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1.
While anthelmintic resistance is now a widely recognized issue in the livestock industries, its existence within companion animal medicine has been rarely established conclusively. We undertook a placebo-controlled in vivo trial to measure the efficacy of pyrantel embonate against pooled isolates of the hookworm Ancylostoma caninum from Brisbane, Australia. A statistically significant fall in adult worm burden was observed among dogs in the pyrantel treatment group compared to the control dogs (178.0+/-24.5 versus 239.7+/-14.0; p=0.02), equating to an efficacy of just 25.7% (95% CI, 15.0-35.1%), as based upon reduction in mean worm burden. Analysis of faecal egg count trends through the course of the study revealed that egg counts rose in both control and pyrantel-treated dogs, with a greater rise observed in the latter group (11.6+/-8.3% versus 17.3+/-7.6%; p=0.04), despite the decrease in adult worm numbers in this group. Our results indicate that high-level anthelmintic resistance does occur in companion animal medicine, and highlight the need for greater vigilance and more judicious use of anthelmintics in small animal practice. They further indicate that the faecal egg count reduction test needs to be used with caution with this parasite.  相似文献   

2.
Veterinarians rely on a relatively limited spectrum of anthelmintic agents to control nematode parasites in domestic animals. Unfortunately, anthelmintic resistance has been an emerging problem in veterinary medicine. In particular, resistance has emerged among the strongyles, a group of gastrointestinal nematodes that infect a variety of hosts that range from large herbivores to small companion animals. Over the last several decades, a great deal of research effort has been directed toward developing an understanding of the mechanisms conferring resistance against the three major groups of anthelmintics: macrocyclic lactones, benzimidazoles, and nicotinic agonists. Our understanding of anthelmintic resistance has been largely formed by determining the mechanism of action for each drug class and then evaluating drug‐resistant nematode isolates for mutations or differences in expression of target genes. More recently, drug efflux pumps have been recognized for their potential contribution to anthelmintic resistance. In this mini‐review, we summarize the evidence for mechanisms of resistance in strongyle nematodes.  相似文献   

3.
The anthelmintic resistance status was investigated of nematode parasites of sheep and goats owned by smallholder farmers in communities that received breeding stock from a source where a high level of anthelmintic resistance has been reported. The investigation used the faecal egg count reduction technique, whereby suitable animals within each of eight separate communities were pooled to achieve the numbers required to conduct separate tests for both sheep and goats. Anthelmintics tested were albendazole (ABZ), tetramisole (TET), a combination (ABZ $+$ TET) and ivermectin (IVM), at the manufacturers' recommended dose rates. Results showed that there was no evidence of anthelmintic resistance in nematode parasites of either sheep an goats in any community. This indicates that dilution of resistant parasites imported with introduced breeding stock, and the low selection pressure imposed by the smallholder farmers themselves, has prevented anthelmintic resistance from emerging in nematode parasites of small ruminants in these communities.  相似文献   

4.
The recent registration in New Zealand of the first new class of broad-spectrum anthelmintic, for use against nematode parasites of ruminants, in nearly three decades has raised the possibility that parasite management practices could be improved to minimise the emergence of resistance to the new drug. A review of knowledge pertaining to the selection of anthelmintic resistance in nematode parasites of sheep highlights a number of management practices which could be altered to achieve this.

A number of previously common practices such as whole-flock treatment of adult ewes around lambing, and treatment of lambs as they are moved onto pastures with low parasite contamination have been clearly identified as high risk for selecting resistant parasites. Once high-risk practices have been identified steps can be taken to either eliminate their use or mitigate the associated risk. Much of the focus on the management of resistance around the world is on the retention of susceptible genotypes in refugia. While approaches to retaining unselected parasites are likely to vary around the world, empirical studies indicate that the practice is likely to be effective at slowing the development of resistance. The challenge for farmers and advisors will be to strike a balance between retaining sufficient susceptible para-sites to usefully delay the development of resistance while not unduly compromising animal performance and farm profitability. The merits of combining different classes of anthelmintic in order to slow the development of resistance remains somewhat contentious in some countries. However, the attributes of oral anthelmintics are such that they seem likely to meet most, if not all, of the criteria for combinations to be highly effective at slowing the build-up of resistance in nematode parasites.

