Ivermectin Plasma Concentration in Iberian Ibex (Capra pyrenaica) Following Oral Administration: A Pilot Study

Introduction

Iberian ibex (Capra pyrenaica) is a wild ungulate native to the mountain ranges of the Iberian Peninsula and has recently been reintroduced in the French side of the Pyrenees. This caprine currently enjoys a favorable conservation status (“least concern” according to the IUCN), which allows sustainable hunting as a valuable game species. Besides its biological and ecological value, ibex trophy hunting and the associated related tourism represent a significant source of revenue for remote and disadvantaged rural communities in Spain (1). As for the majority of large herbivores in Europe, the hunting quotas are established by public conservation agencies, based on the estimated population size, although hunting is banned in specific protected areas such as National Parks (2, 3).

Since the late eighties of the twentieth century, free-ranging Iberian ibex populations suffered from epidemic waves of sarcoptic mange, a contagious skin disease caused by the burrowing mite Sarcoptes scabiei. After the epidemics, mange has remained endemic in all the populations affected. Devastating demographic effects have been recorded in naïve herds, including mortality rates over 90% (4, 5). Sarcoptic mange is now considered the main driver of short to medium term population declines in this wild ruminant (6).

Control of sarcoptic mange epizootics in wildlife is challenging. Amongst other measures like non–intervention (laissez-faire), massive lethal control, and selective culling of clinically-affected animals (7), individual and mass treatments with acaricides have been proposed and empirically implemented at local scale with unknown success (8). However, beyond ethical considerations, treating free-ranging wildlife has disadvantages, such as the impracticability of drug administration on a large population scale, and the potential environmental contamination with drug residues (9, 10). In Spain, the lack of shared protocols among regions to tackle the population decline caused by sarcoptic mange in exposed wild ruminants has promoted the empirical use of acaricides massively administered through medicated mixture feed (6). Nevertheless, no studies support the actual effectiveness of this common practice. In fact, essential gaps in knowledge need to be filled before considering oral mass treatments as a possible control measure for the management of sarcoptic mange in free-ranging Iberian ibex and other susceptible wild ruminants (11, 12). Among the knowledge gaps to fill before implementing any in-field treatment, the pharmacokinetics of orally-administered candidate acaricides in the target hosts are crucial. Pharmacokinetic is the keystone to establish effective drugs, dosages, vehicles, frequency of administration, number of feeding points according to surface area and population, and uptake rates of medicated feed that should be reached in order to obtain a mass effect limiting the impact of the disease under field conditions. Difficulties in recruiting, maintaining and repeatedly handling Iberian ibexes have, so far, understandably limited the necessary trials.

In captive wild ruminants, the macrocyclic lactone ivermectin (IVM) has been used against S. scabiei infection at dose rates of 200–400 μg/kg, and repeated subcutaneous administrations were necessary to eliminate severe clinical signs (8). Oral administration has also been described in wild free-ranging animals (6, 8, 13); nevertheless, the plasma concentration in treated individuals, and the drug plasma therapeutic concentrations against sarcoptic mange were unknown, as well as the proportion of individuals having access to medicated feed. In domestic ruminants, interspecies and intra-species variability in IVM pharmacokinetics has been observed. In domestic goat, a greater plasma clearance of IVM leads to lower plasma concentrations than in cattle and sheep, regardless of the route of drug administration (14). After oral administration, IVM bioavailability is about four times greater and plasma concentrations can be detected longer in sheep than in goats (15). Moreover, IVM pharmacokinetics may depend on sex and age, and the presence of rumen digesta significantly influences the systemic availability of the drug (16).

The main findings related to domestic ruminants and the paucity of data concerning wild species recommend caution when extrapolating treatment protocols (e.g., dose and formulation) from one species to another and, as a consequence, extended pharmacokinetic data in target animal species are much-needed to avoid drug misuse. Therefore, the aim of the present experimental study is to begin filling the existing knowledge gaps by exploring, for the first time, the pharmacokinetic profile of a single oral dose of IVM in Iberian ibexes.

Materials and Methods

Animals

Nine adult healthy Iberian ibexes (seven males and two females, age ranging 1–5 years) were captured in Sierra Nevada Natural Space as part of the regular management of the species and transferred to the “Iberian ibex stock reservoir El Toril”, in Dílar, Granada (37°02′-7°03′N, 3°22′-3°33′W), southern Spain (17). The ibexes were kept isolated from the rest of the reservoir ibex population during all the study period. Average weight was 19 kg for females and 26 kg for males. The study was approved by the Ethics on Animal Welfare Committee of the University of Jaén and authorized by the Dirección General de Producción Agrícola y Ganadera of the Consejería de Agricultura, Pesca y Medio Ambiente of the Junta de Andalucía (Ref: SA/SIS/MD/ps/October 25, 2012). The Sierra Nevada National and Natural Park Administration also approved this study.

