Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 470
Filtrar
1.
Am J Respir Cell Mol Biol ; 61(4): 537-540, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31573336
2.
Indian J Ophthalmol ; 67(10): 1768-1771, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31546560

RESUMO

To describe the optical coherence tomography (OCT) and electrophysiological changes in a case of closantel toxicity. A 25-year-old patient presented with sudden painless defective vision following intake of closantel. Visual acuity (VA) was counting fingers at 5 m in both eyes (BE). OCT revealed disruption of outer retinal layers and electroretinogram (ERG) and visual evoked potential (VEP) were subnormal in BE. The patient was treated with systemic corticosteroids, after which his VA improved to 6/9, OCT revealed preservation of central outer retinal layers, and ERG and VEP responses improved in BE. This is the first case report of successful treatment with systemic steroids for closantel-related reversible blindness.


Assuntos
Cegueira/induzido quimicamente , Retina/patologia , Salicilanilidas/envenenamento , Acuidade Visual , Adulto , Cegueira/diagnóstico , Cegueira/fisiopatologia , Angiofluoresceinografia , Fundo de Olho , Humanos , Inseticidas/envenenamento , Ionóforos , Masculino , Remissão Espontânea , Retina/efeitos dos fármacos , Tomografia de Coerência Óptica
4.
Sci Total Environ ; 694: 133726, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31400674

RESUMO

A complete study about the effects of 3,3',4',5-tetrachlorosalicylanilide (TCS) on organic matter elimination performance, sludge production and on the microbial community of a biological wastewater treatment process has been performed. For this purpose two sequencing batch reactors (SBR) worked in parallel for 43 days with 0.8 mg·L-1 of TCS (SBR-1) and without this metabolic uncoupler (SBR-2). Results indicated that 63.3% of sludge reduction was achieved in SBR-1. However, COD removal efficiency was maintained in similar values in both reactors (89.1% and 92.1% in SBR-1 and SBR-2, respectively). The exhaustive mixed liquor characterization led to know deeply the action mechanism of TCS. In this way, a 69% of adenosine triphosphate (ATP) reduction was observed in SBR-1 in comparison with values measured in SBR-2. On the contrary, an increase in soluble microbial products (SMP) and DNA concentrations occurred as a consequence of TCS addition. Thus, it could be concluded that sludge reduction due to TCS addition was due to both uncoupling effect and cellular lysis. Also, increase in all microbial hydrolytic enzymatic activities measured was observed, which explained the stable performance achieved in SBR-1 despite to the results explained above. It should be highlighted that this uncoupler should not be used in biological treatments that require nitrogen elimination because nitrifying bacteria were affected by its addition (Nitrosomonas and Nitrospira). Finally, the 16S rRNA gene amplicon sequencing informed that an important reduction of bacterial diversity resulted in SBR-1 due to TCS addition.


Assuntos
Reatores Biológicos/microbiologia , Salicilanilidas , Bactérias , Microbiota , Nitrogênio/metabolismo , Águas Residuárias/microbiologia
5.
Eur J Med Chem ; 181: 111578, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31401536

RESUMO

The research of novel antimycobacterial drugs represents a cutting-edge topic. Thirty phenolic N-monosubstituted carbamates, derivatives of salicylanilides and 4-chlorophenol, were investigated against Mycobacterium tuberculosis H37Ra, H37Rv including multidrug- and extensively drug-resistant strains, Mycobacterium avium, Mycobacterium kansasii, Mycobacterium aurum and Mycobacterium smegmatis as representatives of nontuberculous mycobacteria (NTM) and for their cytotoxic and cytostatic properties in HepG2 cells. Since salicylanilides are multi-targeting compounds, we determined also inhibition of mycobacterial isocitrate lyase, an enzyme involved in the maintenance of persistent tuberculous infection. The minimum inhibitory concentrations were from ≤0.5 µM for both drug-susceptible and resistant M. tuberculosis and from ≤0.79 µM for NTM with no cross-resistance to established drugs. The presence of halogenated salicylanilide scaffold results into an improved activity. We have verified that isocitrate lyase is not a key target, presented carbamates showed only moderate inhibitory activity (up to 18% at a concentration of 10 µM). Most of the compounds showed no cytotoxicity for HepG2 cells and some of them were without cytostatic activity. Cytotoxicity-based selectivity indexes of several carbamates for M. tuberculosis, including resistant strains, were higher than 125, thus favouring some derivatives as promising features for future development.


Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Carbamatos/química , Carbamatos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/síntese química , Carbamatos/síntese química , Células Hep G2 , Humanos , Isocitrato Liase/antagonistas & inibidores , Isocitrato Liase/metabolismo , Mycobacterium tuberculosis/enzimologia , Fenóis/síntese química , Fenóis/química , Fenóis/farmacologia , Salicilanilidas/síntese química , Salicilanilidas/química , Salicilanilidas/farmacologia , Tuberculose/tratamento farmacológico
6.
Exp Parasitol ; 204: 107726, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31299264

RESUMO

The aims of this study were to evaluate if the use of copper oxide wire particles, isolated or in association with closantel, in lambs infected with Haemonchus contortus enhances the anthelmintic efficacy of closantel, as well as to evaluate the effects of treatment in hepatic energy metabolism, inflammatory markers and hematological and biochemical tests. The lambs were randomly divided into five groups (6 animals each), as follows: uninfected animals (Control); animals infected with H. contortus (HC); infected and treated with closantel (HC + CL); infected and treated with copper oxide wire particles (HC + Cu); and infected and treated with closantel plus copper oxide wire particles (HC + CL + Cu). The animals of infected groups were infected orally with H. contortus (5,000 L3 -larvae) and on day 14 post infection (p.i) the treatments were initiated. The egg per gram of feces (EPG), butyrylcholinesterase (BuChE), myeloperoxidase (MPO), adenylate kinase (AK) and pyruvate kinase (PK) activities and hematological and biochemical tests were evaluated. Treatments with copper oxide (isolated and associated) were able to reduce the EPG count on days 28, 35, 42 and 49 p.i when compared to HC group, while closantel was able to reduce EPG only from day 35 p.i. Moreover, treatment with closantel (isolated or associated) was able to prevent the inhibition of hepatic AK and PK activities caused by H. contortus infection, which may contribute to efficient intracellular energetic communication in order to maintain the balance between cellular ATP consumption and production. Butyrylcholinesterase and MPO activities were higher in infected lambs compared to uninfected, while treated groups showed lower enzymatic activity compared to the group HC. The use of all therapeutic protocols was able to reduce the EPG count. Based on these evidences, the use of copper oxide plus closantel may be considered an alternative to treat lambs infected by H. contortus.


Assuntos
Anti-Helmínticos/administração & dosagem , Cobre/administração & dosagem , Hemoncose/veterinária , Inflamação/veterinária , Salicilanilidas/administração & dosagem , Doenças dos Ovinos/tratamento farmacológico , Abomaso/metabolismo , Adenilato Quinase/metabolismo , Administração Oral , Animais , Anti-Helmínticos/farmacologia , Anti-Helmínticos/uso terapêutico , Análise Química do Sangue/veterinária , Butirilcolinesterase/sangue , Cápsulas , Metabolismo Energético/efeitos dos fármacos , Contagem de Eritrócitos/veterinária , Fezes/parasitologia , Hemoncose/complicações , Hemoncose/tratamento farmacológico , Hemoncose/metabolismo , Hematócrito/veterinária , Hemoglobinas/análise , Inflamação/tratamento farmacológico , Inflamação/prevenção & controle , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Masculino , Contagem de Ovos de Parasitas/veterinária , Peroxidase/sangue , Piruvato Quinase/metabolismo , Distribuição Aleatória , Salicilanilidas/farmacologia , Salicilanilidas/uso terapêutico , Ovinos , Doenças dos Ovinos/metabolismo , Doenças dos Ovinos/prevenção & controle
7.
Artigo em Inglês | MEDLINE | ID: mdl-31091739

