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Copyright of Taiwanese Journal of Agricultural Chemistry & Food Science is the property of Agricultural Chemical Society of Taiwan and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Drug combinations and repurposing have recently provided promising alternatives to cope with the increasingly severe issue of antibiotic resistance and depletion of natural drug molecular repertoires that undermine traditional antibacterial strategies. Closantel, an effective adjuvant, reverses antibiotic resistance in gram-negative bacteria. Herein, the combined antibacterial enantioselectivity of closantel is presented through separate enantiomer studies. Despite yielding unexpected differences, two closantel enantiomers (R, S) increased colistin activity against gram-negative bacteria both in vitro and in vivo. The fractional inhibitory concentration indices of R-closantel and Sclosantel combined with colistin against Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli ranged from 0.0087 to 0.5004 and from 0.0117 to 0.5312, respectively. This difference was further demonstrated using growth inhibition assays and time-killing curves. Mechanistically, a higher intracellular concentration of R-CLO is more effective in enhancing the antimicrobial activity of combination. A mouse cutaneous infection model confirmed the synergistic stereoselectivity of closantel. This discovery provides novel insights for developing precision medication and containment of increasing antibiotic resistance. [ABSTRACT FROM AUTHOR]

This study was performed to evaluate the efficacy of currently used anthelmintics in an organized central breeding sheep farm (CSBF) in Hisar, Haryana using a fecal egg count reduction test (FECRT). A total of 60 sheep were chosen for this study and divided equally into four groups. Sheep were tested with closantel (@10mg/kg body weight) and two derivatives of macrocyclic lactone, moxidectin, and doramectin (@0.2mg/kg body weight) while the control group did not receive any treatment. Sheep were naturally infected with gastro-intestinal nematodes and had EPG of feces more than 150 counts before treatment was selected. Rectal fecal samples were collected on zero (pre-treatment) and 14th day (post-treatment) from animals of all groups and EPG of feces was carried out by modified McMaster technique. In FECRT, reduction of fecal egg count (FEC) of less than 95%, indicates anthelmintic resistance (AR) in one or more nematode genera for the given anthelmintic. Percent of FEC on the 14th day revealed that closantel, moxidectin, and doramectin had 64%, 69%, and 76% efficacy, respectively. Coprocultures from pre- and post-treated sheep revealed a predominance Haemonchus contortus larvae. The result indicated the development of moderate anthelmintic resistance against three anthelmintics, leading to a change of anthelminthic drugs and regular monitoring for possible anthelmintic resistance on the farm.

The contamination of the environment by some veterinary medicines and their impact on wild animals is of increasing concern. However, there is a lack of information about their residues in wildlife. The sentinel animals most commonly used for monitoring the level of environmental contamination are birds of prey, and information on other carnivores and scavengers scarce. This study examined the livers from 118 foxes for residues of a range of 18 veterinary medicines (16 anthelmintic agents and 2 metabolites) used on farm livestock. The samples were collected from foxes, primarily in Scotland, shot during legal pest control activities conducted between 2014 and 2019. Closantel residues were detected in 18 samples, and the concentrations found ranged from 6.5 µgkg−1 to 1383 µgkg−1. No other compounds were found in significant quantities. The results show a surprising frequency and level of closantel contamination, raising concerns about both the route of contamination and the potential impacts on wild animals and the environment, such as the potential for significant wildlife contamination to contribute to the development of closantel-resistant parasites. The results also suggest that red fox (Vulpes vulpes) could be a useful sentinel species for detecting and monitoring some veterinary medicine residues in the environment.

Copyright of Veterinarska Stanica is the property of Croatian Veterinary Institute and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Simple Summary: Parasitic worms are a major threat to the health and production of sheep and goats worldwide, particularly because many worms have become resistant to commonly applied drugs. This problem is well known around the world, but the situation is currently not well studied in Germany. This study was therefore performed to evaluate the effectiveness of treatments against infection with gastrointestinal nematodes. Faecal samples from animal groups were examined before and after treatment, the worm eggs in the feaces were counted, and the reduction in egg excretion following treatment was calculated. Eggs of Haemonchus contortus (barber's pole worm) were stained to differentiate them from other gastrointestinal nematodes. Treatments were chosen and carried out by farmers together with their local veterinarian. Additional information was collected by questionnaires to check if the treatments were performed correctly. Reduced effectiveness was observed for all available drugs, but some showed better treatment success than others. The barber's pole worm frequently survived treatments by most products. The high percentage of treatment failures is highly concerning, and it is necessary to develop and/or apply alternative methods of worm control to prevent the deterioration of this situation. Widespread anthelmintic resistance is a concern for small ruminant health and production worldwide. The current situation regarding anthelmintic efficacy is, however, not very well studied in Germany. Thus, a nationwide field study was undertaken to assess the effectiveness of 253 treatments performed in 223 small ruminant flocks by faecal egg count reduction test (FECRT) using pooled samples and a modified McMaster method. The percentage of Haemonchus contortus and non-Haemonchus eggs was determined by fluorescence microscopy following peanut agglutinin–fluorescein isothiocyanate staining. Treatments were chosen and performed by farmers together with their local veterinarian, and potentially confounding factors for FECRT results were addressed as far as possible by rigorous inclusion criteria. Reduced effectiveness was observed for treatments with all examined anthelmintic classes, but treatments with benzimidazoles and moxidectin showed significantly poorer results than monepantel, a closantel and mebendazole combination, and levamisole. Low case numbers precluded reliable assessment of avermectins. Unsuccessful treatments were frequently associated with the survival of H. contortus, but this was also observed for non-Haemonchus genera. The results are highly concerning, and sustainable approaches to parasite control are urgently needed to prevent further deterioration of this situation. [ABSTRACT FROM AUTHOR]

This study was performed to evaluate the efficacy of currently used anthelmintics in organized central breeding sheep farm (CSBF) in Hisar, Haryana using faecal egg count reduction test (FECRT). A total of 60 sheep were chosen for this study and divided equally into four groups. Sheep were tested with closantel (@10mg/kg body weight) and two derivatives of macrocyclic lactone, moxidectin and doramectin (@0.2mg/kg body weight) while the control group did not receive any treatment. Sheep were naturally infected with gastro-intestinal nematodes and having EPG of faeces more than 150 counts before treatment were selected. Rectal faecal samples were collected on zero (pre-treatment) and 14th day (post-treatment) from animals of all groups and EPG of faeces were carried out by modified McMaster technique. In FECRT, reduction of faecal egg count (FEC) of less than 95%, indicate anthelmintic resistance (AR) in one or more nematode genera for the given anthelmintic. Per cent of FEC on 14th day revealed that closantel, moxidectin and doramectin had 64%, 69% and 76% efficacy, respectively. Coprocultures from pre- and post-treated sheep revealed predominance Haemonchus contortus larvae. The result indicated development of moderate anthelmintic resistance against three anthelmintics, leading to change of anthelminthic drugs and regular monitoring for possible anthelmintic resistance in the farm. [ABSTRACT FROM AUTHOR]