It is evident that considerable progress has been made in understanding the factors involved in selecting anthelmintic-resistant nematodes since the last broad-spectrum anthelmintic class was released in the early 1980s. Therefore, it should be possible to manage a new class of anthelmintic in such a way as to significantly extend its effective life. The challenge is likely to be in convincing farmers of the merits of adopting such pro-active strategies.  相似文献   

5.
Anthelmintic resistance in nematodes of horses   总被引:1,自引:0,他引:1  
Suppressive anthelmintic treatment strategies originally designed to control Strongylus vulgaris in horses were extremely successful in reducing morbidity and mortality from parasitic disease. Unfortunately, this strategy has inadvertently resulted in the selection of drug-resistant cyathostomes (Cyathostominea), which are now considered the principal parasitic pathogens of horses. Resistance in the cyathostomes to benzimidazole drugs is highly prevalent throughout the world, and resistance to pyrantel appears to be increasingly common. However, there are still no reports of ivermectin resistance in nematode parasites of horses despite 20 years of use. It is unknown why resistance to ivermectin has not yet emerged, but considering that ivermectin is the single most commonly used anthelmintic in horses most parasitologists agree that resistance is inevitable. The fecal egg count reduction test is considered the gold standard for clinical diagnosis of anthelmintic resistance in horses, but diagnosis is complicated by lack of an accepted standard for the performance of this test or for the analysis and interpretation of data. Presently there is very little data available on the molecular mechanisms of anthelmintic resistance in cyathostomes; beta-tubulin gene is the only anthelmintic-resistance associated gene that has been cloned. The increasingly high prevalence of anthelmintic-resistant cyathostomes must be taken into account when designing worm control programs for horses. Strategies to decelerate further selection for drug resistance thereby extending the lifetime of currently effective anthelmintics should be implemented whenever possible. Considering the nature of the equine industry in which horses often graze shared pastures with horses from diverse locations, transmission and widespread dispersal of resistant parasites is virtually assured. A proactive approach to this problem centered on understanding the molecular basis of anthelmintic resistance in cyathostomes is required if we are to expect chemical control of nematodes in horses to remain a viable element of parasite control in the future.  相似文献   

6.
The increase of anthelmintic resistance in the last years in the nematode population of veterinary importance has become a major concern. The objective of the present study was to evaluate the efficacy of the main anthelmintic drugs available in the market against small strongyles of horses in Brazil. A total of 498 horses from 11 horse farms, located in the states of Paraná, São Paulo, Rio de Janeiro and Minas Gerais, in Brazil, were treated with ivermectin, moxidectin, pyrantel and fenbendazole, orally at their recommended doses. The fecal egg count reduction test (FECRT) was used to determine the product's efficacy and fecal culture was used to determine the parasite genus. Reduction on anthelmintic efficacy was found for fenbendazole in all horse farms (11/11), pyrantel in five yards (5/11) and ivermectin had low efficacy in one of the yards studied (1/11). Multidrug resistance of up to 3 drugs classes was found in one of the tested farms (1/11). Cyathostomin were the most prevalent parasite. The results showed that resistance to fenbendazole is widespread; the efficacy of pyrantel is in a critical situation. Although the macrocyclic lactones compounds still showed high efficacy on most farms, suspected resistance to macrocyclic lactones is of great concern.  相似文献   

7.
《Veterinary parasitology》2015,207(3-4):346-349
Resistance to currently available anthelmintics is a serious phenomenon which is prevalent globally. Cyathostomins are one of the major parasites, and are of primary concern in donkeys. There have been reports of emerging resistance to pyrantel, but the status of pyrantel resistance in donkey populations in the UK is largely unknown. This report investigates pyrantel resistance in two geographically isolated donkey herds in the South West of England. The first herd had suspected pyrantel resistance, with already established resistance to other anthelmintics. In the second herd the efficacy of pyrantel was not suspected at the time the study took place. Faecal Egg Count Reduction Test (FECRT) was carried out, revealing large scale resistance. Eighty one percent of the first herd and 73% of the second herd had a FEC of less than 95% after treatment, and anthelmintic resistance was confirmed using the World Association for the Advancement of Veterinary Parasitology guidelines. These findings indicate that anthelmintic resistance to pyrantel exists in both tested donkey populations and illustrate the continuing development of resistance through different classes of chemotherapeutics.  相似文献   