Pharmacotherapy and Blood Sample Collection

After an acclimation period of at least 1 month in the experimental facilities, an ad hoc formulated bolus containing 0.5 mg of IVM per kg of body weight was orally administered to each ibex. For this, specialized wildlife operators physically immobilized, blindfolded, and administered the boluses to the ibexes using commercial applicators. Blood samples (20 ml) were collected from the jugular vein into heparin-coated vacutainers just prior to drug administration (time 0) and 1 (T1), 2 (T2), 3 (T3), 4 (T4), 7 (T5), 10 (T6), 15 (T7), and 45 (T8) days after the bolus administration (dpa). Plasma was obtained immediately after the blood collection by centrifugation at 2,000 g for 20 mins and stored in 2 ml containers at −80°C until analyzed.

Chemical Extraction, Derivatization and HPLC With Fluorescence Detection

IVM was analyzed in the plasma samples by high performance liquid chromatography (HPLC) with automated solid phase extraction and fluorescence detection following a validated method previously described (18). Briefly, 1 ml plasma aliquot was mixed with 5 ng internal standard abamectin and vortexed. The solution was mixed with 1 ml acetonitrile/water solution (4:1) for 30 mins and then centrifuged at 17,000 g at room temperature for 5 mins. The resultant supernatant was applied at 10 mg/ml to a cartridge (Strata-X 33 μm Polymeric Reversed Phase, Phenomenex, Torrance, CA, US), previously activated with 1 ml methanol and 1 ml of water. Elution was performed with 1.3 ml methanol. The dried residue was dissolved in 100 μl N-methylmidazole solution in acetonitrile (1:2) and derivatized with 150 μl trifluoroacetic anhydride solution in acetonitrile (1:3).

A 100-μl aliquot of the derivatized samples was injected into the chromatograph. The mobile phase consisted of acetic acid 0.2% in water/methanol/acetonitrile (10:40:50) pumped at a flow rate of 1.4 ml/min through a column (Gemini C18, 150 x 4.6 mm, Phenomenex) with fluorescence detection. Fluorescence detection (RF 2000 Fluorescence Detector, Dionex) was performed at 365 nm excitation and 475 nm emission wavelength. Recovery rate was calculated for each sample through internal standard recovery correction.

Data Analysis

A Linear Mixed Model (LMM with a normal error distribution and identity link function) was fitted to explore the pharmacokinetics of plasma IVM concentrations (ng/ml, log-transformed) in the study ibexes. Time since drug administration was included as fixed factors whereas ibex identity as a random intercept term in the LMM (19). For the mixed models we used the library lme4 1.1-15 version (19), whereas the library MuMIn 1.43.6 version (20) was employed to assess the marginal and conditional contribution of the fixed and random terms (21). All the statistical analysis were performed with R Statistical Software 4.1.0 version (22).

Results

The limit of quantification was 0.2 ng/ml. Although IVM was detected in plasma from dpa 1 to dpa 45, mean plasma IVM concentration dropped from the initial 3.40 ng/ml in dpa 1 to 0.63 ng/ml in dpa 4 (Figure 1A), and stabilized thereafter around 0.25 ng/ml. This temporal decrease (β = −0.4, SE = 0.04, t = −11.11, p-value < 0.01) explained 61% of the plasma IVM concentration variability in the ibexes of the study. Moreover, the individual contribution to the observed patterns was 8% (Figure 1B).

FIGURE 1

Figure 1. (A) Time trend of the mean plasma ivermectin concentration (ng/ml) in the nine Iberian ibexes orally administered with ivermectin from 1 (T1) to 45 (T8) days post-administration; (B) Differences among individual ibexes in the decrease of plasma ivermectin concentration throughout the study period.

The pharmacokinetic values of orally-administered IVM in the Iberian ibexes are reported in Table 1. No adverse response was observed throughout the study.

TABLE 1

Table 1. Ivermectin pharmacokinetic values in plasma of the experimental Iberian ibexes after the oral administration of a 0.5 mg/kg dose.

Discussion

To the best of our knowledge, this is the first study investigating the pharmacokinetic profile of orally administered IVM in Iberian ibex and in any wild ruminant species. The controlled conditions of the experiment will allow the use of the results as reference for future experimental scenarios and/or field studies. Sarcoptic mange has been pharmacologically treated in captive wildlife, and some experiences in free-ranging wildlife populations have also been carried out, mostly empirically (8, 10, 23).

However, the complete eradication of mange from a population in endemic areas through pharmacological control strategies has been never achieved and so far deemed as unrealistic or inconclusive (10).

