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Self-licking behaviour in cattle has recently been identified as a determinant of the kinetic disposition of topically-administered ivermectin. In the present study, we document the occurrence and extent of transfer between cattle of three topically-administered endectocides, as a consequence of allo-licking. Four groups of two Holstein cows each received one pour-on formulation of doramectin, ivermectin, or moxidectin, or no treatment. The cows were then kept together in a paddock. Systemic exposure to each topically-administered endectocide was observed in at least five of six non-treated cattle. Plasma and faecal drug concentration profiles in non-treated animals were highly variable between animals and within an animal, and sometimes attained those observed in treated animals. Drug exchanges were quantified by measuring plasma and faecal clearances after simultaneous i.v. administration of the three drugs as a cocktail. Plasma clearances were 185+/-43, 347+/-77 and 636+/-130ml/kg/day, faecal clearances representing 75+/-26, 28+/-13, and 39+/-30% of the plasma clearance for doramectin, ivermectin and moxidectin, respectively. The amount of drug ingested by non-treated cattle attained 1.3-21.3% (doramectin), 1.3-16.1% (ivermectin), 2.4-10.6% (moxidectin) of a pour-on dose (500 microg/kg). The total amount of drug ingested by all non-treated cattle represented 29% (doramectin), 19% (ivermectin), and 8.6% (moxidectin) of the total amount of each drug poured on the backs of treated animals. The cumulative amounts of endectocide ingested by each non-treated cow ranged from 1.3 to 27.4% of a pour-on dose. Oral bioavailability after drug ingestion due to allo-licking was 13.5+/-9.4, 17.5+/-3.5 and 26.1+/-11.1% for doramectin, ivermectin and moxidectin, respectively. The extent of drug exchange demonstrated here raises concerns for drug efficacy and safety, emergence of drug resistance, presence of unexpectedly high residue levels in treated and/or untreated animals and high environmental burdens. Moreover, scientific and regulatory aspects of clinical and bioequivalence trials for topical drug administration in cattle should be explored.  相似文献   

3.
We studied the in vitro distribution of macrocyclic lactones (MLs), lipophilic anthelmintic drugs, in the plasma of several animal species including humans. First, in vitro spiking of goat plasma was performed with ivermectin, moxidectin, abamectin, doramectin, or eprinomectin. In parallel, goats were treated with subcutaneous injection of ivermectin. Then, cow, sheep, rabbit, pig, and human plasma were spiked with moxidectin. Four fractions were separated using KBr density gradient ultracentrifugation: very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and lipoprotein-deficient fraction. Cholesterol was analyzed by enzymatic assay and MLs by high-performance liquid chromatography. An average of 96% of MLs was associated with lipoproteins. The five MLs studied distributed similarly into goat plasma fractions with a preferential association with HDL (80-90%). Ivermectin partitioning in goat plasma was similar after in vitro spiking and in vivo treatment. In species displaying various lipoprotein profiles, moxidectin was also mainly associated with HDL. However, in human plasma, moxidectin was associated with a lesser extent to HDL (70%) and more to LDL (22%) when compared to other animal species. A relation between the plasma cholesterol content and pharmacokinetics of the drug is suggested. Our finding will allow further exploration of intestinal lymphatic absorption and milk elimination of these compounds-mechanisms in which lipoproteins are involved. In addition, possible improvements of new drug delivery systems are suggested.  相似文献   

4.
The effect of four avermectins on the population growth of pest mite Lepidoglyphus destructor was tested in laboratory experiments. The avermectins (abamectin, doramectin, emamectin-benzoate and ivermectin) of analytical purity were incorporated into an experimental diet at the same molar concentrations, ranging from 0.16 to 8 nmol/3 g of diet. Using an initial population of 50 mites, the population growth was recorded after 21 days at 85 % relative humidity and 25 °C; 12 repeats were performed per avermectin concentration and control. The diets containing the avermectins successfully suppressed the population growth of L. destructor. The EC(50) recalculated to ng of substance per g of diet showed different suppressive effects of the avermectins: doramectin (181 ng/g diet), abamectin (299 ng/g diet), emamectin-benzoate (812 ng/g diet) and ivermectin (992 ng/g diet). Of the tested avermectins, abamectin is registered for the control of phytophagous mites and ivermectin against parasitic mites, i.e., Psoroptes ovis. Although emamectin-benzoate and ivermectin were less effective on L. destructor, all of the tested avermectins are highly suitable compounds for the control of synanthropic mites.  相似文献   

