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Prospects for Moxidectin as a New Oral Treatment for Human Scabies

  • Kate E. Mounsey ,

    kmounsey@usc.edu.au

    Affiliations Inflammation & Healing Research Cluster, School of Health and Sport Sciences, University of the Sunshine Coast, Maroochydore, Queensland, Australia, Infectious Diseases & Immunology Division, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia

  • Charlotte Bernigaud,

    Affiliation Dermatology Department, Henri Mondor Hospital, AP-HP, UPEC, Créteil, France

  • Olivier Chosidow,

    Affiliations Dermatology Department, Henri Mondor Hospital, AP-HP, UPEC, Créteil, France, Université Paris-est Créteil Val de Marne, Créteil, France

  • James S. McCarthy

    Affiliations Infectious Diseases & Immunology Division, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia, School of Medicine, University of Queensland, Herston, Queensland, Australia

Prospects for Moxidectin as a New Oral Treatment for Human Scabies

  • Kate E. Mounsey, 
  • Charlotte Bernigaud, 
  • Olivier Chosidow, 
  • James S. McCarthy
PLOS
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Scabies: An Underappreciated Global Health Problem

The recent addition of scabies to the World Health Organization’s list of neglected tropical diseases (NTDs) represents an important milestone in the understanding of the burden of disease that this infection imposes [1]. Finally, this most neglected of the neglected diseases may start to get the attention it deserves among global health policy makers and donors. It may also facilitate progress towards a sustainable approach to scabies control worldwide, as previously articulated by Engelman and colleagues [2].

In the 2010 Global Burden of Disease (GBD) study, scabies was among the 50 most common infectious diseases worldwide, with a point prevalence of around 100 million [3], although the precision of this estimate is hard to gauge because of a lack of quality prevalence studies [4]. In terms of morbidity, at 1.5 million disability-adjusted life years, scabies ranks higher than several other important NTDs, including dengue (0.83 million), onchocerciasis (0.43 million), and trypanosomiasis (0.56 million) [5]. It should be emphasised that this figure relates to the impact of scabies alone, with direct effects including itch, subsequent loss of sleep, school and work absences, and psychological distress. If one also considers the complications of scabies, including bacterial skin infection, post-streptococcal glomerulonephritis, and, potentially, rheumatic fever [2], the true global health burden attributed to this tiny ectoparasitic mite is much larger [4]. While frequently associated with poverty and overcrowding, scabies epidemics also remain problematic in developed countries. Why, then, does scabies continue to be relegated to the “nuisance” category, when other diseases attract considerably more research effort and funding?

Inadequacy of Current Treatments for Scabies

The limited treatment options currently available for scabies are inadequate to tackle this global problem. Alternative approaches, such as immunotherapy [6], vaccination [7], or directly targeting mite molecules [8], have been proposed, but given the low research base and lack of interest from pharmaceutical companies, prospects for new drug development are dim. Acaricides that should be of historical interest, such as precipitated sulfur (messy and malodorous) and benzyl benzoate (highly irritating), remain the only affordable option in many developing countries [9]. 5% permethrin is safe and well tolerated, but prohibitively expensive in many countries—in the United States, a single application costs in excess of US$50. Furthermore, despite being deemed the most effective treatment for scabies in systematic reviews [10], clinical trial outcomes may not necessarily translate to the community, where poor adherence with topical regimens is a key determinant of scabies treatment failure. Although there are no publications confirming permethrin resistance in human scabies, anecdotal reports are increasingly common, and a laboratory population of Sarcoptes scabiei var. canis is highly resistant [11]. While permethrin treatment is relatively straightforward (apply the cream from head to toe, leave for at least 8 hours, and rinse off), this is impractical for community mass drug administration (MDA), and indeed, recent studies show limited sustainability of interventions in which treatment was not directly observed [12]. A qualitative study revealed barriers to appropriate use in scabies-endemic communities in northern Australia, including a lack of privacy to undertake whole-body application, insufficient facilities to rinse the cream off, and discomfort using the cream in tropical environments [13]. Similar sentiments regarding cumbersome application have been echoed by health practitioners in aged care facilities, in addition to the reluctance with administering full-body applications to mentally or physically disabled patients [14].