Literature is poorly informative on the efficacy of different doses of orally administered macrocyclic lactones for the treatment of sarcoptic mange in wild ruminants (8). Hence, the IVM dose in this study (0.5 mg/kg) must be intended as an empiric trade-off between a limited number of relevant sources. Amongst them, Yeruham and colleagues (24) successfully treated five ruminant species affected by sarcoptic mange in zoo gardens, including the Nubian ibex (Capra nubiana), a close relative of the Iberian ibex. Their protocol provided for the administration of an oral dose of 0.2 mg/kg of IVM for three consecutive days repeated three times at 2 week intervals. This protocol is clearly unfit for mass use under free-ranging conditions, since regular access of target wildlife to medicated feed is far from being guaranteed; nevertheless, the results are encouraging with respect to possible oral treatment options in Sarcoptes-exposed wild ruminants. Moreover, Leon-Vizcaino and colleagues (25) showed that 0.4 mg/kg of subcutaneously administered IVM were preferable to 0.2 mg/kg for the treatment of spontaneously infested Iberian ibex, and Foreyt (26) reported the successful in-feed use of IVM for 7 consecutive days at the dose of 1 mg/kg for the treatment of Rocky Mountain bighorns (Ovis canadensis) experimentally infested with Psoroptes mites. The 0.5 mg/kg IVM dose in our study took into account the above findings, the lower antiparasitic efficacy of oral IVM when administered at the same dosage recommended via subcutaneous inoculation (27) and, prospectively, the individual variability in medicated food intake by free-ranging wild ruminants.

This study revealed that IVM plasma concentrations in orally-treated Iberian ibexes drop drastically within four dpa. Not surprisingly, the oral route leads to lower IVM plasma concentrations compared to those reached after a subcutaneous administration (28), likely due to the binding to the particulate phase of digesta (14, 29). Moreover, the binding of IVM to plasma albumin and lipoproteins should be taken into account especially in animals with chronic stages of sarcoptic mange usually showing emaciation and poor body condition, in which a decrease in plasma proteins (thus a higher free fraction of IVM in the plasma), might be more likely associated to an unsuccessful treatment (14).

The maximum drug concentration and bioavailability found in Iberian ibex (3.40 ± ng/ml) were lower than those described in goats (6.03 ± 0.95; 15.85 ± 5.29 ng/ml, respectively) after the oral administration of an IVM dose of 0.2 mg/kg (30, 31). By contrast, the time to maximum concentration (1 day) was consistent with previous reports of oral administration in other medium-sized ruminants, sheep (1.7 day), goat (2.8 days), and reindeer (2 days for oral mixture, 1 day for oral paste) (15, 18, 28). By comparing two different oral formulations in reindeer, Oksanen et al. (28) found a lower relative plasma availability for a paste than for an oral liquid drench formulation, which could also partially explain the lower values observed in this study. The solid bolus formulation used in this study does not appear in previous similar trials, but we deemed it: i) better representative, than a liquid drench, of the medicated pellet administration that is already empirically used in Iberian ibex (32); ii) better suited to provide an accurate and precise IVM dosing than medicated pellets.

Several factors known to influence drug absorption and bioavailability may explain the interindividual variability in IVM plasma concentrations, observed in particular at T1-T4 (33). Nevertheless, as anticipated, the variability could be even greater under field conditions (e.g., mass-delivery treatment schemes with delivery of medicated feed), thus the variability in the IVM plasma concentrations reached should likely be greater due to inter-individual variability in medicated food intake, with unpredictable consequences on IVM efficacy. The antiparasitic action of macrocyclic lactones is related to their plasma concentrations, and more specifically to the bioavailability (34). On the other hand, due to its high lipophilic nature, IVM is widely distributed within the body in all species, with highest concentrations achieved in liver and adipose tissue, where it tends to accumulate (14). This might explain the rapid drop of IVM observed in the plasma of Iberian ibexes in this study, as well as the long MRT (30.8), pointing to a possible quick deposit in other tissues. Interestingly, it has been experimentally observed that IVM is detectable in the skin of scabietic pigs for at least 10 days after a single oral administration of 0.2 mg/kg (35).

Therapeutic or effective threshold for IVM plasma concentrations against sarcoptic mange has not been defined in any ruminant model. In cattle, the minimum IVM blood concentration for anthelmintic activity against nematodes ranges from 0.5 to 1 ng/ml (36). By contrast, a higher therapeutic threshold level (8 ng/ml) has been suggested after a subcutaneous injection of 0.6 mg/kg long-acting IVM against common bovine ticks (Boophilus spp) (37), showing that therapeutic blood levels may depend, among others, on the animal species and related metabolism, as well as the target parasite. Moreover, the therapeutic efficacy and the associated threshold of IVM plasma concentrations may vary depending on the severity of sarcoptic mange, with the most affected individuals being less responsive to the therapeutic effect, thus requiring a higher dosage to eliminate the mite and heal (30), as shown in other animal species (31).

