Antinematodal Drugs – Modes of Action and Resistance: And Worms Will Not Come to Thee (Shakespeare: Cymbeline: IV, ii). An antinematodal agent is a type of anthelmintic designed to reduce nematode infection. Antinematodal agent This antiinfective drug article is a stub. Looking for online definition of antinematodal drugs in the Medical Dictionary? antinematodal drugs explanation free. What is antinematodal drugs? Meaning of .
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Anthelmintics are some of the most widely used drugs in veterinary medicine. Here we review the mechanism of action of these compounds on nematode parasites. Included are the older classes of compounds; the benzimidazoles, cholinergic agonists and macrocyclic lactones. We also consider newer anthelmintics, including emodepside, derquantel and tribendimidine. In the absence of vaccines for most parasite species, control of nematode parasites will continue to rely on anthelmintic drugs.
As a consequence, vigilance in detecting drug resistance in parasite populations is required. Since resistance development appears almost inevitable, there is a continued and pressing need to fully understand the mode of action of these compounds.
It is also necessary to identify new antinsmatodal targets and drugs for the continued effective control of nematode parasites. Anthelmintics are drugs that are used to treat infections caused by parasitic worms helminths [ 1 ]. There are three major groups of helminths namely: These groups of helminths are divided into two phyla; nematodes roundworms and platyhelminths trematodes and cestodes [ 2 antinemqtodal.
Anthelmintics either kill worms or cause their expulsion from the body, without causing any significant damage to the host [ 3 ].
Although there is a high prevalence of parasitic worms, the progress of anthelmintic drug discovery and development by pharmaceutical companies has been antinematodak over the years. One contributing factor is that the majority of those suffering from helminth infections live in developing nations who lack the resources to support a profitable drug market [ 4 ].
Development of new anthelmintics is limited by high costs and modest global markets for antiparasitic drugs and chemicals. Antinematodzl anthelmintic drugs used to treat humans were first developed and marketed as veterinary drugs [ 9 — 11 ]. There are only a few classes of anthelmintics including; benzimidazoles, imidazothiazoles, tetrahydopyrimidines, macrocyclic lactones, amino-acetonitrile derivatives, spiroindoles and cyclooctadepsipeptides.
Antinematodal drugs | definition of antinematodal drugs by Medical dictionary
Here we review the mode of action of several classes of drug used to treat infections with parasitic nematodes. Thiabendazole was the first benzimidazole anthelmintic agent produced. Since the introduction of thiabendazole ina number of benzimidazoles with improved efficacy and extended spectrum of action have been developed [ 12 ].
These include mebendazole, albendazole antinemafodal flubendazole Figure 1. The initial mode of action of benzimidazoles was thought to be inhibition of various parasite metabolic enzymes including fumarate reductase and malate dehydrogenase [ 1314 ]. This results in the destruction of cell structure and consequent death of the parasite [ 15 ].
Chemical structures of thiabendazole Amebendazole Balbendazole C and flubendazole D. From [ 12 ].
Imidazothiazoles act as nicotinic acetylcholine receptor nAChR agonists. They bind to nAChRs on body wall muscles, causing spastic paralysis of the worm, and hence, its expulsion from the host [ 16 ]. The Abtinematodal was later demonstrated to be more potent than the racemic mixture or the D-isomer [ 20 antinematodl, 21 ].
Consequently, the D-isomer was removed from the racemic mixture and this led to the development of the L-isomer as levamisole.
The detailed mode of action of levamisole, the only existing drug in this class, has been carefully studied at the single-channel level in nematode body wall muscles [ 22 — 24 ]. Robertson and Martin [ 24 ], showed using the patch-clamp technique that at the single-channel level in A.
The mean open-times for single-channel currents activated by levamisole were 0. This corresponded to the levamisole-sensitive, L-subtype nAChR with a channel conductance of 35 pS, as revealed by Qian et al. In subsequent oocyte expression studies, the reconstituted O. Levamisole not only causes spastic paralysis but it also stimulates egg-laying in wild-type C. From [ 21 ]. Tetrahydropyrimidines share a similar mode of action to imidazothiazoles and are commonly grouped together as nicotinic agonists [ 2728 ].
Examples of this anthelmintic drug class include pyrantel, oxantel and morantel Figure 3. Pyrantel is an imidazothiazole-derived tetrahydropyrimidine that was discovered in as an anthelmintic agent with broad spectrum activity against roundworms and hookworms in domestic animals [ 2930 ]. Pyrantel however lacks activity against whipworms [ 31 ]. Studies on the mode of action of pyrantel at the single-channel level identified the L-subtype nAChR in A. Pyrantel, like levamisole, also causes open channel-block [ 33 ].
Although not characterized at the single-channel level, the O. The search for an agent with activity against whipworms led to the development of oxantel, an m-oxyphenol derivative of pyrantel [ 31 ]. Oxantel, like levamisole and pyrantel, also causes open channel-block in A.
At the single-channel level, morantel causes the activation and block of this receptor subtype [ 38 ]. In oocyte expression studies, morantel was seen to cause a non-competitive voltage-sensitive open channel block of the newly characterized A.
A BRIEF REVIEW ON THE MODE OF ACTION OF ANTINEMATODAL DRUGS
Chemical structures of pyrantel Amorantel B and oxantel C. From [ 28 ]. Macrocyclic lactones avermectins and milbemycins are a group of chemical compounds derived from soil microorganisms of the genus Streptomyces [ 41 — 43 ].
