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Chemical Structure of Macrocyclic Lactones. Avermectin B1a with major sites of substitution shown. The natural products of streptomyces fermentation are mixtures
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The macrocyclic lactones have pharmacokinetic properties which enhance their use against endo- and ectoparasites in animals and man. The most consistent physico-chemical feature of the group which contributes to their kinetic characteristics is high lipid solubility. This appears to be necessary for their pharmacodynamic action as well as common ki...
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Oral drug delivery has always been considered the preferred route of drug administration. Nano-formulations are now constantly being researched for better absorption, higher bioavailability and greater therapeutic efficacy. Lipid based nanoformulations have found much favour with the formulation scientist due to their relatively higher safety profi...
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... There are no known reasons for the apparently slightly variable responses to the avermectin-based treatments against O. ovis observed between sheep and goats. Comparative pharmacokinetic studies support that there may be differences in the processing of parasiticides by the two species of domestic ruminants (Myers et al., 2021), further to factors like age, sex, physiological status, health status, nutritional status or breed which may influence the systemic availability of actives between animals within a species (Martinez and Modric, 2010;Modric and Martinez, 2011;McKellar and Gokbulut, 2012). However, a different exposure may not necessarily be associated with interference to the treatment response when a product is administered at the recommended dose and the parasites are sensitive to the active. ...
The larvae of the nasal bot, Oestrus ovis, mainly parasitize sheep and goats and some species of wild Caprinae but other mammals and humans are also vulnerable to infestation. Eprinomectin 5 mg/mL topical solution (EPRI-NEX® Multi, Boehringer Ingelheim) administered at 1 mg eprinomectin per kg body weight pour on was recently authorized as an anthelmintic for sheep and goats with zero hours milk withdrawal in several countries in Europe. As the product in cattle has claims against a broad range of parasites including insect parasites and activity against O. ovis has previously been reported following extra-label use in sheep, its therapeutic efficacy against ovine and caprine O. ovis myiasis was evaluated in three regulatory compliant, masked clinical studies. Pre-study recovery of O. ovis larvae from five or six of six randomly selected animals per study site (Bulgaria, one site, sheep; Greece, two sites, sheep or goats) supported the inclusion of the animals from those sites into the studies. The study animals (34 animals per study) were ranked based on bodyweight and allocated randomly to remain untreated (control) or to be treated with eprinomectin 5 mg/mL topical solution at 1 mL per 5 kg body weight pour on. Treatment efficacy was determined based on O. ovis larval counts of eprinomectin 5 mg/mL topical solution-treated vs. untreated animals three weeks after treatment administration. Live O. ovis larvae, including all three instars in each study, were recovered from 13 or 16 of the 17 control animals in the sheep studies (range, 1 to 14 or 5 to 18 larvae, respectively) and from all 17 controls in the goat study (range, 7 to 18 larvae). In each study, eprinomectin 5 mg/mL topical solution-treated animals had significantly (p < 0.001) fewer live O. ovis larvae than the controls. Efficacy of the treatment was 100% and 91.3% against the combined parasitic O. ovis larval stages in sheep and in goats, respectively. The treatment was well accepted by all animals and no health problems were observed throughout the studies. The results of these studies demonstrated epri-nomectin 5 mg/mL topical solution administered pour on at 1 mL per 5 kg body weight to be an efficacious and safe treatment of ovine and caprine oestrosis.
... (Weinberg et al. 1998;Fernandez et al. 2011;Ozcan and Weinberg 2014). IVM belongs to a family of anthelmintic macrocyclic lactones and is extensively used to control a wide spectrum of nematode species, including most larvae and adult forms and many arthropod parasites of domestic animals (Lanusse et al. 1997;McKellar and Gokbulut 2012). IVM is also approved by the United States (US) Food and Drug Administration (FDA) for use in human medicine for the treatment of lymphatic filariasis, onchocerciasis, strongyloidiasis and mite infection (Õmura and Crump 2004;Sauerbrey 2008;DailyMed 2022). ...