5.
Bioassays were conducted to study the effect of a single therapeutic dose of injectable ivermectin, doramectin or moxidectin given to cattle and pigs and excreted in their faeces, against larvae of the housefly, Musca domestica L. (Diptera: Muscidae). Five cattle were treated with each of the test products. Cattle faecal samples were collected before treatment and on days 1, 2, 3, 6, 10, 16, 20, 23 and 28 after treatment. Three groups of pigs, each comprising 12-14 pregnant sows and gilts, were used in the experiment. Pig faeces was collected from each group before treatment and on days 1, 3, 5, 7, 9, 11, 13, 15 and 20 after treatment. Thirty, first-stage larvae were placed into 100 g of faeces. Five replicates were examined for each time-point and for each endectocide group. Evaluation was based on the number of larvae surviving to adult emergence. Low numbers of adults emerged from samples taken from cattle 1 day after treatment, indicating that ivermectin and doramectin were rapidly excreted in the faeces and affected the development of the house fly. A larvicidal effect of both drugs in cattle faeces was present for a period of about 3-4 weeks and lasted a few days longer in cattle treated with doramectin than with ivermectin. In cattle, the larvicidal activity of moxidectin was first observed in faecal samples collected 2 days post-treatment; however, it killed fewer larvae than the other two drugs. The larvicidal effect of moxidectin subsequently decreased. Ivermectin and doramectin exhibited a pronounced larvicidal effect against the house fly in the faeces of pigs. The effect of doramectin was of longer duration. Moxidectin gave the weakest larvicidal effect in pig faeces. The main difference between the results obtained for the two livestock species is that peak toxicity occurred relatively later and for a shorter duration in pig than in cattle faeces.  相似文献   

6.
Pour-on formulations of four endectocide products were compared to assess the effect of faecal residues on insects developing in naturally-colonized dung of treated cattle. In each of three independent experiments, suppression of insects was associated with application of doramectin, eprinomectin and ivermectin, but no effect was observed for moxidectin. When data were combined across experiments to increase sample sizes, suppression of insects was observed for each compound, with the least effect being observed for moxidectin. Based on the number of species affected and duration of suppression, doramectin > ivermectin > eprinomectin > moxidectin were ranked in descending order of adverse effect. A second set of three independent experiments was performed to assess the effect of endectocide treatment on dung degradation. Delayed degradation was observed for dung of cattle treated with doramectin, eprinomectin and moxidectin in the first experiment. No effect of treatment was detected in the second experiment. An effect of moxidectin was detected in the third experiment, but differences could not be detected with subsequent post-hoc tests. When data were combined across experiments to increase sample sizes, delayed degradation was detected only for eprinomectin. The apparent discrepancy between the low effect of moxidectin on insects versus its effect of dung degradation suggests the confounding action of other unidentified factors. Results of the current study indicate that use of moxidectin is least likely to affect the natural assemblage of insects associated with cattle dung.  相似文献   

7.
Several formulations of macrocyclic lactones (abamectin, ivermectin, moxidectin), including ivermectin combined with pyrantel (tetrahydropyrimidine) and ivermectin combined with praziquantel (pyrazinoisoquinolin derivative), were tested regarding their efficacy to control gastrointestinal nematodes of horses on a stud farm in southern Brazil. In addition, we tested a pharmaceutically produced generic paste containing ivermectin 4%. Similar formulations of avermectins had different efficacies measured by reduction of EPG. Levels of efficacy of the tested drugs varied against Strongylus edentatus, S. equinus and S. vulgaris. The generic paste (ivermectin 4%) was less effective than the conventional drugs.  相似文献   