8.
During the past two decades anthelmintic resistance in equine parasites has been found in the group of small strongyle species (cyathostomins) and in the ascarid species Parascaris equorum. The ubiquitous nature and possible severe consequences of disease with these nematodes make them the prime targets of current worm control programmes. Traditional control strategies mainly rely on the strategic application of anthelmintics, currently represented by three major drug classes: benzimidazoles (BZ), the tetrahydropyrimidine pyrantel (PYR) and macrocyclic lactones (ML). Following decades of routine and frequent anthelmintic applications, many cyathostomin populations on horse farms in industrialised countries must be considered as resistant to BZ anthelmintics. However, to date no published cases of cyathostomin disease specifically associated with anthelmintic resistance were reported. Possibly this is due to the generally subclinical and unspecific symptoms associated with cyathostomin infections. Nevertheless, exclusive reliance on the ML drug class may increase the threat of clinical disease due to drug-resistant cyathostomins. More recently, P. equorum has been reported as having developed resistance against ivermectin and moxidectin, two representatives of the ML-class. These anthelmintics are currently the most frequently used drug class in horses. This nematode species is mainly found in foals and in younger horses due to the development of immunity following exposure to infection. Infection with P. equorum can result in clinically drastic consequences such as obstruction and/or penetration of the small intestine, the latter usually leading to death. In conclusion, on horse farms the efficacy of anthelmintic treatments should be examined routinely for each drug class. Several factors can influence the rate at which anthelmintic resistance develops; high frequency of treatment being one of the most important. Modern control strategies should therefore attempt to significantly reduce anthelmintic treatments. Several pasture and farm management practices found to be negatively associated with nematode and anthelmintic resistance prevalence will be discussed in the review presented here.  相似文献   

9.
Resistance of the canine hookworm Ancylostoma caninum to anthelmintic therapy with pyrantel is an emerging problem in canine veterinary practice. Detecting anthelmintic resistance in parasites of pets is problematic because traditional resistance-monitoring techniques used with livestock parasites, such as the faecal egg count reduction test, are often impractical for use in small animals. We used two field-collected isolates of A. caninum in an abbreviated critical trial to test their pyrantel resistance status. The strains showed high-level and low-level resistance, with in vivo pyrantel efficacies of 28% and 71%, respectively. We noted a distinct worm density dependence effect on faecal egg count during the critical trial; egg counts in the dogs containing the low-level resistant isolate were 41% higher 6 days after drug treatment, despite the removal of 71% of the adult worms by the drug treatment. We then assessed four candidate in vitro assays for their ability to detect pyrantel resistance in A. caninum larvae, using these two isolates. The assays included a new format termed the larval arrested morphology assay (LAMA), based on observation of the effects of pyrantel on the body shape adopted by infective stage A. caninum larvae in vitro. Our data suggests that three of these assays, the LAMA, the larval motility assay (LMA), and larval feeding inhibition assay (LFIA) show promise with regards to detection of pyrantel resistance in A. caninum, but the complexity of the LFIA would likely limit its suitability for field studies. In vivo pyrantel efficacies of 28% and 71% in the two A. caninum isolates were associated with a 17-fold shift in the in vitro IC(50) values measured using the LAMA. Further testing with isolates of varying degrees of resistance is required to determine which of these assays is suitable as a rapid in vitro laboratory test for pyrantel resistance in A. caninum. The present study also indicates that potential exists for the novel LAMA or the LMA to be of use in detecting pyrantel resistance in the human hookworms, Necator americanus and Ancylostoma duodenale.  相似文献   

10.
To evaluate the efficacy with which recommendations of means to avoid the spread of anthelmintic resistance in parasitic nematode populations are communicated to farmers on dairy goat farms in France, a questionnaire survey was undertaken on their use of antiparasitic drugs. Information was collected from 73 farms in two main areas of dairy goat production. The data referred to three years. Anthelmintics were used in 69 farms, the mean number of treatments per year being 2.74. Changing the drug from one year to another was not practised. Moreover, of the 58 farms using two or more treatments per year, only 37% used anthelmintics from different classes in the lactation and drying-off periods. Benzimidazoles and probenzimidazoles were given in all except two farms and these substances represented more than 80% of all the treatments. Levamisole/pyrantel or avermectins were used in 15% and 27% of the farms, respectively. Double the ovine dose, as recommended in goats to ensure efficacy of benzimidazoles, was applied in 55% of the farms. In addition, in all the flocks, the substances were given on the basis of a mean estimated live weight and not by reference to the heaviest animal. These results indicate that errors in the use of anthelmintics are still frequent in dairy goat farms in France, with probable consequences for the spread of anthelmintic resistance in the populations of parasites.  相似文献   

