Academic literature on the topic 'Robenidine'

In this study, nine anticoccidial drugs commonly used in poultry were tested for efficacy for the prevention and treatment of Goussia carpelli (Apicomplexa) infection in common carp ( Cyprinus carpio L.). To establish experimental infection with G. carpelli , paratenic host oligochaetes of the genera Tubifex and Limnodrilus were infected with oocysts, and laboratory-cultured parasite-free common carp fingerlings were infected by feeding to them oligochaetes containing sporozoites. The anticoccidial drugs (amprolium, narasin, maduramicin, salinomycin Na, lasalocid Na, diclazuril, robenidine HCl, monensin Na and toltrazuril), mixed in the food of the fish in a dose of 200 mg/kg, were fed for 12 days. Common carp fingerlings fed diclazuril, lasalocid, robenidine HCl or maduramicin and killed on day 14 after exposure were free from infection, while other groups treated with amprolium, toltrazuril, monensin Na, narasin or salinomycin Na harboured oocysts in the mucus and epithelium of the gut.

Introduction: Different results have been achieved in the evaluation of antiparasitic drug activity in Mongolian jirds, hamsters, and BALB/c mice infected with Babesia microti. The aims of the present study were to find a preferable method for drug screening and to re-evaluate the activity of several drugs against B. microti. Methodology: The activity of 19 drugs on B. microti-infected BALB/c mice was evaluated. The study was built on Peters' four-day suppressive test, and the pathogenicity of the blood from the treated mice was also used as indicator. Results: The results showed that 15 of the 19 drugs had little or no in vivo effect against B. microti. The inhibitory rates of atovaquone and azithromycin were high at all doses, but the microscopy-negative blood of recovered mice was still infectious. Similar to robenidine hydrochloride at 25 and 50 mg/kg, primaquine at 100 mg/kg had a 100% inhibitory rate. Robenidine hydrochloride achieved a 100% inhibitory rate at 100 mg/kg, and the blood of recovered mice did not result in parasitemia in subpassage experiments. Parasite-negative blood from mice treated with antimalarial drugs (clinically used for babesiosis) still caused parasitemia in subpassage experiments. This suggests that these drugs cannot eradicate the parasites. Conclusions: Peters' four-day suppressive test and the pathogenicity of the blood from the treated mice are suitable methods for preliminary investigating possible drugs against B. microti. Considering that robenidine hydrochloride achieved the best activity against B. microti in BALB/c mice in our study, further studies are needed.

Multidrug-resistant (MDR) Gram-negative pathogens, especially Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli and Enterobacter spp., are recognized by the World Health Organization as the most critical priority pathogens in urgent need of drug development. In this study, the in vitro antimicrobial activity of robenidine analogues NCL259 and NCL265 was tested against key human and animal Gram-negative clinical isolates and reference strains. NCL259 and NCL265 demonstrated moderate antimicrobial activity against these Gram-negative priority pathogens with NCL265 consistently more active, achieving lower minimum inhibitory concentrations (MICs) in the range of 2–16 µg/mL. When used in combination with sub-inhibitory concentrations of polymyxin B to permeabilize the outer membrane, NCL259 and NCL265 elicited a synergistic or additive activity against the reference strains tested, reducing the MIC of NCL259 by 8- to 256- fold and the MIC of NCL265 by 4- to 256- fold. A small minority of Klebsiella spp. isolates (three) were resistant to both NCL259 and NCL265 with MICs > 256 µg/mL. This resistance was completely reversed in the presence of the efflux pump inhibitor phenylalanine-arginine-beta-naphthylamide (PAβN) to yield MIC values of 8–16 µg/mL and 2–4 µg/mL for NCL259 and NCL256, respectively. When NCL259 and NCL265 were tested against wild-type E. coli isolate BW 25113 and its isogenic multidrug efflux pump subunit AcrB deletion mutant (∆AcrB), the MIC of both compounds against the mutant ∆AcrB isolate was reduced 16-fold compared to the wild-type parent, indicating a significant role for the AcrAB-TolC efflux pump from Enterobacterales in imparting resistance to these robenidine analogues. In vitro cytotoxicity testing revealed that NCL259 and NCL265 had much higher levels of toxicity to a range of human cell lines compared to the parent robenidine, thus precluding their further development as novel antibiotics against Gram-negative pathogens.

