See other articles in PMC that cite the published article. Abstract 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.

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Antinematodal Drugs Carlos E. Lanusse, Juan M. Sallovitz, Sergio F. Sanchez Bruni, and Luis I. Alvarez The economic importance of helminth infections in livestock has long been recognized and it is probably for this reason that the most important advances in the chemotherapy of helminthiasis have come from the animal health area Horton, Anthelmintics are used in all animal species and man. A significant part of the economic impact of parasitism in animal production is represented by the investment in control measures.

Although alternative methods have been developed, chemically based treatments are the most important tool to control parasitism. A more complete understanding of the pharmacological properties of existing antiparasitic drugs should assist with more efficient parasite control both in livestock and companion animals. However, the investment in control measures does not always result in the expected therapeutic success.

Among factors responsible for that therapeutic failure are: i inadequate integration between management strategies and chemotherapy; ii incorrect use of anthelmintic drugs due to insufficient knowledge of their pharmacological features; and iii insufficient understanding of the relationship between pharmacological properties and several host-related factors that could lead to modifications of the pharmacokinetic behavior and to a decreased antiparasite efficacy of the chosen drug.

In addition, the availability of many compounds with a common mode of action and the indiscriminate use of these drugs have accounted for the widespread development of drug resistance, mainly in parasites of sheep and goats, but also in parasites of pigs, horses, and cattle. This chapter covers the information available for the different specific antinematodal drug families used in veterinary therapeutics. However, special consideration is given to the description of the large body of pharmacological knowledge generated for the benzimidazole compounds, the most intensively studied anthelmintic chemical group together with the endectocide macrocyclic lactones see Chapter The remarkable overall safety of BZD compounds has been a major factor in their successful worldwide use over four decades.

BZD were introduced into the animal health market primarily for the control of gastrointestinal GI nematodes, not only for use in livestock animals cattle, sheep, goats, swine, and poultry , but also for horses, dogs, and cats.

The use of BZD compounds quickly became widespread because they offered major advantages over previously available drugs in terms of spectrum, efficacy against immature stages, and safety for the host animal. However, no more than 20 of them have been commercially developed for use in domestic animals and man, either as BZDs or pro-BZDs. The BZD structure is a bicyclic ring system in which benzene has been fused to the 4- and 5- positions of the heterocycle imidazole Figure Most of the BZD compounds are white crystalline powders, with fairly high melting point and insoluble or slightly soluble in water.

The BZD compounds can be grouped as follows: BZD thiazolyls: thiabendazole, cambendazole; BZD methylcarbamates: parbendazole, mebendazole, flubendazole, oxibendazole, luxabendazole, albendazole, albendazole sulfoxide, also known as ricobendazole, fenbendazole, oxfendazole; Halogenated BZD thiols: triclabendazole; pro-BZD: thiophanate, febantel, netobimin.

Figure The positions 2- and 5- main substitution sites are shown in the thiabendazole structure. Triclabendazole a halogenated flukicidal BZD is not included here see Chapter Different modifications at positions 2- and 5- of the BZD ring system see Figure Albendazole, fenbendazole and their sulfoxide derivatives albendazole sulfoxide and oxfendazole, respectively ruminants , fenbendazole and oxfendazole horses , febantel, fenbendazole, and mebendazole companion animals , fenbendazole and flubendazole poultry and pigs are currently among the most extensively used BZD methylcarbamate anthelmintics in veterinary medicine.

Pharmacodynamics: Mode of Action Microtubules are hollow tubular organelles that exist in a dynamic equilibrium with tubulin, the microtubule subunit. Competitive binding experiments using tubulin from mammalian, invertebrate, or fungal cells indicate that BZD compounds bind within the colchicine a well recognized microtubule inhibitor binding domain on tubulin.

Thus, all the functions ascribed to microtubules at the cellular level are altered cell division, maintenance of cell shape, cell motility, cell secretion, nutrient absorption, and intracellular transport Lacey, Microtubules are found in animals, plants, and fungi cells.

However, the rate constant for the dissociation of BZD from parasite tubulin is much lower than the rate constant for the dissociation from mammalian tubulin. These differences in dissociation rates between BZD and tubulin in host and parasites may explain the selective toxicity of BZD compounds to parasites and its wide safety margin in the mammalian host.