RESUMO

Batch experiments were completed to assess the sludge reduction of the metabolic uncoupler 3,3',4',5-tetrachlorosalicylanilide (TCS). The effects of various TCS concentrations on sludge yield were evaluated and the mechanisms associated with sludge reduction were assessed. We discovered that TCS addition resulted in a reduction in sludge. Furthermore, a low dose of TCS (≤3 mg/L) resulted in a slight reduction in the efficiency of the wastewater treatment system, while >3 mg/L TCS reduced matrix removal efficiency, with an especially remarkable inhibition effect on ammonia removal. An increase in TCS addition was associated with a gradual decrease in both the electron transport system (ETS) activity and the specific cellular ATP (SATP) in the TCS system. It was demonstrated that TCS plays an important role in metabolic uncoupling. However, with the addition of TCS, both contents and compositions were increased, and the protein content increased more than polysaccharide production in extracellular polymeric substances (EPS). At TCS concentrations of ≤3 mg/L, DNA content was stable, but it increased rapidly from 4.97 mg/L to 15.34 mg/L as the TCS concentration was elevated from 6 mg/L to 12 mg/L. This implied that the mechanisms of sludge reduction were different for different TCS concentrations, including uncoupling metabolism, maintenance metabolism and lysis-cryptic growth.


Assuntos
Salicilanilidas , Esgotos , Eliminação de Resíduos Líquidos/métodos , Amônia/análise , Poluentes da Água/análise
8.
J Antibiot (Tokyo) ; 72(8): 605-616, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31028351

RESUMO

Repurposing nonantibiotic drugs for antimicrobial therapy presents a viable approach to drug discovery. Development of therapeutic strategies that overcome existing resistance mechanisms is important especially against those bacterial infections in which treatment options are limited, such as against multidrug-resistant Gram-negative bacilli. Herein, we provide in vitro data that suggest the addition of anthelmintic salicylanilides, including oxyclozanide, rafoxanide, and closantel, in colistin therapy to treat multidrug-resistant colistin-susceptible but more importantly colistin-resistant Gram-negative bacilli. As a stand-alone agent, the three salicylanilides suffered from limited outer membrane permeation in Pseudomonas aeruginosa, with oxyclozanide also susceptible to efflux. Synergy was apparent for the combinations against multidrug-resistant clinical isolates of P. aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, and Enterobacter cloacae. Susceptibility breakpoints for colistin, but also with polymyxin B, were reached upon addition of 1 µg ml-1 of the corresponding salicylanilide against colistin-resistant Gram-negative bacilli. Furthermore, enhanced bacterial killing was observed in all combinations. Our data corroborate the repositioning of the three salicylanilides as adjuvants to counter resistance to the antibiotic of last resort colistin. Our findings are timely and relevant since the global dissemination of plasmid-mediated colistin resistance had been realized.


Assuntos
Anti-Helmínticos/farmacologia , Antibacterianos/farmacologia , Colistina/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Salicilanilidas/farmacologia , Membrana Externa Bacteriana/efeitos dos fármacos , Combinação de Medicamentos , Reposicionamento de Medicamentos , Sinergismo Farmacológico , Testes de Sensibilidade Microbiana , Oxiclozanida/farmacologia , Rafoxanida/farmacologia
9.
Exp Parasitol ; 199: 74-79, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30840851