11.
The term 'anthelmintic drug resistance' describes the heritable ability of some nematode parasites to survive treatment with anthelmintic drugs at the recommended therapeutic dose levels. Genes for resistance appear to be present in many of the important pathogenic nematodes of ruminants and horses. Under intensive management systems, where heavy reliance is placed on anthelmintic drugs for worm control, the selection of resistant genotypes may result in increased reports of the drugs failing to control the nematode populations against which they are aimed. Anthelmintic resistance has been reported from many parts of the world, and in some countries multiple drug-resistant strains have emerged. In the UK, recent investigations indicate an increasing level of resistance to benzimidazoles among nematodes of sheep and horses. The incidence, diagnosis, epidemiology and implications of anthelmintic resistance are discussed.  相似文献   

12.
Multiple resistance to benzimidazole, imidazothiazole and macrocyclic lactone anthelmintics is an emerging problem in the south-east of Scotland. The general management and nematode control strategies employed in four affected flocks (flocks 1-4) were investigated in an attempt to identify the risk factors which might have led to the appearance of production limiting disease associated with anthelmintic resistance. The important risk factors for multiple anthelmintic resistance could not be confirmed and it proved easier to criticise nematode control practices on theoretical grounds, than to propose practical solutions. It seems likely that different risk factors were involved in the four flocks. Lambs in flocks 1 and 2 had been treated with an anthelmintic at 3-4 weekly intervals with the aim of achieving suppressive nematode control, while sheep in flock 1 had been treated with an anthelmintic after they were moved onto clean grazing. Recently lambed ewes had been treated with moxidectin in three of the four flocks, with the aim of controlling their periparturient rise in faecal nematode egg output. All of these factors might have contributed to the emergence of multiple anthelmintic resistance, because they could have led to anthelmintic treatments at times when the nematode population in refugia was small, compared to that in the sheep. Annual rotation of the anthelmintic group was compromised by the emergence of benzimidazole resistance and did not prevent the emergence of multiple resistance in any of the flocks described, although the practice may have slowed the development of resistance. Underdosing may have selected for benzimidazole and imidazothiazole resistance in flock 2, associated with inaccurate estimation of the weights of terminal sire lambs. These investigations also highlighted problems associated with the diagnosis of anthelmintic resistance, in particular the confounding effects of the onset of host immunity to nematode parasites, the possible influence of the age of the adult nematode population, and the insensitivity of the undifferentiated faecal egg count reduction test in situations where resistance is emerging.  相似文献   

13.
AIMS: To test the hypotheses that when untreated adult ewes are rotationally grazed (follow behind) on pastures after lambs receiving routine anthelmintic treatments, the ewes can function as a source of unselected parasites in refugia, capable of slowing the development of anthelmintic resistance, and suppress the build-up of parasites resulting from the development of anthelmintic resistance. METHODS: Firstly, the potential of untreated adult ewes to slow the development of anthelmintic resistance, and to suppress parasite populations under differing levels of anthelmintic efficacy, was investigated using a simulation model. Secondly, a field trial with three replicates of each treatment compared two grazing systems (lambs only vs lambs followed by ewes) and two types of anthelmintic, viz albendazole (ALB), to which resistance was present (faecal nematode egg count reduction (FECR)=57-59%) and ivermectin plus levamisole (IL), to which resistance was absent (FECR=97-99%), in a factorial treatment structure. Parasite populations were monitored using faecal nematode egg counts (FEC), faecal larval cultures, pasture larval sampling, and slaughter of tracer lambs. Animal performance was measured using liveweight, dag score, body condition score, and fleece weights. RESULTS: Model simulations indicated that parasites cycling in the untreated ewes could slow the development of resistance being selected for by the anthelmintic treatments given to lambs and this could occur without a nett increase in larval numbers on pasture. Further, as worm control in the lambs declined with increasing levels of anthelmintic resistance the ewes increasingly functioned as nett removers of parasite larvae, effectively reducing parasite population size. In the field trial, untreated adult ewes contributed to pasture infestations of most parasite species, but not Nematodirus spp. Parasite species on pasture and infecting lambs changed when ewes were present, but larval populations on pasture in the autumn were no greater than when lambs grazed alone. In the presence of anthelmintic resistance, parasite populations were reduced when ewes grazed in rotation with lambs, implicating the ewes as nett removers of parasite challenge. CONCLUSIONS: Untreated adult ewes were a source of unselected genotypes, capable of slowing the development of anthelmintic resistance in most, but not all, parasite species. Further, the potential of adult ewes to remove from pasture more parasite larvae than they contribute through faecal contamination indicates a potentially useful role in suppressing parasite populations, particularly when worm control in lambs is less effective as a result of anthelmintic resistance.  相似文献   