The efficacy of IVM plasma concentrations against S. scabiei in Iberian ibex and other wild ungulate species should be further investigated, also considering that underdosing is a recognized driver for the development of resistance to endo and ectoparasiticides (8, 10, 38, 39). At present, resistance of S. scabiei against IVM has been described both, in vitro and in vivo, limited to human model (40, 41). In the particular case of sustained oral administration of IVM to free-ranging Iberian ibexes, resistance to the drug could be also developed by generalist nematodes of the digestive tract, eg the blood-feeding Haemonchus contortus, that may be cross-transmitted with sympatric sheep and goats (32, 42). This could result in negative herd health management issues at the wildlife/livestock interface (23).

Some limitations of the present study include the relatively low number of dosed individuals and the absence of time points within the first 24 h post treatment, which would have provided more precise information concerning IVM absorption rate and plasma maximum concentrations.

The pharmacological treatment of sarcoptic mange in wildlife is a complex and controversial management measure, with absence or paucity of protocols regarding dosage, administration times, density of medicated baits per surface or animal population unit, and a lack of knowledge on the pharmacokinetics of macrocyclic lactones in most wildlife species, on the chances for resistance to appear due to underdosage and on the potential environmental consequences of the massive release of antiparasitic drugs in the environment (8, 10, 43–45). In Iberian ibex, traditional management has mostly relied in decreasing host density and/or the selective culling of affected individuals (7, 46). However, short-term strategies including the non-selective mass administration of medicated feed to affected ibex populations has also been tried, with little or no effect on the disease prevalence and demographic impact (6, 47, 48). The rapid drop of plasma IVM concentration in Iberian ibex after a single oral dose found in this study, and the lack of published results on therapeutic trials with oral IVM in scabietic free-ranging individuals suggest caution in promoting the mass delivery of IVM medicated pellets as a measure to efficiently control sarcoptic mange at the individual and population level in this wild caprine. The epidemiological effects of partially ineffective treatment strategies could even be opposite, by lengthening the infective stage of the individuals affected by sarcoptic mange and therefore increasing the dissemination and spread of the disease (25), potentially to other mammal species too (12, 49). Moreover, aspects such as the proportion of the target population actually receiving the treatment, the access to the drug by non-target species, and the environmental effects of the massive release of IVM in the environment, are still in need to be thoroughly investigated and controlled (8, 10). A major concern is that IVM and its metabolites are mainly eliminated in the feces of treated individuals (50), with potential impact of the residues on the biology and reproduction of dung invertebrate fauna (45, 50).

In vitro and in vivo studies carried out with Sarcoptes mites var. suis showed that moxidectin concentration required to kill 50% of mites was lower than that of IVM, and that a single dose of moxidectin or fluralaner were more effective than two consecutive of IVM, suggesting that IVM should be soon replaced in the treatment approach for sarcoptic mange (35, 51, 52). New long-acting oral and topic isoxazolines are emerging as more efficient therapeutic options against sarcoptic mange, as suggested by recent experimental studies in both domestic animals and captive wildlife (52–54).

Nonetheless, and similarly to IVM, numerous gaps in knowledge must be addressed before the in-field use of these alternative drugs may be considered a valid option (10). Recently, Mounsey et al. (55) highlighted the precarious balance between dosage, route of administration, ecotoxicity, drug resistance and efficacy of macrocyclic lactones in the Australian wombats (Vombatus ursinus and Lasiorhinus latifrons), two highly susceptible wildlife species to sarcoptic mange, suggesting that a better cooperation and a continuous debate between stakeholders, including veterinarians, wildlife carers and researchers, should be encouraged to achieve best treatment options for wildlife.

There is therefore a need to further investigate the pharmacokinetics, pharmacodynamics, population target and environmental consequences of the administration of available macrocyclic lactones, isoxazolines and other candidate molecules, including long-acting formulations, before their in-field delivery become a management option to control sarcoptic mange in free-ranging wild ruminants.

Data Availability Statement

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

Ethics Statement

This study complied with all Andalusian, Spanish, and European legal requirements and guidelines regarding experimentation and animal welfare. Handling procedures and sampling frequency were designed to reduce stress and minimize the impact on the health of the subjects, as per European (2010/63/UE) and Spanish (R.D 53/2013) standards. The study was approved by the Ethics on Animal Welfare Committee of the University of Jaén and authorized by the Dirección General de Producción Agrícola y Ganadera of the Consejería de Agricultura, Pesca y Medio Ambiente of the Junta de Andalucía (Ref: SA/SIS/MD/ps/ October 25, 2012). The Sierra Nevada Natural Park staff also approved this study.

Author Contributions

BM, JG, JL-O, JE, AR, GM, PF, LR, MV, ES, BR, and RO conceptualized the project and agreed on the study design. RO prepared the IVM bolus. JG, JE, AR, and BR performed the IVM treatment and obtained blood samples from the ibexes. BM, GG, MP, and MR performed the laboratory analysis and elaborated the results. ES performed the statistical analysis. BM drafted the original manuscript. JG, JL-O, JE, AR, GM, PF, LR, MV, ES, BR, and RO contributed in shaping and revising the manuscript. All the authors have read and agreed to the final version of the manuscript.