Oral Ivermectin for Scabies

These issues with topical treatment adherence meant that the addition of oral ivermectin to the scabies arsenal in the mid-1990s was greeted with optimism [15]. Twenty years later, uptake of ivermectin for scabies has been relatively slow, with the primary indication being for institutional scabies outbreaks and for the treatment of severe crusted scabies, for which it has been mainly used off-label. Ivermectin is available at relatively low cost or has been provided free or heavily subsidized by manufacturers for use in large control programmes. For the treatment of ordinary scabies, it is only licenced in a few countries; in Australia and New Zealand, it is only registered as a second-line treatment where failure with topical creams has been observed, and in France, it is used as a single administration [16]. Meta-analyses [10] have shown that single-dose oral ivermectin is inferior to single-dose permethrin, meaning that two doses are required for maximal efficacy. This likely relates to its short plasma half-life in humans, with no apparent residual activity against eggs that may hatch after application over the 14-day mite life cycle. This is not ideal for MDA, in which administration of a second dose that is separated by several days is logistically problematic [17]. Where two doses were given, follow-up was frequent, and community visitors were continuously screened and treated, ivermectin MDA was more successful [18]. Conversely, recent efforts in Australian indigenous communities with single-dose ivermectin failed to show sustained reductions in scabies prevalence [19].

A major limitation to the use of ivermectin for scabies is its incompletely documented safety profile in key groups. Although millions of doses have been administered for onchocerciasis, with few well-documented serious adverse effects outside Loa loa-endemic areas, there remain concerns regarding its safety in children weighing less than 15 kg and in pregnancy and breastfeeding, although no increased risk has been found in cases of inadvertent exposure in these groups [20,21]. Overwhelmingly, scabies is a disease of the very young. Surveys of clinic attendances in Australian Aboriginal communities show that most presentations occurred in the population under 2 years of age [22], with this age distribution supported by a recent systematic review of scabies prevalence globally [4]. Whereas most literature recommends against administering ivermectin to children under 15 kg (approx. 3 ½ years, according to WHO growth charts), the current Australian package and MDA protocols expand this to children under 5, regardless of weight, which excludes a very large portion of the population at risk for scabies. This, combined with the requirement for pregnancy testing or exclusion of potentially pregnant women, severely limits the utility of ivermectin in community MDAs, with these groups instead receiving conventional topical treatment and the compliance problems they bring, which may partially explain why recent outcomes have been less than desired. Notably, topical 0.5% ivermectin has been approved in the US for the treatment of head lice in infants over 6 months of age, although bioavailability is much lower than that of oral administration [23]. Oral doses of up to 0.4 mg/kg have been administered to children as young as 2 in head lice trials [24]. A 1% topical ivermectin treatment was also recently approved by the US Food and Drug Administration (FDA) for the treatment of rosacea (presumably with activity against Demodex mites) [25,26], which is not explicitly contraindicated in pregnancy or breastfeeding, but rather, treatment may be warranted if benefits to the mother are perceived to outweigh the risk [27].

Another lingering concern with ivermectin is documentation of treatment failure despite multiple doses and in vitro evidence of resistance [28]. This was supported by observations of increasing in vitro survival times over the course of ivermectin treatment, suggesting that selection for resistant mites could occur relatively quickly [29]. The consequence of this is that ivermectin monotherapy is not recommended for cases of crusted scabies, with concomitant therapy with a topical acaricide such as permethrin and keratolytic supplementation required [30]. Observations of resistance in scabies may have implications for the more widespread use of oral or topical ivermectin for head lice and rosacea [26,31]. For crusted scabies, it is possible that the emergence of resistance in these cases may relate to low drug penetration and suboptimal mite exposure in hyperkeratotic areas of skin. However, remarkably little research has been undertaken on the distribution and retention of ivermectin in human skin. In one study, considerable variation in skin ivermectin concentration was reported and related to sebum levels. The authors contended that this could be a factor in determining clinical efficacy for scabies [32]. Concerns have been raised regarding the possibility of reduced activity of ivermectin in patients with xerotic skin, such as the elderly, which may explain treatment failures despite multiple doses in elderly patients [33]. Notably, the dose selection of 200 μg/kg is largely based on its potent activity against nematodes at this concentration, and no formal dose-finding studies have been undertaken for scabies, with some studies reporting reduced efficacy (<70%) at concentrations below 200 μg/kg [3436], suggesting this dose may be around the minimum threshold of mite toxicity.

