola hepatica specimens. For this, the efficacy test was performed on sheep treated with albendazole at the dose recommended for F. hepatica, in which the helminths recovered at necropsy were counted and separated for histology. Spermatogenic cells from parasites recovered from treated and control sheep were examined by microscopy. The fecal egg-count reduction test revealed 97.06% efficacy of albendazole in the treatment of F. hepatica. Changes in testicular tubule cells started 48 hours after treatment and became evident within 72 hours, at which point it became difficult to identify cell types. Primary and secondary spermatogonia became increasingly rare and intercellular vacuolization was more evident. Signs of apoptosis, with pycnotic nuclei and evidence of keriorrexia were observed at all times. Cell debris was identified 96 hours after treatment. The results indicated that parasitic spermatogenesis was severely affected by albendazole and demonstrated the importance of the use of histopathology for the diagnosis of therapeutic efficacy in field strains.