RESUMO

Paramphistomes are important parasites in veterinary medicine. There are few anthelmintic drugs available against them. The development of new drugs is urgently needed and this process can be accelerated through the development of rodent models for in vivo testing. Among the few paramphistomes that develop in rodents is the caecal fluke Zygocotyle lunata, a species with which several biological studies have been performed over several decades. Nevertheless, its use as a model for evaluation of anthelmintic drugs had not yet been evaluated. In the present study, we evaluated the efficacy of praziquantel (PZQ 300 mg/kg 5x), albendazole (ABZ 200 mg/kg 5x) and closantel (CLO 50 mg/kg single dose, 50 mg/kg 3x and 25 mg/kg 3x) for treatment of mice experimentally infected with Z. lunata. The animals were infected with 20 metacercariae of the parasite and were treated 30 days post-infection. Untreated groups were maintained as controls. Seven days after the treatments, the animals were euthanized for recovery and counting of parasites. We found that PZQ and ABZ, at the dosages and therapeutic schedule employed here, did not cause significant alterations in worm burden [worm counts 16.0 ±â€¯2.8 (13-19), 17.6 ±â€¯2.1 (14-19) and 16.2 ±â€¯1.9 (13-18) (p = 0.51) in PZQ, ALB and control, respectively]. CLO 50 mg/kg in a single dose caused significant reduction in the number of parasites [treated: 1.8 ±â€¯0.9 (1-3); control: 15.6 ±â€¯2.5 (12-19)], although it did not result in complete elimination of the parasites in any animal. Despite the fact that three doses of CLO 50 mg/kg or CLO 25 mg/kg caused complete elimination of the parasites in most surviving animals, there was significant host mortality. In general, results here obtained are concordant with those of studies performed on ruminant paramphistomes. Given that Z. lunata can be maintained in laboratory rodents, it is a suitable model for screening anthelmintic drugs against paramphistomes.


Assuntos
Albendazol/uso terapêutico , Anti-Helmínticos/uso terapêutico , Paramphistomatidae/efeitos dos fármacos , Praziquantel/uso terapêutico , Salicilanilidas/uso terapêutico , Infecções por Trematódeos/tratamento farmacológico , Albendazol/química , Albendazol/farmacologia , Análise de Variância , Animais , Anti-Helmínticos/química , Anti-Helmínticos/farmacologia , Fezes/parasitologia , Masculino , Camundongos , Paramphistomatidae/classificação , Paramphistomatidae/isolamento & purificação , Praziquantel/química , Praziquantel/farmacologia , Salicilanilidas/química , Salicilanilidas/farmacologia , Infecções por Trematódeos/parasitologia
10.
Bioorg Med Chem Lett ; 29(9): 1106-1112, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30852084

RESUMO

All living organisms contain a unique class of molecular chaperones called 60 kDa heat shock proteins (HSP60 - also known as GroEL in bacteria). While some organisms contain more than one HSP60 or GroEL isoform, at least one isoform has always proven to be essential. Because of this, we have been investigating targeting HSP60 and GroEL chaperonin systems as an antibiotic strategy. Our initial studies focused on applying this antibiotic strategy for treating African sleeping sickness (caused by Trypanosoma brucei parasites) and drug-resistant bacterial infections (in particular Methicillin-resistant Staphylococcus aureus - MRSA). Intriguingly, during our studies we found that three known antibiotics - suramin, closantel, and rafoxanide - were potent inhibitors of bacterial GroEL and human HSP60 chaperonin systems. These findings prompted us to explore what other approved drugs, natural products, and known bioactive molecules might also inhibit HSP60 and GroEL chaperonin systems. Initial high-throughput screening of 3680 approved drugs, natural products, and known bioactives identified 161 hit inhibitors of the Escherichia coli GroEL chaperonin system (4.3% hit rate). From a purchased subset of 60 hits, 29 compounds (48%) re-confirmed as selective GroEL inhibitors in our assays, all of which were nearly equipotent against human HSP60. These findings illuminate the notion that targeting chaperonin systems might be a more common occurrence than we previously appreciated. Future studies are needed to determine if the in vivo modes of action of these approved drugs, natural products, and known bioactive molecules are related to GroEL and HSP60 inhibition.