Intravenous lipid emulsion (ILE) has been widely used as an effective antidote in both veterinary and human medicine for the treatment of acute intoxications caused by drugs and pesticides with high lipid solubility. This study was conducted to investigate the effect of ILE co-administration on the kinetic dispositions of ivermectin (IVM) and carprofen (CRP) following intravenous bolus administration at subtoxic doses in rabbits.
Twenty-four male New Zealand rabbits weighing 2.78 ± 0.2 kg were used in this study. Rabbits were divided into four groups (Group 1: IVM and Group 2: IVM + ILE or Group 3: CRP and Group 4: CRP + ILE), each group consisting of 6 animals. In the IVM study, Group 1 received IVM (0.6 mg/kg) alone while Group 2 received IVM (0.6 mg/kg) and ILE (2.5 ml/kg). In the CRP study, Group 3 received CRP (12 mg/kg) alone while Group 4 received CRP (12 mg/kg) and ILE (2.5 ml/kg). In both drug groups, ILE was administered 3 times as an i.v. bolus at the 10th min and repeated 4th and 8th h after the drug administration. Blood samples were collected from the auricular vein at various times after drug administration. The drug concentrations in plasma samples were determined by high-pressure liquid chromatography. Kinetic parameters were calculated using a non-compartmental model for both CRP and IVM.
The C0 and area under the concentration–time curve from zero up to ∞ (AUC0–∞) values were significantly greater with ILE co-administration (2136 ng/ml and 360.84 ng.d/ml) compared to the IVM alone (1340.63 ng/ml and 206 ng.d/ml), respectively. Moreover, the volume of distribution (Vdss) and clearance (Cl) of IVM were reduced by approximately 42% and 46% with ILE co-administration compared to IVM alone resulting in a reduction of the distribution and slower elimination, respectively. Similar differences in C0, and Vdss values were also observed in CRP with ILE co-administration compared to CRP alone. ILE co-administration changed significantly the kinetic profile of both IVM and CRP in rabbits, supporting the lipid sink theory in which highly lipid-soluble compounds are absorbed into the lipid phase of plasma from peripheral organs such as the heart and brain affected by the acute toxicity of the compounds.
... We tested the four active ingredients moxidectin ( (Prichard et al. 2012). As MLs, the tested active ingredients have a three-part pharmacophore in common, consisting of a 16-membered macrocycle with fused benzofuran and spiroketal units (McKellar & Gokbulut 2012). There are two ML sub-classes, differing structurally mainly by presence (avermectins) or absence (milbemycins) of a disaccharide substituent at C-13 (McKellar & Gokbulut 2012). ...
... As MLs, the tested active ingredients have a three-part pharmacophore in common, consisting of a 16-membered macrocycle with fused benzofuran and spiroketal units (McKellar & Gokbulut 2012). There are two ML sub-classes, differing structurally mainly by presence (avermectins) or absence (milbemycins) of a disaccharide substituent at C-13 (McKellar & Gokbulut 2012). We studied three avermectins (IVM, ABA and DOR) and one milbemycin (MOX). ...
... Possibly, the slight differences of MLs in molecular structure impact interactions with other molecules, e.g. interaction with P-glycoproteins, to which ivermectin (IVM) and MOX have vastly different affinities (Shoop et al. 1995;Griffin et al. 2005;McKellar & Gokbulut 2012;Lloberas et al. 2013). In animals, this leads to differing excretion rates, since P-glycoproteins are responsible for transporting MLs out of cells back into the intestinal lumen (Griffin et al. 2005;McKellar & Gokbulut 2012;Lloberas et al. 2013). ...
Macrocyclic lactone anthelmintics are widely used to control invertebrate pests in livestock, such as sheep. While anthelmintic effects on non‐target animals, such as dung‐dwelling insects, are well studied, effects on seed germination are largely unknown. Seeds can come into contact with anthelmintics either during passage through the gastro‐intestinal tract of grazing animals or when anthelmintics are excreted with their dung into the environment, which may result in changed germination patterns.