The microtubule loss observed at tegumental and intestinal level in cestodes and nematodes after BZD treatment is followed by loss of transport of secretory vesicles and decreased glucose uptake.

A prolonged storage of secretory material within the cells is followed by cell disintegration. Cell autolysis requires a period of 15—24 hours posttreatment.

Additionally, the inhibition of secretion of nematode acetylcholinesterase and inhibition of some enzymatic activities such as fumarate reductase, malate dehydrogenase, phosphoenol pyruvate reductase, and succinate dehydrogenase have been associated with the BZD anthelmintic action.

However, all these effects may be related to the primary underlying BZD mechanism: the disruption of the tubulin—microtubules dynamic equilibrium. The effects of structural modifications to BZD-like molecules on microtubule inhibitory activity have been intensively investigated reviewed by Lacey, It has been postulated that the presence of a carbamate group in the 2- position is essential for potent microtubule inhibitory activity.

Additionally, regardless of the size of the substituent in the 5- position, the pharmacological effect heavvily depends on the nature of the molecule adjacent to the BZD ring system.

Different studies suggest that not only the chemical substitution in the position 5- of the BZD ring, but also its conformational arrangement, are relevant in the access of the drug to the active site and in the resultant anthelmintic activity.

As a chemical class, the BZD methylcarbamates have only limited water solubility and small differences in drug solubility may have a major influence on their absorption and resultant pharmacokinetic behavior. The lack of water solubility is an important limitation for the formulation of BZD compounds, which mainly allows their preparation as suspensions, pastes, or granules for oral or intraruminal administration.

The mucous surface in the GI tract behaves as a lipid barrier for the absorption of active substances, so that absorption depends on lipid solubility and degree of ionization at GI pH levels. However, drug particles must dissolve in the enteric fluids to facilitate absorption of the BZD molecule through the GI mucosa.

A drug that does not dissolve in the GI contents, passes down and is excreted in the feces without exerting its action. Their dissolution rate, passage along the GI tract, and absorption into the systemic circulation, are markedly slower than those observed for the more hydrosoluble BZD thiazolyls TBZ, thiabendazole.

Such a phenomenon also results in extended residence times for the active metabolites of the BZD methylcarbamates compared to those of TBZ.

This differential pharmacokinetic behavior accounts, in part, for the greater anthelmintic potency of fenbendazole and albendazole compared with thiabendazole.

Absorption The complexity of the ruminant digestive tract in comparison to that of the monogastric animal creates unique problems and opportunities related to the absorption of drugs administered orally. The rumen may substantially influence the absorption pattern and the resultant pharmacokinetics and antiparasite activity of enterally delivered BZD anthelmintics.

When a BZD suspension is deposited in the rumen, solid particles mix and distribute through the digesta volume. Shortly after administration, BZD compounds are almost completely associated adsorbed to the digesta particulate material. The drug reaches an equilibrium between the particulate and fluid portions of the digesta.

The adsorption of BZD particles to digesta solid content, the slow mixing and long digesta residence time, and the large rumen volume assists absorption by delaying the rate of passage of drug down the GI tract Hennessy, The rumen acts as a drug reservoir by slowing the digesta transit time throughout the abomasum, which results in improved systemic availability of BZD compounds as a consequence of a greater dissolution of drug particles in the acid pH of the abomasum Lanusse and Prichard, a.

The plasma levels of the parent sulfides i. Since the main mechanism of drug entry to nematode parasites located in the GI lumen is drug diffusion through its external surface, the higher the concentration of solubilized drug in the GI fluid, the greater the anthelmintic activity. See the text for further explanation. Albendazole ABZ is used as a model drug in the scheme. A lack of proportionality in the relationship between albendazole dose rates and drug systemic exposure has been described in sheep, where area-under-the-curve AUC and maximum peak concentration Cmax values for albendazole sulfoxide increased more than expected from the increase in the dose.

The primary metabolites usually are products of oxidative and hydrolytic processes and are all more polar and water soluble than the parent drug.

In addition, phase II conjugative reactions are highly important in the detoxification of BZD-derived products. Intestinal, liver, and lung metabolism have been implicated in this phenomenon in most animal species. Additionally, GI metabolism is an important concern in ruminant species. Netobimin pro-BZD is an anthelmintically inactive nitrophenylguanidine prodrug.