Assuntos
Produtos Biológicos/química , Chaperonina 10/metabolismo , Chaperonina 60/metabolismo , Rafoxanida/química , Salicilanilidas/química , Suramina/química , Produtos Biológicos/metabolismo , Chaperonina 10/antagonistas & inibidores , Chaperonina 60/antagonistas & inibidores , Escherichia coli/metabolismo , Humanos , Concentração Inibidora 50 , Dobramento de Proteína , Rafoxanida/metabolismo , Salicilanilidas/metabolismo , Suramina/metabolismo
11.
N Z Vet J ; 67(3): 148-154, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30742780

RESUMO

CASE HISTORY: A group of 39, 19-22-month-old Friesian bulls were administered an ivermectin/closantel anthelmintic via intended S/C injection in the ischiorectal fossa on 15 June 2017 (Day 0). Over the next 50 days, 22 affected bulls presented various degrees of anorexia, abdominal pain and urine dribbling. Seventeen bulls were examined by transrectal ultrasonography which revealed urinary bladder distension in all 17, and peritoneal fluid accumulation in some. Overall, eight bulls died or were subjected to euthanasia. On-farm postmortem examination of three bulls revealed urinary bladder rupture. CLINICAL FINDINGS: On Day 50 one affected live bull was admitted to Massey University for further investigation. This bull continuously dribbled urine and had an overtly distended urinary bladder as determined by rectal palpation and ultrasonography. PATHOLOGICAL FINDINGS: Postmortem examination of this bull revealed a markedly distended urinary bladder, massive subcapsular and pericapsular renal oedema with retroperitoneal fluid accumulation, minimal hydronephrosis and no evidence of mechanical urinary outflow obstruction. The right ischiorectal fossa contained multifocal areas of tissue fibrosis that extended into areas innervated by the distal cutaneous branch of the pudendal nerve and the pelvic nerve. Histopathological changes consisted of extensive fibrosis, myonecrosis and neurodegeneration, and evidence of granulation tissue and inflammation at the putative injection site and in surrounding tissues. DIAGNOSIS: A local inflammatory reaction at the presumed injection site together with localised peripheral neurodegeneration and myelopathy may have led to detrusor-sphincter dyssynergia causing urine retention. CLINICAL RELEVANCE: These cases of urine retention and bladder rupture in cattle were of putative iatrogenic origin. Veterinarians should be aware of this rare complication after S/C injections in the ischiorectal fossa.


Assuntos
Doenças dos Bovinos/induzido quimicamente , Ivermectina/efeitos adversos , Salicilanilidas/efeitos adversos , Retenção Urinária/veterinária , Animais , Antiparasitários/administração & dosagem , Antiparasitários/efeitos adversos , Bovinos , Doenças dos Bovinos/etiologia , Doenças dos Bovinos/mortalidade , Combinação de Medicamentos , Ivermectina/administração & dosagem , Masculino , Ruptura , Salicilanilidas/administração & dosagem , Bexiga Urinária/patologia , Doenças da Bexiga Urinária/etiologia , Doenças da Bexiga Urinária/mortalidade , Doenças da Bexiga Urinária/patologia , Doenças da Bexiga Urinária/veterinária , Retenção Urinária/induzido quimicamente , Retenção Urinária/complicações , Retenção Urinária/mortalidade
12.
Regul Toxicol Pharmacol ; 103: 21-33, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30634022

RESUMO

The aim of this study was to determine the potential toxicity risk of an oxyclozanide suspension to the target animal, bovine. In this experiment, 32 Simmental beef cattle were fattened and fed a full-price diet without antimicrobial agents. The test cattle were divided into 4 groups, which were treated with 0, 1, 3, and 5 times the recommended dosage through continuous intermittent oral administration at intervals of 2 days. The body weight of the cattle was recorded before and after the experiment, and the weight changes were calculated. The safety of the drugs was evaluated by weight gain, observation of clinical toxicity, haematology, clinical chemistry and histopathology. The results showed that the cattle had different degrees of diarrhoea, loss of appetite and depression after administration. The results of clinicopathology had no significant effect. The results of pathological examination showed that there was a certain degree of damage in the 5 times recommended dose group. The recommended dose was safe to use. Thus, the recommended dose should be given by a single oral administration to ensure the safe use of this drug in the clinic.