We used four commonly applied macrocyclic lactones to assess their effects on germination: moxidectin, ivermectin, abamectin and doramectin as pure substances; moxidectin and ivermectin also in formulated form. We tested these pharmaceuticals on 17 different temperate grassland species from five plant families. Seeds were exposed to three concentrations of macrocyclic lactones (0.1, 1.0 and 10.0 mg·l ⁻¹ ) under controlled conditions, and germination was assessed over a 6‐week period. From these data, we calculated germination percentage, mean germination time and germination synchrony.
Most of the tested species were significantly affected in germination percentage and/or mean germination time by at least one of the tested pharmaceuticals, with formulated moxidectin having the largest impact. In general, the effects found were species‐ and pharmaceutical‐specific. While formulated substances generally reduced germination percentage and increased mean germination time, pure substances increased germination percentage. Synchrony showed less clear patterns in all pharmaceuticals.
Although effect size and sign varied between species, our study shows that non‐target effects of macrocyclic lactones commonly occur in terrestrial plants. This may impede successful seed exchange between habitats via sheep, and even translate into profound changes to grazed ecosystems.
... These factors could potentially scarify the seed coat so that MOX would more readily reach the embryo. Once contact has been made with the quiescent, dormant or germinating embryo, MOX could affect chloride channels in cells, leading to a change in membrane conductance (McKellar and Gokbulut, 2012). Even though this mode of action has been proven in animal cells, it is theoretically also conceivable in plant cells because they have homologous channel genes (Elter et al., 2007;Ward et al., 2009). ...
Sheep function as effective endozoochorous seed vectors in grasslands. Recent laboratory-based studies showed that this important function can be impaired by macrocyclic lactone anthelmintics, which are used to control parasites and enter into the environment mainly via faeces; however, there is a lack of in vivo studies. We conducted a seed-feeding experiment with sheep that included four temperate grassland species from four different families (Achillea ptarmica, Asteraceae; Agrostis capillaris, Poaceae; Dianthus deltoides, Caryophyllaceae; Plantago lanceolata, Plantaginaceae). A series of three feeding trials was carried out after one of two groups of sheep received a single administration of a common oral formulation of the macrocyclic lactone moxidectin. Faeces were collected to determine seedling emergence rate and emergence timing as well as moxidectin concentration via HPLC. Seedling emergence differed significantly between the anthelmintic-treated sheep and the control group. This impact depended on time of seed uptake after anthelmintic administration. Number of emerging seedlings was significantly reduced (27.1 %) when faeces moxidectin concentrations were high (on average 3153 ng g−1; 1 d post treatment) and significantly increased (up to 68.8 %) when moxidectin concentrations were low (≤86 ng g−1; 7, 14 d pt). Mean emergence time was significantly lowered at low moxidectin concentrations. These results demonstrate dose-related effects of deworming on seedling emergence which might affect endozoochory and eventually plant population dynamics in grasslands.
... MOXI and DORA have low aqueous solubility and high lipid solubility; the latter property facilitates the storage of MOXI and DORA in the adipose tissue, which then acts as a drug reservoir. It has been reported that DORA has a longer plasma half-life (T 1/2el ) in cattle and a longlasting antiparasitic efficacy (McKellar and Gokbulut, 2012) after the administration of a single dose. In fact, the persistence of the antiparasitic or insecticidal efficacy of MLs depends on the disposition kinetics and pattern of plasma/tissue drug exchange (Lifschitz et al., 1999). ...
... ML endectocides are highly lipid-soluble and accumulate in fat tissue, which acts as a drug reservoir. As a result, the animal's live weight and body condition significantly affect the plasma drug concentration of MLs, secondary to tissue distribution and redistribution into adipose tissues (McKellar and Gokbulut, 2012). The small live weight and low adipose tissue of Zebu calves in the present study probably accounted for most of the observed differences. ...