Funding

This project was funded by the Consejería de Medio Ambiente de la Junta de Andalucía (project 173/2009/M/00; 03/15/M/00; 861_11_M_00 and 2016/00014/M), and by the Spanish Ministerio de Economía y Competitividad (projects CGL2012-40043-C02-01, CGL2012-40043-C02-02, and CGL2016-80543-P). The authors' research activities are partially supported by the Plan Andaluz de Investigación (RNM-118 group). MV is supported by a FI-GENCAT Fellowship (2020_FI_B2_00049, co-financiated by Agència de Gestió d'Ajuts Universitaris i de Recerca and European Social Fund) and ES by the Spanish Ministerio de Ciencia Innovación y Universidades (MICINN) through a Ramon y Cajal agreement (RYC-2016-21120). GM is a Serra Húnter Fellow.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Acknowledgments

We are grateful to all the people involved in the experiment. Special thanks goes also to the park wardens and fieldworkers in the SNNS and, in particular, to José López, Isidro Puga, Apolo Sánchez, and Antonio Rodríguez for their professional and personal involvement in the study.

Abbreviations

IVM, ivermectin; HPLC, high pressure liquid chromatography.

References

1. Pérez JM, Granados JE, Soriguer RC, Fandos P, Márquez FJ, Crampe JP. Distribution, status and conservation problems of the Spanish Ibex, Capra pyrenaica (Mammalia: Artiodactyla). Mamm Rev. (2002) 32:26–39. doi: 10.1046/j.1365-2907.2002.00097.x

CrossRef Full Text | Google Scholar

2. Foose TJ, Ballou JD. Population management: theory and practice: Management of small populations. Int Zoo Yb. (1988) 27:26–41. Available online at: https://repository.si.edu/bitstream/handle/10088/4040/Foose1988.pdf?sequence=1

Google Scholar

3. Granados JE, Pérez JM, Marquez FJ, Serrano E, Soriguer RC, Fandos YP. La cabra montés (Capra pyrenaica, SCHINZ 1838). (2001). 1:3–37.

Google Scholar

4. León-Vizcaíno L, Ruíz de Ybáñez MR, Cubero MJ, Ortíz JM, Espinosa J, Pérez L, et al. Sarcoptic mange in Spanish ibex from Spain. J Wildl Dis [Internet]. (1999) 35:647–59. doi: 10.7589/0090-3558-35.4.647

PubMed Abstract | CrossRef Full Text | Google Scholar

5. París FP. La cabra montés (Capra pyrenaica) en el Parque Natural de las Sierras de Cazorla, Segura y Las Villas. Instituto Nacional para la Conservación de la Naturaleza. (1991) 91:257.

Google Scholar

6. Espinosa J, Pérez JM, Raéz–bravo A, Fandos P, Cano–manuel FJ, Soriguer RC, et al. Recommendations for the management of sarcoptic mange in free–ranging iberian ibex populations. Anim Biodivers Conserv. (2020) 43:137–49. doi: 10.32800/abc.2020.43.0137

CrossRef Full Text | Google Scholar

7. Wobeser G. Disease management strategies for wildlife. Rev Sci Tech Int des Epizoot. (2002) 21:159–78. doi: 10.20506/rst.21.1.1326

PubMed Abstract | CrossRef Full Text | Google Scholar

8. Rowe ML, Whiteley PL, Carver S. The treatment of sarcoptic mange in wildlife: a systematic review. Parasit Vectors [Internet]. (2019) 9:1–14. doi: 10.1186/s13071-019-3340-z

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Artois M, Blancou J, Dupeyroux O, Gilot-Fromont E. Sustainable control of zoonotic pathogens in wildlife: how to be fair to wild animals? OIE Rev Sci Tech [Internet]. (2011) 30:733–43. doi: 10.20506/rst.30.3.2069

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Moroni B, Valldeperes M, Serrano E, López-Olvera JR, Lavín S, Rossi L. Comment on: “the treatment of sarcoptic mange in wildlife: A systematic review.” Parasites and Vect. (2020). 13:1–4. doi: 10.1186/s13071-020-04347-0

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Moroni B, Angelone S, Pérez JM, Molinar Min AR, Pasquetti M, Tizzani P, et al. Sarcoptic mange in wild ruminants in Spain: solving the epidemiological enigma using microsatellite markers. Parasit Vectors [Internet]. (2021) 14:171. doi: 10.1186/s13071-021-04673-x

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Valldeperes M, Moroni B, Rossi L, López-Olvera JR, Velarde R, Molinar Min AR, et al. First report of interspecific transmission of sarcoptic mange from Iberian ibex to wild boar. Parasit Vectors [Internet]. (2021) 14:481. doi: 10.1186/s13071-021-04979-w