In the course of the study permeability of intestinal mucosa of chickens suffering from eimeriosis while treating them with various veterinary drugs, including probiotics, was evaluated. The simulation of a typical clinical picture of eimeriosis was carried out by oral administration of suspension with coccidial oocysts (1.6 × 105/head) using a probe. To create different forms and different intensity of inflammatory processes, chickens that received various anticoccidial preparations and probiotic strain Bacillus subtilis were infected with eimeria. According to the data from an autopsy, it was found that the use of a spore probiotic based on Bacillus subtilis and anticoccidial drugs containing robenidine hydrochloride and salinomycin had a positive protective effect when treating chickens from eimeriosis. A similar picture was observed when assessing permeability of intestinal mucosa as affected by bacteriophage, whereby permeability decreased with the use of probiotics and the above-mentioned active agents. In general, the decrease in productivity was significant in all groups. However, the effect of spore-based probiotics was quite pronounced against the background of eimeria polyresistance. In the situation where anticoccidial drugs are less effective, the use of a spore-based probiotic can have a noticeable protective effect. The effect of all anticoccidial drugs under study on the concentration of oocysts and the state of the mucosa was insignificant, which indicated polyresistance of different types of eimeria isolated from biological material to these drugs. The analysis of the intestinal mucosa integrity, based on the study of mucosa permeability to bacteriophages and a Johnson and Reid scoring procedure showed that a spore probiotic based on B. subtilis and anticoccidial drugs containing robenidine and salinomycin had the best protective effect against eimeriosis caused by field isolates of eimeria. When treating chickens suffering from eimeriosis caused by polyresistant forms of E. acervulina and E. tenella, it is advisable to use probiotics alongside with drugs based on robenidine and salinomycin.

Infectious diseases are one of the leading causes of morbidity and mortality worldwide. Diseases caused by single-celled organisms, such as bacteria and protista, cause billions of infections per year. One of the leading weapons in the fight against infectious diseases are antimicrobials. However, the efficacy of antimicrobials is decreasing as the development of antimicrobial resistance increases. At the same time as increasing levels of resistance are observed there is a lack of new antimicrobial agents entering the market and many big pharmaceutical companies have suspended antimicrobial drug discovery programs as financial return is small. Due to the lack of novel treatments for infectious diseases and increasing treatment failures it is essential that new chemical entities are explored to fill this gap. In this thesis a novel library of compounds based on the structure of robenidine, an approved antimicrobial used to prevent coccidiosis in chickens and rabbits, was investigated as potential antimicrobial agents. Initial experiments focussed on the antibacterial activity of the library against representative pathogenic bacteria. Activity was assessed according to CLSI guidelines. The spectrum of activity of the majority of analogues investigated was limited to Gram-positive bacteria, with promising MICs as low as 1.3 μM. However, through the use of outer-membrane permeabilising agents and spheroplast induction, it was discovered that the target site of robenidine and some of the related analogues was also present in Gram-negative organisms. This led to the development of a small subset of analogues which demonstrated intrinsic activity against the Gram-negative pathogens Escherichia coli and Pseudomonas aeruginosa with MICs as low as 52 μM. Furthermore, kill kinetic studies revealed that robenidine and related analogues had a bactericidal mechanism of action. The next series of experiments focussed on the characterisation of the antiparasitic activity of the library against the protists Trypanosoma brucei, Leishmania donovani and Giardia duodenalis. Several of the analogues demonstrated activity against these parasites with some promising results against Leishmania donovani including a small number of analogues with selectivity indices (SI) for the parasite above 20 (an SI of >10 is considered selective). In addition, activity against G. duodenalis was also promising (IC50 <1 μM). In total 121 analogues were tested against G. duodenalis with 13 being selective for Giardia with no antibacterial activity and limited, if any, toxicity towards mammalian cells. MICs for the most promising analogues were ≤ 2.8 μM. Electron microscopy studies to elucidate the mechanism or site of action of this class of antimicrobials against G. duodenalis demonstrated that the two most promising compounds both caused rapid disintegration of the cell membrane and the development of cyst-like structures, while one analogue also appeared to interfere with cell division. Finally, in order to test in vivo efficacy an animal model was effectively established in neonatal mice. In conclusion this thesis demonstrated for the first time the potential for this library of compounds to become therapeutic agents for a range of infectious diseases. In particular, the selective activity of several analogues for Giardia over other microorganisms and mammalian cells was demonstrated for the first time, highlighting the potential for this library of analogues. In addition, insight into the unique mechanism of action of a select group of compounds against G. duodenalis was demonstrated.
Thesis (Ph.D.) -- University of Adelaide, School of Animal and Veterinary Sciences, 2018