... IVER SC injection is available for commercial use as 40% glycerol formal in propylene glycol, and DORA as ethyl oleate in a sesame oil vehicle as an injectable preparation. However, MOXI is relatively soluble in water compared to the other MLs and is formulated as an aqueous injectable solution (McKellar and Gokbulut, 2012). The differences in the physicochemical properties of ML endectocides and the composition of the dosage form may account for the observed variations in insecticidal efficacy (Prichard et al., 2012). ...
Outdoor biting, outdoor resting, and early evening biting of Anopheles arabiensis is a challenge in current malaria control and elimination efforts in Africa. Zooprophylaxis using livestock treated with macrocyclic lactones is a novel approach to control zoophilic vectors. Therefore, the present study aimed to investigate the pharmacokinetics and insecticidal efficacy of ivermectin (IVER), doramectin (DORA), and moxidectin (MOXI) subcutaneous (SC) formulations in treated calves. The study was conducted using indigenous (Bos indicus) calves treated with SC formulation at a dosage of 0.5, 0.2 or 0.05 mg/kg body weight (BW) IVER or DORA and 0.2 or 0.05 mg/kg BW MOXI. Direct skin feeding of mosquitoes and animal blood sampling were performed at 4, 8, 12, and 24 h and on days 2, 3, 5, 7, 10, 14, 21, 28, and 35 post treatment. The survival of fully fed A. arabiensis mosquitoes was monitored for 10 days. Plasma samples were analyzed using UHPLC-MS/MS. A. arabiensis mortality percentages in the 0.5 mg/kg BW DORA and IVER groups were 65.74% (95% CI: [54.98; 76.50]) and 64.53% (95% CI: [53.77; 75.29]), respectively, over 35 days post treatment. At the recommended dose (0.2 mg/kg BW), promising overall A. arabiensis mortality rates of 61.79% (95% CI: [51.55; 72.03]) and 61.78% (95% CI: [51.02; 72.54]) were observed for IVER and DORA, respectively. In contrast, A. arabiensis mortality in the MOXI group was 50.23% (95% CI: [39.87, 60.58]). At 0.2 mg/kg BW dose, area under the plasma concentration versus time curve (AUC0-inf) values for IVER, DORA, and MOXI were 382.53 ± 133.25, 395.41 ± 132.12, and 215.85 ± 63.09 ng day/mL, respectively. An extended elimination half-life (T1/2el) was recorded for DORA (4.28 ± 0.93 d), at 0.2 mg/kg BW dose level, compared to that for IVER (3.16 ± 1.47 d). The T1/2el of MOXI was 2.17 ± 0.44 day. A maximum plasma concentration (Cmax) was recorded earlier for MOXI (10 h) than for IVER (1.6 days) and longer for DORA (3.0 days). For DORA and IVER, significant differences were found in T1/2el (P<0.05), Cmax (P<0.01), and AUC0-inf (P<0.01) between the higher 0.5 mg/kg BW and the lower 0.05 mg/kg BW doses. The T1/2el and AUC0-inf of DORA and IVER in the present study were significantly (p < 0.05) correlated with the observed insecticidal efficacy against A. arabiensis mosquitoes at 0.2 mg/kg a dose. Therefore, treating cattle with IVER or DORA could complement the malaria vector control interventions, especially in Ethiopia, where the zoophilic malaria vector A. arabiensis majorly contribute for residual malaria transmission.
... Moxidectin (MXD), on the other hand, is similar to avermectins in chemical structure but does not contain a saccharide group (Fig. 1). These compounds are anthelmintic drugs most commonly used worldwide for the treatment of internal and external parasitic infections in different animal species, including food animals due to their high efficacy against internal and external parasites at low doses, a broad spectrum of action, and low toxicity for mammals [4]. Due to their high lipophilic properties, these compounds can accumulate in the animal body and cause long-term residue in edible tissues and in milk during the lactation period in small and large ruminant species. ...
... The correlations between mode of administration, drug serum levels and efficacy are not straightforward. Due to the lipophilic nature of macrocyclic lactones, these drugs can deposit in adipose tissue and skin, and be redistributed to blood over time (McKellar and Gokbulut, 2012). Thus, differences in pharmacokinetics between species may reflect different levels of deposition in subcutaneous fat, which may explain persistence in cattle compared to humans and dogs. ...