14.
Sustainable nematode management programs aim to minimise animal production loss and prevent parasitic disease, without increasing the level of anthelmintic resistance. Resistance management strategies are now largely based on the "refugia" concept, by which populations of nematodes not recently exposed to treatment are deliberately allowed to survive. Progeny from the unselected parasites provide a source of less-resistant worms which can dilute resistant worms surviving anthelmintics, and hence reduce the rate of resistance development. This can be achieved by either modifying strategic treatment regimens to ensure the survival of infective worm larvae on pasture, or by avoiding treatments to individual animals identified as best able to cope with parasites. These strategies include "targeted treatment" (based on estimates of worm-burdens) and "targeted selective treatment" (based on indications of parasitic effects). However, the departure from conventional anthelmintic approaches represents a major conceptual challenge to many livestock owners. Factors that may affect the wide adoption of refugia strategies include the increased risk of parasitism and production loss, the effectiveness of reducing the development of resistance, the practicality of implementation, and the direct effects on costs and labour efficiency. The acceptance of particular strategies is likely to vary considerably according to environmental effects, nematode species, animal production aims and resource availability. However, recent indications that comparatively small changes to present practices can provide substantial refugia benefits suggest that appropriate resistance management approaches can be developed for different situations.  相似文献   

15.
Combinations of anthelmintics with a similar spectrum of activity and different mechanisms of action and resistance are widely available in several regions of the world for the control of sheep nematodes. There are two main justifications for the use of such combinations: (1) to enable the effective control of nematodes in the presence of single or multiple drug resistance, and (2) to slow the development of resistance to the component anthelmintic classes. Computer model simulations of sheep nematode populations indicate that the ability of combinations to slow the development of resistance is maximised if certain prerequisite criteria are met, the most important of which appear to concern the opportunity for survival of susceptible nematodes in refugia and the pre-existing levels of resistance to each of the anthelmintics in the combination. Combinations slow the development of a resistant parasite population by reducing the number of resistant genotypes which survive treatment, because multiple alleles conferring resistance to all the component anthelmintic classes must be present in the same parasite for survival. Individuals carrying multiple resistance alleles are rarer than those carrying single resistance alleles. This enhanced efficacy leads to greater dilution of resistant genotypes by the unselected parasites in refugia, thus reducing the proportion of resistant parasites available to reproduce with other resistant adults that have survived treatment. Concerns over the use of anthelmintic combinations include the potential to select for resistance to multiple anthelmintic classes concurrently if there are insufficient parasites in refugia; the potential for shared mechanisms of resistance between chemical classes; and the pre-existing frequency of resistance alleles may be too high on some farms to warrant the introduction of certain combinations. In conclusion, anthelmintic combinations can play an important role in resistance management. However, they are not a panacea and should always be used in accordance with contemporary principles for sustainable anthelmintic use.  相似文献   

16.
Caenorhabditis elegans: how good a model for veterinary parasites?   总被引:1,自引:0,他引:1  
The organism about which most is known on a molecular level is a nematode, the free-living organism Caenorhabditis elegans. This organism has served as a reasonable model for the discovery of anthelmintic drugs and for research on the mechanism of action of anthelmintics. Useful information on mechanisms of anthelmintic resistance has also been obtained from studies on C. elegans. Unfortunately, there has not been a large-scale extension of genetic techniques developed in C. elegans to research on parasitic species of veterinary (or human) parasites. Much can be learned about the essentials of nematode biology by studying C. elegans, but discovering the basic biology of nematode parasitism can only be gained through comparative studies on multiple parasitic species.  相似文献   