MLs were introduced in the s as antiparasitic agents with broad spectrum activity against nematodes and arthropods [ 4445 ]. Examples of commercially available avermectins are ivermectin, abamectin, doramectin and selamectin, while milbemycin oxime and moxidectin, are examples of commercially available milbemycins Figure 4. MLs are selective agonists of glutamate-gated chloride channels GluCls which are present in neurons and pharyngeal muscles of nematodes and arthropods, but absent in humans.
ML activation of GluCls inhibits movement and pharyngeal pumping [ 4647 ]. In addition to GluCl effects, the avermectins also act as antagonists of 4-aminobutyric acid GABA and nicotinic receptors expressed on somatic muscle cells of parasitic nematodes [ 48 — 50 ]. Ivermectin, the first member of the avermectins, although originally developed as a veterinary drug, was later approved for use in humans for the control of onchocerciasis and lymphatic filariasis [ 9 — 1151 ]. The AADs are a new class of synthetic anthelmintics with broad spectrum activity against nematodes that are resistant to the benzimidazoles, imidazothiazoles and macrocyclic lactones [ 54 — 56 ].
Monepantel, also known as AADis the first member of this class to be developed for the control of a broad range of parasitic nemtaodes in sheep Figure 5 [ 56 ]. Genetic screens of C.
In a different study, monepantel by itself did not activate H. Chemical structure of monepantel. From [ 56 ]. Derquantel 2-deoxy-paraherquamide or PNU is the first semi-synthetic member of this new class of anthelmintics Figure 6 [ 6263 ].
Derquantel acts as an antagonist of nAChRs to cause flaccid paralysis which results in the expulsion of parasites from the host [ 64 ]. The combination of derquantel and abamectin has an excellent broad spectrum efficacy against several parasitic nematodes in sheep, including those resistant to benzimidazoles, levamisole and macrocyclic lactones [ 6365 ].
The efficacy of the derquantel and abamectin combination has also been shown in muscle contraction and electrophysiological studies on A. Derquantel or abamectin alone inhibited responses to acetylcholine, and the inhibition was greater when a combination of derquantel and abamectin was used, producing a synergistic greater than additive effect [ 50 ]. The introduction of combination anthelmintics provides a useful tool to increase anthelmintic drug efficacy, overcome resistance to other anthelmintic classes and delay resistance development [ 6667 ].
Chemical structure of derquantel. From [ 63 ].
Cyclooctadepsipeptides were discovered in the antknematodal s. InPFA, the parent compound, was isolated from the fungus, Mycelia steriliawhich grows on the leaves of the plant, Camellia japonica [ 68 ]. PFA is made up of four N-methyl-L-leucine, two D-lactate and two D-phenyllactate residues that are arranged as a cyclic octadepsipeptide with an alternating L-D-L configuration Figure 7 [ 69 ]. Emodepside, formerly PF and BAYis a semisynthetic derivative of PFA, produced by attaching a morpholine ring at the para position of antinematoda, two D-phenyllactic acids [ 70 ].
This modification resulted in improved pharmacokinetic properties. The anthelmintic potential of PFA and emodepside has been reported in numerous in vitro and in vivo studies [ 71 — 76 ]. Interestingly, PFA and emodepside have a broad spectrum of activity against several nematode species including those that atinematodal resistant to benzimidazoles, levamisole and ivermectin [ 77 ]. From [ 69 ]. Studies on the mode of action suggest that emodepside targets the calcium-activated potassium channel SLO-1there is also evidence for the involvement of the latrophilin LAT-1 receptor [ 78 — 80 ].
Mutagenesis screens in C. Inhibition of locomotion was achieved via the action of emodepside on SLO-1 expressed in body wall muscles or neurons, whereas inhibition of feeding was achieved via the action of emodepside on SLO-1 expressed in neurons but not muscle [ 81 ].
These studies suggest that the inhibitory effect of emodepside on feeding is both SLO-1 and latrophilin-dependent. However, emodepside treatment inhibited locomotion in both wild type and lat The sensitivity of nematode SLO-1 channels to calcium is different from that of insects and humans [ 83 ].
Tribendimidine is a symmetrical diamidine derivative of amidantel Figure 8 [ 84 ]. It was developed in the mid s by the National Ajtinematodal of Parasitic diseases in Shanghai, Antine,atodal, as a broad spectrum anthelmintic drug [ 85 ]. Intribendimidine was approved by the Chinese Food and Drug Administration for treatment of helminth infections in humans [ 86 ].
It is the only new anthelmintic drug that has been approved for human use within the past 3 decades [ 87 ]. Tribendimidine has been shown in laboratory and clinical studies to have a broad spectrum of activity against several nematode, trematode and cestode species [ 8488 — 92 ]. The activity of tribendimidine against 20 helminth parasites has been documented [ 93 ].
Earlier studies on the mode of action of tribendimidine in the nematode model C. Parasitic nematodes however, show different nAChR subtype selectivity from C. Thus, confirming their hypothesis that unlike in C. Chemical structures of amidantel A and tribendimidine B. From [ 84 ]. In broad terms, anthelmintic resistance is referred to as the decline in the efficacy of an anthelmintic drug in a population of parasites that were once susceptible to the drug.
The repeated and improper use of currently available anthelmintics has led to the development of resistance in numerous veterinary parasite species worldwide, with increasing concerns that this may extend to human parasites [ 96 — 98 ].
Since anthelmintics within each drug class act in a similar manner, resistance to one anthelmintic in a given drug class is likely to be accompanied by resistance to other anthelmintics of that same class side resistance.
There is also the likelihood for the development of cross resistance from anthelmintics of one drug class to those of another, if the two drug antinematodaal share similar targets [ 99 ].