Tese de mestrado em Química, apresentada à Universidade de Lisboa, através da Faculdade de Ciências, 2014
Os medicamentos veterinários são amplamente utilizados em sistemas de produção intensiva de animais para consumo humano, na profilaxia e terapia de patologias e como promotores de crescimento. Estes compostos são adicionados na água de bebida, em implantes ou como suplementos na alimentação animal. Os compostos avaliados no presente estudo foram os coccidiostáticos que são um grupo de compostos utilizados como aditivos alimentares ou como promotores de crescimento, para prevenção e tratamento de coccidiose, uma doença infecciosa causada por protozoários do género Eimeria. A coccidiose, , incide especialmente em frangos, perus e coelhos, sendo estes os principais sectores a utilizar medidas de controlo a fim de prevenir esta doença mortal. Contudo, pode também atingir bovinos e suínos. A utilização de coccidistáticos está permitida na União Europeia embora sujeita a restrições, estando estabelecidos limites máximos de resíduos (LMR), para cada composto nas diferentes espécies animais e para cada tecido ou produto edível. Este estudo centrou-se no desenvolvimento e na validação de uma metodologia analítica, por cromatografia líquida acoplada a espectrometria de massa sequencial (LC-MS/MS), para a detecção e quantificação simultânea em fígado, de robenidina, halofuginona, diclazuril, nicarbazina, monensina, salinomicina, narasina, lasalocida e maduramicina. O método desenvolvido neste trabalho, cuja validação se baseou nos critérios de validação da Decisão da Comissão 2002/657/CE demonstrou ser selectivo, específico e robusto. Para os compostos estudados os valores de recuperação foram superiores a 90% e inferiores a 102%, para o critério máximo de 80 a 110%, exceptuando os compostos monesina e salinomicina, cujo critério máximo a aplicar foi de 70 a 100%. No estudo de reprodutibilidade os valores obtidos para o composto nicarbazina demonstraram ser os mais reprodutíveis com coeficiente de variação (CV), de 13.48%. Todos os resultados obtidos foram inferiores aos valores resultantes da equação de Horwitz para cada LMR. Os valores de limite de decisão (CCα), e capacidade de detecção (CCα), obtidos variaram entre 2.5 μg/kg e 4.5 μg/kg para a maduramicina e entre 108 μg/kg e 144 μg/kg para a nicarbazina. De acordo com os resultados de validação obtidos para a metodologia desenvolvida conclui-se que este procedimento permite o controlo analítico de amostras de fígado de origem animal para a detecção da presença dos coccidiostáticos referidos nas concentrações de interesse, designadamente nos respectivos limites máximo de resíduo.
Veterinary medicinal compounds are widely used in developed countries to treat and protect animals’ health. Some of these compounds are used as growth promoters and added as supplements for animal feed. Veterinary medicinal compounds are widely used in intensive animal farming for prophylaxis or treatment of diseases and as growth promoters. These compounds are usually added to the water or as supplement of their feed or by means of an implant. The compounds evaluated in this project were the coccidiostats. They are a group of compounds used as food additives or growth promoter agents, for the prevention and treatment of coccidiosis, an infectious disease caused by the protozoa Eimeria. Coccidiosis occurs mainly in chickens, turkeys and rabbits, and therefore these sectors use strict quality control measures in order to prevent this deadly disease. Although in a lower incidence this disease can also occur in cattle and pigs. The use of coccidistats is permitted in the European Union but is subject to restrictions. There are Maximum Residue Limits (MRL) established for each compound, in each different animal species, and for each tissue or edible product. The aim of this study was to develop and validate an analytical procedure for simultaneous detection and quantification of robenidine, halofuginone, diclazuril, nicarbazin, monensin, salinomycin, narasin, lasalocid, and maduramicin in chicken liver using liquid chromatography mass spectrometry sequence (LC-MS/MS) The method developed was performed according to the criteria 2002/657/EC established by the European Union and revealed to be selective, specific and robust. The recoveries values obtained for the compounds studied were higher than 90% and lower than 102%, for the maximum criteria of 80 to 110%, except for monensin and salinomycin where the maximum criteria used was from 70 to 100%. Nicarbazine was the most reproducible compound with a 13.48% of variation coefficient, CV. All results obatained were lower than the calculated values using Horwitz equation for each LMR. The decision limit (CCα) and detection limit (CCα) values ranged from 2.5 μg/kg to 4.5 μg/ kg for maduramycin and from 108 μg/kg to 144 μg/ kg for nicarbazine. It is possible to conclude, following the validation of the results obtained, that the metodology developed in this project allows successful analytical detection of the above-mentioned coccidiostats in animal liver samples.