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Rajković-Janje R, Manojlović L, Gojmerac T. In-feed 0.6% ivermectin formulation for treatment of wild boar in the Moslavina hunting ground in Croatia. Eur J Wildl Res. (2004) 50:41–3. doi: 10.1007/s10344-003-0033-9

CrossRef Full Text | Google Scholar

14. González Canga A, Sahagún Prieto AM, José Diez Liébana M, Martínez NF, Vega MS, Vieitez JJG. The pharmacokinetics and metabolism of ivermectin in domestic animal species. Vet J [Internet]. (2009) 179:25–37. doi: 10.1016/j.tvjl.2007.07.011

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Cerkvenik V, Grabnar I, Skubic V, Doganoc DZ, Beek WMJ, Keukens HJ, et al. Ivermectin pharmacokinetics in lactating sheep. Vet J. (2002) 104:175–85. doi: 10.1016/S0304-4017(01)00612-4

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Steel JW. Pharmacokinetics and metabolism of avermectins in livestock. Vet Parasitol. (1993) 48:45–57. doi: 10.1016/0304-4017(93)90143-B

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Espinosa J, López-olvera JR, Cano-manuel FJ, Fandos P, Pérez JM, López-graells C, et al. Guidelines for managing captive Iberian ibex herds for conservation purposes. J Nat Conserv [Internet]. (2017) 40(June):24–32. Available from: http://dx.doi.org/10.1016/j.jnc.2017.09.002 doi: 10.1016/j.jnc.2017.09.002

CrossRef Full Text | Google Scholar

18. Alvinerie M, Sutra J, Galtier P, Alvinerie M, Sutra J, Ivermectin PG. Ivermectin in goat plasma and milk after subcutaneous injection To cite this version : HAL Id : hal-00902156 Ivermectin in goat plasma and milk. (1993).

Google Scholar

19. Bates D, Mächler M, Bolker B, Walker SC. Fitting linear mixed-effects models using lme4. arXiv [Preprint]. (2014). arXiv:1406.5823. Available online at: https://arxiv.org/pdf/1406.5823.pdf

Google Scholar

20. Barton K. MuMIn multi-model inference, R package version 0.12. 0. (2009). Available online at: https://r-forge.r-project.org/projects/mumin/

Google Scholar

21. Nakagawa S, Schielzeth H. A general and simple method for obtaining R 2 from generalized linear mixed-effects models. Jama. (2013) 2:133–42. doi: 10.1111/j.2041-210x.2012.00261.x

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Team RC. R: A Language and Environment for Statistical Computing. (2013).

Google Scholar

23. Rossi L, Tizzani P, Rambozzi L, Moroni B, Meneguz PG. Sanitary emergencies at the wild/domestic caprines interface in Europe. Animals. MDPI AG;. (2019) 9:922. doi: 10.3390/ani9110922

PubMed Abstract | CrossRef Full Text | Google Scholar

24. Yeruham I, Rosen S, Hadani A, Nyska A. Sarcoptic mange in wild ruminants in zoological gardens in Israel. J Wildl Dis. (1996) 32:57–61. doi: 10.7589/0090-3558-32.1.57

PubMed Abstract | CrossRef Full Text | Google Scholar

25. León-Vizcaíno L, Cubero MJ, González-Capitel E, Simón MA, Pérez L, Ruiz De Ybáñez MR, et al. Experimental ivermectin treatment of sarcoptic mange and establishment of a mange-free population of Spanish ibex. J Wildl Dis. (2001) 37:775–85. doi: 10.7589/0090-3558-37.4.775

PubMed Abstract | CrossRef Full Text | Google Scholar

26. Foreyt WJ. Efficacy of in-feed formulation ivermectin against Psoroptes sp. in bighorn sheep. J Wildl Dis. (1993) 29:85–9. doi: 10.7589/0090-3558-29.1.85

PubMed Abstract | CrossRef Full Text | Google Scholar

27. Oksanen A, Nieminen M, Soveri T. A comparison of topical, subcutaneous and oral administrations of ivermectin to reindeer. Vet Rec. (1993) 133:312–4. doi: 10.1136/vr.133.13.312

PubMed Abstract | CrossRef Full Text | Google Scholar

28. Oksanen A, Åsbakk K, Raekallio M, Nieminen M. The relative plasma availabilities of ivermectin in reindeer (Rangifer tarandus tarandus) following subcutaneous and two different oral formulation applications. Acta Vet Scand [Internet]. (2014) 56:76. doi: 10.1186/s13028-014-0076-9

PubMed Abstract | CrossRef Full Text | Google Scholar

29. Mestorino N, Turic E, Pesoa J, Echeverr\'\ia J, Errecalde JO. Pharmacokinetics in plasma of ivermectin after its oral (solution and tablets) administration to sheep. J Vet Pharmacol Ther. (2003) 26:307–9. doi: 10.1046/j.1365-2885.2003.00485.x