Looking at the prospects for scabies drug development, the target product profile for any new drug must be considered carefully. Of foremost importance is the preference for an oral treatment, ideally effective as a single dose for utility in the MDA setting. Moxidectin is a second-generation macrocyclic lactone, related to ivermectin but with critical pharmacokinetic differences. Currently under development as an alternative treatment for onchocerciasis, moxidectin also offers promise for human scabies. The significant advantage of moxidectin lies in its higher lipophilicity, leading to superior bioavailability (half-life >20 days versus 14 hours for ivermectin, [37]), and superior distribution and retention in tissue compared to ivermectin. When it comes to scabies, this factor could be a game changer—if the drug is retained at therapeutic concentrations in the skin through the 14-day scabies life cycle, a single-dose regimen may be possible.

New Hope with Moxidectin?

Moxidectin is well established in veterinary practice to treat a range of parasites, including sarcoptic mange. This provides a solid foundation for considering its potential translation to human scabies. Some studies show excellent efficacy as a single 0.2 mg/kg dose, with 100% cure at day 14 in cattle [38], whereas sheep required two 0.2 mg/kg doses to achieve cure [39,40], with a single dose reducing mites by 75%–92%. When higher concentrations (1 mg/kg) of a long-acting formulation were used, 100% efficacy was achieved in a single dose [41]. Importantly, both 0.2 mg/kg and 1 mg/kg single-doses prevented reinfection from untreated animals for 25 and 54 days, respectively [41,42]. Differences in observed clinical efficacy may relate to the severity of infestation or pharmacokinetic differences between different species. Differences are also evident between injectable, oral tablet, and liquid formulations, so determining this in human pharmacokinetic profiling, including skin levels, would be ideal, in addition to controlled dose-finding efficacy studies.

Another important consideration is any potential differences in toxicity between ivermectin and moxidectin in target parasites. It is well documented that certain species of arthropods have reduced sensitivity to moxidectin compared to ivermectin. For example, the Anopheles gambiae toxic dose for moxidectin is over 100-fold higher than ivermectin [43], indicating that it may be unsuitable for use as an adjunct malaria control agent. This is especially important given the aforementioned issues with distribution and retention of the drug in the skin at therapeutic concentrations for sufficient periods. Preliminary studies in a porcine model of scabies are encouraging in this respect, with a single 0.3 mg/kg dose of moxidectin achieving high clinical efficacy with prolonged retention in skin [44].

Moxidectin is currently under consideration for regulatory submission for the treatment of onchocerciasis in humans. If successful, this would facilitate its development for scabies and other indications for which a long-acting macrocyclic lactone may be more effective than ivermectin. Early dose-escalation studies demonstrated that moxidectin is well tolerated in a dose range of 3–36 mg (up to ~0.6 mg/kg) [45]. Such doses would likely attain skin levels in therapeutic range for scabies. Limited studies have been done in lactating women, with a relative infant dose of 8.7% via breast milk—higher than ivermectin, but arguably within levels considered safe [46]. Phase II and III studies with moxidectin have now been completed for onchocerciasis [47], with promising results in regards to both efficacy and safety compared to ivermectin. However, as these trials have been conducted at lower concentrations than what may be required for effective treatment of scabies, it would be appropriate to assess its bioavailability and skin concentrations over the course of the mite life cycle. Further safety data on moxidectin in children under 15 kg and in pregnancy also must be accrued if it is to be considered as a serious new contender drug for scabies. In vitro and animal studies are promising in this respect, as they suggest that moxidectin is a poorer substrate for P-glycoproteins than ivermectin, and high-dose moxidectin can be administered to P-glycoprotein–deficient, ivermectin-sensitive dogs, with little evidence of toxicity [37]. This suggests that the risk for central nervous system toxicity associated with blood–brain barrier underdevelopment may be reduced with moxidectin, particularly if mutations in the human MDR1A gene are suspected to be associated with ivermectin severe adverse events [48]. Although in studies of onchocerciasis moxidectin was associated with an increased proportion of mild or moderate Mazzotti reactions (pruitis, rash, decreased blood pressure) [47], presumably related to its more potent microfilaricidal activity, these did not preclude further trials, and there has only been one report of a Mazzotti-type reaction in ivermectin-treated severe crusted scabies [49].