The nitro-reduction and cyclization of netobimin into albendazole in the host are crucial for the pharmacokinetic profile of its active metabolites and resultant anthelmintic activity. Both formulation and route of administration may dramatically affect the rate of netobimin conversion and the bioavailability and disposition of its main plasma metabolites, albendazole sulfoxide and albendazole sulfone. Febantel is a phenylguanidine prodrug, which is hydrolyzed by removal of a methoxyacetyl group and then cyclized to fenbendazole.

Fenbendazole is then converted to oxfendazole and fenbendazole sulfone in subsequent oxidative metabolic steps. Following febantel administration, in both sheep and cattle, the parent drug is not found in plasma, or is detected in low concentrations for only a short period.

Hepatic metabolism appears to be the main site of febantel conversion into fenbendazole, after its oral administration to different animal species. Thiophanate is currently used as an antifungal agent thiophanate-methyl for plants. Hepatic and extrahepatic oxidative metabolism: The metabolism of BZD heavily depends on the substituent present at position 5- of the BZD ring system and involves a variety of reactions.

Phase I reactions have been observed at position Hydroxylations of thiabendazole, albendazole, and fenbendazole have been demonstrated in different animal species. The sulfoxidation of albendazole and fenbendazole at the sulfur atom of the substituent group at the carbon 5- of the BZD nucleus have been widely investigated.

Additionally, the anthelmintically active sulfoxide derivatives undergo a second, slower and irreversible oxidative step, forming the inactive sulfone albendazole sulfone and fenbendazole sulfone metabolites, which are also found in the bloodstream and tissues after administration of their respective parent sulfides. The substitution of the BZD ring in position 5- has been particularly important in determining the metabolic fate of BZD methylcarbamates.

The nature of this substitution at position 5- markedly influences the sequence of BZD liver metabolism. Aromatic BZD derivatives, such as fenbendazole and oxfendazole, require more extensive hepatic oxidative metabolism than aliphatic derivatives albendazole and albendazole sulfoxide to achieve sufficient polarity for excretion Hennessy, MRT, mean plasma residence time h for each molecule.

The width of the arrows represents the magnitude of each metabolic pathway see the text. Both sulfoxide metabolites albendazole sulfoxide and oxfendazole have an asymmetric center in the sulfur atom of their side chains.

This nucleophilic sulfur atom is attached to four different functional groups, which results in an asymmetric molecule nonsuperimposable with its mirror image. The width of the arrows indicates the magnitude of the metabolic reactions. The same pattern is applicable to the sulforeduction of oxfendazole OFZ enantiomers into fenbendazole FBZ see the text for detailed explanation. Biotransformation takes place predominantly in the liver, although metabolic activity is apparent in extrahepatic tissues such as lung parenchyma and small intestine mucosa.

Large quantities of albendazole parent drug were recovered from tissues at parasite locations in both sheep and cattle. Similarly, fenbendazole has been recovered from tissues at parasite locations following oral administration of oxfendazole to cattle.

Altogether, these findings support the need to study the biotransformation of BZD anthelmintics in extrahepatic tissues such as lung parenchyma and small intestinal mucosa.

Although the liver is the main site of albendazole and fenbendazole biotransformation, sulfoxidation in the intestinal mucosa and lung tissue may contribute to the presystemic metabolism of both anthelmintic drugs and should not be underestimated. The administration of thiabendazole results in a rapid conversion of a parent compound into a 5-hidroxy thiabendazole metabolite, formed by aromatic ring hydroxylation. The main mebendazole metabolite results from carbonyl reduction to the secondary alcohol, which was also identified as its glucuronide or sulfate conjugates.

Although, the specific enzymatic system responsible for mebendazole reduction is unknown, several cytosolic ketone reductases are involved in the formation of hydrosoluble metabolites from carbonyl-containing molecules. On the other hand, the combination of carbonyl reduction and carbamate hydrolysis produces the hydrolyzed metabolite of mebendazole. Hydrolysis of the carbamate group eliminates both the anthelmintic activity of the compound and its toxicity. Mebendazole rather than its metabolites appears to be the active anthelmintic molecule.

Mebendazole metabolites are mainly excreted in bile.


Antinematodal Drugs

Its commercial introduction into the U. It is effective against a wide variety of parasites. IM to horses: Gasterophilus intestinalis, Parascaris equorum, Strongylus vulgaris, Strongylus edentatus, Oxyuris equi, Habronema muscae. Adult Trichostrongylus




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