17.
The diseases caused by parasitic nematodes in domestic and companion animals are major factors that decrease production and quality of the agricultural products. Methods available for the control of the parasitic nematode infections are mainly based on chemical treatment, non-chemical management practices, immune modulation and biological control. However, even with integrated pest management that frequently combines these approaches, the effective and long-lasting control strategies are hampered by the persistent exposure of host animals to environmental stages of parasites, the incomplete protective response of the host and acquisition of anthelmintic resistance by an increasing number of parasitic nematodes. Therefore, the challenges to improve control of parasitic nematode infections are multi-fold and no single category of information will meet them all. However, new information, such as nematode genomics, functional genomics and proteomics, can strengthen basic and applied biological research aimed to develop improvements. In this review we will, summarize existing control strategies of nematode infections and discuss ongoing developments in nematode genomics. Genomics approaches offer a growing and fundamental base of information, which when coupled with downstream functional genomics and proteomics can accelerate progress towards developing more efficient and sustainable control programs.  相似文献   

18.
Intestinal nematodes are an important cause of equine disease. Of these parasites, the Cyathostominae are the most important group, both in terms of their prevalence and their pathogenicity. Cyathostomin infections are complex and control is further complicated by ever‐increasing levels of resistance to some of the commonly used anthelmintics. There are no new equine anthelmintics under development, so it is imperative that the efficacy of any currently‐effective drug classes be maintained for as long as possible. It is believed that the proportion of refugia (i.e. the percentage of parasites not exposed to a drug at each treatment) is one of the most crucial factors in determining the rate at which anthelmintic resistance develops. It is important, therefore, that levels of refugia be taken into account when designing nematode control programmes for horses. This can be assisted by knowledge of the local epidemiology of the infection, supplemented by faecal egg count analysis to identify those animals that are making the major contribution to pasture contamination. This type of rational nematode control requires equine veterinary surgeons to get involved in designing and implementing deworming programmes. The advice given must be based on a combination of knowledge of cyathostomin biology and epidemiology as well as an awareness of the parasite population's current drug sensitivity and a sound history of husbandry at the establishment. As anthelmintic resistance will be the major constraint on the future control of cyathostomins, researchers are now actively investigating this area. Studies are underway to develop tests that will enable earlier detection of anthelmintic resistance and an assay that will help identify those horses that require anthelmintic treatments targeted at intestinal wall larvae.  相似文献   

19.
Due to excessive and inappropriate use of dewormers anthelmintic resistance has developed as a significant problem in horse parasites in the Netherlands. Since it is unlikely that new classes of anthelmintics against horse nematodes will be introduced in the near future, it is important to use the present drugs wisely. Veterinarians should advice horse owners about worm control programs with a more targeted approach. The number of anthelmintic treatments should be reduced and, through selective anthelmintic treatments, further development of anthelmintic resistance should be delayed. Preferably, horses with a low faecal egg count should not be treated at all to ascertain a reduction of the selection pressure for anthelmintic resistance. The propensity for low faecal egg counts is hereditary. This implies that mature horses with consistent low egg counts can be detected by faecal examination and that it is not necessary to repeat faecal examination each time in these animals. New horses on the farm should always be dewormed on arrival and should be introduced only after the efficacy of treatment has been determined. Anthelmintic resistance can also be introduced with the arrival of a new animal that is infected with drug-resistant parasites.  相似文献   

20.
Changes in anthelmintic resistance in nematode parasites were monitored in sheep grazing on 2 separate farms, but with the same anthelmintic treatment program, over 16 years. High levels of benzimidazole resistance emerged in Ostertagia and Trichostrongylus spp populations on both farms following 9 years of continuous use of this class of drug. Subsequently, variations in the levels of resistance occurred for the same species between farms and between species on the same farm. A change to levamisole for 2 years resulted in a significant reversion towards benzimidazole susceptibility, but a concomitant rise in levamisole resistance, in Ostertagia on one farm. However, benzimidazole resistance increased rapidly following the re-introduction of oxfendazole into the anthelmintic treatment program. Results from both farms illustrate the pitfalls of using one anthelmintic class for an extended period and provide indirect support for the alternation of anthelmintic classes at approximately yearly intervals.  相似文献   

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