Sarcoptes scabiei is the microscopic burrowing mite responsible for sarcoptic mange, which is reported in approximately 150 mammalian species. In Australia, sarcoptic mange affects a number of native and introduced wildlife species, is particularly severe in bare-nosed wombats (Vombatus ursinus) and an emerging issue in koala and quenda. There are a variety of acaricides available for the treatment of sarcoptic mange which are generally effective in eliminating mites from humans and animals in captivity. In wild populations, effective treatment is challenging, and concerns exist regarding safety, efficacy and the potential emergence of acaricide resistance. There are risks where acaricides are used intensively or inadequately, which could adversely affect treatment success rates as well as animal welfare. While reviews on epidemiology, treatment strategies, and pathogenesis of sarcoptic mange in wildlife are available, there is currently no review evaluating the use of specific acaricides in the context of their pharmacokinetic and pharmacodynamic properties, and subsequent likelihood of emerging drug resistance, particularly for Australian wildlife. This review critically evaluates acaricides that have been utilised to treat sarcoptic mange in wildlife, including dosage forms and routes, pharmacokinetics, mode of action and efficacy. We also highlight the reports of resistance of S. scabiei to acaricides, including clinical and in vitro observations.
... Veterinary antiparasitic drugs, represented by ivermectin (IVM), have been widely used in clinical practice (Ge et al., 2022;Wan et al., 2017;Wang et al., 2016;Zhang et al., 2019;Zhang et al., 2022), but IVM has a long metabolic cycle leading to a large amount of drug residues in the faeces (Mckellar & Gokbulut, 2012); it slows down the rate of treating the animal manure by insects such as dung beetle (Ambrožová et al., 2021). Tenvermectin (TVM) is a novel 16-membered macrolide compound isolated and purified from the fermentation broth of (Ge et al., 2022) ( Figure 1). ...
... Compared to the pharmacokinetic profile of IVM, the half-life of TVM is shorter, only 67% of that of IVM (Mckellar & Gokbulut, 2012 Note: λz, terminal rate constant or terminal slope of the concentration-versus-time curve; T 1/2λz , half-life or apparent elimination half-life; T max , time to maximum concentration; C max , maximum plasma concentration; AUC 0-last , area under the concentration-versus-time curve from time 0 h to the last measured concentration; AUC 0-∞ , area under the concentration-versus-time curve from time 0 h to infinity; Vd/F, volume of distribution corrected for bioavailability or volume of distribution per fraction absorbed; Cl/F, clearance corrected for bioavailability; MRT last , mean residence time. Data were presented as mean ± SD (n = 6). ...
... Previous studies found significant differences in IVM kinetics on swine of different species, age and weight (Craven et al., 2002a;Craven et al., 2002b;Lo et al., 1985). Differences in body composition (fat or lean) and growth period (growth or maintenance) of pigs have been found in previous studies to affect the kinetic parameters of macrolides (Mckellar & Gokbulut, 2012). The high lipophilicity of macrolides, the large amount of fat residues and the important role of fat metabolism suggest that the fat composition of the administered animals may influence the pharmacokinetics of these drugs (Mckellar & Gokbulut, 2012). ...
Tenvermectin (TVM) is a novel 16‐membered macrolide compound isolated and purified from the fermentation broth of genetically engineered Streptomyces avermitilis strain MHJ1011. TVM and ivermectin were administered at the dose of 0.3 mg/kg body weight through a single subcutaneous injection route followed by plasma collectiom and analysis at different time intervals. Plasma concentrations of TVM and IVM were determined by high‐performance liquid chromatography with fluorescence detector. Pharmacokinetic analysis was completed using the non‐compartmental method with WinNonlin™ 6.4 software. TVM is rapidly absorbed after administration with peak plasma concentrations (Cmax, 9.78 ± 2.34 ng/ml) obtained within 6–22 h. AUC0‐last was 586.86 h·ng/ml ± 121.24 h·ng/ml. The mean elimination half‐life of TVM (T1/2λz) was 97.99 h ± 46.41 h. The T1/2λz of IVM was 146.59 h ± 22.26 h in the study. The present study showed that subcutaneous administration of TVM at 0.3 mg/kg body weight (BW) in swine is absorbed more rapidly than IVM in swine. Compared to the pharmacokinetic characteristics of IVM, there was little difference in the half‐life of TVM among different individuals. The data will contribute to refining the formulation and dosage regime for TVM administration.