8.
The macrocyclic lactones (MLs) are probably the anti-parasitic agents most widely used in the treatment of food producing animals, poultry, aquaculture and crops. Ivermectin was the first macrocyclic lactone product to be licensed for use about 20 years ago. A number of alternative products such abamectin, doramectin, emamectin, eprinomectin, moxidectin, milbemycin and selamectin, have been marketed since. Because of the increase in the number of ML drugs, there has been a steady increase in the number of published analytical methods for determination of their residues. In this paper, the structure and properties of the different ML drugs available on the market are described. The occurrence and persistence of ML residues in food is discussed in relation to marker residues and current maximum residue limits (MRLs) as defined in the European Union (EU). Methodologies for determination of ML residues in biological matrices are described in terms of extraction and clean-up methods used for different matrices. Detection systems for determination of ML residues are discussed with a particular emphasis placed on new developments in screening technologies and liquid chromatography with fluorescence or mass spectrometry.  相似文献   

9.
Cattle were treated with topical formulations of endectocides to assess the larvicidal activity of faecal residues against horn fly, Haematobia irritans (L.), house fly, Musca domestica L., and stable fly, Stomoxys calcitrans (L.) (Diptera: Muscidae). In laboratory bioassays, doramectin, eprinomectin and ivermectin suppressed horn fly in dung of cattle treated at least 4 weeks previously and suppressed house fly and stable fly in dung of cattle treated 1-5 weeks previously. Moxidectin suppressed horn fly in dung from cattle treated no more than one week previously and did not suppress house fly and stable fly. Results combined for the three species across two experiments suggested that, ranked in descending order of larvicidal activity, doramectin > ivermectin approximately = eprinomectin > moxidectin.  相似文献   

10.
Avermectins are used worldwide as antiparasitic drugs in the field of veterinary medicine and as agricultural pesticides and insecticides. Carbonic anhydrase (CA, E.C. 4.2.1.1) is a zinc‐containing metalloenzyme that catalyzes the reversible hydration of carbon dioxide (CO2) to yield protons (H+) and bicarbonate (HCO3?). In this study, some avermectins, including abamectin, doramectin, eprinomectin, and moxidectin, were investigated for in vitro inhibitory effects on the CA enzyme purified from goat liver, which was purified (125.00‐fold) using sepharose 4B‐l ‐tyrosine‐sulfanilamide affinity chromatography, with a yield of 68.27% and a specific activity of 21765.31 EU/mg proteins. The inhibition results obtained from this study showed Ki values of 0.283, 0.153, 0.232, and 0.317 nM for abamectin, doramectin, eprinomectin, and moxidectin, respectively. On the other hand, acetazolamide, well‐known clinically established CA inhibitor, possessed a Ki value of 0.707 nM against goat liver CA.  相似文献   

11.
Using [(3)H]inulin uptake as a measure of pharyngeal pumping activity, we have investigated and compared the effects of glutamate, ivermectin, and moxidectin on inulin uptake in susceptible and ivermectin-selected Haemonchus contortus. Inulin uptake is inhibited by glutamate, ivermectin, and moxidectin, at biologically relevant concentrations. Glutamate influences the responses to both ivermectin and moxidectin, suggesting that these three substances share a common mechanism of action. The effects of ivermectin on inulin uptake, but not moxidectin, are significantly altered as a result of selection with ivermectin. These results suggest that ivermectin and moxidectin may differ, to some extent, in their mode of action responses or mechanisms of resistance.  相似文献   

12.
A multi-residue supercritical fluid extraction (SFE) method has been developed for the extraction and isolation of eprinomectin, moxidectin, abamectin, doramectin and ivermectin residues from animal liver. Liver samples are mixed with hydromatrix and packed into a vessel containing 2 g of basic alumina. The samples are extracted at 100°C using unmodified supercritical carbon dioxide (SF-CO2) at a pressure of 300 bar and flow-rate of 5.0 l/min. The analytes are adsorbed in-line on the basic alumina trap, which is later eluted with 4 ml of methanol–ethyl acetate (70:30, v/v). After evaporating to dryness, sample extracts are derivatised using methylimidazole, trifluoroacetic anhydride and acetic acid at 65°C for 30 min. Derivatised sample extracts are analysed by high-performance liquid chromatography (HPLC) with fluorescence detection. The method was validated using bovine liver fortified at levels of 4 and 20 μg/kg with the drugs. The mean recovery ranged between 76 and 97%. The intra- and inter-assay variations showed RSD values <10 and <16%, respectively. The procedure was also applied to ovine and porcine liver, giving similar results. The limit of quantitation of the method is 2 μg/kg.  相似文献   

