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Keywords: Multidrug ABC transporters, P-glycoproteins, Anthelmintic resistance, Macrocyclic lactones Abstract Parasitic helminths cause significant disease in animals and humans. In the absence hotez helminth alternative treatments, anthelmintics remain the principal agents for their control. Resistance extends to the most important class of anthelmintics, the macrocyclic lactone endectocides MLssuch as ivermectin, and presents serious problems for the livestock industries and threatens to severely limit current parasite control strategies in humans.
Understanding drug resistance is important for optimizing and monitoring control, and reducing further selection for resistance.
MDR transporters, such as P-glycoproteins, are essential for many cellular processes that require the transport of substrates across cell membranes. Being overexpressed in response to chemotherapy in tumour cells and to ML-based treatment in nematodes, they lead to therapy failure by decreasing drug concentration at the target.
Several anthelmintics are inhibitors of these efflux pumps and appropriate combinations can result in higher treatment efficacy against parasites and reversal of resistance. However, this hotez helminth to be balanced against hotez helminth increased toxicity to the host, or the components of the combination selecting on the same genes involved in the resistance.
Increased efficacy could result from modifying anthelmintic pharmacokinetics in the host or by blocking parasite transporters involved in resistance. Combination of anthelmintics can be beneficial for delaying selection for resistance. However, it should be based on knowledge of resistance mechanisms and not simply on mode of action classes, and is best started before resistance has been selected to any member of the combination.
Historie[ editovat editovat zdroj ] Prvními objeviteli tenkohlavce jsou lékaři G. Morgagni a G.
Increasing knowledge of the MDR transporters involved in anthelmintic resistance in helminths will play an important role in allowing for the identification of markers to monitor the spread of resistance and to evaluate new tools and management practices aimed at delaying its spread. Introduction Parasite helminths nematodes, trematodes, cestodes, acanthocephala are major causes of morbidity in animals and humans. In livestock animals, these infections can lower growth rates and fertility, decrease production hotez helminth meat and milk, sometimes leading to mortality of animals most infested and are of concern for animal welfare.
Helminths are also major pathogens of humans, infecting more than one billion people worldwide Hotez et al. Besides the huge suffering, they hotez helminth tens of hotez helminth of human deaths each year, reduce life expectancy and condemn millions to poverty Hotez, With the rare exception of a vaccine for Taenia infection in pigs, no vaccines are available for these diseases and by far the major control measures in humans and animals rely on the use of anthelmintic drugs.
Когда я был маленьким мальчиком, лет так восьми или девяти, - начал Макс, - мы с отцом впервые отправились в поход на Озаркское плато, находящееся в нескольких часах ходьбы от нашей фермы.
Several classes of anthelmintics are currently available. Benzimidazoles e. Levamisole, pyrantel and morantel are N-acetylcholine receptor agonists Martin and Robertson,as is the new anthelmintic, monepantel, although the latter hotez helminth to act on a different class of nicotinic receptors Kaminsky et al. Another new anthelmintic, derquantel, appears to be an antagonist of the type of Hotez helminth receptors upon which levamisole acts Qian et al.
Emodepside appears to activate NO hotez helminth protein kinase C signalling pathways to produce slow activation of voltage-activated Ca-dependent SLOlike K channels leading to paralysis of pharyngeal and body muscles in nematodes Buxton et al. Praziquantel is the principal drug used for the control hotez helminth schistosomiasis, some other trematode infections and cestode infections.
Human helminth immune responses: consequences of helminth treatment programmes
It appears to rapidly alter intracellular calcium concentrations in flatworms, leading to a rapid paralysis. Triclabendazole is very effective against Fasciola spp.
Its mode of action is still not known. Today, the macrocyclic lactones MLs are the most widely used anthelmintics in animal health and are important in human health.
MLs include ivermectin, abamectin, eprinomectin, doramectin and selamectin in the ML sub-class of avermectins, and moxidectin and milbemycin oxime which are both milbemycins. The MLs appear to primarily act on hotez helminth chloride channels in nematodes and some ectoparasites Cully et al. They bind allosterically to irreversibly open the channel Hibbs and Gouaux,leading to a permanent hyperpolarisation of the cells hotez helminth flaccid paralysis.
They may also have effects on other ligand-gated chloride channels such as γ-aminobutyric acid GABA Prichard, and dopamine-gated chloride channels Rao et al. Currently used hotez helminth, dose rates, formulations and treatment regimens very often do not achieve the same high level of efficacy hotez helminth nematodes in humans Stepek et al.
Current mass treatment campaigns against onchocerciasis, lymphatic filariasis LFschistosomiasis and soil transmitted helminths STH are based on the use of drugs employed for decades in the veterinary field Hotez et al. However, serious and often dramatic levels of anthelmintic resistance have been recorded in veterinary parasites, mainly in ruminant and horse gastro-intestinal nematodes Kaplan, ; Demeler et al.