The use of medicinal plants as a means of combating parasites is becoming increasingly popular due to general resistance to synthetic anthelmintics. Goats typically respond less well to anthelminthic treatments, which may increase their resistance to nematodes. For this purpose, the anthelmintic effect of Pelargonium quercetorum Agnew (P. quercetorum) extract was tested in an in vivo study against gastrointestinal parasites of goats. A total of 40 goats naturally infected with mixed gastrointestinal nematode species were divided into four groups: the first group was treated with albendazole (7.5 mg/kg), the second group received a single dose of closantel (7.5 mg/kg), the third group received plant extract (7.5 mg/kg), and the fourth group served as an untreated control. Fecal egg counts (FEC) were carried out on day 14, as well as day 0, which was prior to the first treatment dose. According to the results, maximum reduction in FEC percentage was observed in P. quercetorum treated group (63.41%). Furthermore, nematode parasites responded poorly to synthetic drugs, although there was a 4.72% and 45.54% decrease in FEC in the albendazole and closantel-treated groups, respectively. Although no significant difference was found between the treatment groups, the P. quercetorum treated group showed a significant reduction in fecal egg count after treatment. Based on findings, a P. quercetorum based anthelmintic could be a sustainable alternative to combat parasite infestation. Therefore, further studies are needed to determine the optimal dose rate and frequency of doses required for effective control of gastrointestinal parasites in goats. • First report for anthelmintic activity of Pelargonium quercetorum Agnew Tannin and phenol in this plant may be related to its antiparasitic properties • Albendazol and closantel were not effective in gastrointestinal nematodes • Anthelmintic resistance exists in Markhoz goat [ABSTRACT FROM AUTHOR]

Abstract Background Closantel is the best-known anti-parasitic medicine for veterinarians, which is contraindicated in humans. After reviewing the literature on ocular toxicity following mistaken usage of Closantel in humans, this report was found as the first complete restoration of visual function after Closantel intoxication. This report could be useful in anticipating the possibility of a further improvement based on a dose-response relationship. An important point of this report is the apparent reversibility of the vision and Electrophysiological parameters after Closantel intoxication and blindness. To conclude, the present case report demonstrates the importance of immediate referral and management in Closantel intoxication to avoid the long-term adverse effects of drug on visual function. Case presentation A 47-year-old man mistakenly took about 20 cc of Closantel 5% (15.87 mg/kg). Four hours after mistaken usage of Closantel, he was transferred to the district hospital due to dizziness and nausea. His stomach was washed out immediately after hospital arrival. He was being hospitalized in that hospital for 3 days. Then, he was referred to our clinic due to progressive vision loss. Methylprednisolone acetate 250 mg was injected once on 5th day after taking Closantel. His vision was reducing gradually so low that he could only detect hand motion (HM) on the 14th day after taking Closantel. ERG test was requested. It showed an exclusive reduction in b-wave amplitude under photopic and scotopic conditions. Later, his vision surprisingly improved gradually and his visual acuity was fully restored on the 28th day after the incident. After 3 years, we checked him again. His visual acuity was 20/20 in both eyes and the patient did not have any problem and his ERG report was completely normal. Conclusions In low dose of Closantel and immediate referral, ocular toxicity could be resolved.

Background: Haemonchosis is a fatal disease of small ruminants caused by the parasite Haemonchus contortus (H. contortus). The most common drugs used in the treatment of H. contortus include albendazole, oxfendazole, and ivermectin. However, as previously reported in the treatment of haemonchosis, these medicines have acquired drug resistance problems over time. Interestingly, natural plant compounds have demonstrated promising effects in the treatment of H. contortus. Therefore, the current study evaluated the effects of plant extract, Ferula asafetida, against common drugs such as albendazole, oxfendazole, ivermectin, and closantel for the treatment of haemonchosis in small ruminants. Methodology: The current study was conducted on different small ruminant farms in Kasur District, Punjab, Pakistan. The positive animals (n = 720) after coprological examination were selected in this study and divided into two major groups (n = 360 goats and n = 360 sheep). Further, animals were divided into five treatment groups (A–E) and one control group with no treatment (F). Albendazole, oxfendazole, ivermectin, closantel, and Ferula asafetida were administered orally to groups A–E, respectively. The eggs per gram feces (EPG) were determined through the McMaster technique on days 0, 7th, and 14th of treatment. Results: The results showed a significantly higher efficacy of closantel and Ferula asafetida against H. contortus in both goats (100% and 70%; p < 0.05) and sheep (99% and 87%; p < 0.05), respectively. No correlation was observed between EPG reduction with age and gender in both goats and sheep. Conclusion: Allopathic drug closantel and herbal drug, Ferula asafetida, have been proved an effective dewormer against H. contortus in small ruminants. [ABSTRACT FROM AUTHOR]

Background: In recent decades, the problem of toxic damage of the visual system due to poisoning by various medicines has become particularly relevant. The clinical case of a bilateral acute optic neuropathy of toxic genesis in a patient by the unintentional application of closantel used in veterinary practice is presented in the report. Closantel is a structural derivative of the salicylanilides, which is used exclusively in veterinary medicine for the prevention and treatment of large and small-scale cattle. Neurological and ophthalmic symptoms are often associated with the intoxication of closantel. Objective: To describe the toxic damage of the optic nerve due to unintentional poisoning by closantel. Methods: A patient aged 55 years is examined. A standard survey of ophthalmology was carried out. Photoregistration of the ocular fundus was used by a funduscamera Visucam 500 (Carl Zeiss Meditec AG, Germany), from special methods of research - the spectral optical coherence tomography (OCT) with a study of the macular area of the retina and the disc of the optic nerve on the device Zeiss Cirrus 5000 (Carl Zeiss Meditec, USA) and the optical coherence tomography with the function of angiography (OCT-A) of the macular area of the retina using RTVue XR Avanti (Optovue, USA) Results: The patient complained of a severe, yet painless, reduction in vision of both eyes after an accidental intramuscular injection of the medicine called "Closantrem" in dose 4.0 ml. The visual acuity OU - an accounting of fingers on the face at a distance of 10 cm. By ophthalmoscopy OU: the disc of the optic nerve is discolourated, its boundaries are indistinct, the arteries and the veins are narrowed, in the macular area of the retina without a visible physical pathology. The perimetry is in the correct projection of the light. A reduction in the thickness of the external and internal layers of the retina was observed as a result of the OCT of the macular zone OU. According to OCT of the disc of the optic nerve: the thickness of the layer of nerve fibres is in the upper and lower nasal segments. OS – the prominence of the disc of the optic nerve in vitreous. The fascinated changes of the cerebral cortex have not been found during the MRT. The diagnosis was made OU: Acute optic neuropathy of toxic genesis. A course of integrated conservative treatment has been introduced: the anti-inflammatory, metabolic, nootropic, vitamin therapy, magnetotherapy, electrostimulation and electrophoresis. Conclusion: Potentially, any medicines are toxic, which may cause a number of side effects from the visual and central nervous system. The toxic damage of the ganglion cells of the retina was initially occurring due to unintentional application of closantel, resulting in a reduction of the central visual acuity, followed by the development of the optic nerve atrophy.