Assuntos
Fasciolíase/tratamento farmacológico , Oxiclozanida/administração & dosagem , Oxiclozanida/efeitos adversos , Salicilanilidas/administração & dosagem , Administração Oral , Animais , Bovinos , Relação Dose-Resposta a Droga , Feminino , Masculino , Oxiclozanida/uso terapêutico , Salicilanilidas/efeitos adversos
13.
J Helminthol ; 93(5): 529-532, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30039771

RESUMO

This study assessed the efficacy of closantel vis-à-vis herbal extracts with known anti-parasitic properties, against fenbendazole-resistant nematodes in goats maintained under a semi-intensive system of management at the University goat farm, Jabalpur. Fifty goats were randomly assigned to five groups, each comprising 10 animals, irrespective of their breed, age and sex. Each animal in Group I, II and III was orally administered with aqueous leaf extracts of neem (Azadirachta indica) at 1 g/kg body weight, sitaphal (Annona squamosa) at 1.5 g/kg body weight and tobacco (Nicotiana tabacum) at 1 g/kg body weight, respectively, whereas Group IV was an untreated control group. Each animal in Group V was orally treated with closantel at 10 mg/kg body weight. During the course of the study, all animals were maintained under an identical semi-intensive system of management. Compared to the untreated control group (Group IV), there was no conspicuous reduction in post-treatment (day 10) faecal egg counts (FEC) in animals administered with the herbal extracts (Groups I, II and III), which is suggestive of poor anti-parasitic activity. However, using the faecal egg count reduction test (FECRT), the overall efficacy of closantel was recorded as 95.64%. This supports the rotational use of closantel as a preferred choice over the benzimidazole group of anthelmintics and/or herbal extracts to meet the acute challenge of in situ development of drug-resistant gastrointestinal nematodes, especially Haemonchus contortus.


Assuntos
Anti-Helmínticos/uso terapêutico , Fenbendazol/farmacologia , Doenças das Cabras/tratamento farmacológico , Hemoncose/veterinária , Extratos Vegetais/uso terapêutico , Salicilanilidas/uso terapêutico , Administração Oral , Animais , Annona/química , Anti-Helmínticos/administração & dosagem , Azadirachta/química , Resistência a Medicamentos , Feminino , Doenças das Cabras/parasitologia , Cabras/parasitologia , Hemoncose/tratamento farmacológico , Haemonchus/efeitos dos fármacos , Índia , Masculino , Contagem de Ovos de Parasitas , Extratos Vegetais/administração & dosagem , Folhas de Planta/química , Distribuição Aleatória , Salicilanilidas/administração & dosagem , Tabaco/química
14.
Vet Parasitol ; 262: 11-15, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30389005

RESUMO

In a survey involving 34 sheep flocks spread over the Netherlands anthelmintic resistance (AR), based on a fecal egg count reduction (FECR) test, was determined for six different products. The study was conducted in ewes shortly after lambing during spring 2015. A FECR of less than 90%, indicating presence of AR against one or more nematode genera producing strongylid eggs, was found in 22 of 30 (73.3%) flocks against oxfendazole, 18 of 23 (78.3%) flocks against ivermectin, 15 of 32 (46.9%) flocks against moxidectin, and 2 of 26 (7.7%) flocks against monepantel. No AR was observed against levamisole. If oxfendazole resistance was observed, Haemonchus contortus was involved in 90.5% of the cases. If resistance against ivermectin, moxidectin or monepantel was observed, it invariably involved H. contortus. In the majority of cases resistance was also observed for Teladorsagia circumcincta and/or Trichostrongylus spp, between which no distinction was made in this study. Based on FECR 9 of 15 (60.0%) flocks showed resistance against closantel, which was mainly due to closantel not being effective against most other nematode species than H. contortus. However, in 44.4% of flocks showing reduced FECR it did involve H. contortus as well. Multi-drug resistance (excluding closantel) was found in 16 flocks, of which 8 showed resistance against 2 products, 7 against 3 products and 1 flock showed resistance against 4 products. If resistance against 3 or 4 products was present, there invariably was resistance against both ivermectin and moxidectin. Overall, of the 22 flocks in which both macrocyclic lactones (ML) were tested, 4 (18.2%) showed no resistance against both products, 9 (40.9%) showed resistance against ivermectin only, and 9 (40.9%) showed resistance against both MLs. It is concluded that AR is widespread in sheep in the Netherlands and involves products from all major anthelmintic classes, with possibly the exception of levamisole. It appears that the macrocyclic lactones have lost much of their efficacy against sheep nematodes over the last decade.