Clinical trials for assessing acaricidal agents are problematic. Meta-analysis indicates that few published studies pass muster, with significant heterogeneity in study designs evident [10]. Any scabies treatment protocol must not only consider the patient but all potential contacts. Current diagnostic methods for scabies are inadequate, and as such, diagnosis mostly relies on clinical presentation, which can be subjective even when well-defined clinical algorithms are employed. Human challenge trials for scabies would be logistically difficult and ethically problematic, given the long incubation period and potential to spread to personal contacts. Most scabies treatment evaluations have been undertaken in endemic communities, where it can be difficult to conduct adequately powered, well-controlled studies because of the inherent requirement to treat everyone in the community, both from an ethical perspective and to reduce confounding effects of reinfestation from untreated groups.

Given these significant challenges to executing properly powered efficacy studies in human populations and the very limited resources and funding available, a combination approach of conducting initial, preclinical or Phase I efficacy and dose-finding studies using an animal model—to complement the required pharmacokinetic and safety studies in humans—represents a rational strategy prior to conducting larger and more expensive Phase II and III trials in humans. Indeed, under the underutilised FDA “Animal Rule”[50], animal surrogates may be deemed acceptable when human challenge studies are not ethical or feasible. The recent development of a porcine model for human scabies [51] holds significant potential as a tool for scabies drug development, as pigs develop similar clinical responses to S. scabiei infestation and have similar skin physiology. Studies conducted to date suggest similar moxidectin pharmacokinetic profiles in pigs and humans [52], such that results obtained from porcine studies can be expected to inform dose selection and regimen in humans. Critically, in pigs, the opportunity exists to closely control infestation and undertake detailed clinical monitoring beyond that which could be performed in human participants.

Final Remarks

With increasing recognition of scabies as a global health problem, improved control of scabies in endemic communities is achievable, pending support from donors and funding agencies and the availability of new treatments that are more amenable for use in MDA. Moxidectin is very promising, given its proven clinical efficacy against mange in animals, existing safety data in humans, and pharmacokinetic properties that may make it suitable for a single-dose regimen. However, due attention must firstly be paid to key development considerations, including comparative clinical efficacy, dose optimisation, epidermal and systemic pharmacokinetic and pharmacodynamic profile, and the acaricidal sensitivity threshold of S. scabiei to moxidectin. Finally, more data on the safety of moxidectin in young children and in pregnancy, and breastfeeding must be accumulated if this drug is to proceed as a genuine new candidate for the sustainable control of scabies.