A 20‐year‐old girl was referred with vision loss upon closantel use. Plasma exchange and high‐dose corticosteroid pulse therapy were administered. A 2.5‐year follow‐up showed improved vision and increased layer thickness of the peripheral nerve fiber. Early treatment with plasma exchange and high‐dose corticosteroid therapy can be beneficial to reverse closantel toxicity. [ABSTRACT FROM AUTHOR]

Abstract A 20‐year‐old girl was referred with vision loss upon closantel use. Plasma exchange and high‐dose corticosteroid pulse therapy were administered. A 2.5‐year follow‐up showed improved vision and increased layer thickness of the peripheral nerve fiber. Early treatment with plasma exchange and high‐dose corticosteroid therapy can be beneficial to reverse closantel toxicity.

Drug combinations and repurposing have recently provided promising alternatives to cope with the increasingly severe issue of antibiotic resistance and depletion of natural drug molecular repertoires that undermine traditional antibacterial strategies. Closantel, an effective adjuvant, reverses antibiotic resistance in gram-negative bacteria. Herein, the combined antibacterial enantioselectivity of closantel is presented through separate enantiomer studies. Despite yielding unexpected differences, two closantel enantiomers ( R , S ) increased colistin activity against gram-negative bacteria both in vitro and in vivo . The fractional inhibitory concentration indices of R -closantel and S -closantel combined with colistin against Pseudomonas aeruginosa , Klebsiella pneumoniae , and Escherichia coli ranged from 0.0087 to 0.5004 and from 0.0117 to 0.5312, respectively. This difference was further demonstrated using growth inhibition assays and time-killing curves. Mechanistically, a higher intracellular concentration of R -CLO is more effective in enhancing the antimicrobial activity of combination. A mouse cutaneous infection model confirmed the synergistic stereoselectivity of closantel. This discovery provides novel insights for developing precision medication and containment of increasing antibiotic resistance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ding, Guo, Fang, Guo, Yang, Li, Li and He.)

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.

Background: Closantel is the best-known anti-parasitic medicine for veterinarians, which is contraindicated in humans. After reviewing the literature on ocular toxicity following mistaken usage of Closantel in humans, this report was found as the first complete restoration of visual function after Closantel intoxication. This report could be useful in anticipating the possibility of a further improvement based on a dose-response relationship. An important point of this report is the apparent reversibility of the vision and Electrophysiological parameters after Closantel intoxication and blindness. To conclude, the present case report demonstrates the importance of immediate referral and management in Closantel intoxication to avoid the long-term adverse effects of drug on visual function.Case Presentation: A 47-year-old man mistakenly took about 20 cc of Closantel 5% (15.87 mg/kg). Four hours after mistaken usage of Closantel, he was transferred to the district hospital due to dizziness and nausea. His stomach was washed out immediately after hospital arrival. He was being hospitalized in that hospital for 3 days. Then, he was referred to our clinic due to progressive vision loss. Methylprednisolone acetate 250 mg was injected once on 5th day after taking Closantel. His vision was reducing gradually so low that he could only detect hand motion (HM) on the 14th day after taking Closantel. ERG test was requested. It showed an exclusive reduction in b-wave amplitude under photopic and scotopic conditions. Later, his vision surprisingly improved gradually and his visual acuity was fully restored on the 28th day after the incident. After 3 years, we checked him again. His visual acuity was 20/20 in both eyes and the patient did not have any problem and his ERG report was completely normal.Conclusions: In low dose of Closantel and immediate referral, ocular toxicity could be resolved. [ABSTRACT FROM AUTHOR]

The study was conducted to evaluate the status of anthelmintic resistance in Gastro-Intestinal Nematodes (GINs) of goats at an organized farm located in Kashmir, as there is no report of resistance against these parasites of goats from this temperate region, although it has been reported worldwide including India. Caprines reared at this farm exhibited reduced efficacy to multiple anthelmintics following treatments with Fenbendazole (FBZ), Closantel and Ivermectin (IVM) in Faecal Egg Count Reduction Test (FECRT). The results suggested that the overall efficacy was highest for IVM at 83.5% and 90.0% on 7th and 14th day post-treatment, respectively and least for FBZ at 44.3% and 62.5%, respectively, whereas the corresponding figures for closantel were 68.3% and 86.2%, respectively. The pre-treatment faecal culture revealed Haemonchus contortus, Teladorsagia circumcincta and Trichostrongylus colubriformis as predominant strongyles, however, in post-treatment samples, only H. contortus was observed. Further, the infective larvae were subjected to Allele specific PCR (AS-PCR) for accurate diagnosis of BZ resistance. The AS-PCR revealed 52% of H. contortus were homozygous resistant (rr) and 17% were heterozygous (rS) on day “0” before treatment and 100% homozygous resistant (rr) on 7th day post treatment. In both T. colubriformis and T. circumcincta, 100% population was homozygous susceptible (SS) at day “0” before treatment. The overall frequency of resistant (r) allele for H. contortus was 60.5% and for susceptible allele (s) was 39.5%. For T. colubriformis and T. circumcincta the frequency of susceptible allele (s) was 100%. The survey indicated that the GINs of goats on the farm have developed multiple anthelmintic resistance to FBZ, closantel and IVM and the condition is alarming in the farm. Moreover surveillance studies about status of anthelmintic resistance in other farms (Govternment as well as Private) of Kashmir valley should be carried out at large scale to develop effective and sustainable control strategies against GI Nematodes.

Objectives: The antimicrobial resistance of Staphylococcus aureus ( S. aureus ) has become a challenge in the treatment of infectious diseases. It is of great clinical value to discovery effective antimicrobial agents against multi-drug resistant S. aureus and its biofilms. This study aims to explore the antibacterial activity of the antiparasitic drug closantel against methicillin-resistant S. aureus and its biofilms through drug repurposing., Methods: The sensitivity of S. aureus to closantel was assessed using microbroth dilution and disk diffusion methods. The bacteriostatic and bactericidal activities of closantel were determined by time-kill curves and colony count. Scanning electron microscopy combined with SYTOX Green and DiSC3(5) fluorescence probes were used to study the bactericidal mechanism of closantel. The influence of resistance was assessed by continuous exposure to sub-inhibitory concentrations of closantel. The anti-biofilm activity was evaluated using 96-well plates and crystal violet staining, and cytotoxicity was measured using the CCK-8 assay., Results: The minimal inhibitory concentration (MIC) of closantel for both methicillin-sensitive and methicillin-resistant S. aureus ranged from 0.125 to 1.000 μg/mL. Disk diffusion tests showed that 80 μg of closantel created an inhibition zone, which increased in diameter with higher drug amounts. Sub-inhibitory concentrations (0.031 μg/mL) of closantel significantly inhibited S. aureus proliferation, reducing bacterial turbidity from 0.26±0.00 to 0.11±0.01 ( t =16.06, P <0.001), with stronger inhibition at higher concentrations. Closantel at 0.25×MIC inhibited S. aureus proliferation for 12 hours, while 1×MIC inhibited it for over 24 hours, with the number of viable bacteria decreasing as the drug concentration increased. Mechanistic studies indicated that closantel effectively disrupted the integrity of S. aureus cell membranes, significantly increasing SYTOX Green and DiSC3(5) fluorescence intensity. Even after 25 days of continuous exposure to sub-inhibitory concentrations of closantel, no resistance developed. Closantel at 0.0625 μg/mL significantly inhibited biofilm formation, reducing it from 1.29±0.16 to 0.62±0.04 ( t =11.62, P <0.001), showing a clear dose-dependent effect. Closantel at 2 μg/mL also significantly eradicated established biofilms, reducing biofilm mass from 1.62±0.34 to 0.51±0.39 ( t =4.84, P <0.01). Additionally, closantel exhibited extremely low cytotoxicity, with half-maximal lethal concentrations for HepG2 liver cancer cells and normal LO2 liver cells both exceeding 64 μg/mL., Conclusions: Closantel exhibits strong antibacterial activity against S. aureus and its biofilm with low cytotoxicity against human cells, making it a promising candidate for new therapeutic strategies against S. aureus- related infections.

Combination therapy of many anthelmintic drugs has been used to achieve fast animal curing. Q-DRENCH is an oral suspension, containing four different active drugs against GIT worms in sheep, commonly used in Australia and New Zeeland. The anti-parasitic drugs are Albendazole (ALB), Levamisole HCl (LEV), Abamectin (ABA), and Closantel (CLO). The main purpose of this study is to present a new simultaneous stability-indicting HPLC-DAD method for the analysis of the four drugs. The recommended liquid system was 1 mL of Triethylamine/L water, adjusting the pH to 3.5 by glacial acetic acid: acetonitrile solvent (20:80, v/v). Isocratic elusion achieved the desired results of separation at a 2 mL/min flow rate using Zorbax C-18 as a stationary phase. Detection was performed at 210 nm. The linearity ranges were 15.15 to 93.75 μg/mL for ALB, 25 to 150 μg/mL for LEV, 30 to 150 μg/mL for ABA, and 11.7 to 140.63 μg/mL for CLO. Moreover, the final greenness score was 0.62 using the AGREE tool, which reflects the eco-friendly nature. Moreover, the four drugs were determined successfully in the presence of their stressful degradation products. This work presents the first chromatographic method for simultaneous analysis for Q-DRENCH oral suspension drugs in the presence of their stressful degradation products.

Closantel is an antiparasitic drug marketed in a racemic form with one chiral center. It is meaningful to develop a method for separating and analyzing the closantel enantiomers. In this work, two enantiomeric separation methods of closantel were explored by normal-phase high-performance liquid chromatography. The influences of the chiral stationary phase (CSP) structure, the mobile phase composition, the nature and proportion of different mobile phase modifiers (alcohols and acids), and the column temperature on the enantiomeric separation of closantel were investigated in detail. The two enantiomers were successfully separated on the novel CSP of isopropyl derivatives of cyclofructan 6 and n-hexane-isopropanol-trifluoroacetic acid (97:3:0.1, v/v/v) as a mobile phase with a resolution (Rs) of about 2.48. The enantiomers were also well separated on the CSP of tris-carbamates of amylose with a higher Rs (about 3.79) when a mixture of n-hexane-isopropanol-trifluoroacetic acid (55:45:0.1, v/v/v) was used as mobile phase. Thus, the proposed separation methods can facilitate molecular pharmacological and biological research on closantel and its enantiomers.

This work aimed to evaluate the thiol-disulphide homeostasis in serum of lambs naturally infected by gastrointestinal nematodes presenting different levels of parasite load indirectly indicated by faecal worm egg counts (EPG). Furthermore, the possible changes in the thiol-disulphide dynamic after different procedures to reduce the parasitic charge, such as the integrated crop-livestock system or anthelmintic treatment, were assessed. The results were compared with a panel of various oxidative stress and inflammatory biomarkers. The lambs were divided into three groups: animals highly infected (EPG higher than 5000) and packed cell volume (PCV) lower than 24% (G1); animals highly infected (EPG higher than 5000) and normal PCV (>24%) (G2); and animals presenting EPG lower than 5000 and normal PCV (>24%) (G3). The highly infected lambs (G1 and G2) showed lower total thiol (TT) and native thiol (SH) (p ≤ 0.01) than those from G3. After treatment, TT and SH increased significantly in all groups (p ≤ 0.01), and the disulphide (SS)/TT and SS/SH ratios decreased significantly (p < 0.01) in G1 and G2. These results show that the thiol-disulphide balance was impaired in lambs infected by gastrointestinal nematodes and that it could be potentially used as a biomarker to monitor this disease.

Klebsiella pneumoniae is a common causative agent of nosocomial infections with a high level of resistance toward β-lactam antibiotics. Our previous study showed that TEM-1 and SHV-11 are the predominant β-lactamase-encoding genes of K. pneumoniae isolates in the Zhejiangarea, China. In this study, more clinical K. pneumoniae isolates were collected for detecting their β-lactamase-encoding gene profiles by PCR and sequencing. qRT-PCR was then performed to determine the role of cefotaxime or penicillin in low concentrations to induce the β-lactamase gene expression of K. pneumoniae isolates. Moreover, the K. pneumoniae isolates were pretreated with closantel (CLO), a histidine kinase inhibitor, before antibiotic treatment, and qRT-PCR and the β-lactamase phenotype confirmatory test were then applied to determine the effect of CLO on the expression of the β-lactamase genes. The results showed that, except for KPC-2, the 1/4 MIC cefotaxime or penicillin induced significant mRNA elevation of the TEM-1, CTX-M-14, SHV-11 and OXA-1β-lactamase genes, but this induction could be inhibited by CLO. After pretreatment withCLO,78.4~81.4%of the β-lactam-resistant isolates became sensitive and the positive rate of the β-lactamase production phenotype in the isolates was decreased from 100% to 27.1%. The data indicate thatTEM-1 (70.7%), SHV-11 (64.2%) and CTX-M-14 (40.5%) are the predominant β-lactamase genes of the K. pneumoniae isolates in Zhejiang and sublethal dosage of β-lactam antibiotics can induce the β-lactamase gene expression of K. pneumoniae through histidine kinase-mediated two-component signaling systems.

The purpose of the study is to develop new effective treatment of demodicosis in dogs with the use of klozantin and immunomodulators.The materials and methods. The work carried out at 45 home dogs of different breeds aged from 5 months up to 2 years, spontaneously infested demodexes, on the basis of a shelter for dogs and private veterinary clinic in Moscow. For the formation of test groups of animals pre-infestation of dogs was determined by the study of the skin. This is determined by: a) the index number of ticks, b) clinical signs of each animal.The calculation of the dose of klozantin for each animal was performed taking into account body mass prior to treatment. Closantel, were injected subcutaneously at 0, 7th, 14th, 21st, 28th, 35th, 42nd and 49th days in doses of 2.5, 3.5 and 5.0 mg/kg for closantel in each group, respectively. Efficacy against ectoparasites took into account the results of clinical and laboratory examinations of skin scrapings after 4 and 8 weeks after application (on the 28th and 56th days from start of treatment). After determining therapeutic doses worked 4 patterns of use of the drug with different immunomodulators and without them. As the base drug used tablets, sipli" (production of "Forte Dogde", USA) at a dose of 3.0 mg/kg in cythioate with multiplicity 2 times a week for 12 consecutive weeks according to the instructions for use.The results and discussion. Closantel the drug at a dose of 5.0 mg/kg for closantel with 12-fold subcutaneous application with multiplicity 1 time per week in combination with the immunomodulator polyoxidonium-vet, applied subcutaneously 2 times a week at a dose of 0.15-0.3 mg/kg (depending on weight of dog) during the first 3 weeks of beginning treatment, showed 100% efficiency in demodicosis dogs. The effectiveness of klozantin at the same dose and frequency in combination with other immunomodulators (ribotan, Roncoleukin) was significantly lower.

Copyright of Revista Veterinaria is the property of Universidad Nacional del Nordeste and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

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. [ABSTRACT FROM AUTHOR]

Shigella spp. are Gram-negative intracellular pathogenic bacteria belonging to the family Enterobacteriaceae. The pathophysiological impact of the bacteria is highly related to the composition and structural variability of lipopolysaccharides. Serum sensitivity and biofilm forming ability are correlated with the length of these molecules, while bacteria with truncated lipopolysaccharides are more sensitive to hydrophobic antibiotics. Inhibitors of lipopolysaccharide biosynthesis have the potential to develop new antimicrobial agents or antibiotic adjuvants. Bacterial two-component systems enable bacteria to sense and to respond to the changes in different environmental conditions. This study focuses on the inhibition of the rfaD gene encoding the ADP-L-glycero-D-mannoheptose-6-epimerase, which is involved in the lipopolysaccharide biosynthesis. Although, there are some inhibitors presumed for bacterial two-component systems like Closantel, their impact on lipopolysaccharide biosynthesis has not been examined previously. The Shigella sonnei 4303 strain was involved in the experiments with known lipopolysaccharide structure. The effect of Closantel on lipopolysaccharide biosynthesis and the limitations of its use are presented. [ABSTRACT FROM AUTHOR]

Three trials were conducted to evaluate the therapeutic efficacy of closantel (@ 7.5 mg/kg body weight, orally), fenbendazole (@ 7.5 mg/kg body weight, orally) and ivermectin bolus (@ 0.2 mg/kg body weight, orally) against gastrointestinal (GI) helminth parasites of cattle in central zone of Kashmir valley. Twenty cattle suffering from GI helminth infection were randomly selected and divided into two groups in each trial. In each trial, one group comprising of fifteen animals were treated with anthelmintic and second group comprising of five animals were kept as infected untreated control. To determine the therapeutic efficacy of different anthelmintic drugs against GI helminths, faecal samples were directly collected from rectum before treatment and on 7th, 14th and 28th day post treatment and eggs per gram of faeces was determined by using Stoll's method. Then the efficacy of different anthelmintics was calculated by employing Faecal Egg Count Reduction Test. On 14th day post treatment closantel was found to be 100 and 94.44% effective against Fasciola spp. and strongyle worms, respectively, however, it was not found effective against Trichuris spp. The efficacy of fenbendazole was 100% against Fasciola spp., paramphistomes, Moniezia spp., Trichuris spp. and strongyle worms on 14th day post treatment. Ivermectin was found to be 100% effective against Trichuris spp. and strongyle worms on 14th day post treatment, however, it was not effective against Fasciola spp. and paramphistomes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract 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 ± 2.8 (13–19), 17.6 ± 2.1 (14–19) and 16.2 ± 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 ± 0.9 (1–3); control: 15.6 ± 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. Graphical abstract Image 1 Highlights • Praziquantel (300 mg/kg 5x/24 h) was ineffective against Z. lunata. • Albendazole (200 mg/kg 5x/24 h) was ineffective against Z. lunata. • Closantel (50 mg/kg) at single dosage was partially effective against Z. lunata. • Three doses of closantel were effective against Z. lunata , but cause mortality in mice. • Zygocotyle lunata can be used for test experimentally new drugs against paramphistomes. [ABSTRACT FROM AUTHOR]

Control of Fasciola hepatica infection in livestock is based on annual treatment using flukicides such as triclabendazole, albendazole and closantel. However, triclabendazole resistant F. hepatica populations are emerging worldwide and resistance is emerging to albendazole, whereas it has until now never been described for closantel. In Sweden, a topical formulation containing a combination of closantel and ivermectin (Closamectin Pour On) has been registered for use in cattle only since 2011. This study evaluated the efficacy of closantel against F. hepatica in naturally infected beef cattle using both coproantigen and faecal egg count reduction tests. Faecal egg counts (FEC) and coproantigen ELISA examinations were conducted in February 2014 in three beef cattle herds (A, B, C) in south-western Sweden. On each farm, 10 F. hepatica coproantigen-positive and F. hepatica egg-positive animals were allocated after 12–16 weeks of housing into groups and treated topically with a minimum of 20 mg closantel per kg body weight. Faecal samples were collected from selected animals on 0, 7 and 21 day post-treatment (PT). Based on FEC, closantel efficacy 21 days PT was 72% (95% CI: 65–77%) and 97% (95% CI: 95–98%) on farms A and B, respectively. No FEC reduction at all was observed on farm C. In total, 4, 1 and 6 animals remained coproantigen-positive at 21 days PT on farms A, B and C, respectively. Closantel treatment failure was confirmed on two of the farms. As the animals were housed 12–16 weeks before treatment and thereafter during the entire study, failure due to the presence of juvenile flukes was excluded. Although the cause of closantel failure currently remains unclear, development of resistance or/and absorption failure of topical administration should be considered. To our knowledge, this is the first report of closantel treatment failure against F. hepatica in cattle.

Paramphistomosis is considered an emergent disease of ruminants in Europe. Some drugs have been found effective for treating paramphistomid infections in cattle, but data in sheep are currently limited. Thus, faecal samples from 25 adult sheep naturally infected with paramphistomids were collected weekly to test the efficacy of oxyclozanide and closantel. Three groups were performed: nine animals orally treated with a single dose of oxyclozanide (15 mg/kg bodyweight (BW) integrated the G-OXI group, whereas eight sheep orally treated with a single dose of closantel (10 mg/kg BW) were placed in a group called G-CLS. Eight untreated controls constituted the group G-CON. Oxyclozanide showed efficacies up to 90% until week 11 post-treatment, with a maximum efficacy of 98.3%, and significant differences were found between G-OXI and G-CON until the 26th week post-treatment. Closantel was insufficiently active (0–81%) throughout the study and differences compared to G-CON were never found. The present study reveals that oxyclozanide given at a single oral dose of 15 mg/kg BW is highly effective against adult rumen flukes in sheep. In addition, the use of a single oral dose of closantel at 10 mg/kg BW is not recommended for treating paramphistomid infections in sheep.

Abstract An outbreak of Closantel intoxication in sheep in Uruguay is described. The outbreak occurred in a group of 1300 weaning lambs treated orally with a 10% solution of Closantel. One hundred forty eight lambs showed clinical signs of intoxication and 14 died. The clinical signs included mydriasis, nystagmus, and negative pupillary reflex, bilateral blindness, bump into objects, and lateral movement of the head. No macroscopic lesions were observed. The histological lesions of the retina were cytoplasmic vacuolization in ganglion cells and in cells of the inner and outer nuclear layers with different degrees of atrophy. Vacuolization and axonal degeneration were observed in the optic nerve, with multifocal areas of fibrosis and infiltration by lymphocytes and Gitter cells. To reproduce the intoxication, four sheep were given two, four and 10 times the therapeutic dose of Closantel (0.1g/kg of BW). Only the animals receiving 10 times the recommended dose showed clinical signs. The histological examination of the lesions in experimental sheep showed similar results to those described in the accidental outbreak, except for the absence of optic nerve fibrosis and inflammation, characterizing an acute phase. Axonal myelin sheaths loss, fibroblasts and collagen fibers were observed in the ultrastructural study of the optic nerve of accidental intoxicated animals. The optic nerve of experimentally intoxicated animals had vacuoles that separated the myelin sheaths of axons. To prevent outbreaks it is suggested to weigh the animals before Closantel administration to avoid errors in dose calculation.

O presente estudo notifica a intoxicação de ovinos que receberam duas aplicações de closantel, na dosagem terapêutica (7,5mg/kg), com intervalo de 28 dias pré-estabelecido pela eficácia da formulação. Referente aos resultados de eficácia foi possível observar elevado percentual após o primeiro e o segundo tratamento. Cerca de 72 horas após a administração do segundo tratamento (D+30), três animais que receberam closantel demonstraram leve apatia, anorexia, diarréia e cegueira bilateral com ausência de reflexo e midríase bilateral. Estes três ovinos foram observados por cerca de 250 dias após o segundo tratamento, e a cegueira bilateral não regrediu. Os inúmeros casos de animais intoxicados por closantel descritos na literatura enfatizam que a sobredosagem e/ou qualidade nutricional dos animais, são fatores determinantes para que ocorra intoxicação destes animais pelo closantel. Entretanto, no presente trabalho, os sinais de intoxicação (leve apatia, anorexia, diarréia e a alteração oftálmica) observada nos três ovinos clinicamente sadios, ocorreram quando estes receberam duas aplicações de closantel (7,5mg/kg) com o intervalo de 28 dias, evidenciando que o possível efeito residual cumulativo de closantel no organismo animal, desencadeado por duas aplicações consecutivas, também pode ser um fator predisponente para que ovinos demonstrem sinais irreversíveis de intoxicação pelo princípio ativo em questão.

Highlights • Ivermectin resistance was found in 78.3% of sheep flocks. • Moxidectin resistance was found in 46.9% of sheep flocks. • Monepantel resistance was found in 7.7% of sheep flocks 4 years after introduction. • Resistance against macrocyclic lactones and monepantel always involved Haemonchus. • Multi-drug resistance is present in more than half of the flocks. Abstract 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. [ABSTRACT FROM AUTHOR]

Drug development is a dynamic field which undergoes changes continuously. The past decade or so has witnessed huge strides in the field of screening of the drugs as well as target and ligand identifications but unfortunately this has not led to useful drugs. Many diseases still remain untreatable because we do not have proper drugs against them. In case of fungi the situation is graver due to the limited drug targets peculiar to fungi. Thus, in order to combat the fungal diseases the need of the hour is to develop new antifungals that have fewer side effects and broad spectrum activity. The current work deals with closantel, a veterinary drug targeting chitinase, which is utilized as a therapeutic option against helminths. The fact that chitin is an important constituent of the cell wall of the fungi also and it undergoes regular degradation and remodelling through an enzyme called fungal chitinase motivated the authors to test the efficacy of closantel against fungal chitinase. In the present study Cryptococcus neoformans has been used as a model organism against which the antifungal activity of closantel has been tested. In-silico studies carried out using PatchDock and FireDock predicted the global energy (binding energy)involved in docking closantel on chitinase as -47.58 Kcal/mol. Further, the results obtained through the in-silico studies were validated by the minimum inhibitory concentration assay (MIC). It was observed that 736 (±7.024) μg/ml of closantel can inhibit the cryptococcal growth by 80% (MIC80). [ABSTRACT FROM AUTHOR]

• Enantioseparation and detection of closantel were achieved using a reliable LC-MS/MS. • A post-column infusion of ammonia greatly improved closantel's ionization efficiency. • The detection limits of R and S enantiomers in bacteria samples reached 0.15 pg/mL. Reliable analysis of ultratrace antibiotics in bacterial cells may become a new means to elucidate the antibacterial mechanism, drug resistance and environmental fate. In this work, an ultrahigh-sensitive, accurate and enhanced liquid chromatography-tandem mass spectrometric method was first developed for chiral separation and detection of racemic closantel, as an antibacterial adjuvant. Optimizing acetonitrile-water-formic acid system that is compatible with mass spectrometry as a mobile phase, the baseline separation of two enantiomers was achieved by using EnantioPak® Y1-R chiral column, and the resolution of the two analytes was more than 1.95. Further adopt the strategy of postcolumn infusion of ammonia, the mobile phase pH was reversed from acidic condition suitable for the optimal chromatographic separation of R - and S -closantel to alkaline, so that closantel could realize efficient electrospray ionization under the preferred negative ion mode. The bacterial cells were subjected to be frozen-cracked, and the analytes were extracted with acetonitrile after clipping the pointed bottom of the Eppendorf tube into a new tube. The method was linear over concentration ranges of 0.5–50 pg/mL (r2 ≥0.99) for R - and S -closantel. The detection limits of target analytes were all 0.15 pg/mL in bacterial cells. The average recoveries of two enantiomers ranged from 81.2% to 107.8% with relative standard deviations below 15%. The method proposed might be important support for the deep research of the stereoselectivity of biological activity, toxicity and metabolism of closantel enantiomers. [ABSTRACT FROM AUTHOR]

Closantel is widely used in the management of parasitic infestation in livestock, but is contraindicated in humans due to its high toxic to human retina. Thus, development of a fast and selective method for the detection of closantel residues in animal products is highly needed yet still challenging. In the present study, we report a supramolecular fluorescent sensor for closantel detection through a two-step screening process. The fluorescent sensor can detect closantel with a fast response (<10 s), high sensitivity, and high selectivity. The limit of detection is 0.29 ppm, which is much lower than the maximum residue level set by government. Moreover, the applicability of this sensor has been demonstrated in commercial drugs tablets, injection fluids, and real edible animal products (muscle, kidney, and liver). This work provides the first fluorescence analytical tool for accurate and selective determination of closantel, and may inspire more sensor design for food analysis. [Display omitted] • The first fluorescent detection method for closantel is reported. • This sensor can detect closantel with a fast response, high sensitivity, and high selectivity. • The limit of detection to closantel is 0.29 ppm. • This method enables on-site determination of closantel in real food samples. [ABSTRACT FROM AUTHOR]

The anthelmintic resistance in small ruminants is a common problem and concern worldwide. The aim of this study was to verify anthelmintic treatment efficacy in naturally infected sheep. This study was conducted on nine herds that used the same anthelmintic management for over a year. In each farm, the animals were divided into two groups: untreated control group (n = 5) and treated (n = 10) according to the number of eggs per gram of feces (EPG). The treatment effect was checked based on EPG results and larval culture performed before treatment and 10 days after treatment. Significant differences were not observed (P> 0.05) on EPG results between untreated and treated groups. The coproculture showed that the animals were infected primarily byHaemonchus spp., Trichostrongylus spp.,Teladorsagia spp., Cooperia spp. andOesophagostomum spp. In all farms, anthelmintic resistance by genera Haemonchus and Trichostrongylus was found, but this resistance varied greatly between farms.Haemonchus spp. showed resistance to closantel, levamisole, and albendazole. Trichostrongylus spp. was shown to be resistant to closantel, levamisole, and albendazole. The drugs tested showed to be efficient against the genera Teladorsagia,Cooperia, and Oesophagostomum. Based on these results, we conclude that the anthelmintic resistance to the tested drugs is a problem present in the farms evaluated.

Background: Closantel is a veterinary drug used as anthelmintic for ruminants while it is contraindicated for humans. This report describes a rare case of blindness, increased liver enzymes and coagulopathy following closantel poisoning. Case report: A 5-year-old girl was presented with acute blindness following closantel poisoning. She was given mistakenly a dose of 500 mg/day (25mg/kg/day) for 8 days. Clinical examination revealed a well-appearing child with bilateral mydriasis, loss of pupillary light reflex and absence of blinking to threat. Fundoscopic exam revealed bilateral pre-atrophic papilledema. Electroretinogram showed a highly significant decrease in retinal activity. Laboratory examinations revealed 52% increase in prothrombin time, prolongation of activated partial thromboplastin time to 1.3 times the normal and rise of aspartate aminotransferase to 120 IU/L. In addition, creatine kinase peaked at 904 IU/L. Moreover, normocytic normochromic anemia with hemoglobin at 10.7 mg/L and leukocytosis with lymphocytic predominance was noted. The patient received glucocorticoids, vitamin B12 and vitamin K and was discharged after correction of blood and coagulation parameters and normalization of liver enzymes. Partial recovery in visual acuity was found two months after ingestion of the last dose. Discussion:Closantel can cause significant spongiform change (intra-myelin vacuolation) in the white matter of the cerebrum and the cerebellum. It can also induce optic nerve damage as a result of Wallerian degeneration, fibrosis and atrophy. On the retina, closantel leads to papilledema, necrosis of the outer layers, and retinal detachment. It can also cause fatty change and hydropic degeneration in the liver and hepatocellular degeneration. Conclusion: Closantel is a toxic drug for humans causing blindness, hematologic and hepatic disorders. Public awareness should be raised regarding the risks of use of unapproved drugs for human.

Closantel (CLS) is highly effective against adult liver flukes after its oral or subcutaneous (sc) administration in ruminants. Trans-tegumental diffusion and oral ingestion are the two potential routes available for the entry of drugs into Fasciola hepatica . The work reported here contributes to improve the understanding of CLS pharmacology. The main goals of were: I) to determine the pattern of in vivo CLS accumulation into adult F. hepatica and relevant tissues in CLS-treated sheep; II) to investigate the influence of the physicochemical composition of the incubation medium on the CLS diffusion process into adult F. hepatica ; III) to assess the ovicidal activity of CLS against F. hepatica eggs; and IV) to investigate the in vivo effect of CLS treatment on glutathione S-transferases activity in adult liver flukes exposed to CLS. Fourteen healthy sheep were each orally infected with 75 F. hepatica metacercariae. Sixteen (16) weeks after infection, animals were treated with CLS by oral (n = 6, 10 mg/kg) or sub-cutaneous (sc) (n = 6, 5 mg/kg) route. At 12, 24 and 36 h post-treatment, animals were sacrificed (n = 2) and samples of blood, bile and adult F. hepatica were collected. In addition, flukes recovered from non-treated sheep (n = 2) were ex vivo incubated (60 min) in the presence of CLS in either RPMI or bile as incubation medium. CLS concentration was measured by HPLC. The ovicidal activity of CLS was investigated using eggs obtained from the bile of untreated sheep. Finally, glutathione S-transferase activity in F. hepatica recovered from untreated and CLS-treated sheep was assessed. In the in vivo studies, the highest CLS concentrations were measured in plasma and adult liver flukes. A positive correlation was observed between CLS concentration in plasma and in F. hepatica . Results obtained in the current work indicate that the in vivo accumulation of CLS into adult liver flukes occurs mainly by the oral route. After ex vivo incubation, the uptake of CLS by the parasite was markedly diminished in the presence of bile compared with that observed in the presence of RPMI as incubation medium. CLS lacks ovicidal activity at therapeutically relevant concentrations. Lastly, CLS significantly increased glutathione S-transferase activity in flukes recovered at 12 h (oral treatment) and 24 h (sc treatment), compared to the control liver flukes. [ABSTRACT FROM AUTHOR]

Klebsiella pneumoniae is a common causative agent of nosocomial infections with a high level of resistance toward β-lactam antibiotics. Our previous study showed that TEM-1 and SHV-11 are the predominant β-lactamase-encoding genes of K. pneumoniae isolates in the Zhejiang area, China. In this study, more clinical K. pneumoniae isolates were collected for detecting their β-lactamase-encoding gene profiles by PCR and sequencing. qRT-PCR was then performed to determine the role of cefotaxime or penicillin in low concentrations to induce the β-lactamase gene expression of K. pneumoniae isolates. Moreover, the K. pneumoniae isolates were pretreated with closantel (CLO), a histidine kinase inhibitor, before antibiotic treatment, and qRT-PCR and the β-lactamase phenotype confirmatory test were then applied to determine the effect of CLO on the expression of the β-lactamase genes. The results showed that, except for KPC-2, the 1/4 MIC cefotaxime or penicillin induced significant mRNA elevation of the TEM-1, CTX-M-14, SHV-11 and OXA-1 β-lactamase genes, but this induction could be inhibited by CLO. After pretreatment with CLO, 78.4∼81.4% of the β-lactam-resistant isolates became sensitive and the positive rate of the β-lactamase production phenotype in the isolates was decreased from 100% to 27.1%. The data indicate that TEM-1 (70.7%), SHV-11 (64.2%) and CTX-M-14 (40.5%) are the predominant β-lactamase genes of the K. pneumoniae isolates in Zhejiang and sublethal dosage of β-lactam antibiotics can induce the β-lactamase gene expression of K. pneumoniae through histidine kinase-mediated two-component signaling systems. [ABSTRACT FROM AUTHOR]

Copyright of Brazilian Journal of Biology is the property of Instituto Internacional de Ecologia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Haemonchosis is commonly associated with late gestation and parturition in ewes during the spring in Ontario, Canada. Due to widespread anthelmintic resistance, targeted selective treatment (TST) of ewes with closantel, an anthelmintic not previously available in Canada, at lambing was investigated as a potential strategy to manage haemonchosis in both ewes and lambs, while also maintaining parasite refugia (i.e., a population of parasites not exposed to anthelmintic). In a longitudinal pilot study in 2013 and 2014, six client-owned farms were randomly assigned as either whole treatment (WT) farms (n = 3), where all the ewes were treated with oral closantel (10 mg/kg) at lambing, or TST farms (n = 3), where ewes were treated with oral closantel (10 mg/kg) at lambing only if they met at least one of four criteria: a) the last grazing season was their first grazing season; b) body condition score ≤2; c) FAMACHA © score ≥4; and/or d) three or more nursing lambs. Pasture samples to assess larval burdens and fecal samples from a minimum of 20 ewes and 20 lambs on every farm were collected monthly during the grazing season (May-October). Additional anthelmintic treatments given by producers (either fenbendazole or ivermectin) and deaths attributable to parasitism were also recorded. Pre-treatment arithmetic mean Haemonchus sp. fecal egg counts (FECs) on each farm at the beginning of the study in May 2013, ranged from 506 to 2738 eggs per gram of feces. The number of animals treated on TST farms was reduced by as much as 47% compared to WT farms, and there was no significant difference between TST and WT farms in the proportion of additional treatments given by producers throughout the grazing season or the percentage of parasitism deaths reported. In the first year of the study, Haemonchus sp. larval burdens on pasture were generally higher on TST than WT farms at the beginning of the grazing season, but were not significantly different at the end of the grazing season. In the second year, there were no significant differences in Haemonchus sp. larval burdens on pasture between TST and WT farms throughout the grazing season. This study suggests that, under Ontario conditions, when TST indicators are able to accurately identify animals with high Haemonchus sp. FECs, TST of ewes at lambing can be employed to control Haemonchus sp. FEC in the flock, thereby maintaining refugia and delaying the onset of anthelmintic resistance. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the effect of veterinary pharmaceuticals (VPs) used to control endo- and ectoparasites in ruminants, on the survival and reproduction of the collembolan species Folsomia candida . Standard ecotoxicological tests were conducted in Tropical Artificial Soil and the treatments consisted of increasing dosages of four commercial products with different active ingredients: ivermectin, fipronil, fluazuron and closantel. Ecotoxicological effects were related to the class and mode of action of the different compounds. Fipronil and ivermectin were the most toxic compounds causing a significant reduction in the number of juveniles at the lowest doses tested (LOEC reprod values of 0.3 and 0.2 mg kg −1 of dry soil, respectively) and similar low EC 50 values (fipronil: 0.19 mg kg −1 dry soil, CL 95% 0.16–0.22; ivermectin: 0.43 mg kg −1 dry soil, CL 95% 0.09–0.77), although the effects observed in the former compound were possibly related to a low adult survival (LC 50 of 0.62 mg kg −1 dry soil; CL 95% : 0.25–1.06). For the latter compound no significant lethal effects were observed. Fluazuron caused an intermediate toxicity (EC 50 of 3.07 mg kg −1 dry soil, CL 95% : 2.26–3.87), and also here a decrease in adult survival could explain the effects observed at reproduction. Closantel, despite showing a significant reduction on the number of juveniles produced, no dose-response relationship nor effects higher than 50% were observed. Overall, all tested compounds, especially ivermectin, when present in soil even at sub-lethal concentrations, can impair the reproduction of collembolans and possibly other arthropods. However, the actual risk to arthropod communities should be further investigated performing tests under a more realistic exposure (e.g., by testing the dung itself as the contaminated matrix) and by deriving ecotoxicologically relevant exposure concentration in soil derived from the presence of cattle dung. [ABSTRACT FROM AUTHOR]