... As a group, MLs are lipophilic and have a large volume of distribution, although there are differences between the individual MLs. Time to maximum concentration and mean residence time are believed to be influenced by the lipophilicity and efflux potential via ABC transporters, with body fat composition also potentially influencing C max , T max , and T 1/2 [20,21]. In dogs and cats with poor body condition, C max would still be reached; however, potentially T max and T 1/2 could be shorter with less adipose tissue serving as a reservoir. ...
... In dogs and cats with poor body condition, C max would still be reached; however, potentially T max and T 1/2 could be shorter with less adipose tissue serving as a reservoir. In obese animals, T max and T 1/2 could be extended while C max could be lowered [20,22]. Given that most ML preventatives are dosed above the minimum level required for efficacy against D. immitis and have wide safety margins, it is very unlikely that these changes in concentration would affect prevention efficacy or safety in malnourished or obese dogs and cats [9, 23]. ...
Chemotherapy options for the prevention of adult Dirofilaria immitis infections and other filarial species in dogs and cats focus primarily on the use of macrocyclic lactones. While macrocyclic lactones are considered safe when used as per their registered product labels, veterinarians should be aware of their basic mechanisms of action and metabolism to understand potential differences in efficacy and safety in the individual animal. With the advent of D. immitis resistance to macrocyclic lactones and the lack of preventatives or treatments for many other filarial species, supportive measures to decrease exposure to the intermediate host are growing in importance. Chemotherapeutic treatment of adult D. immitis infections is only available for dogs and uses melarsomine as the basis. Treatment guidelines differ with regard to the use of antibiotics and treatment regimen but result in similar efficacy and provide veterinarians with options that can be adapted based on the client and patient.
... Prolonged feed restriction leading to poor nutritional status can negatively affect anthelmintic bioavailability through reduced BZD biotransformation in the liver and resultant pharmacokinetics [81], while body fat composition exerts a major influence on the distribution, metabolism and persistence of ML [60]. Thus, plasma concentrations of moxidectin were higher and persisted for longer in fat than in thin pigs [19]. ...
Increasing anthelmintic resistance (AR) in livestock has stimulated growing efforts to monitor anthelmintic effectiveness (AE) on livestock farms. On-farm assessment of AE relies on measuring the reduction in faecal egg count (FEC) following treatment; and if conducted rigorously, qualifies as a formal FEC reduction test (FECRT) for AR. Substantial research effort has been devoted to designing robust protocols for the FECRT and its statistical interpretation; however, a wide range of factors other than AR can affect FEC reduction on farms. These are not always possible to control, and can affect the outcome and repeatability of AE measurements and confound the on-farm classification of AR using FECRT. This review considers confounders of FEC reduction, focusing on gastrointestinal nematodes of ruminants, including host and parasite physiology and demography; pharmacokinetic variation between drugs, parasites and hosts; and technical performance. Drug formulation and delivery, host condition and diet, and seasonal variation in parasite species composition, can all affect AE and hence observed FEC reduction. Causes of variation in FEC reduction should be attenuated, but this is not always possible. Regular monitoring of AE can indicate a need to improve anthelmintic administration practices, and detect AR early in its progression. Careful interpretation of FEC reduction, however, taking into account possible confounders, is essential before attributing reduced FEC reduction to AR. Understanding of confounders of FEC reduction will complement advances in FECRT design and interpretation to provide measures of anthelmintic efficacy that are both rigorous and accessible.