PubMed Abstract | CrossRef Full Text | Google Scholar

30. Lespine A, Alvinerie M, Pors I, Chartier C. Influence of the route of administration on efficacy and tissue distribution of ivermectin in goat. (2005) 128:251–60. doi: 10.1016/j.vetpar.2004.11.028

PubMed Abstract | CrossRef Full Text | Google Scholar

31. Scott EW, Kinabo LD, McKellar QA. Pharmacokinetics of ivermectin after oral or percutaneous administration to adult milking goats. J Vet Pharmacol Ther. (1990) 13:432–5. doi: 10.1111/j.1365-2885.1990.tb00800.x

PubMed Abstract | CrossRef Full Text | Google Scholar

32. Lavin S, Marco I, Rossi L, Meneguz PG, Viñas L. Haemonchosis in Spanish ibex. J Wildl Dis. (1997) 33:656–9. doi: 10.7589/0090-3558-33.3.656

PubMed Abstract | CrossRef Full Text | Google Scholar

33. Hoener B, Benet LZ. “Factors influencing drug absorption and drug availability,” In: Modern Pharmaceutics. Londno: CRC Press (2002) p. 166–207.

Google Scholar

34. C. Campbell W. History of avermectin and ivermectin, with notes on the history of other macrocyclic lactone antiparasitic agents. Curr Pharm Biotechnol. (2012) 13:853–65. doi: 10.2174/138920112800399095

PubMed Abstract | CrossRef Full Text | Google Scholar

35. Bernigaud C, Fang F, Fischer K, Lespine A, Aho S, Dreau D, et al. Preclinical study of single-dose moxidectin, a new oral treatment for scabies : efficacy, safety, and pharmacokinetics compared to two-dose ivermectin in a porcine model. Jama. (2016) 16:1–18. doi: 10.1371/journal.pntd.0005030

PubMed Abstract | CrossRef Full Text | Google Scholar

36. Lifschitz A, Virkel G, Sallovitz J, Sutra JF, Galtier P, Alvinerie M, et al. Comparative distribution of ivermectin and doramectin to parasite location tissues in cattle. Vet Parasitol. (2000) 87:327–38. doi: 10.1016/S0304-4017(99)00175-2

PubMed Abstract | CrossRef Full Text | Google Scholar

37. Davey RB, Pound JM, Miller JA, Klavons JA. Therapeutic and persistent efficacy of a long-acting (LA) formulation of ivermectin against Rhipicephalus (Boophilus) microplus (Acari: Ixodidae) and sera concentration through time in treated cattle. Vet Parasitol [Internet]. (2010) 169(1–2):149–56. Adoi: 10.1016/j.vetpar.2009.12.040

PubMed Abstract | CrossRef Full Text | Google Scholar

38. Jokelainen P, Moroni B, Hoberg E, Oksanen A, Laaksonen S. “Gastrointestinal parasites in reindeer (Rangifer tarandus tarandus): A review focusing on Fennoscandia,” In: Veterinary Parasitology: Regional Studies and Reports. London: Elsevier. (2019).

PubMed Abstract | Google Scholar

39. Jokelainen P, Moroni B, Hoberg E, Oksanen A, Laaksonen S. Gastrointestinal parasites in reindeer (Rangifer tarandus tarandus) calves from fennoscandia: an epidemiological study. Vet Parasitol Reg Stud Reports. (2019) 16:1277. doi: 10.1016/j.vprsr.2019.100277

PubMed Abstract | CrossRef Full Text | Google Scholar

40. Currie BJ, Harumal P, McKinnon M, Walton SF. First documentation of in vivo and in vitro ivermectin resistance in Sarcoptes scabiei. Clin Infect Dis. (2004) 39:e8–12. doi: 10.1086/421776

PubMed Abstract | CrossRef Full Text | Google Scholar

41. Mounsey KE, Holt DC, McCarthy JS, Currie BJ, Walton SF. Longitudinal evidence of increasing in vitro tolerance of scabies mites to ivermectin in scabies-endemic communities. Arch Dermatol. (2009) 145:840–1. doi: 10.1001/archdermatol.2009.125

PubMed Abstract | CrossRef Full Text | Google Scholar

42. Cardoso B, Pessoa B, Figueiredo P, Rinaldi L, Cringoli G, D\'\iaz A, et al. Comparative survey of gastrointestinal parasites in sympatric Iberian ibex (Capra pyrenaica) and domestic goats using molecular host specific identification. Parasitol Res. (2021) 120:2291–6. doi: 10.1007/s00436-021-07174-z