Assuntos
Anti-Helmínticos/farmacologia , Resistência a Medicamentos , Hemoncose/veterinária , Haemonchus/efeitos dos fármacos , Enteropatias Parasitárias/veterinária , Doenças dos Ovinos/epidemiologia , Aminoacetonitrila/análogos & derivados , Aminoacetonitrila/farmacologia , Animais , Benzimidazóis/farmacologia , Fezes/parasitologia , Hemoncose/tratamento farmacológico , Hemoncose/epidemiologia , Hemoncose/parasitologia , Enteropatias Parasitárias/tratamento farmacológico , Enteropatias Parasitárias/epidemiologia , Enteropatias Parasitárias/parasitologia , Ivermectina/farmacologia , Levamisol/farmacologia , Macrolídeos/farmacologia , Contagem de Ovos de Parasitas/veterinária , Salicilanilidas/farmacologia , Ovinos , Doenças dos Ovinos/tratamento farmacológico , Doenças dos Ovinos/parasitologia
17.
Sci Rep ; 8(1): 11559, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30068935

RESUMO

A poorly exploited paradigm in the antimicrobial therapy field is to target virulence traits for drug development. In contrast to target-focused approaches, antivirulence phenotypic screens enable identification of bioactive molecules that induce a desirable biological readout without making a priori assumption about the cellular target. Here, we screened a chemical library of 678 small molecules against the invasive hyphal growth of the human opportunistic yeast Candida albicans. We found that a halogenated salicylanilide (N1-(3,5-dichlorophenyl)-5-chloro-2-hydroxybenzamide) and one of its analogs, Niclosamide, an FDA-approved anthelmintic in humans, exhibited both antifilamentation and antibiofilm activities against C. albicans and the multi-resistant yeast C. auris. The antivirulence activity of halogenated salicylanilides were also expanded to C. albicans resistant strains with different resistance mechanisms. We also found that Niclosamide protected the intestinal epithelial cells against invasion by C. albicans. Transcriptional profiling of C. albicans challenged with Niclosamide exhibited a signature that is characteristic of the mitochondria-to-nucleus retrograde response. Our chemogenomic analysis showed that halogenated salicylanilides compromise the potential-dependant mitochondrial protein translocon machinery. Given the fact that the safety of Niclosamide is well established in humans, this molecule could represent the first clinically approved antivirulence agent against a pathogenic fungus.


Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Candida/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Salicilanilidas/farmacologia , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Candida/crescimento & desenvolvimento , Candida albicans/crescimento & desenvolvimento , Endocitose/efeitos dos fármacos , Células Epiteliais/microbiologia , Perfilação da Expressão Gênica , Células HT29 , Humanos , Hifas/efeitos dos fármacos , Hifas/crescimento & desenvolvimento , Morfogênese , Virulência/efeitos dos fármacos
18.
Bioorg Chem ; 80: 668-673, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30059892

RESUMO

Based on the presence of carbamate moiety, twenty salicylanilide N-monosubstituted carbamates concomitantly with their parent salicylanilides and five newly prepared 4-chlorophenyl carbamates obtained from isocyanates were investigated using Ellman's method for their in vitro inhibitory activity against acetylcholinesterase (AChE) from electric eel and butyrylcholinesterase (BChE) from equine serum. The carbamates and salicylanilides exhibited mostly a moderate inhibition of both cholinesterase enzymes with IC50 values ranging from 5 to 235 µM. IC50 values for AChE were in a narrower concentration range when compared to BChE, but many of the compounds produced a balanced inhibition of both cholinesterases. The derivatives were comparable or superior to rivastigmine for AChE inhibition, but only a few of carbamates also for BChE. Several structure-activity relationships were identified, e.g., N-phenethylcarbamates produce clearly favourable BChE inhibition. The compounds also share convenient physicochemical properties for CNS penetration.