There have been reports of praziquantel resistance in Schistosoma mansoni Fallon and Doenhoff, ; Botros and Bennett,and more recently, there is evidence of developing ivermectin Hotez helminth or macrocyclic lactone ML resistance in Onchocerca volvulus Osei-Atweneboana et al. Triclabendazole resistance, in Fasciola hepatica has also been reported in many parts of the world Wolstenholme et al. Over the past 40 years, there have been very few new classes of anthelmintic developed, and those new classes, such as monepantel, derquantel and emodepside that have been developed do not appear to have the breadth of spectrum, in terms of target hosts and parasite species, as the MLs and benzimidazoles, and have not so far been developed for use in humans.
Furthermore, even with the introduction of new anthelmintics, the risk of resistance developing relatively quickly should not be under estimated and already it has been possible to experimentally hotez helminth for monepantel resistance in Haemonchus contortus Rufener et al. It is, therefore, a key parasitological research issues to understand the mechanisms and genetics of anthelmintic resistance.
This understanding should be helpful in developing hotez helminth anthelmintics, reducing the selection for resistance and maintaining the efficacy of anthelmintics, for monitoring the extent and spread of anthelmintic resistance using sensitive and specific markers, to ne harapja a körféreg körmöket for anthelmintic combinations or synergists to be used which will not share common mechanisms of resistance, and in some cases for overcoming the resistance or exploiting the genetic changes involved in resistance to specifically target drug resistant parasites.
Drug resistance in hotez helminth results from the selection of a sub-population of the pathogen which can tolerate the lethal or damaging effects of the pharmaceutics which are normally or previously effective against them.
It is based on a selection of genes occurring under drug pressure that will allow the target to survive. As it has a genetic basis, it can be detected as changes in DNA sequences that affect the functioning or expression of gene products.
To some extent, a too simplistic view of anthelmintic resistance has been assumed, based solely on the mode of action receptor. Commonly drug resistance involves more than a single genetic change and very often non-receptor based mechanisms also contribute to the resistance Beech et al.
The latter can be due to i single nucleotide polymorphisms SNPs or other genetic changes e. Such polymorphisms increase in frequency upon treatment and lead hotez helminth treatment failure. Resistance to levamisole is associated with genetic mutation on the nAChR subunits involved in forming the levamisole receptor Boulin et al.
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In the case of resistance to MLs, there is little evidence that genetic changes to glutamate-gated chloride channels are significant for resistance in the field El-Abdellati et al. The major mechanism of resistance to MLs in parasitic nematodes, so far, implicates changes in multidrug ABC transporters, as discussed below.
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Surprisingly, other mechanisms such as overexpression of some MDR transporters may modulate benzimidazole resistance Beugnet et al. In addition, there is evidence that macrocyclic lactones, hotez helminth as ivermectin and moxidectin may select on β-tubulin in nematodes such as H.
Trickle infection and immunity to Trichuris muris
On the basis of these data, we can expect that repeated use of ML anthelmintics may predispose nematodes to benzimidazoles resistance. Interestingly, high affinity binding of the mammalian P-gp linker domain to α- and β-tubulin has been reported Georges,and this finding may provide further insights into P-gp-interactions in the hosts and into drug resistance in parasites.
However, in situ individuals are repeatedly infected with low doses. Therefore, to model natural infection, mice were repeatedly infected trickle infection with low doses of Trichuris muris.
These transporters are involved in non specific mechanisms which can lead to cross-resistance by modulating the concentration of different drugs at their targets, compromising efficacy.
The danger occasioned by this type of resistance is that several classes of drugs having different modes of action may be concerned and their efficiencies can be compromised at the same time.
Active transport of anthelmintics and its role in anthelmintic resistance Cross-resistance occurs through drug receptor-independent mechanisms and arises because the mechanism of resistance to several drugs is the same, hotez helminth identical genetic mutations.
In any case, cross-resistance involving non specific mechanisms is acquired through direct exposure to one drug and may generate resistance to one or more other hotez helminth to which the pathogen has not been exposed. Non-receptor mechanisms of resistance include altered levels of enzymes involved in drug metabolism or transport hotez helminth which modulate subsequently the concentration of the drug that reaches the effector site on a receptor, such as i increased efflux of the drug from cells containing the receptors, ii reduced uptake, iii increased drug metabolism and inactivation or iv reduced activation in the case of pro-drugs.
Mechanisms that alter drug concentration are sometimes referred to as non-specific mechanisms because they may affect pharmaceuticals from different chemical and mode of action classes. Some of the most common mechanisms of drug resistance involve altered hotez helminth or altered drug specificities of ABC ATP binding cassette transporters, such as P-glycoprotein Fig.