References

  1. 1. World Health Organization. Scabies. http://www.who.int/lymphatic_filariasis/epidemiology/scabies/en/. Accessed 27/2/2016.
  2. 2. Engelman D, Kiang K, Chosidow O, McCarthy J, Fuller C, et al. (2013) Toward the global control of human scabies: introducing the International Alliance for the Control of Scabies. PLoS Negl Trop Dis 7: e2167. doi: 10.1371/journal.pntd.0002167. pmid:23951369
  3. 3. Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, et al. (2012) Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380: 2197–2223. doi: 10.1016/S0140-6736(12)61689-4. pmid:23245608
  4. 4. Romani L, Steer AC, Whitfeld MJ, Kaldor JM (2015) Prevalence of scabies and impetigo worldwide: a systematic review. Lancet Infect Dis 15: 960–967. doi: 10.1016/S1473-3099(15)00132-2. pmid:26088526
  5. 5. Hotez PJ, Alvarado M, Basanez MG, Bolliger I, Bourne R, et al. (2014) The global burden of disease study 2010: interpretation and implications for the neglected tropical diseases. PLoS Negl Trop Dis 8: e2865. doi: 10.1371/journal.pntd.0002865. pmid:25058013
  6. 6. Mounsey KE, Murray HC, Bielefeldt-Ohmann H, Pasay C, Holt DC, et al. (2015) Prospective study in a porcine model of Sarcoptes scabiei indicates the association of Th2 and Th17 pathways with the clinical severity of scabies. PLoS Negl Trop Dis 9: e0003498. doi: 10.1371/journal.pntd.0003498. pmid:25730203
  7. 7. Liu X, Walton S, Mounsey K (2014) Vaccine against scabies: necessity and possibility. Parasitology 141: 725–732. doi: 10.1017/S0031182013002047. pmid:24476932
  8. 8. Reynolds SL, Pike RN, Mika A, Blom AM, Hofmann A, et al. (2014) Scabies mite inactive serine proteases are potent inhibitors of the human complement lectin pathway. PLoS Negl Trop Dis 8: e2872. doi: 10.1371/journal.pntd.0002872. pmid:24854034
  9. 9. Chosidow O (2006) Clinical practices. Scabies. N Engl J Med 354: 1718–1727. pmid:16625010
  10. 10. Strong M, Johnstone PW (2010) Interventions for treating scabies (update). Cochrane Database Syst Rev: CD000320.
  11. 11. Pasay C, Arlian L, Morgan M, Gunning R, Rossiter L, et al. (2009) The effect of insecticide synergists on the response of scabies mites to pyrethroid acaricides. PLoS Negl Trop Dis 3: e354. doi: 10.1371/journal.pntd.0000354. pmid:19125173
  12. 12. Andrews R, Kearns T, Connors C, Parker C, Carville K, et al. (2009) A Regional Initiative to Reduce Skin Infections amongst Aboriginal Children Living in Remote Communities of the Northern Territory, Australia. PLoS Negl Trop Dis 3: e554. doi: 10.1371/journal.pntd.0000554. pmid:19936297
  13. 13. La Vincente S, Kearns T, Connors C, Cameron S, Carapetis J, et al. (2009) Community management of endemic scabies in remote aboriginal communities of northern Australia: low treatment uptake and high ongoing acquisition. PLoS Negl Trop Dis 3: e444. doi: 10.1371/journal.pntd.0000444. pmid:19478832
  14. 14. Hewitt KA, Nalabanda A, Cassell JA (2015) Scabies outbreaks in residential care homes: factors associated with late recognition, burden and impact. A mixed methods study in England. Epidemiol Infect 143: 1542–1551. doi: 10.1017/S0950268814002143. pmid:25195595
  15. 15. Lawrence G, Sheridan J, Speare R (1994) We can get rid of scabies: new treatment available soon. Med J Aust 161: 232.
  16. 16. Therapeutic Goods Administration, Australian Govermernment Deartment of Health. Australian Public Assessment Report: Ivermectin. http://tga.gov.au/auspar/auspar-ivermectin. Accessed 22/9/2015
  17. 17. Haar K, Romani L, Filimone R, Kishore K, Tuicakau M, et al. (2014) Scabies community prevalence and mass drug administration in two Fijian villages. Int J Dermatol 53: 739–745. doi: 10.1111/ijd.12353. pmid:24168177
  18. 18. Lawrence G, Leafasia J, Sheridan J, Hills S, Wate J, et al. (2005) Control of scabies, skin sores and haematuria in children in the Solomon Islands: another role for ivermectin. Bull World Health Org 83: 34–42. pmid:15682247