13.
A liquid chromatography-tandem mass spectrometry (LC-MS-MS) method is presented for the qualitative screening for 238 drugs in blood samples, which is considerably more than in previous methods. After a two-step liquid-liquid extraction and C(18) chromatography, the compounds were introduced into a triple quadrupole mass spectrometer equipped with a turbo ion spray ion source operating in the positive ionization mode. Identification was based on the compound's absolute retention time, protonated molecular ion, and one representative fragment ion obtained by multiple reaction monitoring (MRM) at an individually selected collision energy of 20, 35, or 50 eV. The limit of detection (LOD) for the majority of the compounds (80%) was < or = 0.05 mg/l, ranging from 0.002 mg/l (e.g., antihistamines) to 5 mg/l (acidic compounds), and for malathion it was 10 mg/l. The LOD values were sufficiently low to allow the majority of compounds to be detected at therapeutic concentrations in the blood.  相似文献   

14.

Background

Control of onchocerciasis as a public health problem in Africa relies on annual mass ivermectin distribution. New tools are needed to achieve elimination of infection. This study determined in a small number of Onchocerca volvulus infected individuals whether moxidectin, a veterinary anthelminthic, is safe enough to administer it in a future large study to further characterize moxidectin''s safety and efficacy. Effects on the parasite were also assessed.

Methodology/Principal Findings

Men and women from a forest area in South-eastern Ghana without ivermectin mass distribution received a single oral dose of 2 mg (N = 44), 4 mg (N = 45) or 8 mg (N = 38) moxidectin or 150 µg/kg ivermectin (N = 45) with 18 months follow up. All ivermectin and 97%–100% of moxidectin treated participants had Mazzotti reactions. Statistically significantly higher percentages of participants treated with 8 mg moxidectin than participants treated with ivermectin experienced pruritus (87% vs. 56%), rash (63% vs. 42%), increased pulse rate (61% vs. 36%) and decreased mean arterial pressure upon 2 minutes standing still after ≥5 minutes supine relative to pre-treatment (61% vs. 27%). These reactions resolved without treatment. In the 8 mg moxidectin and ivermectin arms, the mean±SD number of microfilariae/mg skin were 22.9±21.1 and 21.2±16.4 pre-treatment and 0.0±0.0 and 1.1±4.2 at nadir reached 1 and 3 months after treatment, respectively. At 6 months, values were 0.0±0.0 and 1.6±4.5, at 12 months 0.4±0.9 and 3.4±4.4 and at 18 months 1.8±3.3 and 4.0±4.8, respectively, in the 8 mg moxidectin and ivermectin arm. The reduction from pre-treatment values was significantly higher after 8 mg moxidectin than after ivermectin treatment throughout follow up (p<0.01).

Conclusions/Significance

The 8 mg dose of moxidectin was safe enough to initiate the large study. Provided its results confirm those from this study, availability of moxidectin to control programmes could help them achieve onchocerciasis elimination objectives.

Trial Registration

ClinicalTrails.gov NCT00300768  相似文献   

15.
Macrocyclic lactones have been the most widely used drugs for equine parasite control during the past four decades. Unlike ivermectin, moxidectin exhibits efficacy against encysted cyathostomin larvae, and is reported to have persistent efficacy with substantially longer egg reappearance periods. However, shortened egg reappearance periods have been reported recently for both macrocyclic lactones, and these findings have raised several questions: (i) are egg reappearance period patterns different after ivermectin or moxidectin treatment? (ii) Are shortened egg reappearance periods associated with certain cyathostomin species or stages? (iii) How does moxidectin’s larvicidal efficacy affect egg reappearance period? To address these questions, 36 horses at pasture, aged 2–5 years old, were randomly allocated to three treatment groups: 1, moxidectin; 2, ivermectin; and 3, untreated control. Strongylid fecal egg counts were measured on a weekly basis, and the egg reappearance period was 5 weeks for both compounds. Strongylid worm counts were determined for all horses: 18 were necropsied at 2 weeks post-treatment (PT), and the remaining 18 at 5 weeks PT. Worms were identified to species morphologically and by internal transcribed spacer-2 (ITS-2) rDNA metabarcoding. Moxidectin and ivermectin were 99.9% and 99.7% efficacious against adults at 2 weeks post treatment, whereas the respective efficacies against luminal L4s were 84.3% and 69.7%. At 5 weeks PT, adulticidal efficacy was 88.3% and 57.6% for moxidectin and ivermectin, respectively, while the efficacy against luminal L4s was 0% for both drugs. Moxidectin reduced early L3 counts by 18.1% and 8.0% at 2 or 5 weeks, while the efficacies against late L3s and mucosal L4s were 60.4% and 21.2% at the same intervals, respectively. The luminal L4s surviving ivermectin treatment were predominantly Cylicocyclus (Cyc.) insigne. The ITS-2 rDNA metabarcoding was in good agreement with morphologic species estimates but suggested differential activity between moxidectin and ivermectin for several species, most notably Cyc. insigne and Cylicocyclus nassatus. This study was a comprehensive investigation of current macrocyclic lactone efficacy patterns and provided important insight into potential mechanisms behind shortened egg reappearance periods.  相似文献   

16.
Macrocyclic lactones (MLs) are widely used parasiticides against nematodes and arthropods, but resistance is frequently observed in parasitic nematodes of horses and livestock. Reports claiming resistance or decreased susceptibility in human nematodes are increasing. Since no target site directed ML resistance mechanisms have been identified, non-specific mechanisms were frequently implicated in ML resistance, including P-glycoproteins (Pgps, designated ABCB1 in vertebrates). Nematode genomes encode many different Pgps (e.g. 10 in the sheep parasite Haemonchus contortus). ML transport was shown for mammalian Pgps, Pgps on nematode egg shells, and very recently for Pgp-2 of H. contortus. Here, Pgp-9 from the equine parasite Cylicocyclus elongatus (Cyathostominae) was expressed in a Saccharomyces cerevisiae strain lacking seven endogenous efflux transporters. Pgp was detected on these yeasts by flow cytometry and chemiluminescence using the monoclonal antibody UIC2, which is specific for the active Pgp conformation. In a growth assay, Pgp-9 increased resistance to the fungicides ketoconazole, actinomycin D, valinomycin and daunorubicin, but not to the anthelmintic fungicide thiabendazole. Since no fungicidal activity has been described for MLs, their interaction with Pgp-9 was investigated in an assay involving two drugs: Yeasts were incubated with the highest ketoconazole concentration not affecting growth plus increasing concentrations of MLs to determine competition between or modulation of transport of both drugs. Already equimolar concentrations of ivermectin and eprinomectin inhibited growth, and at fourfold higher ML concentrations growth was virtually abolished. Selamectin and doramectin did not increase susceptibility to ketoconazole at all, although doramectin has been shown previously to strongly interact with human and canine Pgp. An intermediate interaction was observed for moxidectin. This was substantiated by increased binding of UIC2 antibodies in the presence of ivermectin, moxidectin, daunorubicin and ketoconazole but not selamectin. These results demonstrate direct effects of MLs on a recombinant nematode Pgp in an ML-specific manner.  相似文献   

17.
Studies were conducted to determine the potential of two avermectin compounds, abamectin and emamectin benzoate, for controlling plant-parasitic nematodes when applied by three methods: foliar spray, root dip, and pseudostem injection. Experiments were conducted against Meloidogyne incognita on tomato, M. javanica on banana, and Radopholus similis on banana. Foliar applications of both avermectins to banana and tomato were not effective for controlling any of the nematodes evaluated. Root dips of banana and tomato were moderately effective for controlling M. incognita on tomato and R. similis on banana. Injections (1 ml) of avermectins into banana pseudostems were effective for controlling M. javanica and R similis, and were comparable to control achieved with a conventional chemical nematicide, fenamiphos. Injections of 125 to 2,000 μg/plant effectively controlled one or both nematodes on banana; abamectin was more effective than emamectin benzoate for controlling nematodes.  相似文献   

18.
《Trends in parasitology》2023,39(4):272-284
Ivermectin and moxidectin, two macrocyclic lactones, are potent antiparasitic drugs currently registered and mainly used against filarial diseases; however, their potential value for improved soil-transmitted helminth (STH) control has been acknowledged. This review provides insights on recent studies evaluating the efficacy of ivermectin and moxidectin as single or coadministered therapy against human soil-transmitted helminthiases (including Strongyloides stercoralis infections) and on pharmacokinetic/pharmacodynamic parameters measured in treated populations. Furthermore, we discuss current gaps for research, highlight advantages – but also existing challenges – for uptake of ivermectin and/or moxidectin treatment schemes into routine STH control in endemic countries.  相似文献   

19.
Liquid chromatography-tandem mass spectrometry (LC-MS-MS) might be a complement to GC-MS and HPLC-diode array detection for the general unknown screening (GUS) of drugs and toxic compounds, particularly when using information- or data-dependent acquisition (IDA or DDA), an auto-adaptive MS-MS product-ion scan mode where, at each unit time, the m/z ratios above a given intensity threshold are selected for fragmentation. A new quadrupole-linear ion-trap mass spectrometer (LC-QqQlinear ion-trap) was evaluated for GUS using IDA. For the first detection step (so-called "survey scan") the single quadrupole "enhanced" MS mode (EMS), where ions are accumulated then filtered in the Q3-linear ion-trap, was used. The so-called "enhanced" parent ion scan mode (EPI) used at two alternated fragmentation energies gave the best signal intensity and the best mass spectral information when adding mass spectra obtained in low and high fragmentation conditions, respectively, both in the positive (+20 and +50 eV) and negative (-15 and -40 eV) modes. Solid-phase extracts of serum spiked with eight test compounds (chosen for their retention times distributed along the 30-min long chromatogram and for ionising in both the positive and negative modes) were analysed in parallel with this LC-MS-MS technique and with a reference LC-MS method run on a single-quadrupole instrument where low and high in-source fragmentation conditions in the positive and the negative ion modes are alternated. A C(18), 5 microm (150 x 1 mm I.D.) column and a gradient elution of acetonitrile in pH 3, 2 mM ammonium formate, were used for both. Higher signal-to-noise ratios were obtained with the LC-QqQlinear ion-trap instrument than with the reference technique, resulting in mass spectra devoid of contaminant ions and at least as informative as the reconstructed single-MS spectra. After optimisation of the IDA intensity threshold for the detection of tiny chromatographic peaks in noise, five out of the eight compounds (milrinone, lorazepam, fluometuron, piretanide and warfarin) could be unambiguously identified at the concentration of 0.1 mg/l in serum, in the positive or negative modes, or in both, versus only two by LC-MS. All of them could be identified at 1 mg/l by both techniques. These preliminary results show that the sensitivity and mass structural information brought by this new LC-QqQlinear ion-trap instrument may help design an efficient toxicological GUS procedure.  相似文献   

20.
BACKGROUND: Strongyloides infection may result in clinical disease or confound experimental protocols that utilize non-human primates. There is presently a Strongyloides fulleborni infection rate of approximately 27% in the Tulane National Primate Research Center's breeding colonies despite the routine therapeutic and prophylactic use of ivermectin. METHODS: A study was conducted to determine if moxidectin treatment offers advantages to the intestinal parasite control program. A total of 150 rhesus macaques (Macaca mulatta) that were removed from the breeding colonies due to illness were selected for the study. The animals were randomly assigned to treatment groups with 75 receiving ivermectin and 75 receiving moxidectin. Egg counts were performed on fecal samples collected pre- and post-treatment. RESULTS: Both treatments resulted in decreases in the number of eggs/g in the post-treatment sample as compared with the pre-treatment sample; however, no significant difference was found between treatment groups. CONCLUSIONS: With the data demonstrating a similar efficacy in both ivermectin and moxidectin treated macaques, the benefit of moxidectin treatment relates to biosafety and topical application.  相似文献   

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