PubMed Abstract | CrossRef Full Text | Google Scholar

43. Römbke J, Krogh KA, Moser T, Scheffczyk A, Liebig M. Effects of the veterinary pharmaceutical ivermectin on soil invertebrates in laboratory tests. Arch Environ Contam Toxicol. (2010) 58:332–40. doi: 10.1007/s00244-009-9414-8

PubMed Abstract | CrossRef Full Text | Google Scholar

44. Vokrál I, Michaela Š, Radka P, Jirí L, Lukáš P, Dominika S, et al. Ivermectin environmental impact: Excretion profile in sheep and phytotoxic effect in Sinapis alba. Ecotoxicol Environ Saf. (2019) 169(November 2018):944–9. doi: 10.1016/j.ecoenv.2018.11.097

PubMed Abstract | CrossRef Full Text | Google Scholar

45. Iglesias LE, Saumell CA, Fernández AS, Fusé LA, Lifschitz AL, Rodríguez EM, et al. Environmental impact of ivermectin excreted by cattle treated in autumn on dung fauna and degradation of faeces on pasture. Parasitol Res [Internet]. (2006) 100:93–102. doi: 10.1007/s00436-006-0240-x

PubMed Abstract | CrossRef Full Text | Google Scholar

46. Valldeperes M, Granados JE, Pérez JM, Castro I, Bravo AR, Fandos P, et al. How sensitive and specific is the visual diagnosis of sarcoptic mange in free - ranging Iberian ibexes? Parasit Vectors [Internet]. (2019) 21:1–7. doi: 10.1186/s13071-019-3665-7

PubMed Abstract | CrossRef Full Text | Google Scholar

47. Pérez JM, Giuseppe P, Dipartimento M, Torino U, Paolo L. Biology and management of sarcoptic mange in wild Caprinae populations. (2021) 51:82–94. doi: 10.1111/mam.12213

CrossRef Full Text | Google Scholar

48. Sánchez-Isarria MA, Hermoso J, Theureau de la Peña J, Casanova G, Burgui JM, Sanchis G, et al. La ivermectina como tratamiento de la sarna sarcóptica en el medio natural: vìas de aplicación. In: Granados JE, Cano-Manuel FJ, Fandos P, Cadenas R, editors. Tendencias actuales en el estudio y conservación de los Caprinos Europeos. Granada: Junta de Andalucía (2008). p. 269–76.

Google Scholar

49. Moroni B, Rossi L, Bernigaud C, Guillot J. Zoonotic Episodes of Scabies: A Global Overview. Pathogens. (2022) 11(213). doi: 10.3390/pathogens11020213

PubMed Abstract | CrossRef Full Text | Google Scholar

50. Mancini L, Lacchetti I, Chiudioni F, Cristiano W, Di Domenico K, Marcheggiani S, et al. Need for a sustainable use of medicinal products: the impacts on the environment of ivermectin. Ann Ist Super Sanita. (2020) 56:492−6. doi: 10.4415/ANN_20_04_12

PubMed Abstract | CrossRef Full Text | Google Scholar

51. Mounsey KE, Walton SF, Innes A, Cash-Deans S, McCarthy JS. In vitro efficacy of moxidectin versus ivermectin against Sarcoptes scabiei. Antimicrob Agents Chemother. (2017) 61:8. doi: 10.1128/AAC.00381-17

PubMed Abstract | CrossRef Full Text | Google Scholar

52. Bernigaud C, Fang F, Fischer K, Lespine A, Aho LS, Mullins AJ, et al. Efficacy and pharmacokinetics evaluation of a single oral dose of afoxolaner against sarcoptes scabiei in the porcine scabies model for human infestation. Antimicrob Agents Chemother. (2018) 62:1–12. doi: 10.1128/AAC.02334-17

PubMed Abstract | CrossRef Full Text | Google Scholar

53. Wilkinson V, Takano K, Nichols D, Martin A, Holme R, Phalen D, et al. Fluralaner as a novel treatment for sarcoptic mange in the bare-nosed wombat (Vombatus ursinus): safety, pharmacokinetics, efficacy and practicable use. Parasit Vectors [Internet]. (2021) 14:18. doi: 10.1186/s13071-021-04658-w

PubMed Abstract | CrossRef Full Text | Google Scholar

54. Smith JS, Berger DJ, Hoff SE, Jesudoss Chelladurai JRJ, Martin KA, Brewer MT. Afoxolaner as a treatment for a novel sarcoptes scabiei infestation in a juvenile potbelly pig. Front Vet Sci. (2020) 7:1–6. doi: 10.3389/fvets.2020.00473

PubMed Abstract | CrossRef Full Text | Google Scholar

55. Mounsey K, Harvey RJ, Wilkinson V, Takano K, Old J, Stannard H, et al. Drug dose and animal welfare: important considerations in the treatment of wildlife. Parasitol Res [Internet]. (2022) 21:20. doi: 10.1007/s00436-022-07472-0

PubMed Abstract | CrossRef Full Text | Google Scholar