  19. 19. Kearns TM, Speare R, Cheng AC, McCarthy J, Carapetis JR, et al. (2015) Impact of an Ivermectin Mass Drug Administration on Scabies Prevalence in a Remote Australian Aboriginal Community. PLoS Negl Trop Dis 9: e0004151. doi: 10.1371/journal.pntd.0004151. pmid:26516764
  20. 20. Gyapong JO, Chinbuah MA, Gyapong M (2003) Inadvertent exposure of pregnant women to ivermectin and albendazole during mass drug administration for lymphatic filariasis. Trop Med Int Health 8: 1093–1101. pmid:14641844
  21. 21. Ndyomugyenyi R, Kabatereine N, Olsen A, Magnussen P (2008) Efficacy of ivermectin and albendazole alone and in combination for treatment of soil-transmitted helminths in pregnancy and adverse events: a randomized open label controlled intervention trial in Masindi district, western Uganda. Am J Trop Med Hyg 79: 856–863. pmid:19052293
  22. 22. Clucas D, Carville K, Connors C, Currie B, Carapetis J, et al. (2008) Disease burden and health-care clinic attendances for young children in remote Aboriginal communities of northern Australia. Bull World Health Org 86: 241–320.
  23. 23. Pariser DM, Meinking TL, Bell M, Ryan WG (2012) Topical 0.5% ivermectin lotion for treatment of head lice. N Engl J Med 367: 1687–1693. doi: 10.1056/NEJMoa1200107. pmid:23113480
  24. 24. Chosidow O, Giraudeau B, Cottrell J, Izri A, Hofmann R, et al. (2010) Oral ivermectin versus malathion lotion for difficult-to-treat head lice. N Engl J Med 362: 896–905. doi: 10.1056/NEJMoa0905471. pmid:20220184
  25. 25. Stein L, Kircik L, Fowler J, Tan J, Draelos Z, et al. (2014) Efficacy and safety of ivermectin 1% cream in treatment of papulopustular rosacea: results of two randomized, double-blind, vehicle-controlled pivotal studies. J Drugs Dermatol 13: 316–323. pmid:24595578
  26. 26. Taieb A, Ortonne J, Ruzicka T, Roszkiewicz J, Berth-Jones J, et al. (2015) Superiority of ivermectin 1% cream over metronidazole 0·75% cream in treating inflammatory lesions of rosacea: a randomized, investigator-blinded trial. Br J Dermatol 172: 1103–1110. doi: 10.1111/bjd.13408. pmid:25228137
  27. 27. Food and Drug Administration, U.S Department of Health and Human Serices. Prescribing information, Soolantra. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206255lbl.pdf. Accessed 1/12/15.
  28. 28. Currie BJ, Harumal P, McKinnon M, Walton SF (2004) First documentation of in vivo and in vitro ivermectin resistance in Sarcoptes scabiei. Clin Infect Dis 39: e8–12. pmid:15206075
  29. 29. Mounsey K, Holt D, McCarthy J, Currie B, Walton S (2009) Longitudinal evidence of increasing in vitro tolerance of scabies mites to ivermectin in scabies-endemic communities. Arch Derm 145: 840–841. doi: 10.1001/archdermatol.2009.125. pmid:19620572
  30. 30. Currie B, McCarthy J (2010) Permethrin and Ivermectin for Scabies. N Engl J Med 362: 717–725. doi: 10.1056/NEJMct0910329. pmid:20181973
  31. 31. Chosidow O, Giraudeau B (2012) Topical ivermectin: a step toward making head lice dead lice? N Engl J Med 367: 1750–1752. doi: 10.1056/NEJMe1211124. pmid:23113487
  32. 32. Haas N, Lindemann U, Frank K, Sterry W, Lademann J, et al. (2002) Rapid and preferential sebum secretion of ivermectin: A new factor that may determine drug responsiveness in patients with scabies. Arch Derm 138: 1618–1619. pmid:12472363
  33. 33. Fujimoto K, Kawasaki Y, Morimoto K, Kikuchi I, Kawana S (2014) Treatment for crusted scabies: Limitations and side effects of treatment with Ivermectin. J Nippon Med Sch 81: 157–163. pmid:24998962
  34. 34. Chouela EN, Abeldano AM, Pellerano G, La Forgia M, Papale RM, et al. (1999) Equivalent therapeutic efficacy and safety of ivermectin and lindane in the treatment of human scabies. Arch Derm 135: 651–655. pmid:10376691