Assuntos
Clorofenóis/química , Clorofenóis/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Salicilanilidas/química , Salicilanilidas/farmacologia , Acetilcolinesterase/metabolismo , Animais , Butirilcolinesterase/metabolismo , Carbamatos/química , Carbamatos/farmacologia , Electrophorus , Cavalos , Concentração Inibidora 50 , Relação Estrutura-Atividade
19.
Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi ; 30(2): 202-204, 2018 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-29770666

RESUMO

OBJECTIVE: To evaluate the molluscicidal effect of niclosamidate against Oncomelania hupensis in laboratory and explore its mechanism by determining the enzyme activities of six important enzymes in snail soft tissues. METHODS: O. hupensis snails were treated with niclosamidate at the concentration of 1.25 mg/L for 24 h and the snail soft tissues were separated and prepared for analysis. The enzyme activities of NOS, AChE, SDH, LDH, ACP and AKP were determined by ultraviolet spectrophotometry. The morphology of the snail soft tissue was also observed. RESULTS: Niclosamidate exhibited a potent molluscicidal effect against O. hupensis at the concentration of 5.00 mg/L with a mortality of 96.67% by the immersion method in laboratory. After immersed with niclosamidate (1.25 mg/L) for 24 h, the enzyme activities of NOS, AChE, ACP and AKP were significantly decreased compared with those of the controls (all P < 0.01). There were no significant changes observed in the enzyme activities of SDH and LDH (both P > 0.05). CONCLUSIONS: Niclosamidate possesses a potent molluscicidal effect against O. hupensis and its molluscicidal mechanism is probably by affecting the transmission of neurotransmitters, interfering with the circulation, metabolism and motor functions that require NO, and hindering the digestion and absorption of nutriments, which eventually result in the death of the snails.


Assuntos
Moluscocidas , Salicilanilidas , Caramujos , Animais
20.
Sci Rep ; 8(1): 3701, 2018 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-29487357

RESUMO

There is an urgent need to discover novel antimicrobial therapies. Drug repurposing can reduce the time and cost risk associated with drug development. We report the inhibitory effects of anthelmintic drugs (niclosamide, oxyclozanide, closantel, rafoxanide) against Helicobacter pylori strain 60190 and pursued further characterization of niclosamide against H. pylori. The MIC of niclosamide against H. pylori was 0.25 µg/mL. Niclosamide was stable in acidic pH and demonstrated partial synergy with metronidazole and proton pump inhibitors, such as omeprazole and pantoprazole. Niclosamide administration at 1 × MIC concentration, eliminated 3-log10 CFU of H. pylori adhesion/invasion to AGS cells. Interestingly, no resistance developed even after exposure of H. pylori bacteria to niclosamide for 30 days. The cytotoxic assay demonstrated that niclosamide is not hemolytic and has an IC50 of 4 µg/mL in hepatic and gastric cell lines. Niclosamide administration decreased transmembrane pH as determined by DiSC3(5) assay indicating that the mechanism of action of the anti-H. pylori activity of niclosamide was the disruption of H. pylori proton motive force. Niclosamide was effective in the Galleria mellonella-H. pylori infection model (p = 0.0001) and it can be develop further to combat H. pylori infection. However, results need to be confirmed with other H. pylori and clinical strains.


Assuntos
Anti-Helmínticos/farmacologia , Anti-Infecciosos/farmacologia , Helicobacter pylori/efeitos dos fármacos , Niclosamida/farmacologia , Reposicionamento de Medicamentos/métodos , Sinergismo Farmacológico , Testes de Sensibilidade Microbiana , Omeprazol/farmacologia , Oxiclozanida/farmacologia , Pantoprazol/farmacologia , Inibidores da Bomba de Prótons/farmacologia , Rafoxanida/farmacologia , Salicilanilidas/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA