RESUMEN
A simple and sensitive fluorescent probe has been developed and optimized to detect the non-intentional administration of levamisole (LVM). LVM is used as an anthelmintic therapy in cows, and hence, its residues appear in the drained milk until 60 hours after administering the drug. Meanwhile, levamisole is known to be an adulterant to cocaine and could be detected in addicts' plasma samples. Owing to its severe side effects, including agranulocytosis, which is lethal in many cases, detection and quantification of LVM in milk and plasma samples are of utmost importance. Therefore, a sensitive and selective analytical method is required for this purpose. This work develops a highly fluorescent probe obtained through the reaction between LVM and erythrosine-B in an acidic medium, where the produced ion pair complex has been measured at 553 nm after excitation at 528 nm. The proposed method provides linearity over the concentration range of 0.5-2.0 µg mL-1 for LVM, with a corresponding detection and quantitation limit of 0.5 and 0.3 µg mL-1. Full validation was performed, permitting the application of the suggested method to perform simple extraction steps. All the applied procedures followed the guidelines offered by green analytical chemistry, where the Green Analytical Procedure Index (GAPI) assessed the greenness of the proposed tool, and the yielded pictograms proved the eco-friendliness of the offered tool.
Asunto(s)
Eritrosina , Colorantes Fluorescentes , Levamisol , Leche , Levamisol/análisis , Levamisol/sangre , Animales , Leche/química , Colorantes Fluorescentes/química , Eritrosina/química , Bovinos , Espectrometría de Fluorescencia/métodos , Límite de Detección , Contaminación de MedicamentosRESUMEN
Street cocaine is often mixed with various substances that intensify its harmful effects. This paper proposes a framework to identify attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) intervals that best predict the concentration of adulterants in cocaine samples. Wavelengths are ranked according to their relevance through ReliefF and mRMR feature selection approaches, and an iterative process removes less relevant wavelengths based on the ranking suggested by each approach. Gaussian Process (GP) regression models are constructed after each wavelength removal and the prediction performance is evaluated using RMSE. The subset balancing a low RMSE value and a small percentage of retained wavelengths is chosen. The proposed framework was validated using a dataset consisting of 345 samples of cocaine with different amounts of levamisole, caffeine, phenacetin, and lidocaine. Averaged over the four adulterants, the GP regression coupled with the mRMR retained 1.07â¯% of the 662 original wavelengths, outperforming PLS and SVR regarding prediction performance.
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Cocaína , Contaminación de Medicamentos , Cocaína/análisis , Contaminación de Medicamentos/prevención & control , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Distribución Normal , Cafeína/análisis , Levamisol/análisis , Fenacetina/análisis , Análisis de RegresiónAsunto(s)
Cocaína , Contaminación de Medicamentos , Levamisol , Piodermia Gangrenosa , Humanos , Levamisol/efectos adversos , Piodermia Gangrenosa/inducido químicamente , Piodermia Gangrenosa/tratamiento farmacológico , Piodermia Gangrenosa/diagnóstico , Piodermia Gangrenosa/patología , Cocaína/efectos adversos , Masculino , Trastornos Relacionados con Cocaína/complicaciones , Adulto , FemeninoRESUMEN
Levamisole is an anthelmintic drug restricted to veterinary use but is currently detected as the most widely used cocaine cutting agent in European countries. Levamisole-adulterated cocaine has been linked to acute kidney injury, marked by a decrease in glomerular filtration rate, which involves reduced renal blood flow, but data on the alteration of renovascular response produced by levamisole are scarce. Renal arteries were isolated from healthy rabbits and used for isometric tension recording in organ baths and protein analysis. We provide evidence that depending on its concentration, levamisole modulates renovascular tone by acting as a non-selective α-adrenergic receptor blocker and down-regulates α1-adrenoceptor expression. Furthermore, levamisole impairs the endothelium-dependent relaxation induced by acetylcholine without modifying endothelial nitric oxide synthase (eNOS) expression. However, exposure to superoxide dismutase (SOD) partially prevents the impairment of ACh-induced relaxation by levamisole. This response is consistent with a down-regulation of SOD1 and an up-regulation of NADPH oxidase 4 (Nox4), suggesting that endothelial NO loss is due to increased local oxidative stress. Our findings demonstrate that levamisole can interfere with renal blood flow and the coordinated response to a vasodilator stimulus, which could worsen the deleterious consequences of cocaine use.
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Levamisol , Óxido Nítrico , Arteria Renal , Vasodilatación , Animales , Levamisol/farmacología , Levamisol/toxicidad , Conejos , Arteria Renal/efectos de los fármacos , Arteria Renal/metabolismo , Arteria Renal/fisiopatología , Óxido Nítrico/metabolismo , Vasodilatación/efectos de los fármacos , Masculino , Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Antagonistas de Receptores Adrenérgicos alfa 1/toxicidad , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés Oxidativo/efectos de los fármacos , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Superóxido Dismutasa/metabolismo , NADPH Oxidasa 4/metabolismo , Relación Dosis-Respuesta a Droga , Superóxido Dismutasa-1/metabolismo , Vasodilatadores/farmacologíaRESUMEN
A novel group of biocidal compounds are the Crystal 3D (Cry) and Cytolytic (Cyt) proteins produced by Bacillus thuringiensis (Bt). Some Bt Cry proteins have a selective nematocidal activity, with Cry5B being the most studied. Cry5B kills nematode parasites by binding selectively to membrane glycosphingolipids, then forming pores in the cell membranes of the intestine leading to damage. Cry5B selectively targets multiple species of nematodes from different clades and has no effect against mammalian hosts. Levamisole is a cholinergic anthelmintic that acts by selectively opening L-subtype nicotinic acetylcholine receptor ion-channels (L-AChRs) that have been found on muscles of nematodes. A synergistic nematocidal interaction between levamisole and Cry5B at the whole-worm level has been described previously, but the location, mechanism and time-course of this synergism is not known. In this study we follow the timeline of the effects of levamisole and Cry5B on the Ca2+ levels in enterocyte cells in the intestine of Ascaris suum using fluorescence imaging. The peak Ca2+ responses to levamisole were observed after approximately 10 minutes while the peak responses to activated Cry5B were observed after approximately 80 minutes. When levamisole and Cry5B were applied simultaneously, we observed that the responses to Cry5B were bigger and occurred sooner than when it was applied by itself. It is proposed that the synergism is due to the cytoplasmic Ca2+ overload that is induced by the combination of levamisole opening Ca2+ permeable L-subtype nAChRs and the Ca2+ permeable Cry5B toxin pores produced in the enterocyte plasma membranes. The effect of levamisole potentiates and speeds the actions of Cry5B that gives rise to bigger Ca2+ overloads that accelerates cell-death of the enterocytes.
Asunto(s)
Ascaris suum , Toxinas de Bacillus thuringiensis , Proteínas Bacterianas , Endotoxinas , Proteínas Hemolisinas , Levamisol , Levamisol/farmacología , Animales , Toxinas de Bacillus thuringiensis/farmacología , Endotoxinas/farmacología , Endotoxinas/metabolismo , Proteínas Hemolisinas/farmacología , Proteínas Hemolisinas/metabolismo , Proteínas Bacterianas/metabolismo , Ascaris suum/efectos de los fármacos , Antihelmínticos/farmacología , Intestinos/efectos de los fármacos , Intestinos/parasitología , Sinergismo Farmacológico , Antinematodos/farmacología , Bacillus thuringiensis/efectos de los fármacosRESUMEN
In the current issue of Kidney International, Sinha et al. present data from an open-label, noninferior, randomized controlled trial comparing 12-months of alternate-day prednisolone, given daily during infection, versus levamisole, in children with frequently relapsing or steroid-dependent nephrotic syndrome. This study suggests that both of these strategies are efficacious and safe. Results of this study should redefine the role of levamisole in future guidelines, and a call for global availability of levamisole should be advocated.
Asunto(s)
Levamisol , Síndrome Nefrótico , Niño , Humanos , Levamisol/efectos adversos , Síndrome Nefrótico/tratamiento farmacológico , Prednisolona , Glucocorticoides , RecurrenciaRESUMEN
BACKGROUND: Levamisole is a commonly used steroid-sparing agent (SSA), but the reported incidence of antineutrophil cytoplasmic antibody (ANCA) positivity has been concerning. METHODS: Observational cross-sectional study wherein children aged 2 to 18 years with frequently relapsing/steroid dependent nephrotic syndrome (FRNS/SDNS) on levamisole for ≥ 12 months were tested for ANCA. RESULTS: A total of 210 children (33% female), median age of 7.3 (IQR: 5.6-9.6) years, and a median duration of levamisole exposure of 21 (IQR: 15-30) months were tested. ANCA was positive in 18% (n = 37): 89% (n = 33) perinuclear ANCA (pANCA), 3% (n = 1) cytoplasmic ANCA (cANCA), and 8% (n = 3) both. Of ANCA-positive children, none had reduced eGFR or abnormal urinalysis. The majority of these children were asymptomatic (81%, n = 30). Rash was more common among ANCA-positive children [6/37 (16%) vs. 3/173 (2%), p = 0.0001]. On multivariate analysis, higher age (OR = 1.02, [95th CI: 1.01 to 1.03], p = 0.007) and longer duration of levamisole exposure (OR = 1.05, [95th CI: 1.02 to 1.08], p = 0.0007) were associated with ANCA positivity. Levamisole was stopped in ANCA-positive children with the resolution of any clinical manifestations if present. Repeat ANCA testing was performed in 54% (20/37), and all were ANCA negative by 18 months. CONCLUSIONS: Children with FRNS/SDNS on longer duration of levamisole were associated with increasing prevalence of ANCA positivity, but most of these children were clinically asymptomatic. Prospective studies are required to determine the chronology of ANCA positivity and its clinical implication.
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Anticuerpos Anticitoplasma de Neutrófilos , Levamisol , Síndrome Nefrótico , Humanos , Levamisol/efectos adversos , Niño , Femenino , Masculino , Estudios Transversales , Anticuerpos Anticitoplasma de Neutrófilos/sangre , Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Síndrome Nefrótico/tratamiento farmacológico , Síndrome Nefrótico/inmunología , Síndrome Nefrótico/sangre , Preescolar , Adolescente , Estudios de CohortesRESUMEN
AIMS: Prednisolone is the cornerstone of treatment for idiopathic nephrotic syndrome in children, but is associated with marked side-effects. Therapeutic drug monitoring using saliva would be a patient-friendly option to monitor prednisolone treatment. To assess the feasibility of saliva monitoring, we described the pharmacokinetics (PK) of unbound prednisolone in plasma and saliva of children with first onset steroid-sensitive nephrotic syndrome (SSNS). METHODS: Children (age 2-16 years) with SSNS participating in a randomized, placebo-controlled trial with levamisole were treated with an 18-week tapering schedule of prednisolone. Five serial samples were collected at 4 (saliva) and 8 weeks (saliva and plasma) after first onset. A nonlinear mixed-effects model was used to estimate the PK parameters of unbound prednisolone and the saliva-to-plasma ratio. Monte Carlo simulations were performed to assess the predictive performance of saliva monitoring. RESULTS: From 39 children, 109 plasma and 275 saliva samples were available. Estimates (relative squared error) of unbound plasma clearance and volume of distribution were 93 (5%) L h-1 70 kg-1 and 158 (7%) L 70 kg-1, respectively. Typical saliva-to-plasma ratio was 1.30 (8%). Monte Carlo simulations demonstrated that on basis of 4 saliva samples and a single plasma sample unbound plasma area-under-the-concentration-time curve can be predicted within 20% imprecision in 79% of the patients compared to 87% based on 4 plasma samples. CONCLUSION: Saliva proved to be a reliable and patient-friendly option to determine prednisolone plasma exposure in children with SSNS. This opens opportunities for further PK and pharmacodynamics studies of prednisolone in a variety of paediatric conditions.
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Monitoreo de Drogas , Síndrome Nefrótico , Prednisolona , Saliva , Humanos , Prednisolona/farmacocinética , Prednisolona/administración & dosificación , Niño , Síndrome Nefrótico/tratamiento farmacológico , Saliva/química , Preescolar , Adolescente , Masculino , Femenino , Monitoreo de Drogas/métodos , Levamisol/farmacocinética , Levamisol/administración & dosificación , Levamisol/análisis , Levamisol/uso terapéutico , Glucocorticoides/farmacocinética , Glucocorticoides/administración & dosificación , Método de MontecarloRESUMEN
AIM OF THE STUDY: The growing resistance of helminth parasites to currently available commercial anthelmintic drugs, combined with apprehensions regarding detrimental chemical residues in livestock products, has sparked an interest in exploring medicinal plants as an alternative strategy for treating helminthiasis. As a result, this study was designed to investigate the anthelmintic activity of crude methanolic extracts (CME) of Saussurea costus root on Ascaridia.galli, a pathogenic nematode of poultry. MATERIALS AND METHODS: In vitro, the anthelmintic effect of Saussurea costus root was evaluated in comparison to commercial anthelmintic, levamisole on the adult nematode parasites, A.galli using worm motility inhibition (WMI) test. The CME of S.costus was also evaluated for in vivo anthelmintic activity in chickens experimentally infected with Ascaridia galli. For the in vivo study, one hundred-day-old chickens were orally infected with embryonated eggs of A. galli worms. The efficacy of the plant extract as an anthelmintic was assessed through two tests: faecal egg count reduction (FECR) test and worm count reduction (WCR) test. The study investigated three distinct doses of plant extract under in vivo setup: 500 mg kg-1 body weight (bw), 1000 mg kg-1 bw, and 2000 mg kg-1 bw. RESULTS: In vitro, all the tested concentrations of S.costus (25 mg/ml, 50 mg/ml, and 100 mg/ml) showed a significant (P < 0.001) anthelmintic effects on live adult A. galli worms in terms of inhibition of worm motility at different hours post-treatment. At the highest concentration of the extract, we observed worm motility inhibition of 100% at 24 h post-exposure. On day 14 post-treatment, all birds were slaughtered, and adult A. galli worms were subsequently retrieved from their small intestines. Birds treated with CME extract of S. costus root exhibited a significant (P < 0.001) reduction in faecal egg count. However, the administration of the extract at the dosage of 500 mg kg-1bw to the birds did not reveal any significant (P > 0.05) differences in the worm count compared to the negative control group. The CME of S. costus at a dose of 2000 mg kg-1bw showed the highest anthelmintic activity by inducing 83.10% FECR and 76.47% WCR. CONCLUSION: In conclusion, the root extract of S. costus has a promising anthelmintic activity on A. galli as demonstrated by the results of the present experiment.
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Antihelmínticos , Ascaridia , Ascaridiasis , Pollos , Extractos Vegetales , Enfermedades de las Aves de Corral , Saussurea , Animales , Ascaridia/efectos de los fármacos , Extractos Vegetales/farmacología , Extractos Vegetales/química , Enfermedades de las Aves de Corral/parasitología , Enfermedades de las Aves de Corral/tratamiento farmacológico , Antihelmínticos/farmacología , Pollos/parasitología , Saussurea/química , Ascaridiasis/veterinaria , Ascaridiasis/tratamiento farmacológico , Ascaridiasis/parasitología , Recuento de Huevos de Parásitos , Heces/parasitología , Raíces de Plantas/química , Levamisol/farmacología , Levamisol/uso terapéuticoRESUMEN
OBJECTIVE: To develop a multi-modal deep learning method for automatic classification of immune-mediated glomerular diseases based on images of optical microscopy (OM), immunofluorescence microscopy (IM), and transmission electron microscopy (TEM). METHODS: We retrospectively collected the pathological images from 273 patients and constructed a multi-modal multi- instance model for classification of 3 immune-mediated glomerular diseases, namely immunoglobulin A nephropathy (IgAN), membranous nephropathy (MN), and lupus nephritis (LN). This model adopts an instance-level multi-instance learning (I-MIL) method to select the TEM images for multi-modal feature fusion with the OM images and IM images of the same patient. By comparing this model with unimodal and bimodal models, we explored different combinations of the 3 modalities and the optimal methods for modal feature fusion. RESULTS: The multi-modal multi-instance model combining OM, IM, and TEM images had a disease classification accuracy of (88.34±2.12)%, superior to that of the optimal unimodal model [(87.08±4.25)%] and that of the optimal bimodal model [(87.92±3.06)%]. CONCLUSION: This multi- modal multi- instance model based on OM, IM, and TEM images can achieve automatic classification of immune-mediated glomerular diseases with a good classification accuracy.
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Glomerulonefritis por IGA , Levamisol/análogos & derivados , Humanos , Estudios Retrospectivos , Microscopía Fluorescente , Microscopía Electrónica de TransmisiónAsunto(s)
Ivermectina , Levamisol , Animales , Ivermectina/farmacología , Levamisol/farmacología , Capillaria , Macrólidos/farmacología , ErizosRESUMEN
Haemonchus contortus and Trichostrongylus colubriformis are the most important gastrointestinal nematodes causing serious losses in sheep production of tropical and subtropical regions. Prophylaxis of gastrointestinal nematode infections is based on anthelmintics use, but their frequent administration selects multiple-resistant parasites. To evaluate how the situation has changed over the last decades, the anthelmintic resistance status of gastrointestinal nematodes in sheep flocks was assessed in the current study and compared to previous surveys. In each one of the 15 flocks evaluated, animals (n ≥ 7) were allocated into at least five groups and treated as follows: 1) untreated control; 2) albendazole; 3) levamisole; 4) ivermectin; and 5) monepantel. If more animals were available, two additional groups were included: 6) closantel, and 7) moxidectin. The faecal egg count reduction test (FECRT) was carried out to evaluate the pre- and post-treatment using the SHINY tool. Haemonchus spp. was the most prevalent nematode from faecal cultures. The mean efficacy of albendazole was 40%. Only in two farms, levamisole presented a relatively high percentage of reduction in the FECRT about 90%, while ivermectin and moxidectin presented the worst mean efficacy of 34% and 21% among all farms, respectively. Like other anthelmintics, closantel demonstrated low efficacy (63%) across all farms evaluated. Monepantel presented an overall mean efficacy of 79%, but it was the only anthelmintic that presented efficacy ≥95%, in five farms. The results revealed that gastrointestinal nematodes with multiple anthelmintic resistance were prevalent in all 15 sheep herds. The research suggests that nematodes are becoming more and more resistant to various anthelmintic compounds, which has made the problem worse. This circumstance highlights the necessity to put into practice sustainable and long-lasting methods to prevent gastrointestinal nematode infections in sheep husbandry.
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Aminoacetonitrilo/análogos & derivados , Antihelmínticos , Haemonchus , Macrólidos , Nematodos , Infecciones por Nematodos , Salicilanilidas , Enfermedades de las Ovejas , Animales , Ovinos , Levamisol/farmacología , Levamisol/uso terapéutico , Ivermectina/uso terapéutico , Albendazol/uso terapéutico , Brasil/epidemiología , Antihelmínticos/farmacología , Antihelmínticos/uso terapéutico , Infecciones por Nematodos/tratamiento farmacológico , Infecciones por Nematodos/epidemiología , Infecciones por Nematodos/veterinaria , Heces/parasitología , Enfermedades de las Ovejas/tratamiento farmacológico , Enfermedades de las Ovejas/epidemiología , Enfermedades de las Ovejas/parasitología , Recuento de Huevos de Parásitos/veterinaria , Resistencia a MedicamentosRESUMEN
Initial therapies for children with frequently relapsing nephrotic syndrome include alternate-day prednisolone that is given daily during infections, or levamisole. In this open label, non-inferiority trial, 160 patients, 2 to 18-years-old with frequent relapses, were randomly assigned to receive either prednisolone (0.5-0.7 mg/kg/alternate-day, given daily during infections), or levamisole (2-2.5 mg/kg/alternate-days) for one-year. Patients with relapses on alternate day prednisolone at over 1 mg/kg, prior use of potent steroid-sparing therapies, eGFR under 60 ml/min/1.73 m2 and significant steroid toxicity were excluded. Primary outcome was the proportion of patients with frequent relapses, defined as three-relapses in one-year, or two-relapses within six-months if associated with significant steroid toxicity or loss to follow up. Eighty patients each were randomized to receive prednisolone and levamisole. Baseline features showed preponderance of young patients presenting within two-years of disease onset. On intention-to-treat analysis, frequent relapses were more common in patients administered prednisolone (40% versus 22.5%; risk difference 17.5%; 95% confidence interval 3.4-31.6%). Prednisolone was not non-inferior to levamisole in preventing frequent relapses. However, the two groups showed similar proportions of patients in sustained remission, comparable frequency of relapses, and low frequency of adverse events. The decline in steroid requirement from baseline was higher in the levamisole group. Per-protocol analysis showed similar results. These results have implications for choice of therapy for frequently relapsing nephrotic syndrome. Although therapy with alternate-day prednisolone was not non-inferior to levamisole in preventing frequent relapses, both therapies were effective in other outcome measures. Thus, levamisole was relatively steroid-sparing and may be preferred in patients at risk of steroid toxicity.
Asunto(s)
Síndrome Nefrótico , Prednisolona , Niño , Humanos , Preescolar , Adolescente , Prednisolona/efectos adversos , Síndrome Nefrótico/tratamiento farmacológico , Síndrome Nefrótico/inducido químicamente , Levamisol/efectos adversos , Inmunosupresores/efectos adversos , RecurrenciaRESUMEN
Recently, a S168T variant in the acetylcholine receptor subunit ACR-8 was associated with levamisole resistance in the parasitic helminth Haemonchus contortus. Here, we used the Xenopus laevis oocyte expression system and two-electrode voltage-clamp electrophysiology to measure the functional impact of this S168T variant on the H. contortus levamisole-sensitive acetylcholine receptor, L-AChR-1.1. Expression of the ACR-8 S168T variant significantly reduced the current amplitude elicited by levamisole compared to acetylcholine, with levamisole changing from a full to partial agonist on the recombinant L-AChR. Functional validation of the S168T mutation on modulating levamisole activity at the receptor level highlights its critical importance as both a mechanism and a marker of levamisole resistance.
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Antihelmínticos , Haemonchus , Parásitos , Animales , Levamisol/farmacología , Haemonchus/genética , Haemonchus/metabolismo , Antinematodos/farmacología , Receptores Colinérgicos/genética , Parásitos/metabolismo , Resistencia a Medicamentos/genética , Antihelmínticos/farmacología , Antihelmínticos/metabolismoRESUMEN
Amyotrophic lateral sclerosis is a devastating neurodegenerative disease with a complex genetic basis, presenting both in familial and sporadic forms. The hexanucleotide (G4C2) repeat expansion in the C9orf72 gene, which triggers distinct pathogenic mechanisms, has been identified as a major contributor to familial and sporadic Amyotrophic lateral sclerosis cases. Animal models have proven pivotal in understanding these mechanisms; however, discrepancies between models due to variable transgene sequence, expression levels, and toxicity profiles complicate the translation of findings. Herein, we provide a systematic comparison of 7 publicly available Drosophila transgenes modeling the G4C2 expansion under uniform conditions, evaluating variations in their toxicity profiles. Further, we tested 3 previously characterized disease-modifying drugs in selected lines to uncover discrepancies among the tested strains. Our study not only deepens our understanding of the C9orf72 G4C2 mutations but also presents a framework for comparing constructs with minute structural differences. This work may be used to inform experimental designs to better model disease mechanisms and help guide the development of targeted interventions for neurodegenerative diseases, thus bridging the gap between model-based research and therapeutic application.
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Esclerosis Amiotrófica Lateral , Demencia Frontotemporal , Levamisol/análogos & derivados , Enfermedades Neurodegenerativas , Animales , Drosophila/genética , Esclerosis Amiotrófica Lateral/genética , Proteína C9orf72/genéticaRESUMEN
Our understanding of anthelmintic resistance in the gastrointestinal nematodes of Australian cattle relies exclusively on small-scale phenotypic reports utilising traditional faecal egg count reduction tests. This approach is not readily scalable to establish the national prevalence of resistance, nor is it conducive of routine longitudinal surveillance for the emergence of resistance in its early stages. This study introduces the benefits of applying mixed amplicon metabarcoding longitudinally for timely and cost-efficient molecular surveillance of multiple anthelmintic resistance mutations, as they emerge on farms. Using opportunistically collected faecal samples from a cattle herd in central west New South Wales (2019-2023), we detected the early emergence of Haemonchus spp. levamisole-resistant S168T shortly after levamisole introduction, while benzimidazole-resistant allele frequencies remained constant. Additionally, we observed the possible spill-over of resistant Haemonchus contortus from sheep, along with variations in faecal burdens and species diversity influenced by climate stochasticity and host immunity. This study emphasises the power of molecular diagnostics for farm-level anthelmintic resistance management, providing essential evidence to support its integration into routine surveillance programmes.
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Antihelmínticos , Enfermedades de los Bovinos , Haemonchus , Enfermedades de las Ovejas , Animales , Bovinos , Ovinos , Levamisol/uso terapéutico , Nueva Gales del Sur/epidemiología , Australia , Antihelmínticos/farmacología , Antihelmínticos/uso terapéutico , Heces , Haemonchus/genética , Resistencia a Medicamentos/genética , Recuento de Huevos de Parásitos/veterinaria , Enfermedades de las Ovejas/tratamiento farmacológico , Enfermedades de los Bovinos/tratamiento farmacológico , Enfermedades de los Bovinos/epidemiologíaRESUMEN
BACKGROUND/AIM: Uracil-tegafur+leucovorin (UFT/LV), an oral adjuvant therapy for stage II/III colorectal cancer, is non-inferior to standard weekly fluorouracil and folinate. Although polysaccharide K (PSK) has been evaluated as a postoperative adjuvant colorectal cancer drug, its efficacy remains unclear. This randomized phase II trial compared UFT/LV+PSK with UFT/LV as adjuvant chemotherapy. PATIENTS AND METHODS: Between April 2011 and August 2016, 186 patients who underwent radical resection randomly received 6 months of UFT/LV (Group A: 300 mg/m2/day UFT and 75 mg/day LV, every 35 days for five cycles), 6 months of UFT/LV+PSK (Group B: standard UFT/LV regimen and daily administration of 3 g/day of PSK), or 12 months of UFT/LV+PSK (Group C). The primary endpoint was the 3-year disease-free survival. RESULTS: Groups A, B, and C consisted of 37, 75, and 74 patients, of which treatment was completed by 33 (89.2%), 63 (84.9%), and 53 (70.4%) patients, respectively (p=0.0279). Adverse event incidence for all grades were 59.5%, 52.1%, and 59.2%, and for grade ≥3 were 13.5%, 9.6%, and 9.9%, respectively. The 3-year disease-free survival rates were 72.5%, 82.2%, and 74.2%, respectively, with no significant differences. The preoperative lymphocyte ratio did not significantly differ between groups. CONCLUSION: UFT/LV+PSK is comparable to UFT/LV therapy in terms of prognostic efficacy and reduced adverse effects. Thus, UFT/LV+PSK is a useful adjuvant chemotherapy option for patients with high-risk stage II/III colorectal cancer.
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Quimioterapia Adyuvante , Neoplasias Colorrectales , Humanos , Administración Oral , Quimioterapia Adyuvante/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Leucovorina/uso terapéutico , Levamisol/análogos & derivados , Estadificación de Neoplasias , Tegafur/uso terapéutico , Uracilo/uso terapéuticoRESUMEN
AIMS: To determine the concentration, in comparison with the maximum residue limit (MRL), of anthelmintic marker residues in the target tissues (liver and fat) of sheep treated concurrently with two oral drenches, one containing monepantel and abamectin and the other oxfendazole and levamisole. METHODS: On day 0 of the study, 12 sheep (six male and six female; 8-9-months old) were dosed according to individual body weight determined the day prior. Zolvix Plus (dual-active oral drench containing 25 g/L monepantel and 2 g/L abamectin) was administered to all animals prior to administration of Scanda (dual-active oral drench containing 80 g/L levamisole hydrochloride and 45.3 g/L oxfendazole). Six sheep (three male and three female) were slaughtered 21 and 28 days after treatment and renal fat and liver samples were collected.Using validated methods, analyses for monepantel sulfone, abamectin, levamisole and oxfendazole (expressed as total fenbendazole sulfone following conversion of the combined concentrations of oxfendazole, fenbendazole and fenbendazole sulfone) were performed on liver samples while renal fat specimens were analysed for monepantel sulfone and abamectin residues only. Detected concentrations were compared to the established MRL in sheep for each analyte determined by the Ministry for Primary Industries. RESULTS: All residues detected in samples of liver and fat collected 21 and 28 days after treatment were below the MRL for each analyte. All liver samples collected on day 21 had detectable monepantel sulfone (mean 232 (min 110, max 388) µg/kg) and oxfendazole (mean 98.7 (min 51.3, max 165) µg/kg) residues below the MRL (5,000 and 500 µg/kg, respectively). Monepantel sulfone (mean 644 (min 242, max 1,119) µg/kg; MRL 7,000 µg/kg) residues were detected in 6/6 renal fat samples. Levamisole residues were detected in 3/6 livers (mean 40.0 (min 14.3, max 78.3) µg/kg; MRL 100 µg/kg), and abamectin residues in 1/6 livers (0.795 µg/kg; MRL 25 µg/kg) and 2/6 fat samples, (mean 0.987 (min 0.514, max 1.46) µg/kg; MRL 50 µg/kg) 21 days after treatment. CONCLUSION AND CLINICAL RELEVANCE: These results suggest that concurrent administration of Zolvix Plus and Scanda to sheep is unlikely to result in an extended residue profile for any of the active ingredients, with all analytes measured being under the approved New Zealand MRL 21 days after treatment. This work was not completed in line with guidance for establishing official residue profiles, nor is it sufficient to propose a new withholding period.
Asunto(s)
Aminoacetonitrilo/análogos & derivados , Antihelmínticos , Bencimidazoles , Ivermectina/análogos & derivados , Enfermedades de las Ovejas , Animales , Masculino , Femenino , Ovinos , Levamisol/uso terapéutico , Fenbendazol/uso terapéutico , Antihelmínticos/uso terapéutico , Sulfonas/uso terapéutico , Enfermedades de las Ovejas/tratamiento farmacológicoRESUMEN
PURPOSE: The aim of this study was to report 2 cases of levamisole-adulterated cocaine-induced mucous membrane pemphigoid. METHODS: This study is a review of case reports and literature. RESULTS: Two patients presented with bilateral severe purulent conjunctivitis, corneal ulceration, and rapidly progressive forniceal shortening. Both patients were active cocaine users. A complete blood analysis showed a positive antineutrophil cytoplasmic antibody immunofluorescence with a mixed perinuclear antineutrophil cytoplasmic antibody and cytoplasmic-staining antineutrophil cytoplasmic antibody pattern. Direct immunofluorescence examination of conjunctival tissue showed linear deposition of component 3 and immunoglobulins at the basal membrane. A diagnosis of levamisole-adulterated cocaine-induced mucous membrane pemphigoid was made. In case 1, this suspicion was confirmed by investigating remnants of cocaine on the patient's debit card using mass spectrometry, which contained traces of levamisole. In both cases, aggressive immunosuppressive therapy combining systemic corticosteroids and rituximab was able to control the disease. However, by the time these therapies were initiated, significant corneal injury had occurred requiring corneal grafts in both patients. CONCLUSIONS: Given the rising abuse of cocaine, it is important that ophthalmologists are made aware of its association with severe atypical cicatricial conjunctivitis. To the best of our knowledge, we present the first case proving the causal relationship between levamisole and ocular cicatricial pemphigoid.
Asunto(s)
Trastornos Relacionados con Cocaína , Cocaína , Levamisol , Penfigoide Benigno de la Membrana Mucosa , Humanos , Levamisol/efectos adversos , Penfigoide Benigno de la Membrana Mucosa/diagnóstico , Penfigoide Benigno de la Membrana Mucosa/tratamiento farmacológico , Penfigoide Benigno de la Membrana Mucosa/inducido químicamente , Masculino , Trastornos Relacionados con Cocaína/complicaciones , Cocaína/efectos adversos , Persona de Mediana Edad , Contaminación de Medicamentos , Femenino , Adulto , Glucocorticoides/uso terapéuticoRESUMEN
BACKGROUND: Long Intergenic noncoding RNA predicting CARdiac remodeling (LIPCAR) is a long noncoding RNA identified in plasma of patients after myocardial infarction (MI) to be associated with left ventricle remodeling (LVR). LIPCAR was also shown to be a predictor of early death in heart failure (HF) patients. However, no information regarding the expression of LIPCAR and its function in heart as well as the mechanisms involved in its transport to the circulation is known. The aims of this study are (1) to characterize the transporter of LIPCAR from heart to circulation; (2) to determine whether LIPCAR levels in plasma isolated-extracellular vesicles (EVs) reflect the alteration of its expression in total plasma and could be used as biomarkers of LVR post-MI. METHODS: Since expression of LIPCAR is restricted to human species and the limitation of availability of cardiac biopsy samples, serum-free conditioned culture media from HeLa cells were first used to characterize the extracellular transporter of LIPCAR before validation in EVs isolated from human cardiac biopsies (non-failing and ischemic HF patients) and plasma samples (patients who develop or not LVR post-MI). Differential centrifugation at 20,000g and 100,000g were performed to isolate the large (lEVs) and small EVs (sEVs), respectively. Western blot and nanoparticle tracking (NTA) analysis were used to characterize the isolated EVs. qRT-PCR analysis was used to quantify LIPCAR in all samples. RESULTS: We showed that LIPCAR is present in both lEVs and sEVs isolated from all samples. The levels of LIPCAR are higher in lEVs compared to sEVs isolated from HeLa conditioned culture media and cardiac biopsies. No difference of LIPCAR expression was observed in tissue or EVs isolated from cardiac biopsies obtained from ischemic HF patients compared to non-failing patients. Interestingly, LIPCAR levels were increased in lEVs and sEVs isolated from MI patients who develop LVR compared to patients who did not develop LVR. CONCLUSION: Our data showed that large EVs are the main extracellular vesicle transporter of LIPCAR from heart into the circulation independently of the status, non-failing or HF, in patients. The levels of LIPCAR in EVs isolated from plasma could be used as biomarkers of LVR in post-MI patients.