  35. 35. Glaziou P, Cartel JL, Alzieu P, Briot C, Moulia-Pelat JP, et al. (1993) Comparison of ivermectin and benzyl benzoate for treatment of scabies. Trop Med Parasitol 44: 331–332. pmid:8134777
  36. 36. Ly F, Caumes E, Ndaw CAT, Ndiaye B, Mahe A (2009) Ivermectin versus benzyl benzoate applied once or twice to treat human scabies in Dakar, Senegal: a randomized controlled trial. Bull World Health Org 87: 424–430. pmid:19565120
  37. 37. Prichard R, Menez C, Lespine A (2012) Moxidectin and the avermectins: Consanguinity but not identity. Int J Parasitol: Drugs Drug Resist 2: 134–153.
  38. 38. Losson B, Lonneux JF (1993) Field efficacy of injectible moxidectin in cattle naturally infested with Chorioptes bovis and Sarcoptes scabiei. Vet Parasitol 51: 113–121. pmid:8128574
  39. 39. Fthenakis GC, Papadopolous E, Himonas C, Leontides L, Kritas S, et al. (2000) Efficacy of moxidectin against sarcoptic mange and effects on milk yiled of ewes and growth of lambs. Vet Parasitol 87: 207–216. pmid:10622612
  40. 40. Hidalgo Arguello MR, Diez-Banos N, Martinez-Gonzalez B, Rojo-Vazquez FA (2001) Efficacy of moxidectin 1% injectable against natural infection of Sarcoptes scabiei in sheep. Vet Parasitol 102: 143–150. pmid:11705660
  41. 41. Astiz S, Legaz-Huidobro E, Mottier L (2011) Efficacy of long-acting moxidectin against sarcoptic mange in naturally infested sheep. Vet Rec 169: 637a.
  42. 42. Papadopolous E, Fthenakis GC, Himonas C, Tzora A, Leontides L (2000) Persistent efficacy of moxidectin against Sarcoptes scabiei in sheep. J Vet Pharmacol Ther 23: 111–112. pmid:10849257
  43. 43. Butters MP, Kobylinski KC, Deus KM, da Silva IM, Gray M, et al. (2012) Comparative evaluation of systemic drugs for their effects against Anopheles gambiae. Acta Trop 121: 34–43. doi: 10.1016/j.actatropica.2011.10.007. pmid:22019935
  44. 44. Bernigaud C, Fang F, Fischer K, Lespine A, Kelly A, et al. (2015) Experimental pig model of scabies: comparative activity of oral ivermectin and moxidectin. 25th European Society of Clinical Microbiology and Infectious Diseases. Copenhagen.
  45. 45. Cotreau MM, Warren S, Ryan JL, Fleckenstein L, Vanapalli SR, et al. (2003) The antiparasitic moxidectin: safety, tolerability, and pharmacokinetics in humans. J Clin Pharmacol 43: 1108–1115. pmid:14517193
  46. 46. Korth-Bradley JM, Parks V, Chalon S, Gourley I, Matschke K, et al. (2011) Excretion of moxidectin into breast milk and pharmacokinetics in healthy lactating women. Antimicrob Agents Chemother 55: 5200–5204. doi: 10.1128/AAC.00311-11. pmid:21896908
  47. 47. Awadzi K, Opoku NO, Attah SK, Lazdins-Helds J, Kuesel AC (2014) A randomized, single-ascending-dose, ivermectin-controlled, double-blind study of moxidectin in Onchocerca volvulus infection. PLoS Negl Trop Dis 8: e2953. doi: 10.1371/journal.pntd.0002953. pmid:24968000
  48. 48. Bourguinat C, Kamgno J, Boussinesq M, Mackenzie CD, Prichard RK, et al. (2010) Analysis of the mdr-1 gene in patients co-infected with Onchocerca volvulus and Loa loa who experienced a post-ivermectin serious adverse event. Am J Trop Med Hyg 83: 28–32.
  49. 49. Ito T (2013) Mazzotti reaction with eosinophilia after undergoing oral ivermectin for scabies. J Dermatol 40: 776–777. doi: 10.1111/1346-8138.12243. pmid:23855317
  50. 50. Center for Drug Evaluation,U.S Food and Drug Administration. Guidance for Industry: Product Development Under the Animal Rule. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM399217.pdf. Accessed 22/9/2015.
  51. 51. Mounsey K, Ho MF, Kelly A, Willis C, Pasay C, et al. (2010) A tractable experimental model for study of human and animal scabies. PLoS Negl Trop Dis 4: e756. doi: 10.1371/journal.pntd.0000756. pmid:20668508
  52. 52. Craven J, Bjorn H, Hennessy D, Friis C, Nansen P (2001) Pharmacokinetics of moxidectin and ivermectin following intravenous injection in pigs with different body compositions. J Vet Pharmacol Ther 24: 99–104. pmid:11442783